Search

Background: The association between fire-setting behavior and psychiatric or medical disorders remains poorly understood. Although a link between fire-setting behavior and various organic brain disorders has been established, associations between fire setting and focal brain lesions have not yet been reported. Here, we describe the case of a 24-year-old first time arsonist who suffered Todd's paralysis prior to the onset of a bizarre and random fire-setting behavior., Case Presentation: A case of a 24-year-old man with a sudden onset of a bizarre and random fire-setting behavior is reported. The man, who had been arrested on felony arson charges, complained of difficulties concentrating and of recent memory disturbances with leg weakness. A video-EEG recording demonstrated a close relationship between the focal motor impairment and a clear-cut epileptic ictal discharge involving the bilateral motor cortical areas. The SPECT result was statistically analyzed by comparing with standard SPECT images obtained from our institute (easy Z-score imaging system; eZIS). eZIS revealed hypoperfusion in cingulate cortex, basal ganglia and hyperperfusion in frontal cortex,. A neuropsychological test battery revealed lower than normal scores for executive function, attention, and memory, consistent with frontal lobe dysfunction., Conclusion: The fire-setting behavior and Todd's paralysis, together with an unremarkable performance on tests measuring executive function fifteen months prior, suggested a causal relationship between this organic brain lesion and the fire-setting behavior. The case describes a rare and as yet unreported association between random, impulse-driven fire-setting behavior and damage to the brain and suggests a disconnection of frontal lobe structures as a possible pathogenic mechanism.

Objective: To examine the concept of leukoaraiosis thresholds on working memory, visuoconstruction, memory, and language in dementia., Methods: A consecutive series of 83 individuals with insidious onset/progressive dementia clinically diagnosed with Alzheimer disease (AD) or small vessel vascular dementia (VaD) completed neuropsychological measures assessing working memory, visuoconstruction, episodic memory, and language. A clinical MRI scan was used to quantify leukoaraiosis, total white matter, hippocampus, lacune, and intracranial volume. We performed analyses to detect the lowest level of leukoaraiosis associated with impairment on the neuropsychological measures., Results: Leukoaraiosis ranged from 0.63% to 23.74% of participants' white matter. Leukoaraiosis explained a significant amount of variance in working memory performance when it involved 3% or more of the white matter with curve estimations showing the relationship to be nonlinear in nature. Greater leukoaraiosis (13%) was implicated for impairment in visuoconstruction. Relationships between leukoaraiosis, episodic memory, and language measures were linear or flat., Conclusions: Leukoaraiosis involves specific threshold points for working memory and visuoconstructional tests in AD/VaD spectrum dementia. These data underscore the need to better understand the threshold at which leukoaraiosis affects and alters the phenotypic expression in insidious onset dementia syndromes.

Objective: To investigate the relationship between brain microbleeds (MBs) and the rate of cognitive decline in Alzheimer disease (AD)., Methods: In this cohort study, we studied 221 patients with AD with available baseline MRI scans (1.0 or 1.5 T) and at least 2 Mini-Mental State Examinations (MMSE) scores obtained more than 1 year apart from our memory clinic. Mean ± SD follow-up time was 3 ± 1 years, and patients had a median of 4 MMSE scores (range 2-17). We used linear mixed models with sex and age as covariates to investigate whether MBs influenced the rate of cognitive decline., Results: Mean age was 68 ± 9 years, 109 (49%) patients were female, and the baseline MMSE score was 22 ± 4. There were 39 patients (18%) with MBs (median 2, range 1-27) and 182 without. Linear mixed models showed that overall patients declined 2 MMSE points per year. We found no association of the presence of MBs with baseline MMSE or change in MMSE. Adjustment for atrophy, white matter hyperintensities, lacunes, and vascular risk factors did not change the results nor did stratification for MB location, APOE ε4 carriership, or age at onset (≤65 years vs >65 years). Repeating the analyses with number of MBs as predictor rendered similar results., Conclusion: MBs did not influence the rate of cognitive decline in patients with AD. The formerly reported increased risk of mortality in patients with MBs seems not to be attributable to a steeper rate of decline per se but might be due to vascular events, including (hemorrhagic) stroke.

Rationale: The effects of adolescent marijuana use on the developing brain remain unclear, despite its prevalence. Arterial spin labeling (ASL) is a noninvasive imaging technique that characterizes neurovascular status and cerebral blood flow (CBF), potentially revealing contributors to neuropathological alterations. No studies to date have looked at CBF in adolescent marijuana users., Objectives: This study examined CBF in adolescent marijuana users and matched healthy controls at baseline and after 4 weeks of monitored abstinence., Methods: Heavy adolescent marijuana users (n = 23, >200 lifetime marijuana use days) and demographically matched controls (n = 23) with limited substance exposure underwent an ASL brain scan at an initial session and after 4 weeks of sequential urine toxicology to confirm abstinence., Results: Marijuana users showed reduced CBF in four cortical regions including the left superior and middle temporal gyri, left insula, left and right medial frontal gyrus, and left supramarginal gyrus at baseline; users showed increased CBF in the right precuneus at baseline, as compared to controls (corrected p values < 0.05). No between group differences were found at follow-up., Conclusions: Marijuana use may influence CBF in otherwise healthy adolescents acutely; however, group differences were not observed after several weeks of abstinence. Neurovascular alterations may contribute to or underlie changes in brain activation, neuropsychological performance, and mood observed in young cannabis users with less than a month of abstinence.

Background: Exposure to adverse childhood experiences (ACE) increases the risk of adult physical and mental health disorders, including obsessive-compulsive disorder (OCD), and influences adult cortical neural responses and gray matter (GM) volumes. Robust neuroimaging findings associated OCD with corticostriatal dysfunction and with abnormal morphology and metabolism of cortical areas and basal ganglia., Methods: We explored the GM correlates of ACE in 40 patients with OCD (15 drug-naive and 25 drug-treated patients) with magnetic resonance imaging voxel-based morphometry at 3.0 T. Regional GM volumes were the dependent variable, and drug treatment (naive vs treated) and breadth of exposure to ACE (high vs low) were the factors of interest. Sex, duration of illness, and handedness were considered as nuisance covariates. Whole brain statistical threshold was P < 0.05 familywise error corrected for multiple comparisons., Results: Patients with higher levels of exposure to ACE showed increased GM volume in the head of the left caudate nucleus. Ongoing drug treatment was associated with reduced GM volume in the same area. Earlier age at onset of OCD, need for medication treatment, and mixed handedness were correlated with higher levels of ACE., Conclusions: Exposure to ACE increased, and ongoing drug treatment decreased, caudate GM in OCD. Increased volume and metabolism of the caudate nucleus have been consistently associated with OCD. Our findings suggest a detrimental effect of ACE on the brain underpinnings of OCD, with an opposite effect of medications.

