Integration of valence and conflict processing through cellular-field interactions in human subgenual cingulate during emotional face processing in treatment-resistant depression.

The subgenual anterior cingulate cortex (sgACC) has been identified as a key brain area involved in various cognitive and emotional processes. While the sgACC has been implicated in both emotional valuation and emotional conflict monitoring, it is still unclear how this area integrates multiple functions. We characterized both single neuron and local field oscillatory activity in 14 patients undergoing sgACC deep brain stimulation for treatment-resistant depression. During recording, patients were presented with a modified Stroop task containing emotional face images that varied in valence and congruence. We further analyzed spike-field interactions to understand how network dynamics influence single neuron activity in this area. Most single neurons responded to both valence and congruence, revealing that sgACC neuronal activity can encode multiple processes within the same task, indicative of multifunctionality. During peak neuronal response, we observed increased spectral power in low frequency oscillations, including theta-band synchronization (4-8 Hz), as well as desynchronization in beta-band frequencies (13-30 Hz). Theta activity was modulated by current trial congruency with greater increases in spectral power following non-congruent stimuli, while beta desynchronizations occurred regardless of emotional valence. Spike-field interactions revealed that local sgACC spiking was phase-locked most prominently to the beta band, whereas phase-locking to the theta band occurred in fewer neurons overall but was modulated more strongly for neurons that were responsive to task. Our findings provide the first direct evidence of spike-field interactions relating to emotional cognitive processing in the human sgACC. Furthermore, we directly related theta oscillatory dynamics in human sgACC to current trial congruency, demonstrating it as an important regulator during conflict detection. Our data endorse the sgACC as an integrative hub for cognitive emotional processing through modulation of beta and theta network activity.

Functional brain network features specify DBS outcome for patients with treatment resistant depression.

Deep brain stimulation (DBS) has shown therapeutic benefits for treatment resistant depression (TRD). Stimulation of the subcallosal cingulate gyrus (SCG) aims to alter dysregulation between subcortical and cortex. However, the 50% response rates for SCG-DBS indicates that selection of appropriate patients is challenging. Since stimulation influences large-scale network function, we hypothesized that network features can be used as biomarkers to inform outcome. In this pilot project, we used resting-state EEG recorded longitudinally from 10 TRD patients with SCG-DBS (11 at baseline). EEGs were recorded before DBS-surgery, 1-3 months, and 6 months post surgery. We used graph theoretical analysis to calculate clustering coefficient, global efficiency, eigenvector centrality, energy, and entropy of source-localized EEG networks to determine their topological/dynamical features. Patients were classified as responders based on achieving a 50% or greater reduction in Hamilton Depression (HAM-D) scores from baseline to 12 months post surgery. In the delta band, false discovery rate analysis revealed that global brain network features (segregation, integration, synchronization, and complexity) were significantly lower and centrality of subgenual anterior cingulate cortex (ACC) was higher in responders than in non-responders. Accordingly, longitudinal analysis showed SCG-DBS increased global network features and decreased centrality of subgenual ACC. Similarly, a clustering method separated two groups by network features and significant correlations were identified longitudinally between network changes and depression symptoms. Despite recent speculation that certain subtypes of TRD are more likely to respond to DBS, in the SCG it seems that underlying brain network features are associated with ability to respond to DBS. SCG-DBS increased segregation, integration, and synchronizability of brain networks, suggesting that information processing became faster and more efficient, in those patients in whom it was lower at baseline. Centrality results suggest these changes may occur via altered connectivity in specific brain regions especially ACC. We highlight potential mechanisms of therapeutic effect for SCG-DBS.

Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial.

Theta burst stimulation (TBS) is approved and widely used in the treatment of treatment resistant-major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. Here, we examined the efficacy and safety of accelerated bilateral TBS in major depressive disorder (MDD). In this open label pilot study, 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least one antidepressant, received bilateral TBS, consisting of 5 sequential bilateral intermittent TBS (iTBS) (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treat treatment changes at day 5 and 2-weeks in Hamilton Depression Rating Scale (HDRS-17) scores and response (≥ 50% reduction from the baseline scores) and remission (≤ 7) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2-weeks post treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2-weeks post treatment suggesting delayed clinical effects. However, reduction in symptom scores between two post treatment endpoints was non-significant. 60% of patients could not tolerate the high intensity stimulation. No major adverse events occurred. Open label uncontrolled study with small sample size. These preliminary findings suggest that accelerated bilateral TBS may be clinically effective and safe for treatment resistant depression. Randomized sham-controlled trials are needed to establish the therapeutic role of accelerated bilateral TBS in depression.Trial registration: ClinicalTrials.gov, NCT10001858.

Mapping adaptation, deviance detection, and prediction error in auditory processing.

Various studies have suggested that auditory deviance detection is organized in a hierarchical manner with ascending levels of complexity. Event-related potentials (ERP) are considered to reflect different cortical processing stages. In the current electroencephalographic study, we employed an auditory sequence oddball paradigm to investigate different levels of cortical auditory processing and the contribution of neuronal habituation and prediction error mechanism to N1 and Mismatch Negativity (MMN). Our findings suggest that N1 reflects a lower cortical process primarily involved in the encoding of simple physical features and is thus mainly modulated by neuronal attenuation and not complex top-down mechanisms. By analyzing within-sequence signal differences, we divided the MMN into distinct subcomponents reflecting different hierachical levels of auditory processing. We determined a "first-order" MMN that reflects the processing of simple deviant features (such as frequency) and "higher-order" MMNs that occur at regularity violation of complex patterns or unexpected inputs that do not allow further predictions. In our source localization analysis, both the primary auditory cortex and left IFG were primarily involved in the detection of simple, physically deviant features, while the right IFG was associated with the processing of novel, unexpected auditory inputs and the ACC with regularity violation of known patterns. Summarizing, our results might contribute to a better understanding of the different complexities of neuronal habituation and prediction error mechanisms at different levels of cortical auditory processing.

Intentional action processing results from automatic bottom-up attention: An EEG-investigation into the Social Relevance Hypothesis using hypnosis.

Social stimuli grab our attention. However, it has rarely been investigated how variations in attention affect the processing of social stimuli, although the answer could help us uncover details of social cognition processes such as action understanding. In the present study, we examined how changes to bottom-up attention affects neural EEG-responses associated with intentional action processing. We induced an increase in bottom-up attention by using hypnosis. We recorded the electroencephalographic µ-wave suppression of hypnotized participants when presented with intentional actions in first and third person perspective in a video-clip paradigm. Previous studies have shown that the µ-rhythm is selectively suppressed both when executing and observing goal-directed motor actions; hence it can be used as a neural signal for intentional action processing. Our results show that neutral hypnotic trance increases µ-suppression in highly suggestible participants when they observe intentional actions. This suggests that social action processing is enhanced when bottom-up attentional processes are predominant. Our findings support the Social Relevance Hypothesis, according to which social action processing is a bottom-up driven attentional process, and can thus be altered as a function of bottom-up processing devoted to a social stimulus.

Oxidative stress in schizophrenia: a case-control study on the effects on social cognition and neurocognition.

BACKGROUND: Schizophrenia is a debilitating mental disorder that presents impairments in neurocognition and social cognition. Several studies have suggested that the etiology of schizophrenia can be partly explained by oxidative stress. However, our knowledge about the implications of oxidative stress on illness-related cognitive deficits is still far from being clear. The aim of this work was to study the role of oxidative stress molecules on social cognition and neurocognition in patients with schizophrenia. METHODS: We assessed the peripheral levels of several molecules associated with oxidative stress, namely nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), homocysteine, superoxide dismutase (SOD) and neurotrophin 4/5 (NT4/5), in forty-one patients with schizophrenia and forty-three healthy participants. A battery of tests to measure neurocognition and social cognition was also administered to the schizophrenia group. RESULTS: We found that the schizophrenia group presented substantially higher levels of oxidative stress than the control group, as revealed by elevated quantities of the pro-oxidants NO and MDA, and decreased levels of the antioxidants GSH, SOD and NT4/5. Interestingly, the levels of NT4/5, which have been shown to have antioxidant effects, correlated with executive functioning, as measured by two distinct tests (WCST and TMT). However, social cognition and symptom severity were not found to be associated with oxidative stress. CONCLUSIONS: We propose a protective role of NT4/5 against oxidative stress, which appears to have a potentially beneficial impact on neurocognition in schizophrenia.

Reward in the mirror neuron system, social context, and the implications on psychopathology.

Positive and negative reinforcers guide our behaviors as we interact with others in our social environment. Here, we present evidence that highlights a central role for reward in the general functioning of the mirror neuron system (MNS). We also discuss the relevance of reward-related modulation on other previous findings revealing certain properties of the MNS, and on social context and psychopathology.

Multimodal imaging measures in the prediction of clinical response to deep brain stimulation for refractory depression: A machine learning approach.

OBJECTIVES: This study compared machine learning models using unimodal imaging measures and combined multi-modal imaging measures for deep brain stimulation (DBS) outcome prediction in treatment resistant depression (TRD). METHODS: Regional brain glucose metabolism (CMRGlu), cerebral blood flow (CBF), and grey matter volume (GMV) were measured at baseline using 18F-fluorodeoxy glucose (18F-FDG) positron emission tomography (PET), arterial spin labelling (ASL) magnetic resonance imaging (MRI), and T1-weighted MRI, respectively, in 19 patients with TRD receiving subcallosal cingulate (SCC)-DBS. Responders (n = 9) were defined by a 50% reduction in HAMD-17 at 6 months from the baseline. Using an atlas-based approach, values of each measure were determined for pre-selected brain regions. OneR feature selection algorithm and the naïve Bayes model was used for classification. Leave-out-one cross validation was used for classifier evaluation. RESULTS: The performance accuracy of the CMRGlu classification model (84%) was greater than CBF (74%) or GMV (74%) models. The classification model using the three image modalities together led to a similar accuracy (84%0 compared to the CMRGlu classification model. CONCLUSIONS: CMRGlu imaging measures may be useful for the development of multivariate prediction models for SCC-DBS studies for TRD. The future of multivariate methods for multimodal imaging may rest on the selection of complementing features and the developing better models.Clinical Trial Registration: ClinicalTrials.gov (#NCT01983904).

Early post-treatment blood oxygenation level-dependent responses to emotion processing associated with clinical response to pharmacological treatment in major depressive disorder.

INTRODUCTION: Pre-treatment blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been used for the early identification of patients with major depressive disorder (MDD) who later respond or fail to respond to medication. However, BOLD responses early after treatment initiation may offer insight into early neural changes associated with later clinical response. The present study evaluated both pre-treatment and early post-treatment fMRI responses to an emotion processing task, to further our understanding of neural changes associated with a successful response to pharmacological intervention. METHODS: MDD patients who responded (n = 22) and failed to respond (n = 12) after 8 weeks of treatment with either citalopram or quetiapine extended release, and healthy controls (n = 18) underwent two fMRI scans, baseline (pre-treatment), and early post-treatment (one week after treatment commencement). Participants completed an emotional face matching task at both scans. RESULTS: Using threshold-free cluster enhancement (TFCE) and non-parametric permutation testing, fMRI activation maps showed that after one week of treatment, responders demonstrated increased activation in the left parietal lobule, precentral gyrus, and bilateral insula (all P < 0.05 threshold-free cluster enhancement (TFCE) family-wise error-corrected) to negative facial expressions. Non-responders showed some small increases in the precentral gyrus, while controls showed no differences between scans. Compared to non-responders, responders showed some increased activation in the superior parietal lobule and middle temporal gyrus at the post-treatment scan. There were no group differences between responders, non-responders, and controls at baseline. CONCLUSIONS: One week after treatment commencement, BOLD signal changes in the parietal lobules, insula, and middle temporal gyrus were related to clinical response to pharmacological treatment.

Author Correction: Obesity and addiction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Approach and Avoidance Behavior in Female Patients With Borderline Personality Disorder.

OBJECTIVES: Borderline personality disorder (BPD) is portrayed by unstable relationships, fears of abandonment and heightened sensitivity to social rejection. Research has shown that these characteristics may lead to inappropriate social behavior including altered approach-avoidance behavior. However, it has remained unclear how social exclusion may affect approach-avoidance behavior in patients with BPD. DESIGN: We assessed social approach-avoidance behavior and the impact of social exclusion in a sample of 38 patients with BPD and 40 healthy control participants. METHODS: We used an explicit joystick-based approach-avoidance task (AAT) after playing a virtual ball-tossing game (Cyberball), which simulates the exclusion of the participant by two other players. In the AAT, participants were required to push or pull emotional stimuli, more specifically happy and angry facial expressions, with either direct or averted gaze direction. RESULTS: Patients with BPD approached happy stimuli less and showed overall less differential approach-avoidance behavior toward individuals expressing positive or negative facial emotions compared to healthy participants, who showed more approach behavior for happy compared to angry facial expressions. Moreover, borderline symptom severity correlated inversely with the AAT score for happy facial expressions and positively with subjective unpleasantness during social exclusion as well as rejection sensitivity. However, social exclusion did not influence approach-avoidance tendencies. CONCLUSION: Patients with BPD showed altered approach-avoidance behavior, which might affect social interactions in the patient's everyday lives and may therefore impede social interaction.

Metabolic activity in subcallosal cingulate predicts response to deep brain stimulation for depression.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression (TRD), but response rates in open-label studies were not replicated in a large multicenter trial. Identifying biomarkers of response could improve patient selection and outcomes. We examined SCC metabolic activity as both a predictor and marker of SCC DBS treatment response. Brain glucose metabolism (CMRGlu) was measured with [18F] FDG-PET at baseline and 6 months post DBS in 20 TRD patients in a double-blind randomized controlled trial where two stimulation types (long pulse width (LPW) n = 9 and short pulse width (SPW) n = 11) were used. Responders (n = 10) were defined by a ≥48% reduction in Hamilton Depression Rating Scale scores after 6 months. The response rates were similar with five responders in each stimulation group: LPW (55.6%) and SPW (44.5%). First, differences in SCC CMRGlu in responders and non-responders were compared at baseline. Then machine learning analysis was performed with a leave-one-out cross-validation using a Gaussian naive Bayes classifier to test whether baseline CMRGlu in SCC could categorize responders. Finally, we compared 6-month change in metabolic activity with change in depression severity. All analyses were controlled for age. Baseline SCC CMRGlu was significantly higher in responders than non-responders. The machine learning analysis predicted response with 80% accuracy. Furthermore, reduction in SCC CMRGlu 6 months post DBS correlated with symptom improvement (r(17) = 0.509; p = 0.031). This is the first evidence of an image-based treatment selection biomarker that predicts SCC DBS response. Future studies could utilize SCC metabolic activity for prospective patient selection.

Thalamocortical connectivity in electroconvulsive therapy for major depressive disorder.

BACKGROUND: Electroconvulsive therapy (ECT) can lead to rapid and effective responses in major depressive disorder (MDD). However, the precise neural mechanisms of ECT for MDD are still unclear. Previous work has confirmed that thalamocortical circuits play an important role in emotion and cognition. However, the relationship between mechanisms of ECT for MDD and thalamocortical connectivity has not yet been investigated. METHOD: Thalamocortical functional connectivity analysis was performed on resting-state functional magnetic resonance imaging (fMRI) data collected from 28 MDD patients both pre- and post-ECT treatment, as well as 20 healthy controls. The cortex was parceled into six regions of interest (ROIs), which were used as seeds to assess the functional connectivity between the cortex and each voxel in the thalamus. Then, functional connectivity between the identified thalamic subregions and the rest of the brain was quantified to better localize thalamocortical connectivity related to ECT. Structural connectivity among the functionally abnormal regions was also determined using probabilistic tractography from diffusion tensor imaging (DTI) data. RESULTS: There was decreased parietal cortex-left pulvinar and left pulvinar-bilateral precuneus functional connectivity in post-ECT MDD patients, compared to pre-ECT MDD patients. Furthermore, functional connectivity strength of parietal cortex-left pulvinar and left pulvinar-bilateral precuneus was negative correlation with verbal fluency test scores in post-ECT MDD patients. No significant change was found in structural connectivity analysis. LIMITATIONS: The sample size of our study was not large. CONCLUSION: Our findings implicate that the specific abnormalities in thalamocortical circuit may be associated with cognitive impairment induced by ECT.

Rostral anterior cingulate glutamate predicts response to subcallosal deep brain stimulation for resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) provided benefit for treatment-resistant depression (TRD) in open-label studies but failed in a recent randomized sham-controlled trial. Informed patient selection, based on reliable biomarkers, is needed to optimize outcome. We investigated if rostral anterior cingulate (rACC) glutamate/glutamine concentration could serve as a potential biomarker of response. METHODS: Sixteen adults with TRD (Major Depression; MDD = 14; Bipolar Depression; BD =2) underwent proton magnetic resonance spectroscopy using a short-echo proton spectroscopy with a voxel placed in the rACC, prior to DBS. Improvement in depression was assessed using the 17-item Hamilton Rating Scale for Depression (HDRS). Glutamate and glutamine concentrations at baseline in the rACC were examined in relation to clinical outcomes at six months. RESULTS: Lower baseline glutamate predicted significant reduction in HDRS scores in all TRD patients (p = 0.018), and predicted both HDRS reduction (p = 0.002) and 6-month response outcome in MDD-TRD patients (p = 0.013). Neither baseline glutamine nor glutamine/glutamate ratio significantly related to outcome or symptom improvement. LIMITATIONS: Our study was limited by sample size, though it is large for a DBS study. We measured from a single voxel in the brain, so we cannot be certain our findings are specific to the rACC. CONCLUSIONS: These preliminary results suggest that baseline rACC-glutamate concentration could serve as a response-predictive biomarker for SCC-DBS, particularly in patients with resistant major depression. If our findings are replicated and validated, rACC-glutamate may provide a basis to prospectively select TRD patients to improve likelihood of response to SCC-DBS.

Unchanged food approach-avoidance behaviour of healthy men after oxytocin administration.

The oxytocinergic system has been assumed to contribute to food intake, possibly via interactions with dopamine. However, so far, it is unknown whether oxytocin influences the underlying motivational behaviour towards food. In the present study, we used a food-based approach-avoidance task (AAT) in a randomised, placebo-controlled, double-blind, cross-over design to compare intranasal oxytocin with a placebo. In the AAT, participants pushed or pulled a joystick when images of foods with a high or low craving rating were presented, where differences in response times typically reflect approach and avoidance motivational biases towards positively and negatively valence stimuli, respectively. Thirty-three healthy male participants (age = 25.12 ± 3.51 years; body mass index = 24.25 ± 2.48 kg/m2 ) completed the two-session study, one with placebo and the other with oxytocin. We used mixed-effects models to investigate effects of treatment (oxytocin, placebo), response type (approach, avoid) and stimulus (high, low craving). The results showed that both approach and avoid responses tended to be faster for foods higher in craving compared to foods lower in craving. Most importantly, we did not observe any significant effects of oxytocin compared to placebo in motivational behaviour towards food. Our study demonstrates a general response bias towards foods with different craving values, which could have implications for future studies investigating food-related behaviour. We discuss possible explanations for the null effects of oxytocin and suggest further investigation of the relationship between oxytocin, dopamine and food-reward processing.

Intrinsic thalamocortical connectivity varies in the age of onset subtypes in major depressive disorder.

BACKGROUND: Differences in the thalamocortical system have been shown in patients with major depressive disorder (MDD). Given prior evidence of phenotypic heterogeneity by the age of onset in MDD, we examined whether differences in thalamocortical connectivity could identify biological subtypes of MDD defined by the age of illness onset. METHODS: A total of 94 subjects including 20 early-onset (EO) MDD (onset, 18 years), 34 adult-onset (AO) MDD, and 40 healthy controls (HCs) underwent resting-state functional MRI. Blood-oxygen-level-dependent time courses were extracted from six cortical regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and precentral and postcentral gyri. Each ROI's time course was then correlated with each voxel in thalamus, while covarying out signal from every other ROI. RESULTS: The analysis of variance results showed significant main effects of group in frontal and temporal connectivity with thalamus. Group contrasts showed a right fronto-thalamic hypo-connectivity only in AO-MDD, but not in EO-MDD, when compared to HCs. However, direct comparison between EO-MDD and AO-MDD showed no differences. Furthermore, there was a right temporal-thalamic hyperconnectivity in both EO-MDD and AO-MDD patients relative to HCs. These results were not accounted for by sex, age, or illness burden. CONCLUSION: The age of illness onset may be a source of heterogeneity in fronto-thalamic intrinsic connectivity in MDD.

Impaired Expected Value Computations in Schizophrenia Are Associated With a Reduced Ability to Integrate Reward Probability and Magnitude of Recent Outcomes.

BACKGROUND: Motivational deficits in people with schizophrenia (PSZ) are associated with an inability to integrate the magnitude and probability of previous outcomes. The mechanisms that underlie probability-magnitude integration deficits, however, are poorly understood. We hypothesized that increased reliance on "valueless" stimulus-response associations, in lieu of expected value (EV)-based learning, could drive probability-magnitude integration deficits in PSZ with motivational deficits. METHODS: Healthy volunteers (n = 38) and PSZ (n = 49) completed a learning paradigm consisting of four stimulus pairs. Reward magnitude (3, 2, 1, 0 points) and probability (90%, 80%, 20%, 10%) determined each stimulus's EV. Following a learning phase, new and familiar stimulus pairings were presented. Participants were asked to select stimuli with the highest reward value. RESULTS: PSZ with high motivational deficits made increasingly less optimal choices as the difference in reward value (probability × magnitude) between two competing stimuli increased. Using a previously validated computational hybrid model, PSZ relied less on EV ("Q-learning") and more on stimulus-response learning ("actor-critic"), which correlated with Scale for the Assessment of Negative Symptoms motivational deficit severity. PSZ specifically failed to represent reward magnitude, consistent with model demonstrations showing that response tendencies in the actor-critic were preferentially driven by reward probability. CONCLUSIONS: Probability-magnitude deficits in PSZ with motivational deficits arise from underutilization of EV in favor of reliance on valueless stimulus-response associations. Confirmed by our computational hybrid framework, probability-magnitude integration deficits were driven specifically by a failure to represent reward magnitude. This work provides a first mechanistic explanation of complex EV-based learning deficits in PSZ with motivational deficits that arise from an inability to combine information from different reward modalities.

Cortisol response to stress in schizophrenia: Associations with oxytocin, social support and social functioning.

Previous studies reported attenuated cortisol reactivity as one explanation for poor social functioning in schizophrenia. Recent research has demonstrated that both glucocorticoid and oxytocin systems are central to stress regulation. Here, we studied the associations between basal oxytocin, stress-induced cortisol levels, and social functioning and social support in schizophrenia. A mock job interview was used as an ecologically-valid social stressor in 32 schizophrenia patients. Blood samples were taken before and after stress induction to assess basal oxytocin and cortisol levels. In addition social functioning and social support scales were collected. Patients were divided into cortisol responders and non-responders according to percentage change following stress induction. Our findings revealed a possible subgroup of patients who did not exhibit attenuated cortisol responses. Importantly, cortisol responders had generally better social functioning, but perceived social support was not different between groups. There was also no evidence of a relationship between cortisol and oxytocin. This study highlights the heterogeneity of cortisol responses to stress in a schizophrenia population, and the importance of the relationship between social functioning and cortisol reactivity. These findings could be relevant when considering therapeutic interventions that manipulate endocrinology in order to improve real-world functioning.

The impact of age of onset on amygdala intrinsic connectivity in major depression.

BACKGROUND: Early-onset major depressive disorder (EO-MDD), beginning during childhood and adolescence, is associated with more illness burden and a worse prognosis than adult-onset MDD (AO-MDD), but little is known about the neural features distinguishing these subgroup phenotypes. Functional abnormalities of the amygdala are central to major depressive disorder (MDD) neurobiology; therefore, we examined whether amygdala intrinsic connectivity (IC) can differentiate EO-MDD from AO-MDD in a cohort of adult MDD patients. SUBJECTS AND METHODS: Twenty-one EO-MDD (age of onset ≤18 years), 31 AO-MDD patients (age of onset ≥19 years), and 19 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (7 minutes). Amygdala seed-based resting-state functional connectivity was compared between groups. RESULTS: AO-MDD patients showed loss of inverse left amygdala-left dorsolateral prefrontal cortex IC and increased inverse left amygdala-left inferior parietal IC, compared to both HCs and EO-MDD. EO-MDD showed a switch from inverse to positive IC with right dorsomedial prefrontal cortex, compared to HCs and AO-MDD. This effect was removed when we controlled for illness burden. CONCLUSION: Alterations in amygdala IC with the default-mode network were specifically related to EO-MDD, whereas amygdala IC with executive cognitive control regions was preferentially disrupted in AO-MDD. Increased illness burden, an important clinical marker of EO-MDD, accounted for its specific effects on amygdala IC. Brain imaging has the potential for validation of clinical subtypes and can provide markers of prognostic value in MDD patients.

Motivational Deficits in Schizophrenia Are Associated With Reduced Differentiation Between Gain and Loss-Avoidance Feedback in the Striatum.

BACKGROUND: The current study was designed to test the hypothesis that motivational deficits in schizophrenia (SZ) are tied to a reduced ability to differentially signal gains and instances of loss-avoidance in the brain, leading to reduced ability to form adaptive representations of expected value. METHODS: We administered a reinforcement learning paradigm to 27 medicated SZ patients and 27 control subjects in which participants learned three probabilistic discriminations. In regions of interest in reward networks identified a priori, we examined contrasts between trial types with different expected values (e.g., expected gain-nonmonetary) and between outcomes with the same prediction error valence but different experienced values (e.g., gain-loss-avoidance outcome, miss-loss outcome). RESULTS: Both whole-brain and region of interest analyses revealed that SZ patients showed reduced differentiation between gain and loss-avoidance outcomes in the dorsal anterior cingulate cortex and bilateral anterior insula. That is, SZ patients showed reduced contrasts between positive prediction errors of different objective values in these areas. In addition, we observed significant correlations between gain-loss-avoidance outcome contrasts in the ventral striatum and ratings for avolition/anhedonia and between expected gain-nonmonetary contrasts in the ventral striatum and ventromedial prefrontal cortex. CONCLUSIONS: These results provide further evidence for intact prediction error signaling in medicated SZ patients, especially with regard to loss-avoidance. By contrast, components of frontostriatal circuits appear to show reduced sensitivity to the absolute valence of expected and experienced outcomes, suggesting a mechanism by which motivational deficits may emerge.