frontal lobe stroke case study

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Case Report

Behavioural changes as the first manifestation of a silent frontal lobe stroke, rafael garcía carretero.

1 Internal Medicine, Hospital Universitario de Mostoles, Mostoles, Spain

Blanca-Nieves Beamonte-Vela

Jose-david silvano-cocinero, ana alvarez-mendez.

2 Intensive Care Medicine, Hospital Universitario de Mostoles, Mostoles, Spain

A 67-year-old man was admitted to our hospital after his relatives found him to have severe personality and behavioural changes. His behaviour was inappropriate and uninhibited. The patient reported no symptoms and he showed poor insight into his own behaviour. Neuroimaging showed an orbitofrontal lesion, due to an infarction of the anterior cerebral artery. The patient was diagnosed with frontal lobe syndrome.

Frontal behavioural syndromes caused by strokes are rarely reported, it therefore remains unclear whether a frontal lobe infarction is actually silent or asymptomatic. 1 The frontal lobe, due to its size, is commonly involved in strokes. Most strokes are caused by ischaemic or haemorrhagic involvement of the middle cerebral artery, and clinical manifestations are therefore mainly due to injury to the precentral gyrus (pre-Rolandic area), which is a motor cortex.

However, strokes due to involvement of the anterior cerebral artery confined to the prefrontal cortex have been designated as silent or asymptomatic, but whether they are truly asymptomatic is not clear, since psychiatric symptoms, personality and behavioural changes must be considered as neurological manifestations. 1

Clinical manifestation of frontal lobe involvement depends on the size of the lesion, side (left or right), depth and type of injury. These personality changes in the frontal lobe can be hard to recognise because of their subacute onset. The clinical spectrum can be wide: from impulsiveness and disinhibition, to apathy, abulia or amotivational state. 2

Case presentation

A 67-year-old man was admitted to our hospital after his relatives found him to have changes in his personality for the last 10–15 days. He had been a responsible, mild-mannered man, who worked as a bank manager. For the past 2 weeks, he had been showing behavioural changes: he was rude when eating food; he did not wait until his relatives were at the table; he did not always use a knife and fork; he used foul language while eating; he sometimes used inappropriate sexual words when addressing his relatives; his wife said he showed inappropriate sexual behaviour, such as masturbation without shame while she was present. However, he showed no concern regarding these changes. Aggression or verbal abuse were not present as behavioural symptoms.

He had hypertension and type 2 diabetes mellitus, and was on ramipril 2.5 mg daily and metformin 1 g twice a day.

On physical examination, his temperature was 36.2°C, he had a heart rate of 78 bpm, blood pressure of 143/84 mm Hg and oxygen saturation of 97% on room air. On auscultation, heart sounds and lungs were normal. On neurological examination, the patient did not show any focal or lateralising neurological signs.

Investigations

Laboratory tests were normal, with a white cell count of 6.7×10 9 /L, haemoglobin 14.1 g/L and platelets 179×10 9 /L. Kidney and liver panels were also normal. The chest X-ray showed no acute process. However, the brain CT scan showed a right frontal cortical–subcortical hypodensity area (5.5×2×6 cm), with no mass effect and no abnormal enhancement after intravenous contrast administration ( figure 1A ). As the lesion could have resembled a non-aggressive brain tumour, a brain MRI was performed. The MRI ( figure 1 , slides B–D) showed a right frontal cortical–subcortical hyperintensity in T2 and hypointensity in T1. These radiological findings led us to establish the diagnosis of subacute anterior cerebral artery stroke.

Neuroimaging (brain CT scan and MRI) of the frontal lobe. Slide A shows a right frontal cortical–subcortical hypodense area (arrow); this lesion causes no mass effect and no abnormal enhancement after intravenous contrast administration. Slide B (T1-weighted MRI) shows a hypodense lesion in a sagittal plane of the wide frontal lobe lesion (arrow). Slides C (fluid-attenuated inversion recovery) and D (T2-weighted turbo spin-echo) show a right frontal cortical–subcortical hyperintensity (axial plane, arrows pointing the lesion).

Outcome and follow-up

Echocardiography, carotid ultrasound, 24 hours Holter monitoring and electroencephalogram were also performed, but they did not find any abnormalities. We started aspirin 100 mg daily and atorvastatin 20 mg daily.

Our patient remained in the admissions ward for 1 week to complete the work-up. During his stay, the patient got better and his neurological symptoms improved. As a plausible hypothesis, we think the patient started recovering some days before he was admitted. It sounds reasonable, since the onset was subacute. His relatives said he once again became nice, judicious, prudent, thoughtful and well-mannered. He was discharged and was scheduled for a follow-up 3 months later. Generally speaking, he continued to be the person he was before the stroke, but he was never aware of his changes, and his family said he had problems in interpreting others’ moods.

Mental changes after frontal lobe injury have been reported since the 1940s. It is well known that higher mental functions are affected after frontal lobe damage. 3 Human behaviour is involved, and emotions, attention, interest and will are therefore affected. Patients with so-called frontal lobe syndrome can have a complete change in personality as an expression of the above-mentioned damage. Size, extension and side of the lesion are essential in developing certain symptoms. 1 4

Diffuse neurodegenerative diseases, as well as focal lesions such as stroke, head trauma, neoplasm and bacterial abscess formation, can cause personality changes when the frontal lobe is involved, by compromising the frontal cortical and subcortical structures. 4

The most common denomination of frontal lobe syndromes is ‘frontal lobe personality’. Clinical manifestations of these syndromes, in which mood, behaviour and cognition are involved, include not only disinhibition and impulsiveness, but also apathy and abulia. 4

There are several ways to classify frontal lobe syndrome, in an attempt to develop a clinical-topographic correspondence. Patients with orbitofrontal syndrome show impulsiveness, fearlessness, abnormal sexual behaviour, hyperactivity and disregard for others’ emotions. Patients with anterior cingulate syndrome are apathetic and aboulic, and they become quiet. Patients with dorsolateral prefrontal cortex syndrome tend to be less organised and lack the ability to plan (the so-called executive dysfunction). However, if the lesion involves the subcortical circuitry, patients can have combined syndromes. Therefore, clinical manifestations can sometimes be heterogeneous, since the frontal lobe disorder may be caused by a wide cortical lesion or interruption of the frontal-subcortical circuitry. 4 However, predicting symptoms based on neuroanatomic injuries can be challenging, and patients with a lesion in the frontal lobe might not develop personality or behavioural changes. 4 5 It is worth noting that lateralisation is important due to the functional differences between both cerebral hemispheres, as some clinicopathological correlations can be set. Therefore, behavioural changes correlate with the involved arterial domain. If left anterior cerebral artery is involved, amotivational and apathetic features may arise. On the contrary, delayed response deficits with impulsivity, social improprieties, deficient social pragmatics, social anarchy and emotional regulation deficits may arise on stroke of the right anterior cerebral artery. 6–9

Probably due to the above-mentioned reasons (low incidence of stroke in the frontal lobe, heterogeneous clinical presentation, difficulties in predicting symptoms and outcome), frontal behavioural syndromes due to stroke are uncommon in the medical literature and have been rarely reported, when compared with other diseases (such as abscesses and brain tumours). 5

Some instruments have been developed in order to measure personality, in an attempt to compare premorbid traits of personality versus current changes, but these tools have proven not to be useful for assessing real-life predictions. 4

Therapy is not easy to initiate, as identification and assessment of these frontal syndromes can be difficult. Furthermore, patients often have no insight into the disorder, and cannot identify situations in which their behaviour is inappropriate. This leads to a failure to respond to reinforcers trying to modify emotional responses. 10

Learning points

• Stroke is characterised by an acute onset of neurological symptoms, which are usually motor-related. However, personality changes such as impulsiveness and disinhibition can be explained by fronto-cortical damage.
• Frontal lobe personality includes emotional disorders or executive dysfunction, but the symptoms are uncommon and sometimes difficult to identify: abnormal emotional responses, jealousy, abnormal sense of humour, lack of empathy, apathy.
• Frontal lobe syndromes can be misdiagnosed and therefore left untreated. Clinicians should be aware when relatives are concerned about personality or behavioural changes in the patient, particularly when patients are unable to control emotions or experience emotional changes.
• Frontal strokes will remain silent only if clinicians are unable to identify characteristic symptoms.

Contributors: RGC wrote the first draft. BNBV fixed spelling and grammar mistakes. JDSC edited the MRI images. AAM revised the final manuscript.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared.

Patient consent: Obtained.

Provenance and peer review: Not commissioned; externally peer reviewed.

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• Volume 13, Issue 8
• Clinical course of a 66-year-old man with an acute ischaemic stroke in the setting of a COVID-19 infection
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• http://orcid.org/0000-0002-7441-6952 Saajan Basi 1 , 2 ,
• Mohammad Hamdan 1 and
• Shuja Punekar 1
• 1 Department of Stroke and Acute Medicine , King's Mill Hospital , Sutton-in-Ashfield , UK
• 2 Department of Acute Medicine , University Hospitals of Derby and Burton , Derby , UK
• Correspondence to Dr Saajan Basi; saajan.basi{at}nhs.net

A 66-year-old man was admitted to hospital with a right frontal cerebral infarct producing left-sided weakness and a deterioration in his speech pattern. The cerebral infarct was confirmed with CT imaging. The only evidence of respiratory symptoms on admission was a 2 L oxygen requirement, maintaining oxygen saturations between 88% and 92%. In a matter of hours this patient developed a greater oxygen requirement, alongside reduced levels of consciousness. A positive COVID-19 throat swab, in addition to bilateral pneumonia on chest X-ray and lymphopaenia in his blood tests, confirmed a diagnosis of COVID-19 pneumonia. A proactive decision was made involving the patients’ family, ward and intensive care healthcare staff, to not escalate care above a ward-based ceiling of care. The patient died 5 days following admission under the palliative care provided by the medical team.

• respiratory medicine
• infectious diseases
• global health

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bcr-2020-235920

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SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a new strain of coronavirus that is thought to have originated in December 2019 in Wuhan, China. In a matter of months, it has erupted from non-existence to perhaps the greatest challenge to healthcare in modern times, grinding most societies globally to a sudden halt. Consequently, the study and research into SARS-CoV-2 is invaluable. Although coronaviruses are common, SARS-CoV-2 appears to be considerably more contagious. The WHO figures into the 2003 SARS-CoV-1 outbreak, from November 2002 to July 2003, indicate a total of 8439 confirmed cases globally. 1 In comparison, during a period of 4 months from December 2019 to July 2020, the number of global cases of COVID-19 reached 10 357 662, increasing exponentially, illustrating how much more contagious SARS-CoV-2 has been. 2

Previous literature has indicated infections, and influenza-like illness have been associated with an overall increase in the odds of stroke development. 3 There appears to be a growing correlation between COVID-19 positive patients presenting to hospital with ischaemic stroke; however, studies investigating this are in progress, with new data emerging daily. This patient report comments on and further characterises the link between COVID-19 pneumonia and the development of ischaemic stroke. At the time of this patients’ admission, there were 95 positive cases from 604 COVID-19 tests conducted in the local community, with a predicted population of 108 000. 4 Only 4 days later, when this patient died, the figure increased to 172 positive cases (81% increase), illustrating the rapid escalation towards the peak of the pandemic, and widespread transmission within the local community ( figure 1 ). As more cases of ischaemic stroke in COVID-19 pneumonia patients arise, the recognition and understanding of its presentation and aetiology can be deciphered. Considering the virulence of SARS-CoV-2 it is crucial as a global healthcare community, we develop this understanding, in order to intervene and reduce significant morbidity and mortality in stroke patients.

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A graph showing the number of patients with COVID-19 in the hospital and in the community over time.

Case presentation

A 66-year-old man presented to the hospital with signs of left-sided weakness. The patient had a background of chronic obstructive pulmonary disease (COPD), atrial fibrillation and had one previous ischaemic stroke, producing left-sided haemiparesis, which had completely resolved. He was a non-smoker and lived in a house. The patient was found slumped over on the sofa at home on 1 April 2020, by a relative at approximately 01:00, having been seen to have no acute medical illness at 22:00. The patients’ relative initially described disorientation and agitation with weakness noted in the left upper limb and dysarthria. At the time of presentation, neither the patient nor his relative identified any history of fever, cough, shortness of breath, loss of taste, smell or any other symptoms; however, the patient did have a prior admission 9 days earlier with shortness of breath.

The vague nature of symptoms, entwined with considerable concern over approaching the hospital, due to the risk of contracting COVID-19, created a delay in the patients’ attendance to the accident and emergency department. His primary survey conducted at 09:20 on 1 April 2020 demonstrated a patent airway, with spontaneous breathing and good perfusion. His Glasgow Coma Scale (GCS) score was 15 (a score of 15 is the highest level of consciousness), his blood glucose was 7.2, and he did not exhibit any signs of trauma. His abbreviated mental test score was 7 out of 10, indicating a degree of altered cognition. An ECG demonstrated atrial fibrillation with a normal heart rate. His admission weight measured 107 kg. At 09:57 the patient required 2 L of nasal cannula oxygen to maintain his oxygen saturations between 88% and 92%. He started to develop agitation associated with an increased respiratory rate at 36 breaths per minute. On auscultation of his chest, he demonstrated widespread coarse crepitation and bilateral wheeze. Throughout he was haemodynamically stable, with a systolic blood pressure between 143 mm Hg and 144 mm Hg and heart rate between 86 beats/min and 95 beats/min. From a neurological standpoint, he had a mild left facial droop, 2/5 power in both lower limbs, 2/5 power in his left upper limb and 5/5 power in his right upper limb. Tone in his left upper limb had increased. This patient was suspected of having COVID-19 pneumonia alongside an ischaemic stroke.

Investigations

A CT of his brain conducted at 11:38 on 1 April 2020 ( figure 2 ) illustrated an ill-defined hypodensity in the right frontal lobe medially, with sulcal effacement and loss of grey-white matter. This was highly likely to represent acute anterior cerebral artery territory infarction. Furthermore an oval low-density area in the right cerebellar hemisphere, that was also suspicious of an acute infarction. These vascular territories did not entirely correlate with his clinical picture, as limb weakness is not as prominent in anterior cerebral artery territory ischaemia. Therefore this left-sided weakness may have been an amalgamation of residual weakness from his previous stroke, in addition to his acute cerebral infarction. An erect AP chest X-ray with portable equipment ( figure 3 ) conducted on the same day demonstrated patchy peripheral consolidation bilaterally, with no evidence of significant pleural effusion. The pattern of lung involvement raised suspicion of COVID-19 infection, which at this stage was thought to have provoked the acute cerebral infarct. Clinically significant blood results from 1 April 2020 demonstrated a raised C-reactive protein (CRP) at 215 mg/L (normal 0–5 mg/L) and lymphopaenia at 0.5×10 9 (normal 1×10 9 to 3×10 9 ). Other routine blood results are provided in table 1 .

CT imaging of this patients’ brain demonstrating a wedge-shaped infarction of the anterior cerebral artery territory.

Chest X-ray demonstrating the bilateral COVID-19 pneumonia of this patient on admission.

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Clinical biochemistry and haematology blood results of the patient

Interestingly the patient, in this case, was clinically assessed in the accident and emergency department on 23 March 2020, 9 days prior to admission, with symptoms of shortness of breath. His blood results from this day showed a CRP of 22 mg/L and a greater lymphopaenia at 0.3×10 9 . He had a chest X-ray ( figure 4 ), which indicated mild radiopacification in the left mid zone. He was initially treated with intravenous co-amoxiclav and ciprofloxacin. The following day he had minimal symptoms (CURB 65 score 1 for being over 65 years). Given improving blood results (declining CRP), he was discharged home with a course of oral amoxicillin and clarithromycin. As national governmental restrictions due to COVID-19 had not been formally announced until 23 March 2020, and inconsistencies regarding personal protective equipment training and usage existed during the earlier stages of this rapidly evolving pandemic, it is possible that this patient contracted COVID-19 within the local community, or during his prior hospital admission. It could be argued that the patient had early COVID-19 signs and symptoms, having presented with shortness of breath, lymphopaenia, and having had subtle infective chest X-ray changes. The patient explained he developed a stagnant productive cough, which began 5 days prior to his attendance to hospital on 23 March 2020. He responded to antibiotics, making a full recovery following 7 days of treatment. This information does not assimilate with the typical features of a COVID-19 infection. A diagnosis of community-acquired pneumonia or infective exacerbation of COPD seem more likely. However, given the high incidence of COVID-19 infections during this patients’ illness, an exposure and early COVID-19 illness, prior to the 23 March 2020, cannot be completely ruled out.

Chest X-ray conducted on prior admission illustrating mild radiopacification in the left mid zone.

On the current admission, this patient was managed with nasal cannula oxygen at 2 L. By the end of the day, this had progressed to a venturi mask, requiring 8 L of oxygen to maintain oxygen saturation. He had also become increasingly drowsy and confused, his GCS declined from 15 to 12. However, the patient was still haemodynamically stable, as he had been in the morning. An arterial blood gas demonstrated a respiratory alkalosis (pH 7.55, pCO 2 3.1, pO 2 6.7 and HCO 3 24.9, lactate 1.8, base excess 0.5). He was commenced on intravenous co-amoxiclav and ciprofloxacin, to treat a potential exacerbation of COPD. This patient had a COVID-19 throat swab on 1 April 2020. Before the result of this swab, an early discussion was held with the intensive care unit staff, who decided at 17:00 on 1 April 2020 that given the patients presentation, rapid deterioration, comorbidities and likely COVID-19 diagnosis he would not be for escalation to the intensive care unit, and if he were to deteriorate further the end of life pathway would be most appropriate. The discussion was reiterated to the patients’ family, who were in agreement with this. Although he had evidence of an ischaemic stroke on CT of his brain, it was agreed by all clinicians that intervention for this was not as much of a priority as providing optimal palliative care, therefore, a minimally invasive method of treatment was advocated by the stroke team. The patient was given 300 mg of aspirin and was not a candidate for fibrinolysis.

Outcome and follow-up

The following day, before the throat swab result, had appeared the patient deteriorated further, requiring 15 L of oxygen through a non-rebreather face mask at 60% FiO 2 to maintain his oxygen saturation, at a maximum of 88% overnight. At this point, he was unresponsive to voice, with a GCS of 5. Although, he was still haemodynamically stable, with a blood pressure of 126/74 mm Hg and a heart rate of 98 beats/min. His respiratory rate was 30 breaths/min. His worsening respiratory condition, combined with his declining level of consciousness made it impossible to clinically assess progression of the neurological deficit generated by his cerebral infarction. Moreover, the patient was declining sharply while receiving the maximal ward-based treatment available. The senior respiratory physician overseeing the patients’ care decided that a palliative approach was in this his best interest, which was agreed on by all parties. The respiratory team completed the ‘recognising dying’ documentation, which signified that priorities of care had shifted from curative treatment to palliative care. Although the palliative team was not formally involved in the care of the patient, the patient received comfort measures without further attempts at supporting oxygenation, or conduction of regular clinical observations. The COVID-19 throat swab confirmed a positive result on 2 April 2020. The patient was treated by the medical team under jurisdiction of the hospital palliative care team. This included the prescribing of anticipatory medications and a syringe driver, which was established on 3 April 2020. His antibiotic treatment, non-essential medication and intravenous fluid treatment were discontinued. His comatose condition persisted throughout the admission. Once the patients’ GCS was 5, it did not improve. The patient was pronounced dead by doctors at 08:40 on 5 April 2020.

SARS-CoV-2 is a type of coronavirus that was first reported to have caused pneumonia-like infection in humans on 3 December 2019. 5 As a group, coronaviruses are a common cause of upper and lower respiratory tract infections (especially in children) and have been researched extensively since they were first characterised in the 1960s. 6 To date, there are seven coronaviruses that are known to cause infection in humans, including SARS-CoV-1, the first known zoonotic coronavirus outbreak in November 2002. 7 Coronavirus infections pass through communities during the winter months, causing small outbreaks in local communities, that do not cause significant mortality or morbidity.

SARS-CoV-2 strain of coronavirus is classed as a zoonotic coronavirus, meaning the virus pathogen is transmitted from non-humans to cause disease in humans. However the rapid spread of SARS-CoV-2 indicates human to human transmission is present. From previous research on the transmission of coronaviruses and that of SARS-CoV-2 it can be inferred that SARS-CoV-2 spreads via respiratory droplets, either from direct inhalation, or indirectly touching surfaces with the virus and exposing the eyes, nose or mouth. 8 Common signs and symptoms of the COVID-19 infection identified in patients include high fevers, severe fatigue, dry cough, acute breathing difficulties, bilateral pneumonia on radiological imaging and lymphopaenia. 9 Most of these features were identified in this case study. The significance of COVID-19 is illustrated by the speed of its global spread and the potential to cause severe clinical presentations, which as of April 2020 can only be treated symptomatically. In Italy, as of mid-March 2020, it was reported that 12% of the entire COVID-19 positive population and 16% of all hospitalised patients had an admission to the intensive care unit. 10

The patient, in this case, illustrates the clinical relevance of understanding COVID-19, as he presented with an ischaemic stroke underlined by minimal respiratory symptoms, which progressed expeditiously, resulting in acute respiratory distress syndrome and subsequent death.