Study Design: Case-control study., Objective: The aim of this study was to assess the levels of psychological distress in patients with back pain who expressed claustrophobia at the time of their magnetic resonance imaging (MRI) scan, compared with sex and age-matched normal controls who did not exhibit claustrophobia. The secondary aim was to document the level of disability and intervention rates in this group., Summary of Background Data: Psychosocial factors influence the outcomes of low back pain treatment with psychological distress being associated with poorer surgical outcomes in patients with low back pain. Up to 14% of patients experience claustrophobia during MRI scans requiring sedation to complete the scan. The effect of claustrophobia on back pain disability and outcomes has not been previously reported., Methods: Twenty females and 13 males all requiring MRI scan under sedation for claustrophobia (group 1) were compared with an age and sex-matched cohort that had MRI scan without sedation (group 2). Both groups were drawn from a chronic back clinic. Average age in both groups was 54 years (range, 27 to 79 y). Both groups had standard conservative therapy, together with psychometric evaluation: Zung Depression Index and Modified Somatic Perception Questionnaire. Disability was measured by Oswestry Disability Index. Primary outcome measures were intervention rates (surgery, injections, and physiotherapy sessions) and prevalence of psychological distress., Results: Mean Zung Depression Index in group 1 was significantly higher than in group 2 (59.5 vs. 28.9, P<0.05) as was the mean Modified Somatic Perception Questionnaire score (13.3 vs. 9.2, P<0.05.) Prevalence of psychological distress was higher in group 1 (75.8% vs. 18.2%, P<0.05). Oswestry Disability Index was the same in both groups (50% vs. 48%). Group 1 had 13 interventions (13 patients=39.4%) compared with 26 in group 2 (26 patients=78.8%) (P< 0.05). Twenty-two patients (66.7%) in group 1 were discharged after their MRI scan with no intervention compared with 7 patients (21.2%) in group 2 (P<0.05)., Conclusions: Claustrophobic patients with back pain showed higher levels of depression than nonclaustrophobic patients, with a higher rate of psychological distress. Disability, however, was not higher. The majority of claustrophobic patients did not require surgical intervention. The reasons for this are unclear and require further investigation. Claustrophobia requiring sedation for MRI scans may be a proxy for psychological distress in these patients and psychometric testing is advised during assessment to help with surgical decision making.

Rationale: Biased processing of drug-associated stimuli is believed to be a crucial feature of addiction. Particularly, an attentional bias seems to contribute to the disorder's maintenance. Recent studies suggest differential effects for stimuli associated with the beginning (BEGIN-smoking-stimuli) or the terminal stage of the smoking ritual (END-smoking-stimuli), with the former but not the later evoking high cue-reactivity., Objective: The current study investigated the neuronal network underlying an attentional bias to BEGIN-smoking-stimuli and END-smoking-stimuli in smokers and tested the hypothesis that the attentional bias is greater for BEGIN-smoking-stimuli., Methods: Sixteen non-deprived smokers and 16 non-smoking controls participated in an fMRI study. Drug pictures (BEGIN-smoking-stimuli, END-smoking-stimuli) and control pictures were overlaid with geometrical figures and presented for 300 ms. Subjects had to identify picture content (identification-task) or figure orientation (distraction-task). The distraction-task was intended to demonstrate attentional bias., Results: Behavioral data revealed an attentional bias to BEGIN-smoking-stimuli but not to END-smoking-stimuli in both groups. However, only smokers showed mesocorticolimbic deactivations in the distraction-task with BEGIN-smoking-stimuli. Importantly, these deactivations were significantly stronger for BEGIN- than for END-smoking-stimuli and correlated with the attentional bias score., Conclusions: Several explanations may account for missing group differences in behavioral data. Brain data suggest smokers using regulatory strategies in response to BEGIN-smoking-stimuli to prevent the elicitation of motivational responses interfering with distraction-task performance. These strategies could be reflected in the observed deactivations and might lead to a performance level in smokers that is similar to that of non-smokers.

Background: Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects., Methods: Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants., Results: Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma., Conclusions: The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Methylphenidate improves motor response inhibition, typically assessed with the stop-signal task. The exact underlying mechanism for this, however, remains unknown. In addition, recent studies highlight that stop signals can have a confounding attentional-capture effect because of their low frequency in the task. In the current study, we assessed the effects of methylphenidate on neural networks of inhibitory control and attentional-capture within the context of two inhibitory control tasks., Methods: The effects of methylphenidate (40 mg) were assessed using functional magnetic resonance imaging in 16 healthy volunteers in a within-subject, double-blind, placebo-controlled design., Results: Methylphenidate significantly reduced activation of different regions within the right inferior frontal gyrus/insula to infrequent stimuli associated with successful inhibition, failed inhibition, and attentional capture. These inferior frontal gyrus regions showed different interregional connections with inhibitory and attention networks. For failed inhibitions, methylphenidate increased activation within performance-monitoring regions, including the superior frontal, anterior cingulate, and parietal-occipital cortices, but only after controlling for attentional capture., Conclusions: Our findings suggest that the improvement of response inhibition seen following methylphenidate administration is due to its influence on underlying attentional mechanisms linked to response control requirements., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Although frontal dysexecutive disorders are frequently considered to be due to working memory deficit, this has not been systematically examined and very little evidence is available for impairment of working memory in frontal damage. The objective of this study was to examine the components of working memory, their anatomy and the relations with executive functions in patients with stroke involving the frontal or posterior cortex. The study population consisted of 29 patients (frontal: n=17; posterior: n=12) and 29 matched controls. Phonological loop (letter and word spans, phonological store; rehearsal process), visuospatial sketchpad (visuospatial span) and the central executive (working memory span, dual task and updating process) were examined. The group comparison analysis showed impairment in the frontal group of: (i) verbal spans (P<0.03); (ii) with a deficit of the rehearsal process (P=0.006); (iii) visuospatial span (P=0.04); (iv) working memory span (P=0.001) that disappeared after controlling for verbal span and (v) running memory (P=0.05) unrelated to updating conditions. The clinical anatomical correlation study showed that impairment of the central executive depended on frontal and posterior lesion. Cognitive dysexecutive disorders were observed in 11/20 patients with central executive deficit and an inverse dissociation was observed in two patients. Receiver operating characteristic curve analysis indicated that cognitive dysexecutive disorders had the highest ability to discriminate frontal lesions (area under curve=0.844, 95% confidence interval: 0.74-0.95; P=0.0001; central executive impairment: area under curve=0.732, 95% confidence interval: 0.57-0.82; P=0.006). This study reveals that frontal lesions induce mild impairment of short-term memory associated with a deficit of the rehearsal process supporting the role of the frontal lobe in this process; the central executive depends on lesions in the frontal lobe and posterior regions accounting for its low frequency and the negative results of group studies. Finally, the frontal dysexecutive syndrome cannot be attributed to central executive impairment, although it may contribute to some dysexecutive disorders.

