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Background Over the past few decades, neuroimaging research in Bipolar Disorder (BD) has identified neural differences underlying cognitive and emotional processing. However, substantial clinical and methodological heterogeneity present across neuroimaging experiments potentially hinders the identification of consistent neural biomarkers of BD. This meta-analysis aims to comprehensively reassess brain activation and connectivity in BD in order to identify replicable differences that converge across and within resting-state, cognitive, and emotional neuroimaging experiments. Methods Neuroimaging experiments (using fMRI, PET, or arterial spin labeling) reporting whole-brain results in adults with BD and controls published from December 1999—June 18, 2019 were identified via PubMed search. Coordinates showing significant activation and/or connectivity differences between BD participants and controls during resting-state, emotional, or cognitive tasks were extracted. Four parallel, independent meta-analyses were calculated using the revised activation likelihood estimation algorithm: all experiment types, all resting-state experiments, all cognitive experiments, and all emotional experiments. To confirm reliability of identified clusters, two different meta-analytic significance tests were employed. Results 205 published studies yielding 506 individual neuroimaging experiments (150 resting-state, 134 cognitive, 222 emotional) comprising 5745 BD and 8023 control participants were included. Five regions survived both significance tests. Individuals with BD showed functional differences in the right posterior cingulate cortex during resting-state experiments, the left amygdala during emotional experiments, including those using a mixed (positive/negative) valence manipulation, and the left superior and right inferior parietal lobules during cognitive experiments, while hyperactivating the left medial orbitofrontal cortex during cognitive experiments. Across all experiments, there was convergence in the right caudate extending to the ventral striatum, surviving only one significance test. Conclusions Our findings indicate reproducible localization of prefrontal, parietal, and limbic differences distinguishing BD from control participants that are condition-dependent, despite heterogeneity, and point towards a framework for identifying reproducible differences in BD that may guide diagnosis and treatment.

Background Trauma exposure is associated with a more severe, persistent course of affective and anxiety symptoms. Markers of reward neural circuitry function, specifically activation to reward prediction error (RPE), are impacted by trauma and predict the future course of affective symptoms. This study’s purpose was to determine how lifetime trauma exposure influences relationships between reward neural circuitry function and the course of future affective and anxiety symptoms in a naturalistic, transdiagnostic observational context. Methods A total of 59 young adults aged 18–25 (48 female and 11 male participants, mean ± SD = 21.5 ± 2.0 years) experiencing psychological distress completed the study. Participants were evaluated at baseline, 6, and 12 months. At baseline, the participants reported lifetime trauma events and completed a monetary reward functional magnetic resonance imaging task. Affective and anxiety symptoms were reported at each visit, and trajectories were calculated using MPlus. Neural activation during RPE and other phases of reward processing were determined using SPM8. Trauma and reward neural activation were entered as predictors of symptom trajectories. Results Trauma exposure moderated prospective relationships between left ventral striatum (β = −1.29, p = .02) and right amygdala (β = 0.58, p = .04) activation to RPE and future hypo/mania severity trajectory: the interaction between greater trauma and greater left ventral striatum activation to RPE was associated with a shallower increase in hypo/mania severity, whereas the interaction between greater trauma and greater right amygdala activation to RPE was associated with increasing hypo/mania severity. Conclusions Trauma exposure affects prospective relationships between markers of reward circuitry function and affective symptom trajectories. Evaluating trauma exposure is thus crucial in naturalistic and treatment studies aiming to identify neural predictors of future affective symptom course.

The learned helplessness (LH) paradigm, developed in experimental animals, has had great influence on the development of models of mood and anxiety disorders. However, the insights from this paradigm have not always translated straightforwardly into human experimental work. In particular, instrumental contingency learning experiments yielded the contradictory finding of more accurate contingency knowledge in depressed individuals (“depressive realism”: DR). A growing literature involving the application of computational modelling applied to human learning studies suggest that possible sequelae of LH in humans may be manifest in one or more potential candidate reinforcement learning-based mechanisms. This analysis suggests that the DR effect is theoretically and empirically independent of LH, despite both LH and DR being related to depression. Overall, the review highlights recent developments within the complex literature of learning and choice in depression and proposes a variety of testable predictions which may serve to delineate more precisely the presence, and neural basis, of LH-like sequelae across social and non-social learning and choice paradigms in depressed patients.

