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Simultaneous measures of Event Related Potentials (ERP) and electrodermal activity (EDA) allow the delineation of ERPs that did, and did not, evoke an electrodermal 'Orienting Reflex' (OR). The OR is an automatic reflex invoked by novel or significant stimuli. Our group have developed a model to quantify electrodermal OR activity acquired in conventional late component ERP paradigms with short interstimulus intervals. Target late component (N100, P200, N200, P300) ERPs (acquired in an auditory oddball paradigm) and EDA was examined in 15 Parkinson's disease (PD) subjects and 50 normal controls. Single-trial target ERPs were averaged according to whether or not they elicited an electrodermal OR. Compared with controls, the PD group showed significantly decreased N100 and N200 amplitudes in the OR related ERPs ('Orienting ERPs'). These preliminary findings suggest that conventional late component ERPs can be delineated according to whether or not they evoked an OR. The 'orienting ERPs' in PD showed more significant disturbances compared with controls, than ERPs that did not evoke an OR.

Deep dyslexia is an acquired reading disorder that is characterized by the production of semantic reading errors, greater success when reading aloud concrete and highly imageable words, frequent visual and visual-semantic errors, morphological errors and very poor reading of nonwords. The right hemisphere hypothesis proposes that in deep dylsexia the patient is not reading with an impaired version of the normal left hemisphere reading system, and cannot use that system for reading at all. Instead, a different reading system, located in the right hemisphere is used. The right hemisphere hypothesis was examined in this study by investigating the amount of cortical activation in the left and right cerebral hemispheres of a deep dyslexic patient (L.H.) during visual word recognition. Three experimental tasks were devised to isolate a Visual Word Recognition process and a Spoken Word Production process and these tasks were administered to the deep dyslexic patient as well as another patient with left-...

Objective: To examine the individual and combined impact that traumatic brain injury (TBI) and heavy social use of alcohol have on electrophysiologic correlates of working memory and evaluation of task-relevant information. Design: Case-control study Setting: University hospital brain injury rehabilitation unit. Participants: Forty male volunteers divided into four groups on the basis of their history of TBI and alcohol intake. Subjects with TBI had experienced a severe closed head injury at least 1 year before testing. Main Outcome Measure: Event-related potentials (ERPs) and neuropsychometric tests. Results: Groups showed no significant differences in average age or neuropsychological tests. TBI groups did not differ in time postinjury or on severity measures. Alcohol use measures were significantly greater in the two alcohol groups. N200 latency and P300 amplitude were impaired in heavy social drinkers and in nondrinking subjects with TBI relative to controls, but were significantly impaired in subjects with TBI who were also heavy social drinkers. Conclusion: The results indicate that although alcohol use and TBI independently produce mild alterations in some aspects of late ERP components, the ERP changes are significantly greater when alcohol use and TBI are combined. This study provides evidence that heavy social drinking after TBI has a measurable impact on electrophysiologic correlates of cognition.

Late component event related potentials (ERP) and concomitant electrodermal activity (EDA) measures of the orienting reflex (OR) were undertaken in 50 normal subjects. Our group recently developed a model to quantify electrodermal activity in conventional ERP paradigms (auditory oddball) with short interstimulus intervals (ISI). The method was used to classify the presence or absence of skin conductance response following each auditory target stimulus. Using a conventional paradigm in which data is traditionally averaged, single-trial target ERPs were sorted into those with a skin conductance response OR (ERP[+OR]) and those without (ERP[-OR]) an OR, and ERP sub-averages of the two groups were derived. The ERP(+OR) showed significantly larger P300 amplitudes and relatively earlier N200 and P300 latency than those of the ERP(-OR). These findings suggest that using concomitant SCR-ERP measures, separate ERP related processes can be determined, that are complementary to the traditional average measure.

The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3β gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B = 0.082, 95% confidence interval = 0.037-0.128) and intracranial volume (summary B = 0.113, 95% confidence interval = 0.082-0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders.

A core feature of post-traumatic stress disorder (PTSD) is hypervigilence to threatening material. This study measured processing of threat material in PTSD with simultaneously acquired initial eye movements and electrodermal activity, following presentation of threatening and neutral words. Ten PTSD subjects and 10 controls were presented with 4 words in parafoveal range. On trials in which a threat word was present, PTSD subjects demonstrated initial eye fixations on the threat word more than controls. PTSD subjects also demonstrated more orienting responses on all trials than controls. These results suggest that processing of threat information in PTSD can be usefully investigated with convergent psychophysiological methodologies.

This event-related potential study systematically varied the number of nontargets (1, 3, 5, 7, 9) preceding the target tone in an oddball experiment and examined the effect of this on N 2 , P 3 , and reaction time measures in schizophrenic patients and normal volunteers. Schizophrenic patients were found to have reduced P 3 amplitudes, but this reduction was restricted to series when the targets followed an intermediate number (3–7) of nontargets, and not when targets followed a short (1) or long series (9) of nontargets. Although other interpretations of this finding are possible, the pattern of results could be explained by the hypothesis that the refractory period governing the generation of the P 3 component was prolonged in schizophrenia.