Background and Objectives: We aimed to investigate the effect on children undergoing Computed Tomography (CT) or Magnetic Resonance Imaging (MRI), their parents and attending anesthesiologist of "multiphase sedation" which we define as "the intended sedation level achieved with one or more agents through the same or different routes with more than one administration"., Material and Methods: One hundred children and their parents were randomly allocated to one of two study groups. In phase 1; in Group I the patients were given midazolam (0.5mg.kg(-1)) in 5 mL fruit juice, and the ones in control group (Group II) were given only fruit juice. After intravenous (iv) cannulation; in phase II, boluses of propofol were given to achieve the adequate sedation for imaging. Anxiety scores of children and their parents were recorded using Oucher scale and STAI, respectively, and parental satisfaction was evaluated by visual analogue scale (VAS). The number of attempts for iv cannulation, length of time for preparation, and amount of hypnotics were recorded., Results: Anxiety state of children was similar between groups before premedication, but later it was lower in Group I. Before procedure, STAI score of parents was similar and later it was lower in Group I. Parental satisfaction in Group I was higher. The number of attempts for iv cannulation and required propofol dose was less in Group I., Conclusion: "Multiphase sedation" procedure provides children to feel less pain and anxiety, and decreases parental anxiety while increasing their satisfaction. It supplies a comfortable and safe sedation, as it provides a short and problem-free preparation process for the attending anesthetist as well., (Copyright © 2012 Elsevier Editora Ltda. All rights reserved.)

Objective: Psychopathy is a personality disorder associated with severely antisocial behavior and a host of cognitive and affective deficits. The neuropathological basis of the disorder has not been clearly established. Cortical thickness is a sensitive measure of brain structure that has been used to identify neurobiological abnormalities in a number of psychiatric disorders. The authors assessed cortical thickness and corresponding functional connectivity in psychopathic prison inmates., Method: Using T1 MRI data, the authors computed cortical thickness maps in a sample of adult male prison inmates selected on the basis of psychopathy diagnosis (21 psychopathic inmates and 31 nonpsychopathic inmates). Using restingstate functional MRI data from a subset of these inmates (20 psychopathic inmates and 20 nonpsychopathic inmates), the authors then computed functional connectivity within networks exhibiting significant thinning among psychopaths., Results: Relative to nonpsychopaths, psychopaths had significantly thinner cortex in a number of regions, including the left insula and dorsal anterior cingulate cortex, the left and right precentral gyri, the left and right anterior temporal cortices, and the right inferior frontal gyrus. These neurostructural differences were not due to differences in age, IQ, or substance use. Psychopaths also exhibited a corresponding reduction in functional connectivity between the left insula and the left dorsal anterior cingulate cortex., Conclusions: Psychopathy is associated with a distinct pattern of cortical thinning and reduced functional connectivity.

The neural basis of language comprehension and production has been associated with superior temporal (Wernicke's) and inferior frontal (Broca's) cortical areas, respectively. However, recent resting-state functional connectivity (RSFC) and lesion studies have implicated a more extended network in language processing. Using a large RSFC data set from 970 healthy subjects and seed regions in Broca's and Wernicke's, we recapitulate this extended network that includes not only adjoining prefrontal, temporal and parietal regions but also bilateral caudate and left putamen/globus pallidus and subthalamic nucleus. We also show that the language network has predominance of short-range functional connectivity (except posterior Wernicke's area that exhibited predominant long-range connectivity), which is consistent with reliance on local processing. Predominantly, long-range connectivity was left lateralized (except anterior Wernicke's area that exhibited rightward lateralization). The language network also exhibited anti-correlated activity with auditory (only for Wernicke's area) and visual cortices that suggests integrated sequential activity with regions involved with listening or reading words. Assessment of the intra-subject's reproducibility of this network and its characterization in individuals with language dysfunction is required to determine its potential as a biomarker for language disorders.

Although progressive supranuclear palsy is defined by its akinetic rigidity, vertical supranuclear gaze palsy and falls, cognitive impairments are an important determinant of patients' and carers' quality of life. Here, we investigate whether there is a broad deficit of modality-independent social cognition in progressive supranuclear palsy and explore the neural correlates for these. We recruited 23 patients with progressive supranuclear palsy (using clinical diagnostic criteria, nine with subsequent pathological confirmation) and 22 age- and education-matched controls. Participants performed an auditory (voice) emotion recognition test, and a visual and auditory theory of mind test. Twenty-two patients and 20 controls underwent structural magnetic resonance imaging to analyse neural correlates of social cognition deficits using voxel-based morphometry. Patients were impaired on the voice emotion recognition and theory of mind tests but not auditory and visual control conditions. Grey matter atrophy in patients correlated with both voice emotion recognition and theory of mind deficits in the right inferior frontal gyrus, a region associated with prosodic auditory emotion recognition. Theory of mind deficits also correlated with atrophy of the anterior rostral medial frontal cortex, a region associated with theory of mind in health. We conclude that patients with progressive supranuclear palsy have a multimodal deficit in social cognition. This deficit is due, in part, to progressive atrophy in a network of frontal cortical regions linked to the integration of socially relevant stimuli and interpretation of their social meaning. This impairment of social cognition is important to consider for those managing and caring for patients with progressive supranuclear palsy.

Semantic dementia is a progressive neurodegenerative condition characterized by the profound and amodal loss of semantic memory in the context of relatively preserved episodic memory. In contrast, patients with Alzheimer's disease typically display impairments in episodic memory, but with semantic deficits of a much lesser magnitude than in semantic dementia. Our understanding of episodic memory retrieval in these cohorts has greatly increased over the last decade, however, we know relatively little regarding the ability of these patients to imagine and describe possible future events, and whether episodic future thinking is mediated by divergent neural substrates contingent on dementia subtype. Here, we explored episodic future thinking in patients with semantic dementia (n=11) and Alzheimer's disease (n=11), in comparison with healthy control participants (n=10). Participants completed a battery of tests designed to probe episodic and semantic thinking across past and future conditions, as well as standardized tests of episodic and semantic memory. Further, all participants underwent magnetic resonance imaging. Despite their relatively intact episodic retrieval for recent past events, the semantic dementia cohort showed significant impairments for episodic future thinking. In contrast, the group with Alzheimer's disease showed parallel deficits across past and future episodic conditions. Voxel-based morphometry analyses confirmed that atrophy in the left inferior temporal gyrus and bilateral temporal poles, regions strongly implicated in semantic memory, correlated significantly with deficits in episodic future thinking in semantic dementia. Conversely, episodic future thinking performance in Alzheimer's disease correlated with atrophy in regions associated with episodic memory, namely the posterior cingulate, parahippocampal gyrus and frontal pole. These distinct neuroanatomical substrates contingent on dementia group were further qualified by correlational analyses that confirmed the relation between semantic memory deficits and episodic future thinking in semantic dementia, in contrast with the role of episodic memory deficits and episodic future thinking in Alzheimer's disease. Our findings demonstrate that semantic knowledge is critical for the construction of novel future events, providing the necessary scaffolding into which episodic details can be integrated. Further research is necessary to elucidate the precise contribution of semantic memory to future thinking, and to explore how deficits in self-projection manifest on behavioural and social levels in different dementia subtypes.

The long-term effect of regular cannabis use on brain function underlying cognitive control remains equivocal. Cognitive control abilities are thought to have a major role in everyday functioning, and their dysfunction has been implicated in the maintenance of maladaptive drug-taking patterns. In this study, the Multi-Source Interference Task was employed alongside functional magnetic resonance imaging and psychophysiological interaction methods to investigate functional interactions between brain regions underlying cognitive control. Current cannabis users with a history of greater than 10 years of daily or near-daily cannabis smoking (n=21) were compared with age, gender, and IQ-matched non-using controls (n=21). No differences in behavioral performance or magnitude of task-related brain activations were evident between the groups. However, greater connectivity between the prefrontal cortex and the occipitoparietal cortex was evident in cannabis users, as compared with controls, as cognitive control demands increased. The magnitude of this connectivity was positively associated with age of onset and lifetime exposure to cannabis. These findings suggest that brain regions responsible for coordinating behavioral control have an increased influence on the direction and switching of attention in cannabis users, and that these changes may have a compensatory role in mitigating cannabis-related impairments in cognitive control or perceptual processes.

