Intrinsic Functional Connectomes Characterize Neuroticism in Major Depressive Disorder and Predict Antidepressant Treatment Outcomes.

BACKGROUND: Antidepressant efficacy in people with major depressive disorder remains modest, yet identifying treatment-predictive neurobiological markers may improve outcomes. While disruptions in functional connectivity within and between large-scale brain networks predict poorer treatment outcome, it is unclear whether higher trait neuroticism, which has been associated with generally poorer outcomes, contributes to these disruptions and to antidepressant-specific treatment outcomes. Here, we used whole-brain functional connectivity analysis to identify a neural connectomic signature of neuroticism and tested whether this signature predicted antidepressant treatment outcome. METHODS: Participants were 226 adults with major depressive disorder and 68 healthy control subjects who underwent functional magnetic resonance imaging and were assessed on clinical features at baseline. Participants with major depressive disorder were then randomized to 1 of 3 commonly prescribed antidepressants and after 8 weeks completed a second functional magnetic resonance imaging and were reassessed for depressive symptom remission/response. Baseline intrinsic functional connectivity between each pair of 436 brain regions was analyzed using network-based statistics to identify connectomic features associated with neuroticism. Features were then assessed on their ability to predict treatment outcome and whether they changed after 8 weeks of treatment. RESULTS: Higher baseline neuroticism was associated with greater connectivity within and between the salience, executive control, and somatomotor brain networks. Greater connectivity across these networks predicted poorer treatment outcome that was not mediated by baseline neuroticism, and connectivity strength decreased after antidepressant treatment. CONCLUSIONS: Our findings demonstrate that neuroticism is associated with organization of intrinsic neural networks that predict treatment outcome, elucidating its biological underpinnings and opportunity for better treatment personalization.

Antidepressant side effects and their impact on treatment outcome in people with major depressive disorder: an iSPOT-D report.

Side effects to antidepressant medications are common and can impact the prognosis of successful treatment outcome in people with major depressive disorder (MDD). However, few studies have investigated the severity of side effects over the course of treatment and their association with treatment outcome. Here we assessed the severity of side effects and the impact of treatment type and anxiety symptoms over the course of treatment, as well as whether side effects were associated with treatment outcome. Participants were N = 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic MDD. Participants were randomised to receive escitalopram, sertraline, or venlafaxine-extended release with equal probability and reassessed at 8 weeks regarding Hamilton Rating Scale Depression (HRSD17) and Quick Inventory of Depressive Symptomatology (QIDS-SR16) remission and response. Severity of side effects were assessed using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale and assessed at day 4 and weeks 2, 4, 6, and 8. Frequency, intensity, and burden of side effects were greatest at week 2, then only frequency and intensity of side effects gradually decreased up to week 6. Treatment type and anxiety symptoms did not impact the severity of side effects. A greater burden-but not frequency or intensity-of side effects was associated with poorer treatment outcome and as early as 4 days post-treatment. Together, this work provides an informative mapping of the progression of side effects throughout the treatment course and their association with treatment outcome. Importantly, the burden of side effects that are present as early as 4 days post-treatment predicts poorer treatment outcome and should be monitored closely. iSPOT-D: Registry name: ClinicalTrials.gov. Registration number: NCT00693849.

Dimensions of anxiety in Major depressive disorder and their use in predicting antidepressant treatment outcome: an iSPOT-D report.

BACKGROUND: Major depressive disorder (MDD) commonly co-occurs with clinically significant levels of anxiety. However, anxiety symptoms are varied and have been inconsistently associated with clinical, functional, and antidepressant treatment outcomes. We aimed to identify and characterise dimensions of anxiety in people with MDD and their use in predicting antidepressant treatment outcome. METHOD: 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic, MDD were assessed at baseline on clinical features and cognitive/physiological functioning. Participants were then randomised to one of three commonly prescribed antidepressants and reassessed at 8 weeks regarding symptom change, as well as remission and response, on the 17-item Hamilton Rating Scale Depression (HRSD17) and the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16). Exploratory factor analysis was used on items from scales assessing anxiety symptoms, and resulting factors were assessed against clinical features and cognitive/physiological functioning. Factors were also assessed on their ability to predict treatment outcome. RESULTS: Three factors emerged relating to stress, cognitive anxiety, and somatic anxiety. All factors showed high internal consistency, minimal cross-loadings, and unique clinical and functional profiles. Furthermore, only higher somatic anxiety was associated with poorer QIDS-SR16 remission, even after adjusting for covariates and multiple comparisons. CONCLUSIONS: Anxiety symptoms in people with MDD can be separated onto distinct factors that differentially respond to treatment outcome. Furthermore, these factors do not align with subscales of established measures of anxiety. Future research should consider cognitive and somatic symptoms of anxiety separately when assessing anxiety in MDD and their use in predicting treatment outcome.

