A Longitudinal Magnetoencephalographic Study of the Effects of Deep Brain Stimulation on Neuronal Dynamics in Severe Anorexia Nervosa.

Anorexia Nervosa (AN) is a debilitating psychiatric disorder characterized by the relentless pursuit of thinness, leading to severe emaciation. Magnetoencephalography (MEG)was used to record the neuronal response in seven patients with treatment-resistant AN while completing a disorder-relevant food wanting task. The patients underwent a 15-month protocol, where MEG scans were conducted pre-operatively, post-operatively prior to deep brain stimulation (DBS) switch on, twice during a blind on/off month and at protocol end. Electrodes were implanted bilaterally into the nucleus accumbens with stimulation at the anterior limb of the internal capsule using rechargeable implantable pulse generators. Three patients met criteria as responders at 12 months of stimulation, showing reductions of eating disorder psychopathology of over 35%. An increase in alpha power, as well as evoked power at latencies typically associated with visual processing, working memory, and contextual integration was observed in ON compared to OFF sessions across all seven patients. Moreover, an increase in evoked power at P600-like latencies as well as an increase in γ-band phase-locking over anterior-to-posterior regions were observed for high- compared to low-calorie food image only in ON sessions. These findings indicate that DBS modulates neuronal process in regions far outside the stimulation target site and at latencies possibly reflecting task specific processing, thereby providing further evidence that deep brain stimulation can play a role in the treatment of otherwise intractable psychiatric disorders.

Pre-stimulus Alpha Activity Modulates Face and Object Processing in the Intra-Parietal Sulcus, a MEG Study.

Face perception is crucial in all social animals. Recent studies have shown that pre-stimulus oscillations of brain activity modulate the perceptual performance of face vs. non-face stimuli, specifically under challenging conditions. However, it is unclear if this effect also occurs during simple tasks, and if so in which brain regions. Here we used magnetoencephalography (MEG) and a 1-back task in which participants decided if the two sequentially presented stimuli were the same or not in each trial. The aim of the study was to explore the effect of pre-stimulus alpha oscillation on the perception of face (human and monkey) and non-face stimuli. Our results showed that pre-stimulus activity in the left occipital face area (OFA) modulated responses in the intra-parietal sulcus (IPS) at around 170 ms after the presentation of human face stimuli. This effect was also found after participants were shown images of motorcycles. In this case, the IPS was modulated by pre-stimulus activity in the right OFA and the right fusiform face area (FFA). We conclude that pre-stimulus modulation of post-stimulus response also occurs during simple tasks and is therefore independent of behavioral responses.

Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity.

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.

Semantic Processing in Autism Spectrum Disorders Is Associated With the Timing of Language Acquisition: A Magnetoencephalographic Study.

Individuals with autism show difficulties in using sentence context to identify the correct meaning of ambiguous words, such as homonyms. In this study, the brain basis of sentence context effects on word understanding during reading was examined in autism spectrum disorder (ASD) and typical development (TD) using magnetoencephalography. The correlates of a history of developmental language delay in ASD were also investigated. Event related field responses at early (150 ms after the onset of a final word) and N400 latencies are reported for three different types of sentence final words: dominant homonyms, subordinate homonyms, and unambiguous words. Clear evidence for semantic access was found at both early and conventional N400 latencies in both TD participants and individuals with ASD with no history of language delay. By contrast, modulation of evoked activity related to semantic access was weak and not significant at early latencies in individuals with ASD with a history of language delay. The reduced sensitivity to semantic context in individuals with ASD and language delay was accompanied by strong right hemisphere lateralization at early and N400 latencies; such strong activity was not observed in TD individuals and individuals with ASD without a history of language delay at either latency. These results provide new evidence and support for differential neural mechanisms underlying semantic processing in ASD, and indicate that delayed language acquisition in ASD is associated with different lateralization and processing of language.

Dissociable auditory mismatch response and connectivity patterns in adolescents with schizophrenia and adolescents with bipolar disorder with psychosis: A magnetoencephalography study.

BACKGROUND: There is overlap between schizophrenia and bipolar disorder regarding genetic risk as well as neuropsychological and structural brain deficits. Finding common and distinct event-response potential (ERP) responses and connectivity patterns may offer potential biomarkers to distinguish the disorders. OBJECTIVE: To examine the neuronal auditory response elicited by a roving mismatch negativity (MMN) paradigm using magnetoencephalography (MEG). PARTICIPANTS: 15 Adolescents with schizophrenia (ASZ), 16 adolescents with bipolar disorder with psychosis (ABP), and 14 typically developing individuals (TD) METHODS: The data were analysed using time-series techniques and dynamic causal modelling (DCM). OUTCOME MEASURES: MEG difference wave (deviant - standard) at primary auditory (~90ms), MMN (~180ms) and long latency (~300ms). RESULTS: The amplitude of difference wave showed specific patterns at all latencies. Most notably, it was significantly reduced ABP compared to both controls and ASZ at early latencies. In contrast, the amplitude was significantly reduced in ASZ compared to both controls and ABP. The DCM analysis showed differential connectivity patterns in all three groups. Most notably, inter-hemispheric connections were strongly dominated by the right side in ASZ only. CONCLUSIONS: Dissociable patterns of the primary auditory response and MMN response indicate possible developmentally sensitive, but separate biomarkers for schizophrenia and bipolar disorder.