Fluency tasks have been widely used to tap the voluntary generation of responses. The anatomical correlates of fluency tasks and their sensitivity and specificity have been hotly debated. However, investigation of the cognitive processes involved in voluntary generation of responses and whether generation is supported by a common, general process (e.g. fluid intelligence) or specific cognitive processes underpinned by particular frontal regions has rarely been addressed. This study investigates a range of verbal and non-verbal fluency tasks in patients with unselected focal frontal (n=47) and posterior (n=20) lesions. Patients and controls (n=35) matched for education, age and sex were administered fluency tasks including word (phonemic/semantic), design, gesture and ideational fluency as well as background cognitive tests. Lesions were analysed by standard anterior/posterior and left/right frontal subdivisions as well as a finer-grained frontal localization method. Thus, patients with right and left lateral lesions were compared to patients with superior medial lesions. The results show that all eight fluency tasks are sensitive to frontal lobe damage although only the phonemic word and design fluency tasks were specific to the frontal region. Superior medial patients were the only group to be impaired on all eight fluency tasks, relative to controls, consistent with an energization deficit. The most marked fluency deficits for lateral patients were along material specific lines (i.e. left-phonemic and right-design). Phonemic word fluency that requires greater selection was most severely impaired following left inferior frontal damage. Overall, our results support the notion that frontal functions comprise a set of specialized cognitive processes, supported by distinct frontal regions.

Alzheimer's disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimer's disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimer's disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and [(11)C]Pittsburgh compound-B binding/[(18)F]fluorodeoxyglucose uptake as dependent variables. There was no main effect of age for [(11)C]Pittsburgh compound-B or [(18)F]fluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of [(11)C]Pittsburgh compound-B binding and [(18)F]fluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased [(11)C]Pittsburgh compound-B binding and decreased [(18)F]fluorodeoxyglucose uptake in the parietal cortex of younger patients (both P<0.05). Linear regression analyses showed negative associations between visuo-spatial functioning and parietal [(11)C]Pittsburgh compound-B binding for younger patients (standardized β: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized β: -0.39). For [(18)F]fluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (standardized β: 0.55), attention (standardized β: 0.39) and executive functioning (standardized β: 0.37) in younger patients, and between posterior cingulate uptake and memory in older patients (standardized β: 0.41, all P<0.05). These in vivo findings suggest that clinical differences between younger and older patients with Alzheimer's disease are not restricted to topographical differentiation in downstream processes but may originate from distinctive distributions of early upstream events. As such, increased amyloid burden, together with metabolic dysfunction, in the parietal lobe of younger patients with Alzheimer's disease may contribute to the distinct cognitive profile in these patients.

Oxytocin (OT) enhances social behaviors such as attachment and parental caretaking. Neural correlates of maternal attachment are found in reward-related brain regions, for example, in the globus pallidus (GP). The present work investigates the effects of OT on the neural correlates of parental attachment. Fathers viewed pictures of their own child (oC), a familiar child (fC), and an unfamiliar child (uC) after intranasal application of OT vs placebo. OT reduced activation and functional connectivity of the left GP with reward- and attachment-related regions responsive to pictures of the oC and the uC. The present results emphasize the key role of OT in human parental attachment and suggest that OT reduces neural reactivity to social cues as a function of social salience. Our results together with previous findings speak to a selective reduction of neural reactivity to social stimuli, irrespective of their valence. We argue that one major pathway by which OT exerts its positive effects on affiliative and social behaviors is the attenuation of automatic neural responses, which in turn leads to increased approach behaviors and decreased social avoidance.

Objective: Amygdala dysfunction has been reported to exist in youths and adults with psychopathic traits. However, there has been disagreement as to whether this dysfunction reflects a primary emotional deficit or is secondary to atypical attentional control. The authors examined the validity of the contrasting predictions., Method: Participants were 15 children and adolescents (ages 10–17 years) with both disruptive behavior disorders and psychopathic traits and 17 healthy comparison youths. Functional MRI was used to assess the response of the amygdala and regions implicated in top-down attentional control (the dorsomedial and lateral frontal cortices) to emotional expression under conditions of high and low attentional load., Results: Relative to youths with disruptive behavior disorders and psychopathic traits, healthy comparison subjects showed a significantly greater increase in the typical amygdala response to fearful expressions under low relative to high attentional load conditions. There was also a selective inverse relationship between the response to fearful expressions under low attentional load and the callous-unemotional component (but not the narcissism or impulsivity component) of psychopathic traits. In contrast, the two groups did not differ in the significant recruitment of the dorsomedial and lateral frontal cortices as a function of attentional load., Conclusions: Youths with disruptive behavior disorders and psychopathic traits showed reduced amygdala responses to fearful expressions under low attentional load but no indications of increased recruitment of regions implicated in top-down attentional control. These findings suggest that the emotional deficit observed in youths with disruptive behavior disorders and psychopathic traits is primary and not secondary to increased top-down attention to nonemotional stimulus features.

The common genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been related to depressive symptoms, in particular after stressful life events. Although it has been investigated in the past, results suggesting that the 5-HTTLPR genotype also affects hippocampal volume are often inconsistent and it remains unclear to what extent reduced hippocampal volume is influenced by the effect of stressful life events and 5-HTTLPR genotype. Moreover, sex, which is known to affect the prevalence of depression substantially, has not been taken into account when trying to disentangle the interactive effect of common genetic variation and environmental stressors on the hippocampus. We investigated this potentially relevant three-way interaction using an automatic magnetic resonance imaging (MRI)-based segmentation of the hippocampus in 357 healthy individuals. We determined the 5-HTTLPR genotype as a biallelic locus and childhood adversity (CA) using a standard questionnaire. An interaction for hippocampal volume was found between the factors sex, genotype, and severe CA (p=0.010) as well as an interaction between genotype and severe CA (p=0.007) in men only. Post hoc tests revealed that only male S'-allele carriers with severe CA had smaller hippocampi (p=0.002). Interestingly, there was no main effect of genotype in men, while female S'-allele carriers had smaller hippocampi than L'L' carriers (p=0.023). Our results indicate that sex modulates the interactive effect of the 5-HTTLPR genotype and CA on hippocampal volume. While the S'-allele is associated with hippocampal volume independent of CA in women, men only have smaller hippocampi if they carry the risk allele and experienced severe CA.

