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tDCS efficacy and utility of anhedonia and rumination as clinical predictors of response to tDCS in major depressive disorder (MDD)
Abstract
Background:
Anhedonia and rumination are mental disorders' transdiagnostic features but remain difficult to treat. Transcranial direct current stimulation (tDCS) is a proven treatment for depression, but its effects on anhedonia and rumination and whether anhedonia and rumination can be used as a predictive biomarker of treatment response is not well known. This study aimed to investigate the tDCS efficacy and identify the predictive role of anhedonia and rumination in response to tDCS in patients with MDD.
Methods:
182 patients received 10 tDCS sessions delivered at 2 mA to left (anode) dorsolateral prefrontal cortex (DLPFC). Hamilton Rating Scale for Depression (HRSD-17), Snaith-Hamilton Pleasure Scale (SHAPS), and the 10-item Ruminative Response Scale (RRS-10) was administered to patients with MDD before treatment, following it, and after two weeks of tDCS.
Results:
There was an overall significant improvement in anhedonia from pre- to post-treatment. Regression analyses revealed that responders had higher baseline anhedonia and rumination (reflective pondering) scores. We found that the reduction in HRSD scores after tDCS was significantly associated with anhedonia's baseline values while no relation was found between baseline rumination and tDCS treatment response.
Conclusion:
These results provide new evidence that pronounced anhedonia may be a significant clinical predictor of response to tDCS. Patients with severe or low baseline rumination had an equal chance of achieving clinical response. Prospective tDCS studies are necessary to validate the predictive value of the derived model.
... Although there has been a great deal of research over the past few years confirming that neuromodulation techniques can be used to treat depression, especially major depressive depression (MMD), the response mechanism has not been very clear yet. Hypothesis based on experiments that neuromodulation techniques do improve the symptom of depression [4,5]. These suggest that neuromodulation techniques may have impact on synaptic plasticity, functional connectivity structure of the brain, and neural pathway. ...
Depression is a prevalent mental disorder that can lead to negative emotional states and physical reactions, including pain, insomnia, cognitive disorder and even suicidal tendencies, which largely effect one’s daily life. With the increasing pressures of modern life, the incidence of depression has risen, highlighting the importance of effective treatment. While antidepressants are commonly used, they often come with side effects and may lose effectiveness over time, especially in cases of Treatment-Resistant Depression (TRD) and major depressive disorder (MDD). In order to find a more efficient and safer way to cure depression, neuromodulation techniques has been involved in the treatment. Neuromodulation techniques such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have emerged as promising alternatives for depression treatment. These techniques modulate brain activity by applying electric currents or magnetic fields to specific areas of the brain. This study aims to compare tDCS and TMS in the treatment of depression by reviewing their advantages and disadvantages. Results indicate that both tDCS and TMS show promise in treating depression, with tDCS demonstrating moderate effectiveness for acute depression and TMS proving effective, especially for TRD. While both techniques have shown improvements in depressive symptoms, they differ in terms of mechanism, efficacy, safety, and convenience.
... I 2 = 61.64. Krepel et al., 2020;Lazary et al., 2021;Rezaei et al., 2023;Russo et al., 2018;Wang et al., 2021;Zhu et al., 2022), and one concerned both clinical groups (Bodén et al., 2021). Three studies on patients with depression combined NIBS with medications or psychological interventions (Krepel et al., 2020;Russo et al., 2018;Zhu et al., 2022), and another study recruited patients with bipolar depression (Diederichs et al., 2021). ...
Anhedonia is a transdiagnostic symptom found in patients with schizophrenia and depression. Current pharmacological interventions for anhedonia are unsatisfactory in a considerable proportion of patients. There has been growing interest in applying noninvasive brain stimulation (NIBS) to patients with anhedonia. However, evidence for the efficacy of NIBS for anhedonia remain inconsistent. This study systematically identified all studies that measured anhedonia and applied NIBS in patients with schizophrenia or depression. We conducted a search using the various databases in English (PubMed, EBSCOHost (PsycInfo/PsycArticles), Web of Science) and Chinese (China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform) languages, and reviewed original research articles on NIBS published from January 1989 to July 2023. Our search had identified 15 articles for quantitative synthesis, with three concerning schizophrenia samples, 11 concerning samples with depression, and one concerning both clinical samples. We conducted a meta‐analysis based on the 15 included studies, and the results suggested that NIBS could improve anhedonia symptoms in schizophrenia patients and patients with depression, with a medium‐to‐large effect size. Our findings are preliminary, given the limited number of included studies. Future NIBS research should measure anhedonia as a primary outcome and should recruit transdiagnostic samples.
