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Background: Prose memory tests exhibit ecological validity, but the influence of non-memory functions on immediate recall in elderly subjects with memory complaints has not been fully investigated. This study examined (1) whether the ability to immediately recall a story can distinguish among clinical controls, amnesic mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) and (2) which cognitive functions contribute to immediate recall performance., Methods: A total of 73 consecutive volunteers (50 women and 23 men) aged 47-88 (mean age = 71.85 ± 9.41) and with a mean schooling level of 12.51 (SD = 4.09) participated in the experiment. All individuals were seeking specialized evaluation because of memory complaints. Diagnoses were made by considering clinical, neuropsychological, and MRI assessments collected by a multidisciplinary team of neurologists, neuropsychologists, and speech-language therapists. A total of 26 individuals were classified as clinical controls; 27 as MCI patients; and 20 as having AD dementia. All individuals in the AD group had a Clinical Dementia Rating (CDR) ≤ 1., Results: Immediate recall was only able to distinguish AD subjects from MCI patients and clinical controls (p > 0.05). Stepwise multiple linear regression analysis revealed that mental status (MMSE), semantic memory (WAIS-III vocabulary) and episodic memory (RAVLT primacy) explained approximately 62% of the variance in immediate recall., Conclusions: Understanding the value and limitations of immediate story recall in distinguishing between MCI and AD may help clinicians in better choosing cognitive tests to diagnose MCI.

The causal role played by damage to the pyramidal tracts in the production of spastic hemiplegia in man has been hotly debated over the past hundred years. Two broad streams of thought have emerged from this dispute. The first, which is grounded on the clinicopathological schools of Jean-Martin Charcot (1825-1893) and Paul Flechsig (1847-1929), claimed that the four cardinal signs of hemiplegia, namely (i) paralysis, (ii) spasticity, (iii) hyperactive phasic muscle reflexes ("tendon jerks") and (iv) the sign of Babinski, are caused by injury or dysfunction of the pyramidal tracts. The second school, championed by John Farquhar Fulton (1899-1960) and Derek Denny-Brown (1901-1981), reflects the increasing influence of experimental neurology on clinicopathological concepts after World War II. According to this school, most elements of the pyramidal syndrome are caused by the added release or injury of extrapyramidal structures at different levels of the forebrain and brainstem. Most symptoms of spastic hemiplegia were thus interpreted as signs of extrapyramidal (e.g., reticulospinal) release or damage. However, consensus on which symptoms of spastic hemiplegia were due to pyramidal or extrapyramidal changes was never reached. To add to this uncertainty, a number of clinicopathological cases that supported the old view were sporadically published over the same period. The purpose of the present essay is to provide clinicoanatomic perspective to the neurological literature in support of the hypothesis that damage to the pyramidal tracts is a necessary and sufficient condition for the production of the complete pyramidal syndrome in man., (Copyright © 2015. Published by Elsevier Ltd.)

We assessed correlates of obsessive-compulsive (OCPD), schizotypal (SPD) and borderline (BPD) personality disorders in 110 obsessive-compulsive disorder (OCD) patients. We found OCD patients with OCPD (20.9%) to exhibit higher rates of hoarding and bipolar disorders, increased severity of hoarding and symmetry, lower prevalence of unacceptable thoughts involving sex and religion and less non-planning impulsivity. Conversely, OCD patients with SPD (13.6%) displayed more frequently bipolar disorder, increased severity of depression and OCD neutralization, greater prevalence of "low-order" behaviors (i.e., touching), lower low-planning impulsivity and greater "behavioral" compulsivity. Finally, in exploratory analyses, OCD patients with BPD (21.8%) exhibited lower education, higher rates of several comorbid psychiatric disorders, greater frequency of compulsions involving interpersonal domains (e.g. reassurance seeking), increased severity of depression, anxiety and OCD dimensions other than symmetry and hoarding, more motor and non-planning impulsivity, and greater "cognitive" compulsivity. These findings highlight the importance of assessing personality disorders in OCD samples., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Language batteries used to assess the skills of elderly individuals, such as naming and semantic verbal fluency, present some limitations in differentiating healthy controls from patients with amnestic mild cognitive impairment (a-MCI). Deficits in narrative discourse occur early in dementia caused by Alzheimer's disease (AD), and the narrative discourse abilities of a-MCI patients are poorly documented. The present study sought to propose and evaluate parameters for investigating narrative discourse in these populations. After a pilot study of 30 healthy subjects who served as a preliminary investigation of macro- and micro-linguistic aspects, 77 individuals (patients with AD and a-MCI and a control group) were evaluated. The experimental task required the participants to narrate a story based on a sequence of actions visually presented. The Control and AD groups differed in all parameters except narrative time and the total number of words recalled. The a-MCI group displayed mild discursive difficulties that were characterized as an intermediate stage between the Control and AD groups' performances. The a-MCI and Control groups differed from the AD group with respect to global coherence, discourse type and referential cohesion. The a-MCI and AD groups were similar to one another but differed from the Control group with respect to the type of words recalled, the repetition of words in the same sentence, the narrative structure and the inclusion of irrelevant propositions in the narrative. The narrative parameter that best distinguished the three groups was the speech effectiveness index. The proposed task was able to reveal differences between healthy controls and groups with cognitive decline. According to our findings, patients with a-MCI already present narrative deficits that are characterized by mild discursive difficulties that are less severe than those found in patients with AD.

