Economic and social values in the brain: evidence from lesions to the human ventromedial prefrontal cortex.

Making good economic and social decisions is essential for individual and social welfare. Decades of research have provided compelling evidence that damage to the ventromedial prefrontal cortex (vmPFC) is associated with dramatic personality changes and impairments in economic and social decision-making. However, whether the vmPFC subserves a unified mechanism in the social and non-social domains remains unclear. When choosing between economic options, the vmPFC is thought to guide decision by encoding value signals that reflect the motivational relevance of the options on a common scale. A recent framework, the "extended common neural currency" hypothesis, suggests that the vmPFC may also assign values to social factors and principles, thereby guiding social decision-making. Although neural value signals have been observed in the vmPFC in both social and non-social studies, it is yet to be determined whether they have a causal influence on behavior or merely correlate with decision-making. In this review, we assess whether lesion studies of patients with vmPFC damage offer evidence for such a causal role of the vmPFC in shaping economic and social behavior.

Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating LAMB1 Variations.

Objectives: To refine the clinical spectrum of a very recently identified phenotype associated with LAMB1 end-truncating pathogenic variations. Methods: Detailed clinical, neuropsychological, and MRI investigation of 6 patients from 2 unrelated families segregating end-truncating LAMB1 variations. Results: All patients harbored a LAMB1 end-truncating pathogenic variation. The specific association of a hippocampal type episodic memory dysfunction and a diffuse leukoencephalopathy was observed in all 4 patients aged older than 50 years, slightly worsening over time in 2 patients with several years of follow-up. Additional unspecific neurologic symptoms are reported, such as episodes of numbness, language troubles, or faintness in these 4 patients and the 2 younger ones. Discussion: The association of an extensive leukoencephalopathy with an episodic memory dysfunction of the hippocampal type is strongly suggestive of a LAMB1 end-truncating variation in adults older than 50 years. Early cognitive complaints and imaging abnormalities might exist decades before. Additional transient manifestations can be observed, and this association should lead to LAMB1 screening to avoid unnecessary invasive investigations.

Effort avoidance as a core mechanism of apathy in frontotemporal dementia.

Apathy is a core symptom in patients with behavioural variant frontotemporal dementia (bvFTD). It is defined by the observable reduction in goal-directed behaviour, but the underlying mechanisms are poorly understood. According to decision theory, engagement in goal-directed behaviour depends on a cost-benefit optimization trading off the estimated effort (related to the behaviour) against the expected reward (related to the goal). In this framework, apathy would thus result from either a decreased appetence for reward, or from an increased aversion to effort. Here, we phenotyped the motivational state of 21 patients with bvFTD and 40 matched healthy controls using computational analyses of behavioural responses in a comprehensive series of behavioural tasks, involving both expression of preference (comparing reward value and effort cost) and optimization of performance (adjusting effort production to the reward at stake). The primary finding was an elevated aversion to effort, consistent across preference and performance tasks in patients with bvFTD compared to controls. Within the bvFTD group, effort avoidance was correlated to cortical atrophy in the dorsal anterior cingulate cortex and to apathy score measured on a clinical scale. Thus, our results highlight elevated effort aversion (not reduced reward appetence) as a core dysfunction that might generate apathy in patients with bvFTD. More broadly, they provide novel behavioural tests and computational tools to identify the dysfunctional mechanisms producing motivation deficits in patients with brain damage.

A neuro-computational account of procrastination behavior.

Humans procrastinate despite being aware of potential adverse consequences. Yet, the neuro-computational mechanisms underlying procrastination remain poorly understood. Here, we use fMRI during intertemporal choice to inform a computational model that predicts procrastination behavior in independent tests. Procrastination is assessed in the laboratory as the preference for performing an effortful task on the next day as opposed to immediately, and at home as the delay taken in returning completed administrative forms. These procrastination behaviors are respectively modeled as unitary and repeated decisions to postpone a task until the next time step, based on a net expected value that integrates reward and effort attributes, both discounted with delay. The key feature that is associated with procrastination behavior across individuals (both in-lab and at-home) is the extent to which the expected effort cost (signaled by the dorsomedial prefrontal cortex) is attenuated by the delay before task completion. Thus, procrastination might stem from a cognitive bias that would make doing a task later (compared to now) appear as much less effortful but not much less rewarding.