Our case is an example of a new and ever-evolving clinical correlation, between patients who present with a radiological confirmed ischaemic stroke and severe COVID-19 pneumonia. As of April 2020, no comprehensive data of the relationship between ischaemic stroke and COVID-19 has been published, however early retrospective case series from three hospitals in Wuhan, China have indicated that up to 36% of COVID-19 patients had neurological manifestations, including stroke. 11 These studies have not yet undergone peer review, but they tell us a great deal about the relationship between COVID-19 and ischaemic stroke, and have been used to influence the American Heart Associations ‘Temporary Emergency Guidance to US Stroke Centres During the COVID-19 Pandemic’. 12

The relationship between similar coronaviruses and other viruses, such as influenza in the development of ischaemic stroke has previously been researched and provide a basis for further investigation, into the prominence of COVID-19 and its relation to ischaemic stroke. 3 Studies of SARS-CoV-2 indicate its receptor-binding region for entry into the host cell is the same as ACE2, which is present on endothelial cells throughout the body. It may be the case that SARS-CoV-2 alters the conventional ability of ACE2 to protect endothelial function in blood vessels, promoting atherosclerotic plaque displacement by producing an inflammatory response, thus increasing the risk of ischaemic stroke development. 13

Other hypothesised reasons for stroke development in COVID-19 patients are the development of hypercoagulability, as a result of critical illness or new onset of arrhythmias, caused by severe infection. Some case studies in Wuhan described immense inflammatory responses to COVID-19, including elevated acute phase reactants, such as CRP and D-dimer. Raised D-dimers are a non-specific marker of a prothrombotic state and have been associated with greater morbidity and mortality relating to stroke and other neurological features. 14

Arrhythmias such as atrial fibrillation had been identified in 17% of 138 COVID-19 patients, in a study conducted in Wuhan, China. 15 In this report, the patient was known to have atrial fibrillation and was treated with rivaroxaban. The acute inflammatory state COVID-19 is known to produce had the potential to create a prothrombotic environment, culminating in an ischaemic stroke.

Some early case studies produced in Wuhan describe patients in the sixth decade of life that had not been previously noted to have antiphospholipid antibodies, contain the antibodies in blood results. They are antibodies signify antiphospholipid syndrome; a prothrombotic condition. 16 This raises the hypothesis concerning the ability of COVID-19 to evoke the creation of these antibodies and potentiate thrombotic events, such as ischaemic stroke.

No peer-reviewed studies on the effects of COVID-19 and mechanism of stroke are published as of April 2020; therefore, it is difficult to evidence a specific reason as to why COVID-19 patients are developing neurological signs. It is suspected that a mixture of the factors mentioned above influence the development of ischaemic stroke.

If we delve further into this patients’ comorbid state exclusive to COVID-19 infection, it can be argued that this patient was already at a relatively higher risk of stroke development compared with the general population. The fact this patient had previously had an ischaemic stroke illustrates a prior susceptibility. This patient had a known background of hypertension and atrial fibrillation, which as mentioned previously, can influence blood clot or plaque propagation in the development of an acute ischaemic event. 15 Although the patient was prescribed rivaroxaban as an anticoagulant, true consistent compliance to rivaroxaban or other medications such as amlodipine, clopidogrel, candesartan and atorvastatin cannot be confirmed; all of which can contribute to the reduction of influential factors in the development of ischaemic stroke. Furthermore, the fear of contracting COVID-19, in addition to his vague symptoms, unlike his prior ischaemic stroke, which demonstrated dense left-sided haemiparesis, led to a delay in presentation to hospital. This made treatment options like fibrinolysis unachievable, although it can be argued that if he was already infected with COVID-19, he would have still developed life-threatening COVID-19 pneumonia, regardless of whether he underwent fibrinolysis. It is therefore important to consider that if this patient did not contract COVID-19 pneumonia, he still had many risk factors that made him prone to ischaemic stroke formation. Thus, we must consider whether similar patients would suffer from ischaemic stroke, regardless of COVID-19 infection and whether COVID-19 impacts on the severity of the stroke as an entity.

Having said this, the management of these patients is dependent on the likelihood of a positive outcome from the COVID-19 infection. Establishing the ceiling of care is crucial, as it prevents incredibly unwell or unfit patients’ from going through futile treatments, ensuring respect and dignity in death, if this is the likely outcome. It also allows for the provision of limited or intensive resources, such as intensive care beds or endotracheal intubation during the COVID-19 pandemic, to those who are assessed by the multidisciplinary team to benefit the most from their use. The way to establish this ceiling of care is through an early multidisciplinary discussion. In this case, the patient did not convey his wishes regarding his care to the medical team or his family; therefore it was decided among intensive care specialists, respiratory physicians, stroke physicians and the patients’ relatives. The patient was discussed with the intensive care team, who decided that as the patient sustained two acute life-threatening illnesses simultaneously and had rapidly deteriorated, ward-based care with a view to palliate if the further deterioration was in the patients’ best interests. These decisions were not easy to make, especially as it was on the first day of presentation. This decision was made in the context of the patients’ comorbidities, including COPD, the patients’ age, and the availability of intensive care beds during the steep rise in intensive care admissions, in the midst of the COVID-19 pandemic ( figure 1 ). Furthermore, the patients’ rapid and permanent decline in GCS, entwined with the severe stroke on CT imaging of the brain made it more unlikely that significant and permanent recovery could be achieved from mechanical intubation, especially as the damage caused by the stroke could not be significantly reversed. As hospitals manage patients with COVID-19 in many parts of the world, there may be tension between the need to provide higher levels of care for an individual patient and the need to preserve finite resources to maximise the benefits for most patients. This patient presented during a steep rise in intensive care admissions, which may have influenced the early decision not to treat the patient in an intensive care setting. Retrospective studies from Wuhan investigating mortality in patients with multiple organ failure, in the setting of COVID-19, requiring intubation have demonstrated mortality can be up to 61.5%. 17 The mortality risk is even higher in those over 65 years of age with respiratory comorbidities, indicating why this patient was unlikely to survive an admission to the intensive care unit. 18

Regularly updating the patients’ family ensured cooperation, empathy and sympathy. The patients’ stroke was not seen as a priority given the severity of his COVID-19 pneumonia, therefore the least invasive, but most appropriate treatment was provided for his stroke. The British Association of Stroke Physicians advocate this approach and also request the notification to their organisation of COVID-19-related stroke cases, in the UK. 19

Learning points

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is one of seven known coronaviruses that commonly cause upper and lower respiratory tract infections. It is the cause of the 2019–2020 global coronavirus pandemic.

The significance of COVID-19 is illustrated by the rapid speed of its spread globally and the potential to cause severe clinical presentations, such as ischaemic stroke.

Early retrospective data has indicated that up to 36% of COVID-19 patients had neurological manifestations, including stroke.

Potential mechanisms behind stroke in COVID-19 patients include a plethora of hypercoagulability secondary to critical illness and systemic inflammation, the development of arrhythmia, alteration to the vascular endothelium resulting in atherosclerotic plaque displacement and dehydration.

It is vital that effective, open communication between the multidisciplinary team, patient and patients relatives is conducted early in order to firmly establish the most appropriate ceiling of care for the patient.

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• Wang X-G , et al
• Grasselli G ,
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• Wang M , et al
• American Stroke Assocation, 2020
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• Zhang Y-huan ,
• Dong X-F , et al
• Li X , et al
• Hu C , et al
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• British Association of Stroke Physicians

Contributors SB was involved in the collecting of information for the case, the initial written draft of the case and researching existing data on acute stroke and COVID-19. He also edited drafts of the report. MH was involved in reviewing and editing drafts of the report and contributing new data. SP oversaw the conduction of the project and contributed addition research papers.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent for publication Next of kin consent obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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• Open access
• Published: 16 November 2013

Performance on the Frontal Assessment Battery is sensitive to frontal lobe damage in stroke patients

• Bruno Kopp 1 , 2 , 3 ,
• Nina Rösser 1 , 2 ,
• Sandra Tabeling 1 , 4 ,
• Hans Jörg Stürenburg 4 ,
• Bianca de Haan 5 ,
• Hans-Otto Karnath 5 , 6 &
• Karl Wessel 1 , 2  

BMC Neurology volume  13 , Article number:  179 ( 2013 ) Cite this article

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The Frontal Assessment Battery ( FAB ) is a brief battery of six neuropsychological tasks designed to assess frontal lobe function at bedside [Neurology 55:1621-1626, 2000]. The six FAB tasks explore cognitive and behavioral domains that are thought to be under the control of the frontal lobes, most notably conceptualization and abstract reasoning, lexical verbal fluency and mental flexibility, motor programming and executive control of action, self-regulation and resistance to interference, inhibitory control, and environmental autonomy.

We examined the sensitivity of performance on the FAB to frontal lobe damage in right-hemisphere-damaged first-ever stroke patients based on voxel-based lesion-behavior mapping.

Voxel-based lesion-behavior mapping of FAB performance revealed that the integrity of the right anterior insula (BA13) is crucial for the FAB global composite score, for the FAB conceptualization score, as well as for the FAB inhibitory control score. Furthermore, the FAB conceptualization and mental flexibility scores were sensitive to damage of the right middle frontal gyrus (MFG; BA9). Finally, the FAB inhibitory control score was sensitive to damage of the right inferior frontal gyrus (IFG; BA44/45).

Conclusions

These findings indicate that several FAB scores (including composite and item scores) provide valid measures of right hemispheric lateral frontal lobe dysfunction, specifically of focal lesions near the anterior insula, in the MFG and in the IFG.

Peer Review reports

The Frontal Assessment Battery ( FAB ) is a brief battery of six neuropsychological tasks that was specifically designed to assess frontal lobe function at bedside [ 1 ]. The historical roots of the six FAB tasks can be found in the careful observation of dysexecutive behavior in patients with frontal lobe lesions, pioneered by Luria [ 2 ], Lhermitte, Pillon, and Serdaru [ 3 ], and others in the second half of the 20th century. The six FAB tasks explore cognitive and behavioral domains of executive functioning that are thought to be critically dependent on the integrity of the frontal lobes. The use of the FAB is becoming increasingly popular for a variety of applications in neurology, most notably the early diagnosis of neurodegenerative dementing diseases such as the behavioral variant of fronto-temporal lobar degeneration (bvFTLD; [ 4 , 5 ]). The FAB is easy to administer, requires less than ten minutes to complete, and is well accepted by patients. The reported psychometrics of FAB reliability and validity are satisfactory [ 1 ], yet the anatomical correlation between FAB scores and frontal lobe damage has never been established in studies of stroke patients. The claim that the FAB yields indices of frontal lobe damage was derived from data obtained with similar tasks, but never from the FAB tasks themselves [ 1 ].

In the present study, we investigated the sensitivity of performance on the FAB to frontal lobe damage in stroke patients using voxel-based lesion-behavior mapping (VLBM; [ 6 – 8 ]). In contrast to traditional overlap designs of neuropsychological patient groups [ 9 ], voxel-based lesion-behaviour analysis yields a sophisticated statistical approach to uncover brain-behaviour relationships. Voxelwise statistical analysis objectively estimates which brain regions indeed are associated with behavioral deficits without any prior categorization of stroke patients into, e.g., groups with more anterior versus more posterior brain damage. A major problem of the latter approach is that lesion boundaries are often overlapping in individual patients from different patient groups, thereby limiting the validity of such simple overlap group lesion studies (cf. [ 6 ]). Moreover, previous research on the behavioural effects of frontal brain damage often rested upon a comparison between groups of patients with lesions from many different etiologies (for a critical discussion see [ 10 ]).

To our knowledge, the VLBM method was applied for the first time to FAB performance in stroke patients.

Thirty-one acute first-ever, right-hemisphere-damaged stroke patients with frontal lobe involvement participated in the study (see Table  1 for details). The logic behind the restriction to right-hemisphere-damaged stroke patients was to exclude patients with a paresis of the dominant right hand and/or with apraxia, possibly distorting task performance of these patients due to impaired motor functions. Further, left-hemisphere strokes might have hampered the capability to understand task instructions, due to the potential presence of sensory aphasia. a Patients with diffuse or bilateral brain lesions due to traumatic brain injury, brain tumors, subcortical arteriosclerotic encephalopathy, or any other dementing disease were excluded. Patients had no history of psychiatric disease or alcohol or drug abuse. Further, patients with gross neurological defects (pronounced pain as reported by the patient, left homonymous hemianopia as revealed by clinical examination, hemispatial visual neglect) were also excluded to make sure that these symptoms did not interfere with task performance. a Spatial neglect was diagnosed when a patient showed the characteristic clinical behaviour such as orienting toward the ipsilesional side when addressed from the front or the left and/or ignoring contralesionally located people or objects. Table  1 shows demographic and neuropsychological participant characteristics.

Standard protocol approvals, registrations, and patient consents

All patients gave their informed written consent to participate in the study, in accordance with the ethical standards of the Declaration of Helsinki (1964). Appropriate ethical approval for the study was obtained from the Ethics Committee at Technische Universität Braunschweig (Faculty for Life Sciences; Ref 37–2010).

Test description, administration and scoring

The FAB consists of the following six tasks:

Similarities (conceptualization). In this task, patients are required to identify the superordinate concept of two or more objects from the same semantic category. Specifically, patients were asked “In what way are the following objects alike?”: (1) a banana and an orange, (2) a table and a chair, and (3) a tulip, a rose, and a daisy. Only category responses (fruits, furniture, flowers) were considered correct. If patients achieved three correct responses, the score was 3; if they achieved two correct responses, the score was 2; if they achieved one correct response, the score was 1; if they achieved no correct response, the score was 0.

Lexical verbal fluency (mental flexibility). This task requires the formation and exertion of self-organised cognitive strategies for efficient retrieval from semantic memory. It is well-documented in the neuropsychological literature that frontal lesions tend to decrease verbal fluency, particularly lexical verbal fluency [ 17 , 18 ], and that in right-handed people, unilateral right frontal lesions are related to the presence of noticeable deficits in lexical verbal fluency [ 17 ]. Patients were instructed to say in 60 seconds as many words as possible beginning with the letter S , any words that came to their mind except surnames or proper nouns. If patients achieved more than nine words, the score was 3; if they achieved six to nine words, the score was 2; if they achieved three to five words, the score was 1; if they achieved less than three words, the score was 0.

Motor series (programming). This task requires the ability to program and execute a correctly ordered series of motor acts. Patients were asked to perform the Luria series ‘fist, edge, palm’ by initially copying the administrator three times, and then by repeating the series six times alone. If patients achieved six consecutive series by themselves, the score was 3; if they achieved at least three consecutive series on their own, the score was 2; if they failed at achieving at least three consecutive series alone, but achieved three when copying the examiner, the score was 1; otherwise the score was 0.

Conflicting instructions (sensitivity to interference). This task challenges self-regulation in a behavioural interference paradigm by instructing patients to execute one action in response to the observation of a different action, thereby requiring the inhibition of imitative response tendencies [ 3 , 19 , 20 ]. Luria [ 2 ] had coined the term echopractic responses to signify his observation that patients with frontal lesions tend to display unintended imitative response tendencies. Patients were asked to hit the table once when the administrator hit it twice, or to hit the table twice when the administrator hit it only once. To ensure the patient had clearly understood the task, a practice trial was performed in which the examiner first hit the table once, three times in succession, and then twice, three more times. After the practice trial, the examiner completed the following series: 1–1–2–1–2–2–2–1–1–2. If patients made no errors, the score was 3; if they made one or two errors, the score was 2; for more than two errors, the score was 1, unless the patient copied the examiner at least four consecutive times, in which case the score was 0.

Go – Nogo (inhibitory control). Patients were told that now, when the examiner hit the table once, they should also hit it once, but when the examiner hit twice, they should do nothing. To ensure the patient had clearly understood the task, a practice trial was performed in which the examiner hit the table once, three times in succession, and then twice, three more times. After the practice trial the examiner completed the following series: 1–1–2–1–2–2–2–1–1–2. If patients made no errors, the score was 3; for one or two errors the score was 2; for more than two errors the score was 1, unless the patient copied the examiner at least four consecutive times, in which case the score was 0.

Prehension behavior (environmental autonomy). This task is designed to assess the tendency to activate patterns of behaviour that are involuntarily triggered by sensory stimulation, in some cases even against an explicit instruction not to show these activities. Following Dubois et al. [ 1 ], a particular sign of deficient environmental autonomy can be observed when the sensory perception (visual and/or tactile) of the experimenter’s hand compels patients to take them (prehension behaviour). The patient’s hands were placed palm up on the knees of the patient. The examiner touched both palms without saying anything. If the patient took the examiner’s hands, the examiner tried again after having asked the patient, not to take his hands. If patients did not take the examiner’s hands, the score was 3; if the patient hesitated and asked what to do, the score was 2; if the patient took the hands without hesitation, the score was 1; if the patient took the hands even after having been told not to do so, the score was 0.

The FAB global composite score was computed (range: 0 … 18) by summing up the six individual FAB task scores.

Lesion analysis

Magnetic resonance imaging (MRI) was performed in 28 stroke patients and computed tomography (spiral CT) scanning was performed in three patients. The initial scanning was optionally repeated during the following days until the infarcted area became clearly demarcated. The mean time interval between lesion onset and the MRI scan that was used for the present analysis was 4.3 days ( SD  = 3.1); the mean time interval between time of lesion and CT scanning lasted 2.6 days ( SD  = 3.7). MRI scans were obtained on a 1.5 T echo planar imaging (EPI) capable system (Philips Intera, Philips Medical Systems, Best, The Netherlands). The MRI protocol used diffusion-weighted imaging (DWI, N = 12) and T2-weighted fluid-attenuated inversion-recovery imaging (FLAIR, N = 16). DWI was performed with a single-shot EPI spin echo sequence (25 axial slices; repetition times (TR), either 3690, 4000, 4452, 5060, 5300, or 6360 ms; echo times (TE), either 90, 95, or 120 ms; field of view (FOV), 230 × 230 mm 2 ; matrix 64 × 64 pixels; slice thickness, 5 mm; gap, 5.5 mm). The FLAIR sequences were acquired with 25 axial slices (thickness, 5 mm) with an interslice gap of 5.5 mm, a FOV of 220 × 220 mm 2 , TR of either 4000, 5397, 5500, or 6000 ms, and TE of either 89, 91, 100, or 120 ms. CTs were obtained on a spiral scanning system (Somatom Sensation 16, Siemens Healthcare, Erlangen, Germany) with a slice thickness of 3 mm infratentorial and 6 mm supratentorial and an in-plane resolution of 0.5 × 0.5 mm.

Lesion location was evaluated using MRIcroN software ([ 7 ], http://www.mricro.com ). For patients with MRI scans, the boundaries of lesions were delineated directly on the individual MRI scans. Both the MRI scan and the lesion shape were then mapped into stereotaxic space using the normalization algorithm provided by SPM5 ( http://www.fil.ion.ucl.ac.uk/spm/software/spm5/ ). Cost–function masking was employed [ 21 ] for determination of the transformation parameters.

In patients with spiral CT scans, lesions were drawn directly by an experienced neurologist (H.-O. K.; blinded for test performance) on the slices of a normalized T 1 -weighted template MRI scan from the Montreal Neurological Institute (MNI) with a 1 × 1 mm in-plane resolution, distributed with the MRIcroN toolset. Lesions were mapped onto the slices that correspond to MNI Z-coordinates [-16, -8, 0, 8, 16, 24, 32, and 40 mm] by using the identical or the closest matching axial slices of each individual patient.

To evaluate the relationship between lesion location and performance on the FAB , a voxel-based lesion-behavior analysis was performed using the Liebermeister test implemented in the MRIcroN toolset [ 7 ]. The non-parametric Liebermeister test is performed on two binomial variables; it is a small-sample test for 2 by 2 tables. In the present context, one of the variables was ‘lesion present’ vs. ‘lesion absent’ in a particular voxel. Application of the Liebermeister test further requires patients to be assigned to two different groups based on a behavioural measure; given this, the Liebermeister test can identify voxels that when injured predict the presence of behavioral disturbance. The Liebermeister tests were based on median splits on the FAB global composite score and on the six individual FAB task scores (see Table  2 for the medians of the scores). Median splits were performed such that a “0” was assigned when task scores fell below the median (i.e., “0-2” for the items scores), whereas a score of “1” resulted from task scores that equalled or outranged the median (i.e., “3” for the item scores). Test statistics are maximum Liebermeister z-score (Lz) and critical Liebermeister z-score (z crit ); Lz > z crit indicates that there were voxels that when injured predicted the presence of behavioral disturbance.

Only voxels that were damaged in at least three patients were included in the analysis ( N  = 150.132 voxels). We controlled for multiple comparisons using permutation-based thresholding using 4000 iterations, as advocated in [ 7 , 22 ]. All results presented survived a 5% permutation-based false positive probability threshold.

Neuropsychological test results on the FAB

Table  2 summarizes the performance of the patients on the FAB . The average FAB global composite score amounted to M  = 15.06 ( SD  = 3.0). Task difficulty differed between the six FAB tasks, with FAB environmental autonomy being the easiest task and FAB inhibitory control being the most difficult task. The FAB conceptualizing score, the FAB mental flexibility score, and the FAB inhibitory control score showed relatively large variability compared to the FAB motor programming score, the FAB interference score, and the FAB environmental autonomy score.

Table  2 also summarizes the results obtained with the nonparametric Liebermeister test over all FAB scores (FAB global composite score and the six individual FAB task scores) to identify whether or not there were voxels that, when injured, were associated with the presence of behavioral disturbances on the FAB . Statistical significance was found for the FAB global composite score, the FAB conceptualizing score, the FAB mental flexibility score, and the FAB inhibitory control.