The phenotypes of the behavioral variant of frontotemporal dementia and the corticobasal syndrome present considerable clinical and anatomical overlap. The respective patterns of white matter damage in these syndromes have not been directly contrasted. Beyond cortical involvement, damage to white matter pathways may critically contribute to both common and specific symptoms in both conditions. Here we assessed patients with the behavioral variant of frontotemporal dementia and corticobasal syndrome with whole-brain diffusion tensor imaging to identify the white matter networks underlying these pathologies. Twenty patients with the behavioral variant of frontotemporal dementia, 19 with corticobasal syndrome, and 15 healthy controls were enrolled in the study. Differences in tract integrity between (i) patients and controls, and (ii) patients with the corticobasal syndrome and the behavioral variant of frontotemporal dementia were assessed with whole brain tract-based spatial statistics and analyses of regions of interest. Behavioral variant of frontotemporal dementia and the corticobasal syndrome shared a pattern of bilaterally decreased white matter integrity in the anterior commissure, genu and body of the corpus callosum, corona radiata and in the long intrahemispheric association pathways. Patients with the behavioral variant of frontotemporal dementia showed greater damage to the uncinate fasciculus, genu of corpus callosum and forceps minor. In contrast, corticobasal syndrome patients had greater damage to the midbody of the corpus callosum and perirolandic corona radiata. Whereas several compact white matter pathways were damaged in both the behavioral variant of frontotemporal dementia and corticobasal syndrome, the distribution and degree of white matter damage differed between them. These findings concur with the distinctive clinical manifestations of these conditions and may improve the in vivo neuroanatomical and diagnostic characterization of these disorders.

Humans spend a substantial share of their lives mind-wandering. This spontaneous thinking activity usually comprises autobiographical recall, emotional, and self-referential components. While neuroimaging studies have demonstrated that a specific brain "default mode network" (DMN) is consistently engaged by the "resting state" of the mind, the relative contribution of key cognitive components to DMN activity is still poorly understood. Here we used fMRI to investigate whether activity in neural components of the DMN can be differentially explained by active recall of relevant emotional autobiographical memories as compared with the resting state. Our study design combined emotional autobiographical memory, neutral memory and resting state conditions, separated by a serial subtraction control task. Shared patterns of activation in the DMN were observed in both emotional autobiographical and resting conditions, when compared with serial subtraction. Directly contrasting autobiographical and resting conditions demonstrated a striking dissociation within the DMN in that emotional autobiographical retrieval led to stronger activation of the dorsomedial core regions (medial prefrontal cortex, posterior cingulate cortex), whereas the resting state condition engaged a ventral frontal network (ventral striatum, subgenual and ventral anterior cingulate cortices) in addition to the IPL. Our results reveal an as yet unreported dissociation within the DMN. Whereas the dorsomedial component can be explained by emotional autobiographical memory, the ventral frontal one is predominantly associated with the resting state proper, possibly underlying fundamental motivational mechanisms engaged during spontaneous unconstrained ideation.

Why do humans born without the corpus callosum, the major interhemispheric commissure, lack the disconnection syndrome classically described in callosotomized patients? This paradox was discovered by Nobel laureate Roger Sperry in 1968, and has remained unsolved since then. To tackle the hypothesis that alternative neural pathways could explain this puzzle, we investigated patients with callosal dysgenesis using structural and functional neuroimaging, as well as neuropsychological assessments. We identified two anomalous white-matter tracts by deterministic and probabilistic tractography, and provide supporting resting-state functional neuroimaging and neuropsychological evidence for their functional role in preserved interhemispheric transfer of complex tactile information, such as object recognition. These compensatory pathways connect the homotopic posterior parietal cortical areas (Brodmann areas 39 and surroundings) via the posterior and anterior commissures. We propose that anomalous brain circuitry of callosal dysgenesis is determined by long-distance plasticity, a set of hardware changes occurring in the developing brain after pathological interference. So far unknown, these pathological changes somehow divert growing axons away from the dorsal midline, creating alternative tracts through the ventral forebrain and the dorsal midbrain midline, with partial compensatory effects to the interhemispheric transfer of cortical function.

In Ridley Scott's film "Blade Runner", empathy-detection devices are employed to measure affiliative emotions. Despite recent neurocomputational advances, it is unknown whether brain signatures of affiliative emotions, such as tenderness/affection, can be decoded and voluntarily modulated. Here, we employed multivariate voxel pattern analysis and real-time fMRI to address this question. We found that participants were able to use visual feedback based on decoded fMRI patterns as a neurofeedback signal to increase brain activation characteristic of tenderness/affection relative to pride, an equally complex control emotion. Such improvement was not observed in a control group performing the same fMRI task without neurofeedback. Furthermore, the neurofeedback-driven enhancement of tenderness/affection-related distributed patterns was associated with local fMRI responses in the septohypothalamic area and frontopolar cortex, regions previously implicated in affiliative emotion. This demonstrates that humans can voluntarily enhance brain signatures of tenderness/affection, unlocking new possibilities for promoting prosocial emotions and countering antisocial behavior.