Individuals avoid spending cognitive effort unless expected rewards offset the perceived costs. Recent work employing tasks that provide explicit information about demands and incentives suggests causal involvement of the frontopolar cortex (FPC) in effort-based decision-making. Using transcranial direct current stimulation (tDCS), we examined whether the FPC's role in motivating effort generalizes to sequential choice problems in which task demand and reward rates vary indirectly and as a function of experience. In a double-blind, within-subject design, 46 participants (36 female, 8 male, 1 “neither/other”) received anodal (i.e., excitatory) or sham stimulation over the right FPC during an Effort Foraging Task, which required choosing between harvesting patches for successively decreasing resources or traveling to replenished patches by performing a cognitive task with environment-specific difficulty. As expected, participants exited patches later (i.e., exhibited lower exit thresholds) when traveling required greater (versus less) effort, indicating increased travel costs in high-effort environments. Under anodal tDCS, the difference in exit thresholds between environments was significantly smaller relative to sham. Finally, individual differences analyses hint that participants with lower self-reported motivation to exert effort exhibited greater travel cost reductions following tDCS. Together, these findings support the theorized causal role of the FPC in motivating cognitively effortful behavior, expand its role to more ecologically valid serial decisions, and highlight the potential for tDCS as a tool to increase motivation with potential clinical applications.
Individuals avoid spending cognitive effort unless expected rewards offset the perceived costs. Recent work employing tasks that provide explicit information about demands and incentives, suggests causal involvement of the Frontopolar Cortex (FPC) in effort-based decision-making. Using transcranial direct current stimulation (tDCS), we examined whether the FPC’s role in motivating effort generalizes to sequential choice problems in which task demand and reward rates vary indirectly and as a function of experience. In a double-blind, within- subject design, 46 participants received anodal (i.e., excitatory) or sham stimulation over the right FPC during an Effort Foraging Task, which required choosing between harvesting patches for successively decreasing resources or traveling to replenished patches by performing a cognitive task with environment-specific difficulty. As expected, participants exited patches later (i.e., displayed lower exit thresholds) when travelling required greater (versus less) effort, indicating increased travel costs in high-effort environments. Under anodal tDCS, the difference in exit thresholds between environments was significantly smaller relative to sham. Finally, individual differences analyses hint that participants with lower self-reported motivation to exert effort exhibited greater travel cost reductions following tDCS. Together, these findings support the theorized causal role of the FPC in motivating cognitively effortful behavior, expand its role to more ecologically valid serial decisions and highlight the potential for tDCS as a tool to increase motivation with potential clinical applications.
Significance statement
Uncovering the neural mechanisms regulating engagement in effortful behavior is crucial, as it will improve our understanding and treatment of conditions characterized by reduced motivation, e.g., apathy and anhedonia. The Frontopolar Cortex (FPC) has been implicated in increasing effort exertion in settings that provide explicit information about effort demand and reward. Using transcranial direct current stimulation (tDCS), we investigated whether the FPC retains its motivating capacity in sequential choice problems that vary effort and reward indirectly. We demonstrate that FPC stimulation decreases cognitive effort-based travel costs in an Effort Foraging Task, indicating a causal and general involvement of the FPC in motivating effortful behavior, highlighting the potential of tDCS as a new avenue for increasing motivation with potential clinical applications.
