Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

A New Treatment Program: Focused Integrated Team-based Treatment Program for Bipolar Disorder (FITT-BD).

OBJECTIVE: Bipolar disorder (BD) is complicated by a dynamic, chronic course along with multiple comorbid psychiatric and medical conditions, making it challenging for clinicians to treat and patients to thrive. To efficiently manage the complexity of BD and help patients recover, we developed a Focused Integrated Team-based Treatment Program for Bipolar Disorder (FITT-BD). The purpose of this paper is to describe how we developed this clinic and the lessons we learned. METHODS: We developed FITT-BD by integrating strategies from stepped care, collaborative care, and learning health care systems. We describe the rationale, details, and lessons learned in developing FITT-BD. RESULTS: By integrating stepped care, collaborative care, and a learning health care system approach, FITT-BD aims to reduce barriers to care, leverage the expertise of a multidisciplinary treatment team, ensure patient-centeredness, and use assessments to inform and continuously improve outcomes in real time. We learned that there are challenges in the creation of a web-based application that tracks the treatment of patients within a network of hospitals. CONCLUSIONS: The success of FITT-BD will be determined by the degree to which it can increase treatment access, improve treatment adherence, and help individuals with BD achieve their treatment goals. We expect that FITT-BD will improve outcomes in the context of ongoing clinical care. PUBLIC HEALTH SIGNIFICANCE: The treatment of BD is challenging and complex. We propose a new treatment model for BD: FITT-BD. We expect that this program will be a patient-centered approach that improves outcomes in the context of ongoing clinical care for patients with BD.

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.

Healthy hearts healthy minds: A randomized trial of online interventions to improve physical activity.

INTRODUCTION: Depressed individuals are more likely to die from cardiovascular disease (CVD) than those without depression. People with CVD have higher rates of depression than those without and have higher mortality rates if they have comorbid depression. While physical activity (PA) improves both, few people engage in enough. We compared self-guided internet-based cognitive behavior therapy (CBT) + Fitbit or mindfulness-based cognitive therapy (MBCT) + Fitbit, with Fitbit only to increase daily steps for participants with depression who have low PA. METHODS: Adult participants (N = 340) were recruited from two online patient-powered research networks and randomized to one of three study interventions for 8 weeks with an additional 8 weeks of follow-up. Using linear mixed effects models, we evaluated the effect of the intervention on average daily steps (NCT03373110). RESULTS: Average daily steps increased 2.8 steps per day in MBCT+Fitbit, 2.9 steps/day in CBT + Fitbit, but decreased 8.2 steps/day in Fitbit Only. These changes were not statistically different between the MBCT+Fitbit and CBT + Fitbit groups, but were different from Fitbit Only across the initial 8-week period. Group differences were not maintained across follow-up. Exploratory analyses identified comorbid anxiety disorders, self-reported PA, and employment status as moderators. DISCUSSION: Changes in daily steps over both 8- and 16-week periods-regardless of intervention group-were minimal. The results emphasize the limits of using self-guided web-based psychotherapy with an activity tracker to increase PA in participants with a history of depression and low PA.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.

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.

C-reactive protein and affective inhibition in bipolar disorder.

BACKGROUND: Individuals with bipolar disorder (BD) experience cognitive and affective processing deficits that often persist beyond the remission of acute mood symptoms. One possible biological mechanism for these deficits involves the potential effects of chronic low-grade peripheral inflammation on brain function. Peripheral inflammation has been associated with reduced executive functioning and memory performance, as well as altered reward processing in BD, but whether it is also implicated in cognitive-affective processing remains unknown. METHOD: Peripheral inflammation was measured by serum C-reactive protein (CRP) in 119 adults with BD I or II, age 18-65. All participants completed the Affective Go/No-Go Task, a measure of cognitive-emotional processing. Correlations of CRP with discrimination of and response times to Negative, Positive, and Neutral words were performed before and after adjustment for severity of residual depressive symptoms and other demographic and clinical characteristics associated with inflammation. RESULTS: Increased CRP was significantly associated with reduced negative target discriminability, which was also significantly reduced compared to positive and neutral target conditions. Additionally, greater CRP was associated with faster response times for both negative hits and commissions, as well as positive commissions. CONCLUSIONS: This study adds to existing research demonstrating associations between inflammation and cognition or reward sensitivity and motivation separately in BD, by raising the possibility that inflammation is also implicated in the integration of cognitive-affective processing. Assessment of these associations over time is warranted to determine involvement of inflammation and cognitive-emotional processing in course of illness and identify critical periods for possible modulation of inflammation.