Elevated Effort Cost Identified by Computational Modeling as a Distinctive Feature Explaining Multiple Behaviors in Patients With Depression.

BACKGROUND: Motivational deficit is a core clinical manifestation of depression and a strong predictor of treatment failure. However, the underlying mechanisms, which cannot be accessed through conventional questionnaire-based scoring, remain largely unknown. According to decision theory, apathy could result either from biased subjective estimates (of action costs or outcomes) or from dysfunctional processes (in making decisions or allocating resources). METHODS: Here, we combined a series of behavioral tasks with computational modeling to elucidate the motivational deficits of 35 patients with unipolar or bipolar depression under various treatments compared with 35 matched healthy control subjects. RESULTS: The most striking feature, which was observed independent of medication across preference tasks (likeability ratings and binary decisions), performance tasks (physical and mental effort exertion), and instrumental learning tasks (updating choices to maximize outcomes), was an elevated sensitivity to effort cost. By contrast, sensitivity to action outcomes (reward and punishment) and task-specific processes were relatively spared. CONCLUSIONS: These results highlight effort cost as a critical dimension that might explain multiple behavioral changes in patients with depression. More generally, they validate a test battery for computational phenotyping of motivational states, which could orientate toward specific medication or rehabilitation therapy, and thereby help pave the way for more personalized medicine in psychiatry.

Unravelling the impact of frontal lobe impairment for social dysfunction in myotonic dystrophy type 1.

Myotonic dystrophy type 1 is an autosomal dominant multisystemic disorder affecting muscular and extra muscular systems, including the central nervous system. Cerebral involvement in myotonic dystrophy type 1 is associated with subtle cognitive and behavioural disorders, of major impact on socio-professional adaptation. The social dysfunction and its potential relation to frontal lobe neuropsychology remain under-evaluated in this pathology. The neuroanatomical network underpinning that disorder is yet to disentangle. Twenty-eight myotonic dystrophy type 1 adult patients (mean age: 46 years old) and 18 age and sex-matched healthy controls were included in the study. All patients performed an exhaustive neuropsychological assessment with a specific focus on frontal lobe neuropsychology (motivation, social cognition and executive functions). Among them, 18 myotonic dystrophy type 1 patients and 18 healthy controls had a brain MRI with T1 and T2 Flair sequences. Grey matter segmentation, Voxel-based morphometry and cortical thickness estimation were performed with Statistical Parametric Mapping Software SPM12 and Freesurfer software. Furthermore, T2 white matter lesions and subcortical structures were segmented with Automated Volumetry Software. Most patients showed significant impairment in executive frontal functions (auditory working memory, inhibition, contextualization and mental flexibility). Patients showed only minor difficulties in social cognition tests mostly in cognitive Theory of Mind, but with relative sparing of affective Theory of Mind and emotion recognition. Neuroimaging analysis revealed atrophy mostly in the parahippocampal and hippocampal regions and to a lesser extent in basal ganglia, regions involved in social navigation and mental flexibility, respectively. Social cognition scores were correlated with right parahippocampal gyrus atrophy. Social dysfunction in myotonic dystrophy type 1 might be a consequence of cognitive impairment regarding mental flexibility and social contextualization rather than a specific social cognition deficit such as emotion recognition. We suggest that both white matter lesions and grey matter disease could account for this social dysfunction, involving, in particular, the frontal-subcortical network and the hippocampal/arahippocampal regions, brain regions known, respectively, to integrate contextualization and social navigation.

Rescue stenting versus medical care alone in refractory large vessel occlusions: a systematic review and meta-analysis.