Background: Individuals with paranoid personality disorder (PPD) usually suffer from impulsive behavior and anxiety and constantly imagine others trying to humiliate, harm, or threaten them. This disorder causes mistrust towards others and may interfere with a person's ability to form close relationships. Objectives: The present study aimed to investigate the effects of transcranial direct-current stimulation (tDCS) on impulsivity and anxiety in patients with PPD. Methods: This quasi-experimental research adopted a pretest-posttest control group design. The statistical population included all patients aged 30 – 50 years with PPD referred to psychological and psychiatric clinics and hospitals in Yazd, (Iran), in 2022. Convenience sampling was employed to select 30 individuals with PPD. The participants were randomly assigned to an experimental group (n = 15) and a control (n = 15) group using a table of random numbers. The participants completed impulsivity and anxiety questionnaires during the pretest and posttest stages. The experimental group received ten 20-minute sessions of tDCS. The collected data were analyzed using SPSS v25.0. Results: The participants included 30 men and women with PPD with an average age of 41.23 ± 8.40 years. In the posttest, the mean ± SD of impulsivity for tDCS and control groups were 54.67 ± 4.03 and 93.93 ± 3.67, respectively. Moreover, the mean ± SD of anxiety in tDCS and control groups in the posttest were 16.40 ± 2.79 and 42.39 ± 2.99, respectively. The results indicated that tDCS significantly improved impulsivity and reduced anxiety at the posttest stage (P < 0.001). Conclusions: Transcranial direct-current stimulation can alleviate impulsivity and anxiety in patients with PPD. Therefore, therapists can implement the tDCS method as a complementary therapy to improve impulsivity and anxiety in patients with PPD.
Background
Anhedonia is one of the defining features of depression but it remains difficult to target and treat. Transcranial magnetic stimulation (TMS) is a proven treatment for depression, but its effects on anhedonia and whether anhedonia can be used as a predictive biomarker of response is not well known.
Methods
Snaith–Hamilton Pleasure Scale was administered to patients with depression before and after a standard course of TMS in a naturalistic outpatient setting.
Results
144 patients were analyzed. There was an overall significant improvement in anhedonia from pre- to post-treatment (7.69 ± 3.88 vs. 2.96 ± 3.45; p < .001). Significant correlations between improvements in anhedonia and other depressive symptoms were present (r = 0.55, p < .001). Logistic regression revealed that baseline anhedonia severity was not a significant predictor of clinical outcome.
Conclusion
This is the first large, naturalistic study examining the effects of standard, non-research TMS on anhedonia. Among depressed patients, TMS resulted in significant improvements in anhedonia. Patients with severe baseline anhedonia had an equal chance of achieving clinical response/remission. Patients with anhedonia should not be excluded from treatment if they are safe for outpatient care and otherwise appropriate candidates for treatment.
Background
Transcranial direct current stimulation (tDCS) is a promising nonpharmacological intervention for treating depression. We aimed to provide an updated meta-analysis assessing the anti-depressant efficacy of tDCS.
Methods
We searched the literature from the first available date to 30 December 2020 to identify relevant randomized controlled trials (RCTs).
Results
27 RCTs (N = 1204 patients, 653 in active tDCS and 551 in sham tDCS) were included. Active tDCS was superior to sham tDCS (g = 0.46, 95 % CI 0.15−0.76) in modulating depressive symptoms measured by depression rating scales. Active tDCS was also superior to sham tDCS in reducing response and remission rates, but these differences did not reach statistically significant levels (ORresponse = 1.75, 95 % CI 0.85–3.58; ORremission = 1.29, 95 % CI 0.59–2.83). The two groups had comparable dropout rates (OR = 1.28, 95 % CI 0.62–1.64).
Conclusion
For treatments of depressive episodes, tDCS may be efficacious. Specific tDCS parameters (e.g., a 2-mA stimulation current and 30-min sessions) and clinical characteristics (e.g., antidepressant-free) may augment the treatment efficacy of tDCS.
Backgrounds: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique for the treatment of several psychiatric disorders, e.g., mood disorders and schizophrenia. Therapeutic effects of tDCS are suggested to be produced by bi-directional changes in cortical activities, i.e., increased/decreased cortical excitability via anodal/cathodal stimulation. Although tDCS provides a promising approach for the treatment of psychiatric disorders, its neurobiological mechanisms remain to be explored.