Impulsivity (rash action with deleterious outcomes) is common to many psychiatric disorders. While some studies indicate altered amygdala and prefrontal cortical (PFC) activity associated with impulsivity, it remains unclear whether these patterns of neural activity are specific to impulsivity or common to a range of affective and anxiety symptoms. To elucidate neural markers specific to impulsivity, we aimed to differentiate patterns of amygdala–PFC activity and functional connectivity associated with impulsivity from those associated with affective and anxiety symptoms, and identify measures of this circuitry predicting future worsening of impulsivity. Using a face emotion processing task that reliably activates amygdala–PFC circuitry, neural activity and connectivity were assessed in a transdiagnostically-recruited sample of young adults, including healthy (N = 47) and treatment-seeking individuals (N = 67). Relationships were examined between neural measures and impulsivity, anhedonia, and affective and anxiety symptoms at baseline (N = 114), and at 6 months post scan (N = 30). Impulsivity, particularly negative urgency and lack of perseverance, was related to greater amygdala activity (beta = 0.82, p = 0.003; beta = 0.68, p = 0.004; respectively) and lower amygdala–medial PFC functional connectivity (voxels = 60, tpeak = 4.45, pFWE = 0.017; voxels = 335, tpeak = 5.26, pFWE = 0.001; respectively) to facial fear. Left vlPFC, but not amygdala, activity to facial anger was inversely associated with mania/hypomania (beta = −2.08, p = 0.018). Impulsivity 6 months later was predicted by amygdala activity to facial sadness (beta = 0.50, p = 0.017). There were no other significant relationships between neural activity and 6-month anhedonia, affective, and anxiety symptoms. Our findings are the first to associate amygdala–PFC activity and functional connectivity with impulsivity in a large, transdiagnostic sample, providing neural targets for future interventions to reduce predisposition to impulsivity and related future mental health problems in young adults.

Background: Functional abnormalities in emotion processing neural circuitry in adolescents with a history of suicide attempt relative to depressed adolescents with no history of suicide and healthy controls have been identified, typically utilizing static face presentations. Objective: The objective of the present work was to characterize functional activations associated with emotional face processing in adolescents with and without a history of suicide attempt. Methods: 64 adolescents including 19 with a history of depression and suicide attempt (ATT), 22 with a history of depression but no suicide attempt (NAT) and 23 healthy controls (HC) performed an implicit emotional-faces task during functional neuroimaging, in which they identified a color label superimposed on neutral faces that dynamically morphed into one of four emotional faces (angry, fearful, sad, and happy). Results: HC showed greater Blood Oxygenation Level Dependent (BOLD) responses compared with ATT in the Right Dorsolateral Prefrontal Cortex (rDLPFC) to all emotional faces compared to shapes. A similar pattern of group differences was seen when both ATT and NAT groups were compared with HC. Across all participants, an association between child trauma and rDLPFC activation was seen, although this was not corrected for multiple comparisons. Conclusions: Together, the findings are consistent with prior observations of emotion-related alterations in neural function in suicide attempters. However, they also suggest that adequate control groups are necessary to dissociate specific correlates of suicide risk from depression or trauma severity, which may contribute to prefrontal alterations in emotion processing.

OBJECTIVE Bipolar disorder (BD) has been associated with abnormal reward functioning including pleasure-seeking and impulsivity. Here we sought to clarify whether these changes can be attributed to abnormalities in the neural processing of reward valuation or error prediction. Moreover, we tested whether abnormalities in these processes are associated with familial vulnerability to BD. METHODS We obtained functional magnetic resonance imaging data from patients with recently diagnosed BD (n = 85), their unaffected first-degree relatives (n = 44), and healthy control participants (n = 66) while they were performing a monetary card game. We used a region-of-interest approach to test for group differences in the activation of the midbrain, the ventral striatum, and the prefrontal cortex during reward valuation and error prediction. RESULTS Patients with BD showed decreased prediction error signal in ventrolateral prefrontal cortex and the unaffected relatives showed decreased prediction error signal in the supplementary motor area in comparison to healthy controls. There were no significant group differences in the activation of the ventral striatum during the task. In healthy controls, prediction error signal in dorsal anterior cingulate cortex correlated with an out-of-scanner measure of motor inhibition but this association was absent in patients and relatives. CONCLUSIONS The findings indicate that abnormal reward processing in BD is primarily related to deficits in the engagement of prefrontal regions involved in inhibitory control during error prediction. In contrast, deficient activation in supplementary motor cortex involved in planning of movement emerged as a familial vulnerability to BD.

