Neurobiological mechanisms of ECT and TMS treatment in depression: study protocol of a multimodal magnetic resonance investigation.

BACKGROUND: Noninvasive neurostimulation treatments are increasingly being used to treat major depression, which is a common cause of disability worldwide. While electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are both effective in treating depressive episodes, their mechanisms of action are, however, not completely understood. ECT is given under general anesthesia, where an electrical pulse is administered through electrodes placed on the patient's head to trigger a seizure. ECT is used for the most severe cases of depression and is usually not prescribed before other options have failed. With TMS, brain stimulation is achieved through rapidly changing magnetic fields that induce electric currents underneath a ferromagnetic coil. Its efficacy in depressive episodes has been well documented. This project aims to identify the neurobiological underpinnings of both the effects and side effects of the neurostimulation techniques ECT and TMS. METHODS: The study will utilize a pre-post case control longitudinal design. The sample will consist of 150 subjects: 100 patients (bipolar and major depressive disorder) who are treated with either ECT (N = 50) or TMS (N = 50) and matched healthy controls (N = 50) not receiving any treatment. All participants will undergo multimodal magnetic resonance imaging (MRI) as well as neuropsychological and clinical assessments at multiple time points before, during and after treatment. Arterial spin labeling MRI at baseline will be used to test whether brain perfusion can predict outcomes. Signs of brain disruption, potentiation and rewiring will be explored with resting-state functional MRI, magnetic resonance spectroscopy and multishell diffusion weighted imaging (DWI). Clinical outcome will be measured by clinician assessed and patient reported outcome measures. Memory-related side effects will be investigated, and specific tests of spatial navigation to test hippocampal function will be administered both before and after treatment. Blood samples will be stored in a biobank for future analyses. The observation time is 6 months. Data will be explored in light of the recently proposed disrupt, potentiate and rewire (DPR) hypothesis. DISCUSSION: The study will contribute data and novel analyses important for our understanding of neurostimulation as well as for the development of enhanced and more personalized treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05135897.

Deficits in specific executive functions manifest by severity in major depressive disorder: a comparison of antidepressant naïve inpatient, outpatient, subclinical, and healthy control groups.

Introduction: Previous research has highlighted the executive function (EF) deficits present in depressed patients; however, conflicting results exist regarding the impact of depression severity on the size of these deficits. This study aimed to compare deficits in EF between antidepressant naïve inpatient and outpatient depressed, a group with subclinical depression symptoms, and a healthy control group while controlling for education, sex, and age. Methods: In cross-sectional research, 245 antidepressant naive participants (46 inpatient, 68 outpatient, 65 subclinical, and 67 healthy control individuals) were recruited by convenience sampling. The Structured Clinical Interview for DSM-5 Disorders (SCID-5) and Beck Depression Inventory-II (BDI-II) were used to assess depression. EF was measured using several neuropsychological tests, including the Stroop Color-Word Test, the Wisconsin Card Sorting Test, and the N-back Test, which assessed the components of Inhibition, Shifting, and Updating, respectively. Multivariate analysis of covariance revealed a significant difference between the groups in EF components (p < 0.001). Pairwise comparisons further showed that inpatient and outpatient patients had more depressive symptoms and worse EF performance than subclinical and healthy control groups (p < 0.05). Results: In the analysis of EF measures, a significant difference was found among the four groups, with post-hoc tests revealing variations in specific EF components. Overall, patients with more severe depressive symptoms show more deficits in EF. Additionally, correlations between clinical characteristics and EF measures varied across patient groups, but many correlations became non-significant after adjusting for the false discovery rate (FDR). Discussion: This study emphasizes the impact of depression severity on deficits in the EF of depressed patients and at-risk populations. Consequently, it is important to consider executive dysfunctions as an underlying vulnerability in the development and persistence of depressive disorder.

Neurocognitive Functioning in Patients with Painful Temporomandibular Disorders.