Verbal memory predicts treatment outcome in syndromal anxious depression: An iSPOT-D report.

BACKGROUND: Major Depressive Disorder (MDD), anxiety disorders, and high levels of anxious symptoms are associated with impaired cognitive functioning. However, little is known of how cognitive functioning is impaired in people with anxious depression. Here, we compared cognitive functioning between people with anxious depression, non-anxious depression, and healthy controls. We also tested whether anxious depression moderated the relationship between cognitive functioning and treatment outcome. METHODS: 1008 adults with MDD and 336 healthy controls completed IntegNeuro: a computerized cognitive functioning test battery. Participants were then randomised to one of three antidepressants and reassessed at 8 weeks using the 17-item Hamilton Depression Rating Scale (HRSD17) and the 16-Item Quick Inventory of Depressive Symptomatology-Self-Rated for remission and response. Syndromal anxious depression was defined as MDD with a comorbid anxiety disorder. HRSD anxious depression was defined as MDD with a comorbid HRSD17 anxiety/somatisation factor score ≥ 7. RESULTS: Syndromal anxious depression was associated with better psychomotor functioning and poorer working memory, cognitive flexibility and information processing speed compared to their non-anxious counterparts. HRSD anxious depression was associated with better psychomotor functioning compared to their non-anxious counterparts. Syndromal anxious depression moderated the relationship between verbal memory and treatment outcome. In people with syndromal anxious depression, poorer baseline verbal memory predicted poorer treatment outcome. LIMITATIONS: As DSM-IV criteria was used, the DSM-5 anxious distress specifier characterisation of anxious depression could not be assessed CONCLUSIONS: Syndromal anxious depression is characterised by impaired executive functions and moderates the relationship between verbal memory functioning and treatment outcome.

Characterising anxiety in major depressive disorder and its use in predicting antidepressant treatment outcome: An iSPOT-D report.

OBJECTIVE: Major depressive disorder commonly co-occurs with one or more anxiety disorders or with clinically significant levels of anxiety symptoms. Although evidence suggests that anxious forms of depression are prognostic of poorer antidepressant outcomes, there is no clear definition of anxious depression, and inferences about clinical outcomes are thus limited. Our objective was to compare and evaluate definitions of anxious depression and anxiety-related scales according to clinical and antidepressant outcome criteria. METHOD: A total of 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic, major depressive disorder were assessed at baseline on clinical features. Participants were then randomised to one of three antidepressants and reassessed at 8 weeks regarding remission and response of the 17-item Hamilton Rating Scale Depression (HRSD17) and the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16). Anxious depression was defined as major depressive disorder with one or more anxiety disorders or major depressive disorder with a HRSD17 anxiety/somatisation factor score ⩾7. Anxiety-related scales included the HRSD17 anxiety/somatisation factor and the 42-item Depression Anxiety Stress Scales (DASS42) anxiety and stress subscales. RESULTS: Anxious depression definitions showed poor agreement (κ = 0.15) and the HRSD17 anxiety/somatisation factor was weakly correlated with both DASS42 anxiety (r = 0.24) and stress subscales (r = 0.20). Anxious depression definitions were also associated with few impairments on clinical features and did not predict poorer antidepressant treatment outcome. However, higher DASS42 anxiety predicted poorer HRSD17 and QIDS-SR16 remission, and item-level analysis found higher scores on items 9 (situational anxiety) and 23 (somatic anxiety) of the DASS42 predicted poorer treatment outcome, even after adjusting for covariates and multiple comparisons. CONCLUSION: Common definitions of anxious depression show poor agreement and do not predict poorer treatment outcome. Anxiety symptoms may be better characterised dimensionally using DASS42 when predicting treatment outcome.