Lesion analyses: lesion overlap

Figure  1 shows overlay lesion plots of all thirty-one patients in eight axial slices of a standard brain (i.e., in MNI space). Inspection of Figure  1 reveals that the maximum lesion overlap occurred in the right prefrontal cortex (PFC) where up to twelve patients showed overlapping lesions in single voxels.

Overlay lesion plots of all thirty-one patients in MNI space. Eight axial slices. The number of overlapping lesions is illustrated by colour, from violet ( N  = 1) to red ( N  = 31). Maximum overlap occurred in the right frontal lobe. The area coloured light blue indicates overlapping lesions in twelve patients (39% lesion overlap). Numbers indicate MNI coordinates.

Lesion analyses: FAB global composite score

Figure  2 displays the results of a lesion subtraction analysis for global composite score. Figure  2 A shows the overlay lesion plot of those patients who achieved a FAB global composite score below the median ( Mdn  = 16). The overlay lesion plot of those patients who achieved a FAB global composite score equal to or above the median is presented in Figure  2 B. Figure  2 C displays the results of a lesion subtraction analysis (patients below the median vs. patients equal to or above the median). The right frontal lobe was more frequently damaged in the group of patients who achieved low FAB global composite scores.

Anatomical results obtained from the lesion subtraction analysis on the FAB global composite score. A . Overlay lesion plots for those patients who achieved a FAB global composite score below the median ( Mdn  = 16; N  = 15). The number of overlapping lesions is illustrated by colour, from violet ( N  = 1) to red ( N  = 15). B . Overlay lesion plots for those patients who achieved a FAB global composite score equal to or above the median ( Mdn  = 16; N  = 16). The number of overlapping lesions is illustrated by colour, from violet ( N  = 1) to red ( N  = 16). C . Overlay plots of the subtracted superimposed lesions of the patients who achieved a FAB global composite score below the median minus patients who achieved a FAB global composite score equal to or above the median. Colours code increasing frequencies from dark red (difference 1% to 20%) to white-yellow (difference 81% to 100%), indicating regions damaged more frequently in patients who achieved a FAB global composite score below the median. The colours from dark blue (difference -1 to -20%) to light green (difference -81 to -100%) indicate regions damaged more frequently in patients who achieved a FAB global composite score equal to or above the median.

Figure  3 A depicts the location of those voxels for which the voxel-based lesion-behavior analysis revealed a significant association between voxel damage and the FAB global composite score. This analysis revealed a small area around MNI coordinates X = 35, Y = 6, Z = 16, a sub-lobar gray matter coordinate within the anterior insula (BA13).

Anatomical results obtained from the voxel-based lesion-behavior mapping (A) on the FAB global composite score, (B) on the FAB conceptualization score, (C) on the FAB mental flexibility score, and (D) on the FAB inhibitory control score. The location of voxels for which the voxel-based lesion-behavior mapping indicated that the observed Lz surpassed z crit is shown. See text for details. Numbers indicate MNI coordinates.

Lesion analyses: FAB individual task scores

Figure  3 B depicts the location of those voxels for which the voxel-based lesion-behavior analysis revealed a significant association between voxel damage and the FAB conceptualization score. Inspection of this map reveals that damage to lateral prefrontal subcortical brain areas is statistically associated with below-median performance in the FAB conceptualization score. Voxel-based statistical analysis revealed three regions: First, an area around MNI coordinates X = 32, Y = 6, Z = 16, a sub-lobar white matter coordinate near the anterior insula (BA13). Second, an area around MNI coordinates X = 28, Y = 15, Z = 24, a sub-gyral white matter coordinate near the claustrum. Third, an area around MNI coordinates X = 37, Y = 19, Z = 32, a sub-gyral white matter coordinate underneath the MFG (BA9).

Figure  3 C depicts the location of those voxels for which the voxel-based lesion-behavior analysis revealed a significant association between voxel damage and the FAB mental flexibility score. Inspection of this map reveals that damage to lateral prefrontal subcortical brain areas is statistically associated with below-median performance in the FAB mental flexibility score. Voxel-based statistical analysis revealed an area around MNI coordinates X = 40, Y = 20, Z = 32, a white matter coordinate within the right MFG (BA9).

Figure  3 D depicts the location of those voxels for which the voxel-based lesion-behavior analysis revealed a significant association between voxel damage and the FAB inhibitory control score. Inspection of this map reveals that damage to lateral prefrontal cortical and subcortical brain areas is statistically associated with below-median performance in FAB inhibitory control score. Voxel-based statistical analysis revealed two regions: First, an area around MNI coordinates X = 37, Y = 0, Z = 16 (also X = 31, Y = -2, Z = 24), sub-lobar white matter coordinates within near the anterior insula (BA13). Second, an area around MNI coordinates X = 53-58, Y = 7-18, Z = 8-16-24, sub-gyral white matter coordinates underneath the IFG (BA44/45).

The results from the remaining three FAB tasks (programming, sensitivity to interference, environmental autonomy) were negative.

Our voxel-based lesion-behavior mapping data give evidence to the proposition that FAB performance is sensitive to focal frontal lobe damage in the right cerebral hemisphere following stroke. Specifically, several FAB performance indices (i.e., FAB global composite score, FAB conceptualization score, FAB mental flexibility score, and FAB inhibitory control score) are significantly associated with the presence of lateral prefrontal lesions. Even more specifically, we found anatomical correlates of disturbed performance on the FAB global composite score, on the FAB conceptualization score, and on FAB inhibitory control score in or near the anterior insula (BA13). In addition to that, disturbed performance on the FAB mental flexibility score was related to lesions in the MFG (BA9), and performance on the FAB inhibitory control score was sensitive to damage of the right IFG (BA44/45). We did not, however, find evidence for a frontal contribution to performance on the FAB programming, on the FAB sensitivity to interference, and on the FAB environmental autonomy scores. Taken together, our voxel-based lesion-behavior mapping data support the proposition that some, yet not all, FAB measures are sensitive to lateral frontal lobe damage in the right cerebral hemisphere.

No earlier study was published which analyzed the effects of focal brain lesions following stroke on performance indices derived from the FAB , despite the fact that demonstrating the sensitivity of any neuropsychological measure to frontal damage is crucial to validating it as a suitable technique for assessing frontal functioning. Our voxel-based lesion-behavior mapping data fill this gap, providing initial evidence for the claim that performance indices on the FAB provide valid measures of frontal dysfunction.

The rapidly-growing literature on the FAB is mainly focused on two issues: First, on its capability to support the early diagnosis and differential diagnosis of neurodegenerative diseases (most notably the early diagnosis of bvFTLD as well as the differential diagnosis of bvFTLD and Alzheimer’s disease; [ 4 , 23 – 25 ]). In this realm, it is worth noting that degenerative brain atrophy affects most notably the anterior insular cortex during the earliest stages of the bvFTLD [ 26 ], suggesting that the sensitivity of FAB global performance for early-stage bvFTLD might be attributable, at least in part, to the anatomical association between FAB global composite score, FAB conceptualization score, FAB mental flexibility score, and FAB inhibitory control score and anterior insular dysfunction. Second, the capability of the FAB to detect executive dysfunctions in various diseases affecting fronto-striatal circuits constitutes a recent issue. Specifically, the FAB has been effectually used to document the presence of executive dysfunctions in various neurological diseases (e.g., amyotrophic lateral sclerosis [ 27 , 28 ]; Huntington’s disease [ 29 ]; multiple system atrophy and progressive supranuclear palsy [ 30 ]; Parkinson’s disease [ 31 – 34 ]) and psychiatric disorders (e.g., addictive substance abuse [ 35 , 36 ]; depression in Parkinson’s disease [ 37 , 38 ]). The results of the current study add to this rapidly-growing body of knowledge by strengthening the claim that various indices of FAB performance can be considered as valid assessments of lateral prefrontal, notably anterior insular, functioning.

There are three studies showing relationships between brain perfusion, as assessed by single photon emission computed tomography (SPECT), and FAB performance in patients suffering from various neurodegenerative diseases [ 39 – 41 ]. Although relationships between frontal perfusion and FAB performance have been consistently reported in each of these studies, the exact localization within the frontal lobes as well as the hemispheric lateralization of the anatomical basis of these relationships varied from study to study. A longitudinal study assessed MRI and behavioral measures of disease progression in FTLD [ 42 ]. Changes in FAB performance were associated with changes in whole brain MRI atrophy measures, though not uniformly across the three FTLD subgroups (i.e., bvFTLD, semantic dementia, progressive non-fluent aphasia).

Focal injuries to the right anterior insula (BA13) were associated with disturbed performance on the FAB global composite score, on the FAB conceptualization score, and on FAB inhibitory control score. These findings can hardly surprise, given the well-documented capability of the FAB to support the early diagnosis of bvFTLD (see above), and given the already mentioned relationship between degenerative brain atrophy in the anterior insular cortex during the earliest stages of the bvFTLD [ 24 ]. Further, anterior insula activations are often observed in functional neuroimaging studies, as detailed below.

The human anterior insular cortex participates in social-emotional processing (e.g., [ 43 ]). Other researchers have portrayed it as being part of a hedonic cortical network (e.g., [ 44 ]). According to Craig [ 45 ], ascending interoceptive pathways terminate in the posterior insula, whereas activation in the anterior insular cortex, possibly organized asymmetrically in an opponent fashion, correlates directly with subjective feelings from the body and with all emotional feelings. Lesions in the right posterior insula are associated with anosognosia for the functioning of one’s own limbs [ 46 ] and with the loss of the sense of limb ownership [ 47 ]. The right insular cortex seems to constitute a central node of a network involved in human body scheme representation [ 48 ].

The anterior insula/frontal operculum is also known to be involved in some basic cognitive functions. First, the right anterior insula/frontal operculum plays an important role in cognitive control [ 49 – 52 ], and the right anterior insula/frontal operculum seems to be involved in the control over the generation of appropriate behavioral responses to salient stimuli [ 53 , 54 ]. Second, activity in the anterior insula is related to the conscious perception of action errors, possibly enabling an orienting response when action errors are detected [ 55 , 56 ]. These relationships between activity in the (right) anterior insula and attentional control provide a possible explanation for the observed relationship between lesions in the right anterior insular cortex and FAB inhibitory control scores. Third, performance on tests of fluid intelligence produced extensive activity on the lateral frontal surface, in particular around the inferior frontal sulcus and anterior insula/frontal operculum in functional imaging studies (e.g., [ 57 ]), and lesions in these regions are associated with reduced fluid intelligence [ 58 , 59 ]. These relationships between activity in the anterior insula/frontal operculum and fluid intelligence provide a possible explanation for the observed relationship between lesions in the right anterior insular cortex and FAB conceptualization scores.

At first glance it may seem surprising that performance on FAB mental flexibility, actually reflecting lexical verbal fluency, was disturbed in stroke patients with injuries in the right frontal lobe. Henry and Crawford [ 17 ] reported strong evidence that lexical verbal fluency is more sensitive to frontal than nonfrontal lesions and left as opposed to right cortical lesions. Overall, their results were thus consistent with Ramier and Hecaen’s [ 60 ] suggestion that lexical verbal fluency performance is mediated by a verbal factor located in the left hemisphere and an executive component that reflects the integrity of the frontal lobes. When viewed from this perspective, the sensitivity of FAB mental flexibility scores to right frontal lesions reflects the degree of integrity of the executive component of lexical verbal fluency. This interpretation is further corroborated by our recent finding that injuries in similar areas of the right frontal lobe (i.e., BA9) are associated with deficient performance accuracy on Form B of the Trail Making Test [ 61 ] which requires to continuously switch back and forth between cognitive sets ([ 62 ]).

Further, it has extensively been documented in the literature on imaging and patient studies that the right IFG is closely related to response inhibition (e.g., [ 63 – 73 ]). Our finding contributes to this body of knowledge by showing that performance on the FAB Go – Nogo task, which is a simple clinical assessment technique for the ability to inhibit context-inappropriate responses, is actually sensitive to right IFG lesions in acute stroke patients.

Our results show that specific aspects of FAB performance can be predicted from the presence of lateral prefrontal lesions, as discussed above. One could express the objection that a biased selection of patients entered the current study. Specifically, most study patients showed prefrontal lesions, whereas only a small number of patients with posterior lesions could be included in our study, thereby biasing the chance to detect reliable brain-behavior relationships in favour of prefrontal regions and to the disadvantage of posterior regions. It is important that we do not wish to claim that the hereby documented sensitivity of performance on the FAB towards prefrontal lesions is specific with regard to this particular lesion location. To date, solid information about the specificity of relationships between performance on the FAB and prefrontal lesions is not available. Another limitation of the current study is the lack of patients with lesions in the left hemisphere, thereby precluding any conclusion on hemispheric asymmetry. As noted by one of the reviewers, poor FAB composite or item scores could localize to areas within the left frontal lobe, but the present data cannot address this possibility.

Our findings are mainly reported in the white matter, while our discussion is essentially addressed on a cortical point of view and in relationship with previous findings in other pathological models. The FAB has formerly been validated on samples of patients with various neurodegenerative syndromes that affect several cortical and subcortical brain structures and white matter tracts. Although there was probably degeneration of frontal cortex in many of these cases, the pathology was clearly not restricted to the frontal cortex, raising the question whether the cognitive impairments observed could be ascribed solely or even primarily to frontal cortex damage. The difficulties in performance on the FAB might have been due to lesions in parts of the brain other than the frontal cortex, including multiple white matter regions. Here, we found disturbed performance on several FAB scores of patients who had damage limited to the frontal cortex and to no more than the immediately subjacent white matter. As it stands now, lesions of white matter subjacent to frontal cortex might be primarily responsible for the observed difficulties in performance on the FAB.

a A possible statistical solution to the problem would be to use the severity of hemiparesis, apraxia, aphasia, pain, hemianopia, neglect and other neuropsychological disturbances as covariates. However, covariance analysis presupposes the separation of patients into meaningful groups of individuals, as in neuropsychological group studies, and it further requires a number of restrictive conditions to be met such as, for example, that the slopes of the regression lines (which relate covariates and dependent variables), fitted to the groups, to be parallel.

Abbreviations

Brodmann’s area

Behavioural variant of frontotemporal lobar degeneration

Center for epidemiologic studies depression scale

Computed tomography

Diffusion-weighted imaging

Echo planar imaging

Frontal assessment battery

Fluid-attenuated inversion-recovery imaging

Field of view

Frontotemporal lobar degeneration

Inferior frontal gyrus

Modified card sorting test

Middle frontal gyrus

Mini-mental-state-examination

Montreal neurological institute

Magnetic resonance imaging

Prefrontal cortex

Regensburger Wortflüssigkeits-test [Regensburger word fluency test]

Single photon emission computed tomography

Repetition time

Voxel-based lesion-behavior mapping

Wortschatz-test [vocabulary test].

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Acknowledgements

BK, NR, ST and KW were supported by the ZNS – Hannelore Kohl Stiftung, Bonn, Germany [grant number 2004007] and by the Erwin-Röver-Stiftung, Hannover, Germany [grant number 20082014]. BdH and H-OK were supported by the Deutsche Forschungsgemeinschaft [grant numbers KA1258/15-1, HA 58393/3-1].

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BK contributed to the work by obtaining funding, designing the study, analyzing and interpreting the data, and drafting the manuscript. NR contributed to the work by acquiring and analyzing the data, and drafting the manuscript. ST contributed to the work by acquiring and analyzing the data. HJS contributed to the work by obtaining funding and drafting the manuscript. BdH contributed to the work by analyzing and interpreting the data, and drafting the manuscript. H-OK contributed to the work by obtaining funding, analyzing and interpreting the data, and drafting the manuscript. KW contributed to the work by obtaining funding and drafting the manuscript. All authors read and approved the final manuscript.

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Kopp, B., Rösser, N., Tabeling, S. et al. Performance on the Frontal Assessment Battery is sensitive to frontal lobe damage in stroke patients. BMC Neurol 13 , 179 (2013). https://doi.org/10.1186/1471-2377-13-179

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• Published: 16 October 2017

A Study of the Brain Abnormalities of Post-Stroke Depression in Frontal Lobe Lesion

• Yu Shi 1   na1 ,
• Yanyan Zeng 1   na1 ,
• Lei Wu 1   na1 ,
• Wei Liu 1 ,
• Ziping Liu 1 ,
• Shanshan Zhang 1 ,
• Jianming Yang 2 &

Scientific Reports volume  7 , Article number:  13203 ( 2017 ) Cite this article

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Post stroke depression (PSD) is a serious complication of stroke. Brain imaging is an important method of studying the mechanism of PSD. However, few studies have focused on the single lesion location. The aim of this study was to investigate the brain mechanism of frontal lobe PSD using combined voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI). In total, 30 first-time ischemic frontal lobe stroke patients underwent T1 weighted MRI and resting-state fMRI scans. Clinical assessments included the 24-item Hamilton Rating Scale for Depression, the National Institutes of Health Stroke Scale, and the Mini-Mental State Examination. In our result, decreased gray matter (GM) volume in patients was observed in the prefrontal cortex, limbic system and motor cortex. The anterior cingulate cortex, selected as a seed to perform connectivity analyses, showed a greatly decreased functional connectivity with the prefrontal cortex, cingulate cortex, and motor cortex, but had an increased functional connectivity with the hippocampus gyrus, parahippocampa gyrus, insular, and amygdala. Stroke lesion location reduces excitability of brain areas in the ipsilateral brain. PSD affects mood through the brain network of the prefrontal-limbic circuit. Some brain networks, including motor cortex and the default mode network, show other characteristics of PSD brain network.

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Introduction

Post stroke depression (PSD) is a serious complication of stroke patients and occurs at a high incidence. Some studies have shown that at least 30–60% of post-stroke patients present symptoms of depression, which seriously restricts their rehabilitation 1 , 2 . At present, the PSD mechanism is unclear and treatment outcome is unsatisfactory, which greatly affects the prognosis of patients. PSD has become a prominent factor in stroke rehabilitation 3 . Therefore, understanding the mechanism of PSD is the key to precise targeted therapy 4 . Brain imaging technology provides an important means of studying brain network of PSD.

Many researchers have proposed different brain network mechanisms of PSD. Yang et al . 5 suggested that PSD produces emotional disorders through a depression-related subnetwork, based on the emotional network 5 ; In contrast, Vataja et al . 6 suggested that the prefrontal subcortical circuits (such as caudate, pallidum and anterior capsule) in the left side are linked to PSD 6 . In our previous research, we also observed decreases in gray matter density (GMD) of the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and hippocampus gyrus (HP) in PSD patients 7 . Other research groups have described the mechanism of an emotional circuit of PSD 8 .

However, most of the these studies (including ours) did not analyze the brain network of PSD in different patient types 9 , 10 . Instead, all types of patients were analyzed together, without paying attention to the basic factors of stroke such as type of stroke, location of lesion, size of lesion and duration of disease. Numerous studies have shown that some factors, including type of stroke and duration of disease, affect the development of PSD 11 , and that there is an association between PSD and some specific lesion locations or the hemisphere. Mood disorders of PSD are more likely to occur at specific lesion locations of stroke, such as the ganglia and left prefrontal cortex (PFC) 12 , which illustrates that different lesion locations have different effects on the disease. Therefore, putting all types of patients together for analysis results in a high heterogeneity of subjects. It is important to conduct brain network research on single types of PSD patients, which would improve the reliability of the conclusions.

In clinical practice, frontal lobe stroke is the most common type of stroke that causes PSD 13 . This may be due to the frontal lobe being closely related to the emotion, cognitive, memory and other advanced functions of the brain 14 . The frontal lobe is an important part of emotional processing and has a wide range of neural connections with many brain regions (e.g., thalamus, cingulate cortex and hippocampus). Consequently, frontal lobe damage is more likely to cause mood disorders 15 . We selected patients with frontal lobe strokes in this study as it is easier to explore the impact of lesion location on emotional networks, and then explore the brain network mechanism of PSD. In addition, the selection of a single lesion location allows a reduction in the heterogeneity of the study, and improves the reliability of the conclusion.

In brain imaging technology, voxel-based morphometry (VBM) can reflect the cortical volume density of the brain areas 16 , and resting-state fMRI (rs-fMRI) can reflect the functional connectivity (FC) of the brain network 17 , Both are useful methods to study the brain response of PSD. Seed-based analyses are frequently applied to resting-state data. The seed-based method is a hypothesis-driven approach wherein a seed region is selected as a reference, and the temporal correlations between the seed region and other brain regions are calculated. This allows the identification of a set of plausible FC alterations in neuropsychiatric disorders. Given that the ACC is commonly identified as the elementary structure related to emotional evaluation, it has been frequently chosen as the reference region in neuropsychiatric disorder studies. ACC, as part of the limbic system, is involved in the integration of the limbic cortex 18 . It is an important node of the emotional network including the default mode network (DMN) and the attention network, and has rich neural connections with the amygdala, thalamus and hippocampus. ACC also performs extensive information transmission with prefrontal cortex 19 . Therefore, the choice of ACC as a regions of interest (ROI) is an important entry way to explore the brain network mechanism of PSD.

To identify brain abnormalities of depression in a systemic manner, we employed the VBM and resting-state FC approaches to investigate structural alterations and potentially disrupted FC, respectively. To reduce heterogeneity, we chose patients with frontal lobe lesions of similar stroke type, duration, size of lesion and other basic factors. Our aim was to compare the brain response of PSD and non-PSD by grouping fMRI and T1 MRI datasets in frontal lobe lesions. We hypothesized that frontal lobe PSD is a unique feature of the brain network. Through this research, we hope to further the understanding of the mechanism of PSD, and provide a bridge for future research.