PURPOSE: Mechanical thrombectomy (MT) failure is associated with very poor prognosis. Permanent intracranial stenting (PIS) may be useful in such refractory occlusions. However, this strategy requires an aggressive antithrombotic regimen that may be harmful in extended strokes. The aim of this study was to compare clinical outcomes between patients with refractory acute large vessel occlusions (LVOs) treated by PIS versus patients for whom the procedure was stopped without recanalization. METHODS: We conducted a systematic review by searching for articles in PubMed, the Cochrane Library, and ClinicalTrials.gov from January 2015 to September 2019. Two reviewers independently selected studies comparing PIS after failed MT in addition to usual care versus usual care only. A comparative meta-analysis was performed using random-effects models to estimate odds ratios of favorable clinical outcome at 90 days, defined as a modified Rankin scale 0-2, mortality and symptomatic intracranial hemorrhage (SICH). RESULTS: Four comparative studies were included for a total of 352 patients: 149 in the PIS group versus 203 in the control group. PIS was associated with significantly higher rates of 90-day favorable clinical outcome (odds ratio [OR], 2.87 [95% confidence interval (95% CI), 1.77-4.66]; p < 0.001; I2, 0%) and lower mortality (OR, 0.39 [0.16-0.93]; p = 0.03; I2, 43%), whereas SICH rates did not significantly differ (OR, 0.68 [0.37-1.27]; p = 0.23; I2, 0%). CONCLUSION: From observational study results, attempting PIS after failed MT seems to improve clinical outcomes without increasing the risk of intracranial bleeding. Randomized trials are needed to confirm these results.

Miming neurological syndromes improves medical student's long-term retention and delayed recall of neurology.

Basic examination and diagnostic skills in neurology are important for every graduating medical student. However, a majority of medical students consider neurology as complex and difficult to master. We evaluate the impact a learner-friendly, innovative simulation-based training programme has on long-term retention and delayed recall of neurological semiology amongst third-year medical students from the University Pierre et Marie Curie in Paris, France. The 2013 class received standard teaching in neurological semiology. The 2015 class who received the same standard teaching in neurological semiology were also invited to voluntarily participate in The Move, a mime-based role-play training programme of neurological semiology. During the Move, students were trained to simulate a patient with a neurological syndrome or the physician examining the patient. Students were evaluated with an assessment thirty months after their neurological rotation, including 15 questions to evaluate long-term retention of neurological semiology, and 10 to test background knowledge in general semiology. The semiology test was performed by 366/377 students from the 2013 class (standard education group) and by 272/391 students from the 2015 class, among which 186 participated in The Move (The Move group) and 86 did not (standard education group). The mean neurological semiology score was higher in the 2015 class compared to the 2013 class (p = 0.007) and remained so after adjustment for the general semiology performance (p = 0.003). The adjusted mean neurological semiology score was 1.21/15 points higher [95% CI 0.66, 1.75] in The Move group compared to the standard education group, corresponding to a 14% better ranking. The Move programme improves medical student's long-term retention and delayed recall of neurological semiology. This learner-friendly interactive teaching may in turn enhance clinical proficiency of future physicians in neurological semiology.

Efficacy of Endovascular Therapy in Acute Ischemic Stroke Depends on Age and Clinical Severity.

BACKGROUND AND PURPOSE: Efficacy of endovascular treatment (EVT) for ischemic stroke because of large vessel occlusion may depend on patients' age and stroke severity; we, therefore, developed a prognosis score based on these variables and examined whether EVT efficacy differs between patients with good, intermediate, or poor prognostic score. METHODS: A total of 4079 patients with an acute ischemic stroke were identified from the Paris Stroke Consortium registry. We developed the stroke checkerboard (SC) score (SC score=1 point per decade ≥50 years of age and 2 points per 5 points on the National Institutes of Health Stroke Scale) to predict spontaneous outcome. The primary outcome was the adjusted common odds ratio for an improvement in the modified Rankin Scale at 90 days after EVT, in patients with low, intermediate, or high SC scores. To rule out potential selection biases, a nested case-control analysis, with individual matching for all major prognostic factors, was also performed, to compare patients with large vessel occlusion in the anterior circulation treated or not with EVT. RESULTS: In patients untreated with EVT, SC scores <8 were predictive of good outcomes (modified Rankin Scale score, 0-2; area under the curve, 0.87), whereas SC scores >12 were predictive of poor outcomes (modified Rankin Scale score, 4-6; area under the curve, 0.88). In the overall population, there was an interaction between EVT and prognosis group (P<0.001). EVT was associated with improved outcome in patients with SC scores >12 (common odds ratio, 1.70; 95% confidence interval, 1.13-2.56) and SC scores 8 to 12 (odds ratio, 1.37; 95% confidence interval, 1.11-1.69) but not in patients with SC scores <8 (odds ratio, 0.72; 95% confidence interval, 0.56-0.93). Similar results were obtained in the case-control analysis among 449 patients treated with EVT and 449 matched patients untreated with EVT. CONCLUSIONS: In patients stratified with the SC score, EVT was associated with improved functional outcome in older and more severe patients but not in younger and less severe patients.