Attachment to one's kin as an in-group emerges from a fundamental human motivation and is vital for human survival. Despite important recent advances in the field of social neuroscience, the neural mechanisms underlying family-related in-group perception remain obscure. To examine the neural basis of perceiving family-related in-group boundaries in response to written kinship scenarios, we used functional magnetic resonance imaging in 27 healthy adults and obtained self-report ratings of family-related entitativity, which measures to what degree participants perceive their family as a coherent and distinct group in society. We expected that activity in the subgenual cingulate cortex and septo-hypothalamic region would track individual differences in entitativity. Perceiving one's family as a distinct and cohesive group (high entitativity) was associated with increased subgenual cortex response to kinship scenarios. The subgenual cingulate cortex may represent a key link between kin-related emotional attachment and group perception, providing a neurobiological basis for group belongingness.

Changes in socio-emotional behavior and conduct, which are characteristic symptoms of frontal lobe damage, have less often been described in patients with focal subcortical injuries. We report on a case of pathological generosity secondary to a left lenticulocapsular stroke with hypoperfusion of several anatomically intact cortical areas. A 49-year-old man developed excessive and persistent generosity as he recovered from a left lenticulocapsular hematoma. His symptoms resembled an impulse control disorder. (99m)Tc-HMPAO SPECT demonstrated hypoperfusion mostly in the ipsilateral striatum, dorsolateral, and orbitofrontal cortex. This case study adds pathological generosity to the range of behavioral changes that may result from discrete unilateral lesions of the lenticular nucleus and nearby pathways. In our particular case, post-stroke pathological generosity was not ascribable to disinhibition, apathy, mania, or depression. Because pathological generosity may lead to significant distress and financial burden upon patients and their families, it may warrant further consideration as a potential type of impulse control disorder.

Proton magnetic resonance spectroscopy (MRS) of the human brain has proven to be a useful technique in several neurological and psychiatric disorders and benefits from higher field scanners as signal intensity and spectral resolution are proportional to the magnetic field strength., Objective: To investigate the effects of the magnetic field on the measurement of brain metabolites in a typical routine clinical setting., Methods: Single voxel spectra were acquired from the posterior cingulate cortex in 26 healthy subjects. Each subject was scanned consecutively at 1.5T and 3.0T in a randomly distributed order., Results: SNR and peak width improvements were observed at higher fields. However, SNR improvement was lower than the theoretical two-fold improvement. Other than the values obtained for creatine (Cre) and myo-Inositol (mI), which were both higher at 3.0T, all metabolite concentrations obtained were roughly the same at both field strengths. All the metabolite concentrations were estimated with a Cramer Rao lower bounds (CRLB) lower than 15% of the calculated concentrations., Conclusions: Even though the present study supports the expected benefits of higher field strength for MRS, there are several factors that can lead to different quantitative results when comparing 1.5T to 3.0T MRS. Future comparative studies are necessary to refine the metabolite thresholds for early detection and quantification of distinct neurological and psychiatric disorders using 3.0T MRS., Competing Interests: Disclosure: The authors report no conflicts of interest.

The term "extrapyramidal" originally described a collection of tegmentospinal pathways that conveyed the propagation of cortically-induced seizures to the spinal cord of dogs with bilateral transection of the pyramidal tracts. The extrapyramidal concept developed into unwarranted avenues to include forebrain structures involved in motor control, such as the basal ganglia, or as a broad synonym of clinical syndromes characterized by nonparalytic abnormal involuntary movements and postures. Clinicians and pathologists assumed that, similarly to mammals in general, the human extrapyramidal system was also organized in parallel with the pyramidal tracts. Several inconsistencies of this model, as applied to humans, were overlooked despite compelling clinicoanatomic evidence showing that (i) bilateral damage to the pyramidal tracts at any level from the pontomedullary transition to the motor cortex produces the locked-in syndrome and (ii) the extrapyramidal tracts are sparse in man. In the present essay I advance the hypothesis that the human extrapyramidal system is fundamentally different from its mammalian counterparts both anatomically and functionally. To test this hypothesis, a systematic analysis of the residual motor patterns observed on a natural model of a bilateral section of the human pyramidal tracts, the locked-in syndrome, is provided. This analysis reveals that the human extrapyramidal system underpins the organization of the following categories of motor synergies: (i) oculofacial and oculocephalic, (ii) faciorespiratory, (iii) axial-appendicular, and (iv) plurisegmental. Anatomically, these functional repertoires of motor integration are mediated by six collections of axons defined by their brainstem nuclei of origin and spinal cord destinations: reticulospinal (medial and lateral), vestibulospinal (medial and lateral), rubrospinal (lateral only), and tectospinal (medial only) fiber systems. I conclude that the extrapyramidal concept can reliably be extended to humans, albeit its physiological and anatomical scope is considerably narrower than traditionally assumed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The concept of the extrapyramidal system comprises an amalgam of disparate and often conflicting ideas with a tortuous history. To the theoretical neuroscientist or practicing clinician, it promptly evokes semantic associations that are hardly reminiscent of its original meaning. The purpose of this article is to revisit the sources of the extrapyramidal concept and to examine the transformations that it went through from its inception, in the late 1890s, up to the neuroimaging revolution of the 1980s. Our review shows that the use of "extrapyramidal" as a surrogate for the basal ganglia, disorders of movement, or certain manifestations of spastic hemiplegia does not apply to humans; rather, it represents the historical product of the unwarranted translation of results of animal experimentation into the interpretation of clinical findings on human patients, misguided clinico-anatomic deductions, and fanciful phylogenetic notions. We conclude that the extrapyramidal concept is a valid and robust anatomic concept as long as it strictly refers to the collection of descending fibers originating in a few discrete brainstem tegmental motor nuclei that project to the spinal cord.