Method and Subjects

Participants.

This study is part of the research project ‘Brain imaging of post-stroke depression’ (Clinical Research Foundation of Southern Medical University (CRFSMU) (LC2016PY037)). In this part of the project, we reviewed the charts of 133 patients admitted for ischemic stroke to the Zhujiang Hospital of Southern Medical University between Dec 2012 and Nov 2016. Briefly, all the patients and comparison subjects met the following criteria: meet the World Health Organization (WHO) criteria for the diagnosis of cerebral infarction based on both the presence of neurological symptoms and a compatible lesion, as demonstrated by magnetic resonance imaging (MRI); in the recovery period (3 months < disease duration < 1 year) with stable symptoms; have a single infarcted brain area (3–5 cm) in the right frontal lobe; National Institutes of Health Stroke Score (NIHSS) score < 6; be conscious and able to cooperate with the interview, provide informed consent, complete the scale evaluations and a clinical interview for the diagnosis of depression; Barthel Index score ≥ 60; aged 60 ~70 years old; without a history of hemorrhagic or ischemic stroke; without obvious cognitive dysfunction disorder and language understanding disorder; without a history of schizophrenia, major depression, anxiety, dementia, drug abuse or antidepressant use at stroke onset, or a family history of mental disorders; alcoholics or drug abusers removed; right-handed. After a detailed evaluation of inclusion and exclusion criteria, 30 patients were included in the study. The following information was collected from each subject: demographics (i.e., age, gender, education level and whether they lived alone) and stroke severity, as measured by the NIHSS at the time of admission to the hospital. Simultaneously, we obtained scores on the Mini Mental State Examination (MMSE) and the Barthel Index (BI).

All experiments and protocols were approved by the Ethics Committee of Zhujiang Hospital which is affiliated with the Southern Medical University, China 20 . According to the dictates of the State Council of China, each subject provided written informed consent after receiving detailed instructions and full explanations on the experimental procedures. All methods were performed in accordance with the relevant guidelines and regulations.

An experienced neuropsychologist performed the clinical interview to diagnose depression according to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. The severity of depression was assessed using the 24-item Hamilton Rating Scale for Depression (HAMD-24). To be included in the depression group (PSD group) in our final analysis, participants had to meet DSM-IV criteria for depressive disorder and score at least 17 on the HAMD. The other participants were assigned to the control group (non-PSD group).

Brain imaging

The experiment was performed in the Department of Radiology of Zhujiang Hospital, Southern Medical University, China. Anatomical scans of the brain were collected prior to stimulation imaging. Then, all subjects were subjected to a T1 weighted MRI and an rs-fMRI scan, each of which took 6 min.

Structural and functional scans were acquired with a 3.0 T Philips Achieva MRI System (Royal Philips Electronics, Eindhoven, The Netherlands) with an eight-channel head array coil equipped for echo planar imaging. The images were axial and parallel to the anterior commissure–posterior commissure line, which covered the whole brain. Structural images were collected prior to functional imaging using a T1-weighted fast spin echo sequence [repetition time (TR) = 25 ms, echo time (TE) = 3 ms, flip angle (FA) = 30°, field of view (FOV) = 230 mm × 230 mm, acquisition matrix = 192 × 256, slice thickness = 2 mm]. Blood oxygenation level-dependent functional imaging was acquired using a T2*-weighted, single-shot, gradient-recalled echo planar imaging sequence (TR = 2000 ms, TE = 40 ms, FA = 90°, FOV = 220 mm × 220 mm, acquisition matrix = 144 × 144, slice thickness = 1 mm). In addition, T1 MRI and fMRI image collection was preceded by five dummy scans to minimize gradient distortion.

Voxel-based morphometry analysis

VBM analyses were carried out using Statistical Parametric Mapping software (SPM8: Wellcome Trust Centre for Neuroimaging, London, UK) run on Matlab 2010a (Math-Works, Natick, MA, USA). First, all images were checked for artifacts, structural abnormalities and pathologies. MR images were segmented into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) using the standard unified segmentation module in SPM8. Second, study-specific GM templates were generated from the entire image dataset using the diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) method, an improved VBM method for greater accuracy in inter-subject brain registration. Third, after an initial affine registration of the GM DARTEL templates to the corresponding tissue probability maps in the Montreal Neurological Institute (MNI) space, non-linear warping of GM images were conducted to match the corresponding MNI space GM DARTEL templates. Fourth, images were modulated to ensure that relative volumes of GM were preserved following the spatial normalization procedure. Lastly, the modulated, normalized GM images (voxel size 1.5 × 1.5 × 1.5 mm 3 ) were smoothed with an 8-mm full-width at half-maximum Gaussian kernel.

Resting-state FC analysis

The fMRI image data were preprocessed and analyzed using the Data Processing Assistant for Resting-State fMRI (DPARSF, http://www.restfmri.net ) by routines in MATLAB R2010a. The blood oxygen level-dependent (BOLD) time series preprocessing steps included removal of the first 10 volumes, slice-time correction, motion correction, intensity normalization, spatial smoothing, and linear high-pass temporal filtering. The first 10 volumes of each scan were discarded in order to eliminate any non-equilibrium effects of magnetization and to allow subjects to become familiar with the scanning environment. The motion time courses were used to select subjects’ head movements of < 2 mm in translation and 2° in rotation, which were used for further analysis (no subjects were excluded). Each individual’s functional images were normalized using the symmetric echo-planar imaging templates and resampled at a resolution of 3 mm × 3 mm × 3 mm. The normalized functional images were smoothed spatially using a 6 mm full width at half maximum (FWHM) Gaussian kernel. Finally, voxel-wise linear trend removal and temporal high-pass filtering (0.01 Hz < f < 0.08 Hz) were applied.

Data selection of both side of ACC for the ROI (3 × 3 × 3mm 3 ) was based on the results of a previous MRI study 21 . MNI brain region coordinates were selected as the central voxel ROI (x = ±5, y = −10, z = 47). A function (FC) of DPARSF software was used. The individual time course of activity from the ROIs relative to the standard echo-planar imaging template for ACC was extracted, and six motion correction parameters and their global gray matter, white matter, and cerebrospinal fluid were removed. By analyzing Pearson correlation coefficients of the seed point and whole-brain voxel time series and using the Fisher’s Z-transformation of correlation coefficients into z values for standardization, brain functionality images for each subject were ultimately obtained.

Statistical analysis

SPSS 18.0 software (SPSS, Chicago, IL, USA) was used to calculate descriptive statistics (mean ± SD) for psychophysical data. All statistical assessments were two-tailed, and we considered results to be significant at p < 0.05, consistent with the preliminary status of the trial.

VBM was used to compare gray matter volumes between the two groups using two-tailed, two simple t-test and corrected for multiple comparisons [false discovery rate (FDR), P < 0.05] in SPM 8. The FC value differences between PSD and non-PSD were calculated using two-tailed, two simple t-test, and corrected for multiple comparisons [FDR, P < 0.05].

Demographic characteristics and clinical symptoms

We recruited 30 patients (female = 14) to the study. The mean age of the study sample was 65.23 ± 4.13 (range 61–69) years. Thirteen patients (43.3%) were diagnosed with PSD. A statistical difference was found in HAMD score between the PSD group and non-PSD group (p < 0.05). There were no significant differences in the basic data (i.e., age, sex, education, duration and whether they lived alone) and functional assessment scores (i.e., MMSE score, BI score and NIHSS score) between the PSD and non-PSD groups (p > 0.05) (Table  1 ).

Compared with non-PSD patients, PSD patients displayed decreased volume in the prefrontal cortex [e.g., orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC) and ventromedial prefrontal cortex (VMPFC)], limbic system [hippocampus gyrus (HP), parahippocampa gyrus (PHP), ACC, mid-cingulate cortex (MCC), amygdala, mammillary body and insular], primary motor cortex (M1), primary sensory area (S1), secondary sensory area (S2), and supplementary motor area (SMA) (Fig.  1 and Table  2 ). Most of the decreased gray matter volume of the brain areas (especially in the limbic system) were located in the right hemisphere. The prefrontal cortex showed a decreased volume in both hemispheres.

Regions showing significantly altered GM volume in PSD compared to non-PSD.

In follow-up analysis of resting-state brain activity, both sides of ACC were chosen as seed regions. FC maps for the whole brain were generated for each group. In the FC map of left ACC, Fig.  2 and Table  3 demonstrate that PSD displayed increased FC in the cerebellum, temporal pole (TP), PHP, insular, amygdala, HP and S2, when compared to the non-PSD. In contrast, PSD showed decreased FC in the OFC, DLPFC, VMPFC, MCC, posterior cingulate cortex (PCC), S1 and SMA. The most decreased FC of brain regions were located in the bilateral hemisphere; the most increased FC of brain regions were located in unilateral hemisphere.

Regions showing significantly altered connectivity with the right ACC with PSD compared to non-PSD.

In the FC map of right ACC, Fig.  3 and Table  4 demonstrate that PSD displayed increased FC in the cerebellum, PHP, HP and insular, when compared to the non-PSD. Also, right ACC had a significantly decreased FC with prefrontal cortex, TP, MCC, PCC, thalamus, M1 and S1. In contrast to the FC map of the left ACC, the FC changes of the brain areas of the right ACC were located in the unilateral hemisphere.

Regions showing significantly altered connectivity with the left ACC with PSD compared to non-PSD.

Stroke is prevalent worldwide, and has been ranked the third deadliest disease 22 . According to the WHO, 15 million people worldwide have a stroke each year 23 . However, the biological mechanism underlying PSD is still poorly understood. There is growing interest in probing structural and functional patterns of brain abnormities related to PSD. To our knowledge, the present study is the first to combine VBM and resting-state FC to investigate brain abnormalities with PSD in frontal lobe lesion. In PSD patients, we observed structural deficits in the right side of TP, HP, amygdala, PHP, mammillary body, insular, ACC, MCC, S2 and both sides of OFC, PFC, S1 and SMA. ACC is the important node of the emotional network and limbic system so was selected as a seed region for FC analyses. Regions with aberrant connectivity showed a large overlap with regions of decreased GM volume such as prefrontal cortex, the right side of the limbic system (e.g., MCC, insular, PHP and HP), and further corroborated previous findings that the prefrontal-limbic circuit is strongly implicated in PSD.

We observed no differences in the basic data (i.e., age, sex and educational level) between the PSD and non-PSD groups, which suggests that homogeneous data can reduce the heterogeneity between subjects and improve the reliability of the conclusion. Additionally, studies have shown that PSD is caused by major trauma and nerve damage caused by stroke, and concluded that stroke severity is the important factor for PSD 24 . However, in our study, there were no significant differences in NIHSS, MMSE and BI scores between the PSD and non-PSD groups. Despite both PSD and non-PSD patients suffering severe stroke trauma, there were some subjects who did not show depressive symptoms or had a low HAMD score. This suggests that nerve damage may not be a key factor for PSD development, and there must be other factors that influence its generation.

Our findings are in agreement with previous neuroimaging studies which showed that PSD displays significantly decreased GM volume in the ACC, MCC, PFC and insular. As an important node of emotional information exchange and integration, the decreased GM volume of the prefrontal cortex can seriously affect the integrity of the neural circuits, and also reduce the speed of emotional information transmission 25 . Furthermore, the brain regions with decreased GM volume were mainly distributed in the ipsilateral cerebral hemisphere, suggesting that the lesion location of the stroke had an inhibitory effect on the ipsilateral brain areas. Additionally, some motor and sensory cortices (e.g., M1, S1 and S2) had a decreased GM volume, which may explain the phenomenon of abnormal sensation and movement relaxation in PSD patients 26 .

Central to a broad array of cognitive, sensorimotor, affective and visceral functions, the ACC has emerged as a locus of information processing and regulation in the brain 27 . It is also involved in certain higher-level functions, such as reward anticipation, decision-making, impulse control and emotion 28 . The decreased GM volume in ACC would reduce the function of ACC acting on reward system, emotion, etc. In addition, in our study, ACC had significantly increased FC with HP, PHP, amygdala, insular and S2. As an important node of emotional transmission, abnormal FC of ACC may be linked to transmission of negative emotions.

Prefrontal cortex

Our study found that both sides of the ACC had significantly decreased FC connection with OFC, PFC, MCC, PCC, S1 and angular gyrus. The lesion location would lose its original function due to stroke, and show a decreased FC with other brain areas. However, ACC also showed a decreased FC with PFC of unaffected hemispheres. This discovery has not been mentioned in previous studies. It is well known that the prefrontal lobe has a wide range of neural connections and complex structural schemas, as well as rich, complex bidirectional linkages involved in the processing of emotional information 29 . OFC is a combination of cortical areas that is involved in the integration of the prefrontal cortex, and is associated with higher levels of emotion. Decreased FC between OFC and ACC reduces the emotional information integration and transfer functions of OFC, and plays a role in the brain network of PSD. The left PFC and ACC are closely related to the reward system, which can promote the secretion of dopamine 30 . The decreased FC between PFC and ACC could reduce the occurrence of reward mechanism, and aggravate the negative state of the stroke patients. Impairments in the development of the ACC, together with impairments in the VMPFC, may constitute a neural substrate for socio-cognitive deficits in autism 31 , which would play a role in PSD and affect patient rehabilitation.

Limbic system

The amygdala is considered part of the limbic system, and plays a primary role in the processing of memory, decision-making, and emotional reactions 32 . Studies show that damage to the amygdala can interfere with memory that is strengthened by emotion. Convergent evidence from therapeutics, neuroimaging and lesion studies suggests that amygdala disturbance is implicated in the pathophysiology of depressive illness 33 . Our finding of decreased GM volume in the right side of amygdala of PSD further supports the critical role of the amygdala in the network of PSD. ACC has neural connections with multiple brain regions such as HP, PHP and thalamus. The left side of the amygdala showed an increased FC with ACC, which may be related to increased negative emotions. Moreover, as the amygdala is closely linked to social phobia 34 , increased FC of amygdala would increase the level of social avoidance, thereby affecting the patient’s return to society and life.

The HP is a major component of the brains of humans, and is a critical part of the limbic system. The HP is thought to be related to recent memory and emotional reactions or control 35 . Increased FC between right ACC and HP would improve the speed of negative emotion transmission, and break down the abnormal emotion. Also, HP is involved in emotional memory, as well as the etiology and persistence of depressive symptoms. Our results suggest that the excessive activation of HP would increase the negative emotional memory, thereby making patients more anxious and pessimistic. Moreover, compared to the left HP, the right HP showed a decreased GM volume in PSD, which would affect the function of emotional reactions or control of the right HP, and play a role in brain network of PSD.

Thalamus is the most important part of the limbic system, and is associated with changes in emotional reactivity 36 . In emotional conduction, the thalamus has nerve connections with multiple brain areas. The medial dorsal nucleus makes connections with cortical zones of the prefrontal lobe 37 . The anterior nuclei connect with the mammillary bodies, and through them (via fornix), with the HP and the cingulate cortex (CC) 38 . Consequently, it is believed that the thalamus is the relay station of emotional conduction. In our study, ACC had a decreased FC with thalamus and mammillary body, which can affect or block the emotional pathway. Studies have also shown that the frontal lobe and thalamus together constitute the awareness system, which is the main center of spiritual activity 39 . Decreased GM volume in both brain regions may affect the awareness system, which may be the reason for the thinking-slow symptom of PSD.

The CC is another part of the limbic system. It receives the information from the thalamus and the neocortex, and projects to the entorhinal cortex via the cingulum. CC is involved with emotion formation and processing, and memory 40 . This role renders the cingulate cortex highly important in disorders such as depression and schizophrenia. The decreased FC between ACC and MCC would lead to a reduction in the function of emotion formation and processing. Several studies have suggested that the PCC plays an essential role in self-appraisal and internal monitoring, as well as emotional memory 41 , 42 . Compared with non-PSD, the decreased functional connection of PCC would reduce the emotion control and the speed of emotional memory processing.

The insula is located in the central part of the cerebral hemisphere, and is widely associated with other brain regions, such as sensory cortex, cingulate cortex and prefrontal cortex. The abnormal function of insular is a factor in the development of PSD. The insula posterior has been implicated in the detection and interpretation of internal bodily states, which is closely linked to anxiety and body sensitivity 43 . The present findings suggest that the structural deficits in the insula, and the increased FC related to the ACC, are centralized in the insula posterior region, and that these brain abnormalities may be associated with elevated sensitivity to anxiety. The insular is believed to be involved in consciousness and play a role in diverse functions usually linked to emotion. The anterior insular cortex is thought to be responsible for emotions and processes a person’s sense of disgust socially 44 . The increased FC between insular and ACC may aggravate disgust symptoms of PSD.

The temporal lobe is involved in emotional processes, and is responsible for recognizing familiar facial emotions and understanding a person’s emotions from their body posture. There is also some evidence that the TP may be involved in precipitating emotional empathy and enhancing mood stability 45 . We observed that right ACC had a decreased FC with both side of TP, suggesting that TP would reduce its function of emotion control and increase unstable negative nerve impulses. A significant phenomenon was found in the study, that is, the FC between TP and Left ACC and between TP and right ACC was opposite. PFC, ACC and TP belong to limbic system 46 . As an important node of the limbic system, PFC has an important role in the transfer of emotional information. Our findings suggest that frontal stroke lesions can interrupt conduction circuit of limbic system of the ipsilateral hemisphere. Because of that, the FC between TP and ACC of the ipsilateral hemisphere decreases, while the FC between TP and ACC of the contralateral hemisphere enhances compensatorily. At the same time, some scholars propose that the FC between ACC and TP is modulated by the frontal cortex 47 . Due to right frontal stroke, the FC between TP and ACC of the ipsilateral hemisphere is out of control, while that of the contralateral hemisphere appeared functional compensation. These results suggest that frontal lobe plays an important role in depression, which may be the reason of high incidence of PSD in frontal lobe.

HP and PHP are the relay station of emotional conduction, and directly connect with the temporal lobe. The damage from stroke evokes HP/PHP to transmit more negative emotions, leading to enhanced HP/PHP activation.

Motor cortex and default mode network

Our results demonstrated that ACC had a decreased FC with M1 and SMA, suggesting that PSD may reduce the function of motor cortex. It may also explain why PSD patients have more severe motor impairment than the non-PSD patients 48 . PFC, PCC, angular gyrus and TP all belong to the default mode network (DMN) 49 . As DMN has the function of awakening and feeling emotion, decreased FC of DMN would reduce the level of arousal, whilst ignoring other people’s emotional changes. This may be why PSD patients are indifferent and avoid society.

Selection was based solely on lesion location, which reduced the heterogeneity of the subjects. The reliability of the conclusions would be improved by analyzing more lesion locations. Assessment was only performed on elderly patients, but younger patients may exhibit a different brain response. Moreover, the sample size of this study was small; future investigations need a larger sample size for statistically accurate analysis. In addition, multimodal brain imaging (i.e., diffusion tensor imaging) is a useful tool for studying the anatomical connectivity of the PSD brain, and will be included in future work.

Stroke lesion location reduces the excitability of brain areas in the ipsilateral brain. PSD affects mood through the brain network of the prefrontal-limbic circuit. Some brain networks, included motor cortex and default mode network, show other characteristics of the brain network of PSD.

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Acknowledgements

We thank Yang JM from the Department of Neurology, Zhujiang Hospital, Southern Medical University in China for assistance. We thank all subjects for the assistance in the scanning. This work was supported by National Natural Science Foundation of China (NNSFC), China; Contract grant number: 81473769. National Natural Science Foundation of China (NNSFC), China; Contract grant number: 81772430. Clinical Research Foundation of Southern Medical University, China; Contract grant number: LC2016PY037.

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Yu Shi, Yanyan Zeng and Lei Wu contributed equally to this work.

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Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China

Yu Shi, Yanyan Zeng, Lei Wu, Wei Liu, Ziping Liu, Shanshan Zhang & Wen Wu

Department of Radiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China

Jianming Yang

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S.Y., Z.Y.Y., W.L. and W.W. designed the experiments. S.Y., Z.Y.Y., Z.S.S. and Y.J.M. conducted the experiments and analyzed the data. S.Y., Z.Y.Y., L.W., L.Z.P. and W.W. wrote the manuscript. W.L. and Z.S.S. prepared all the figures, tables and supplementary materials. All authors reviewed the manuscript.

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Shi, Y., Zeng, Y., Wu, L. et al. A Study of the Brain Abnormalities of Post-Stroke Depression in Frontal Lobe Lesion. Sci Rep 7 , 13203 (2017). https://doi.org/10.1038/s41598-017-13681-w

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The Effects of a Frontal Lobe Stroke

A stroke involving the frontal lobe of the brain can cause noticeable effects, such as leg weakness, arm weakness on one side of the body, or behavioral changes.

The brain's left and right frontal lobes are relatively large and control many important functions in everyday life. The symptoms depend on which area of the frontal lobe was affected, the size of the stroke, and whether a person has had a previous stroke or other conditions that affect the brain.

This article discusses the symptoms of a frontal lobe stroke and how they may differ depending on the individual.