This study sought to systematically investigate whether prefrontal cortex grey matter volume reductions are valid endophenotypes for schizophrenia, specifically investigating their presence in unaffected relatives, heritability, genetic overlap with the disorder itself and finally to contrast their performance on these criteria with putative neuropsychological indices of prefrontal functioning. We used a combined twin and family design and examined four prefrontal cortical regions of interest. Superior and inferior regions were significantly smaller in patients. However, the volumes of these same regions were normal in unaffected relatives and therefore, we could confirm that such deficits were not due to familial effects. Volumes of the prefrontal and orbital cortices were, however, moderately heritable, but neither shared a genetic overlap with schizophrenia. Total prefrontal cortical volume reductions shared a significant unique environmental overlap with the disorder, suggesting that the reductions were not familial. In contrast, prefrontal (executive) functioning deficits were present in the unaffected relatives, were moderately heritable and shared a substantial genetic overlap with liability to schizophrenia. These results suggest that the well recognized prefrontal volume reductions are not related to the same familial influences that increase schizophrenia liability and instead may be attributable to illness related biological changes or indeed confounded by illness trajectory, chronicity, medication or substance abuse, or in fact a combination of some or all of them.

We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.

In recent years, a large number of human studies have investigated large-scale network properties of the brain, typically during the resting state. A critical gap in the knowledge base concerns the understanding of network properties of a focused set of brain regions during task conditions engaging these regions. Although emotion and motivation recruit many brain regions, it is currently unknown how they affect network-level properties of inter-region interactions. In the present study, we sought to characterize network structure during "mini-states" engendered by emotional and motivational cues investigated in separate studies. To do so, we used graph-theoretic network analysis to probe network-, community-, and node-level properties of the trial-by-trial functional connectivity between regions of interest. We used methods that operate on weighted graphs that make use of the continuous information of connectivity strength. In both the emotion and motivation datasets, global efficiency increased and decomposability decreased. Thus, processing became less segregated with the context signaled by the cue (potential shock or potential reward). Our findings also revealed several important features of inter-community communication, including notable contributions of the bed nucleus of the stria terminalis, anterior insula, and thalamus during threat and of the caudate and nucleus accumbens during reward. Together, the results suggest that one way in which emotional and motivational processing affect brain responses is by enhancing signal communication between regions, especially between cortical and subcortical ones.

Understanding the relationship between brain and cognition critically depends on data from brain-damaged patients since these provide major constraints on identifying the essential components of brain-behavior systems. Here we relate structural and functional fMRI data with behavioral data in 21 human patients with chronic left hemisphere (LH) lesions and a range of language impairments to investigate the controversial issue of the role of the hemispheres in different language functions. We address this issue within a dual neurocognitive model of spoken language comprehension in which core linguistic functions, e.g., syntax, depend critically upon an intact left frontotemporal system, whereas more general communicative abilities, e.g., semantics, are supported by a bilateral frontotemporal system and may recover from LH damage through normal or enhanced activity in the intact right hemisphere. The fMRI study used a word-monitoring task that differentiated syntactic and semantic aspects of sentence comprehension. We distinguished overlapping interactions between structure, neural activity, and performance using joint independent components analysis, identifying two structural-functional networks, each with a distinct relationship with performance. Syntactic performance correlated with tissue integrity and activity in a left frontotemporal network. Semantic performance correlated with activity in right superior/middle temporal gyri regardless of tissue integrity. Right temporal activity did not differ between patients and controls, suggesting that the semantic network is degenerately organized, with regions in both hemispheres able to perform similar computations. Our findings support the dual neurocognitive model of spoken language comprehension and emphasize the importance of linguistic specificity in investigations of language recovery in patients.

It is widely held that the interaction between instrumental and Pavlovian conditioning induces powerful motivational biases. Pavlovian-Instrumental Transfer (PIT) is one of the key paradigms demonstrating this effect, which can further be decomposed into a general and specific component. Although these two forms of PIT have been studied at the level of amygdalar subregions in rodents, it is still unknown whether they involve different areas of the human amygdala. Using a high-resolution fMRI (hr-fMRI) protocol optimized for the amygdala in combination with a novel free operant task designed to elicit effects of both general and specific PIT, we demonstrate that a region of ventral amygdala within the boundaries of the basolateral complex and the ventrolateral putamen are involved in specific PIT, while a region of dorsal amygdala within the boundaries of the centromedial complex is involved in general PIT. These results add to a burgeoning literature indicating different functional contributions for these different amygdalar subregions in reward-processing and motivation.

Cognitive models have long distinguished between "automatic" associative processes that can be triggered in a bottom-up fashion, and "controlled" processes, where internal goals guide information processing in a deliberate, top-down manner. However, recent behavioral studies have cast doubt on the validity of this dichotomy, showing that implicit contextual cues can modulate performance in a way suggestive of an associative triggering of specific top-down control states. Here, we harnessed functional magnetic resonance imaging in humans to test whether these behavioral findings truly reflect online, bottom-up priming of top-down attentional control settings. Using a flanker interference task where stimulus location cued the likelihood of incongruent trials, we found that the behavioral phenomenon of implicit, context-specific improvements in interference resolution was mirrored in hemodynamic activity in the medial superior parietal lobule (mSPL), previously implicated in voluntary (as opposed to primed) attention shifts. Moreover, the mSPL displayed context-specific functional coupling with visual regions involved in processing the flanker stimuli, and the modulation of the latter was predictive of the behavioral effects. Finally, the implementation of this contextual control was "on the fly," that is, it was primed online by a switch to the context associated with high conflict. These results suggest that top-down control states can be bound into episodic event representations and can subsequently be primed by other features of those representations. Together, our findings illustrate a more intimate link between associative and controlled processing than is traditionally assumed, and place the neural substrate of that linkage in the posterior parietal cortex.

According to the neurotrophic hypothesis of depression, stress can lead to brain atrophy by modifying brain-derived neurotrophic factor (BDNF) levels. Given that BDNF secretion is affected by a common polymorphism (rs6265, Val66Met), which also is associated with depression, we investigated whether this polymorphism modifies the effect of childhood adversity (CA) on local gray matter (GM) volume in depression-relevant brain regions, using data from two large cohorts of healthy subjects. We included 568 healthy volunteers (aged 18-50 years, 63% female) in our study, for whom complete data were available, with magnetic resonance imaging data at 1.5 Tesla (N=275) or 3 Tesla (N=293). We used a whole brain optimized voxel-based morphometry (VBM) approach assessing genotype-dependent GM differences, with focus on the amygdala, hippocampus and medial prefrontal cortex (PFC; including anterior cingulate cortex (ACC) and orbitomedial PFC). CA was assessed using a validated questionnaire. In both cohorts, we found that BDNF methionine (Met)-allele carriers with a history of CA had significantly less GM in subgenual ACC (P<0.05) compared with Met-allele carriers without CA and Val/Val homozygotes with CA. No differences were found in hippocampus, amygdala and orbitomedial PFC. On the basis of our findings, we conclude that BDNF Met-allele carriers are particularly sensitive to CA. Given the key role of the subgenual ACC in emotion regulation, this finding provides an important mechanistic link between stress and BDNF on one hand and mood impairments on the other hand.