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. Neuroimaging studies have implicated altered connectivity among the functional networks of the cerebral cortex in the pathophysiology of OCD. However, there has been no comprehensive investigation of the cross-talk between the cerebellum and functional networks in the cerebral cortex.This functional neuroimaging study was completed by 44 adult participants with OCD and 43 healthy control participants. We performed large-scale data-driven brain network analysis to identify functional connectivity patterns using resting-state functional magnetic resonance imaging data.Participants with OCD showed lower functional connectivity within the somatomotor network and greater functional connectivity among the somatomotor network, cerebellum, and subcortical network (e.g., thalamus and pallidum; all p.005). Network-based statistics analyses demonstrated one component comprising connectivity within the somatomotor network that showed lower connectivity and a second component comprising connectivity among the somatomotor network, and motor regions in particular, and the cerebellum that showed greater connectivity in participants with OCD relative to healthy control participants. In participants with OCD, abnormal connectivity across both network-based statistics-derived components positively correlated with OCD symptom severity (p = .006).To our knowledge, this study is the first comprehensive investigation of large-scale network alteration across the cerebral cortex, subcortical regions, and cerebellum in OCD. Our findings highlight a critical role of the cerebellum in the pathophysiology of OCD.

BackgroundDepressive episodes experienced in unipolar (UD) and bipolar (BD) disorders are characterized by anhedonia and have been associated with abnormalities in reward processes related to reward valuation and error prediction. It remains however unclear whether these deficits are associated with familial vulnerability to mood disorders.MethodsIn a functional magnetic resonance imaging study, we evaluated differences in the expected value (EV) and reward prediction error (RPE) signals in ventral striatum (VS) and prefrontal cortex between three groups of monozygotic twins: affected twins in remission for either UD or BD (n = 53), their high-risk unaffected co-twins (n = 34), and low-risk twins with no family history of mood disorders (n = 25).ResultsCompared to low-risk twins, affected twins showed lower EV signal bilaterally in the frontal poles and lower RPE signal bilaterally in the VS, left frontal pole and superior frontal gyrus. The high-risk group did not show a significant change in the EV or RPE signals in frontostriatal regions, yet both reward signals were consistently lower compared with low-risk twins in all regions where the affected twins showed significant reductions.ConclusionOur findings strengthen the notion that reduced valuation of expected rewards and reduced error-dependent reward learning may underpin core symptom of depression such as loss of interest in rewarding activities. The trend reduction in reward-related signals in unaffected co-twins warrants further investigation of this effect in larger samples and prospective follow-up to confirm possible association with increased familial vulnerability to mood disorders.

Delivery of effective antidepressant treatment has been hampered by a lack of objective tools for predicting or monitoring treatment response. This study aimed to address this gap by testing novel dynamic resting-state functional network markers of antidepressant response.The Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study randomized adults with major depressive disorder to 8 weeks of either sertraline or placebo, and depression severity was evaluated longitudinally. Participants completed resting-state neuroimaging pretreatment and again after 1 week of treatment (n = 259 eligible for analyses). Coactivation pattern analyses identified recurrent whole-brain states of spatial coactivation, and computed time spent in each state for each participant was the main dynamic measure. Multilevel modeling estimated the associations between pretreatment network dynamics and sertraline response and between early (pretreatment to 1 week) changes in network dynamics and sertraline response.Dynamic network markers of early sertraline response included increased time in network states consistent with canonical default and salience networks, together with decreased time in network states characterized by coactivation of cingulate and ventral limbic or temporal regions. The effect of sertraline on depression recovery was mediated by these dynamic network changes. In contrast, early changes in dynamic functioning of corticolimbic and frontoinsular-default networks were related to patterns of symptom recovery common across treatment groups.Dynamic resting-state markers of early antidepressant response or general recovery may assist development of clinical tools for monitoring and predicting effective intervention.

Contains fulltext : 233041.pdf (Publisher’s version ) (Open Access) Over the past three decades, functional MRI (fMRI) has become key to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (n = 272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (n = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared to full in-person psychiatric screening), recruited at least partly from convenience samples (compared to community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias. 14 p.

Young adults are at high risk for suicide, yet there is limited ability to predict suicidal thoughts and behaviors. Machine learning approaches are better able to examine a large number of variables simultaneously to identify combinations of factors associated with suicidal thoughts and behaviors. The current study used LASSO regression to investigate extent to which a number of demographic, psychiatric, behavioral, and functional neuroimaging variables are associated with suicidal thoughts and behaviors during young adulthood. 78 treatment seeking young adults (ages 18-25) completed demographic, psychiatric, behavioral, and suicidality measures. Participants also completed an implicit emotion regulation functional neuroimaging paradigm. Report of recent suicidal thoughts and behaviors served as the dependent variable. Five variables were identified by the LASSO regression: Two were demographic variables (age and level of education), two were psychiatric variables (depression and general psychiatric distress), and one was a neuroimaging variable (left amygdala activity during sad faces). Amygdala function was significantly associated with suicidal thoughts and behaviors above and beyond the other factors. Findings inform the study of suicidal thoughts and behaviors among treatment seeking young adults, and also highlight the importance of investigating neurobiological markers.