Frontal evoked γ activity modulates behavioural performance in Autism Spectrum Disorders in a perceptual simultaneity task.

Autism spectrum disorders (ASDs) are associated with anomalies in time perception. In a perceptual simultaneity task, individuals with ASD demonstrate superior performance compared to typically developing (TD) controls. γ-activity, a robust marker of visual processing, is reportedly altered in ASD in response to a wide variety of tasks and these differences may be related to superior performance in perceptual simultaneity. Using time-frequency analysis, we assessed evoked γ-band phase-locking in magnetoencephalographic recordings of 16 ASD individuals and 17 age-matched TD controls. Individuals judged whether presented visual stimuli were simultaneous or asynchronous. We identified left frontal γ-activity in ASD, which was associated with a reduced perception of simultaneity. Where feature binding was observed at a neurophysiological level in parieto-occipital cortices in ASD in apparent simultaneity (asynchronous stimuli with short delay between them), this did not predict the correct behavioural outcome. These findings suggest distinct γ profiles in ASD associated with the perception of simultaneity.

Enhanced Early Neuronal Processing of Food Pictures in Anorexia Nervosa: A Magnetoencephalography Study.

Neuroimaging studies in Anorexia Nervosa (AN) have shown increased activation in reward and cognitive control regions in response to food, and a behavioral attentional bias (AB) towards food stimuli is reported. This study aimed to further investigate the neural processing of food using magnetoencephalography (MEG). Participants were 13 females with restricting-type AN, 14 females recovered from restricting-type AN, and 15 female healthy controls. MEG data was acquired whilst participants viewed high- and low-calorie food pictures. Attention was assessed with a reaction time task and eye tracking. Time-series analysis suggested increased neural activity in response to both calorie conditions in the AN groups, consistent with an early AB. Increased activity was observed at 150 ms in the current AN group. Neuronal activity at this latency was at normal level in the recovered group; however, this group exhibited enhanced activity at 320 ms after stimulus. Consistent with previous studies, analysis in source space and behavioral data suggested enhanced attention and cognitive control processes in response to food stimuli in AN. This may enable avoidance of salient food stimuli and maintenance of dietary restraint in AN. A later latency of increased activity in the recovered group may reflect a reversal of this avoidance, with source space and behavioral data indicating increased visual and cognitive processing of food stimuli.

Corrigendum: Society, Organizations and the Brain: Building toward a Unified Cognitive Neuroscience Perspective.

[This corrects the article on p. 289 in vol. 9, PMID: 26042022.].

Enhanced access to early visual processing of perceptual simultaneity in autism spectrum disorders.

We compared judgements of the simultaneity or asynchrony of visual stimuli in individuals with autism spectrum disorders (ASD) and typically-developing controls using Magnetoencephalography (MEG). Two vertical bars were presented simultaneously or non-simultaneously with two different stimulus onset delays. Participants with ASD distinguished significantly better between real simultaneity (0 ms delay between two stimuli) and apparent simultaneity (17 ms delay between two stimuli) than controls. In line with the increased sensitivity, event-related MEG activity showed increased differential responses for simultaneity versus apparent simultaneity. The strongest evoked potentials, observed over occipital cortices at about 130 ms, were correlated with performance differences in the ASD group only. Superior access to early visual brain processes in ASD might underlie increased resolution of visual events in perception.

Magnetoencephalography: fundamentals and established and emerging clinical applications in radiology.

Magnetoencephalography is a noninvasive, fast, and patient friendly technique for recording brain activity. It is increasingly available and is regarded as one of the most modern imaging tools available to radiologists. The dominant clinical use of this technology currently centers on two, partly overlapping areas, namely, localizing the regions from which epileptic seizures originate, and identifying regions of normal brain function in patients preparing to undergo brain surgery. As a consequence, many radiologists may not yet be familiar with this technique. This review provides an introduction to magnetoencephalography, discusses relevant analytical techniques, and presents recent developments in established and emerging clinical applications such as pervasive developmental disorders. Although the role of magnetoencephalography in diagnosis, prognosis, and patient treatment is still limited, it is argued that this technology is exquisitely capable of contributing indispensable information about brain dynamics not easily obtained with other modalities. This, it is believed, will make this technology an important clinical tool for a wide range of disorders in the future.

COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.

BACKGROUND: Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. METHODS: Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. RESULTS: In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. CONCLUSIONS: Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.

Contextual integration the unusual way: a magnetoencephalographic study of responses to semantic violation in individuals with autism spectrum disorders.