The silver effect of admission glucose level on excellent outcome in thrombolysed stroke patients.

Higher admission glucose levels (AGL) are associated with less favorable outcome in thrombolysis. But, could AGL's impact on outcome vary by onset-to-treatment (OTT) time? Is hyperglycemia associated with a shorter therapeutic time window for excellent outcome for thrombolysed stroke patients? We assessed predictive values of AGL, baseline NIHSS, age, and OTT time quartiles on excellent outcome (3-month modified Rankin score of 0-1) in 773 patients treated by rt-Pa. We added the AGL × OTT time quartile interaction in the model and separately analyzed the predictive values of AGL, age, and NIHSS for each OTT time quartile if the interaction was significant. AGL, baseline NIHSS, age, and OTT time quartiles were significant predictors. When added in the model, the AGL × OTT interaction was significant (OR: 0.96, 95% CI: 0.94-0.99, p: 0.0009). AGL was predictive only during the third OTT time quartile (181-224 min). During this period, the predicted rate of excellent outcome was 16% for AGL = 6.5 mmol/L and 8% for AGL = 8 mmol/L. The rate of excellent outcome was not decreased in hyperglycemic patients for OTT time ≤ 180 min (20 vs. 24.5% p: 0.37), but was decreased for OTT time > 180 min (9.6 vs. 26.7% p: 0.00001). Similar results were found in patients with MCA recanalization, but not in patients without recanalization. The therapeutic time window for excellent outcome is shortened in hyperglycemic patients. This would support the design of "freezing penumbra" randomized trials based on ultra-early AGL control.

[Motivation in all Ks: computational approach to neuro-psychiatric diseases]. / La motivation dans tous ses K - Approche computationnelle des pathologies neuropsychiatriques.

Motivation can be defined as the function that orients and activates the behavior. Motivation deficits such as apathy are pervasive in both neurological and psychiatric diseases, and are currently assessed with clinical scales that do not give any mechanistic insight. Here, we present another approach that consists in phenotyping the behaviour of patients in motivation tests, using computational models. These formal models impose a precise and operational definition of motivation that is embedded in decision theory. We then review basic and clinical studies that have investigated the neural bases of motivation processes and shown the involvement of specific cortical, subcortical and neuromodulatory systems. Finally, we emphasize the promises of computational phenotyping for clinical purposes, as it may not only give insight into motivation deficits but also help personalize treatment.

Why not try harder? Computational approach to motivation deficits in neuro-psychiatric diseases.

Motivation deficits, such as apathy, are pervasive in both neurological and psychiatric diseases. Even when they are not the core symptom, they reduce quality of life, compromise functional outcome and increase the burden for caregivers. They are currently assessed with clinical scales that do not give any mechanistic insight susceptible to guide therapeutic intervention. Here, we present another approach that consists of phenotyping the behaviour of patients in motivation tests, using computational models. These formal models impose a precise and operational definition of motivation that is embedded in decision theory. Motivation can be defined as the function that orients and activates the behaviour according to two attributes: a content (the goal) and a quantity (the goal value). Decision theory offers a way to quantify motivation, as the cost that patients would accept to endure in order to get the benefit of achieving their goal. We then review basic and clinical studies that have investigated the trade-off between the expected cost entailed by potential actions and the expected benefit associated with potential rewards. These studies have shown that the trade-off between effort and reward involves specific cortical, subcortical and neuromodulatory systems, such that it may be shifted in particular clinical conditions, and reinstated by appropriate treatments. Finally, we emphasize the promises of computational phenotyping for clinical purposes. Ideally, there would be a one-to-one mapping between specific neural components and distinct computational variables and processes of the decision model. Thus, fitting computational models to patients' behaviour would allow inferring of the dysfunctional mechanism in both cognitive terms (e.g. hyposensitivity to reward) and neural terms (e.g. lack of dopamine). This computational approach may therefore not only give insight into the motivation deficit but also help personalize treatment.