BACKGROUND: Drifts between wakefulness and sleep are common during resting state functional MRI (rsfMRI). Among healthy adults, within-scanner sleep can impact functional connectivity of default mode (DMN), task-positive (TPN), and thalamo-cortical networks. Because dysfunctional arousal states (i.e., sleepiness, sleep disturbance) are common in affective disorders, individuals with affective psychopathology may be more prone to unstable wakefulness during rsfMRI, hampering the estimation of clinically meaningful functional connectivity biomarkers. METHODS: A transdiagnostic sample of 150 young adults (68 psychologically distressed; 82 psychiatrically healthy) completed rsfMRI and reported whether they experienced within-scanner sleep. Symptom scales were reduced into depression/anxiety and mania proneness dimensions using principal component analysis. We evaluated associations between within-scanner sleep, clinical status, and functional connectivity of the DMN, TPN, and thalamus. RESULTS: Within-scanner sleep during rsfMRI was reported by 44% of participants (n=66) but was unrelated to psychiatric diagnoses or mood symptom severity (p-values>0.05). Across all participants, self-reported within-scanner sleep was associated with connectivity signatures akin to objectively-assessed sleep, including lower within-DMN connectivity, lower DMN-TPN anti-correlation, and altered thalamo-cortical connectivity (p0.05). LIMITATIONS: Subjective report of within-scanner sleep. CONCLUSIONS: Findings implicate within-scanner sleep as a source of variance in network connectivity; careful monitoring and correction for within-scanner sleep may enhance our ability to characterize network signatures underlying affective psychopathology.

Bipolar Disorder is costly and debilitating, and many treatments have side effects. Transcranial Direct Current Stimulation (tDCS) is a well-tolerated neuromodulation technique that may be a useful treatment for Bipolar Disorder if targeted to neural regions implicated in the disorder. One potential region is the left ventrolateral prefrontal cortex (vlPFC), which shows abnormally elevated activity during reward expectancy in individuals with Bipolar Disorder. We used a counterbalanced repeated-measures design to assess the impact of cathodal (inhibitory) tDCS over the left vlPFC on reward circuitry activity, functional connectivity, and affect in adults with Bipolar Disorder, as a step toward developing novel interventions for individuals with the disorder. −1mA cathodal tDCS was administered over the left vlPFC versus a control region, left somatosensory cortex, concurrently with neuroimaging. Affect was assessed pre and post scan in remitted Bipolar Disorder(n=27) and age/gender-matched healthy (n=31) adults. Relative to cathodal tDCS over the left somatosensory cortex, cathodal tDCS over the left vlPFC lowered reward expectancy-related left ventral striatal activity (F(1,51)=9.61,p=.003), and was associated with lower negative affect post scan, controlling for pre-scan negative affect, (F(1,49)=5.57,p=.02) in all participants. Acute cathodal tDCS over the left vlPFC relative to the left somatosensory cortex reduces reward expectancy-related activity and negative affect post tDCS. Building on these findings, future studies can determine whether chronic cathodal tDCS over the left vlPFC has sustained effects on mood in individuals with Bipolar Disorder, to guide new treatment developments for the disorder. ISRCTN11314056

Transcranial direct current stimulation (tDCS) is a promising method for altering the function of neural systems, cognition, and behavior. Evidence is emerging that it can also influence psychiatric symptomatology, including major depression and schizophrenia. However, there are many open questions regarding how the method might have such an effect, and uncertainties surrounding its influence on neural activity, and human cognition and functioning. In the present critical review, we identify key priorities for future research into major depression and schizophrenia, including studies of the mechanism(s) of action of tDCS at the neuronal and systems levels, the establishment of the cognitive impact of tDCS, as well as investigations of the potential clinical efficacy of tDCS. We highlight areas of progress in each of these domains, including data which appears to favor an effect of tDCS on neural oscillations rather than spiking, and findings that tDCS administration to the prefrontal cortex during task training may be an effective way to enhance behavioral performance. Finally, we provide suggestions for further empirical study that will elucidate the impact of tDCS on brain and behavior, and may pave the way for efficacious clinical treatments for psychiatric disorders.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. 222 unmedicated adults with MDD randomized to receive sertraline (n=110) or placebo (n=112) in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study completed demographic and clinical assessments, and pre-treatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on Week-8 depression levels (Fs≥9.67,ps≤0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower Week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pre-treatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pre-treatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment. Trial Registration: NCT01407094; http://clinicaltrials.gov/show/NCT01407094