Verywell / Hugo Lin

Effects of a Frontal Lobe Stroke

The complications that can occur after a frontal lobe stroke fall into four main categories. If you or a loved one has experienced a frontal lobe stroke, you may experience any combination of these effects:

• Muscle weakness on one side of the body
• Speech and language problems
• A decline in thinking skills
• Behavior and personality changes

Some of these effects depend on which side of the brain was affected by the stroke and whether a person is right-handed or left-handed .

Muscle Weakness

The frontal lobe of the brain controls the movement of the opposite side of the body. A stroke that causes weakness (hemiparesis) or paralysis (hemiplegia) may produce obvious arm or leg weakness, and it can also cause any of the following symptoms as well:

• Dysphagia or difficulty swallowing
• Ataxia or damage to the body's ability to coordinate movement (balance, posture, walking)
• Urinary incontinence or inability to urinate due to loss of muscle control

Over time, weak muscles that are not regularly moved can develop painful contractures (severe stiffness) or atrophy (thinning of the muscle).

Physical therapy and occupational therapy after a stroke can help a person attain their best ability to control movement, and help to prevent muscle contractures and muscle atrophy.

Weakness or paralysis on one side of the body is the most dramatic and noticeable effect of a frontal lobe stroke.

Speech and Language Problems

The different language areas of the brain are located in the frontal lobe, the temporal lobe, and the parietal lobe.

Language function is primarily located in the dominant side of the brain, which is usually the side opposite the dominant hand. Since most people are right-handed, this is most often the left side.

The comprehension of language is controlled by a region in the dominant temporal and parietal lobes of the brain, while fluent speech is produced by a region in the dominant frontal lobe of the brain.

A dominant frontal lobe stroke affects a stroke survivor's ability to produce fluent speech and can result in a choppy speech pattern, sometimes with normal or nearly normal language comprehension.

This speech pattern characteristic of a dominant-sided frontal lobe stroke is called Broca’s aphasia.

Thinking Skills

The cognitive changes after a frontal lobe stroke may be subtle. Some people who repeatedly experience several small strokes involving the frontal lobes of the brain may develop a type of dementia called vascular dementia .

When a stroke produces dementia, it can be difficult to distinguish whether it's due to stroke or another cause. It is important to get an accurate diagnosis because the medical management of the two conditions is not the same.

Other characteristic cognitive changes caused by a frontal lobe stroke include the following:

• Lack of initiative, mood changes, and inattentiveness
• Difficulty solving problems (goal-directed behavior) in different realms of cognition including psycholinguistic, constructive, logical, and arithmetical

Behavior and Personality Changes

Sometimes, behavioral changes may develop after a frontal lobe stroke. Some specific behavioral changes include excessive jealousy, loss of sense of humor, or an uncharacteristic lack of empathy.

Other common behavioral changes after a frontal lobe stroke include the following:

• Profound lack of motivation
• Spontaneous expression of rude or odd remarks
• Irritability
• Carelessness and apathy
• Inappropriate and seemingly random persistence and repetition of certain behaviors
• Bowel or bladder emptying when it is not socially appropriate

The Frontal Lobe of the Brain

The left and right frontal lobes of the brain are large regions at the front of the brain that extend back towards the middle of the brain, accounting for approximately 1/3 to 1/2 of the cerebral cortex. We have a left frontal lobe and a right frontal lobe.

A Word From Verywell

When it comes to the brain, it's not  what  you have but  where  you have it that dictates your symptoms. Since a number of conditions can start in the frontal lobe (including stroke), it's important not to wait for medical evaluation when you develop new symptoms, as time is often of the essence for treatment.

Blood Vessels That Supply the Frontal Lobe

Like all strokes, a frontal lobe stroke is caused by an interruption of blood flow to a region of the brain. This can be caused by a blocked blood vessel or by a bleeding blood vessel .

A frontal lobe stroke is caused by interrupted blood flow through any of the following arteries:

• The internal carotid artery or its branches
• The middle cerebral artery or its branches
• The anterior cerebral artery or its branches

Usually, a frontal lobe stroke involves only the left frontal lobe or the right frontal lobe because each side receives blood from arteries on its own side.

Size of a Frontal Lobe Stroke

A frontal lobe stroke can be large or small, depending on whether interruption of blood flow occurs in one of the large blood vessels or in a small branch of a blood vessel.

Because the frontal lobes are substantial in size, specific regions of the frontal lobe may be damaged by a stroke, while other regions are spared. If there is a great deal of swelling or bleeding immediately after a stroke, the short-term phase may be uncertain as the bleeding and swelling slowly resolves .

A frontal lobe stroke can produce a variety of symptoms, some of which are more clearly related to strokes (weakness) and some of which can be confused with depression or dementia. Language can be affected by a frontal lobe stroke if the stroke affects the dominant side of the brain.

When a stroke produces weakness, physical rehabilitation is an essential part of recovery . Strokes that lead to dementia can seem similar to those caused by another condition. It's important to see your healthcare provider for appropriate treatment.

National Institute of Neurological Disorders and Stroke. Post-stroke rehabilitation fact sheet .

Cherni Y, Tremblay A, Simon M, Bretheau F, Blanchette AK, Mercier C. Corticospinal responses following gait-specific training in stroke survivors: A systematic review . Int J Environ Res Public Health . 2022 Nov 24;19(23):15585. doi:10.3390/ijerph192315585

Corballis MC. Left brain, right brain: facts and fantasies . PLoS Biol. 2014;12(1):e1001767. doi:10.1371/journal.pbio.1001767

Kourtidou E, Kasselimis D, Angelopoulou G, Karavasilis E, Velonakis G, Kelekis N, Zalonis I, Evdokimidis I, Potagas C, Petrides M. Specific disruption of the ventral anterior temporo-frontal network reveals key implications for language comprehension and cognition . Commun Biol. 2022 Oct 10;5(1):1077. doi:10.1038/s42003-022-03983-9

Caswell J. American Heart Association. When stroke affects the frontal lobe . Stroke Connection .

Vu M, Mohamed M, Stead TS, Mangal R, Ganti L. Frontal lobe hemorrhage with surrounding edema and subarachnoid hemorrhage . Cureus . 2022 Nov 10;14(11):e31345. doi:10.7759/cureus.31345

• Motor system plasticity after unilateral injury in the developing brain , Williams PTJA, Jiang YQ, Martin JH, Dev Med Child Neurol. 2017 Dec;59(12):1224-1229. doi: 10.1111/dmcn.13581. Epub 2017 Oct 3.

By Jose Vega MD, PhD Jose Vega MD, PhD, is a board-certified neurologist and published researcher specializing in stroke.

Frontal Lobe Syndrome

Affiliations.

• 1 California Northstate University
• 2 CA Northstate Uni, College of Med
• PMID: 30422576
• Bookshelf ID: NBK532981

Neuroanatomically, the frontal lobe is the largest lobe of the brain lying in front of the central sulcus. It is divided into 3 major areas defined by their anatomy and function. They are the primary motor cortex, the supplemental and premotor cortex, and the prefrontal cortex. Damage to the primary motor, supplemental motor, and premotor areas lead to weakness and impaired execution of motor tasks of the contralateral side. The inferolateral areas of the dominant hemisphere are the expressive language area (Broca area, Brodmann areas 44 and 45), to which damage will result in a non-fluent expressive type of aphasia. Frontal lobe syndrome, in general, refers to a clinical syndrome resulting from damage, and impaired function of the prefrontal cortex, which is a large association area of the frontal lobe. The areas involved may include the anterior cingulate, the lateral prefrontal cortex, the orbitofrontal cortex, and the frontal poles.

Frontal lobe syndrome is a broad term used to describe the damage of higher functioning processes of the brain such as motivation, planning, social behavior, and language/speech production. Although the etiology may range from trauma to neurodegenerative disease, regardless of the cause frontal lobe syndrome poses a difficult and complicated condition for physicians. Classically considered unique among humans, the frontal lobes are involved in a variety of higher functioning processing, such as regulating emotions, social interactions, and personality. The frontal lobes are critical for more difficult decisions and interactions that are essential for human behavior. However, with the spread of neurosurgery and procedures such as lobotomy and leucotomy for the treatment of psychiatric disorders, a variety of cases have illustrated the significant behavioral and personality changes due to frontal lobe damage. Harlow first described this collection of symptoms as "frontal lobe syndrome" after his research on the famous Phineas Gage who suffered a dramatic change in behavior as a result of trauma. Thus, an abnormality in the frontal lobe could dramatically change not only processing but personality and goal-oriented directed behavior.

Prior research has sought to identify the major areas where lesions may occur to cause the behavioral changes in frontal lobe disorders.

Ventromedial Orbitofrontal Cortex

Commonly known to cause “frontal lobe personality”, lesions in the orbitofrontal areas classically cause dramatic changes in behavior leading to impulsivity and a lack of judgment. Lesions usually found in Broadmann’s Areas 10, 11, 12, and 47 are associated with a loss of inhibition, emotional lability, and inability to function appropriately in social interactions. The most popular case involving a lesion in this area is the case of Phineas Gage who had major behavioral changes after his trauma. However, in a study by Tranel and Damasio et al., a variety of other etiologies such as stroke and neoplasms may cause “frontal lobe personality.”

Anterior Cingulate and Dorsolateral Syndromes

Lesions in the areas around Brodmann areas 9 and 46 may cause deficits within working memory, rule-learning, planning, attention, and motivation. Recent studies have reinforced that DLPFC is critical for working memory function and in particular for monitoring and manipulating the content of working memory. DLPFC may also affect attention as several cases have documented patients complaining of attentional deficits after brain trauma. There are also psychiatric implications due to injury to DPFMC. Previous studies have researched how lesions in the DLPFC may cause "pseudo-depressive" syndrome associated with DLPFC associated with a loss of initiative, decreased motivation, reduced verbal output, and behavioral slowness (abulia). Other processing issues include rule learning, task switching, planning/ problem solving, and novelty detection and exogenous attention. The anterior cingulate cortex is important for the motivation behind attention, but may also be involved in a variety of psychiatric disorders such as depression, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD).

A new area of research within the dorsolateral frontal cortices revolves around "intuition." The frontal lobes can communicate with the limbic system and association cortex. In turn, this emotional influence is associated with abstract decisions to create more efficient or “intuitive” decisions in a short span of time.

Copyright © 2024, StatPearls Publishing LLC.

• Continuing Education Activity
• Introduction
• Epidemiology
• Pathophysiology
• Histopathology
• History and Physical
• Treatment / Management
• Differential Diagnosis
• Complications
• Deterrence and Patient Education
• Pearls and Other Issues
• Enhancing Healthcare Team Outcomes
• Review Questions

Publication types

• Study Guide

A Tale About the Frontal Lobes as Told by a Neurologist

A full understanding of frontal lobe function continues to elude neurologists and neuroscientists. Neurologists caring for patients with frontal lobe damage describe dramatic changes in their cognition and personality. Cognitive neuroscientists who study healthy individuals in the lab have discovered various frontal lobe functions, such as working memory, inhibition, and cognitive flexibility. Do the findings in the lab explain the real-life impact of frontal lobe damage? Can we ever develop a theory of frontal lobe function without incorporating clinical observations of individuals with frontal lobe damage? Through the lens of the neurological patients Mark D’Esposito has encountered and from what he has learned in his lab, he attempts here to answer these crucial questions.

The following article, a transcript of D’Esposito’s acceptance speech upon receiving the Cognitive Neuroscience Society’s Distinguished Career Contributions Award (March 2023), was originally published in the Journal of Cognitive Neuroscience ( September 2023 issue ).

My tale starts in 1988 when I was a neurology resident at Boston University and rotating through the Boston VA Hospital. The patients most fascinating to me were in the Behavioral Neurology ward. It was where some of the most eminent behavioral neurologists, such as Norman Geschwind, Frank Benson, Marty Albert, and Mick Alexander, saw patients, which they elegantly described in the neurology literature. And some of the most eminent neuropsychologists, such as Edith Kaplan and Harold Goodglass, sharpened their assessment tools with these patients. It was a big, open 16-bed ward, and making rounds in the morning was always a neurological adventure. The deficits I observed in patients with frontal lobe damage, whether from a cerebral aneurysm rupture, a stroke, or trauma, were always the most challenging for me to understand.

Dr. Benson described one frontal patient in this ward in his book, “The Neurology of Thinking.” This patient had a condition called diabetes insipidus, which required that the amount of water he drank each day be restricted. The patient was instructed, “Don’t drink any water; don’t go near the water fountain.” Within a few minutes, the patient would be observed having a drink at the water fountain. When he was asked what he had just been told, he would immediately reply: “Don’t drink any water; don’t go near the water fountain.” He understood and remembered the instructions but did not use that knowledge to guide his actions appropriately.

As a Neurology resident, I attended a lecture by Pat Goldman-Rakic at the Boston Society of Psychiatry and Neurology meeting. I was blown away by her physiological studies of frontal lobe function in monkeys. She showed that single neurons in the prefrontal cortex (PFC) were active while the monkey was temporarily holding information in mind. And a small lesion in the PFC caused a “memory scotoma”; that is, the monkey could not temporarily retain a specific location of a stimulus presented to them. She said these findings were the neural basis of representational memory, which she said was akin to what others called working memory.

After she said that, my first thought was, what the heck is working memory? I spent 4 years in medical school and 3 years in a neurology residency, and I had never heard of working memory. Working memory was not mentioned in neurology textbooks. Neurologists did not test working memory in patients with frontal lobe damage. Sure, we tested short-term memory; I would ask my patients to repeat after me: 4–3–7–1–5–0–6, but is that working memory? And I never heard of a patient complaining of difficulty performing a delayed saccade task.

“I spent 4 years in medical school and 3 years in a neurology residency, and I had never heard of working memory.”

Without a smartphone that I could pull out of my pocket, all I could do was go to the medical library to figure this all out. But at the library, I could not find anything in the clinical neurology journals written about working memory. For the younger folks reading this, a library is a big building with rows and rows of shelves of hard copies of books and journals. This building usually has no windows, you cannot talk or Zoom there, and it smells musty.

Next, I went over to the main campus library, and lo and behold, I found a book, just written in 1986, called “Working Memory” by a psychologist, Alan Baddeley. I checked out the book and read it cover to cover. Like the data presented by Pat Goldman-Rakic in her monkey physiology studies, I had a hard time linking the data from these sophisticated cognitive experiments in healthy individuals to my clinical observations of frontal patients. At that time, it seemed to me that I was being confronted with monkey neurophysiology data loosely tied to human behavior and human behavioral data loosely tied to the brain.

So, this is where my tale begins. We have really tasty peanut butter (aka monkey physiology data) and really tasty milk chocolate (aka human behavioral data). But what I wanted was a Reese’s peanut butter cup. Two great tastes that taste even better together.

Working Memory

Working memory is the ability to temporarily maintain and manipulate information without relevant sensory input. The term working memory was introduced by George Miller over 50 years ago in a book called “Plans and the Structure of Behavior.” Subsequently, Karl Pribham proposed that the neural machinery supporting working memory likely includes the PFC.

If you type “working memory” into Google Scholar, you will get over 6 million hits. If you type “working memory” into ChatGPT, the Web site may crash. I think it is safe to say that mine is not the only interest to have been sparked by Pat Goldman-Rakic and Alan Baddeley over the past 40+ years.

In this tale, I will attempt to unpackage this definition of working memory in mechanistic neural terms and tie it to frontal lobe function. And what I mean by “mechanism” is the “process by which something takes place,” which, of course, can be described at many levels of detail. Because this is my tale, I have decided to give you the “light and airy” level of “detail” of these mechanisms rather than the “deep dive” level of detail.

The first mechanism critical for working memory is one that underlies the online maintenance of relevant information necessary for a goal-directed behavior. Our ability to hold information in mind allows us to bridge time and act based on internal goals and intentions rather than be at the mercy of the constant sensory input in our environment.

Our understanding of the neural basis of working memory took a significant leap forward in 1971 when Joquain Fuster at UCLA (and Kubota and Niki in Japan) first discovered neurons within monkey PFC that exhibited activity during the retention interval of a delayed match-to-sample task. In this type of working memory task, food, such as a piece of apple, is placed in one of two wells in front of the monkey where they can clearly see it. Subsequently, a blind is lowered, preventing the monkey from seeing the food. Finally, after a short delay, the blind is lifted, and the monkey is allowed to reach with their hand one of the wells to test their ability to temporarily retain information.

In the early 1990s, our laboratory attempted to determine if human PFC also exhibited activity during the delay period of working memory tasks, but I was not sure at the time that we had the tools to address this question. fMRI had just been discovered, and it did not seem to me that this method had the temporal resolution to observe brief behavioral events, such as the delay period, within a single trial. A shout-out to Geoff Aguirre and Eric Zarahn, my first two graduate students at the University of Pennsylvania, who developed a method to do this , and my first post-doc, Brad Postle, who implemented and refined this method for working memory tasks. And other shout-outs to Clay Curtis, Jason Druzgal, Charan Ranganath, Bart Rypma, and Eric Schumacher in these early years who helped make this method, which we called “trial-based functional MRI,” a reliable tool for the questions we were asking.

With fMRI, we and others have consistently shown that the PFC in humans, like in monkeys, exhibits delay activity while maintaining task-relevant information. Arguing against the idea that these findings were epiphenomenon of the fMRI signal, Clay Curtis showed that this delay activity tracks, on a trial-by-trial basis, the accuracy of the participant in remembering information over a short period. That is, this delay activity reflects the fidelity of the actively maintained representation.

How information is maintained has been an active area of research. The early view that online maintenance occurs via persistent spiking activity is evolving into the idea that representations can also be maintained by sparse bursts of neuronal spiking that induce changes in synaptic weights. Moreover, it has also become clear that direct thalamic input into the lateral PFC is critical for sustaining delay activity.

We soon discovered that the PFC is not the only brain region that exhibits delay activity. In fact, many brain regions exhibit delay activity. For example, holding the image of someone’s face in mind will evoke delay activity in the fusiform face area. Likewise, holding in mind the smell of a flower will evoke delay activity in olfactory cortex. These observations suggest that the online maintenance of any type of information activates the same neural circuits engaged while perceiving that information.

On the basis of our work and others investigating online maintenance, we reasoned that any ensemble of neurons could serve as a working memory buffer through delay activity. This mechanism eliminates the need for currently relevant representations to be transferred from perceptual systems to dedicated, specialized buffers in the brain. This idea is referred to as the sensorimotor recruitment model of working memory. If perceptual systems temporarily store the same information they process, what type of information is stored in the PFC?

In a landmark article published over 20 years ago , Earl Miller and Jon Cohen proposed that the PFC “represents goals and the means to achieve them.” And that cognitive control stems from the active maintenance of these goal representations. However, the PFC covers a lot of territory. The lateral portion of the PFC, where these goal representations are proposed to reside, comprises at least 12 functionally distinct areas, each with distinct cytoarchitecture and connectivity patterns. Thus, a significant focus of our laboratory over the years has been to understand how goal representations might be organized throughout this heterogeneous portion of the PFC.

Frontal Hierarchy

Twenty years ago, Etienne Koechlin and colleagues published an article that hypothesized that the lateral frontal cortex is organized hierarchically ; as you move anteriorly in the PFC, regions are involved in higher-order processing of plans en route to action. This idea led to numerous studies investigating whether a frontal hierarchy exists and, if it does, what the nature of this hierarchy might be.

David Badre, when he was a postdoc in our laboratory, did a fMRI study in healthy individuals to test this idea, where he convincingly demonstrated that a functional gradient along the posterior-to-anterior axis of the frontal cortex does exist, which he described as a representational hierarchy. He found that when an action is selected based on less abstract representations (such as a color corresponding to one particular finger response), posterior regions of the frontal cortex are engaged. However, when an action is selected based on more abstract representations (such as when color only corresponds to one particular finger response only when matched to one specific shape), activity moves forward in location in the PFC.

In collaboration with Bob Knight’s laboratory, Brad Voytek analyzed data from intracranial neuronal recordings of four epilepsy patients performing a task similar to the one David used in his fMRI study with healthy individuals. A directional analysis between frontal regions revealed that theta-phase encoding in the PFC was a stronger predictor of gamma activity in the more posterior, premotor/motor cortex than the reverse. This finding suggested that there was information flow from the higher-order, more anterior regions of the frontal cortex to lower-order, more posterior regions.

Representational Hierarchy

For over 20 years since I moved from Penn to Berkeley, Bob Knight has been a great mentor, colleague, and friend. Bob’s ability to play golf, however, is not so great. But his attempt at golf is a perfect example of the type of representational hierarchy that likely exists in the lateral PFC. Bob always finds himself in a situation where he really needs his frontal lobes. When Bob’s golf ball lands behind a bush, the most posterior portion of his lateral PFC is maintaining the location of the green that he is aiming for because he cannot see it through the bushes. A more anterior portion of Bob’s PFC is maintaining a more abstract representation — the rules of golf — which prevents him from kicking the ball into the fairway and being penalized two strokes. And finally, the most anterior portion of Bob’s PFC is maintaining the most abstract representation of all — that golf will make him healthier and live longer by lowering his cholesterol level and blood pressure.

And I know how important it is in today’s world to replicate one’s scholarly work, so I want to assure you that Bob’s wayward golf shots have been replicated over and over again.

The fMRI and intracranial neuronal recording studies I mentioned, and my observations of Bob playing golf, support the idea that there is a functional gradient across the lateral PFC that may be organized hierarchically. However, the precise nature of this functional gradient remains debated, and the jury is still out. Some argue that what distinguishes one level of the hierarchy from the next is the type of processes that are engaged rather than the type of stored representations. Others argue that it is the complexity of action rules being represented that is the organizing principle. Regardless of the ground truth, everyone agrees that hierarchical representation and processing of information in the brain is advantageous because it is computationally efficient and flexible.