The spread of desires among individuals is widely believed to shape motivational drives in human populations. However, objective evidence for this phenomenon and insights into the underlying brain mechanisms are still lacking. Here we show that participants rated objects as more desirable once perceived as the goals of another agent's action. We then unravel the mechanisms underpinning such goal contagion, using functional neuroimaging. As expected, observing goal-directed actions activated a parietofrontal network known as the mirror neuron system (MNS), whereas subjective desirability ratings were represented in a ventral striatoprefrontal network known as the brain valuation system (BVS). Crucially, the induction of mimetic desires through action observation involved the modulation of BVS activity through MNS activity. Furthermore, MNS-BVS effective connectivity predicted individual susceptibility toward mimetic desires. We therefore suggest that MNS-BVS interaction represents a fundamental mechanism explaining how nonverbal behavior propagates desires without the need for explicit, intentional communication.

An organism's behavior is sensitive to different reinforcements in the environment. Based on extensive animal literature, the reinforcement sensitivity theory (RST) proposes three separate neurobehavioral systems to account for such context-sensitive behavior, affecting the tendency to react to punishment, reward, or goal-conflict stimuli. The translation of animal findings to complex human behavior, however, is far from obvious. To examine whether the neural networks underlying humans' motivational processes are similar to those proposed by the RST model, we conducted a functional MRI study, in which 24 healthy subjects performed an interactive game that engaged the different motivational systems using distinct time periods (states) of punishment, reward, and conflict. Crucially, we found that the different motivational states elicited activations in brain regions that corresponded exactly to the brain systems underlying RST. Moreover, dynamic causal modeling of each motivational system confirmed that the coupling strengths between the key brain regions of each system were enabled selectively by the appropriate motivational state. These results may shed light on the impairments that underlie psychopathologies associated with dysfunctional motivational processes and provide a translational validity for the RST.

Human perception is supported by regions of ventral visual cortex that become active when specific types of information appear in the environment. This coupling has led to a common assumption in cognitive neuroscience that stimulus-evoked activity in these regions only reflects information about the current stimulus. Here we challenge this assumption for how scenes are represented in a scene-selective region of parahippocampal cortex. This region treated two identical scenes as more similar when they were preceded in time by the same stimuli compared to when they were preceded by different stimuli. These findings suggest that parahippocampal cortex embeds scenes in their temporal context to determine what they represent. By integrating the past and present, such representations may support the encoding and navigation of complex environments.

Impulsive behavior is thought to reflect a traitlike characteristic that can have broad consequences for an individual's success and well-being, but its neurobiological basis remains elusive. Although striatal dopamine D₂-like receptors have been linked with impulsive behavior and behavioral inhibition in rodents, a role for D₂-like receptor function in frontostriatal circuits mediating inhibitory control in humans has not been shown. We investigated this role in a study of healthy research participants who underwent positron emission tomography with the D₂/D₃ dopamine receptor ligand [¹⁸F]fallypride and BOLD fMRI while they performed the Stop-signal Task, a test of response inhibition. Striatal dopamine D₂/D₃ receptor availability was negatively correlated with speed of response inhibition (stop-signal reaction time) and positively correlated with inhibition-related fMRI activation in frontostriatal neural circuitry. Correlations involving D₂/D₃ receptor availability were strongest in the dorsal regions (caudate and putamen) of the striatum, consistent with findings of animal studies relating dopamine receptors and response inhibition. The results suggest that striatal D₂-like receptor function in humans plays a major role in the neural circuitry that mediates behavioral control, an ability that is essential for adaptive responding and is compromised in a variety of common neuropsychiatric disorders.

Primate electrophysiological and lesion studies indicate a prominent role of the left dorsal premotor cortex (PMd) in action selection based on learned sensorimotor associations. Here we applied transcranial magnetic stimulation (TMS) to human left PMd at low or high intensity while right-handed individuals performed externally paced sequential key presses with their left hand. Movements were cued by abstract visual stimuli, and subjects either freely selected a key press or responded according to a prelearned visuomotor mapping rule. Continuous arterial spin labeling was interleaved with TMS to directly assess how stimulation of left PMd modulates task-related brain activity depending on the mode of movement selection. Relative to passive viewing, both tasks activated a frontoparietal motor network. Compared with low-intensity TMS, high-intensity TMS of left PMd was associated with an increase in activity in medial and right premotor areas without affecting task performance. Critically, this increase in task-related activity was only present when movement selection relied on arbitrary visuomotor associations but not during freely selected movements. Psychophysiological interaction analysis revealed a context-specific increase in functional coupling between the stimulated left PMd and remote right-hemispheric and mesial motor regions that was only present during arbitrary visuomotor mapping. Our TMS perturbation approach yielded causal evidence that the left PMd is implicated in mapping external cues onto the appropriate movement in humans. Furthermore, the data suggest that the left PMd may transiently form a functional network together with right-hemispheric and mesial motor regions to sustain visuomotor mapping performed with the left nondominant hand.

Sleep deprivation (SD) has detrimental effects on cognition, but the affected psychological processes and underlying neural mechanisms are still essentially unclear. Here we combined functional magnetic resonance imaging and computational modeling to examine how SD alters neural representation of specific choice variables (subjective value and decision conflict) during reward-related decision making. Twenty-two human subjects underwent two functional neuroimaging sessions in counterbalanced order, once during rested wakefulness and once after 24 h of SD. Behaviorally, SD attenuated conflict-dependent slowing of response times, which was reflected in an attenuated conflict-induced decrease in drift rates in the drift diffusion model. Furthermore, SD increased overall choice stochasticity during risky choice. Model-based functional neuroimaging revealed attenuated parametric subjective value signals in the midbrain, parietal cortex, and ventromedial prefrontal cortex after SD. Conflict-related midbrain signals showed a similar downregulation. Findings are discussed with respect to changes in dopaminergic signaling associated with the sleep-deprived state.

Value-based choices are influenced both by risk in potential outcomes and by whether outcomes reflect potential gains or losses. These variables are held to be related in a specific fashion, manifest in risk aversion for gains and risk seeking for losses. Instead, we hypothesized that there are independent impacts of risk and loss on choice such that, depending on context, subjects can show either risk aversion for gains and risk seeking for losses or the exact opposite. We demonstrate this independence in a gambling task, by selectively reversing a loss-induced effect (causing more gambling for gains than losses and the reverse) while leaving risk aversion unaffected. Consistent with these dissociable behavioral impacts of risk and loss, fMRI data revealed dissociable neural correlates of these variables, with parietal cortex tracking risk and orbitofrontal cortex and striatum tracking loss. Based on our neural data, we hypothesized that risk and loss influence action selection through approach-avoidance mechanisms, a hypothesis supported in an experiment in which we show valence and risk-dependent reaction time effects in line with this putative mechanism. We suggest that in the choice process risk and loss can independently engage approach-avoidance mechanisms. This can provide a novel explanation for how risk influences action selection and explains both classically described choice behavior as well as behavioral patterns not predicted by existing theory.