The averaging of individual late component event related potential (ERP) responses, particularly P300, has revealed significant differences between schizophrenic patients and normal subjects. However, the averaging process removes the variability of the individual epochs that constitute that average. The response-variance-curve (RVC) method quantifies the variability of the individual epochs and allows examinations of windows of maximum variance. In this study, we examine the complementary nature of the RVC method to the traditional averaging approach. The averaged N200 and P300 ERP components differed significantly between the schizophrenic and normal groups, but not between the unmedicated and medicated schizophrenic patients. The RVC measure, on the other hand, revealed systematic differences in variability, maximal between 190 and 240 ms, between the unmedicated and medicated schizophrenic patients. The RVC measure therefore provides a focused time frame in which to examine dysfunctions in information processing and macroscopic scale changes in brain function due to medication.

The response-variance-curve (RVC) method quantifies the variability of the individual epochs that constitute the average event related potential (ERP), providing complementary information to that offered by ERPs. Numerous studies have found that average ERP late components of an auditory "oddball" paradigm can differentiate schizophrenic patients from normal subjects. Our previous study of the RVC measure revealed significant differences between medicated and unmedicated schizophrenic patients in the maximum ERP variability from 190 to 240 ms. In the present study of unmedicated schizophrenic patients and normal control subjects, we examined the influence of intertarget intervals (generated by pseudorandom stimulus sequences in an auditory oddball paradigm) on the intratrial effects of ERP variability measured by the RVC. The ERPs of unmedicated schizophrenic patients were characterized by an instability in a latency window corresponding to the N200 component. The effect was particularly large at an intertarget interval of 7.8 s and was significantly reduced on either side of this intertarget interval.

Examination of the single trials which are traditionally averaged to form late-component ERPs reveals a number of different sub-types of response. This study introduces an automated and robust approach to objectively classify these ERP sub-types. Auditory oddball ERP (target tones) data were examined in 25 normal subjects. Globally optimal vector quantization using simulated annealing (the “Metropolis algorithm”) was employed to determine the natural groupings of the single-trial responses that constitute the average ERP. No prior assumptions about the ERP patterns were imposed. This is the first study to employ a cluster analysis technique with globally optimal properties in ERP research. We demonstrate that, due to the presence of many different undesirable local minima, a globally optimal solution is crucial if the classification of the single-trial ERPs is to reflect their real structure. The results of this study showed that only around 40% of single trials had a morphology which resembled the averaged ERP wave form. The remaining single trials had a response morphology which was different from the average, in terms of the amplitude and latency of the components. Single-trial ERP response sub-types may provide fundamental complementary functional information to the ERP average.

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This study explores SPECT measured in schizophrenic patients at rest. Left temporal lobe activity was found to be decreased with increasing positive symptom's scores scores. Medicated patients showed a reversal of this pattern underlying this positive symptom effect. Patients with a recent history of auditory hallucinations showed an atypical right temporal lobe dominance, which occurred independently of medication status. These preliminary data are suggestive of the potential utility of SPECT to elucidate symptom/medication/brain activity interrelationships in schizophrenia.

A number of measures of brain function have suggested that depression is associated with cerebral hypoactivity. This study examines the late components of the event-related potential (ERP), in particular the P300 component, in depression. The P300 component is thought to index the updating of neurocognitive models which are concerned with the prediction of future events. Cognitive theories of depression include the proposition that depression may be characterized by abnormalities in the prediction of future events. The P300 component may therefore provide one neurophysiological index of cognitive dysfunction in depression. Twenty-seven subjects (14 medicated, 13 drug-free) fulfilling DSM-III criteria for Major Depression were compared to 27 age- and sex-matched normal controls. The amplitudes and latencies of N100, P200, N200 and P300 ERP components, reaction time and task accuracy were recorded during a standard auditory discrimination task. No significant differences were found in any ERP component measure or in reaction-time between the groups. Depressed subjects performed the experimental task significantly less accurately than normal controls, but this was not reflected in the ERPs.

Few standardized tools are available for time-efficient screening of emotional health status across diagnostic categories, especially in primary care. We evaluated the 45-question Brief Risk-resilience Index for SCreening (BRISC) and the 15-question mini-BRISC in identifying poor emotional health and coping capacity across a range of diagnostic groups – compared with a detailed clinical assessment – in a large sample of adult outpatients. Participants 18–60 years of age (n = 1079) recruited from 12 medical research and clinical sites completed the computerized assessments. Three index scores were derived from the full BRISC and the mini-BRISC: one for risk (negativity–positivity bias) and two for coping (resilience and social capacity). Summed answers were converted to standardized z-scores. BRISC scores were compared with detailed health assessment and diagnostic interview (for current psychiatric, psychological, and neurological conditions) by clinicians at each site according to diagnostic criteria. Clinicians were blinded to BRISC scores. Clinical assessment stratified participants as having “clinical” (n = 435) or “healthy” (n = 644) diagnostic status. Receiver operating characteristic analyses showed that a z-score threshold of −1.57 on the full BRISC index of emotional health provided an optimal classification of “clinical” versus “healthy” status (sensitivity: 81.2%, specificity: 92.7%, positive predictive power: 80.2%, and negative predictive power: 93.1%). Comparable findings were revealed for the mini-BRISC. Negativity–positivity bias index scores contributed the most to prediction. The negativity–positivity index of emotional health was most sensitive to classifying major depressive disorder (100%), posttraumatic stress disorder (95.8%), and panic disorder (88.7%). The BRISC and mini-BRISC both offer a brief, clinically useful screen to identify individuals at risk of disorders characterized by poor emotion regulation, from those with good emotional health and coping.