These initial models of a frontal hierarchy were derived from data using neurophysiological methods, such as fMRI or electrocorticography in humans or single-unit recording in monkeys, which only provide indirect evidence for such a hierarchy. Direct evidence for hierarchical relationships between brain regions can only be obtained from methods where one can disrupt function at one level and observe its effects on another level. One way to understand the logic of this approach is to visualize a hierarchy as a pyramid. If a hierarchy exists, damage to the lowest level of the pyramid will affect all levels above it. In contrast, damage to the highest pyramid level will not disrupt levels beneath it. The effects of damage would be asymmetric.

A shout-out to the lesion method, which can directly test if an asymmetric pattern of deficits is observed in a group of patients with focal frontal lesions in different locations. We administered the tasks from our fMRI study to our frontal patients and observed that if a patient had a frontal lesion at one level, their impairment was more likely to occur on tasks that required that level and the next higher level. However, damage at one particular level did not affect performance on tasks at a level beneath it. These findings are direct evidence that goal representations in the lateral PFC are organized hierarchically.

There is one minor conceptual problem with the idea that a frontal hierarchy exists where the most anterior portion of the frontal cortex is at the top. A grant reviewer elegantly stated this problem. Here is the direct quote: “The logic of this experiment seems to dictate that a fourth level of abstraction (‘metacontext’ if there is such a thing) would be represented just in front of the forehead.”

As a postdoc in our laboratory, Derek Nee performed several elegant studies that produced results that offer a resolution to this conundrum regarding where the “top” or the “apex” of the frontal hierarchy is. Using fMRI, where he analyzed connectivity patterns between frontal regions, and TMS, where he disrupted function in different frontal regions, Derek did not find support that the top of the frontal hierarchy was located in the most anterior portion of the frontal cortex or a location just in front of the forehead. Instead, he found evidence that a mid-lateral region of the PFC appears to be the apex of the frontal hierarchy. He proposed that this region serves as a convergence zone for information that receives inputs from more anterior and posterior frontal regions. The most posterior frontal regions likely represent concrete contextual information, and the most anterior frontal regions likely represent more abstract information, such as future goals and plans. Both of these regions feed into this mid-lateral prefrontal region, allowing these different levels of representation to be integrated. In this way, this mid-frontal region is an area of functional convergence, sometimes referred to in the literature as a dynamic hub.

It turns out that this mid-lateral prefrontal region has unique characteristics that have been underappreciated and support this version of the organization of a frontal hierarchy. First, based on monkey anatomical data, the mid-lateral frontal cortex sends more projections to other areas, as compared with receiving projections, than any other area of the frontal cortex. Second, the mid-lateral frontal cortex, and not the frontal pole, is the last area of the frontal cortex to develop fully. And third, the mid-lateral frontal cortex has the highest concentration of dopamine receptors in the frontal cortex.

So that is a rough sketch of the likely architecture of the lateral PFC. I will now turn to how these different levels of frontal representations can serve as top–down control signals that can modulate processing in the rest of the brain.

Feedback Signals

The PFC projects to and receives projections from all other areas of the cortex. It also has extensive reciprocal connections with all subcortical regions, such as the amygdala, hippocampus, basal ganglia, thalamus, and brainstem neuromodulatory systems. This massive connectivity places it in a highly privileged position to provide feedback signals to the rest of the brain. What is the evidence that feedback signals emanate from the PFC? The first direct evidence came from a study by Joaquin Fuster almost 40 years ago in monkeys, during which he disrupted prefrontal cortical function while simultaneously recording neural activity in the visual association cortex. Surprisingly, this brilliant study has gotten relatively little attention over the years.

In this study, lateral PFC function was disrupted with a cooling probe while simultaneously recording single unit activity in the inferior temporal cortex during a delayed match-to-sample task. Cooling of the PFC caused a decrease in delay activity in the temporal cortex, providing direct evidence that the PFC was the source of a feedback signal that could modulate temporal cortex activity.

In addition to modulating the gain of temporal cortex activity, Fuster also discovered that the PFC modulates the selectivity of activity in the temporal cortex. For example, temporal cortex neurons that coded for specific color attributes became less color selective after the PFC cooling. In other words, a neuron that responded only to the color “green” before the PFC was cooled was equally responsive to any color after cooling. Think about that finding for a moment. Patches of visual association cortex that we have conceptualized as coding for highly specialized information — color, faces, motion — are less selective when not under the influence of the PFC.

Our laboratory attempted to replicate these findings in two ways. First, by performing fMRI studies in healthy individuals after perturbation of prefrontal function with TMS, and second by scanning patients with focal PFC lesions. A shout-out to Brian Miller and Taraz Lee for doing these two studies .

Selectiveness

In these studies, we investigated the effect of disrupting PFC function on the selectivity of category representations of faces or scenes in the temporal cortex. Different object categories, such as faces and scenes, are represented by spatially distributed yet overlapping areas in the extrastriate visual cortex and can be easily identified with fMRI. We reasoned that, like Fuster’s finding that color selectivity is reduced in the temporal cortex without frontal feedback, we would find less selectivity to faces and scenes after disruption of PFC function with TMS in healthy individuals or in patients with focal frontal lesions. And this is precisely what we found. The face and scene areas were less selective to their corresponding category after frontal TMS in healthy participants. In addition, in the patients with unilateral focal frontal lesions, the face and scene areas in the same hemisphere as the frontal lesion were less selective to their corresponding category than in the other hemisphere. Moreover, participants with the greatest reduction in category tuning following frontal TMS also exhibited the greatest working memory deficit. Together, this causal evidence clearly supports the notion that the lateral PFC is one source of top–down feedback signals that act via both gain and selectivity mechanisms.

Neurochemistry

The cerebral cortex is strongly modulated by diffuse inputs from subcortical and brainstem systems transmitting dopamine, norepinephrine, acetylcholine, and serotonin. However, how these neurochemical systems modulate the PFC is still relatively underspecified because the number of studies using pharmacological manipulations is small.

I first learned about the chemistry of the frontal lobes as a Neurology Fellow when I read a landmark monkey study published in 1979 by Pat Goldman-Rakic and colleagues. In that study, dopamine was depleted in the PFC, which caused monkeys to perform poorly on a working memory task. The deficit was as severe as in monkeys with a frontal lesion. Importantly, the depletion of other neurotransmitters, such as serotonin, did not impair their working memory function, just the depletion of dopamine. And dopaminergic drugs administered to these dopamine-depleted monkeys reversed their working memory deficits.

As a neurologist in training, I was taken aback by the idea that there could be such a tight link between a single neurotransmitter and a specific cognitive proc e ss. At the time, we had no drugs to prescribe to patients to improve cognitive function.

When I was a resident at the Boston VA Hospital, there was a ward full of patients with Parkinson’s disease because it was common then to adjust their medications in the hospital rather than at their home. Because these patients had severe dopamine depletion off their medications, I reasoned that I could test them on tasks before and after they took their dopaminergic replacement drug to determine the effects of dopamine on cognition.

When I was a resident and on call, requiring me to stay overnight in the hospital, I would wander over to the Neurology ward early in the morning before the nurses gave my patients their first dopaminergic medication of the day and tested them on a few cognitive tests at the bedside. Then, I would return and test them after they got their dopaminergic medication. I consistently observed that my Parkinson’s disease patients were worse on cognitive tasks thought to be sensitive to frontal lobe function before taking their medications, that is when they were dopamine depleted, compared with when they had their dopamine replenished with their medications. These observations gave me an initial glimpse into the role of dopamine in human frontal lobe function but left me with many questions that I hoped I could answer someday.

After I began my first faculty position at Penn in the Neurology department, I would regularly exit the medical center at lunchtime onto Spruce Street to go to my favorite food truck. At that truck, I was always stuck waiting in line behind undergraduates. One day while waiting patiently, I realized that these undergraduates might be interested in volunteering for a study I had in mind. Given the safety of the dopaminergic drugs I prescribed to my Parkinson’s patients, I thought that another way to test the effect of dopamine on frontal lobe function was to give these same drugs to healthy young individuals. These dopaminergic drugs were short-acting, safe, and free of side effects, and I was proposing to improve their working memory function rather than harm them in any way.

With this approach, I was asking my graduate students and postdocs if they wanted to perform the most uncontrolled studies they would ever do in their careers. Unlike pharmacological studies in animals, in human studies, we cannot precisely control the amount of dopamine that enters their brains or target a specific location. Metaphorically, we could only cut open their skull, pour dopamine all over their brain, and observe what happens. A huge shout-out to all the brave souls in our laboratory over the years that were willing to do this — Esther Aarts, Roshan Cools, Charlotte Boettiger, Ian Cameron, Daniella Furman, Sasha Gibbs, Andy Kayser, Dan Kimberg, Sharon McDowell, Margeret Sheridan, Michael Silver, Deanna Wallace, Rob White, and Bianca Wittmann.

Individuals with lower baseline working memory capacity improve on working memory tasks with dopamine augmentation, whereas those with higher baseline working memory get worse.

We observed that young, healthy individuals perform better on working memory tasks when given dopaminergic medications than when given a placebo. We also discovered that the effect of a dopaminergic medication was not the same for everyone but interacted with their working memory capacity. Individuals with lower baseline working memory capacity improve on working memory tasks with dopamine augmentation, whereas those with higher baseline working memory get worse. This observed U-shaped dose–response was consistent with monkey studies, indicating that “more” dopamine in the PFC is not “better.” Rather, there is an optimal dopamine concentration necessary for optimal function of the PFC.

When Roshan Cools joined our laboratory, our dopamine studies became turbocharged when she designed experiments aimed at testing precise mechanisms that were less exploratory in nature, as well as adding PET imaging, where we could measure dopamine in the brain to complement our pharmacological fMRI studies. The story of the relationship between dopamine and the PFC is complex and still evolving. The short summary of our main findings is that there is an intimate relationship between dopamine that acts on the striatum versus dopamine that acts on the PFC, as well as a differential role in working memory for different classes of dopamine receptors. A critical finding by Roshan that still motivates our work today is that high dopamine levels within the PFC likely optimize the maintenance of task-relevant representations, whereas high dopamine levels within the striatum optimize the flexible updating of that maintained information.

Estradiol and Working Memory

When Emily Jacobs was a graduate student in our laboratory, she enlightened me, in a gentle, nonconfrontational sort of midwestern way, that I was ignoring hormones in this dopamine story. She then delivered papers to my e-mail inbox, again, in a gentle, nonconfrontational midwestern sort of way, that demonstrated that estradiol enhances dopamine activity in the brain, estradiol levels are higher in the PFC than other cortical areas, and studies of postmenopausal women on estrogen suggest a direct link between estrogen and working memory. For her thesis, she performed a heroic study to test the hypothesis that the modulation of prefrontal dopamine activity mediates estradiol’s effects on working memory. On 24 young, healthy women, she performed fMRI scans during a working memory task at two points in their menstrual cycle when their estradiol levels, based on blood samples, were at their lowest and highest. She found that estradiol levels modulated prefrontal cortical activity depending on one’s baseline dopamine levels, as measured by the COMT enzyme in their blood. Moreover, the extent of this modulation predicted an individual’s performance on the working memory task. Since leaving Berkeley, Emily has made it loud and clear that findings such as these have direct ramifications for women’s health that must be addressed.

The take-home message from these studies is that neurotransmitters and hormones matter. We can only develop a complete model of cognition by incorporating the role of brainstem neuromodulatory and hormonal systems. And importantly, studying neurotransmitters and hormones’ effects on brain function provides a blueprint for potential therapies to remediate frontal lobe function deficits.

Studying neurotransmitters and hormones’ effects on brain function provides a blueprint for potential therapies to remediate frontal lobe function deficits.

My focus in this tale has been on one frontal system, the lateral PFC. The medial and orbital PFC comprise other distinct frontal systems. Clinically, damage to these different frontal systems leads to different cognitive and behavioral profiles. The whole tale of the frontal lobes will require an understanding of the relationship between these systems. And we must also understand how these frontal systems are embedded within the large-scale organization of the brain. The boon in network neuroscience in recent years has given us the tools to make significant progress in this area.

As I reflect on the mechanisms I have described in this tale, I believe there are plausible links between the breakdown of these mechanisms and the behaviors seen in my patients.

Faulty Online Maintenance

For example, faulty online maintenance of goal representations may explain why frontal patients often stop what they do before their intended task is completed or abruptly switch to doing something else rather than what they originally intended to do. In his book “The Working Brain,” the eminent Russian neuropsychologist Alexander Luria described a patient he sent from his office to the patient’s hospital bed to fetch the patient’s cigarettes. The patient fully understood Dr. Luria’s instructions and made his way to his hospital bed, but when he met a group of patients coming toward him, he turned around and then followed them, never following through on his original plan.

A breakdown in the hierarchical organization of goal representations may explain why patients can achieve low-level goals but do not always reach their higher-level goals. Myrna Schwartz described a patient at the Moss Rehabilitation Research Institute in Philadelphia whom she asked to wrap a present as a gift. The patient performed all the lower-level subgoals that are required to successfully wrap a gift box, such as properly cutting the wrapping paper, but the patient did not succeed at reaching the ultimate, highest-level goal because she omitted to insert the gift into the box before wrapping it.

Imitation and Utilization Behavior

A failure of top–down feedback signals emanating from the PFC may lead to what Dr. Francois Lhermitte, a French neurologist , called imitation and utilization behavior . This behavior is the remarkable tendency for frontal patients to imitate the gestures and behaviors of the clinician examining them without the clinician instructing them to do so, even when these behaviors are contextually inappropriate and might be expected to cause embarrassment. For example, in one frontal patient, when Dr. Lhermitte put on his eyeglasses, the patient picked up a pair of eyeglasses that were sitting on a table in front of them and put them on, although the patient was already wearing eyeglasses. A former nurse with a frontal lobe tumor saw a tongue depressor on a table, grabbed it, placed it in front of Dr. Lhermitte’s mouth, and examined his throat. She also picked up a blood pressure gauge and took his blood pressure. The mere sight of an object, without feedback from the PFC providing the proper context, results in behavior that is not appropriate for the situation.

As mentioned previously, when Parkinson’s disease patients are “off” their dopaminergic medications and in a state of dopamine depletion, their behavior is strikingly similar to patients with focal frontal lesions.

Frontal Lobe Behavior

The breakdown of these mechanisms leads to the behaviors I have observed in my neurology clinic and those observed by family and friends of patients with frontal damage. In retrospect, I now realize there was a link between the neural mechanisms of working memory that Pat Goldman-Rakic and Joaquin Fuster had discovered and what I observed in my patients as a neurologist in training. I was just too young to see it, but I see it now, loud and clear. I believe they call this wisdom, which is one of the benefits of getting old.

Over the past 30 years, tremendous progress has been made in understanding these mechanisms. I believe we have reached a point where this knowledge can be translated into meaningful therapeutic interventions for patients with frontal lobe damage. Many neurological disorders can damage the PFC. These include traumatic brain injury, stroke, cerebral aneurysm rupture, neoplasms, herpes encephalitis, epilepsy, and neurodegenerative diseases such as frontotemporal dementia. Dysfunction of the PFC is also proposed to underlie many psychiatric disorders such as schizophrenia, depression, and obsessive–compulsive disorder, as well as developmental disorders such as attention-deficit hyperactivity disorder and autism. And the normal function of the PFC can be affected by many other conditions, such as stress, sleep disorders, and normal aging. In this much broader context, frontal lobe syndromes are highly prevalent in our society.

A behavior commonly seen in patients with frontal lobes is called preservation , an abnormal repetition of a specific behavior, such as a motor act, verbalization, drawing, or writing. For example, when one individual was asked to write a single word, a repetitive string of letters was produced — “ho – ho – ho – ho -lo- ho – lo – ho – ho – lo -lo -lo….” — which filled an entire page. However, this writing sample was produced by my daughter Zoe when she was about 3 years old, showing off her writing skills at the time. My wife was very impressed, but all I could see was how undeveloped her frontal lobes were. It is not easy being the kid of a neurologist. To me, frontal lobe syndromes are everywhere I look.

Frontal Lobe Therapy

The pharmaceutical industry, rightly so, focuses on developing drugs that will cure neurological and psychiatric diseases. But unfortunately, it has yet to focus on drugs targeting specific brain systems that may improve cognitive deficits in the disorders I have highlighted here. Neurologists in clinical practice regularly prescribe medications to patients with frontal lobe deficits that have been approved for other conditions. For example, the dopaminergic drugs I have described that are approved for Parkinson’s disease are prescribed to patients with a traumatic brain injury and are somewhat effective in improving their behavioral and cognitive deficits. But that is not good enough, and we need a more significant effort by the pharmacological industry to develop novel therapies that can improve cognition in a meaningful way.

A promising approach that can potentially be as effective as drugs is novel cognitive therapies designed to target and strengthen the mechanisms I have discussed today. These cognitive therapies can be either therapist driven or technology driven.

One example of a therapist-driven approach for improving frontal lobe function is goal management training, developed by Brian Levine and Ian Robertson at the University of Toronto. And a shout-out to Tony Chen and Gary Turner when they were in our laboratory, and our colleague Tatjana Novakovic-Agopian, for testing, refining, augmenting, and implementing this training in patients with traumatic brain injury and healthy elders. These 5 weeks of training comprise extensive learning and practice of strategies for performing progressively complex tasks to complete projects based on subject-defined goals. Specifically, patients learn to achieve realistic goals through individual projects, such as planning a meal, or through group projects, such as planning an outing or a presentation. After this training, significant behavioral improvements in frontal lobe function were found in traumatic brain injury patients and healthy elders.

Frontal lobe function can also be enhanced with technology-driven interventions. A shout-out to another member of our laboratory, Adam Gazzaley, a world leader in pushing forward this approach that involves designing immersive video games that again target the mechanisms I have discussed. The first game he developed in his laboratory is called NeuroRacer , which was specifically designed to target multitasking abilities. After training, improvements in multitasking were found, which persisted for 6 months. The novel finding, however, was that participants also improved in cognitive control abilities that were not trained. More recently, Adam’s team has developed another game called Endeavor, the first and only video game approved by the Food and Drug Administration to treat cognitive deficits . It is now approved for children with attention-deficit disorder and hopefully will be approved for other cognitive disorders. Physicians can prescribe it, and hopefully paid for by health insurance companies. This approach, called digital medicine, can pave the way into a new era for treating cognitive deficits in brain disorders.

These cognitive therapy approaches deviate from those implemented in rehabilitation hospitals when I was in training over 30 years ago. At that time, the idea was to observe a symptom, such as poor memory, and target a therapy to mitigate that symptom, which usually meant teaching compensatory strategies, such as instructing patients how to use a memory aid, such as a diary, rather than offering them a treatment for their memory deficit. Goal management training, Neuroracer, and Endeavor are not compensatory strategies; they are therapies that have evolved from understanding the neural mechanisms underlying frontal system function that they are targeted to treat.

When a person suffers damage to their PFC, they are no longer the person they used to be. Phineas Gage was “no longer Gage” after his accident, and the family and friends of my patients who have suffered frontal damage tell me that their loved ones are no longer the people they used to be.

A patient with damage to their fusiform gyrus, who develops an inability to recognize faces, no longer interacts with the world in the same way, but in my experience, they seem to be the same person after their injury.

“The way I see it, we can learn so much from observing individuals who, unfortunately, have suffered a brain injury, and we owe it to them to do so.”

A patient with damage to Broca’s area, who develops a complete inability to speak a single word, no longer interacts with the world in the same way, but in my experience, they seem to be the same person after their injury.

To me, this makes the frontal lobes special.

Mike Gazzaniga, whom I cannot thank enough for the impact he has had on my career, and for that matter, on the career of all of us in the field of cognitive neuroscience, had similar experiences to me when he observed his split-brain patients. In a video where Alan Alda is interviewing Mike for a Scientific American television special, they watch a patient do multiple tachistoscopic experiments, and each hemisphere seems to have a mind of its own. Alan Alda sees Mike looking amazed and asks, “Are you having a moment?” And Mike says, “I’ve been doing this for 35 years, and it gets me every time.”

The way I see it, we can learn so much from observing individuals who, unfortunately, have suffered a brain injury, and we owe it to them to do so. My patients who participate in our research studies always say they do it because they hope the knowledge we gain from them will help others.

If you are a graduate student or postdoc interested in figuring out how the brain works, I encourage you to seek a greater appreciation of what happens when the brain does not work. You can do that by reading the literature or finding an opportunity to have direct contact with patients with brain disorders. I have no doubt that your research can be translated at some level into knowledge that can help our patients.

And that ends my tale about the frontal lobes.

Dr. Mark D’Esposito is a Distinguished Professor of Neuroscience and Psychology and Founder and former Director of the Henry H. Wheeler, Jr. Brain Imaging Center (2000-2020) at the Helen Wills Neuroscience Institute at the University of California, Berkeley. He is also a staff neurologist at the Northern California VA Health Care System. This article first appeared in the Journal of Cognitive Neuroscience .

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Understanding a Frontal Lobe Stroke: Causes, Side Effects, and Recovery

Last updated on January 16, 2023 Flibanserin

The frontal lobe is the largest lobe of the brain and is responsible for higher cognitive functions. This includes language, memory, problem solving, and judgment. The frontal lobe also plays a big role in our emotional expression, personalities, and movement. Naprosyn

Since the frontal lobe is involved in so many cognitive, emotional, and motor processes, recovery from a frontal lobe stroke can be particularly difficult. In this article we will discuss what to expect from a frontal lobe stroke and how to promote a successful recovery.