Mechanical Thrombectomy in Perioperative Strokes: A Case-Control Study.

BACKGROUND AND PURPOSE: Perioperative strokes (POS) are rare but serious complications for which mechanical thrombectomy could be beneficial. We aimed to compare the technical results and patients outcomes in a population of POS versus non-POS (nPOS) treated by mechanical thrombectomy. METHODS: From 2010 to 2017, 25 patients with POS (ie, acute ischemic stroke occurring during or within 30 days after a procedure) who underwent mechanical thrombectomy (POS group) were enrolled and paired with 50 consecutive patients with nPOS (control group), based on the occlusion's site, National Institute of Health Stroke Scale, and age. RESULTS: Respectively, mean age was 68.3±16.6 versus 67.2±16.6 years (P=0.70), and median National Institute of Health Stroke Scale score at admission was 20 (interquartile range, 15-25) versus 19 (interquartile range, 17-25; P=0.79). Good clinical outcome (modified Rankin Scale score of 0-2 at 3 months) was achieved by 33.3% (POS) versus 56.5% (nPOS) of patients (P=0.055). Successful reperfusion (modified Thrombolysis In Cerebral Infarction score of ≥2b) was obtained in 76% (POS) versus 86% (nPOS) of cases (P=0.22). Mortality at 3 months was 33.3% in the POS group versus 4.2% (nPOS) (P=0.002). The rate of major procedural complications was 4% (POS) versus 6% (nPOS); none were lethal. Average time from symptoms' onset to reperfusion was 4.9 hours (±2.0) in POS versus 5.2 hours (±2.6). CONCLUSIONS: Successful reperfusion seems accessible in POS within a reasonable amount of time and with a good level of safety. However, favorable outcome was achieved with a lower rate than in nPOS, owing to a higher mortality rate.

Delay discounting of gains and losses, glycemic control and therapeutic adherence in type 2 diabetes.

OBJECTIVE: Delay discounting is the tendency to prefer smaller, sooner rewards to larger, later ones. Poor adherence in type 2 diabetes could be partially explained by a discounted value of health, as a function of delay. Delay discounting can be described with a hyperbolic model characterized by a coefficient, k. The higher k, the less future consequences are taken into account when making decisions. This study aimed to determine whether k would be correlated with glycated hemoglobin and adherence in type 2 diabetes. METHODS: Ninety-three patients were recruited in two diabetology departments. Delay discounting coefficients were measured with a computerized task. HbA1c was recorded and adherence was assessed by questionnaires. Potential socio-demographic and clinical confounding factors were collected. RESULTS: There was a positive correlation between delay discounting of gains and HbA1c (r=0.242, P=0.023). This association remained significant after adjusting for potential confounding factors (F=4.807, P=0.031, η2=0.058). This association was partially mediated by adherence to medication (ß=0.048, 95% CI [0.004-0.131]). CONCLUSIONS: Glycemic control is associated with delay discounting in patients suffering from type 2 diabetes. Should these findings be replicated with a prospective design, they could lead to new strategies to improve glycemic control among these patients.

Computational Dissection of Dopamine Motor and Motivational Functions in Humans.