This study investigated attention (P300 amplitude) and orienting (skin conductance amplitude) to auditory tones in a standard oddball task in early trauma-exposed groups (Acute Stress Disorder: ASD) (n=12) or no ASD (n=13), compared to individuals with chronic posttraumatic stress disorder (PTSD) (n=17) and non-trauma-exposed controls (n=17). Individuals with ASD displayed significantly higher SCR and P3 amplitudes to target tones than individuals with PTSD, non-traumatized controls, and traumatized controls. These findings suggest that attention and orienting responses are greater to neutral, task-relevant target tones in ASD than PTSD and traumatized and non-traumatized controls.

Contains fulltext : 99540.pdf (Publisher’s version ) (Open Access) Chronic pain has been associated with impaired cognitive function. We examined cognitive performance in patients with severe chronic pancreatitis pain. We explored the following factors for their contribution to observed cognitive deficits: pain duration, comorbidity (depression, sleep disturbance), use of opioids, and premorbid alcohol abuse. The cognitive profiles of 16 patients with severe pain due to chronic pancreatitis were determined using an extensive neuropsychological test battery. Data from three cognitive domains (psychomotor performance, memory, executive functions) were compared to data from healthy controls matched for age, gender and education. Multivariate multilevel analysis of the data showed decreased test scores in patients with chronic pancreatitis pain in different cognitive domains. Psychomotor performance and executive functions showed the most prominent decline. Interestingly, pain duration appeared to be the strongest predictor for observed cognitive decline. Depressive symptoms, sleep disturbance, opioid use and history of alcohol abuse provided additional explanations for the observed cognitive decline in some of the tests, but to a lesser extent than pain duration. The negative effect of pain duration on cognitive performance is compatible with the theory of neurodegenerative properties of chronic pain. Therefore, early and effective therapeutic interventions might reduce or prevent decline in cognitive performance, thereby improving outcomes and quality of life in these patients. 9 p.

Background Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators. Methods/Design The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm. Discussion First enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide. Trial registration International Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849 URL: http://clinicaltrials.gov/ct2/show/NCT00693849?term=International+Study+to+Predict+Optimized+Treatment+for+Depression&rank=1

The present experiment was carried out to investigate elicitation and habituation of the electrodermal Orienting Response with stimulus trains utilising a short interstimulus interval (ISI) of 1.1 s. We sought evidence for within-train response decrement to repeated stimulus presentation, response recovery to a change stimulus and dishabituation following the change stimulus — the three properties necessary to unequivocally identify a decremental process as habituation. No autonomic study could be found using such a short ISI. Autonomic studies on this time scale are necessary if these measures are to be integrated with central event-related potential (ERP) measures of electrical brain function. Overcoming this paradigm gap required the development of novel measurement procedures to estimate the small electrodermal responses obtained, usually occurring on the recovery slope of the response to the previous stimulus in the train. With our novel measurement procedures, evidence was found indicating that electrodermal activity in such a paradigm exhibited the three classic criteria of habituation.

White matter (WM) has been shown to be affected in elderly patients with major depressive disorders (MDD). There is only limited evidence of WM structural abnormalities in nongeriatric MDD patients. This study investigates WM microstructural integrity in nongeriatric MDD patients recruited as part of the International Study to Predict Optimized Treatment in Depression clinical trial and establishes the validity of diffusion tensor imaging measures for the investigation of depression. Baseline diffusion tensor imaging data from 29 nongeriatric MDD participants (11 with melancholia) and 39 healthy control participants were used in this analysis. We performed tract‐based spatial statistics analyses to evaluate WM microstructural integrity (1) between all healthy controls and all MDD participants, (2) between melancholic and nonmelancholic MDD participants, and (3) between each subgroup (melancholic and nonmelancholic) and controls. Significant WM integrity deficits were seen only for the melancholic MDD participants compared with controls. Compared with controls, melancholic participants showed an average reduction of 7.8% in fractional anisotropy over WM regions associated with the limbic system, dorsolateral prefrontal cortex, thalamic projection fibers, corpus callosum, and other association fibers. These fractional anisotropy deficits were also associated with decreased axial and increased radial diffusivity in these WM regions, suggesting a pattern of decreased myelination or other degeneration change. Our findings of WM structural abnormalities associated with the limbic system, the frontal cortex, and the thalamus support the prevailing theory of limbic‐dorsolateral prefrontal cortex‐thalamic dysfunction in depression. Our results also suggest that these deficits are most prominent in the melancholic subtype of MDD. Hum Brain Mapp, 2011. © 2010 Wiley Periodicals, Inc.

The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42CT polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing.Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed.The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident.These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.

Background: Identification of the biological markers of anorexia nervosa (AN) is crucial for the development of new treatments. We aimed to determine whether AN is associated with disturbances in the nonconscious neural processing of innate signals of emotion and whether these disturbances persist after weight gain. Methods: In a retest design, 28 adolescent females with AN were tested at first admission to hospital and again after they had gained weight. Matched healthy control participants were tested at the same times. We assessed emotion-elicited event-related potentials (ERPs) during overt and covert presentation of emotion expressions, scores on an emotion-identification behavioural task, and symptom measures. We performed between and within group analyses. Results: Individuals with AN had a marked alteration in ERPs relative to healthy controls. Irrespective of the form of stimulus, early and late ERP components were significantly reduced in AN patients at baseline (when underweight) and on retest (after weight gain), especially in the temporo-occipital regions, suggesting a persistent disruption of the early automatic appraisal of salient emotional signals. Limitations: This study could have been improved with a longer standardized retest interval. Conclusion: There is likely a core, generic disturbance in AN in the early “automatic” neural processing of emotion irrespective of weight or nutritional status. New innovative emotion-based psychologic or pharmacologic treatments targeting these nonconscious processes may prove beneficial.

