Neurophysiological evidence of motor preparation in inner speech and the effect of content predictability.

Self-generated overt actions are preceded by a slow negativity as measured by electroencephalogram, which has been associated with motor preparation. Recent studies have shown that this neural activity is modulated by the predictability of action outcomes. It is unclear whether inner speech is also preceded by a motor-related negativity and influenced by the same factor. In three experiments, we compared the contingent negative variation elicited in a cue paradigm in an active vs. passive condition. In Experiment 1, participants produced an inner phoneme, at which an audible phoneme whose identity was unpredictable was concurrently presented. We found that while passive listening elicited a late contingent negative variation, inner speech production generated a more negative late contingent negative variation. In Experiment 2, the same pattern of results was found when participants were instead asked to overtly vocalize the phoneme. In Experiment 3, the identity of the audible phoneme was made predictable by establishing probabilistic expectations. We observed a smaller late contingent negative variation in the inner speech condition when the identity of the audible phoneme was predictable, but not in the passive condition. These findings suggest that inner speech is associated with motor preparatory activity that may also represent the predicted action-effects of covert actions.

Neurofeedback for post-traumatic stress disorder: systematic review and meta-analysis of clinical and neurophysiological outcomes.

Background: Posttraumatic stress disorder (PTSD) is a debilitating condition affecting millions of people worldwide. Existing treatments often fail to address the complexity of its symptoms and functional impairments resulting from severe and prolonged trauma. Electroencephalographic Neurofeedback (NFB) has emerged as a promising treatment that aims to reduce the symptoms of PTSD by modulating brain activity.Objective: We conducted a systematic review and meta-analysis of ten clinical trials to answer the question: how effective is NFB in addressing PTSD and other associated symptoms across different trauma populations, and are these improvements related to neurophysiological changes?Method: The review followed the Preferred Reporting Items for Systematic Reviews and Meta analyses guidelines. We considered all published and unpublished randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) involving adults with PTSD as a primary diagnosis without exclusion by type of trauma, co-morbid diagnosis, locality, or sex. Ten controlled studies were included; seven RCTs and three NRSIs with a total number of participants n = 293 (128 male). Only RCTs were included in the meta-analysis (215 participants; 88 male).Results: All included studies showed an advantage of NFB over control conditions in reducing symptoms of PTSD, with indications of improvement in symptoms of anxiety and depression and related neurophysiological changes. Meta-analysis of the pooled data shows a significant reduction in PTSD symptoms post-treatment SMD of -1.76 (95% CI -2.69, -0.83), and the mean remission rate was higher in the NFB group (79.3%) compared to the control group (24.4%). However, the studies reviewed were mostly small, with heterogeneous populations and varied quality.Conclusions: The effect of NFB on the symptoms of PTSD was moderate and mechanistic evidence suggested that NFB leads to therapeutic changes in brain functioning. Future research should focus on more rigorous methodological designs, expanded sample size and longer follow-up.

Neurofeedback (NFB) was found to have moderate beneficial effects on PTSD symptoms, and positive effects on secondary outcomes such as depression and anxiety, according to a meta-analysis of seven randomised controlled trials (RCTs).The beneficial effects of NFB were observed across diverse populations, including those with different types of trauma (military and civilians) and from different ethnic backgrounds.Results suggest that modulation of alpha rhythm might be a viable NFB protocol in patients with PTSD, as changes in neurophysiological functioning, such as connectivity in the Default Mode Network (DMN) and Salience Network (SN), were observed post-NFB and were correlated with a decrease in PTSD severity.

Continuity of mental health care during the transition from prison to the community following brief periods of imprisonment.