Functional neuroimaging (fMRI) studies show activation in mesolimbic circuitry in tasks involving reward processing, like the Monetary Incentive Delay Task (MIDT). In voltammetry studies in animals, mesolimbic dopamine release is associated with reward salience. This study examined the relationship between fMRI activation and magnitude of dopamine release measured with Positron emission tomography study (PET) in the same subjects using MIDT in both modalities to test if fMRI activation is related to dopamine release. Eighteen healthy subjects were scanned with [¹¹C]raclopride PET at baseline and after MIDT. Binding potential (BP(ND)) was derived by equilibrium analysis in striatal subregions and percent change across conditions (∆BP(ND)) was measured. Blood oxygen level dependence (BOLD) signal changes with MIDT were measured during fMRI using voxelwise analysis and ROI analysis and correlated with ∆BP(ND). ∆BP(ND) was not significant in the ventral striatum (VST) but reached significance in the posterior caudate. The fMRI BOLD activation was highest in VST. No significant associations between ∆BP(ND) and change in fMRI BOLD were observed with VST using ROI analysis. Voxelwise analysis showed positive correlation between BOLD activation in anticipation of the highest reward and ∆BP(ND) in VST and precommissural putamen. Our study indicates that endogenous dopamine release in VST is of small magnitude and is related to BOLD signal change during performance of the MIDT in only a few voxels when rewarding and nonrewarding conditions are interspersed. The lack of correlation at the ROI level may be due to the small magnitude of release or to the particular dependence of BOLD on glutamatergic signaling.

Background: Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and may be a marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Thus, we examined the neuroanatomical changes associated with depressive symptoms in MCI., Methods: Two-hundred forty-three MCI subjects from the Alzheimer's Disease Neuroimaging Initiative who had brain magnetic resonance imaging scans at baseline and 2-year follow-up were classified into depressed (n = 44), nondepressed with other neuropsychiatric symptoms (n = 93), and no-symptom (NOSYMP; n = 106) groups based on the Neuropsychiatric Inventory Questionnaire. Tensor-based morphometry was used to create individual three-dimensional maps of 2-year brain changes that were compared between groups., Results: Depressed subjects had more frontal (p = .024), parietal (p = .030), and temporal (p = .038) white matter atrophy than NOSYMP subjects. Those whose depressive symptoms persisted over 2 years also had higher conversion to AD and more decline on measures of global cognition, language, and executive functioning compared with stable NOSYMP subjects. Nondepressed with other neuropsychiatric symptoms and NOSYMP groups exhibited no differences in rates of atrophy., Conclusions: Depressive symptoms were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes, including prodromal AD, and may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). However, there is a controversy regarding how the cholinergic lesion in AD relates to early and incipient stages of the disease. In vivo imaging studies on the structural integrity of the BFCS in normal and pathologic aging are rare., Methods: We applied automated morphometry techniques in combination with high-dimensional image warping and a cytoarchitectonic map of basal forebrain cholinergic nuclei to a large cross-sectional data set of high-resolution magnetic resonance imaging scans, covering the whole adult age range (20-94 years; n = 211) as well as patients with very mild AD (Clinical Dementia Rating = .5; n = 69) and clinically manifest AD (AD; Clinical Dementia Rating = 1; n = 28). For comparison, we investigated hippocampus volume using automated volumetry., Results: Volume of the BFCS declined from early adulthood on, and atrophy aggravated in advanced age. Volume reductions in very mild AD were most pronounced in posterior parts of the nucleus basalis of Meynert, whereas in AD, atrophy was more extensive and included the whole BFCS. In clinically manifest AD, the diagnostic accuracy of BFCS volume reached the diagnostic accuracy of hippocampus volume., Conclusions: Our findings indicate that cholinergic degeneration in AD occurs against a background of age-related atrophy and that exacerbated atrophy in AD can be detected at earliest stages of cognitive impairment. Automated in vivo morphometry of the BFCS may become a useful tool to assess BF cholinergic degeneration in normal and pathologic aging., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory γ-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two single-nucleotide polymorphisms (SNPs) and haplotypes were more likely to have alcohol dependence symptoms (rs279858, P=0.01; rs279826, P=0.05; haplotype, P=0.02) and higher NEO Personality Inventory-Revised (NEO-PI-R) Impulsiveness scores (rs279858, P=0.016; rs279826, P=0.012; haplotype, P=0.032) with a stronger effect in women (rs279858, P=0.011; rs279826, P=0.002; haplotype, P=0.006), all P-values are corrected for family history and age. A subset of offspring from these families (n=44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r(2)=0.4; P=0.026) and loss (r(2)=0.38; P=0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (P's<0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.

Depression has been associated with changes in responses within the medial prefrontal cortex (mPFC) during emotional information processing. Antidepressant drug treatment has been shown to modify neural responses in healthy volunteers early in treatment within similar circuitry. It is unclear, however, whether the same early effect occurs in depressed patients, before changes in mood. The current study therefore investigated the effects of 7-days administration of the selective serotonin-uptake inhibitor citalopram vs placebo in volunteers (n=29) at a high risk for the development of depression, using the personality phenotype of high neuroticism in a double-blind, between-groups design. On the last day of treatment, resting haemoperfusion and functional magnetic resonance imaging (MRI) data were acquired during a self-referential words categorisation task. A significant activation in a cluster of mPFC areas, including dorsal anterior cingulate and right orbitofrontal cortex was revealed, driven by decreased responses to the negative self-descriptors following citalopram compared with placebo, in the absence of any mood differences. These findings show a normalisation of neural abnormalities in- and at-risk population early in treatment, supporting the theory that antidepressants may indeed act by modifying specific neural dysfunctions correlated to negative cognitive biases.

Objective: To report the phenotypic characterization of monozygotic twins with mutations encoding progranulin (PGRN)., Methods: We studied a twin pair with an exon 4 gene deletion in the PGRN gene. Both twins had clinical and neuropsychological examinations as well as structural MRI and fluorodeoxyglucose PET (FDG-PET) scans. PGRN gene sequencing was performed followed by progranulin ELISA in plasma., Results: Both twins manifested symptoms within 3 years of each other, with early behavioral, language, dysexecutive, and memory problems. MRI and FDG-PET imaging demonstrated a strikingly similar topography of findings with clear left hemisphere predominance. Serum progranulin levels in both were well below those from a normal population sample., Conclusions: Compared with the heterogeneity seen in many families with PGRN mutations, these monozygotic twins demonstrated strong clinical, neuroimaging, and serum progranulin level similarities, demonstrating the importance of shared genetic profiles beyond environmental influences in the symptomatic expression of the disease.