Table of Contents

• Rehabilitation process

Understanding the Frontal Lobe’s Function

Located at the front of the brain, the frontal lobe makes up over one-third of the brain’s volume and helps control many important functions. For example, the frontal lobe contains the prefrontal cortex , which is the area of the brain responsible for controlling cognition, emotional processing, and decision-making. The frontal lobe also houses the motor cortex , which initiates voluntary or purposeful movement.

To help you understand the workings of the frontal lobe, let’s summarize some of its primary functions:

• Speech and language . The left half of the frontal lobe, specifically Broca’s area , helps form thoughts into verbal language. Other parts of the frontal lobe also help with language skills.
• Motor skills.  The frontal lobe is home to the primary motor cortex, a region that controls muscle movement. The motor cortex directs active movements that allow you to walk, run, pick up an object, and perform any other physical movement you can think of.
• Executive functioning.  The frontal lobe plays a critical role in a person’s ability to plan, make decisions, manage their needs, and multitask. It also plays a big role in attention and concentration.
• Empathy and social skills.  The frontal lobe helps us empathize and understand the feelings of others. Additionally, this area of the brain is responsible for impulse control and emotional regulation.

Due to its involvement in so many critical functions, frontal lobe stroke can result in many secondary effects. It is important to talk with your neurologist about which hemisphere of the brain was affected by the frontal lobe stroke, as that can have implications for recovery.

Causes of Stroke in the Frontal Lobe

There are two main types of stroke that can affect the frontal lobe (and all other  areas of the brain ). First, an  ischemic stroke  occurs when a blood clot obstructs an artery in the brain, depriving this part of the brain of oxygen. Second and less common, a  hemorrhagic stroke  occurs when an artery in the brain bursts, causing bleeding in the brain. 

Since the frontal lobe accounts for a large portion of the brain, the chances of a frontal lobe stroke are higher than subcortical strokes that occur deep within the brain. The frontal lobe is especially susceptible to injury if there is damage to the anterior cerebral artery , or ACA.

The entire brain, including the frontal lobe, is divided into two halves. These halves are called hemispheres and are designated as left and right. Each hemisphere of the brain controls the opposite side of the body, so the left hemisphere controls the body’s right side and vice versa.

As a result, impairments usually occur on the side of the body opposite the stroke. In other words, a right frontal lobe stroke may impair movement on the left side of the body, and a left frontal lobe stroke may impair the right side.

Secondary Effects of Frontal Lobe Stroke

The frontal lobe controls a wide array of functions, both motor and non-motor. When this area of the brain becomes damaged by the impact of a stroke, any of these functions can be disrupted.

Here are some of the most common secondary effects of frontal lobe stroke:

• Hemiparesis or hemiplegia . Hemiparesis refers to weakness of one half of the body, generally occurring on the opposite side of the stroke. Hemiplegia is even more involved, resulting in paralysis of half the body. Since the frontal lobe controls voluntary movement, motor issues are common after frontal lobe stroke.
• Speech difficulties . Speech-language impairments, such as aphasia , are particularly common after left frontal lobe stroke. This is because the left hemisphere of the frontal lobe is usually the language center of the brain. Every brain is wired a bit differently though, and no brain function is controlled solely in one hemisphere alone.
• Dysphagia . Difficulty swallowing, a condition known as dysphagia , can occur after frontal lobe stroke. Left untreated, dysphagia can lead to other complications including choking, pneumonia, or malnutrition. Following severe strokes, some patients may even require a feeding tube.
• Ataxia . Difficulty with coordinated movement (a condition known as ataxia ) can occur when the frontal lobe’s control of voluntary movement is compromised. Ataxia can affect movement of the limbs, eye movements, and even speech and swallowing. When the frontal lobe sustains damage due to stroke, ataxia may be especially evident during gait (walking).  
• Incontinence . When a survivor sustains damage to the frontal lobe, they may lose the ability to control their bladder or bowels (which are controlled by muscles) and experience incontinence . For survivors of frontal lobe stroke, bladder incontinence is especially prevalent,
• Impaired spatial reasoning . Since the frontal lobe controls our spatial awareness, a frontal lobe stroke may affect a patient’s ability to navigate their environment. Additionally, survivors may have significant difficulty pinpointing the location of things they see, feel, or hear.
• Vascular dementia . This refers to a loss of several important cognitive skills including impulse control, memory, and attention. It can also be associated with strange behaviors. Vascular dementia occurs when blood flow to the brain is reduced during a stroke, although it can also be a result of other neurological disorders. Vascular dementia is especially prevalent following damage to the left hemisphere and is thought to affect 25-30% of ischemic stroke survivors.
• Behavior and personality changes . Not all side effects are as extreme as dementia, but many survivors of frontal lobe stroke experience shifts in behavior. Since the frontal lobe is involved in emotional regulation, survivors may exhibit behaviors such as irritability or impulsiveness. Frontal lobe stroke can also result in global personality changes including apathy, anxiety, or decreased motivation.
• Cognitive deficits . As we discussed earlier, the frontal lobe plays a strong role in executive functioning. A stroke in this area of the brain may impair a survivor’s ability to think critically, make decisions, and manage their needs.

As you can see, there are many possible secondary effects following frontal lobe stroke because the frontal lobe controls a wide array of functions. Every stroke is unique, and every brain is wired a bit differently. Therefore, every frontal lobe stroke survivor will experience different secondary effects.

The good news is that the brain can heal itself after a frontal lobe stroke. Through hard work and intensive therapies, some (if not all) secondary effects can be minimized or improved.

How to Heal the Brain After Frontal Lobe Stroke

While the effects of frontal lobe stroke can be damaging, they may not all be permanent. In fact, the brain can reassign functions to healthy portions of the brain to help “pick up the slack” and compensate for or regain lost skills.

This process is known as  neuroplasticity , and it allows patients to recover, at least partially, from the secondary effects of stroke. Through massed practice , you can activate neuroplasticity and retrain your brain to recover abilities lost after frontal lobe stroke.

To understand how neuroplasticity works, think of it as paving new roads. These new roads are the neural pathways, or connections, between your brain and the rest of your body, including your muscles. The more you practice something, the stronger and more efficient these roads become.

Repetition is how all skills are originally learned when you are young — and it’s how skills are re-learned during rehabilitation from frontal lobe stroke. The more you engage in massed practice and consistently practice skills long-term, the stronger these neural pathways become and the more your function improves. Therefore, even if you’ve suffered damage to the frontal lobe, you may still be able to regain function through dedicated rehabilitation.

How Frontal Lobe Stroke Rehabilitation Works

To regain function after frontal lobe stroke, you will need to take part in rigorous therapy and rehabilitation. Here are a few types of therapies that can promote a successful recovery from frontal lobe stroke:

• Speech therapy .  If your frontal lobe stroke caused  aphasia  (difficulty speaking and/or understanding language) or  dysphagia  (swallowing difficulties), begin speech therapy exercises right away. A speech therapist can teach you how to retrain your brain and regain language skills. They can also help you improve your swallowing and recommend techniques for safe eating.
• Physical therapy .  To recover muscle strength and coordination, make sure you participate in physical therapy exercises . Daily stroke exercises are the key to recovery in order to improve function and independence. By exercising the affected parts of your body, you will stimulate your brain and rekindle the neural networks that help you move. 
• Occupational therapy . After a stroke, it may be difficult to perform self-care activities, also known as “activities of daily living.” Working with an occupational therapist will help you regain some of these functional skills so you can return to being more independent. Interventions provided by your OT can also help you with skills needed for doing things around your home, returning to work or school, and potentially driving.
• Cognitive-behavioral therapy.  CBT helps people develop positive strategies to avoid harmful actions. It can be especially helpful for stroke victims who struggle with impulsivity. A trained therapist will be able to help you recognize triggers or negative behaviors and help you develop strategies to avoid or regulate these behaviors.
• Cognitive training exercises .  This training, which is often guided by a speech therapist, can help improve memory, attention, problem-solving, and learning skills. You can do this through intensive repetition of cognitive exercises for stroke recovery. 
• Positive psychology.  Depression and grief are commonly experienced after stroke due to major life changes and loss of function or independence. To address this, positive psychology can help retrain the brain to experience more positive emotions. To learn more about this, check out our book  Healing & Happiness After Stroke .

It is crucial to work closely with your rehab team to develop a rehabilitation plan that is unique to you. This will allow you to work toward your specific goals, regain lost function, and recover more quickly from frontal lobe stroke.

Understanding Frontal Lobe Stroke

The frontal lobe is the biggest lobe of the brain and plays a role in many different functions. Therefore, a stroke in the frontal lobe can result in a wide variety of side effects including hemiparesis or hemiplegia, cognitive deficits, ataxia, and speech-language impairments.

Fortunately, thanks to the brain’s neuroplasticity, recovery is possible. By participating in various forms of therapy, you can help rewire the brain and retrain the functions that may have been lost.

The key to recovery from frontal lobe stroke is finding therapies that fit your specific needs and goals and to prioritize consistent, repetitive practice. We hope this article helped you better understand common secondary effects following frontal lobe stroke as well as the best methods to boost recovery.

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ORIGINAL RESEARCH article

Closing-in behavior and parietal lobe deficits: three single cases exhibiting different manifestations of the same behavior.

• 1 Laboratory for Cognition and Neural Stimulation, Neurology Department, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
• 2 Neuroscience Area, Scuola Internazionale Superiore di Studi Avanzati, Trieste, Italy
• 3 Azienda Sanitaria Università Integrata di Trieste, Trieste, Italy

Closing-in behavior (CIB) is observed in copying tasks (graphic or gestural) when the copy is performed near or on the top of the model. This symptom has been classically considered to be a manifestation of constructional apraxia and is often associated with a visuospatial impairment. More recent work emphasizes the attentional and/or executive nature of the behavior and its association with frontal lobe dysfunction. We describe three patients in whom CIB was associated with posterior parietal deficits of different etiologies (stroke in Patient 1 and dementia in Patients 2 and 3). In copying figures, Patient 1 produced the shape with high accuracy but the rendering overlapped the model, while for Patients 2 and 3 the copies were distorted but overlapping or in close proximity to the target. In gesture imitation, Patient 2 performed the gestures toward the examiner’s space, while Patient 1 showed a peculiar form of CIB: when he was asked to place the ipsilesional arm in a position that mirrored the contralesional hand, Patient 1 moved his hand toward his contralesional hand. Patient 3 did not present gestural CIB. While CIB in Patient 1 was associated with selective deficits in executive functions and attention, additional visuospatial deficits were observed in Patients 2 and 3. The latter two patients showed a general visuoconstructional deficit. These case studies support a primary attentional account of CIB but also suggest that visuoconstructional impairments may contribute to the emergence of CIB, in some subjects. This evidence argues for different types of CIB with different cognitive and neural underpinnings. Furthermore, the data support the hypothesis of a differential involvement of fronto-parietal network in CIB.

Introduction

Neuropsychological examination of constructional abilities encompasses copy drawing, drawing from memory, and three-dimensional constructions. When testing constructional abilities in patients suffering from different diseases (e.g., dementia, stroke, encephalitis, Parkinson disease, and corticobasal degeneration), clinicians occasionally observe a peculiar behavior in graphic copying, known as closing-in behavior (CIB) ( Ambron and Della Sala, 2017 ). Patients with CIB place the copy abnormally close to the model (Near CIB) or overlap the copy with the model (Overlap CIB) ( Ambron and Della Sala, 2017 ). This tendency is often associated with poor accuracy of the copy reproduction, leading to the interpretation of CIB as an aspect of constructional apraxia ( Critchley, 1953 ).

However, CIB is not only observed in graphic copying, but it has also been noted in writing ( Stengel, 1944 ; Suzuki et al., 2003 ) and gesture imitation ( Kwon et al., 2002 ; McIntosh et al., 2008 ). In writing, CIB has been manifested as a tendency to superimpose writing upon previously written letters ( Stengel, 1944 ), to anchor the writing to visible marks on the paper ( Mayer Gross, 1935 ), or in copying kanji characters ( Suzuki et al., 2003 ). Several authors have described CIB in gesture imitation ( Mayer Gross, 1935 ; De Ajuriaguerra et al., 1949 ; Kwon et al., 2002 ; McIntosh et al., 2008 ). Kwon et al. (2002) described the case of a patient with corticobasal degeneration who exhibited severe ideomotor apraxia. When asked to imitate meaningless gestures presented by the examiner, this patient showed the tendency to approach, to touch and overlap his hand with the examiner’s hand. A similar tendency was noted also in a patient suffering from Alzheimer’s disease (AD) ( McIntosh et al., 2008 ), who showed CIB in both graphic copying and imitation of gestures. In this patient, the presence of CIB co-occurred with the presence of both limb and constructional apraxia.

The cognitive and neuroanatomical bases of CIB are still a matter of debate. There are two major, competing interpretations of CIB ( Ambron and Della Sala, 2017 ; Ambron et al., 2018a ). The “compensation” hypothesis links CIB to visuoconstructional, visuospatial and working memory deficits, so that patients have difficulty in the visuospatial analysis of the model and/or in holding this representation in visual working memory. In contrast, the “attraction” account provides CIB an independent status from constructional deficits and considers CIB to be an extreme manifestation of a default tendency of the motor system, so that the actions would be performed toward the focus of attention. Further specification of this interpretation proposes that CIB would represent a primitive coupling between attention and action released by a decrease of attention and/or executive resources ( McIntosh et al., 2008 ; Ambron et al., 2018a , b ). The accounts make different predictions regarding the anatomic bases of CIB. As the compensation account postulates an association between CIB and visuo-contructional and working memory impairments, it predicts an association between CIB and involvement of posterior brain areas including the parietal lobe. On the contrary, the attraction account proposes that CIB is a consequence of a deficit in attention and/or executive resources and consequently implicates frontal lobe dysfunction ( Kwon et al., 2002 ; Lepore et al., 2005 ).

Both accounts have received some support from single case and correlational studies. In single case descriptions, CIB has been reported in association with visuospatial and/or memory deficits, as well as with executive and attentional deficits (see Ambron and Della Sala, 2017 for a review). Most commonly, CIB has been reported in association with severe constructional deficits ( Ambron and Della Sala, 2017 ), but it was noted with mild constructional deficits in patients suffering from corticobasal degeneration ( Conson et al., 2009 ) and right fronto-temporal stroke ( Conson et al., 2016 ).

Correlational studies have focused on identifying the difference in cognitive performance between patients with or without CIB or on specifying the best predictor of the phenomenon. Cohort studies in patients with AD ( Ambron et al., 2009b ; De Lucia et al., 2013 ) showed a preferential association between the presence of CIB and attentional/executive and visuo-contructional impairment; whereas visuospatial or memory deficits did not account for the presence of CIB in these samples. Similarly, a study exploring CIB in patients with mild cognitive impairment (MCI) showed that the phenomenon is more common in multidomain than amnestic MCI and that the decrease in executive functions (measured with the Frontal Assessment Battery) rather than memory or visuoconstructional abilities, distinguished between patients with and without CIB. These results were replicated in patients with Parkinson’s disease ( De Lucia et al., 2015 ), in whom impairment in executive functions, but no other cognitive or motor impairments, predicted the presence of CIB. Finally, a cohort study ( Ambron et al., 2009a ) has shown that CIB is as common in AD as in FTD, but it presents different characteristics in these two populations. CIB in FTD is not influenced by the visuo-spatial demand of the copying task, whereas in AD the frequency of CIB increased with the complexity of the task, suggesting a possible additional role of visuospatial abilities in the appearance of CIB in this population. A different study in subjects with AD supported the compensation hypothesis ( Serra et al., 2010 ). Indeed, Serra et al. (2010) found patients with CIB to be more impaired in visuospatial tasks than patients without CIB, while similar performance in executive tasks and frequency of frontal lobe associated-symptoms, were observed between the two groups.

Regarding the neuroanatomical bases of CIB, findings are also controversial. In single cases, CIB has been reported in patients suffering from damage to posterior parietal lobe ( Critchley, 1953 ; Suzuki et al., 2003 ) and parietal-temporal areas ( Kwon et al., 2002 ) as well as subjects with frontal ( Lepore et al., 2005 ) or fronto-temporal regions ( Conson et al., 2016 ). At the group level, studies have focused on inferring the neuroanatomical bases of CIB based on the frequency of CIB in different clinical groups. CIB is more common in patients suffering from dementia than in focal brain damage ( Gainotti, 1972 ). CIB has been reported in AD ( Ambron et al., 2009b ; De Lucia et al., 2013 , 2014 ), FTD, and vascular dementia ( Ambron et al., 2009a ; De Lucia et al., 2014 ; Grossi et al., 2015 ). The preferential association between CIB and dementia, and the observation that CIB is as frequent in AD as FTD when patients are matched for dementia severity ( Ambron et al., 2009a ), suggests that CIB may appear as a consequence of lesions in different brain areas ( Ambron and Della Sala, 2017 ). A direct investigation of the neuroanatomical bases of CIB has been carried out only in one group study with patients with AD and matched controls ( Kwon et al., 2015 ). Using, voxel-based morphometry (VBM), the results of this study showed that decrease of the distance between the model and copy was associated with a reduction of gray matter volume in the orbitofrontal cortex. Based on these data, one may suggest that CIB reflects disruption in the fronto-parietal network.

The investigation of CIB has benefited greatly from single case investigations. Our present study is in this tradition. We describe three patients who exhibit different forms of CIB. In one patient with stroke, CIB appeared independent of constructional and severe visuospatial and memory deficits; in two patients with dementia, in contrast, CIB was associated with profound deficits in visuo-constructional abilities, praxis and dressing. Imaging data showed abnormalities in parietal areas in all three patients, but further analyses in patients with dementia showed alterations in the connections between fronto-parietal regions. These cases are discussed with reference to the theoretical accounts of CIB and provide important evidence regarding the nature and anatomical bases of CIB.

Materials and Methods

Three single cases were examined by different clinicians at different hospitals and therefore underwent different cognitive assessment. Imaging data were acquired for clinical purposes. Patient 1 underwent Computed Tomography (CT), while Patients 2 and 3 underwent structural magnetic resonance imaging (MRI) and functional MRI (fMRI). This study was approved by the Regional Ethics Committee of Friuli-Venezia Giulia (Italy) at the “Ente per la Gestione Accentrata dei Servizi Condivisi (E.G.A.S.)” (Udine, Italy) and participants signed an informed consent prior the cognitive and imaging testing.

Patients underwent different constructional tasks, but the same scoring criteria were applied to identify the presence of CIB and constructional deficits. Specifically, we scored the presence of Overlap CIB, when the copy touched or overlapped the model; Near CIB was identified when the copy was ≤10 mm from the model. Constructional abilities for each copied figure were rated using a score from 0 to 2, with 0 indicating poor accuracy of the copy (the copy was unrecognizable); 1 indicating moderate accuracy (the copy is partially recognizable, as some elementals are missing or spatially misplaced); 2 indicating good accuracy (the copy is recognizable and well reproduced).

Cases Description

Patient 1 was a late-middle-aged patient who suffered from a hemorrhagic stroke in the right posterior parietal lobe. After 1 month from the accident, this patient was admitted to the Rehabilitation ward of Ospedale Riuniti (Trieste), where s/he underwent a neuropsychological evaluation and an intensive rehabilitation program for left hemiparesis.

General neuropsychological assessment

During the neuropsychological evaluation, Patient 1 showed temporal disorientation, as s/he was unable to provide the date and time of the evaluation, but preserved personal and spatial orientation.

Language abilities (both comprehension and production) were preserved, but the contents of his/her communication were often vague and confused. Cognitive examination confirmed this observation, as Patient 1 performed within the normal limits in the language tasks (see Table 1 ). Importantly, Patient 1 showed preserved visuospatial and working memory abilities (both verbal and visuospatial). S/he showed inconsistent performance when asked to recall items from long-term memory (i.e., his/her performance was below the normal range in one test and within the normal range in the other). The core cognitive alterations in Patient 1 were observed in attention and executive tasks. When tested for cognitive flexibility and the ability to change cognitive strategies depending on the task requirement (Weigl’s and Wisconsin Sorting card test), Patient 1 showed difficulty in disengaging attention from his/her current cognitive set to shift toward a new cognitive strategy. Significant impairment was also observed in the ability to shift attention across visual stimuli, as measured by the Trail Making Test. Patient 1 did not exhibit neglect on line bisection or letter cancellation tasks (see Table 1 ). S/he showed marked difficulties in exploring and identifying stimuli randomly distributed in space (Star Cancellation Test). S/he rescanned the same portion of space showing perseverations, but his/her performance was consistent across hemispaces, suggesting a difficulty disengaging and shifting attention to a new target. Personal neglect was clinically tested in the acute phase but not observed. It was not noted during the time of the neuropsychological assessment and neither during the period of rehabilitation.

TABLE 1. Patients’ raw (and adjusted) performance in the neuropsychological tasks.