Predictors of functional impairment in bipolar disorder: Results from 13 cohorts from seven countries by the global bipolar cohort collaborative.

OBJECTIVES: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. METHODS: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. RESULTS: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. CONCLUSIONS: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Neural basis of associative learning in Trichotillomania and skin-picking disorder.

Disorders such as Trichotillomania (TTM) and skin-picking disorder (SPD) are associated with reduced flexibility and increased internally focused attention. While the basal ganglia have been hypothesized to play a key role, the mechanisms underlying learning and flexible accommodation of new information is unclear. Using a Bayesian Learning Model, we evaluated the neural basis of learning and accommodation in individuals with TTM and/or SPD. Participants were 127 individuals with TTM and/or SPD (TTM/SPD) recruited from three sites (age 18-57, 84% female) and 26 healthy controls (HC). During fMRI, participants completed a shape-button associative learning and reversal fMRI task. Above-threshold clusters were identified where the Initial Learning-Reversals BOLD activation contrast differed significantly (p < .05 FDR-corrected) between the two groups. A priori, effects were anticipated in predefined ROIs in bilateral basal ganglia, with exploratory analyses in the hippocampus, dorsolateral prefrontal cortex (dlPFC), and dorsal anterior cingulate cortex (dACC). Relative to HC, individuals with TTM/SPD demonstrated reduced activation during initial learning compared to reversal learning in the right basal ganglia. Similarly, individuals with TTM/SPD demonstrated reduced activation during initial learning compared to reversal learning in several clusters in the dlPFC and dACC compared to HC. Individuals with TTM/SPD may form or reform visual stimulus-motor response associations through different brain mechanisms than healthy controls. The former exhibit altered activation within the basal ganglia, dlPFC, and dACC during an associative learning task compared to controls, reflecting reduced frontal-subcortical activation during initial learning. Future work should determine whether these neural deficits may be restored with targeted treatment.

Inflammation, depressive symptoms, and emotion perception in adolescence.

BACKGROUND: Individuals with depression often demonstrate an altered peripheral inflammatory profile, as well as emotion perception difficulties. However, correlations of inflammation with overall depression severity are inconsistent and inflammation may only contribute to specific symptoms. Moreover, measurement of the association between inflammation and emotion perception is sparse in adolescence, despite representing a formative window of emotional development and high-risk period for depression onset. METHODS: Serum interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1ß were measured in 34 adolescents aged 12-17 with DSM-IV depressive disorders (DEP) and 29 healthy controls (HC). Participants were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and symptom subscales were extracted based on factor analysis. Participants also completed a performance-based measure of emotion perception, the Facial Emotion Perception Test (FEPT), which assesses the accuracy of categorizing angry, fearful, sad, happy, and neutral facial emotions. RESULTS: IL-6 and TNF-α correlated with reported depressed mood and somatic symptoms, respectively, but not total CDRS-R score, anhedonia or observed mood, across both DEP and HC. DEP demonstrated lower accuracy for identifying angry facial expressions. Higher IL-6 was inversely related to accuracy and discrimination of angry and neutral faces across all participants. IL-1ß was associated with reduced discrimination of fearful faces. CONCLUSIONS: Inflammatory markers were sensitive to affective and somatic symptoms of depression and processing of emotional threat in adolescents. In particular, IL-6 was elevated in depressed adolescents and therefore may represent a specific target for modulating depressive symptoms and emotion processing.

In vivo human brain expression of histone deacetylases in bipolar disorder.

The etiology of bipolar disorder (BD) is unknown and the neurobiological underpinnings are not fully understood. Both genetic and environmental factors contribute to the risk of BD, which may be linked through epigenetic mechanisms, including those regulated by histone deacetylase (HDAC) enzymes. This study measures in vivo HDAC expression in individuals with BD for the first time using the HDAC-specific radiotracer [11C]Martinostat. Eleven participants with BD and 11 age- and sex-matched control participants (CON) completed a simultaneous magnetic resonance - positron emission tomography (MR-PET) scan with [11C]Martinostat. Lower [11C]Martinostat uptake was found in the right amygdala of BD compared to CON. We assessed uptake in the dorsolateral prefrontal cortex (DLPFC) to compare previous findings of lower uptake in the DLPFC in schizophrenia and found no group differences in BD. Exploratory whole-brain voxelwise analysis showed lower [11C]Martinostat uptake in the bilateral thalamus, orbitofrontal cortex, right hippocampus, and right amygdala in BD compared to CON. Furthermore, regional [11C]Martinostat uptake was associated with emotion regulation in BD in fronto-limbic areas, which aligns with findings from previous structural, functional, and molecular neuroimaging studies in BD. Regional [11C]Martinostat uptake was associated with attention in BD in fronto-parietal and temporal regions. These findings indicate a potential role of HDACs in BD pathophysiology. In particular, HDAC expression levels may modulate attention and emotion regulation, which represent two core clinical features of BD.