Increased chronic stress predicts greater emotional negativity bias and poorer social skills but not cognitive functioning in healthy adults.

Background and Objectives: Chronically stressed individuals report deficits spanning cognitive and emotional functioning. However, limitations to clinical populations and measures of stress have impeded the generalisability and scope of results. This study investigated whether chronic stress predicted cognitive and emotional functioning, and whether these relationships differed between males and females, in a large representative sample of healthy participants. Design: Cross-sectional study. Method: 1883 healthy adults sampled from the Brain Resource International Database reported stress using the 21-item Depression Anxiety Stress Scales. Participants then completed a cognitive and emotional assessment battery (IntegNeuro), as well as questionnaires related to sleep, emotional functioning, and self-regulation. Results: In contrast to previously reported results, chronic stress did not predict cognitive functioning. However, higher stress predicted a greater negativity bias and poorer social skills, confirming previous research identifying these links. Conclusions: Cognitive deficits related to stress are absent in healthy participants when stress is measured using the 21-items Depression Anxiety Stress Scales. Identifying how chronic stress is associated with aspects of emotional functioning can lead to personalized interventions for individuals to better manage the negative outcomes resulting from stress.

Use of respiratory rates and heart rate variability in the assessment and treatment of children and adolescents with functional somatic symptoms.

Functional somatic symptoms (FSS) emerge when the stress system is activated in response to physical or emotional stress that is either chronic or especially intense. In such cases, the heightened state of physiological arousal and motor activation can be measured through biological markers. Our team have integrated the use of biological markers of body state - respiratory rate, heart rate (HR) and heart rate variability (HRV) measurements - as a way of helping families to understand how physical symptoms can signal activation of the body's stress systems. This study measured respiratory rates, HR and HRV in children and adolescents with FSS (and healthy controls) during baseline assessment to determine whether these biological markers were effective at differentiating patients with FSS. The study also implemented a biofeedback intervention during the assessment to determine whether patients with FSS were able to slow their respiratory rates and increase HRV. Patients with FSS had faster respiratory rates, faster HR, and lower HRV, suggesting activation of the autonomic nervous system coupled with activation of the respiratory motor system. Like controls, patients were able to slow their respiratory rates, but in contrast to controls, they were unable to increase their HRV. Our findings suggest that patients with FSS present in a state of physiological activation and struggle to regulate their body state. Patients with FSS are likely to need ongoing training and practice to regulate body state coupled with interventions that target regulatory capacity across multiple systems.

"Motoring in idle": The default mode and somatomotor networks are overactive in children and adolescents with functional neurological symptoms.

Objective: Children and adolescents with functional neurological symptom disorder (FND) present with diverse neurological symptoms not explained by a disease process. Functional neurological symptoms have been conceptualized as somatoform dissociation, a disruption of the brain's intrinsic organization and reversion to a more primitive level of function. We used EEG to investigate neural function and functional brain organization in children/adolescents with FND. Method: EEG was recorded in the resting eyes-open condition in 57 patients (aged 8.5-18 years) and 57 age- and sex-matched healthy controls. Using a topographical map, EEG power data were quantified for regions of interest that define the default mode network (DMN), salience network, and somatomotor network. Source localization was examined using low-resolution brain electromagnetic tomography (LORETA). The contributions of chronic pain and arousal as moderators of differences in EEG power were also examined. Results: Children/adolescents with FND had excessive theta and delta power in electrode clusters corresponding to the DMN-both anteriorly (dorsomedial prefrontal cortex [dmFPC]) and posteriorly (posterior cingulate cortex [PCC], precuneus, and lateral parietal cortex)-and in the premotor/supplementary motor area (SMA) region. There was a trend toward increased theta and delta power in the salience network. LORETA showed activation across all three networks in all power bands and localized neural sources to the dorsal anterior cingulate cortex/dmPFC, mid cingulate cortex, PCC/precuneus, and SMA. Pain and arousal contributed to slow wave power increases in all three networks. Conclusions: These findings suggest that children and adolescents with FND are characterized by overactivation of intrinsic resting brain networks involved in threat detection, energy regulation, and preparation for action.