Autism is a neurodevelopmental disorder associated with deficits in language and social communication. Behavioural studies indicate abnormal semantic organization in individuals with autism, but little is known about the neural mechanism underlying the processing of language in context. Magnetoencephalography was used to record neural responses in 11 able adults with autism spectrum disorders reading meaningful sentences and sentences ending with a semantically incongruous word (e.g. 'He sent a photo to the trumpet'). Spatially extended evoked signals at 400 ms (N4) and 750 ms (LPC), as well as synchronized gamma-oscillations, provided clear evidence for specific neuronal processes sensitive to sentence context that differed in individuals with autism compared with typically developing individuals (11 healthy volunteers). Amongst other differences, N4 responses following incongruous words were weaker over left temporal cortices, whereas LPC responses to incongruous words and long-latency gamma-oscillations following congruous words were stronger over central and prefrontal regions in individuals with autism compared with the control group. Also, incongruous words elicited long-lasting gamma-oscillations above 40 Hz in the clinical group, but not in typically developing subjects. These findings may indicate unusual strategies for resolving semantic ambiguity in autism. Moreover, the observed gamma-band responses provide evidence for sustained cortical synchronization across segregated areas in individuals with autism, contrary to claims that a general deficit in either temporal binding or long-range connectivity may explain autism.

Face- and gaze-sensitive neural responses in children with autism: a magnetoencephalographic study.

Face and gaze processing were studied using magnetoencephalography in 10 children with autism and 10 normally developing children, aged between 7 and 12 years. The children performed two tasks in which they had to discriminate whether images of faces presented sequentially in pairs were identical. The images showed four different categories of gaze: direct gaze, eyes averted (left or right) and closed eyes but there was no instruction to focus on the direction of gaze. Images of motorbikes were used as control stimuli. Faces evoked strong activity over posterior brain regions at about 100 ms in both groups of children. A response at 140 ms to faces observed over extrastriate cortices, thought to be homologous to the N170 in adults, was weak and bilateral in both groups and somewhat weaker (approaching significance) in the children with autism than in the control children. The response to motorbikes differed between the groups at 100 and 140 ms. Averted eyes evoked a strong right lateralized component at 240 ms in the normally developing children that was weak in the clinical group. By contrast, direct gaze evoked a left lateralized component at 240 ms only in children with autism. The findings suggest that face and gaze processing in children with autism follows a trajectory somewhat similar to that seen in normal development but with subtle differences. There is also a possibility that other categories of object may be processed in an unusual way. The inter-relationships between these findings remain to be elucidated.

Face and gaze processing in normally developing children: a magnetoencephalographic study.

Magnetoencephalography (MEG) was used to study the neural mechanisms underlying face and gaze processing in ten normally developing boys aged between 8 and 11 years and 12 adult males. The participants performed two tasks in which they had to decide whether images presented sequentially in pairs, depicted the same person or the same motorbike. In the first task, the participants saw pictures of faces in which the eyes were either open or shut and pictures of motorbikes. In the second task, participants saw pairs of faces with gaze averted to the left or right. In children there was no evidence of the face sensitive, low amplitude short latency (30-60 ms) activity seen previously in adults. A strong, midline posterior response at approximately 100 ms was observed in children, which was earlier and somewhat stronger to faces than to motorbikes; in adults the signal at this latency was weak. A clear face sensitive response was seen in adults at 135 ms, predominantly over the right inferior occipito-temporal regions. Although activity was observed in the children at the same latency, it was less prominent, not lateralized and was evoked similarly by faces and motorbikes. Averted gaze conditions evoked strong right-lateralized activity at approximately 245 ms in children only. These findings indicate that even in middle childhood the neural mechanisms underlying face processing are less specialized than in adults, with greater early activation of posterior occipital cortices and less specific activation of ventral occipito-temporal cortex.

Neuroeconomics--from neural systems to economic behaviour.

Neuroeconomics is a new and highly interdisciplinary field. Drawing from theories and methodologies employed in both economics and neuroscience, it aims at understanding the neural systems supporting and affecting economically relevant behaviour in real-life situations. Although incomplete, the evidence is beginning to clarify with the possibility that neuroeconomic methodology might eventually trace whole processes of economically relevant behaviour. This paper accompanies the author's ConNEcs 2004 keynote speech on applications of neuroeconomic research.

Abnormal activation of face processing systems at early and intermediate latency in individuals with autism spectrum disorder: a magnetoencephalographic study.

The neurological basis of developmental psychopathology in autism is a matter of intense debate. Magnetoencephalography (MEG) was used to study the neuronal responses associated with the processing of faces in 12 able adults with autism spectrum disorders (ASD), performing image categorization and image identification tasks. The neuromagnetic data were analysed using nonparametric time-series analysis and equivalent current dipole estimation. Comparison data were obtained from 22 normally developing adults. In individuals with ASD, the neural responses to images of faces, observed in right extrastriate cortices at approximately 145 ms after stimulus onset, were significantly weaker, less lateralized and less affected by stimulus repetition than in control subjects. Early latency (30-60 ms) responses to face images, over right anterior temporal regions, differed significantly between the two subject groups in the image identification task. No such difference was observed for images of mugs or meaningless geometrical patterns. These findings suggest that, during the course of development in individuals with ASD, the cortical activity associated with the processing of human faces assumes a different-from-normal localization in extrastriate brain regions. This abnormal localization may be associated with unusual, but nevertheless face-specific, fast processing pathways.