Localized MRS reliability of in vivo glutamate at 3 T in shortened scan times: a feasibility study.

Glutamate is the prime excitatory neurotransmitter in the mammalian brain and has been implicated in a wide range of psychiatric conditions. To improve the applicability and clinical reach of magnetic resonance spectroscopy (MRS), research is needed to develop shortened, yet reliable, MRS scanning procedures for standard 1.5-3-T clinical magnetic resonance imaging (MRI) systems, particularly with young or vulnerable populations unable to tolerate longer protocols. To this end, we evaluated the test-retest reliability of a shortened J-resolved MRS sequence in healthy adolescents (n = 22) aged 12-14 years. Participants underwent a series of sequential 6-min MRS scans, with the participants remaining in situ between successive scans. Glutamate and other metabolites were acquired from the rostral anterior cingulate cortex, as glutamatergic function in this region has been implicated in a number of psychiatric illnesses. Thirteen neurochemicals were quantified as ratios to total creatine, and reliability scores were expressed as the percentage difference between the two scans for each metabolite. Test-retest assessment of glutamate was reliable, as scores were less than 10% different (7.1 ± 4.2%), and glutamate values across scans were significantly correlated (Pearson r = 0.680, p < 10-4 ). Several other neurochemicals demonstrated satisfactory reliability, including choline (Cho) (7.4 ± 5.6%), glutathione (GSH) (8.6 ± 4.1%), myo-inositol (mI) (6.5 ± 7.1%) and N-acetylaspartate (NAA) (3.5 ± 3.6%), with test-retest correlations ranging from 0.747 to 0.953. A number of metabolites, however, did not demonstrate acceptable test-retest reliability using the current J-resolved MRS sequence, ranging from 13.8 ± 13.7% (aspartate, Asp) to 45.9 ± 38.3% (glycine, Gly). Collectively, test-retest analyses suggest that clinically viable quantitative data can be obtained on standard MRI systems for glutamate, as well as the other metabolites, during short scan times in a traditionally challenging brain region.

The effects of psychotherapy for anhedonia on subcortical brain volumes measured with ultra-high field MRI.

BACKGROUND: Anhedonia is a transdiagnostic symptom often resistant to treatment. The identification of biomarkers sensitive to anhedonia treatment will aid in the evaluation of novel anhedonia interventions. METHODS: This is an exploratory analysis of changes in subcortical brain volumes accompanying psychotherapy in a transdiagnostic anhedonic sample using ultra-high field (7-Tesla) MRI. Outpatients with clinically impairing anhedonia (n = 116) received Behavioral Activation Treatment for Anhedonia, a novel psychotherapy, or Mindfulness-Based Cognitive Therapy (ClinicalTrials.gov Identifiers NCT02874534 and NCT04036136). Subcortical brain volumes were estimated via the MultisegPipeline, and regions of interest were the amygdala, caudate nucleus, hippocampus, pallidum, putamen, and thalamus. Bivariate mixed effects models estimated pre-treatment relations between anhedonia severity and subcortical brain volumes, change over time in subcortical brain volumes, and associations between changes in subcortical brain volumes and changes in anhedonia symptoms. RESULTS: As reported previously (Cernasov et al., 2023), both forms of psychotherapy resulted in equivalent and significant reductions in anhedonia symptoms. Pre-treatment anhedonia severity and subcortical brain volumes were not related. No changes in subcortical brain volumes were observed over the course of treatment. Additionally, no relations were observed between changes in subcortical brain volumes and changes in anhedonia severity over the course of treatment. LIMITATIONS: This trial included a modest sample size and did not have a waitlist-control condition or a non-anhedonic comparison group. CONCLUSIONS: In this exploratory analysis, psychotherapy for anhedonia was not accompanied by changes in subcortical brain volumes, suggesting that subcortical brain volumes may not be a candidate biomarker sensitive to response to psychotherapy.

Relationship between sleep disturbance and depression, anxiety, and functioning in college students.

BACKGROUND: Sleep disturbance (SD) has complex associations with depression, both preceding and following the onset and recurrence of depression. We hypothesized that students with depressive symptoms with SD would demonstrate a greater burden of comorbid psychiatric symptoms and functional impairment compared to students with depressive symptoms without SD. METHODS: During a mental health screening, 287 undergraduate students endorsed symptoms of depression (Beck Depression Inventory [BDI] ≥ 13) and filled out the following self-report measures: demographic questionnaire, BDI, Anxiety Symptom Questionnaire-intensity and frequency (ASQ), Beck Hopelessness Scale (BHS), Beck Anxiety Inventory (BAI), Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ), and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ). SD was measured using the BDI sleep item #16 dichotomized (score 0: no SD; or score > 0: some SD). RESULTS: Students with depressive symptoms and SD (n = 220), compared to those without SD (n = 67), endorsed significantly more intense and frequent anxiety and poorer cognitive and physical functioning. Students with depressive symptoms with and without SD did not significantly differ in depressive severity, hopelessness, or quality of life. CONCLUSIONS: College students with depressive symptoms with SD may experience a greater burden of comorbid anxiety symptoms and hyperarousal, and may have impairments in functioning, compared to students with depressive symptoms without SD. These findings require replication.