Purpose: The prison-to-community transition period is one of high risk and need, particularly for those with mental illness. Some individuals cycle in and out of prison for short periods with little opportunity for mental health stabilization or service planning either in prison or the community. This study describes the socio-demographic, clinical and criminal justice characteristics of individuals with mental illness and frequent, brief periods of imprisonment, examines continuity of mental health care between prison and the community for this group, and reports on their post-release mental health and criminal justice outcomes. Design/methodology/approach: This study examined a sample of 275 men who had recently entered prison in New South Wales (NSW), Australia, who had been charged with relatively minor offenses and had been identified on reception screening as having significant mental health needs. Baseline demographic and mental health information was collected via interview and file review and contacts with the prison mental health service were recorded for the period of incarceration. Follow-up interviews were conducted 3 months post-release to determine level of health service contact and mental health symptoms. Information on criminal justice contact during the 3 month period was also collected. Findings: The majority (85.5%) of the sample had contact with a mental health professional during their period of incarceration. Mental health discharge planning was, however, lacking, with only one in 20 receiving a referral to a community mental health team (CMHT) and one in eight being referred for any kind of mental health follow-up on release. Of those followed up 3 months post-release (n = 113), 14.2% had had contact with a CMHT. Of those released for at least 3 months (n = 255), one in three had received new charges in this period and one in five had been reincarcerated. Conclusion: Continuity of mental health care for those exiting prison is poor, particularly for those with mental health needs experiencing brief periods of imprisonment, and rates of CMHT contact are low in the immediate post-release period. These findings suggest a need for early identification of individuals in this group for timely commencement of intervention and release planning, and opportunities for diversion from prison should be utilized where possible.

Common and differential neural mechanisms underlying mood disorders.

BACKGROUND: Despite homogenous clinical presentations between bipolar and unipolar disorders, there are distinct neurobiological differences. Chronicity of illness may be a factor impacting and sustaining certain neural features. The goal of this study was to investigate common and shared neural mechanisms underlying mood disorders, and possible sustained neural changes relating to illness chronicity by investigating a cohort of euthymic patients with bipolar disorder (BD), unipolar depression who had responded to treatment (treatment-sensitive depression, TSD), and a chronically treatment-resistant depressed (TRD) group. METHODS: One hundred and seventy-two participants (40 BD, 39 TSD, 40 TRD, and 53 age-gender-matched healthy controls) underwent resting-state fMRI scans. Seed-based and independent component analyses were performed to investigate group differences in resting-state connectivity between the four groups. RESULTS: All three clinical groups had significantly lower connectivity within the frontoparietal network (FPN) relative to controls. TRD and BD were significantly different from TSD (TRD, BD > TSD) but were not significantly different from each other. TRDs were also significantly different from both BD and TSD for salience network connectivity with the posterior cingulate (DMN) and the FPN with frontal pole (DMN). Additionally, the BD group exhibited greater DMN-FPN (sgACC-RDLPFC) connectivity relative to TRD, TSD, and controls, which was correlated with a previous number of depressive episodes, in the BD group only. CONCLUSIONS: BD demonstrated shared and differential connectivity features relative to symptomatic TRD and euthymic TSD groups. The increased sgACC-RDLPFC connectivity in BD and its correlation with a number of depressive episodes could be a neural feature associated with illness chronicity.

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.

Default-mode and fronto-parietal network connectivity during rest distinguishes asymptomatic patients with bipolar disorder and major depressive disorder.

Bipolar disorder (BD) is commonly misdiagnosed as major depressive disorder (MDD). This is understandable, as depression often precedes mania and is otherwise indistinguishable in both. It is therefore imperative to identify neural mechanisms that can differentiate the two disorders. Interrogating resting brain neural activity may reveal core distinguishing abnormalities. We adopted an a priori approach, examining three key networks documented in previous mood disorder literature subserving executive function, salience and rumination that may differentiate euthymic BD and MDD patients. Thirty-eight patients with BD, 39 patients with MDD matched for depression severity, and 39 age-gender matched healthy controls, completed resting-state fMRI scans. Seed-based and data-driven Independent Component analyses (ICA) were implemented to examine group differences in resting-state connectivity (pFDR < 0.05). Seed analysis masks were target regions identified from the fronto-parietal (FPN), salience (SN) and default-mode (DMN) networks. Seed-based analyses identified significantly greater connectivity between the subgenual cingulate cortex (DMN) and right dorsolateral prefrontal cortex (FPN) in BD relative to MDD and controls. The ICA analyses also found greater connectivity between the DMN and inferior frontal gyrus, an FPN region in BD relative to MDD. There were also significant group differences across the three networks in both clinical groups relative to controls. Altered DMN-FPN functional connectivity is thought to underlie deficits in the processing, management and regulation of affective stimuli. Our results suggest that connectivity between these networks could potentially distinguish the two disorders and could be a possible trait mechanism in BD persisting even in the absence of symptoms.