Background The prefrontal cortex regulates behavioural adaptation in response to feedback. However, the causal role of different prefrontal regions remains unclear, based on indirect evidence derived from functional neuroimaging. Neuroimaging studies show dorsomedial prefrontal activation during feedback monitoring, whereas the ventrolateral prefrontal cortex engages during behavioural adaptation (shifting). Objective We used high-definition transcranial direct current stimulation (HD-tDCS) to elucidate the roles of the ventrolateral prefrontal cortex (vlPFC) and the dorsomedial prefrontal cortex (dmPFC) in behaviour change, using a probabilistic reversal learning task (PRLT). Method Fifty-two healthy adults were randomly assigned to receive cathodal HD-tDCS to inhibit the vlPFC or the dmPFC versus sham stimulation, prior to completing the PRLT. The outcome measures were the number of perseverative errors and the electroencephalography (EEG) signals of feedback-related negativity (FRN) in the PRLT. We hypothesised that inhibition of the vlPFC would be specifically associated with more perseverative errors and weaker FRNs. Results We found that vlPFC inhibition was associated with higher perseverative errors compared to sham and dmPFC stimulation conditions. Although there were no statistically significant differences in FRN amplitudes, the effect sizes indicate an association between inhibition of the vlPFC and lower FRN amplitudes. Conclusion Our findings support a causal role of the vlPFC on feedback-based behavioural adaptation, which is critical for adaptive goal-driven behaviour.

Obsessive-compulsive disorder (OCD) is a disabling condition, often associated with a chronic course. Given its role in attentional control, decision-making, and emotional regulation, the anterior cingulate cortex is considered to have a key role in the pathophysiology of the disorder. Notably, the cingulum bundle, being the major white matter tract connecting to this region, has been historically a target for the surgical treatment of intractable OCD. In this study, we aimed to identify the extent to which focal—more than diffuse—abnormalities in fiber collinearity of the cingulum bundle could distinguish 48 adults with OCD (mean age [SD] = 23.3 [4.5] years; F/M = 30/18) from 45 age- and sex-matched healthy control adults (CONT; mean age [SD] = 23.2 [3.8] years; F/M = 28/17) and further examine if these abnormalities correlated with symptom severity. Use of tract-profiles rather than a conventional diffusion imaging approach allowed us to characterize white matter microstructural properties along (100 segments), as opposed to averaging these measures across, the entire tract. To account for these 100 different segments of the cingulum bundle, a repeated measures analysis of variance revealed a main effect of group (OCD

OBJECTIVE: Suicide deaths and suicidal thoughts and behaviors are considered a public health emergency, yet their brain underpinnings remain elusive. We aim to examine the classification accuracy of individual, environmental, and clinical characteristics, as well as multimodal brain imaging correlates of suicidal thoughts and behaviors in a US population-based sample of school-aged children. METHODS: Children aged 9–10 years (n=7,994) from a population-based sample from the Adolescent Brain Cognitive Development study were assessed for lifetime suicidal thoughts and behaviors. Following quality control, we examined structural magnetic resonance imaging (sMRI) (n=6,238), resting state functional MRI (rs-fMRI) (n=4,134), and task-based fMRI (range n=4,075 to 4,608). We examined differences with Welch’s t-test and Equivalence Tests, with observed effect sizes (Cohen’s d) and their 90% confidence interval (CI) < |0.15|. Classification accuracy was examined with area under precision-recall curves (AUPRC). RESULTS: Among the 7,994 unrelated children (3,757 females [47.0%]), those with lifetime suicidal thoughts and behaviors based on children (n=684 [8.6%]), caregiver (n=654 [8.2%]) or concordant reports (n=198 [2.5%]), presented higher levels of social adversity and psychopathology on themselves and their caregivers compared to never-suicidal children (n=6,854 [85.7%]). Only one imaging test survived statistical correction: caregiver-reported suicidal thoughts and behaviors were associated with a thinner left bank of the superior temporal sulcus (d=−0.17, 95%CI −0.26, −0.08, p(FDR)=0.019). Based on the prespecified bounds of |0.15|, ~48% of the group mean differences for child-reported suicidal thoughts and behaviors comparisons and a ~22% for parent-reported suicidal thoughts and behaviors comparisons were considered equivalent. All observed effect sizes were relatively small (d≤ǀ0.30|) and both non-imaging and imaging correlates had low classification accuracy (AUPRC≤0.10). CONCLUSIONS: Using commonly applied neuroimaging measures, we were unable to find a discrete brain signature related to suicidal thoughts and behaviors in youth. There is a great need for improved approaches to the neurobiology of suicide.