Cognitive Testing to Identify Children With ADHD Who Do and Do Not Respond to Methylphenidate.

OBJECTIVE: To explore the utility of cognitive measures for predicting response of children and adolescents to methylphenidate (MPH). METHOD: Participants from the International Study to Predict Optimized Treatment-in ADHD (iSPOT-A) completed a cognitive test battery prior to receiving 6 weeks of MPH. The responder criterion was a 25% reduction in ADHD-Rating Scale-IV scores. Receiver Operator Characteristics (ROC) classified non-responders from responders with maximal sensitivity and specificity. RESULTS: Overall, 62% of participants responded to MPH. Response rates for ROC-identified groups ranged from 18% to 85%. Non-responders showed compromised cognition related to switching of attention, sustained attention, planning, and impulsivity. One group of responders were 10 years of age or older and had impaired switching of attention and impulsivity; a second group had enhanced switching of attention, normal or higher Continuous Performance Task (CPT) scores, and above average scores on digit span. CONCLUSION: Cognitive tests may provide a simple, low-cost tool for treatment planning for children and adolescents with ADHD.

EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study.

OBJECTIVE: To determine whether EEG occipital alpha and frontal alpha asymmetry (FAA) distinguishes outpatients with major depression (MDD) from controls, predicts antidepressant treatment outcome, and to explore the role of gender. METHODS: In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, randomized, prospective open-label trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-extended release. The study also recruited 336 healthy controls. Treatment response was established after eight weeks and resting EEG was measured at baseline (two minutes eyes open and eyes closed). RESULTS: No differences in EEG alpha for occipital and frontal cortex, or for FAA, were found in MDD participants compared to controls. Alpha in the occipital and frontal cortex was not associated with treatment outcome. However, a gender and drug-class interaction effect was found for FAA. Relatively greater right frontal alpha (less cortical activity) in women only was associated with a favorable response to the Selective Serotonin Reuptake Inhibitors escitalopram and sertraline. No such effect was found for venlafaxine-extended release. CONCLUSIONS: FAA does not differentiate between MDD and controls, but is associated with antidepressant treatment response and remission in a gender and drug-class specific manner. SIGNIFICANCE: Future studies investigating EEG alpha measures in depression should a-priori stratify by gender.

Reduction of autonomic regulation in children and adolescents with conversion disorders.

OBJECTIVE: Conversion symptoms--functional neurological disturbances of body function--occur in association with extreme arousal, often in the context of emotional distress. The mechanisms that determine how and why such symptoms occur remain unknown. In this study, we used cardiac measures to assess arousal and cardiac autonomic regulation in children and adolescents who presented with acute conversion symptoms. METHODS: Heart rate was recorded in 57 children and adolescents (41 girls; 8.5-18 years old) with acute conversion symptoms and 57 age- and sex-matched healthy controls, during a resting condition and then during tasks involving cognitive and emotional activation. Arousal and autonomic regulation were assessed by measures of heart rate and heart rate variability. Psychological measures included attachment and emotional distress. RESULTS: Children and adolescents with conversion symptoms displayed higher autonomic arousal than did the controls, both at baseline and during task conditions (higher heart rate: baseline mean [standard deviation] = 82 [9.49] versus 74 [10.79] beats/min, p < .001; lower root mean squared successive differences-heart rate variability: 45.35 [27.97] versus 58.62 [25.69] ms(2), p = .012; and lower high-frequency heart rate variability: 6.50 [1.19] versus 7.01 [0.95] ln[ms(2)] p = .017), and decreased autonomic regulation (attenuation of heart rate increases across tasks). The baseline pattern of increased autonomic arousal was especially pronounced in children with coercive-preoccupied patterns of attachment. Autonomic measures were not correlated with measures of emotional distress. CONCLUSIONS: High autonomic arousal may be a precondition for generating conversion symptoms. Functional dysregulations of the cardiac, respiratory, and circulatory systems may mediate fainting episodes and nonepileptic seizures, and aberrant patterns of functional connectivity between motor areas and central arousal systems may be responsible for generating motor conversion symptoms.

Frontal and rostral anterior cingulate (rACC) theta EEG in depression: implications for treatment outcome?

In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram (EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression (HRSD17). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome.

Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial.