The discovery of the pyramidal syndrome and tract is briefly reviewed with emphasis on a few key historical aspects. The pursuit of the relationship between the lateralized deficits resulting from contralateral head trauma begins in the fourth century BC with the Hippocratic School and continues until the present day.

Unlabelled: IntroductionThe aim of this study was to investigate white matter (WM) abnormalities in obsessive-compulsive disorder (OCD) and its relationship to severity of obsessive-compulsive symptoms., Methods: Conventional and diffusion tensor imaging were acquired in nine patients with OCD and nine gender- and age-matched healthy volunteers. Changes in fractional anisotropy (FA) and mean diffusivity (MD) were investigated using selected regions of interest (ROIs) analyses and whole brain tract-based spatial statistic analyses. A priori ROIs were placed bilaterally in internal capsule (IC), superior longitudinal fascicule (SLF), cingulate bundle (CB), and corpus calosum (CC)., Results: ROIs analyses showed that, as compared to healthy volunteers, patients with OCD exhibited reduced FA values bilaterally in regions of the posterior limb of the IC and in the SLF and increased MD values bilaterally in the posterior limb of the IC, in the left CB, and in the splenium of CC. Voxelwise analysis showed that, as compared to controls, patients with OCD exhibited reduced FA and increased MD in regions of the cortical spinal tract (genu and posterior limb of internal capsule and corona radiata) and the SLF. Severity of OCD correlated with WM alterations in different brain regions, ie, the left (rho=0.70 [MD]) and right (rho=0.70 [MD]) anterior limb of the IC, the left (rho=0.97 [MD]) and right SLF (rho=0.81 [MD]), and the genu of CC (rho=0.66 [MD]; rho=-0.69 [FA])., Conclusion: Our findings support the involvement of different WM tracts in OCD and suggest that greater impairment in WM integrity is associated with increased severity of OCD symptoms.

Poets and philosophers have long acknowledged moral sentiments as key motivators of human social behavior. Prosocial sentiments, which include guilt, pity and embarrassment, enable us to care about others and to be concerned about our mistakes. Functional imaging studies have implicated frontopolar, ventromedial frontal and basal forebrain regions in the experience of prosocial sentiments. Patients with lesions of the frontopolar and ventromedial frontal areas were observed to behave inappropriately and less prosocially, which could be attributed to a generalized emotional blunting. Direct experimental evidence for brain regions distinctively associated with moral sentiment impairments is lacking, however. We investigated this issue in patients with the behavioral variant of frontotemporal dementia, a disorder in which early and selective impairments of social conduct are consistently observed. Using a novel moral sentiment task, we show that the degree of impairment of prosocial sentiments is associated with the degree of damage to frontopolar cortex and septal area, as assessed with 18-Fluoro-Deoxy-Glucose-Positron Emission Tomography, an established measure of neurodegenerative damage. This effect was dissociable from impairment of other-critical feelings (anger and disgust), which was in turn associated with dorsomedial prefrontal and amygdala dysfunction. Our findings suggest a critical role of the frontopolar cortex and septal region in enabling prosocial sentiments, a fundamental component of moral conscience., (Published by Elsevier Inc.)

Background: Psychopathy is a disorder of personality characterized by severe impairments of social conduct, emotional experience, and interpersonal behavior. Psychopaths consistently violate social norms and bring considerable financial, emotional, or physical harm to others and to society as a whole. Recent developments in analysis methods of magnetic resonance imaging (MRI), such as voxel-based-morphometry (VBM), have become major tools to understand the anatomical correlates of this disorder. Nevertheless, the identification of psychopathy by neuroimaging or other neurobiological tools (e.g., genetic testing) remains elusive., Methods/principal Findings: The main aim of this study was to develop an approach to distinguish psychopaths from healthy controls, based on the integration between pattern recognition methods and gray matter quantification. We employed support vector machines (SVM) and maximum uncertainty linear discrimination analysis (MLDA), with a feature-selection algorithm. Imaging data from 15 healthy controls and 15 psychopathic individuals (7 women in each group) were analyzed with SPM2 and the optimized VBM preprocessing routines. Participants were scanned with a 1.5 Tesla MRI system. Both SVM and MLDA achieved an overall leave-one-out accuracy of 80%, but SVM mapping was sparser than using MLDA. The superior temporal sulcus/gyrus (bilaterally) was identified as a region containing the most relevant information to separate the two groups., Conclusion/significance: These results indicate that gray matter quantitative measures contain robust information to predict high psychopathy scores in individual subjects. The methods employed herein might prove useful as an adjunct to the established clinical and neuropsychological measures in patient screening and diagnostic accuracy.