Aim: To investigate psychosocial factors in painful TMD (pTMD) which could have consequences for mastering chronic pain. Methods: Our study included 22 patients (20 women, 2 men) with pTMD, refractory to conservative treatment, and 19 healthy controls. The control group was matched for gender, age, and educational level, and IQ tested on the Wechsler Abbreviated Scale of Intelligence. Neurocognitive function was tested with the Color-Word Interference Test (CWIT). Pain intensity was reported according to the General Pain Intensity Questionnaire (GPI), using the Numeric Rating Scale (NRS). Self-perceived cognitive difficulties were reported by the Perceived Deficits Questionnaire-Depression 5-item (PDQ-5). Two measures of rumination were included: the Rumination-Reflection Questionnaire (RRQ) and the Ruminative Response Scale (RRS). The Montgomery Åsberg Depression Rating Scale Self-report (MADRS-S) was used to measure depressive symptoms, and the Oral Health Impact Profile-TMD (OHIP-TMD) to measure QoL related to oral health. Results: There were no statistical differences in age (median pTMD: 55 years, median control: 53 years), educational level, and IQ between pTMD and controls. Median pain intensity in pTMD was NRS 8 at maximum and the median pain duration was 18 years. There were no significant differences in CWIT between pTMD and controls. Self-perceived cognitive function (PDQ) was significantly poorer in pTMD. Rumination scores from both measures, and the depression score from MADRS, were significantly higher in pTMD. The OHIP-TMD score revealed a significantly poorer QoL in pTMD. Conclusion: The group of pTMD patients have self-perceived cognitive difficulties that may make it more difficult to master chronic pain and common everyday tasks. They reported significantly more self-perceived cognitive difficulties, higher rumination, more depressive symptoms, and lower QoL compared to healthy controls, suggesting that these psychosocial factors could be targeted in treatment and interventions. However, the tested neurocognitive performance was equivalent to the control group.

Improvement in self-reported cognitive functioning but not in rumination following online working memory training in a two-year follow-up study of remitted major depressive disorder.

Self-reported subjective cognitive difficulties (subjective deficits) and rumination are central residual cognitive symptoms following major depressive disorder (MDD). These are risk factors for more a severe course of illness, and despite the considerable relapse risk of MDD, few interventions target the remitted phase, a high-risk period for developing new episodes. Online distribution of interventions could help close this gap. Computerized working memory training (CWMT) shows promising results, but findings are inconclusive regarding which symptoms improve following this intervention, and its long-term effects. This study reports results from a longitudinal open-label two-year follow-up pilot-study of self-reported cognitive residual symptoms following 25 sessions (40 min), five times a week of a digitally delivered CWMT intervention. Ten of 29 patients remitted from MDD completed two-year follow-up assessment. Significant large improvements in self-reported cognitive functioning on the behavior rating inventory of executive function-adult version appeared after two-years (d = 0.98), but no significant improvements were found in rumination (d < 0.308) measured by the ruminative responses scale. The former showed moderate non-significant associations to improvement in CWMT both post-intervention (r = 0.575) and at two-year follow-up (r = 0.308). Strengths in the study included a comprehensive intervention and long follow-up time. Limitations were small sample and no control group. No significant differences between completers and drop-outs were found, however, attrition effects cannot be ruled out and demand characteristics could influence findings. Results suggested lasting improvements in self-reported cognitive functioning following online CWMT. Controlled studies with larger samples should replicate these promising preliminary findings.

Computerized Working Memory Training in Remission From Major Depressive Disorder: Effects on Emotional Working Memory, Processing Speed, Executive Functions, and Associations With Symptoms.

Introduction: Remission from major depressive disorder (MDD) is associated with residual symptoms related to reduced functioning, quality of life, and relapse risk. Previous studies have raised questions about mechanisms involved-in and affected by cognitive training. This study investigated the associations and changes among depressive symptoms, rumination, processing speed (PS), executive functioning (EF), and emotional working memory (e-WM) pre- post computerized working memory training (CWMT). Method: Twenty-nine remitted participants were included in a pre- post pilot study of within-subject effects of online CWMT. A total of 20 participants completed the intervention and pre- post tests of EF and PS, e-WM, in addition to symptom and rumination measures. Associations between changes in symptoms and cognition were investigated pre- post. Associations between improvements in CWMT, depression history, and changes in cognition were explored. Hypotheses and statistics were preregistered before data were analyzed. Results: Manipulation of negatively valanced stimuli in e-WM showed an inverse association with rumination pre-intervention, but the association disappeared post-intervention. Cognitive functioning improved in most conditions with largest effects in EF. Symptoms did not change in the remitted sample. CWMT improvements were related to improvements in some aspects of EF and PS, but also to worse self-reported attention. Depression history was related to less improvement in EF. Limitations: Sample size was small and there was dropout from the study. There was no control group, thus precluding practice and placebo effects and causal relationships. Conclusions: Computerized WM training improves cognitive functions and could influence associations between e-WM and rumination. This could counteract functional impairment following MDD.

