Change in brain activation after transcranial pulsed electromagnetic fields in treatment-resistant depression.

BACKGROUND: Preliminary evidence suggests antidepressant effects of transcranial pulsed electromagnetic fields (tPEMF). However, the precise mechanism of action in the brain is still unknown. The aim of this study was to investigate the influence of tPEMF on brain activation in patients with treatment-resistant depression (TRD) by studying two processes that might be of particular interest in relation to the symptoms of depression: emotional processing and reward processing. METHODS: Eligible participants (n = 50) with TRD in this sham-controlled double-blind multicenter trial [registered at the Dutch Trial Register ( http://www.trialregister.nl ), NTR3702] were randomly assigned to five weeks daily active or sham tPEMF. Pre- and post-treatment functional MR-scans were made during which participants performed a social-emotional task and a reward task. RESULTS: Participants in the active treatment group showed a stronger decrease in activation post-treatment compared to sham during reward-outcome processing in the left inferior frontal gyrus and in a cluster comprising the right lingual gyrus and the posterior part of the middle temporal gyrus. No effect of tPEMF was found on activation during the social-emotional task. Neurostimulation with tPEMF did also not affect behavioral performance for both tasks. CONCLUSIONS: We found a decrease in reward-related activation as a result of tPEMF stimulation, while no effect of tPEMF on social-emotional processing was found. The treatment-related reduction in activation of regulatory regions may reflect normalization and may have implications for anhedonia. These findings suggest that there is an effect of tPEMF on brain activation of relevant circuits, albeit in the absence of a clinical antidepressant effect.

Decreased reward circuit connectivity during reward anticipation in major depression.

An important symptom of major depressive disorder (MDD) is the inability to experience pleasure, possibly due to a dysfunction of the reward system. Despite promising insights regarding impaired reward-related processing in MDD, circuit-level abnormalities remain largely unexplored. Furthermore, whereas studies contrasting experimental conditions from incentive tasks have revealed important information about reward processing, temporal difference modeling of reward-related prediction error (PE) signals might give a more accurate representation of the reward system. We used a monetary incentive delay task during functional MRI scanning to explore PE-related striatal and ventral tegmental area (VTA) activation in response to anticipation and delivery of monetary rewards in 24 individuals with MDD versus 24 healthy controls (HCs). Furthermore, we investigated group differences in temporal difference related connectivity with a generalized psychophysiological interaction (gPPI) analysis with the VTA, ventral striatum (VS) and dorsal striatum (DS) as seeds during reward versus neutral, both in anticipation and delivery. Relative to HCs, MDD patients displayed a trend-level (p = 0.052) decrease in temporal difference-related activation in the VS during reward anticipation and delivery combined. Moreover, gPPI analyses revealed that during reward anticipation, MDD patients exhibited decreased functional connectivity between the VS and anterior cingulate cortex / medial prefrontal cortex, anterior cingulate gyrus, angular/middle orbital gyrus, left insula, superior/middle frontal gyrus (SFG/MFG) and precuneus/superior occipital gyrus/cerebellum compared to HC. Moreover, MDD patients showed decreased functional connectivity between the VTA and left insula compared to HC during reward anticipation. Exploratory analysis separating medication free patients from patients using antidepressant revealed that these decreased functional connectivity patterns were mainly apparent in the MDD group that used antidepressants. These results suggest that MDD is characterized by alterations in reward circuit connectivity rather than isolated activation impairments. These findings represent an important extension of the existing literature since improved understanding of neural pathways underlying depression-related reward dysfunctions, may help currently unmet diagnostic and therapeutic efforts.

No Self Without Salience: Affective and Self-relevance Ratings of 552 Emotionally Valenced and Neutral Dutch Words.

It is unknown how self-relevance is dependent on emotional salience. Emotional salience encompasses an individual's degree of attraction or aversion to emotionally-valenced information. The current study investigated the interconnection between self and salience through the evaluation of emotional valence and self-relevance. 56 native Dutch participants completed a questionnaire assessing valence, intensity, and self-relevance of 552 Dutch nouns and verbs. One-way repeated-measures ANCOVA investigated the relationship between valence and self, age and gender. Repeated-measures ANCOVA also tested the relationship between valence and self with intensity ratings and effects of gender and age. Results showed a significant main effect of valence for self-relevant words. Intensity analyses showed a main effect of valence but not of self-relevance. There were no significant effects of gender and age. The most important finding presents that self-relevance is dependent on valence. These findings concerning the relationship between self and salience opens avenues to study an individual's self-definition.

Impaired reward-related learning signals in remitted unmedicated patients with recurrent depression.