Objective: To examine resting awake EEG in adolescent AN participants before and after refeeding to determine if EEG abnormalities in Anorexia Nervosa (AN) are reversible. Method: In 37 adolescent first admission AN patients and 45 healthy controls, EEG was recorded during short duration “eyes open” and “eyes closed” awake resting conditions. Repeat testing occurred in 28 AN participants after refeeding and subsequent weight gain. Results: In “eyes open,” underweight AN participants exhibit reduced relative alpha power and increased beta power in frontal brain regions. A significant increase in alpha, and decrease in beta and delta power was observed within participants after refeeding. In “eyes closed”, underweight AN participants had elevated theta in parietal-occipital regions which remained after refeeding. Discussion: EEG abnormalities (reduced alpha/increased beta power) in AN normalizes with refeeding, while increased theta power persists in parietal-occipital regions in an eyes closed context. © 2010 by Wiley Periodicals, Inc. (Int J Eat Disord 2011; 44:65–75)

This study examined the N100 component of the event related potential in a habituation paradigm with shorrt interstimulus intervals. The paradigm was designed to be relatively brief in duration (approx. 4 min for each of two conditions), so that it could be used for clinical populations with cognitive dysfunction, in which compliance may be a problem with long paradigms. Two conditions — Ignore and Attend — were employed with normal subjects. In each condition, 15 stimulus trains, each consisting of 10 innocuous tones, were presented. The eighth tone was a change stimulus. There was a fixed interstimulus interval of 1.1 s and an inter-train interval of 5 s. From the perspective of traditional Orienting Response theory, evidence was sought for within-train habituation in terms of diminished N100 amplitude to repeated stimuli, response recovery to the change stimulus, and dishabituation of the response to the following standard stimuli. Habituation was suggested by significant decreases of approx. 50% with stimulus repetition, and response recovery to the change stimulus in both conditions. However, there was no evidence of dishabituation following the change stimulus. These results confirm that N100 fails to meet the formal requirements of response habituation, suggesting instead that it may index an earlier process than the Orienting Response.

A number of studies have suggested that schizophrenics fail to integrate complex information in the eadier phases of processing. Studies such as Frith et al (1983) have compared schizophrenics and normals on their ability to sort faces and socially meaningless obi~cts. These authors concluded that the schizophrenics' perception of faces was essentially by sequential composition of features, in contrast to a more integrated gestalt approach undertaken by the normals. Eye-movement parameters have been shown to reflect asr, ects of attention and cognition (Just and Carpenter 1976; Rayner 1978). Fixations, defined as consecutive gaze positions within a narrow area, related closely to the recall of information in a complex picture (Rayner 1978). Only two previous studies have examined the eye movements of schizophrenics in a "free-viewing" task. Gaebel et al (1987) examined eye movements over a l-min period in response to a hand-drawn complex picture, and showed that schizophrenics with pronounced negative symptoms exhibited "minimal scanning" behavior, whereas schizophrenics with pronounced positive symptoms exhibited ~'extenswe scanning"

Objective Novelty and routinization-related information processing disturbances were examined in adolescent males with ADHD using an oddball paradigm and electrophysiological measurement of theta (4–7 Hz) activity. Methods Fifty-four unmedicated adolescent males (12–18 years) with Attention Deficit Hyperactivity Disorder (ADHD) and matched controls performed an auditory oddball task. Theta activity was sub-averaged, and Fourier Integrals with simultaneous measurement of electrodermal activity (EDA) was used to index response to stimulus novelty and routinization. Results ADHD participants showed an overall increase in theta activity to both novel and routine stimuli relative to controls. While controls showed increased theta activity in response to novel compared to routine targets across the brain, ADHD participants did not show this novelty-related increase in theta activity in the right anterior/frontal brain. Conclusions The findings of this study are consistent with disturbances in theta activity and the brain substrates of novelty relative to routinization-related processing in ADHD. Significance These findings show that there are distinct alterations in theta activity related to stimulus novelty and routinization during an auditory oddball task in ADHD, and they highlight the value of using an event-related approach to elucidate the neural substrates of stimulus processing in ADHD.

Measures of cognition support diagnostic and treatment decisions in attention deficit hyperactivity disorder. We used an integrative neuroscience framework to assess cognition and associated brain-function correlates in large attention deficit hyperactivity disorder and healthy groups. Matched groups of 175 attention deficit hyperactivity disorder children/adolescents and 175 healthy control subjects were assessed clinically, with the touch screen-based cognitive assessment battery "IntegNeuro" (Brain Resource Ltd., Sydney, Australia) and the "LabNeuro" (Brain Resource Ltd., Sydney, Australia) platform for psychophysiologic recordings of brain function and body arousal. IntegNeuro continuous performance task measures of sustained attention classified 68% of attention deficit hyperactivity disorder patients with 76% specificity, consistent with previous reports. Our additional cognitive measures of impulsivity, intrusive errors, inhibition, and response variability improved sensitivity to 88%, and specificity to 91%. Positive predictive power was 96%, and negative predictive power, 88%. These metrics were stable across attention deficit hyperactivity disorder subtypes and age. Consistent with their brain-based validity, cognitive measures were correlated with corresponding brain-function and body-arousal measures. We propose a combination of candidate cognitive "markers" that define a signature for attention deficit hyperactivity disorder: "sustained attention," "impulsivity," "inhibition," "intrusions," and "response variability." These markers offer a frame of reference to support diagnostic and treatment decisions, and an objective benchmark for monitoring outcomes of interventions.

Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial sample of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120-280ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression.

The INTEGRATE Model draws on the framework of ‘integrative neuroscience’ to bring together brain–body and behavioral concepts of emotion, thinking and feeling and their regulation. The key organizing principle is the drive to ‘minimize danger and maximize reward’ that determines what is significant to us at each point in time. Traits of ‘negativity bias’ reflect the tendency to perceive danger rather than reward related information, and this bias influences emotion, thinking and feeling processes. Here, we examined a self-report measure of Negativity Bias in relation to its impact on brain and body correlates of emotion processing. The contributions of the serotonin transporter (5-HTT-LPR) allelic variants and early life stress to both negativity bias and these correlates were also examined. Data were accessed in collaboration with the Brain Resource International Database (BRID) which provides standardized data across these domains of measurement. From an initial sample of 303 nonclinical subjects from the BRID, subjects scoring one standard deviation below (n = 55) and above (n = 47) the mean on the measure of negativity bias were identified as ‘Negativity Bias’ and ‘Positivity Bias’ groups for analysis, respectively. These subjects had been genotyped for 5-HTT-LPR Short allele versus LL homozygote status, and completed the early life stress scale, and recording of startle responses and heart rate for conscious and nonconscious fear conditions. A matched subset (n = 39) of BRID subjects completed functional MRI with the same facial emotion tasks. The Negativity Bias (compared to Positivity Bias) group was distinguished by both arousal and brain function correlates: higher startle amplitude, higher heart rate for conscious and nonconscious fear conditions, and heightened activation in neural circuitry for both fear conditions. Regions of heightened activation included brainstem and bilateral amygdala, anterior cingulate and ventral and dorsal medial prefrontal cortex (mPFC) for conscious fear, and brainstem and right-sided amygdala, anterior cingulate and ventral, mPFC for nonconscious fear. The 5-HTT-LPR Short allele (versus LL) conferred a similar pattern of arousal and neural activation. For those with the 5-HTT-LPR Short allele, the addition of early life stress contributed to enhanced negativity bias, and to further effects on heart rate and neural activation for nonconscious fear in particular. These findings suggest that traits of negativity bias impact brain–body arousal correlates of fear circuitry. Both genetic variation and life stressors contribute to the impact of negativity bias. Given that negativity bias is a feature of conditions such as depression and associated biological alterations, the findings have implications for translation into clinical decision support.

Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P=0.005) and symptoms (depression and anxiety, P

Attentional impairment in depression is a cardinal feature of depression and has been proposed as a candidate endophenotype for major depressive disorder. Event‐related potentials (ERPs) elicited by oddball signal detection tasks provide objective markers of selective stimulus processing, and are pertinent endophenotypic markers for depression. While previous studies have sought to determine objective markers for attentional impairment in depression, evidence is inconsistent and may involve heterogeneity in relatively small samples. Here, we brought together oddball ERP recording with source localization of neural correlates of selective attention in outpatients with major depressive disorder (MDD; n = 78) and participants with depressed mood (PDM; n = 127) relative to healthy controls (CTL; n = 116). The key finding was a dimensional exaggeration of the P200 (140–270 ms) to both target (signal) and non‐target (noise) stimuli, most pronounced in MDD, followed by PDM, relative to CTL. This exaggeration was coupled with slower and more variable response times, suggesting that neural systems are attempting to compensate for a difficulty in discriminating signal from noise. P200 alterations were localised to limbic (hippocampal), temporal and ventral prefrontal regions, key components of the signal detection network. A subsequent reduction and delay in the P300 was also revealed for MDD indicating that the pronounced lack of discrimination in clinical depression may also lead to impaired stimulus evaluation. This P200 increase in depression could provide a potential mechanism for the attentional impairment frequently observed in depression and consequent alterations in the P300 may differentiate clinically significant depression. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

Reduced ventral anterior cingulate (vACC) activity to threat is thought to reflect an impairment in regulating arousal networks in posttraumatic stress disorder (PTSD). Concurrent functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) recording were used to examine neural functioning when arousal networks are engaged. Eleven participants with PTSD and 11 age- and sex-matched non-traumatized controls performed an oddball task that required responding to salient, non-trauma-related auditory target tones embedded in lower frequency background tones. Averaged target-background analyses revealed significantly greater dorsal ACC, supramarginal gyrus, and hippocampal activity in PTSD relative to control participants.With-SCR target responses resulted in increased vACC activity in controls, and dorsal ACC activity in PTSD. PTSD participants had reduced vACC activity relative to controls to target tones when SCR responses were present. This reduction in vACC in PTSD relative to controls was not apparent in without-SCR responses. These findings suggest that a reduction in vACC in PTSD occurs specifically when arousal networks are engaged.