Background/aims: The diagnosis of mild or questionable Alzheimer's disease (AD) depends on clinical criteria that often leave a margin for doubt. We aim to verify the diagnostic accuracy of amnestic mild cognitive impairment (aMCI) and AD with proton spectroscopy (1H-MRS) combined with brief cognitive-functional scales., Methods: The relationship between 1H-MRS of the posterior cingulate cortex and the cognitive performance in Mini Mental State Examination, Blessed-Roth Dementia Rating and Functional Assessment Staging of Alzheimer Disease scales were investigated in 25 AD, 10 aMCI and 33 normal control (NC) individuals., Results: The N-acetylaspartate (NAA)/creatine and myoinositol/NAA ratios distinguished AD patients from NC (p<0.005), and added value in diagnostic accuracy and specificity by discriminant function analysis when combined to clinical diagnosis and simple neuropsychiatric scales; an increase of 3.7% (for aMCI patients) and of 5% (for AD individuals) was observed in diagnostic accuracy, and one of 5.5% (aMCI) and of 11.1% (AD) in specificity., Conclusion: 1H-MRS combined with brief cognitive-functional scales provided maximum diagnostic accuracy of AD patients, and can be useful when subtle cognitive and memory dysfunction is present., (Copyright © 2012 S. Karger AG, Basel.)

Recent fMRI studies linked subgenual cingulate cortex (SCC) activity with feelings of guilt for acting counter to social values and altruistic donations towards societal causes. We hypothesized that SCC activity across those different tasks was driven by feelings of attachment. In order to investigate this further, we used fMRI to probe the association of empathic concern and strength of SCC activation in response to guilt- and compassion-evoking verbal descriptions of social behaviour. We were able to confirm our prediction that participants with higher empathic concern had increased activity in the SCC in the guilt condition, whereas there was no association for compassion. These results shed new light on the role of the SCC which shows abnormalities in clinical depression.

Major advances have been made in the understanding of the neurobiology of psychopathy in the past years, yet the distribution and extent of neuroanatomical abnormalities underlying the disorder are still poorly known. It is also unclear if different dimensions of the construct of psychopathy (e.g., emotional callousness, antisocial behavior) correspond to structural abnormalities in distinct regions of the brain. We tested the following hypotheses: (1) psychopathy is related to grey matter reductions in regions of the brain that underlie moral conduct and (2) the severity of psychopathy is related to the degree of structural abnormalities. Optimized voxel-based morphometry and the screening version of the Psychopathy Checklist (PCL: SV) were employed to investigate a matched sample of 15 community psychiatric patients with high PCL: SV scores, and 15 healthy normal volunteers. The analyses controlled for total grey matter, white matter and cerebrospinal fluid volumes. Grey matter reductions were observed in the frontopolar, orbitofrontal and anterior temporal cortices, superior temporal sulcus region, and insula of the patients. The degree of structural abnormalities was significantly related to the interpersonal/affective dimension of psychopathy. The pattern of grey matter reductions in patients with high psychopathy scores comprised a distributed fronto-temporal network which plays a critical role in moral sensibility and behavior.

The human moral nature has perplexed laymen and academics for millennia. Recent developments in cognitive neuroscience are opening new venues for unveiling the complex psychological and neurobiological mechanisms underling human morality and its impairments. Here we review these lines of evidence and key topics of debate and explain why investigating the mechanisms of cognition-emotion interaction and of the neural bases of moral sentiments and values will be critical for our understanding of the human moral mind.

Clozapine has become a keystone in the treatment of schizophrenia because of its efficacy as an antipsychotic with negligible neuroleptic effects. The long-term stability of its effects, however, is poorly understood, because most studies have probed the usefulness of clozapine over a period of weeks to several months at the most. Knowing whether clozapine's benefits are sustained over the very long-term, i.e., more than 5 years, may be critical for cost-benefit analyses., Objective: To report the results of an open study on the efficacy of clozapine over the very long-term., Methods: Thirty-three adults (26 men) with severe (kraepelinian) schizophrenia were assessed at regular intervals using a brief neuropsychiatric battery over a 5-year period., Results: A significant improvement was observed between the pre-clozapine and the first "on-clozapine" evaluation. This improvement was paralleled by a remarkable conversion of schizophrenia from "active" (mostly paranoid) into "residual" in 70% of all patients. Eight patients became functionally productive to the point of being capable of living an independent life. Roughly one-third of our cases showed no improvement., Conclusions: Clozapine is a safe and effective drug for patients with severe schizophrenia who have failed to improve on other antipsychotic drugs. Clozapine's maximal benefit is established by the end of the first year of treatment and continues unabated for many years thereafter. Clozapine-resistant patients remain a major challenge calling for the discovery of new treatments for schizophrenia.

Experimental studies in nonhuman primates have questioned the selectivity of pyramidal tract damage in giving rise to the classical pyramidal syndrome in humans, characterized by permanent spastic hemiplegia (PSH). According to this view, concomitant injury of extrapyramidal pathways is necessary for the development of both hemiplegia and spasticity. In this study we used conventional magnetic resonance imaging and diffusion tensor imaging tractography to characterize the anatomical correlates of PSH in a patient with a rare and discrete unilateral lesion of the medullary pyramid. Our findings support the hypothesis that damage confined to the medullary pyramid/pyramidal tract is sufficient to produce PSH. In contrast to nonhuman primates, the human 'pyramidal' and 'pyramid' syndromes are equivalent clinico-anatomic concepts.