OBJECTIVE: The study aims were 1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2) to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications. METHOD: Participants 18-65 years of age (N=1,008) who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed-effects model using the intent-to-treat sample compared the groups' symptom score trajectories, and logistic regression compared likelihood of remission (defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report). RESULTS: Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect. CONCLUSIONS: There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection.

Toward an online cognitive and emotional battery to predict treatment remission in depression.

PURPOSE: To evaluate the performance of a cognitive and emotional test battery in a representative sample of depressed outpatients to inform likelihood of remission over 8 weeks of treatment with each of three common antidepressant medications. PATIENTS AND METHODS: Outpatients 18-65 years old with nonpsychotic major depressive disorder (17 sites) were randomized to escitalopram, sertraline or venlafaxine-XR (extended release). Participants scored ≥12 on the baseline 16-item Quick Inventory of Depressive Symptomatology - Self-Report and completed 8 weeks of treatment. The baseline test battery measured cognitive and emotional status. Exploratory multivariate logistic regression models predicting remission (16-item Quick Inventory of Depressive Symptomatology - Self-Report score ≤5 at 8 weeks) were developed independently for each medication in subgroups stratified by age, sex, or cognitive and emotional test performance. The model with the highest cross-validated accuracy determined the participant proportion in each arm for whom remission could be predicted with an accuracy ≥10% above chance. The proportion for whom a prediction could be made with very high certainty (positive predictive value and negative predictive value exceeding 80%) was calculated by incrementally increasing test battery thresholds to predict remission/non-remission. RESULTS: The test battery, individually developed for each medication, improved identification of remitting and non-remitting participants by ≥10% beyond chance for 243 of 467 participants. The overall remission rates were escitalopram: 40.8%, sertraline: 30.3%, and venlafaxine-XR: 31.1%. Within this subset for whom prediction exceeded chance, test battery thresholds established a negative predictive value of ≥80%, which identified 40.9% of participants not remitting on escitalopram, 77.1% of participants not remitting on sertraline, and 38.7% of participants not remitting on venlafaxine-XR (all including 20% false negatives). CONCLUSION: The test battery identified about 50% of each medication group as being ≥10% more or less likely to remit than by chance, and identified about 38% of individuals who did not remit with ≥80% certainty. Clinicians might choose to avoid this specific medication in these particular patients.

The international Study to Predict Optimized Treatment in Depression (iSPOT-D): outcomes from the acute phase of antidepressant treatment.

We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder (MDD). The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients (18-65 years old) at 17 sites (five countries). At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the "none" to minimal/mild range for intensity and burden. Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.

Conversion disorder in children and adolescents: a disorder of cognitive control.

OBJECTIVE: To assess cognitive function in children and adolescents presenting with acute conversion symptoms. METHODS: Fifty-seven participants aged 8.5-18 years (41 girls and 16 boys) with conversion symptoms and 57 age- and gender-matched healthy controls completed the IntegNeuro neurocognitive battery, an estimate of intelligence, and self-report measures of subjective emotional distress. RESULTS: Participants with conversion symptoms showed poorer performance within attention, executive function, and memory domains. Poorer performance was reflected in more errors on specific tests: Switching of Attention (t(79) = 2.17, p = .03); Verbal Interference (t(72) = 2.64, p = .01); Go/No-Go (t(73) = 2.20, p = .03); Memory Recall and Verbal Learning (interference errors for memory recall; t(61) = 3.13, p < .01); and short-delay recall (t(75) = 2.05, p < .01) and long-delay recall (t(62) = 2.24, p = .03). Poorer performance was also reflected in a reduced span of working memory on the Digit Span Test for both forward recall span (t(103) = -3.64, p < .001) and backward recall span (t(100) = -3.22, p < .01). There was no difference between participants and controls on IQ estimate (t(94) = -589, p = .56), and there was no correlation between cognitive function and perceived distress. CONCLUSIONS: Children and adolescents with acute conversion symptoms have a reduced capacity to manipulate and retain information, to block interfering information, and to inhibit responses, all of which are required for effective attention, executive function, and memory.

Specific biases for identifying facial expression of emotion in children and adolescents with conversion disorders.