Parsing within & between-person dynamics of therapy homework completion and clinical symptoms in two cognitive behavioral treatments for adults with anhedonia.

OBJECTIVE: Homework is a key theoretical component of cognitive-behavioral therapies, however, the effects of homework on clinical outcomes have largely been evaluated between-persons rather than within-persons. METHODS: The effects of homework completion on treatment response were examined in a randomized trial comparing Behavioral Activation Treatment for Anhedonia (BATA, n = 38), a novel psychotherapy, to Mindfulness-Based Cognitive Therapy (MBCT, n=35). The primary endpoint was consummatory reward sensitivity, measured weekly by the Snaith Hamilton Pleasure Scale (SHAPS), up to 15 weeks. Multilevel models evaluated change in SHAPS scores over time and the effects of clinician-reported and participant-reported homework. RESULTS: BATA and MBCT resulted in significant, equivalent reductions in SHAPS scores. Unexpectedly, participants who completed greater mean total amounts of homework did not improve at a faster rate (i.e., no between-person effect). However, sessions with greater than average participant-reported homework completion were associated with greater than average reductions in SHAPS scores (i.e., a within-person effect). For clinician-reported homework, this effect was only evident within the BATA condition. CONCLUSION: This study shows psychotherapy homework completion relates to symptomatic improvement in cognitive-behavioral treatments for anhedonia when session-to-session changes are examined within-person. On the contrary, we found no evidence that total homework completion predicted greater improvements between-person. When possible, psychotherapy researchers should evaluate their constructs of interest across multiple sessions (not just pre/post) to allow more direct tests of hypotheses predicted by theoretical models of individual change processes.

Neural signatures of saliency-mapping in anhedonia: A narrative review.

Anhedonia is the loss of pleasure or motivation to engage in previously enjoyable activities, and is a transdiagnostic symptom associated with significant clinical impairment. Anhedonia is implicated in several different psychiatric disorders, presenting a promising opportunity for transdiagnostic treatment. Thus, developing targeted treatments for anhedonia is of critical importance for population mental health. An important first step in doing so is establishing a thorough understanding of the neural correlates of anhedonia. The Triple Network Model of Psychopathology provides a frame for how brain activity may go awry in anhedonia, specifically in the context of Salience Network (SN) function (i.e., saliency-mapping). We present a narrative review examining saliency-mapping as it relates to anhedonia severity in depressed and transdiagnostic adult samples. Results revealed increased anhedonia to be associated with hyperactivity of the SN at rest and in the context of negative stimuli, as well as a global lack of SN engagement in the context of positive stimuli. Potential treatments for anhedonia are placed within this model, and future directions for research are discussed.

Reward Functioning Abnormalities in Adolescents at High Familial Risk for Depressive Disorders.

BACKGROUND: A parental history of major depressive disorder (MDD) is an established risk factor for MDD in youth, and clarifying the mechanisms related to familial risk transmission is critical. Aberrant reward processing is a promising biomarker of MDD risk; accordingly, the aim of this study was to test behavioral measures of reward responsiveness and underlying frontostriatal resting activity in healthy adolescents both with (high-risk) and without (low-risk) a maternal history of MDD. METHODS: Low-risk and high-risk 12- to 14-year-old adolescents completed a probabilistic reward task (n = 74 low-risk, n = 27 high-risk) and a resting-state functional magnetic resonance imaging scan (n = 61 low-risk, n = 25 high-risk). Group differences in response bias toward reward and resting ventral striatal and medial prefrontal cortex (mPFC) fractional amplitude of low-frequency fluctuations (fALFFs) were examined. Computational modeling was applied to dissociate reward sensitivity from learning rate. RESULTS: High-risk adolescents showed a blunted response bias compared with low-risk adolescents. Computational modeling analyses revealed that relative to low-risk adolescents, high-risk adolescents exhibited reduced reward sensitivity but similar learning rate. Although there were no group differences in ventral striatal and mPFC fALFFs, groups differed in their relationships between mPFC fALFFs and response bias. Specifically, among high-risk adolescents, higher mPFC fALFFs correlated with a blunted response bias, whereas there was no fALFFs-response bias relationship among low-risk youths. CONCLUSIONS: High-risk adolescents exhibit reward functioning impairments, which are associated with mPFC fALFFs. The blunted response bias-mPFC fALFFs association may reflect an excessive mPFC-mediated suppression of reward-driven behavior, which may potentiate MDD risk.