The investigation of the neural and cognitive mechanisms underlying the moral mind is of paramount importance for understanding complex human behaviors, from altruism to antisocial acts. A new study on patients with prefrontal damage provides key insights on the neurobiology of moral judgment and raises new questions on the mechanisms by which reason and emotion contribute to moral cognition.

Cases of "adolescent insanity" were known to Kraepelin's forerunners and lay at the core of his concept of dementia præcox. In the post-neuroleptic era it became clear that dementia may also occur in schizophrenia as a fully reversible state depending on psychopathological status. In the present review we discuss the validity of applying the concept of dementia to schizophrenia. We concur with the view that schizophrenia may lead to a true dementia both (i) as a fixed end-stage consequence of the disease process itself, or (ii) as a drug-responsive reversible state. There is an urgent need to examine the patterns of dementia in other common neuropsychiatric disorders, employing current methods of neurobehavioral investigation.

Callosal dysgenesis (CD) is observed in many neurodevelopmental conditions, but its subjacent mechanisms are unknown, despite extensive research on animals. Here we employ magnetic resonance diffusion tensor imaging and tractography in human CD to reveal the aberrant circuitry of these brains. We searched particularly for evidence of plasticity. Four main findings are described--1) in the presence of a callosal remnant or a hypoplastic corpus callosum (CC), fibers therein largely connect the expected neocortical regions; 2) callosal remnants and hypoplastic CCs display a fiber topography similar to normal; 3) at least 2 long abnormal tracts are formed in patients with defective CC: the well-known Probst bundle (PB) and a so far unknown sigmoid, asymmetrical aberrant bundle connecting the frontal lobe with the contralateral occipitoparietal cortex; and 4) whereas the PB is topographically organized and has an ipsilateral U-connectivity, the sigmoid bundle is a long, heterotopic commissural tract. These observations suggest that when the developing human brain is confronted with factors that hamper CC fibers to cross the midline, some properties of the miswired fibers are maintained (such as side-by-side topography), whereas others are dramatically changed, leading to the formation of grossly abnormal white matter tracts.

The human brain is inherently able to understand the world in moral ways, endowing most of us with an intuitive sense of fairness, concern for others, and observance of cultural norms. We have argued that this moral sensitivity ability depends on a sophisticated integration of cognitive, emotional, and motivational mechanisms, which are modulated by individual experience in different cultural milieus. Different lines of investigation on agency and morality have pointed to overlapping neural systems. Therefore, understanding the relationships between morality and agency may provide key insights into the mechanisms underlying human behavior in several clinical and societal settings. We used functional MRI to investigate the contribution of agency and of specific moral emotions to brain activation using action scripts. Results showed that emotionally neutral agency recruited neural networks previously associated with agency, intentionality and moral cognition, encompassing ventral and subgenual sectors of the medial prefrontal cortex (PFC), insula, anterior temporal cortex and superior temporal sulcus (STS). Compared to emotionally neutral agency, different categories of moral emotions led to distinct activation patterns: (1) prosocial emotions (guilt, embarrassment, compassion) activated the anterior medial PFC and STS, with (2) empathic emotions (guilt and compassion) additionally recruiting the mesolimbic pathway; (3) other-critical emotions (disgust and indignation) were associated with activation of the amygdala-parahippocampal and fusiform areas. These findings indicate that agency related to norm-abiding social behaviors of emotionally neutral scripts share neural substrates both with the "default mode" of brain function and with the moral sensitivity network. Additional activation in specific components of this network is elicited by different classes of moral emotions, in agreement with recent integrative models of moral cognition and emotion.

Humans often sacrifice material benefits to endorse or to oppose societal causes based on moral beliefs. Charitable donation behavior, which has been the target of recent experimental economics studies, is an outstanding contemporary manifestation of this ability. Yet the neural bases of this unique aspect of human altruism, which extends beyond interpersonal interactions, remain obscure. In this article, we use functional magnetic resonance imaging while participants anonymously donated to or opposed real charitable organizations related to major societal causes. We show that the mesolimbic reward system is engaged by donations in the same way as when monetary rewards are obtained. Furthermore, medial orbitofrontal-subgenual and lateral orbitofrontal areas, which also play key roles in more primitive mechanisms of social attachment and aversion, specifically mediate decisions to donate or to oppose societal causes. Remarkably, more anterior sectors of the prefrontal cortex are distinctively recruited when altruistic choices prevail over selfish material interests.

Moral cognitive neuroscience is an emerging field of research that focuses on the neural basis of uniquely human forms of social cognition and behaviour. Recent functional imaging and clinical evidence indicates that a remarkably consistent network of brain regions is involved in moral cognition. These findings are fostering new interpretations of social behavioural impairments in patients with brain dysfunction, and require new approaches to enable us to understand the complex links between individuals and society. Here, we propose a cognitive neuroscience view of how cultural and context-dependent knowledge, semantic social knowledge and motivational states can be integrated to explain complex aspects of human moral cognition.