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.

The impact of online brain training exercises on experiences of depression, anxiety and emotional wellbeing in a twin sample.

This study assessed the effectiveness of cognitive and emotional brain training and transfer effects to wellbeing and depression and anxiety symptoms. 352 healthy adult twins were randomised to a training group where they were asked to play brain training games over a 30-day period, or a waitlist control group. This study focused on the impact of the brain training on explicit and implicit emotional cognition, and analysed effects using both Intention-To-Treat (ITT) and Per-Protocol (PP) approaches. Both analyses revealed significant training effects for improvement in the explicit identification of fear expressions (ITT: p < 0.001, d = 0.33; PP training 3 h+: p < 0.001, d = 0.55), and a reduction in implicit bias for anger expressions amongst males (ITT: p < 0.001, d = 0.94; PP training 3 h+: p = 0.04, d = 0.90). Female participants also showed improvements in implicit bias for happy expressions (ITT: p = 0.003, d = 0.34; PP training 3 h+: p = 0.03, d = 0.47). Improvements resulting from training in emotional cognition did not directly improve wellbeing, depression or anxiety symptoms. Regression modelling also suggested training improvements in emotional cognition yielded no indirect transfer effects for the mental health and wellbeing measures. The results suggest brain training in healthy populations has potential for improving emotional cognition, but the subsequent impact on improving wellbeing and mental health symptoms is still equivocal.

Does Adding Social Cognitive Remediation Therapy to Neurocognitive Remediation Therapy Improve Outcomes in Young People With a Severe Mental Illness?-The Advantage Trial.

Introduction: Cognitive impairments are a common and significant issue for young people with a severe mental illness. Young people with schizophrenia, bipolar disorder and major depression all experience significant cognitive problems that impede their ability to return to work or study. These neurocognitive problems are frequently exacerbated by social cognitive deficits that interfere with their ability to integrate into the community and understand the social and emotional nuances about them. This study aimed to assess if the addition of a social cognitive remediation treatment to a neurocognitive remediation therapy improved functional outcome. Methods: Five youth mental health services were trained in both the Neuropsychological Educational Approach to Remediation (NEAR) and the Social Cognition and Interaction Training (SCIT) treatments. Participants were randomised between receiving either NEAR + SCIT or NEAR + treatment as usual (TAU) over a 20-week period, with all participants receiving the NEAR treatment first. Symptoms, neurocognition, social cognition and functioning were examined at baseline, end of treatment and at 3 months follow-up and compared between the two arms of the study. The primary outcome was function. Results: Thirty-nine participants were randomised to treatment (Schizophrenia spectrum = 28, Bipolar disorder = 7, Major Depression = 2). The trial was curtailed by Covid-related service restrictions. There was an overall significant improvement in function over time with a trend towards a greater improvement in the NEAR + SCIT arm. No changes in symptoms, neurocognitive or social cognitive measures were seen. While 74% completed treatment only 49% agreed to follow up at 3 months affecting our ability to interpret the findings. Attrition did not differ by arm. Conclusions: In a pragmatic, service-based research project, treatment aimed at improving cognition enhanced functional outcome in young people with a range of severe mental illnesses. There was a trend towards improved function in young people who had a combined NEAR + SCIT approach. Clinical Trial Registration: Identifier: ACTRN12622000192785.

Investigating neural circuits of emotion regulation to distinguish euthymic patients with bipolar disorder and major depressive disorder.