Research is needed that investigates the correlates of emotional intelligence (EI) as a function of sex, especially biological and psychological correlates such as personality, brain activity, cognitions and mood. A large group of healthy males and females were tested for EI, personality, mood, cognitive function, brain activity and heart rate variability. Females were found to have slightly higher EI scores than males while a similar profile of personality was found to predict EI in both sexes. Factors like extraversion, conscientiousness and openness were found to contribute positively to EI in both sexes, meaning a higher level of emotional capacity was associated with a person who is outgoing, dependable, and independent-minded. Cortical under-arousal contributed to low EI in both males and females, consistent with the proposal that somatic markers are needed to guide human behaviour. While frontal asymmetry was associated with low EI in females, the contribution of this finding to overall variance in EI was small (1%) and should be treated with caution. Overall, findings suggest that personality and brain activity factors are correlates of EI that may contribute to individual differences in EI manifest in males and females. © 2008 Elsevier Ltd. All rights reserved.

Previous body image studies have suggested that dieting-disordered patients (anorexia and bulimia nervosa) differ from normal subjects in their estimation of body size and desired body shape. It was hypothesized that overconcern with body shape in these patients would be reflected in their visual analyses of specific parts of their bodies. This hypothesis was investigated using a system that combines an infrared light source, video camera, dedicated microprocessor, and computer to monitor eye-gaze direction at 50 times per second. Fifteen dieting-disordered patients and 10 control subjects were examined in this way while simultaneously being shown a picture of themselves on a TV screen. Preliminary results suggest that the patients tend to focus on those parts of their body with which they are dissatisfied, while normal subjects scan their whole body shape. Objective assessment of areas of specific bodily concern among dieting-disordered patients, as well as the examination of voluntary and involuntary processing of self-referential stimuli, is offered by the use of such technology.

The effects of age on event-related potentials (ERPs) elicited during a two-tone discrimination (“oddball”) task were examined in 97 normal subjects aged from 17–80 years. Strong relationships were found between age and the latencies of the later ERP components N200 and P300. Furthermore the correlation between age and N200 latency at Pz was marginally higher than that of age and P300 latency. For the entire sample, the increase in P300 latency as a function of age was best described at Cz and Pz by linear regression equations. However, a segmented line model better described the P300/age relationship at Fz — the increase in P300 latency with age in subjects over 61 was five times that of subjects younger than 61 years. In this study the task required button-press identification of the targets — the significance of increased age and a delay in N200 latency is discussed with reference to the possibility of N200 latency indexing the speed of cognitive processing.

There is a growing evidence that elevated body mass index (BMI) is associated with adverse neurocognitive outcome, though no study has examined whether morphometric differences are found in persons across the adult life span. We compared 201 healthy individuals in normal weight, overweight, and obese groups (aged 17-79). After correcting for demographic differences, obese individuals showed smaller whole brain and total gray matter volume than normal weight and overweight individuals. These findings support an independent relationship between BMI and brain structure and demonstrate that these differences are not limited to older adults.

Posttraumatic stress disorder (PTSD) involves deficits in information processing that may reflect hypervigilence and deficient inhibitory control. To date, however, no PTSD neuroimaging study has directly examined PTSD-related changes in executive inhibition. Our objective was to investigate the hypothesis that executive inhibitory control networks are compromised in PTSD.Functional magnetic resonance imaging (fMRI) was used during a Go/No-Go inhibition task completed by a sample of patients with PTSD (n = 23), a matched sample of healthy (i.e. without trauma exposure) control participants (n = 23) and a sample of control participants with trauma exposure who did not meet criteria for PTSD (n = 17).Participants with PTSD showed more inhibition-related errors than did individuals without trauma exposure. During inhibition, control participants activated a right-lateralized cortical inhibitory network, whereas patients with PTSD activated only the left lateral frontal cortex. PTSD was associated with a reduction in right cortical activation and increased activation of striatal and somatosensory regions.The increased inhibitory error and reduced right frontal cortical activation are consistent with compromised inhibitory control in PTSD, while the increased activation of brain regions associated with sensory processing and a greater demand on inhibitory control may reflect enhanced stimulus processing in PTSD, which may undermine cortical control mechanisms.

Both general and social cognition are important in providing endophenotypic markers and predicting real-world functional outcomes of clinical psychiatric disorders. However, to date, focus has been on general cognition, rather than on core domains of social/emotional cognition. This study sought to determine core domains of emotion processing for both explicit identification and implicit recognition and their relationships with core domains of general cognition. Age effects and sex differences were also investigated. A sample of 1,000 healthy individuals (6 to 91 years, 53.5% female) undertook the WebNeuro tests of emotion identification and recognition and tests of general cognitive function. Factor analysis revealed seven core domains of emotion processing: speed of explicit emotion identification, speed of implicit emotion recognition, implicit emotion recognition accuracy, "threat" processing, sadness-disgust identification, "positive emotion" processing, and general "face perception." Seven corresponding core domains of general cognition were identified: information-processing speed, executive function, sustained attention/vigilance, verbal memory, working-memory capacity, inhibition/impulsivity, and sensorimotor function. Factors of emotion processing generally showed positive associations with those of general cognitive function, suggesting commonality in processing speed in particular. Moreover, age had a consistent nonlinear impact on both emotion processing and general cognitive factors, while sex differences were more specific. These findings contribute to a normative and standardized structure for assessment of emotional and general cognition in clinical groups.