Malleability of rumination: An exploratory model of CBT-based plasticity and long-term reduced risk for depressive relapse among youth from a pilot randomized clinical trial.

CLINICAL TRIALS REGISTRATION: NCT01905267, https://clinicaltrials.gov/ct2/show/NCT01905267.

A Lifespan Model of Interference Resolution and Inhibitory Control: Risk for Depression and Changes with Illness Progression.

The cognitive processes involved in inhibitory control accuracy (IC) and interference resolution speed (IR) or broadly - inhibition - are discussed in this review, and both are described within the context of a lifespan model of mood disorders. Inhibitory control (IC) is a binary outcome (success or no for response selection and inhibition of unwanted responses) for any given event that is influenced to an extent by IR. IR refers to the process of inhibition, which can be manipulated by task design in earlier and later stages through use of distractors and timing, and manipulation of individual differences in response proclivity. We describe the development of these two processes across the lifespan, noting factors that influence this development (e.g., environment, adversity and stress) as well as inherent difficulties in assessing IC/IR prior to adulthood (e.g., cross-informant reports). We use mood disorders as an illustrative example of how this multidimensional construct can be informative to state, trait, vulnerability and neuroprogression of disease. We present aggregated data across numerous studies and methodologies to examine the lifelong development and degradation of this subconstruct of executive function, particularly in mood disorders. We highlight the challenges in identifying and measuring IC/IR in late life, including specificity to complex, comorbid disease processes. Finally, we discuss some potential avenues for treatment and accommodation of these difficulties across the lifespan, including newer treatments using cognitive remediation training and neuromodulation.

Rumination-focused cognitive behavioral therapy decreases anxiety and increases behavioral activation among remitted adolescents.

OBJECTIVES: Rumination involves a repetitive, passive focus on one's thoughts and feelings and has been hypothesized as a mechanism contributing to multiple psychopathologies. The current investigation explores secondary outcomes from a pilot study to examine whether rumination-focused cognitive behavior therapy (RFCBT) alleviates symptoms of anxiety, increases behavioral activation, or increases global functioning among adolescents with a history of Major Depressive Disorder (MDD). METHODS: Thirty-three adolescents were randomized to receive either RFCBT (n = 17) or assessment only (AO; n = 16) over the course of eight weeks. Mixed effects regression models were used to conduct intent-to-treat (ITT) analyses. RESULTS: The quadratic interaction for group-by-time-by-time was significant for anxiety. Adolescents in the RFCBT group experienced a significant decrease in anxiety across the first six weeks of intervention (F = 7.01, df = 108.49, p = .009). The group-by-time interaction was significant for the behavioral activation outcome (F = 4.28, df = 25.60, p = .049) with youth randomized to RFCBT demonstrating increasing activation compared to AO. Global functioning did not significantly differ between groups (F = .40, df = 1, p > .05). CONCLUSIONS: Preliminary evidence suggests that RFCBT may hold promise as an intervention that alleviates both depressive and anxiety symptoms when comorbid.

Memory differences by sex, but not by previous diagnosis of major depressive disorder.

Memory difficulties are consistently reported in Major Depressive Disorder (MDD). Nonetheless, it has not been thoroughly investigated as to whether these deficits persist during remission from MDD. A group of 32 healthy young adults with no history of a mood disorder (Mage = 20.8, SD = 2.1) and 62 remitted depressed young adults (Mage = 21.1, SD = 1.9) completed a neuropsychological battery. The test battery included two measures of nonverbal memory, two measures of verbal memory, and a measure of performance validity. The testing session was repeated three to six weeks later to determine performance stability. No differences were found between healthy controls and remitted depressed patients in either memory domain (all ps > .05) and improvement in performance was exhibited over time for both groups (p = 0.004). Potential practice effects are examined. We found a stronger performance for women than men (p = 0.003), particularly for the Semantic List Learning Task (SLLT) (p = .047). Verbal and nonverbal memory and effort may not be impacted in those who are in a remitted state of MDD, early in the course of the illness. Women demonstrated auditory memory superiority over men, similar to prior research.

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.

Interplay between pro-inflammatory cytokines, childhood trauma, and executive function in depressed adolescents.