OBJECTIVE: This study aimed to assess how children and adolescents with conversion disorders identify universal facial expressions of emotion and to determine whether identification of emotion in faces relates to subjective emotional distress. METHODS: Fifty-seven participants (41 girls and 16 boys) aged 8.5 to 18 years with conversion disorders and 57 age- and sex-matched healthy controls completed a computerized task in which their accuracy and reaction times for identifying facial expressions were recorded. To isolate the effect of individual emotional expressions, participants' reaction times for each emotion (fear, anger, sadness, disgust, and happiness) were subtracted from their reaction times for the neutral control face. Participants also completed self-report measures of subjective emotional distress. RESULTS: Children/Adolescents with conversion disorders showed faster reaction times for identifying expressions of sadness (t(112) = -2.2, p = .03; 444 [609] versus 713 [695], p = .03) and slower reactions times for happy expressions (t(99.3) = 2.28, p ≤ .024; -33 [35] versus 174 [51], p = .024), compared with controls (F(33.75, 419.81) = 3.76, p < .001). There were no significant correlations (at the corrected p value of .01) between reaction times and subjective reports of perceived distress (r values ranged from 092 to 0.221; p > .018). There were also no differences in identification accuracy for any emotion (p > .82). CONCLUSIONS: The observation of faster reaction times to sad faces in children and adolescents with conversion disorders suggests increased vigilance and motor readiness to emotional signals that are potential threats to self or to close others. These effects may occur before conscious processing.

EEG alpha asymmetry in schizophrenia, depression, PTSD, panic disorder, ADHD and conduct disorder.

Models of laterality infer distinct aspects of EEG alpha asymmetry in clinical disorders, which has been replicated for over three decades. This biomarker now requires a more fine-grained assessment of its clinical utility as a diagnostic and treatment predictive marker. Here, within the same study we assessed resting brain laterality across six clinical disorders, for which deviant laterality has been implicated as core dysfunction. These disorders were evaluated in comparison to a large normative dataset (approximately 1,900) from the Brain Resource International Database. EEG alpha asymmetry was assessed in the frontocentral region, for resting Eyes Closed and Eyes Open conditions. Schizophrenia was characterized by significantly greater left lateralized alpha power than controls, indicating a deficit in left frontal activity at rest, which may relate to "disconnections" across wider fronto-temporal networks. The depression group showed a trend-level tendency towards the opposite pattern of greater right-lateralized activity than controls. The remaining anxiety and behavioral disorders did not show any significant deviance in alpha asymmetry from the normative control group. However, at a non-significant level laterality for these groups was generally consistent with expected directions, suggesting a propensity towards a particular lateralization but still remaining within the normative range. Overall, the results of the current study indicate that EEG alpha asymmetry may show the most clinical utility as a biomarker for schizophrenia and depression in comparison to other clinical disorders.

A polymorphism of the MAOA gene is associated with emotional brain markers and personality traits on an antisocial index.

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.

Explicit identification and implicit recognition of facial emotions: I. Age effects in males and females across 10 decades.

A number of psychiatric and neurological disorders are characterized by impairments in facial emotion recognition. Recognition of individual emotions has implicated limbic, basal ganglionic, and frontal brain regions. Since these regions are also implicated in age-related decline and sex differences in emotion processing, an understanding of normative variation is important for assessing deficits in clinical groups. An internet-based test ("WebNeuro") was administered to 1,000 healthy participants (6 to 91 years, 53% female) to assess explicit identification of basic expressions of emotion (happiness, sadness, fear, anger, disgust, neutral). A subsequent implicit recognition condition was based on a priming protocol, in which explicit identification provided the "study" phase. Responses were most accurate for happiness and slowest for fear in the explicit condition, but least accurate for happiness and fastest for fear in the implicit condition. The effects of age, by contrast, showed a similar pattern for both explicit and implicit conditions, following a nonlinear distribution in which performance improved from childhood through adolescence and early adulthood and declined in later adulthood. Females were better than males at explicit identification of fear in particular. These findings are consistent with the priority of threat-related signals, but indicate opposing biases depending on whether emotion processing is conscious or nonconscious. The lifespan trends in emotion processing over 10 decades point to an interaction of brain-based (maturation, stability, and then atrophy of cortical and subcortical systems) and experiential contributing factors. These findings provide a robust normative platform for assessing clinical groups.