Sensation Seeking, the proclivity toward novel and stimulating experiences, is associated with greater left ventrolateral prefrontal cortex (vlPFC) activity during uncertain reward expectancy. Here, we examined relationships between sensation seeking and vlPFC oscillatory dynamics using electroencephalography (EEG).In 26 adolescents/young adults (16 female; 22.3 ± 1.7yrs), EEG was measured during uncertain reward expectancy. Event-related spectral perturbations (ERSP) from 15-80 Hz (beta/gamma bands) were compared as a function of uncertain reward expected value and assessed for relationships with feedback-related negativity (FRN) response to outcome feedback and response tendency measures of risk for BD.Event-related synchronization (ERS) between 15-25 Hz (beta) over left vlPFC was sensitive to the expected value of uncertain reward (rho=0.46; p = 0.048), and correlated with sensation seeking (r = 0.49, p 0.01) and feedback-related negativity (FRN), where greater beta ERS was related to larger FRN (r = -0.39, p = 0.047). FRN was also related to behavioral inhibition (r = 0.49, p 0.01).It is unknown whether results may extrapolate to clinical populations, given the healthy sample used here. Further, although we have confidence that the beta-band signal we measure in this study arises from left prefrontal cortex, we largely infer a left vlPFC source.These findings highlight the role of left vlPFC in evaluation of immediate rewards. We now provide a link between reward expectancy-related left vlPFC activity and the well-characterized FRN, with a known role in attentive processing. These findings can guide treatment development for mania/hypomania at-risk individuals, including transcranial alternating current stimulation.

Highlights • Deficits in reward processing are thought to play a major role in autism spectrum disorders (ASD). • Not only social, but also non-social rewards are associated with striatal hypoactivation in ASD. • Our meta-analysis highlights the striatum as a central hub with altered activation patterns., Functional imaging studies have found differential neural activation patterns during reward-paradigms in patients with autism spectrum disorder (ASD) compared to neurotypical controls. However, publications report conflicting results on the directionality and location of these aberrant activations. We here quantitatively summarized relevant fMRI papers in the field using the anatomical likelihood estimation (ALE) algorithm. Patients with ASD consistently showed hypoactivations in the striatum across studies, mainly in the right putamen and accumbens. These regions are functionally involved in the processing of rewards and are enrolled in extensive neural networks involving limbic, cortical, thalamic and mesencephalic regions. The striatal hypo-activations found in our ALE meta-analysis, which pooled over contrasts derived from the included studies on reward-processing in ASD, highlight the role of the striatum as a key neural correlate of impaired reward processing in autism. These changes were present for studies using social and non-social stimuli alike. The involvement of these regions in extensive networks associated with the processing of both positive and negative emotion alike might hint at broader impairments of emotion processing in the disorder.

The resting state paradigm is ubiquitous in clinical neuroimaging, being convenient and practical to run, and yielding robust and theoretically salient individual differences in functional connectivity. The richness of the data, and the consequential variety of analyses that can be performed is both a blessing and a curse, providing many potential leads but few decisive observations. The problems of this complexity are compounded when the method is applied to multidimensional phenotypes such as mood disorders. In particular, I explore several potential accounts of the nature of the underlying alteration(s) of functional connectivity in major depression, including structural deficits, Hebbian mechanisms, mood and arousal-related alterations and neurotransmitter-based mechanisms. Evidence for and against each mechanism is described, with methodological heterogeneity and state-related factors being emphasized as areas of particular significance for future work. In summary, I describe the considerable progress that has been made, outlining the many challenges but also successful attempts to make progress toward the goal of identifying replicable and generalizable markers of major depression.

BackgroundLow intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation (tACS or tDCS), applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional magnetic resonance imaging (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies.ObjectiveTo develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency, and reproducibility (ContES Checklist).MethodsA two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists (EP) through the International Network of the tES-fMRI (INTF) Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC based on a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed using the checklist.ResultsExperts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (1) technological factors, (2) safety and noise tests, and (3) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article.ConclusionsUse of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies, and increase methodological transparency and reproducibility.