Multilevel growth curve analyses of behavioral activation for anhedonia (BATA) and mindfulness-based cognitive therapy effects on anhedonia and resting-state functional connectivity: Interim results of a randomized trial✰.

BACKGROUND: The neural mechanisms associated with anhedonia treatment response are poorly understood. Additionally, no study has investigated changes in resting-state functional connectivity (rsFC) accompanying psychosocial treatment for anhedonia. METHODS: We evaluated a novel psychotherapy, Behavioral Activation Therapy for Anhedonia (BATA, n = 38) relative to Mindfulness-Based Cognitive Therapy (MBCT, n = 35) in a medication-free, transdiagnostic, anhedonic sample in a parallel randomized controlled trial. Participants completed up to 15 sessions of therapy and up to four 7T MRI scans before, during, and after treatment (n = 185 scans). Growth curve models estimated change over time in anhedonia and in rsFC using average region-of-interest (ROI)-to-ROI connectivity within the default mode network (DMN), frontoparietal network (FPN), salience network, and reward network. Changes in rsFC from pre- to post-treatment were further evaluated using whole-network seed-to-voxel and ROI-to-ROI edgewise analyses. RESULTS: Growth curve models showed significant reductions in anhedonia symptoms and in average rsFC within the DMN and FPN over time, across BATA and MBCT. There were no differences in anhedonia reductions between treatments. Within-person, changes in average rsFC were unrelated to changes in anhedonia. Between-person, higher than average FPN rsFC was related to less anhedonia across timepoints. Seed-to-voxel and edgewise rsFC analyses corroborated reductions within the DMN and between the DMN and FPN over time, across the sample. CONCLUSIONS: Reductions in rsFC within the DMN, FPN, and between these networks co-occurred with anhedonia improvement across two psychosocial treatments for anhedonia. Future anhedonia clinical trials with a waitlist control group should disambiguate treatment versus time-related effects on rsFC.

Reward Network Modulation as a Mechanism of Change in Behavioral Activation.

Behavioral Activation (BA) is a contemporary third-wave psychosocial treatment approach that emphasizes helping individuals become more active in ways that are meaningful to them as a means of improving mood and quality of life. BA has been designated as a well-established, validated treatment for depression by the American Psychological Association following several decades of accumulated empirical support demonstrating that BA techniques successfully reduce depression symptoms and produce other desirable outcomes across a variety of populations and contexts. The purported mechanism of change underlying BA treatment lies in increasing activation, which in turn increases contact with positive reinforcement thereby reversing the cycle of depression. Current studies are further investigating how increasing activation and subsequent contact with mood reinforcers can influence mood and behavior. Specifically, there is growing evidence that BA modifies function of reward-related networks in the brain, and that these changes are associated with clinical improvement. Herein, we provide a brief history of BA, describe the primary components of BA treatment, and describe BA's purported mechanisms of change at behavioral, neural, and subjective activation levels. We present limitations as well as gaps in the current state of knowledge regarding mechanisms of action of BA.

Delineating the social valuation network in adolescents.

Adolescents strive for peer approval, and an increased sensitivity to peers' opinions is normative. However, among vulnerable adolescents, peer evaluation can be detrimental, contributing to affective disorders. It is, therefore, critical to improve our understanding of neural underpinnings of peer evaluation. Prior research has investigated averaged neural responses to peer acceptance or rejection, neglecting to probe trial-by-trial computations that mirror real-time updating of daily activities. In non-social decision-making, a common neural valuation system centered on the medial prefrontal cortex (mPFC) has emerged, which evaluates different reward types on a common scale to guide choices. However, it is unclear whether the mPFC also tracks complex social scenarios involving peer feedback. To address this gap, we acquired fMRI data from 55 healthy adolescents during the Chatroom Task, which probes peer evaluation, and implemented a computational approach to characterize trial-by-trial social value, thereby allowing us to interrogate the neural correlates of social value. Consistent with our hypothesis, social value signals were encoded in the mPFC. Interestingly, analyses also revealed a wider social-specific valuation network including the precuneus and amygdala. Understanding how adolescents make social decisions and neural markers associated with it, may, ultimately, help us clarify promising targets for intervention.

Altered reward processing following an acute social stressor in adolescents.