BACKGROUND: Pro-inflammatory cytokines have been linked to depression, early childhood trauma, and impairment in executive function in adults. Whether these links are present during adolescence, a time when vulnerability to depression is heightened, a point more proximal to childhood trauma, and a critical period of brain development, is not well understood. METHOD: Serum levels of interleukin (IL)-6, IL-1ß, and tumor necrosis factor alpha (TNF-α) were measured in 70 adolescents aged 12-17, including 40 with a DSM-IV depressive disorder (DEP), a sub-set (n = 22) of whom reported a history of childhood trauma (DEP-T), and 30 healthy controls (HCs). Participants completed performance-based (Parametric Go/No-Go Task) and observer-rated (Behavior Rating Inventory of Executive Function) measures of executive function. Procedures were conducted at a subspecialty clinic (Dec 2015-June 2017). RESULTS: IL-6 was elevated in DEP and DEP-T adolescents compared to controls (p = .014) and TNF-α was elevated in DEP participants only (p = .040) compared to controls, whereas no group differences were found in IL-1ß (p = .829). Additionally, DEP-T participants demonstrated relative deficits in performance-based (p = .044) and observer-rated inhibitory control (p = .049) compared to controls. Across the whole sample, TNF-α was associated with performance-based (r = -0.25, p = .039) and observer-rated (r = 0.32, p = .009) inhibitory control deficits. In subgroup analyses, TNF-α was associated with increased observer-rated inhibitory deficits in DEP, and at the trend level, with reduced inhibitory control performance in DEP-T. CONCLUSIONS: The current results suggest that inflammation may be a marker of disease processes in adolescent depression. Though longitudinal studies are needed, depressed adolescents with childhood trauma exposure appear to constitute a uniquely vulnerable group in terms of objective risk for executive dysfunction. Immune dysregulation may partly contribute to this risk.

Pre-scan cortisol is differentially associated with enhanced connectivity to the cognitive control network in young adults with a history of depression.

BACKGROUND: We have previously demonstrated that pre-scan salivary cortisol is associated with attentuated frontal-subcortical brain activation during emotion processesing and semantic list-learning paradigms in depressed subjects. Additionally, altered functional connectivity is observed after remission of acute depression symptoms (rMDD). It is unknown whether cortisol also predicts altered functional connectivity during remission. METHODS: Participants were 47 healthy controls (HC) and 73 rMDD, 18-30 years old who provided salivary cortisol samples before and after undergoing resting-state fMRI. We tested whether salivary cortisol by diagnosis interactions were associated with seed-based resting connectivity of the default mode (DMN) and salience and emotion (SN) networks using whole-brain, cluster-level corrected (p < .01) regression in SPM8. RESULTS: Pre-scan cortisol predicted decreased (HC) and increased (rMDD) cross-network connectivity to the dorsal anterior cingulate, dorso-medial and lateral- prefrontal cortex, brain stem and cerebellum (all seeds) and precuneus (DMN seeds). By and large, pre/post-scan cortisol change predicted the same pattern of findings. In network analyses, cortisol predominantly predicted enhanced cross-network connectivity to cognitive control network regions in rMDD. CONCLUSIONS: The association of cortisol with connections of default and salience networks to executive brain networks differs between individuals with and without a history of depression. Further investigation is needed to better understand the role of cortisol and related stress hormones as a potential primary and interactive driver of network coherence in depression.

Multidimensional imaging techniques for prediction of treatment response in major depressive disorder.

A large number of studies have attempted to use neuroimaging tools to aid in treatment prediction models for major depressive disorder (MDD). Most such studies have reported on only one dimension of function and prediction at a time. In this study, we used three different tasks across domains of function (emotion processing, reward anticipation, and cognitive control, plus resting state connectivity completed prior to start of medication to predict treatment response in 13-36 adults with MDD. For each experiment, adults with MDD were prescribed only label duloxetine (all experiments), whereas another subset were prescribed escitalopram. We used a KeyNet (both Task derived masks and Key intrinsic Network derived masks) approach to targeting brain systems in a specific match to tasks. The most robust predictors were (Dichter et al., 2010) positive response to anger and (Gong et al., 2011) negative response to fear within relevant anger and fear TaskNets and Salience and Emotion KeyNet (Langenecker et al., 2018) cognitive control (correct rejections) within Inhibition TaskNet (negative) and Cognitive Control KeyNet (positive). Resting state analyses were most robust for Cognitive control Network (positive) and Salience and Emotion Network (negative). Results differed by whether an -fwhm or -acf (more conservative) adjustment for multiple comparisons was used. Together, these results implicate the importance of future studies with larger sample sizes, multidimensional predictive models, and the importance of using empirically derived masks for search areas.