The aim of the paper is to describe a standardized "Integrative Neuroscience" Platform that can be applied to elucidate brain-body mechanisms. This infrastructure includes a theoretical integration (the INTEGRATE Model). To demonstrate this infrastructure, hypotheses from the INTEGRATE Model are applied in an example investigation of the cognitive, brain and body markers of individual differences in the trait characteristic of Negativity Bias (the tendency to see oneself and one's world as negative). A sample of 270 healthy participants (18-65 years old) were grouped into equal sized matched subsets of high "Negativity Bias" and high "Positivity Bias" (n = 135 in each group). Participants were assessed using a standardized battery of psychological traits, cognition and brain and body (autonomic) activity. Greater "Negativity Bias" relative to "Positivity Bias" was characterized by greater autonomic reactivity and early neural excitation to signals of potential danger, at the timescale of Emotion (200 ms). Concomitantly, there was a relatively lower level of "Thinking", reflected in cognitive dimensions and associated electrical brain measures of working memory and EEG Theta power. By contrast, Negativity and Positivity Bias did not differ in levels of emotional resilience and social skills at the longer time scale of Self Regulation. This paper provides a demonstration of how an Integrative Neuroscience infrastructure can be used to elucidate the brain-body basis of trait characteristics, such as Negativity Bias, that are key indicators of risk for poor well-being and psychopathology.

Schizophrenia may be understood as a disorder of neural synchrony. There is also increasing evidence that emotional and social cognitive impairments are central to this disorder. In patients with first-episode schizophrenia, we examined whether emotion perception is associated with disruptions to high-frequency (40 Hz) gamma synchrony and whether these disruptions predict self-regulatory adaptive compensations reflected in social cognitive behaviours.We obtained electroencephalography recordings from 28 patients with first-episode schizophrenia and matched healthy controls during perception of facial emotion under both conscious and nonconscious conditions. We extracted gamma-band synchrony from the electroencephalogram. We also used behavioural measures of emotion identification, emotional intelligence, negativity bias and social function, along with ratings of first-episode schizophrenia symptoms. We analyzed group differences and predicted social cognition to assess the potential contribution of medication.Within 200 ms poststimulus, patients with first-episode schizophrenia showed alterations in gamma synchrony during both conscious and nonconscious emotion perception. Stimulus-locked synchrony was reduced in patients, particularly over the temporal cortex, whereas complementary enhancements in absolute gamma synchrony (independent of stimuli) were more distributed over temporal and left parieto-occipital regions. This pattern of altered synchrony predicted poor performance on each measure of social cognition among these patients. Medication dosage did not correlate significantly with either gamma synchrony or behavioural measures in this group.Limitations to our study include the lack of comparison between medicated and unmedicated patients or between types of medication.These findings suggest that disruptions in integrative processing of motivationally important stimuli show promise as a potential biological marker of social cognitive impairments, present from the first episode of schizophrenia, and their outcomes.

This study was undertaken using the INTEGRATE Model of brain organization, which is based on a temporal continuum of emotion, thinking and self regulation. In this model, the key organizing principle of self adaption is the motivation to minimize danger and maximize reward. This principle drives brain organization across a temporal continuum spanning milliseconds to seconds, minutes and hours. The INTEGRATE Model comprises three distinct processes across this continuum. Emotion is defined by automatic action tendencies triggered by signals that are significant due to their relevance to minimizing danger-maximizing reward (such as abrupt, high contrast stimuli). Thinking represents cognitive functions and feelings that rely on brain and body feedback emerging from around 200 ms post-stimulus onwards. Self regulation is the modulation of emotion, thinking and feeling over time, according to more abstract adaptions to minimize danger-maximize reward. Here, we examined the impact of dispositional factors, age and genetic variation, on this temporal continuum. Brain Resource methodology provided a standardized platform for acquiring genetic, brain and behavioral data in the same 1000 healthy subjects. Results showed a "paradox" of declining function in the "thinking" time scale over the lifespan (6 to 80+ years), but a corresponding preservation or even increase in automatic functions of "emotion" and "self regulation". This paradox was paralleled by a greater loss of grey matter in cortical association areas (assessed using MRI) over age, but a relative preservation of subcortical grey matter. Genetic polymorphisms associated with both healthy function and susceptibility to disorder (including the BDNFVal(66)Met, COMTVal(158/108)Met, MAOA and DRD4 tandem repeat and 5HTT-LPR polymorphisms) made specific contributions to emotion, thinking and self regulatory functions, which also varied according to age.

Altered hippocampal volume, the brain‐derived neurotrophic factor (BDNF) Val66Met polymorphism, and neuroticism have each been implicated in the etiology of psychiatric disorders, especially depression. However, the relationship between these variables is not well understood. Here, we determined the effects of the BDNF Val66met polymorphism on the five‐factor personality dimensions (assessed using the NEO‐FFI), trait depression (assessed with the DASS‐21) in a cross‐sectional cohort of 467 healthy volunteers. A large matched subset of this cohort was also assessed for grey matter volume of the hippocampus and contiguous temporal cortical regions using magnetic resonance imaging. In Met carriers, elevations in neuroticism and trait depression and stress were associated with lower mean hippocampal volume, but there were no such associations in Val homozygotes. Trait depression, in particular, was found to moderate the effects of BDNF genotypes on hippocampal volume. Met carriers with high trait depression showed a reduction in grey matter volume of the mean hippocampus compared with Val homozygotes. These findings suggest that even in otherwise healthy subjects, trait depression may contribute to the susceptibility of Met carriers to hippocampal grey matter loss. Hum Brain Mapp 2009. © 2008 Wiley‐Liss, Inc.