Cognitive Impairment and Neurocognitive Profiles in Major Depression-A Clinical Perspective.

Increasingly, studies have investigated cognitive functioning from the perspective of acute state- to remitted phases of Major Depressive Disorder (MDD). Some cognitive deficits observed in the symptomatic phase persist in remission as traits or scars. The etiological origin and clinical consequences of the neurocognitive profiles reported in the literature are still unclear and may vary across populations. Deficits are suspected to influence the association between MDD and neurodegenerative disorders and could thus be of particular clinical consequence. The aim of this review is to describe the clinical neuropsychological profile in MDD and how it is related to research during the past decade on cognitive deficits in MDD from a state, trait, and scar perspective. This review, with a clinical perspective, investigates research from the past decade regarding cognitive functioning in MDD in a long-term perspective. We focus on the clinical manifestation of deficits, and the potential neurodegenerative consequences of the neurocognitive profile in MDD. Searches in Medline, PsycINFO and Embase were conducted targeting articles published between 2010 and 2020. Examination of the evidence for long-lasting neurocognitive deficits in major depression within the cognitive domains of Memory, Executive Functions, Attention, and Processing Speed was conducted and was interpreted in the context of the State, Scar and Trait hypotheses. Defining the neurocognitive profiles in MDD will have consequences for personalized evaluation and treatment of residual cognitive symptoms, and etiological understanding of mood disorders, and treatments could potentially reduce or delay the development of neurodegenerative disorders.

A Longitudinal 5-Year Follow-Up Study of Cognitive Function After First Episode Major Depressive Disorder: Exploring State, Scar and Trait Effects.

Major depression (MDD) is associated with cognitive deficits in processing speed and executive function (EF) following first episode (FE). It is unclear whether deficits are state or trait related. Studies following FE MDD over longer periods are lacking, making it uncertain how cognition and symptoms develop after the initial episode. The present study assessed cognitive function and symptoms 5 years following FE MDD. In addition, the study explored relationships between MDD symptoms, rumination, and cognitive deficits with regards to the trait, state, and scar perspective. Twenty-three participants with previous FE MDD, and 20 matched control participants were compared on Delis-Kaplan Executive Function System measures of processing speed and EF, in a 5-year longitudinal follow-up study. Correlations between current symptoms- and history of MDD, rumination, cognition were investigated. Findings indicated that cognitive deficits persisted with no clear signs of exacerbation after initial episode. Inhibition appeared independent of current and previous symptoms of depression. Processing speed was related to depressive- symptoms and rumination. In conclusion, results indicated persisting, stable deficits in both EFs and processing speed. Findings further suggest that depressive symptoms could be related to deficits in processing speed, indicating state effects. There was limited support for worsening of cognition after initial episode. Some aspects of EF like Inhibition could show persistent deficits independent of depressive symptoms indicating trait effects.

Facing recovery: Emotional bias in working memory, rumination, relapse, and recurrence of major depression; an experimental paradigm conducted five years after first episode of major depression.

Identifying vulnerability factors for relapse of depression is essential in planning preventive interventions. Emotional face processing in major depression (MDD) shows promise as a potential cognitive marker for depression. The current study investigates how working memory (WM) load in face processing relates to rumination and new episodes of MDD in a novel explorative paradigm. It was expected that history of MDD is associated with reduction of the ability to process sad stimuli in high WM load conditions and reduction of the ability to process happy stimuli in low WM conditions. It was further predicted that these relations are associated with rumination and risk for relapse. The experiment was included as a cross sectional part in a follow-up study of a population that previously experienced first episode (FE) depression. The FE (N = 23) and a healthy control group (N = 22) completed a WM face processing task. In the task, three happy or sad faces were presented, processed in either a high or low WM taxing manner, followed by a target stimulus consisting of one of the previous pictures. Response time and accuracy were dependent variables. Rumination and number of relapses or recurrences were measured. The FE group recalled the placement of significantly fewer happy faces in the low WM load condition, and significantly fewer sad faces in the high WM load condition compared to controls. Significantly different scores between groups predicted trait rumination. Poor accuracy in the sad high WM load condition correlated with high degree of rumination. Relapse or recurrence was predicted by rumination. The present study supports an emotional WM deficit in remitted MDD. This suggests that deficits in manipulation of sad faces could represent a trait bias related to rumination and depression.