Recent investigations in cognitive neuroscience have shown that ordinary human behavior is guided by emotions that are uniquely human in their experiential and interpersonal aspects. These "moral emotions" contribute importantly to human social behavior and derive from the neurobehavioral reorganization of the basic plan of emotions that pervade mammalian life. Disgust is one prototypic emotion with multiple domains that include viscerosomatic reaction patterns and subjective experiences linked to (a) the sensory properties of a class of natural stimuli, (b) a set of aversive experiences and (c) a unique mode of experiencing morality. In the current investigation, we tested the hypotheses that (a) the experience of disgust devoid of moral connotations ("pure disgust") can be subjectively and behaviorally differentiated from the experience of disgust disguised in the moral emotion of "indignation" and that (b) pure disgust and indignation may have partially overlapping neural substrates. Thirteen normal adult volunteers were investigated with functional magnetic resonance imaging as they read a series of statements depicting scenarios of pure disgust, indignation, and neutral emotion. After the scanning procedure, they assigned one basic and one moral emotion to each stimulus from an array of six basic and seven moral emotions. Results indicated that (a) emotional stimuli may evoke pure disgust with or without indignation, (b) these different aspects of the experience of disgust could be elicited by a set of written statements, and (c) pure disgust and indignation recruited both overlapping and distinct brain regions, mainly in the frontal and temporal lobes. This work underscores the importance of the prefrontal and orbitofrontal cortices in moral judgment and in the automatic attribution of morality to social events. Human disgust encompasses a variety of emotional experiences that are ingrained in frontal, temporal, and limbic networks.

Morality has been at the center of informal talks and metaphysical discussions since the beginning of history. Recently, converging lines of evidence from evolutionary biology, neuroscience and experimental psychology have shown that morality is grounded in the brain. This article reviews the main lines of investigation indicating that moral behavior is a product of evolutionary pressures that shaped the neurobehavioral processes related to the selective perception of social cues, the experience of moral emotions and the adaptation of behavioral responses to the social milieu. These processes draw upon specific cortical-subcortical loops that organize social cognition, emotion and motivation into uniquely human forms of experience and behavior. We put forth a model of brain-behavior relationships underlying moral reasoning and emotion that accommodates the impairments of moral behavior observed in neuropsychiatric disorders. This model provides a framework for empirical testing with current methods of neurobehavioral analysis.

A 71-year-old man presented with a 6-month history of fainting. Consciousness was quickly regained without clouding or confusion. Ancillary investigations were inconclusive and he was treated with carbamazepine. The fainting spells did not cease and he was referred for a tilt-table test exam. In the head-up position (table tilted at 60 degrees), massage of the carotid sinus was immediately followed by asystole, unconsciousness, and a sharp drop in arterial pressure for 5 seconds. The same procedure in the lying position did not elicit clinical symptoms or haemodynamic imbalance. A diagnosis of carotid sinus hypersensitivity with a cardio-inhibitory response pattern was made. Carbamazepine was withdrawn and a double-chamber pacemaker was implanted in his right ventricle. He remained symptom-free for the ensuing 18 months. This case supports the diagnostic utility of carotid sinus massage during the head-up tilt test in patients with unexplained non-convulsive loss of consciousness.

The trail making test (TMT) pertains to a family of tests that tap the ability to alternate between cognitive categories. However, the value of the TMT as a localizing instrument remains elusive. Here we report the results of a functional magnetic resonance imaging (fMRI) study of a verbal adaptation of the TMT (vTMT). The vTMT takes advantage of the set-shifting properties of the TMT and, at the same time, minimizes the visuospatial and visuomotor components of the written TMT. Whole brain BOLD fMRI was performed during the alternating execution of vTMTA and vTMTB in seven normal adults with more than 12 years of formal education. Brain activation related to the set-shifting component of vTMTB was investigated by comparing performance on vTMTB with vTMTA, a simple counting task. There was a marked asymmetry of activation in favor of the left hemisphere, most notably in dorsolateral prefrontal cortex (BA 6 lateral, 44 and 46) and supplementary motor area/cingulate sulcus (BA 6 medial and 32). The intraparietal sulcus (BA 7 and 39) was bilaterally activated. These findings are in line with clinico-anatomic and functional neuroimaging data that point to a critical role of the dorsolateral and medial prefrontal cortices as well as the intraparietal sulci in the regulation of cognitive flexibility, intention, and the covert execution of saccades/anti-saccades. Many commonly used neuropsychological paradigms, such as the Stroop, Wisconsin Card Sorting, and go - no go tasks, share some patterns of cerebral activation with the TMT.

Reading daily newspaper articles often evokes opinions and social judgments about the characters and stories. Social and moral judgments rely on the proper functioning of neural circuits concerned with complex cognitive and emotional processes. To examine whether dissociable neural systems mediate emotionally charged moral and nonmoral social judgments, we used a visual sentence verification task in conjunction with functional magnetic resonance imaging (fMRI). We found that a network comprising the medial orbitofrontal cortex, the temporal pole and the superior temporal sulcus of the left hemisphere was specifically activated by moral judgments. In contrast, judgment of emotionally evocative, but non-moral statements activated the left amygdala, lingual gyri, and the lateral orbital gyrus. These findings provide new evidence that the orbitofrontal cortex has dedicated subregions specialized in processing specific forms of social behavior.