There is overlap between the behavioural symptoms and disturbances associated with Attention-Deficit/Hyperactivity Disorder (AD/HD) and sleep problems. The aim of this study was to examine the extent of overlap in cognitive and electrophysiological disturbances identified in children experiencing sleep problems and children with AD/HD or both. Four groups (aged 7-18) were compared: children with combined AD/HD and sleep problems (n = 32), children with AD/HD (n = 52) or sleep problems (n = 36) only, and children with neither disorder (n = 119). Electrophysiological and cognitive function measures included: absolute EEG power during eyes open and eyes closed, event-related potential (ERP) components indexing attention and working memory processes (P3), and a number of standard neuropsychological tests. Children with symptoms of both AD/HD and sleep problems had a different profile from those of children with either AD/HD or sleep problems only. These findings suggest it is unlikely that disturbances in brain and cognitive functioning associated with sleep problems also give rise to AD/HD symptomatology and consequent diagnosis. Furthermore, findings suggest that children with symptoms of both AD/HD and sleep problems may have a different underlying aetiology than children with AD/HD-only or sleep problems-only, perhaps requiring unique treatment interventions.

Summary: This study investigated whether children and adolescents diagnosed with the predominantly inattentive and combined subtypes of attention deficit/hyperactivity disorder (AD/HD-in and AD/HD-com, respectively) differed on psychophysiological indices of working memory updating off- and on-stimulant medication, as compared with control subjects and each other. ERPs were recorded in AD/HD and control participants during a one-back working memory task. The N100 (discrimination), P150 (selection), N300 (memory retrieval), and P450wm (updating) components after nontarget stimuli, which served to update working memory with target identity, were assessed. Premedication abnormalities were obtained for the N300 component, delayed in the child AD/HD-com group, and attenuated in the adolescent AD/HD-in group and P450wm component for all AD/HD groups, expressed as either delayed latency and/or attenuated amplitude. ERP abnormalities were predominantly ameliorated after stimulant medication. There were no psychophysiological differences between the subtypes. A general feature of the disorder relates to a deficit in the conscious updating of working memory systems with newly relevant information (P450wm), which varies with age and subtype. Children with AD/HD-com and adolescents with AD/HD-in also exhibit abnormalities in the retrieval of relevant prior memories (N300). This study indicates that AD/HD is related to abnormalities in the capacity to modulate the content of working memory stores.

Objective This study examines the utility of new measures of event-related spatio-temporal waves in the EEG as a marker of ADHD, previously shown to be closely related to the P3 ERP in an adult sample. Methods Wave activity in the EEG was assessed during both an auditory Oddball and a visual continuous performance task (CPT) for an ADHD group ranging in age from 6 to 18 years and comprising mostly Combined and Inattentive subtypes, and for an age and gender matched control group. Results The ADHD subjects had less wave activity at low frequencies (∼1 Hz) during both tasks. For auditory Oddball targets, this effect was shown to be related to smaller P3 ERP amplitudes. During CPT, the ∼1 Hz wave activity in the ADHD subjects was inversely related to clinical and behavioral measures of hyperactivity and impulsivity. CPT wave activity at ∼1 Hz was seen to “normalise” following treatment with stimulant medication. Conclusions The results identify a deficit in low frequency wave activity as a new marker for ADHD associated with levels of hyperactivity and impulsivity. Significance The marker is evident across a range of tasks and may be specific to ADHD. While lower ∼1 Hz activity partly accounts for reduced P3 ERPs in ADHD, the effect also arises for tasks that do not elicit a P3. Deficits in behavioral inhibition are hypothesized to arise from underlying dysregulation of cortical inhibition.

This study examined the hypothesis that negative symptoms are associated with abnormalities of smooth pursuit in schizophrenic patients. The pursuit eye movements of 25 subjects with schizophrenia and 25 matched normal control subjects were recorded using an infrared eye tracking system and quantified using the log of signal-to-noise ratio (1n S/N). The severity of negative symptoms within the schizophrenic group was rated using the Scale for the Assessment of Negative Symptoms. Previous findings of pursuit abnormalities among schizophrenic patients as a group were replicated. There was, however, no significant association between the eye tracking dysfunction and the severity of negative symptoms.

A two-tone-discrimination task was used to elicit the P300 component of event-related (brain) potentials (ERPs) from patients with presumed Alzheimer's dementia of mild or moderate severity, depressed patients of older age, and cognitively normal individuals. Although the average P300 latency of the Alzheimer patients was greater than that of the depressed patients, which in turn was greater than that of older aged normals, none of the group differences in latency were statistically significant. Moreover, when latency was examined on an individual basis, less than one-quarter of the Alzheimer patients had an abnormally delayed P300 for their age. Reaction times and the percentage of correct behavioral responses to the tones did distinguish the Alzheimer from the normal group; on both measures the patients' scores were significantly worse. It was concluded that the performance of a simple tone discrimination task requiring a button-press response does not sufficiently tax those cognitive functions impaired in the earlier stages of Alzheimer's dementia to result in abnormally slowed cognitive processing of the kind reflected in P300 latency.