Neural signatures of suicide risk likely reflect a combination of specific and non-specific factors, and clarifying specific factors may facilitate development of novel treatments. Previously, we demonstrated an altered pattern of resting state connectivity between the dorsal and ventral posterior cingulate cortex (d/vPCC) and the dorsal anterior cingulate cortex (dACC), as well as altered low frequency oscillations in these regions, in individuals with a history of suicidal thoughts and behaviors (STBs) compared to healthy controls. It remains uncertain, however, whether these markers were directly related to STBs or, more generally, reflect a trait-level risk factor for depression. Here, we examined data from a 3-generational longitudinal study of depression where resting state fMRI data were analyzed from 2nd and 3rd generation offspring of probands with (FH+ = 44: STB+ = 32, STB- = 12) and without (FH- = 25: STB+ = 15, STB- = 10) a family history of major depressive disorder (MDD). Standard seed-based methods and a frequency-based analysis of intrinsic neural activity (ALFF/fALFF) were employed. FH of MDD, but not a personal history of STBs or MDD, was associated with relatively reduced dPCC-dACC, and enhanced vPCC-dACC functional connectivity. FH of MDD showed a pattern of reduced ALFF in the dPCC whereas an STB history was associated with an increase. All findings were invariant to confounding by lifetime MDD and current depression severity. Overall, contrary to predictions, resting state functional connectivity within the default mode network (DMN) was associated with FH of depression rather than STBs. These findings confirm the relevance of DMN functional connectivity for mood disorders and underscore the importance of disambiguating biological factors that differentially relate to mental disorders versus STBs.

Highlights • We investigated goal-directed processing in OCD and healthy controls using a rule-based devaluation paradigm. • OCD patients with longer illness duration showed poorer goal-directed performance. • Neural differences were observed in orbitofrontal cortex, premotor cortex, inferior frontal gyrus and the caudate, relating to group and individual differences in devaluation performance. • Together the findings identify neural correlates of goal-directed deficits in OCD, and support a dual-process model of actions and habits., Obsessive-Compulsive Disorder (OCD) is characterized by repetitive avoidance behavior which is distressing and associated with marked impairment of everyday life. Recently, paradigms have been designed to explore the hypothesis that avoidance behavior in OCD is consistent with a formal conception of habit. Such studies have involved a devaluation paradigm, in which the value of a previously rewarded cue is altered so that avoidance is no longer necessary. We employed a rule-based avoidance task which included a devaluation, examining behavioral performance on the task and their neural correlates using functional MRI in groups of participants with OCD (n = 44) and healthy control participants (n = 46). Neuroimaging data were analyzed using a general linear model (GLM), modelling valued, devalued and control cues, as well as feedback events. First, while no overall effect of OCD was seen on devaluation performance, patients with longer illness duration showed poorer devaluation performance (χ2 = 13.84, p

Depression and anxiety have been linked to poor quality of life (QoL) - one's subjective perception of relationships, physical health, daily functioning, general sense of well-being and life satisfaction. Elucidating abnormal white matter microstructure associated with mood and other symptoms and QoL is important to facilitate treatment. Ninety-six young adults (18-25 years old) seeking help for psychological distress, irrespective of presence or absence of psychiatric diagnosis completed diffusion weighted and anatomical scans, clinical and behavioral measures, and QoL assessment. We examined relationships between diffusion imaging properties in major white matter tracts involved in emotion processing and regulation, symptoms, and QoL. Depression and general distress levels fully mediated the relationship between fractional anisotropy (FA), an indirect index of fiber collinearity, and radial diffusivity (RD), an index sensitive to axonal/myelin damage, in right uncinate fasciculus and QoL. The relationship between reduced FA (and increased RD) in right uncinate fasciculus and poor QoL was explained by greater severity of depression and general distress. These findings underscore the role of white matter microstructure in right uncinate fasciculus in relation to depressive and general distress symptoms and, in turn, QoL. Importantly, they suggest that measures of white matter microstructure in this tract can be used as putative objective markers of emotion dysregulation, to inform and monitor the impact of interventions to reduce affective symptoms and improve QoL in young adults.

The 'default mode network' (DMN), a collection of brain regions including the posterior cingulate cortex (PCC), shows reliable inter-regional functional connectivity at rest. It has been implicated in rumination and other negative affective states, but its role in suicidal ideation is not well understood. We employed seed based functional connectivity methods to analyze resting state fMRI data in 34 suicidal ideators and 40 healthy control participants. Whole-brain connectivity with dorsal PCC or ventral PCC was broadly intact between the two groups, but while the control participants showed greater coupling between the dorsal anterior cingulate cortex (dACC) and dorsal PCC, compared to the dACC and ventral PCC, this difference was reversed in the ideators. Furthermore, ongoing low frequency BOLD signal in these three regions (dorsal, ventral PCC, dACC) was reduced in the ideators. The structural integrity of the cingulum bundle, as measured using diffusion tensor imaging (DTI), also explained variation in the functional connectivity measures but did not abolish the group differences. Together, these findings provide evidence of abnormalities in the DMN underlying the tendency towards suicidal ideation.

Background Personality dysfunction represents one of the only predictors of differential response between active treatments for depression to have replicated. We examine whether depressed patients with higher neuroticism scores, a marker of personality dysfunction, show differences compared with depressed patients with lower scores in the functioning of two brain regions associated with treatment response, the anterior cingulate and anterior insula cortices. Methods Functional magnetic resonance imaging data during an emotional Stroop task were collected from 135 adults with major depressive disorder at four academic medical centers participating in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) study. Secondary analyses were conducted including a sample of 28 healthy subjects. Results In whole-brain analyses, higher neuroticism among adults with depression was associated with increased activity in and connectivity with the right anterior insula cortex to incongruent compared with congruent emotional stimuli (all k ≥ 281, all p p Conclusions This study provides convergent evidence for the importance of the right anterior insula cortex as a brain-based marker of clinically meaningful individual differences in neuroticism among adults with depression. This is a critical next step in linking personality dysfunction, a replicated clinical predictor of differential antidepressant treatment response, with differences in underlying brain function.

Background High trait impulsive sensation seeking (ISS), the tendency to engage in behavior without forethought and to seek out new or extreme experiences, is a transdiagnostic risk factor for externalizing and mood disorders, particularly bipolar disorder. We published a positive association between trait ISS and reward expectancy–related activity in the left ventrolateral prefrontal cortex (L vlPFC) and the ventral striatum. We aimed to replicate this finding and extend it by testing for mediation effects of ISS on relationships between reward expectancy–related activity and measures denoting hypomania. Methods A transdiagnostic sample of 127 adults, 18 to 25 years of age, completed a card-guessing functional magnetic resonance imaging task as well as measures of ISS (inattention, motor impulsivity, fun seeking, positive and negative urgency) and the Moods Spectrum as a measure of hypomania. An original sample of 98 was included for confirmatory and mediation analyses. Results We replicated a positive relationship between reward expectancy–related L vlPFC activity and negative urgency, an ISS component (β = .28, t = 2.44, p = .0169). We combined these data with the original sample, confirming this finding (β = .27, t = 2.41, p = .0184). Negative urgency statistically mediated the relationship between reward expectancy–related L vlPFC activity and Moods Spectrum factors associated with hypomania. No other associations between ISS measures and reward expectancy–related activity were replicated. Conclusions We replicated findings showing that reward expectancy–related L vlPFC activity is a biomarker for negative urgency, the tendency to react with frustration during distressing conditions. Negative urgency also statistically mediated the relationship between L vlPFC activity and measures indicative of hypomanic symptoms.

Background The aim of this study was to apply multivariate pattern recognition to predict the severity of behavioral traits and symptoms associated with risk for bipolar spectrum disorder from patterns of whole-brain activation during reward expectancy to facilitate the identification of individual-level neural biomarkers of bipolar disorder risk. Methods We acquired functional neuroimaging data from two independent samples of transdiagnostically recruited adults (18–25 years of age; n = 56, mean age 21.9 ± 2.2 years, 42 women; n = 36, mean age 21.2 ± 2.2 years, 24 women) during reward expectancy task performance. Pattern recognition model performance in each sample was measured using correlation and mean squared error between actual and whole-brain activation–predicted scores on behavioral traits and symptoms. Results In the first sample, the model significantly predicted severity of a specific hypo/mania-related symptom, heightened energy, measured by the energy manic subdomain of the Mood Spectrum Structured Interviews (r = .42, p = .001; mean squared error = 9.93, p = .001). The region with the highest contribution to the model was the left ventrolateral prefrontal cortex. Results were confirmed in the second sample (r = .33, p = .01; mean squared error = 8.61, p = .01), in which the severity of this symptom was predicted using a bilateral ventrolateral prefrontal cortical mask (r = .33, p = .009, mean squared error = 9.37, p = .04). Conclusions The severity of a specific hypo/mania-related symptom was predicted from patterns of whole-brain activation in two independent samples. Given that emerging manic symptoms predispose to bipolar disorders, these findings could provide neural biomarkers to aid early identification of individual-level bipolar disorder risk in young adults.

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. While a cortico-striatal-limbic network has been implicated in the pathophysiology of OCD, the neural correlates of this network in OCD are not well understood. In this study, we examined resting state functional connectivity among regions within the cortico-striatal-limbic OCD neural network, including the rostral anterior cingulate cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, thalamus and caudate, in 44 OCD and 43 healthy participants. We then examined relationships between OCD neural network connectivity and OCD symptom severity in OCD participants. OCD relative to healthy participants showed significantly greater connectivity between the left caudate and bilateral dorsolateral prefrontal cortex. We also found a positive correlation between left caudate-bilateral dorsolateral prefrontal cortex connectivity and depression scores in OCD participants, such that greater positive connectivity was associated with more severe symptoms. This study makes a significant contribution to our understanding of functional networks and their relationship with depression in OCD.