BACKGROUND: Up to 40% of patients with bipolar disorder (BD) are initially diagnosed as having major depressive disorder (MDD), and emotional lability is a key aspect of both sets of mood disorders. However, it remains unknown whether differences in the regulation of emotions through cognitive reappraisal may serve to distinguish BD and MDD. Therefore, we examined this question in euthymic BD and MDD patients. METHODS: Thirty-eight euthymic BD, 33 euthymic MDD and 37 healthy control (HC) participants, matched for age, gender and depression severity, engaged in an emotion regulation (ER) cognitive reappraisal task during an fMRI scan were examined. Participants either reappraised (Think condition) or passively watched negative (Watch condition) or neutral (Neutral condition) pictures and rated their affect. Activation and connectivity analyses were used to examine group differences in reappraisal (Think vs Watch) and reactivity (Watch vs Neutral) conditions in ER-specific neural circuits. RESULTS: Irrespective of group, participants rated most negatively the images during the Watch condition relative to Think and Neutral conditions, and more negatively to Think relative to Neutral. Notably, BD participants exhibited reduced subgenual anterior cingulate activation (sgACC) relative to MDD during reappraisal, but exhibited greater sgACC activation relative to MDD during reactivity, whereas MDD participants elicited greater activation in right amygdala relative to BD during reactivity. We found no group differences in task-related connectivity. CONCLUSIONS: Euthymic BD and MDD patients engage differential brain regions to process and regulate emotional information. These differences could serve to distinguish the clinical groups and provide novel insights into the underlying pathophysiology of BD.

Neurophysiological markers of attention distinguish bipolar disorder and unipolar depression.

BACKGROUND: Attentional deficits are common in both symptomatic and symptom-remitted patients with bipolar disorder (BP) and major depressive disorder (MDD). However, whether the level of neurocognitive impairment in attentional processing is different between these two disorders, or not, is still unclear. Thus, we investigated the P300 event-related potential component as a biomarker of cognitive dysfunction to differentiate BP and MDD. METHODS: Twenty-three age and gender matched BP, 20 MDD and 23 healthy controls (HC) were part of a discovery cohort to identify neurophysiological differences between groups and build a classification model of these disorders. The replication of this model was then tested in an independent second cohort of 17 BP, 19 MDD and 19 HC. All participants were symptom-remitted for at least two weeks. We compared neural responses to target stimuli during an auditory oddball task, computing peak amplitude and latency of the P300 component extracted from the midline centro-parietal electrode. RESULTS: BP had significantly smaller P300 amplitudes compared to both MDD and HC, whereas there were no differences between MDD and HC. The differences between groups were replicated in the second cohort, however the accuracy level of the classification model was only 53.5%. LIMITATIONS: Small sample sizes may have led to low accuracy levels of the classification model. CONCLUSION: Specific neural mechanisms of attention and context updating seem not to recover with symptom remission in BP. These findings contribute to the detection of a potential electrophysiological marker for BP, which may allow its differentiation from unipolar major depressive disorder.

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.

Evaluation of Neurofeedback for Posttraumatic Stress Disorder Related to Refugee Experiences Using Self-Report and Cognitive ERP Measures.

Background. Neurofeedback holds promise as an intervention for the psychophysiological dysfunction found in posttraumatic stress disorder (PTSD). Few empirical studies have assessed the efficacy of neurofeedback for PTSD, and none in individuals with refugee trauma. A proposed mechanism for neurofeedback efficacy in PTSD is through remediating deficits in cognitive control. We assessed pre- and postchanges in symptoms and neurocognitive functioning of refugee clients participating in a neurofeedback intervention for PTSD. Methods. Clinical data for 13 adult refugees with chronic PTSD who participated in neurofeedback combined with trauma counseling (NFT) was compared with 13 adult refugees placed on a waitlist to receive neurofeedback. Waitlist clients continued to receive trauma counseling alone (TC). NFT was additionally assessed pre- and posttherapy for changes in event-related potentials (ERPs) and behavioral indices of cognitive control using a visual continuous performance task (VCPT). Comparison VCPT data from healthy controls (HC) was available from the Human Brain Index database. Results. Posttherapy, NFT had significantly lower symptoms of trauma, anxiety, and depression compared with TC. NFT demonstrated an increased P3 amplitude and improved behavioral performance suggesting a normalization of cognitive control. Conclusions. These preliminary observations are consistent with a possible benefit of neurofeedback for remediating PTSD. This may be achieved at least partially by an improvement in cognitive control. Further confirmation of the effectiveness of the treatment now requires a randomized controlled trial that considers issues such as placebo response, nonspecific therapist effects, and duration of treatment.

Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review.

Objectives: Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. Methods: The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. Results: This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Discussion: Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted neurological outcome measures. Future research would benefit from the investigation of both in vivo cortical GSH concentration and peripheral plasma GSH in a population of individuals with chronic schizophrenia.

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.

Characterizing neurocognitive markers of familial risk for depression using multi-modal imaging, behavioral and self-report measures.

BACKGROUND: Major depressive disorder (MDD) is associated with poorer behavioral performance in domains of working memory and associated cognitive systems for cognitive control and attention. Functional neuroimaging studies show altered functioning in MDD in frontal executive control circuits implicated in these cognitive processes. It is not yet known whether poor cognitive performance involving these circuits is part of the familial risk for MDD, and we addressed this issue using a multi-modal imaging, behavioral and self-report approach in unaffected first-degree relatives of parent probands with MDD. METHODS: 72 unaffected adult first-degree relatives of probands with MDD (mean age 30.5 ± 13.4 years) with and 66 case-wise matched non-relative controls underwent functional magnetic resonance imaging during performance of 'n-back' working memory task, a Go/No-go task assessing cognitive control and an Auditory Oddball test of selective attention. Groups were compared on imaging data analyzed voxel wise with a focus on dorsolateral prefrontal cortex, anterior cingulate cortex and insula regions of interest, and on corresponding behavioral accuracy and reaction time data. Symptoms were assessed using self-report scales. RESULTS: Relatives were distinguished by comparatively decreased activation in the left dorsolateral prefrontal cortex (DLPFC) during updating of working memory. Behaviorally, relatives also showed more errors of omission during working memory updating. DLPFC hypo-activation was associated with greater depressive symptom severity. CONCLUSIONS: Deficits in cognitive processing may be part of the profile of familial risk for depression, preceding illness onset, specifically in the domain of working memory.

Inner speech is accompanied by a temporally-precise and content-specific corollary discharge.

When we move our articulator organs to produce overt speech, the brain generates a corollary discharge that acts to suppress the neural and perceptual responses to our speech sounds. Recent research suggests that inner speech - the silent production of words in one's mind - is also accompanied by a corollary discharge. Here, we show that this corollary discharge contains information about the temporal and physical properties of inner speech. In two experiments, participants produced an inner phoneme at a precisely-defined moment in time. An audible phoneme was presented 300 ms before, concurrently with, or 300 ms after participants produced the inner phoneme. We found that producing the inner phoneme attenuated the N1 component of the event-related potential - an index of auditory cortex processing - but only when the inner and audible phonemes occurred concurrently and matched on content. If the audible phoneme was presented before or after the production of the inner phoneme, or if the inner phoneme did not match the content of the audible phoneme, there was no attenuation of the N1. These results suggest that inner speech is accompanied by a temporally-precise and content-specific corollary discharge. We conclude that these results support the notion of a functional equivalence between the neural processes that underlie the production of inner and overt speech, and may provide a platform for identifying inner speech abnormalities in disorders in which they have been putatively associated, such as schizophrenia.

Amygdala Activation and Connectivity to Emotional Processing Distinguishes Asymptomatic Patients With Bipolar Disorders and Unipolar Depression.