Assessment of CIB

When tested for constructional apraxia, this patient was able to reproduce the model accurately, but his/her reproduction touched and overlapped the model to be copied. S/he was asked to copy the following visual stimuli: a square, a diamond, a star, a lateral extended geometrical shape, a complex triangular shape, a house, two cubes, and Luria’s figure. S/he was also asked to copy complex figures including one with a big rectangular triangle-triangle-diamond-small isosceles triangle and another containing a small square, big circle and big isosceles triangle. CIB was noted in seven copying tasks: Overlap CIB was observed in four tasks (cubes, house, diamond), while Near CIB was noted in the square, the Greek and in Luria’s figure. In line with previous observations of CIB in Luria’s figure ( Luria, 1966 ), Patient 1’s line drawing veered progressively toward the model. Interestingly, Patient 1’s copy of the figures was accurate; there was no constructional apraxia (see Figure 1 ). In copying a house, this patient anchored his lines drawing to the original model, so that it appeared to be shifted toward the right side of the paper (see Figure 1 ). If this performance reminds of the one observed in patients’ with neglect, the presence of visuospatial neglect was not noted in neuropsychological assessment and could not account for Patient 1’s performance in this line drawing task, which rather reflected the presence of CIB. The only errors were an omission in the complex triangular shape, and the omission of an edge of a cube due to the presence of CIB (see Figure 2 ). Drawing from memory was also preserved as shown from the performance within the normal range in a clock drawing from memory task (score 8.5; test range 0–10, cut off < 3) (Mondini et al., 2003).

FIGURE 1. Representations of the graphic copying of Patient 1 showing CIB and good accuracy of the copy.

FIGURE 2. Patient 1 (A) , Patient 2 (B) and Patient 3 (C) graphic copying of the cube: all patients showed overlap CIB. Patient 1 shows a good accuracy of the copy, while Patient 2 and 3 shows CIB in association with constructional apraxia.

During motor rehabilitation, the physiotherapist noted a peculiar tendency of this patient to move toward attended stimuli. During upper limb rehabilitation, the therapist moved the paretic limb in a specific position on the table and asked the patient to move the right ipsilesional hand in a position that mirrored the contralesional hand. When blindfolded, Patient 1 was unable to do so and moved his/her hand toward the contralesional hand and positioned the ipsilesional hand very close to the contralesional hand (cf, McIntosh et al., 2008 ). To the best of our knowledge, this represents the first observation of CIB toward the patient’s own body part; gestural CIB was not assessed.

Patient 2 was a late-middle-aged patient who received a diagnosis of dementia 1 year before the assessment reported here. At the time of the assessment, this patient presented with delusional jealousy and repetitive formed visual hallucinations. S/he tended to get lost in familiar places and his/her partner reported episodes of misrecognition of his/her home. Patient 2’s daily life was highly compromised and s/he relied on the partner for most indoor and outdoor activities. On examination, Patient 2 showed good language skills, however, the structure of his/her communication was chaotic and hard to follow. S/he was cooperative, but with difficulty in sustaining attention. S/he presented masked facies, rapid mood changes, and profound anosognosia for his/her deficits.

Neuropsychological examination revealed a global deterioration, as shown by low performance in Addenbrooke’s Cognitive Examination, the Mini Mental State Exam and other cognitive measures (see Table 1 ). Patient 2 did not show optic ataxia or neglect. Patient 2 was presented with 16 Navon stimuli comprised of small letters in the shape of a large letter. S/he was unable to name the global shape but named the local shape on 14/16 trials; she produced visual errors apparently involving the small letter on two trials.

Patient 2 showed profound constructional, limb and dressing apraxias. She was impaired in imitation of meaningless and meaningful gestures, and was unable to demonstrate the use of an object even when permitted to hold it. She was unable to dress herself; s/he was not able to put on gloves and showed additional difficulties in recognizing left and right gloves. She was unable to determine if she or the examiner were wearing clothes correctly. Although she could name doll’s clothing items (albeit imperfectly) and describe the manner in which a doll should be dressed, she was unable to dress the doll.

Patient 2 was asked to copy 4 figures (square, two overlapped squares, a cube, and Luria’s figure); s/he showed poor accuracy in the copy of all the figures (2/8). CIB was not observed when copying the easier shapes but Overlap CIB emerged in copying the cube (see Figure 1 ). Gestural CIB was also tested asking Patient 2 to imitate the examiner gesture (fist or “V” hand shape) in a specific working space, while the examiner performed the gesture at the right or left side of the patient ( McIntosh et al., 2008 ). Division lines delimited the patient’s working space and in two occasions Patient 2 performed the gesture on the division line, while in one s/he crossed the division line and performed the gesture in the examiner working space (near CIB) (see Figure 3 ). Drawing from memory was also impaired (1/5 in the clock drawing of the Addenbrooke’s Cognitive Examination).

FIGURE 3. Example of Overlap (Top) and Near (Bottom) CIB observed in imitation of gestures in Patient 2.

Patient 3 was an elderly retired architect with a history of slowly progressive dementia.

At the time of testing s/he had a moderate impairment, scoring 17/30 on the MMSE; s/he was able to take walks alone in her immediate neighborhood but required assistance with personal hygiene. On examination, s/he had marked difficulties in sustaining attention but was aware of her/his difficulties and showed frustration. S/he showed impaired performance in most cognitive tasks presented during the neuropsychological examination (see Table 1 ), suggesting that deficits encompassed multiple cognitive domains.

Patient 3 performed poorly (2/8) when asked to copy the same figures presented to Patient 2 (square, two overlapped squares, a cube, and Luria’s Figure). Near CIB was observed in copying the square and Luria’s Figure, while overlap CIB was observed in copying the overlapped squares and the cube (see Figure 2 ). The presence of constructional apraxia was also confirmed from the low score in immediate copy (score of 11/36) and delayed production (score of 3/36) of Rey’s Figure ( Caffarra et al., 2002 ) and the clock drawing task of the Addenbrooke’s Cognitive Examination (score of 0/5). As Patient 2, Patient 3 was also tested for the presence of CIB in gesture imitation and although s/he was not able to copy gestures accurately but s/he did not show CIB.

Patient 3’s neuropsychological examination revealed a similar cognitive profile as Patient 2, with a global cognitive impairment that affected visuospatial, memory, attention, and executive functions. In addition, the language impairment was profound, involving both production and comprehension. Like Patient 2, Patient 3 showed difficulties recognizing and naming different items of clothing (score of 21/43) and reported dressing apraxia. S/he did not show neglect but had difficulty reaching to non-foveated targets. When shown Navon figures, s/he named the local figure first but with additional prompting named the global figure on 10/16 trials.

Brain Analyses

Lesion mapping.

Patient 1 underwent a CT scan in the acute stage 1 month before neuropsychological examination. For every slice, an expert neuroradiologist traced the Volume-of-Interest (VOI) using MRIcron 1 ; the lesion and scan were then normalized to MNI space using statistical parametric mapping (SPM12) software 2 .

Structural and Functional Magnetic Resonance Imaging Analyses

For Patient 2 and Patient 3, both structural and resting fMRI data were collected. Structural T1-weighted images were acquired with the following parameters: flip angle = 12°, TR/TE = 8.1/3.7 ms, number of slices = 170, and voxel size = 1 mm × 1 mm × 1 mm. The imaging protocol also included the acquisition of an echo-planar imaging sequence with flip angle = 90°, TR/TE = 2500/35 ms, number of slices = 36, voxel size = 3.5 mm × 3.5 mm × 3 mm, number of volumes = 200. Imaging data were also collected for 20 controls (13 women; age M = 70.2; SD = 4.2; education M = 11.5; SD = 3.2) with a Mini Mental State Examination within the normal range (scores > 25), without any history of severe neurological and psychological disorders, and without CIB in the graphic copying tasks.

Structural MRI scans were pre-processed using the computational anatomy toolbox (cat12 3 ) of SPM12. Images were segmented into gray matter, white matter and CSF, and subsequently were normalized to Montreal Neurological Institute (MNI) space. Finally, images were smoothed with a full-width half maximum (FWHM) kernel of 8 mm. Healthy controls pre-processed images were used to compute a mean and a standard deviation image, in order to transform patients’ images (Patients 2 and 3) into z -scores maps. Z -scores maps thresholds were set below −3.

Resting state fMRI was acquired with 3 Tesla MRI (Philips Medical Systems Achieva). fMRI scans were pre-processed and analyzed using conn 4 ( Whitfield-Gabrieli and Nieto-Castanon, 2012 ). Pre-processing included slice-time correction, realignment, normalization (MNI space) and smoothing with an 8 mm FWHM kernel. Moreover, images were de-noised (white matter, CSF, and movement parameters) and first-level connectivity analyses were performed correlating fluctuations over time in BOLD-related activity between specific atlas-based ( Tzourio-Mazoyer et al., 2002 ) regions-of-interests (ROI). As we were specifically interested in parietal and frontal regions, we included 6 ROIs: left and right superior frontal gyri (SFG), anterior supramarginal gyri (SMG) and inferior lateral occipital cortices (LOC). To compare correlations in the activity patterns in resting state data for Patients 2 and 3 to control group data we used the method of Crawford and Garthwaite (2002) with one-tailed p -values.

Patient 1 exhibited a large (29,168 mm 3 ) lesion in the right parietal lobe (lateral, superior, and inferior), which extended toward the paracentral and precentral gyrus.

VBM and Resting State Analyses

The VBM analysis in Patient 2 demonstrated reduced gray matter volume in most the right fusiform and, inferior and middle temporal areas of the right hemisphere. Atrophy was also observed in the left inferior frontal, right parietal (both superior and inferior), and lateral occipital areas. Similar patterns of brain atrophy were also observed in Patient 3. In this patient, major GM volume reduction with respect to controls was observed in the right inferior temporal and in both right and left middle temporal gyri. GM changes encompassed superior parietal lobe, middle occipital and fusiform areas of the right hemisphere. Lesions extended also to right anterior cingulate cortex.

In Patients 2 and 3 we found reduced correlations between right superior frontal gyrus and the anterior portion of the right and left SMG, and right and left LOC (all p s < 0.05, except for Patient 2: correlation between right superior frontal gyrus and right LOC p = 0.059); the correlation between left and right SFG was not different than healthy controls ( p > 0.05) (see Tables 2 , 3 ). Reductions in the correlation between left SFG and right LOC in Patient 2 ( p < 0.05), and right ( p < 0.01) and left (marginally significant: p = 0.07) SMG, and right LOC (marginally significant: p = 0.07) in Patient 3, and were also found. All the other comparisons did not reach the significance level (all p s > 0.05).

TABLE 2. Pattern of functional connectivity of Patient 2.

TABLE 3. Pattern of functional connectivity of Patient 3.

Comparison Across Patients

The lesions maps of the three patients with CIB are shown Figure 4 . Areas of overlaps across the three patients can be noted in the right inferior and superior parietal cortex. In addition, minor points of lesions overlap were also observed in right supplementary motor and superior frontal areas. Additional similarities were observed in the GM reduction of Patient 2 and 3, effecting in particular the right inferior temporal area and the middle temporal gyrus bilaterally, left inferior frontal, and middle occipital area.

FIGURE 4. Maps of the damaged area of Patient 1 (red map) as result of lesion mapping, and of Patient 2 (blue map), and Patient 3 (green map) as result of VBM (slices 82, 92, 102, 112, 122, and 132). A common area of overlap is observed in the right posterior parietal lobe.

Three case studies of patients with CIB are presented: one suffering from stroke (Patient 1) and two from dementia (Patients 2 and 3). All three patients showed clear CIB (Overlap CIB) as their copies of figures often overlapped the model space. The patients differed in other, important respects, however. Patients 2 and 3 were unable to copy figures reliably, whereas Patient 1 performed adequately on this task. The association between CIB and constructional apraxia has often been observed, particularly when testing patients with dementia, leading some to suggest that CIB is a direct manifestation of constructional apraxia ( Critchley, 1953 ; see also Ambron and Della Sala, 2017 for a review). This account, however, has been questioned in the past ( McIntosh et al., 2008 ; Ambron et al., 2009b , 2012 ; Conson et al., 2009 ); data from Patient 1 further undermines the argument that CIB and constructional apraxia share a common basis and provides strong evidence that CIB can be observed as an independent phenomenon (see also Ambron et al., 2009b ; Ambron and Della Sala, 2017 ).

The co-occurrence of CIB and constructional apraxia demonstrated by Patients 2 and 3 is common in patients with dementia, in whom the frequency and severity of both CIB and constructional deficits increases with the severity of dementia ( Ambron et al., 2009a ). As both Patients 2 and 3 were in moderate dementia stage, the co-occurrence of CIB and constructional apraxia in these patients is not surprising. Interestingly, in addition to constructional apraxia, both patients showed limb and dressing apraxia. These data suggest that these patients had a profound impairment of construction and action performance affecting both external and personal space.

Closing-in behavior was not observed only in copy drawing, but also in gesture imitation. When asked to imitate meaningless gesture, Patient 2 occasionally performed the gesture in the examiner’s action space. This observation supports and extends the single case description of a patient with dementia, who showed CIB in graphic copying and gesture imitation ( McIntosh et al., 2008 ). Also, Patient 1 showed a peculiar form of CIB: when asked to move the ipsilesional hand in a position that mirrored contralesional hand, s/he moved the ipsilesional hand toward contralesional hand. This represents the first evidence of which we are aware that CIB can occur not only toward external stimuli, but also toward one’s own body. As praxis was not tested in this patient, we do not know whether gestural CIB observed in Patient 1 reflected a specific manifestation of CIB toward the patient’s own body or the appearance of the phenomenon across a wide range of gesture imitation tasks. On the other hand, alternative interpretations can be proposed to account for this peculiar behavior. Indeed, this patient’s brain lesion is compatible with the presence of personal neglect ( Committeri et al., 2018 ) and body representational deficits ( Schwoebel and Coslett, 2005 ). Personal neglect was not noted during the acute phase or during the neuropsychological assessment but its presence was not systematically tested. However, patients with personal neglect show a different behavior from the one observed in the present case study, in that they tend to neglect the contralesional side of the body, while Patient 1’s movements veered toward it. Furthermore, Patient 1 was not tested for alterations of body representation. It is possible that difficulties in identifying the position of his/her own body in space might have influenced the performance of the patients on this task which required proprioceptively guided reaching movements toward his/her own body.

In relation to the cognitive underpinning of CIB, all three patients showed alterations in attention and executive functions. For Patient 1 these represented the core cognitive alterations whereas for Patients 2 and 3 with moderate dementia all cognitive domains were affected. These data support the attraction account of CIB and the hypothesis that CIB may be caused by diminished attentional and executive capacities. More specifically, our data are consistent with the hypothesis that CIB is attributable to a difficulty in shifting attention from the model space and to a different action space ( McIntosh et al., 2008 ; Ambron and Della Sala, 2017 ). Indeed, it is possible to speculate that CIB might reflect a specific difficulty in shifting attention from the specific elements of the figure. This interpretation would also account for the strong association between CIB and visuospatial deficits ( Serra et al., 2010 ), as these deficits could reflect the secondary effect of a difficulty in shifting attention from the site of the model.

It should be noted that a number of aspects of the patients’ performance are consistent with those that of patients with the syndrome of “posterior cortical atrophy,” a disorder characterized by profound visuo-spatial deficits that is commonly observed in patients with Alzheimer Disease ( Crutch et al., 2012 ). We have reported patients with this disorder, for example, who showed profound difficulties in identifying the global shape in Navon figures despite a preserved ability to recognize the local shape ( Coslett et al., 1995 ). This behavior, as well as an inability to read or identify large words or objects with relatively preserved ability to recognize the same stimuli where presented in a smaller size (see also Saffran et al., 1990 ), was attributed to a reduction in the size of the “spotlight of visual attention.”

We suggest that impairment in the ability to shift attention, perhaps with an associated reduction in the domain to which attention can be allocated can account for many of the deficits exhibited by our patients. This account, for example, could explain the poor performance of these patients in the Trail Making or Star Cancellation tasks. This interpretation is also in line with the evidence that patients with CIB are more prone to distractor interference than patients without CIB, showing a marked deviation of the movement trajectory toward the focus of attention ( Ambron et al., 2018b ). This account further predicts that CIB would be more likely to appear as the size of the shape to be copied increases. Although the latter prediction has never been tested directly, the observation that CIB increases with the complexity of the figure to be copied seems to support this view ( Ambron and Della Sala, 2017 ). Furthermore, extending the putative deficit in switching attention to other domains could explain several other aspects of the patients’ behavior. For example, the finding that gestures are copied in unusually close proximity to the examiner’s model is consistent with the hypothesis that attentional restriction affects both perceptual and action systems.

Finally, in this context, it should be noted that the proposal that CIB is related to an impairment in switching attention may also apply to Patient 1. Although we have no direct experimental evidence of such an impairment in this Patient, it is well known that parietal lobe lesions of the type exhibited by this Patient are associated with deficits in switching attention that may be profound ( Posner et al., 1984 ; Hamilton et al., 2010 ).

In relation to the neural underpinning of CIB, the lesion overlaps showed a common region of damage in the right inferior and superior parietal lobe. This evidence supports previous reports of an association between CIB and parietal lobe lesions ( Kwon et al., 2002 ; Suzuki et al., 2003 ) and the interpretation of CIB as a symptom of parietal damage ( Critchley, 1953 ). Previous work has argued for an association between frontal brain damage and CIB ( Kwon et al., 2002 ; Lepore et al., 2005 ; De Lucia et al., 2013 ). These findings might be reconciled by arguing that CIB is associated with alterations in the fronto-parietal network ( Ambron and Della Sala, 2017 ). The fMRI data from Patients 2 and 3 support this interpretation. When compared with 20 controls, both patients showed a reduced correlation between the activity of the right superior frontal gyrus and right supramarginal gyrus as well as between the right superior frontal gyrus and right lateral occipital cortex.

The absence of constructional deficits in Patient 1, despite damage in parietal area, is also interesting for the discussion regarding the role of parietal lobe in the emergence of constructional apraxia ( Gainotti and Trojano, 2018 ). Indeed, the classical interpretation of constructional apraxia as a specific symptom of parietal lobe damage has been recently revised: it has been proposed that the different streams connecting parietal with occipital and frontal lobes may have a prominent role in the different manifestations of constructional apraxia ( Gainotti and Trojano, 2018 ).

To summarize, the single case descriptions provided in the present study inform the theoretical debate regarding the nature of CIB in several respects. First, the presence of CIB with good constructional skills reinforces the view of CIB as a disorder that may be independent of constructional apraxia. Second, the observation of CIB in imitation of gesture of own hand postures, suggests that this attraction toward the model to be reproduced can occur not only in external space, but also toward one’s own body. Third, the evidence that attentional deficits represent an impairment common to all the three patients, despite the difference across patients in CIB manifestations, supports the attraction hypothesis of CIB. However, this observation does not exclude an additional involvement of visuospatial and visuo-constructional deficits in the genesis of CIB in some patients ( Serra et al., 2010 ). This evidence supports the hypothesis that CIB manifestations may across patients’ populations and may present different cognitive and neurological underpinnings ( Ambron and Della Sala, 2017 ). On this line, imaging analyses point at the importance of parietal structures in the appearance of CIB, but further suggests that the connection between these areas and frontal and occipital region might be crucial in the appearance of CIB. It is possible that changes at distinctive levels of this network might induce different manifestation of CIB. Future studies should further investigate these interpretations.

A limitation of the present study is that as we described single cases observed in clinical practice the patients underwent different cognitive assessments and neuroimaging analyses. Most importantly, both graphic and gestural CIB were assessed using different tasks. For graphic CIB, patients underwent tasks of different complexity that, as previously discussed, might have enhanced the presence of CIB to different degrees. Gestural CIB was systematically investigated only in patients with dementia (Patients 2 and 3), while its presence was not tested in the patient with stroke (Patient 1). This represents an important limitation in the description of the latter case study. Indeed the peculiar behavior consisting in the tendency to move toward his/her own body during rehabilitation was not experimentally tested and definitive conclusions regarding the nature of this behavior cannot be drawn based on the present data. Furthermore, the use of different neuroimaging measures did not permit comparisons across all three patients. Although a common area of overlap in patients’ lesions was observed in parietal regions, definitive conclusion regarding the relationship between this area and CIB cannot be drawn. Indeed, lesions of patients with dementia were not limited to the parietal lobe but extended to a large variety of regions including fronto-occipital cortices. Furthermore, as functional connectivity data were not available for Patient 1, the involvement of the fronto-parietal network, beyond the damage of parietal areas, in the emergency of CIB cannot be totally excluded.

Despite these limitations, these single case descriptions represent a good example of how important and informative single case studies can be in particular when describing the peculiar and fascinating neuropsychological syndrome of CIB.

Author Contributions

EA collected part of the data and drafted the manuscript. LP collected part of the data, analyzed the data, and revised the manuscript. AL collected part of the data and revised the manuscript. HC revised the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

• ^ http://people.cas.sc.edu/rorden/mricron/index.html
• ^ http://www.fil.ion.ucl.ac.uk/spm/software/spm12/
• ^ http://www.neuro.uni-jena.de/cat/
• ^ http://www.conn-toolbox.org

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Keywords : closing-in behavior, drawing, attention, executive functions, motor control

Citation: Ambron E, Piretti L, Lunardelli A and Coslett HB (2018) Closing-in Behavior and Parietal Lobe Deficits: Three Single Cases Exhibiting Different Manifestations of the Same Behavior. Front. Psychol. 9:1617. doi: 10.3389/fpsyg.2018.01617

Received: 29 April 2018; Accepted: 13 August 2018; Published: 13 September 2018.

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*Correspondence: Elisabetta Ambron, [email protected] ; [email protected]

† These authors have contributed equally to this work as first authors

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