Humans are endowed with a natural sense of fairness that permeates social perceptions and interactions. This moral stance is so ubiquitous that we may not notice it as a fundamental component of daily decision making and in the workings of many legal, political, and social systems. Emotion plays a pivotal role in moral experience by assigning human values to events, objects, and actions. Although the brain correlates of basic emotions have been explored, the neural organization of "moral emotions" in the human brain remains poorly understood. Using functional magnetic resonance imaging and a passive visual task, we show that both basic and moral emotions activate the amygdala, thalamus, and upper midbrain. The orbital and medial prefrontal cortex and the superior temporal sulcus are also recruited by viewing scenes evocative of moral emotions. Our results indicate that the orbital and medial sectors of the prefrontal cortex and the superior temporal sulcus region, which are critical regions for social behavior and perception, play a central role in moral appraisals. We suggest that the automatic tagging of ordinary social events with moral values may be an important mechanism for implicit social behaviors in humans.

The present paper reports the results of a fMRI subtraction study of the pattern of cortical activation induced by an ideational praxis paradigm in six normal right-handed subjects. The control task consisted of a sequence of complex meaningless hand movements. A complete study was done for each hand in each subject. The left intraparietal sulcus was the only structure activated in all subjects regardless of the hand used in the task. These findings, albeit preliminary, suggest that the organization of actions involving the mediation of tools and utensils are strongly lateralized to the left hemisphere and that damage to the dominant intraparietal sulcus may be critical for the development of the clinical syndrome of conceptual apraxia.

Behaviors, actions and movements may take place as purely mental events, as in the obsessions of obsessive-compulsive disorder, phantom limbs or sensory tics. In the present paper we report on the case of a 43-year-old diabetic hypertensive man who developed an incomplete form of the Dejerine-Roussy syndrome. Whenever he lay down or withdrew the leg from the ground, he experienced the illusion that the left intermediate toes painfully twisted and mounted each other. Conversely, as he stood up or firm pressure was artificially exerted against the sole, there was a dramatic relief from the "cramp" whose illusory character could he be certain of only by looking down at the foot. By passively moving his toes into the referred position we realized that the experienced deformity conformed to the pattern of a fixed dystonia not outwardly expressed through the motor system. There was severe proprioceptive loss in the same toes that harbored the cramp. MRI showed the appropriate lesion in the posteroventrolateral thalamus (VPL) and wallerian degeneration of thalamo-cortical projections. SPECT showed hypoperfusion of the overlying ipsilateral parietal cortex as well as of the basal nuclei bilaterally, besides the expected image of thalamic exclusion. We hypothesize that the infarct disconnected the somatic sensory cortex (S-1) from critical proprioceptive input with relative sparing of superficial sensibility. Lifting the foot deprived S-1 of tonic inputs conveyed by undamaged contact-pressure pathways, a functional effect promptly reversed by placing the foot back against the ground. The case illustrates how a capricious deafferentation of S-1 by a discrete VPL thalamic infarct might facilitate the emergence of autochthonous activity.

An 81-year-old woman developed left hemiplegia and coma due to a right hemisphere infarct and died 6 days later. When first seen in coma she had the classical signs of descending central herniation in the diencephalic stage. The CT scan of the third day showed a large hypodense area occupying the superficial and deep territories of the middle and anterior cerebral arteries on the left as well as a frontal cortico-subcortical hypodense area indicative of an older infarct on the opposite hemisphere. No mass effects were apparent. She followed a downhill course with signs of brainstem deterioration. A second CT scan a few hours before death revealed the expected pattern of brain shift and herniations. This case adds to the available evidence showing that the clinical signs of encroachment of supratentorial structures upon the basal forebrain can be reproduced by an acute mono-hemispheral lesion without visible mass effects. It indicates, further, that the role of intracranial displacements in the genesis and short-term prognosis of coma remains an unsettled matter. In at least a few number of cases, diaschisis might play a major role.

The tegmentum of the midbrain is a complex area traversed by a number of anatomical and functional systems, including local circuits, ascending activating systems and descending fibers from the cerebral hemispheres. In the present paper we report on the case of a 67-year-old man who suffered a spontaneous central tegmental hemorrhage and was initially supposed to be in coma due to bilateral ptosis and lack of speech and initiative. By the second hospital week, however, he was shown to be able to respond to verbal commands, sit, stand and walk. He died in sepsis one month later. This case shows that the clinical diagnosis of coma may be misleading in certain patients in whom wakefulness is preserved, though concealed from a casual bedside examination due to abulia and ophthalmoplegia.

A 64-year-old man presented with pathologic crying and right hemiplegia due to a unilateral pontine infarct from probable branch disease of the basilar artery. The circumscribed nature of the lesion was supported by MRI and short-latency evoked potentials. The weeping spells ceased after a few days of imipramine in low doses. Pathologic laughing and crying can be viewed as a limbic-motor disconnection syndrome, in which the faciovocal motor system is released from forebrain afferents carrying information of emotional content. The inclusion of pathologic laughing and crying in the syndrome pseudobulbar palsy is inaccurate and misleading, since each is related to distinct functional and anatomic systems intrinsic to the human brainstem.