BACKGROUND: Mechanistically based neural markers, such as amygdala reactivity, offer one approach to addressing the challenges of differentiating bipolar and unipolar depressive disorders independently from mood state and acute symptoms. Although emotion-elicited amygdala reactivity has been found to distinguish patients with bipolar depression from patients with unipolar depression, it remains unknown whether this distinction is traitlike and present in the absence of an acutely depressed mood. We addressed this gap by investigating patients with bipolar disorder (BP) and unipolar major depressive disorder (MDD) in remission. METHODS: Supraliminal and subliminal processing of faces exhibiting threat, sad, happy, and neutral emotions during functional magnetic resonance imaging was completed by 73 participants (23 BP patients and 25 MDD patients matched for age and gender, number of depressive episodes and severity; 25 age- and gender-matched healthy control subjects). We compared groups for activation and connectivity for the amygdala. RESULTS: BP patients had lower left amygdala activation than MDD patients during supraliminal and subliminal threat, sad, and neutral emotion processing and for subliminal happy faces. BP patients also exhibited lower amygdala connectivity to the insula and hippocampus for threat and to medial orbitofrontal cortex for happy supraliminal and subliminal processing. BP patients also demonstrated greater amygdala-insula connectivity for sad supraliminal and subliminal face processing. Both patient groups were distinct from control subjects across several measures for activation and connectivity. CONCLUSIONS: Independent of valence or level of emotional awareness, amygdala activation and connectivity during facial emotion processing can distinguish BP patients and MDD patients. These findings provide evidence that this neural substrate could be a potential trait marker to differentiate these two disorders largely independent of illness state.

A negative association between brainstem pontine grey-matter volume, well-being and resilience in healthy twins

Background: Associations between well-being, resilience to trauma and the volume of grey-matter regions involved in affective processing (e.g., threat/reward circuits) are largely unexplored, as are the roles of shared genetic and environmental factors derived from multivariate twin modelling. Methods: This study presents, to our knowledge, the first exploration of well-being and volumes of grey-matter regions involved in affective processing using a region-of-interest, voxel-based approach in 263 healthy adult twins (60% monozygotic pairs, 61% females, mean age 39.69 yr). To examine patterns for resilience (i.e., positive adaptation following adversity), we evaluated associations between the same brain regions and well-being in a trauma-exposed subgroup. Results: We found a correlated effect between increased well-being and reduced grey-matter volume of the pontine nuclei. This association was strongest for individuals with higher resilience to trauma. Multivariate twin modelling suggested that the common variance between the pons volume and well-being scores was due to environmental factors. Limitations: We used a cross-sectional sample; results need to be replicated longitudinally and in a larger sample. Conclusion: Associations with altered grey matter of the pontine nuclei suggest that basic sensory processes, such as arousal, startle, memory consolidation and/or emotional conditioning, may have a role in well-being and resilience.

Electrocortical reactivity to negative and positive facial expressions in individuals with a family history of major depression.

Facial expressions signaling threat and mood-congruent loss have been used to probe abnormal neural reactivity in major depressive disorder (MDD) and may be implicated in genetic vulnerability to MDD. This study investigated electro-cortical reactivity to facial expressions in 101 unaffected, adult first-degree relatives of probands with MDD and non-relative controls (n = 101). We investigated event-related potentials (ERPs) to five facial expressions of basic emotion: fear, anger, disgust, sadness and happiness under both subliminal (masked) and conscious (unmasked) presentation conditions, and the source localization of group differences. In the conscious condition, controls showed a distinctly positive-going shift in responsive to negative versus happy faces, reflected in a greater positivity for the VPP frontally and the P300 parietally, and less negativity for the N200. By contrast, relatives showed less differentiation of emotions, reflected in less VPP and P300 positivity, particularly for anger and disgust, which produced an enhanced N200 for sadness. These group differences were consistently source localized to the anterior cingulate cortex. The findings contribute new evidence for neural disruptions underlying the differentiation of salient emotions in familial risk for depression. These disruptions occur to the appraisal (∼200 ms post-stimulus) through to the context evaluation (∼300 ms+ post-stimulus) phases of emotion processing, consistent with theories that risk for depression involves biased or attenuated processing of emotion.