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.

Magnetic Resonance Spectroscopy in Depressed Subjects Treated With Electroconvulsive Therapy-A Systematic Review of Literature.

Electroconvulsive therapy (ECT) is considered to be the most effective acute treatment for otherwise treatment resistant major depressive episodes, and has been used for over 80 years. Still, the underlying mechanism of action is largely unknow. Several studies suggest that ECT affects the cerebral neurotransmitters, such as gamma-aminobutyric acid (GABA) and glutamate. Magnetic resonance spectroscopy (MRS) allows investigators to study neurotransmitters in vivo, and has been used to study neurochemical changes in the brain of patients treated with ECT. Several investigations have been performed on ECT-patients; however, no systematic review has yet summarized these findings. A systematic literature search based on the Prisma guidelines was performed. PubMed (Medline) was used in order to find investigations studying patients that had been treated with ECT and had undergone an MRS examination. A search in the databases Embase, PsycInfo, and Web of Science was also performed, leading to no additional records. A total of 30 records were identified and screened which resulted in 16 original investigations for review. The total number of patients that was included in these studies, ignoring potential overlap of samples in some investigations, was 325. The metabolites reported were N-acetyl aspartate, Choline, Myoinositol, Glutamate and Glutamine, GABA and Creatine. The strongest evidence for neurochemical change related to ECT, was found for N-acetyl aspartate (reduction), which is a marker of neuronal integrity. Increased choline and glutamate following treatment was also commonly reported.

A Longitudinal Comparison Between Depressed Patients Receiving Electroconvulsive Therapy and Healthy Controls on Specific Memory Functions.

OBJECTIVE: To examine the short- and long-term effect of electroconvulsive therapy on verbal, visual, and autobiographical memory functions in patients treated for a severe depressive episode. Patients were compared with healthy controls undergoing neurocognitive assessments at the same time points to account for normal forgetfulness and potential learning effects. METHODS: A pre-post intervention design included patients (n = 38) and controls (n = 16) referred to Haukeland University Hospital for electroconvulsive therapy (ECT) from September 2013 to September 2018. Patients diagnosed with a major depressive episode (according to ICD-10 criteria) underwent right unilateral ECT with brief-pulse, square-wave, constant current. Neurocognitive assessments were administered pretreatment and, on average, 19 days and 6 months posttreatment. Performance on the California Verbal Learning Test Second Edition, Rey Osterrich Complex Figure, and Autobiographical Memory Interview-Short Form were the main outcome measures, examining verbal, visual, and autobiographical memory, respectively. RESULTS: Patients performed significantly worse compared to controls on all measures of verbal and visual memory at every assessment (P ≤ .001). Within-group analyses showed no impaired visual or verbal memory function due to ECT. However, autobiographical consistency was significantly decreased for patients (70.30%) compared to controls (82.03%) 6 months posttreatment (P = .0005). CONCLUSIONS: Patients' ability to acquire new general knowledge is considered as unaffected by ECT. Deficits in autobiographic memory were found 6 months posttreatment, indicating both an iatrogenic effect of treatment and an effect of depression on retrograde memory functions. For patients, the risk of this iatrogenic effect of treatment must be evaluated against the symptomatic and potential functional recovery due to ECT. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04348825.

The effect of electroconvulsive therapy (ECT) on serum tryptophan metabolites.

BACKGROUND: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. OBJECTIVE: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. METHODS: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5'-phosphat (PLP), riboflavin, neopterin and cotinine were measured. RESULTS: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. CONCLUSION: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway.

Volume of the Human Hippocampus and Clinical Response Following Electroconvulsive Therapy.

BACKGROUND: Hippocampal enlargements are commonly reported after electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT-induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome. METHODS: Longitudinal neuroimaging and clinical data from 10 independent sites participating in the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) were obtained for mega-analysis. Hippocampal volumes were extracted from structural magnetic resonance images, acquired before and after patients (n = 281) experiencing a major depressive episode completed an ECT treatment series using right unilateral and bilateral stimulation. Untreated nondepressed control subjects (n = 95) were scanned twice. RESULTS: The linear component of hippocampal volume change was 0.28% (SE 0.08) per ECT session (p < .001). Volume change varied by electrode placement in the left hippocampus (bilateral, 3.3 ± 2.2%, d = 1.5; right unilateral, 1.6 ± 2.1%, d = 0.8; p < .0001) but not the right hippocampus (bilateral, 3.0 ± 1.7%, d = 1.8; right unilateral, 2.7 ± 2.0%, d = 1.4; p = .36). Volume change for electrode placement per ECT session varied similarly by hemisphere. Individuals with greater treatment-related volume increases had poorer outcomes (Montgomery-Åsberg Depression Rating Scale change -1.0 [SE 0.35], per 1% volume increase, p = .005), although the effects were not significant after controlling for ECT number (slope -0.69 [SE 0.38], p = .069). CONCLUSIONS: The number of ECT sessions and electrode placement impacts the extent and laterality of hippocampal enlargement, but volume change is not positively associated with clinical outcome. The results suggest that the high efficacy of ECT is not explained by hippocampal enlargement, which alone might not serve as a viable biomarker for treatment outcome.