Altered reward processing is a transdiagnostic factor implicated in a wide range of psychiatric disorders. While prior animal and adult research has shown that stress contributes to reward dysfunction, less is known about how stress impacts reward processing in youth. Towards addressing this gap, the present study probed neural activation associated with reward processing following an acute stressor. Healthy adolescents (n = 40) completed a clinical assessment, and fMRI data were acquired while participants completed a monetary guessing task under a no-stress condition and then under a stress condition. Based on prior literature, analyses focused on a priori defined regions-of-interest, specifically the striatum (win trials) and dorsal anterior cingulate cortex [dACC] and insula (loss trials). Two main findings emerged. First, reward-related neural activation (i.e., striatum) was blunted in the stress relative to the no-stress condition. Second, the stress condition also contributed to blunted neural response following reward in loss-related regions (i.e., dACC, anterior insula); however, there were no changes in loss sensitivity. These results highlight the importance of conceptualizing neural vulnerability within the presence of stress, as this may clarify risk for mental disorders during a critical period of development.

Neuroanatomical Prediction of Anhedonia in Adolescents.

Anhedonia is a transdiagnostic risk factor implicated in mental illness onset, treatment non-response, and suicidal behaviors. Prior cross-sectional research in adults has shown that anhedonia is associated with reduced dorsal striatal volume, but it is unknown whether this relationship extends to adolescents and whether reduced striatal volume prospectively predicts anhedonia. To address these gaps, the current study investigated whether striatal volume predicted anhedonia severity in adolescents. At baseline, healthy female adolescents aged 12-14 years (n=50) completed a clinical assessment, and structural MRI data were acquired on a 3 Tesla MR scanner. While in the scanner, participants also completed a peer feedback task where subjective ratings following peer 'acceptance' or 'rejection' were obtained. At the three-month follow-up, participants provided self-report assessments of anhedonia, depression, and anxiety symptoms. Three main findings emerged. First, in cross-sectional analyses, right nucleus accumbens volume was inversely related to anhedonia severity. Second, reduced bilateral putamen volume prospectively predicted anhedonia severity while controlling for baseline anhedonia, depression, and anxiety symptoms. Third, a blunted subjective response to peer acceptance (ie, neutral response to positive feedback), but not a more negative subjective response to peer rejection, contributed to anhedonia severity, but only among youth with smaller putamen volume. Collectively, these results suggest that smaller volume in striatal regions critically implicated in reward processing is associated with current and future anhedonic symptoms among healthy female youth. These anatomical features may confer vulnerability to anhedonia and thus, may inform early identification of individuals at high risk for mental illness.

Efficacy of ziprasidone monotherapy in patients with anxious depression: a 12-week, randomized, double-blind, placebo-controlled, sequential-parallel comparison trial.

UNLABELLED: Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be difficult to treat with traditional antidepressant monotherapy. The purpose of this study was to assess the efficacy of ziprasidone monotherapy in patients with anxious depression versus non-anxious depression. One hundred and twenty outpatients were enrolled in a 12-week study that was divided into two 6-week periods according to the sequential parallel comparison design. Patients were randomized in a 2:3:3 multi-ratio to receive ziprasidone for 12 weeks, placebo for 6 weeks, followed by ziprasidone for 6 weeks, or placebo for 12 weeks. Efficacy was measured according to the 17-item Hamilton Depression Rating Scale (HRDS-17), Quick Inventory of Depressive Symptomatology Self-Rated (QIDS-SR). Anxious depression was defined as a score of ≥7 on the HDRS-17 anxiety/somatization subscale. In phase I and II, ziprasidone monotherapy led to no significant changes compared with placebo on the HDRS-17 and QIDS-SR scores in patients with both anxious and non-anxious depression. In the pooled analysis, ziprasidone monotherapy also produced no significance on the HDRS-17 (Z = 0.25, P = 0.80) and QIDS-SR (Z = 0.43, P = 0.67) in patients with anxious depression. In conclusion, treatment with ziprasidone monotherapy may produce no significant improvement compared with placebo in patients with in anxious depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00555997.

Near-Infrared Transcranial Radiation for Major Depressive Disorder: Proof of Concept Study.

Transcranial near-infrared radiation (NIR) is an innovative treatment for major depressive disorder (MDD), but clinical evidence for its efficacy is limited. Our objective was to investigate the tolerability and efficacy of NIR in patients with MDD. We conducted a proof of concept, prospective, double-blind, randomized study of 6 sessions of NIR versus sham treatment for patients with MDD, using a crossover design. Four patients with MDD with mean age 47 ± 14 (SD) years (1 woman and 3 men) were exposed to irradiance of 700 mW/cm(2) and a fluence of 84 J/cm(2) for a total NIR energy of 2.40 kJ delivered per session for 6 sessions. Baseline mean HAM-D17 scores decreased from 19.8 ± 4.4 (SD) to 13 ± 5.35 (SD) after treatment (t = 7.905; df = 3; P = 0.004). Patients tolerated the treatment well without any serious adverse events. These findings confirm and extend the preliminary data on NIR as a novel intervention for patients with MDD, but further clinical trials are needed to better understand the efficacy of this new treatment. This trial is registered with ClinicalTrials.gov NCT01538199.