One of the core symptoms of major depressive disorder is anhedonia, an inability to experience pleasure. In patients with major depressive disorder, a dysfunctional reward-system may exist, with blunted temporal difference reward-related learning signals in the ventral striatum and increased temporal difference-related (dopaminergic) activation in the ventral tegmental area. Anhedonia often remains as residual symptom during remission; however, it remains largely unknown whether the abovementioned reward systems are still dysfunctional when patients are in remission. We used a Pavlovian classical conditioning functional MRI task to explore the relationship between anhedonia and the temporal difference-related response of the ventral tegmental area and ventral striatum in medication-free remitted recurrent depression patients (n = 36) versus healthy control subjects (n = 27). Computational modelling was used to obtain the expected temporal difference errors during this task. Patients, compared to healthy controls, showed significantly increased temporal difference reward learning activation in the ventral tegmental area (PFWE,SVC = 0.028). No differences were observed between groups for ventral striatum activity. A group × anhedonia interaction [t(57) = -2.29, P = 0.026] indicated that in patients, higher anhedonia was associated with lower temporal difference activation in the ventral tegmental area, while in healthy controls higher anhedonia was associated with higher ventral tegmental area activation. These findings suggest impaired reward-related learning signals in the ventral tegmental area during remission in patients with depression. This merits further investigation to identify impaired reward-related learning as an endophenotype for recurrent depression. Moreover, the inverse association between reinforcement learning and anhedonia in patients implies an additional disturbing influence of anhedonia on reward-related learning or vice versa, suggesting that the level of anhedonia should be considered in behavioural treatments.

Validity of the Maudsley Staging Method in Predicting Treatment-Resistant Depression Outcome Using the Netherlands Study of Depression and Anxiety.

OBJECTIVE: We investigated if the degree of treatment resistance of depression, as measured by the Maudsley Staging Method (MSM), is predictive of a worse depression outcome by using a large naturalistic cohort of depressed patients. METHODS: 643 subjects from the general population, primary care, and secondary care who suffered from current depressive disorder were included from the Netherlands Study of Depression and Anxiety baseline assessment. The diagnostic criterion was major depressive disorder (MDD) in the last month, based on the Composite Interview Diagnostic Instrument (CIDI), or a CIDI diagnosis of MDD in the past 6 months with an Inventory of Depressive Symptomatology Self-Report score > 24 at baseline. In these subjects, composite scores of the MSM, based on duration, severity, and treatment history of current episode, were determined retrospectively. We then determined if the MSM score prospectively predicted the 2-year course of depression after baseline. The primary outcomes were percentage of follow-up time spent in a depressive episode and being "mostly depressed" (≥ 50% of the follow-up) between baseline and 2-year follow-up. RESULTS: The MSM predicted "percentage of follow-up time with depression" (P < .001) and was associated with being "mostly depressed" (OR = 1.40; 95% CI, 1.23-1.60; P < .001). These effects were not modified by having received treatment. CONCLUSIONS: The current study shows that the MSM is a promising tool to predict worse depression outcomes in depressed patients. In this study that adds to previous work, we show the applicability of MSM in a wider range of primary and secondary care patients with depression.

Associations Between Daily Affective Instability and Connectomics in Functional Subnetworks in Remitted Patients with Recurrent Major Depressive Disorder.

Remitted patients with major depressive disorder (rMDD) often report more fluctuations in mood as residual symptomatology. It is unclear how this affective instability is associated with information processing related to the default mode (DMS), salience/reward (SRS), and frontoparietal (FPS) subnetworks in rMDD patients at high risk of recurrence (rrMDD). Sixty-two unipolar, drug-free rrMDD patients (⩾2 MDD episodes) and 41 healthy controls (HCs) were recruited. We used experience sampling methodology to monitor mood/cognitions (10 times a day for 6 days) and calculated affective instability using the mean adjusted absolute successive difference. Subsequently, we collected resting-state functional magnetic resonance imaging data and performed graph theory to obtain network metrics of integration within (local efficiency) the DMS, SRS, and FPS, and between (participation coefficient) these subnetworks and others. In rrMDD patients compared with HCs, we found that affective instability was increased in most negative mood/cognition variables and that the DMS had less connections with other subnetworks. Furthermore, we found that rrMDD patients, who showed more instability in feeling down and irritated, had less connections between the SRS and other subnetworks and higher local efficiency coefficients in the FPS, respectively. In conclusion, rrMDD patients, compared with HCs, are less stable in their negative mood and these dynamics are related to differences in information processing within- and between-specific functional subnetworks. These results are a first step to gain a better understanding of how mood fluctuations in real life are represented in the brain and provide insights into the vulnerability profile of MDD.

Vulnerability for new episodes in recurrent major depressive disorder: protocol for the longitudinal DELTA-neuroimaging cohort study.

INTRODUCTION: Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD-recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission. METHODS AND ANALYSIS: In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35-65 years) with ≥ 2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination. ETHICS AND DISSEMINATION: The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings. TRIAL REGISTRATION NUMBER: NTR3768.