UNLABELLED: Motor dysfunction (e.g., bradykinesia) and motivational deficit (i.e., apathy) are hallmarks of Parkinson's disease (PD). Yet, it remains unclear whether these two symptoms arise from a same dopaminergic dysfunction. Here, we develop a computational model that articulates motor control to economic decision theory, to dissect the motor and motivational functions of dopamine in humans. This model can capture different aspects of the behavior: choice (which action is selected) and vigor (action speed and intensity). It was used to characterize the behavior of 24 PD patients, tested both when medicated and unmedicated, in two behavioral tasks: an incentive motivation task that involved producing a physical effort, knowing that it would be multiplied by reward level to calculate the payoff, and a binary choice task that involved choosing between high reward/high effort and low reward/low effort options. Model-free analyses in both tasks showed the same two effects when comparing unmedicated patients to medicated patients: dopamine depletion (1) decreased the amount of effort that patients were willing to produce for a given reward and (2) slowed down the production of this effort, regardless of reward level. Model-based analyses captured these effects with two independent parameters, namely reward sensitivity and motor activation rate. These two parameters were respectively predictive of medication effects on clinical measures of apathy and motor dysfunction. More generally, we suggest that such computational phenotyping might help characterizing deficits and refining treatments in neuropsychiatric disorders. SIGNIFICANCE STATEMENT: Many neurological conditions are characterized by motor and motivational deficits, which both result in reduced behavior. It remains extremely difficult to disentangle whether these patients are simply unable or do not want to produce a behavior. Here, we propose a model-based analysis of the behavior produced in tasks that involve trading physical efforts for monetary rewards, to quantify parameters that capture motor dynamics as well as sensitivity to reward, effort, and fatigue. Applied to Parkinson's disease, this computational analysis revealed two independent effects of dopamine enhancers, which predicted clinical improvement in motor and motivational deficits. Such computational profiling might provide a useful explanatory level, between neural dysfunction and clinical manifestations, for characterizing neuropsychiatric disorders and personalizing treatments.

Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics.

Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation.

Imaging social motivation: distinct brain mechanisms drive effort production during collaboration versus competition.

Collaborative and competitive interactions have been investigated extensively so as to understand how the brain makes choices in the context of strategic games, yet such interactions are known to influence a more basic dimension of behavior: the energy invested in the task. The cognitive mechanisms that motivate effort production in social situations remain poorly understood, and their neural counterparts have not been explored so far. A dominant idea is that the motivation provided by the social context is reducible to the personal utility of effort production, which decreases in collaboration and increases in competition. Using functional magnetic resonance imaging, we scanned human participants while they produced a physical effort in a collaborative or competitive context. We found that motivation was indeed primarily driven by personal utility, which was reflected in brain regions devoted to reward processing (the ventral basal ganglia). However, subjects who departed from utility maximization, working more in collaborative situations, showed greater functional activation and anatomical volume in a brain region implicated previously in social cognition (the temporoparietal junction). Therefore, this region might mediate a purely pro-social motivation to produce greater effort in the context of collaboration. More generally, our findings suggest that the individual propensity to invest energy in collaborative work might have an identifiable counterpart in the brain functional architecture.

My belief or yours? Differential theory of mind deficits in frontotemporal dementia and Alzheimer's disease.

Theory of mind reasoning-the ability to understand someone else's mental states, such as beliefs, intentions and desires-is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone else's mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimer's disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone else's mental perspective requires two distinct processes: inferring someone else's belief and inhibiting one's own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimer's disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimer's disease were matched for age, gender, education and global cognitive impairment. [(18)F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind reasoning; patients with Alzheimer's disease had a predominant deficit in inferring someone else's belief, whereas patients with behavioural variant frontotemporal dementia were selectively impaired in inhibiting their own mental perspective. Moreover, inhibiting one's own perspective was strongly correlated with inhibition in a Stroop task but not with other subprocesses of executive functions. This finding suggests that self-perspective inhibition may depend on cognitive processes that are not specific to the social domain. Last, the severity of the deficit in inferring someone else's beliefs correlated significantly over all subjects with hypometabolism in the left temporoparietal junction, whereas the severity of the deficit in self-perspective inhibition correlated significantly with hypometabolism in the right lateral prefrontal cortex. In conclusion, our findings provided clinical and imaging evidence to support differential deficits in two components of theory of mind reasoning (subserved by distinct brain regions) in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia.