Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Predicting Dimensional Antidepressant Response to Repetitive Transcranial Magnetic Stimulation using Pretreatment Resting-state Functional Connectivity.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression and has been shown to modulate resting-state functional connectivity (RSFC) of depression-relevant neural circuits. To date, however, few studies have investigated whether individual treatment-related symptom changes are predictable from pretreatment RSFC. We use machine learning to predict dimensional changes in depressive symptoms using pretreatment patterns of RSFC. We hypothesized that changes in dimensional depressive symptoms would be predicted more accurately than scale total scores. Patients with depression (n=26) underwent pretreatment RSFC MRI. Depressive symptoms were assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17). Random forest regression (RFR) models were trained and tested to predict treatment-related symptom changes captured by the HDRS-17, HDRS-6 and three previously identified HDRS subscales: core mood/anhedonia (CMA), somatic disturbances, and insomnia. Changes along the CMA, HDRS-17, and HDRS-6 were predicted significantly above chance, with 9%, 2%, and 2% of out-of-sample outcome variance explained, respectively (all p<0.01). CMA changes were predicted more accurately than the HDRS-17 (p<0.05). Higher baseline global connectivity (GC) of default mode network (DMN) subregions and the somatomotor network (SMN) predicted poorer symptom reduction, while higher GC of the right dorsal attention (DAN) frontoparietal control (FPCN), and visual networks (VN) predicted reduced CMA symptoms. HDRS-17 and HDRS-6 changes were predicted with similar GC patterns. These results suggest that RSFC spanning the DMN, SMN, DAN, FPCN, and VN subregions predict dimensional changes with greater accuracy than syndromal changes following rTMS. These findings highlight the need to assess more granular clinical dimensions in therapeutic studies, particularly device neuromodulation studies, and echo earlier studies supporting that dimensional outcomes improve model accuracy.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this common causal network (CCN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis (Principal Component Analysis, PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CCN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CCN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes. This evidence further supports that treatment interventions converge on a CCN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Brain volumetric correlates of electroconvulsive therapy versus transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) are effective neuromodulation therapies for treatment-resistant depression (TRD). While ECT is generally considered the most effective antidepressant, rTMS is less invasive, better tolerated and leads to more durable therapeutic benefits. Both interventions are established device antidepressants, but it remains unknown if they share a common mechanism of action. Here we aimed to compare the brain volumetric changes in patients with TRD after right unilateral (RUL) ECT versus left dorsolateral prefrontal cortex (lDLPFC) rTMS. METHODS: We assessed 32 patients with TRD before the first treatment session and after treatment completion using structural magnetic resonance imaging. Fifteen patients were treated with RUL ECT and seventeen patients received lDLPFC rTMS. RESULTS: Patients receiving RUL ECT, in comparison with patients treated with lDLPFC rTMS, showed a greater volumetric increase in the right striatum, pallidum, medial temporal lobe, anterior insular cortex, anterior midbrain, and subgenual anterior cingulate cortex. However, ECT- or rTMS-induced brain volumetric changes were not associated with the clinical improvement. LIMITATIONS: We evaluated a modest sample size with concurrent pharmacological treatment and without neuromodulation therapies randomization. CONCLUSIONS: Our findings suggest that despite comparable clinical outcomes, only RUL ECT is associated with structural change, while rTMS is not. We hypothesize that structural neuroplasticity and/or neuroinflammation may explain the larger structural changes observed after ECT, whereas neurophysiological plasticity may underlie the rTMS effects. More broadly, our results support the notion that there are multiple therapeutic strategies to move patients from depression to euthymia.

Augmenting the unified protocol with transcranial direct current stimulation: Effects on emotion regulation and executive dysfunction.

The aim of the current study was to compare the unified protocol for transdiagnostic treatment of emotional disorders (UP) with and without transcranial direct current stimulation (tDCS) for the treatment of emotion regulation and executive control dysfunction in individuals diagnosed with generalized anxiety disorder (GAD) and comorbid major depressive disorder (MDD). A total of 43 individuals with GAD and co-morbid MDD were randomly assigned to three groups including UP with tDCS (UP+tDCS; n = 15), UP alone (UP; n = 13) or wait-list control (n = 15). Difficulties in emotion regulation, reappraisal, suppression, inhibition and working memory were assessed at baseline, post-treatment and 3-month follow-up. Treatment with both UP+tDCS and UP alone resulted in significant improvements in difficulties in emotion regulation, cognitive reappraisal, and working memory, and significant reductions in suppression and inhibition relative to wait-list controls at post-treatment and 3-month follow-up. Relative to UP alone, UP+tDCS showed significantly greater improvements in difficulties in emotion regulation, cognitive reappraisal, inhibition, and working memory at post-treatment and 3-month follow-up. These results suggest combination of UP treatment with tDCS may be an efficacious intervention to improve emotion regulation and executive function in GAD with co-morbid MDD. Trial registration reference is IRCT20140929019334N1 (see https://irct.ir/trial/27988).

Neural correlates of learning accommodation and consolidation in generalised anxiety disorder.

OBJECTIVE.: Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviours to determine how much of a new behaviour is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalised anxiety disorder (GAD). METHODS.: Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus was compared between groups during first reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS. RESULTS.: Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the first reversal compared with controls. This difference was not present in the initial learning and second reversal. CONCLUSION.: Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short- to long-term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.

Closed-loop enhancement and neural decoding of cognitive control in humans.

Deficits in cognitive control-that is, in the ability to withhold a default pre-potent response in favour of a more adaptive choice-are common in depression, anxiety, addiction and other mental disorders. Here we report proof-of-concept evidence that, in participants undergoing intracranial epilepsy monitoring, closed-loop direct stimulation of the internal capsule or striatum, especially the dorsal sites, enhances the participants' cognitive control during a conflict task. We also show that closed-loop stimulation upon the detection of lapses in cognitive control produced larger behavioural changes than open-loop stimulation, and that task performance for single trials can be directly decoded from the activity of a small number of electrodes via neural features that are compatible with existing closed-loop brain implants. Closed-loop enhancement of cognitive control might remediate underlying cognitive deficits and aid the treatment of severe mental disorders.

Electroconvulsive therapy effects on anhedonia and reward circuitry anatomy: A dimensional structural neuroimaging approach.

BACKGROUND: Anhedonia is a core symptom of major depressive disorder (MDD) resulting from maladaptive reward processing. Electroconvulsive therapy (ECT) is an effective treatment for patients with MDD. No previous neuroimaging studies have taken a dimensional approach to assess whether ECT-induced volume changes are specifically related to improvements in anhedonia and positive valence emotional constructs. We aimed to assess the relationship between ECT-induced brain volumetric changes and improvement in anhedonia and reward processing in patients with MDD. METHODS: We evaluated 15 patients with MDD before and after ECT. We used magnetic resonance imaging, clinical scales (i.e., Quick Inventory of Depressive Symptomatology for syndromal depression severity and Snaith-Hamilton Pleasure Scale for anhedonia) and the Temporal Experience of Pleasure Scale for anticipatory and consummatory experiences of pleasure. We identified 5 regions of interest within the reward circuit and a 6th control region relevant for MDD but not core to the reward system (Brodmann Area 25). RESULTS: Anhedonia, anticipatory and consummatory reward processing improved after ECT. Volume increases within the right reward system separated anhedonia responders and non-responders. Improvement in anticipatory (but not consummatory) reward correlated with increases in volume in hippocampus, amygdala, ventral tegmental area and nucleus accumbens. LIMITATIONS: We evaluated a modest sample size of patients with concurrent pharmacological treatment using a subjective psychometric assessment. CONCLUSIONS: We highlight the importance of a dimensional and circuit-based approach to understanding target engagement and the mechanism of action of ECT, with the goal to define symptom- and circuit-specific response biomarkers for device neuromodulation therapies.

Convergence between behavioral, neural, and self-report measures of cognitive control: The Frontal Systems Behavior Scale in bipolar disorder.

The Frontal Systems Behavior Scale (FrSBe) is a self-report measure that assesses difficulties with cognitive and emotional control such as apathetic behavior, lack of inhibitory control, and executive dysfunction. Previous neuroimaging studies highlight the involvement of the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex (DLPFC) in these processes. In this study, we investigated whether there was convergence across subjective and objective measures of apathy, disinhibition, and executive dysfunction. Specifically, we studied whether ACC, OFC, and DLPFC activation during a modified version of the Multi-Source Interference Task (MSIT), is associated with FrSBe apathy, disinhibition, and executive dysfunction scores, in healthy controls (HC) and individuals with Bipolar Disorder (BD), who commonly exhibit difficulties in these domains. Individuals with BD (n = 31) and HCs (n = 31) with no current or past psychiatric illness completed the FrSBe and the MSIT during fMRI scanning. We investigated task-specific changes in the ACC, DLPFC, and OFC and their correlations with FrSBe apathy, disinhibition, and executive dysfunction subscale scores, respectively. Individuals with BD and the HC group demonstrated greater ACC, DLPFC, and OFC activation during MSIT interference conditions compared with non-interference conditions. Furthermore, there was a significant negative correlation between OFC activation and disinhibition scores, which remained significant after accounting for medication load. Together, these results demonstrate the FrSBe disinhibition subscale, in particular, can be a self-report measure that converges with behavioral and neural markers of disinhibition in BD.

Dimensional Affective Processing in BD.

Bipolar Disorder (BD) involves altered neural affective processing, but studies comparing BD patients to controls have yielded inconsistent results. This might relate to substantial variability in the nature and severity of mood symptoms among individuals with BD. Hence, we dimensionally examined the relationship between depressive and manic symptom severity and neural responses to positive and negative affective stimuli. 39 Participants with BD completed measures of depression and mania severity prior to completing a cognitive-affective processing task during fMRI. A multiple regression model was run in SPM to identify brain regions correlated with depressive and manic symptoms during positive-neutral and negative-neutral contrasts. A-priori anatomical ROIs were defined bilaterally in frontal, parietal and limbic regions. Results showed that depression severity was associated with increased activation in frontal, parietal, and limbic ROIs, regardless of valence. Mania severity was correlated with both increased and decreased activation, particularly within frontal subdivisions and during the processing of positively valenced images. In conclusion, dimensional modeling of symptom severity captures variance in neural responses to affect, which may have been previously undetected due to heterogeneity when examined at the group level. Future fMRI studies comparing BD patients and controls should account for symptom variability in BD.

Augmenting the unified protocol for transdiagnostic treatment of emotional disorders with transcranial direct current stimulation in individuals with generalized anxiety disorder and comorbid depression: A randomized controlled trial.

BACKGROUND: The aim of the current study was to compare the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) with and without transcranial direct current stimulation (tDCS) in individuals suffering from generalized anxiety disorder (GAD) and comorbid depression. METHODS: A total of 43 individuals diagnosed with GAD and comorbid depression enrolled in a randomized controlled trial (IRCT20140929019334N1). Participants were randomly assigned to three groups including UP with tDCS (UP+tDCS; n = 15), UP alone (UP; n = 13) or wait-list control (n = 15). GAD and depression symptoms, worry severity, anxiety sensitivity, and intolerance of uncertainty were assessed at baseline, post-treatment and 3-month follow-up. RESULTS: Treatment with both UP+tDCS and UP alone resulted in significant lower ratings across all measures relative to wait-list controls at post-treatment and 3-month follow-up (all p-values <0.001). UP+tDCS showed significantly greater reductions in anxiety (p = 0.001 post-treatment; p = 0.003 follow-up), worry (p = 0.001 post-treatment; p = 0.002 follow-up), and anxiety sensitivity (p = 0.003 post-treatment; p = 0.002 follow-up) relative to UP alone. LIMITATIONS: The present study had some limitations. First, the sample size was low. Another limitation was the use of a short-term follow-up. CONCLUSIONS: These results suggest augmenting UP treatment with tDCS may be an efficacious strategy to improve treatment outcomes in GAD with comorbid depression. Trial registration reference is IRCT20140929019334N1 (see https://irct.ir/trial/27988).

Neural correlates of the ADHD self-report scale.

BACKGROUND: The ADHD Self Report Scale is a self-report measure that assesses attentional problems. We sought to validate the ASRS by establishing neural correlates using functional magnetic imaging in healthy controls and individuals with bipolar disorder (BD), who commonly exhibit attentional problems. METHODS: ASRS questionnaires and functional MRI data in conjunction with the Multi-source Interference Task (MSIT) were collected from 36 healthy control and 36 BD participants. We investigated task specific changes in the dorsal anterior cingulate cortex (dACC, Brodmann area 32) and their correlations with ASRS subscale scores, inattention and hyperactivity, in both cohorts. RESULTS: As hypothesized, the dACC showed significant increases in BOLD activation between the interference and noninterference conditions. For the ASRS scale as well as its Inattention and Hyperactivity subscales, there was a significant negative correlation with the dACC BOLD for the whole group. CONCLUSIONS: The ASRS is sensitive to attentional difficulties in BD, suggesting that it is a valid tool for assessing attentional difficulties in patients with BD.

Feasibility and Acceptability of a Lifestyle Intervention For Individuals With Bipolar Disorder.

Individuals with bipolar disorder are at greater risk for cardiovascular disease and are less likely to adhere to lifestyle interventions than the general population. To decrease cardiovascular risk and improve adherence to lifestyle interventions, we developed the Nutrition Exercise and Wellness Treatment (NEW Tx). NEW Tx is an 18-session, 20-week cognitive behavioral therapy-based treatment comprising 3 modules: Nutrition, Exercise, and Wellness. To evaluate the feasibility and acceptability of this intervention as well as predictors of treatment satisfaction and expectations, 38 adult outpatients with bipolar disorder were randomized to either NEW Tx or a waitlist control condition. There was no statistically significant difference in dropout rates between the groups (26.3% in NEW Tx, 31.6% in the control condition). In the NEW Tx condition, participants attended a mean of 66.7% of sessions and reported moderate to high satisfaction. There were no study-related adverse events. We also found that expectations, but not perceived credibility (or believability), of NEW Tx (as measured by the Credibility/Expectancy Questionnaire) at baseline predicted treatment satisfaction (as measured by the Care Satisfaction Questionnaire) posttreatment. Manic symptoms at baseline predicted treatment satisfaction, and marital status predicted one's expectations of lifestyle interventions. Data suggest that NEW Tx is a feasible and acceptable intervention for individuals with bipolar disorder and that further research is warranted to explore potential moderators of treatment expectations and credibility in this clinical population.

The Neural Basis of Approach-Avoidance Conflict: A Model Based Analysis.

Approach-avoidance conflict arises when the drives to pursue reward and avoid harm are incompatible. Previous neuroimaging studies of approach-avoidance conflict have shown large variability in reported neuroanatomical correlates. These prior studies have generally neglected to account for potential sources of variability, such as individual differences in choice preferences and modeling of hemodynamic response during conflict. In the present study, we controlled for these limitations using a hierarchical Bayesian model (HBM). This enabled us to measure participant-specific per-trial estimates of conflict during an approach-avoidance task. We also employed a variable epoch method to identify brain structures specifically sensitive to conflict. In a sample of 28 human participants, we found that only a limited set of brain structures [inferior frontal gyrus (IFG), right dorsolateral prefrontal cortex (dlPFC), and right pre-supplementary motor area (pre-SMA)] are specifically correlated with approach-avoidance conflict. These findings suggest that controlling for previous sources of variability increases the specificity of the neuroanatomical correlates of approach-avoidance conflict.

Pilot study of a lifestyle intervention for bipolar disorder: Nutrition exercise wellness treatment (NEW Tx).

BACKGROUND: Individuals with bipolar disorder (BD) are more likely than the general population to develop risk factors associated with cardiovascular disease, one of the leading causes of morbidity and mortality in this clinical population. To address this disproportionate medical burden, we developed Nutrition Exercise and Wellness Treatment (NEW Tx), a lifestyle intervention for individuals with BD. METHODS: In this study, participants were randomized to NEW Tx (n = 19) or a treatment as usual waitlist (n = 19). We examine the intervention's efficacy to improve the physical and psychological outcomes of individuals with BD. Assessors were blind to participant condition throughout study duration. RESULTS: The NEW Tx group reported increased weekly exercise duration and overall functioning, and decreased depression and illness severity over the study duration. However, only improvements in functioning were significantly greater in the NEW Tx group than in the control group. There were no group differences in weight loss or mood symptoms over the study duration. LIMITATIONS: Limitations to this study include lack of objective measurement of exercise and a small and relatively homogeneous sample. CONCLUSIONS: These data suggest that a manualized lifestyle intervention for BD may not be ideal to improve lifestyle changes in this clinical population. Further research is needed to pilot personalized approaches to creating a healthy lifestyle in BD.

Deficits in frontoparietal activation and anterior insula functional connectivity during regulation of cognitive-affective interference in bipolar disorder.

OBJECTIVES: Bipolar disorders (BD) are characterized by emotion and cognitive dysregulation. Mapping deficits in the neurocircuitry of cognitive-affective regulation allows for potential identification of intervention targets. This study used functional MRI data in BD patients and healthy controls during performance on a task requiring cognitive and inhibitory control superimposed on affective images, assessing cognitive and affective interference. METHODS: Functional MRI data were collected from 39 BD patients and 36 healthy controls during performance on the Multi-Source Interference Task overlaid on images from the International Affective Picture System (MSIT-IAPS). Analyses examined patterns of activation in a priori regions implicated in cognitive and emotional processing. Functional connectivity to the anterior insula during task performance was also examined, given this region's role in emotion-cognition integration. RESULTS: BD patients showed significantly less activation during cognitive interference trials in inferior parietal lobule, dorsomedial prefrontal cortex, anterior insula, mid-cingulate, and ventrolateral prefrontal cortex regardless of affective valence. BD patients showed deviations in functional connectivity with anterior insula in regions of the default mode and frontoparietal control networks during negatively valenced cognitive interference trials. CONCLUSIONS: Our findings show disruptions in cognitive regulation and inhibitory control in BD patients in the presence of irrelevant affective distractors. Results of this study suggest one pathway to dysregulation in BD is through inefficient integration of affective and cognitive information, and highlight the importance of developing interventions that target emotion-cognition integration in BD.

Intrinsic functional neurocircuitry associated with treatment response to transdiagnostic CBT in bipolar disorder with anxiety.

BACKGROUND: Anxiety in bipolar disorder (BD) exacerbates emotion dysregulation and reduces treatment response. We recently conducted a pilot trial of transdiagnostic CBT to target anxiety and emotion dysregulation in BD adjunctive to pharmacotherapy. Reductions in depression and anxiety symptoms were significantly predicted by baseline levels of neuroticism and perceived affective control, as well as changes over time in emotion regulation skills. The present study investigates mechanism of treatment response by examining the relationship between baseline emotion regulation-related neural circuitry and trial outcomes. METHODS: Nineteen patients completed baseline resting state fMRI scans prior to treatment randomization. Functional connectivity between the anterior insula (AI) and regions in the salience network (SN), default mode network (DMN), and executive control network (ECN) were examined as predictors of baseline and treatment-related changes in emotion regulation. RESULTS: Greater improvements in emotion regulation were predicted by weaker right dorsal AI - right ventrolateral prefrontal cortex (VLPFC; SN) and stronger bilateral dorsal AI - bilateral amygdala functional connectivity. Baseline neuroticism was negatively correlated with right dorsal AI- inferior parietal lobule (ECN) functional connectivity, and baseline deficits in perceived affective control were positively associated with ventral AI - bilateral dACC (SN) connectivity. LIMITATIONS: Small sample limits interpretability of treatment-specific effects. CONCLUSION: Baseline functional connectivity of emotion-regulation related neural circuitry significantly predicted change in emotion regulation-related dimensions associated with anxiety and depression symptom reduction. Future studies are needed to determine if employing methods such as neuromodulation to rehabilitate relevant neural circuitry may improve ultimate treatment outcomes of transdiagnostic CBT for BD and anxiety.

Functional Connectivity Between Anterior Insula and Key Nodes of Frontoparietal Executive Control and Salience Networks Distinguish Bipolar Depression From Unipolar Depression and Healthy Control Subjects.

BACKGROUND: Patients with bipolar depression are characterized by dysregulation across the full spectrum of mood, differentiating them from patients with unipolar depression. The ability to switch neural resources among the default mode network, salience network, and executive control network (ECN) has been proposed as a key mechanism for adaptive mood regulation. The anterior insula is implicated in the modulation of functional network switching. Differential connectivity between anterior insula and functional networks may provide insights into pathophysiological differences between bipolar and unipolar mood disorders, with implications for diagnosis and treatment. METHODS: Resting-state functional magnetic resonance imaging data were collected from 98 subjects (35 unipolar, 24 bipolar, and 39 healthy control subjects). Pearson correlations were computed between bilateral insula seed regions and a priori defined target regions from the default mode network, salience network, and ECN. After r-to-z transformation, a one-way multivariate analysis of covariance was conducted to identify significant differences in connectivity between groups. Post hoc pairwise comparisons were conducted and Bonferroni corrections were applied. Receiver-operating characteristics were computed to assess diagnostic sensitivity. RESULTS: Patients with bipolar depression evidenced significantly altered right anterior insula functional connectivity with the inferior parietal lobule of the ECN relative to patients with unipolar depression and control subjects. Right anterior insula-inferior parietal lobule connectivity significantly discriminated patients with bipolar depression. CONCLUSIONS: Impaired functional connectivity between the anterior insula and the inferior parietal lobule of the ECN distinguishes patients with bipolar depression from those with unipolar depression and healthy control subjects. This finding highlights a pathophysiological mechanism with potential as a therapeutic target and a clinical biomarker for bipolar disorder, exhibiting reasonable sensitivity and specificity.