Fluid reasoning is the ability to think flexibly and logically, analyze novel problems and identify the relationships that underpin these problems independent of acquired knowledge. Although many functional imaging studies have investigated brain activation during fluid reasoning tasks, the neural correlates of fluid reasoning remain elusive. In the present study, we aimed to uncover the neural correlates of fluid reasoning by analyzing correlations between Raven's Standard Progressive Matrices (RSPM), an effective measure of fluid reasoning, and measures of regional gray matter volume (GMV) and regional homogeneity (ReHo) in a voxel-wise manner throughout the whole brain in 297 healthy young adults. The most important finding was that RSPM scores were positively correlated with both GMV and ReHo values in brain areas that belong to the salience network, including the dorsal anterior cingulate cortex and the fronto-insular cortex. Additionally, we found positive or negative correlations between RSPM scores and GMV or ReHo values in brain areas of the central-executive, default-mode, sensorimotor and visual networks. Our findings suggest that fluid reasoning ability is related to a variety of brain areas and emphasize the important contribution of the salience network to this ability., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Imaging studies have shown that major depressive disorder (MDD) is associated with altered activity patterns of the default mode network (DMN). However, the neural correlates of the resting-state DMN and MDD-related pathopsychological characteristics, such as depressive rumination and overgeneral autobiographical memory (OGM) phenomena, still remain unclear., Methods: Using independent component analysis, we analyzed resting-state functional magnetic resonance imaging data obtained from 35 first-episode, treatment-naive young adults with MDD and from 35 matched healthy control subjects., Results: Patients with MDD exhibited higher levels of rumination and OGM than did the control subjects. We observed increased functional connectivity in the anterior medial cortex regions (especially the medial prefrontal cortex and anterior cingulate cortex) and decreased functional connectivity in the posterior medial cortex regions (especially the posterior cingulate cortex/precuneus) in MDD patients compared with control subjects. In the depressed group, the increased functional connectivity in the anterior medial cortex correlated positively with rumination score, while the decreased functional connectivity in the posterior medial cortex correlated negatively with OGM score., Conclusions: We report dissociation between anterior and posterior functional connectivity in resting-state DMNs of first-episode, treatment-naive young adults with MDD. Increased functional connectivity in anterior medial regions of the resting-state DMN was associated with rumination, whereas decreased functional connectivity in posterior medial regions was associated with OGM. These results provide new evidence for the importance of the DMN in the pathophysiology of MDD and suggest that abnormal DMN activity may be an MDD trait., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The neural mechanisms supporting social bonds between adult men remain uncertain. In this double-blind, placebo-controlled study, we investigate the impact of intranasally administered oxytocin (OT) and vasopressin (AVP) on behavior and brain activity among men in the context of an iterated Prisoner's Dilemma game, which models a real-life social situation. fMRI results show that, relative to both AVP and placebo, OT increases the caudate nucleus response to reciprocated cooperation, which may augment the reward of reciprocated cooperation and/or facilitate learning that another person can be trusted. OT also enhances left amygdala activation in response to reciprocated cooperation. Behaviorally, OT was associated with increased rates of cooperation following unreciprocated cooperation in the previous round compared with AVP. AVP strongly increased cooperation in response to a cooperative gesture by the partner compared with both placebo and OT. In response to reciprocated cooperation, AVP increased activation in a region spanning known vasopressin circuitry implicated in affiliative behaviors in other species. Finally, both OT and AVP increase amygdala functional connectivity with the anterior insula relative to placebo, which may increase the amygdala's ability to elicit visceral somatic markers that guide decision making. These findings extend our knowledge of the neural and behavioral effects of OT and AVP to the context of genuine social interactions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The neural bases of emotion are most often studied using short non-natural stimuli and assessed using correlational methods. Here we use a brain perturbation approach to make causal inferences between brain activity and emotional reaction to a long segment of dance., Objective/hypothesis: We aimed to apply offline rTMS over the brain regions involved in subjective emotional ratings to explore whether this could change the appreciation of a dance performance., Methods: We first used functional magnetic resonance imaging (fMRI) to identify regions correlated with fluctuating emotional rating during a 4-min dance performance, looking at both positive and negative correlation. Identified regions were further characterized using meta-data interrogation. Low-frequency repetitive TMS was applied over the most important node in a different group of participants prior to them rating the same dance performance as in the fMRI session., Results: FMRI revealed a negative correlation between subjective emotional judgement and activity in the right posterior parietal cortex. This region is commonly involved in cognitive tasks and not in emotional task. Parietal rTMS had no effect on the general affective response, but it significantly (P<0.05 using exact t-statistics) enhanced the rating of the moments eliciting the highest positive judgements., Conclusion: These results establish a direct link between posterior parietal cortex activity and emotional reaction to dance. They can be interpreted in the framework of competition between resources allocated to emotion and resources allocated to cognitive functions. They highlight potential use of brain stimulation in neuro-æsthetic investigations., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Context: Posttraumatic stress disorder (PTSD) has been associated with executive or attentional dysfunction and problems in emotion processing. However, it is unclear whether these two domains of dysfunction are related to common or distinct neurophysiological substrates., Objective: To examine the hypothesis that greater neuropsychological impairment in PTSD relates to greater disruption in prefrontal-subcortical networks during emotional anticipation., Design: Case-control, cross-sectional study., Setting: General community and hospital and community psychiatric clinics., Participants: Volunteer sample of 37 women with PTSD related to intimate partner violence and 34 age-comparable healthy control women., Main Outcome Measures: We used functional magnetic resonance imaging (fMRI) to examine neural responses during anticipation of negative and positive emotional images. The Clinician-Administered PTSD Scale was used to characterize PTSD symptom severity. The Wechsler Adult Intelligence Scale, Third Edition, Digit Symbol Test, Delis-Kaplan Executive Function System Color-Word Interference Test, and Wisconsin Card Sorting Test were used to characterize neuropsychological performance., Results: Women with PTSD performed worse on complex visuomotor processing speed (Digit Symbol Test) and executive function (Color-Word Interference Inhibition/Switching subtest) measures compared with control subjects. Posttraumatic stress disorder was associated with greater anterior insula and attenuated lateral prefrontal cortex (PFC) activation during emotional anticipation. Greater dorsolateral PFC activation (anticipation of negative images minus anticipation of positive images) was associated with lower PTSD symptom severity and better visuomotor processing speed and executive functioning. Greater medial PFC and amygdala activation related to slower visuomotor processing speed., Conclusions: During emotional anticipation, women with PTSD show exaggerated activation in the anterior insula, a region important for monitoring internal bodily state. Greater dorsolateral PFC response in PTSD patients during emotional anticipation may reflect engagement of cognitive control networks that are beneficial for emotional and cognitive functioning. Novel treatments could be aimed at strengthening the balance between cognitive control (dorsolateral PFC) and affective processing (medial PFC and amygdala) networks to improve overall functioning for PTSD patients.

Objective: The caudate nucleus (CN) is a crucial component of the ventral striatum, which is part of a prefrontal-striatal-thalamic circuit that is modulated by limbic structures to subserve emotional processing. Bipolar disorder is thought to be underpinned by dysfunctional anterior limbic networks, although MRI studies examining the CN have shown equivocal results. As gross volumetric analyses may not detect subtle regional change, we aimed to clarify the role of the CN in bipolar disorder by undertaking shape analysis to detect regional reductions., Methods: The CN was manually traced on MRI scans from 27 patients with bipolar-I disorder and 24 matched controls. A non-parametric spherical harmonic shape analysis was undertaken using the SPHARM toolkit., Results: Whilst the left CN volume was consistently larger in the sample, there was no effect of group or gender or significant interactions between these variables. Volume did not correlate with illness duration or lithium dosage, but was larger in those with a history of psychosis at trend level. However, left caudate shape differed significantly between groups, with deflation in an area along the ventromedial surface (connecting to dorsolateral prefrontal regions) in bipolar patients. Psychotic patients showed increases in the dorsal head and body at trend level overall, in regions connecting to medial and orbitofrontal regions., Conclusions: These findings suggest that subtle rather than gross structural changes occur in the CN, which may not be detectable by volumetric analysis alone, and reflect alterations in specific frontostriatal circuitry in the disorder.