Objectives: To review recent findings from neurophysiological, chemical, and brain-network studies, and consider how tDCS ameliorates psychiatric conditions.
Findings: Enhancement of excitatory synaptic transmissions through anodal tDCS stimulation is likely to facilitate glutamate transmission and suppress gamma-aminobutyric acid transmission in the cortex. On the other hand, it positively or negatively modulates the activities of dopamine, serotonin, and acetylcholine transmissions in the central nervous system. These neural events by tDCS may change the balance between excitatory and inhibitory inputs. Specifically, multi-session tDCS is thought to promote/regulate information processing efficiency in the cerebral cortical circuit, which induces long-term potentiation (LTP) by synthesizing various proteins.
Conclusions: This review will help understand putative mechanisms underlying the clinical benefits of tDCS from the perspective of neurotransmitters, network dynamics, intracellular events, and related modalities of the brain function.
Background
Transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) hypothetically modulates cognitive functions by facilitating or inhibiting neuronal activities chiefly in the cerebral cortex. The effect of tDCS in the deeper brain region, the basal ganglia-cortical circuit, remains unknown.
Objective
To investigate the interaction between γ-aminobutyric acid (GABA) concentrations and dopamine release following tDCS.
Method
This study used a randomized, placebo-controlled, double-blind, crossover design. Seventeen healthy male subjects underwent active and sham tDCS (13 min twice at an interval of 20 min) with the anode placed at the left DLPFC and the cathode at the right DLPFC, followed by examinations with [¹¹C]-raclopride positron emission topography (PET) and GABA-magnetic resonance spectroscopy (MRS). MRS voxels were set in the left DLPFC and bilateral striata. Paired t-tests and regression analyses were performed for PET and MRS parameters.
Results
MRS data analyses showed elevations in GABA in the left striatum along with moderate reductions in the right striatum and the left DLPFC after active tDCS. PET data analyses showed that reductions in [¹¹C]-raclopride binding potentials (increase in dopamine release) in the right striatum were inversely correlated with those in the left striatum after active tDCS. GABA reductions in the left DLPFC positively correlated with elevations in GABA in the left striatum and with increases in right striatal dopamine release and negatively correlated with increases in left striatal dopamine release.
Conclusion
The present results suggest that tDCS to the DLPFC modulates dopamine-GABA functions in the basal ganglia-cortical circuit.
Introduction. Broadly considered a transdiagnostic feature of psychological disorders, rumination is associated with lower treatment response, slower recovery rates, and higher relapse rates. Accordingly, research has focused on the development of interventions to alleviate rumination. Recently, transcranial Direct Current Stimulation (tDCS) has emerged as a promising tool to do so.
Methods. We performed a systematic review of sham-controlled tDCS studies targeting rumination among healthy participants or patients with psychiatric disorders, investigating the effectiveness of tDCS in reducing rumination, and assessing the research quality of this nascent field.
Results. We identified nine studies, with five reporting a significant impact of tDCS on rumination. We also outlined a few tDCS parameters (e.g., stimulation duration, electrode size) and research methods' features (e.g., within- versus between-research designs) characterizing those positive-finding studies. However, these studies were characterized by substantial heterogeneity (e.g., methodological flaws, lack of open science practices), precluding any definite statement about the best way to target rumination via tDCS. Moreover, several strong methodological limitations were also present across those studies.
Discussion. Although our systematic review identifies the strengths and weaknesses of the available research about the impact of tDCS on rumination, it calls for strong efforts to improve this nascent field's current methodological caveats. We discuss how open science practices can help to usher this field forward.
Importance
Anhedonia, a reduced capacity for pleasure, is described for many psychiatric and neurologic conditions. However, a decade after the Research Domain Criteria launch, whether anhedonia severity differs between diagnoses is still unclear. Reference values for hedonic capacity in healthy humans are also needed.
Objective
To generate and compare reference values for anhedonia levels in adults with and without mental illness.
Data Sources
Web of Science, Scopus, PubMed, and Google Scholar were used to list all articles from January 1, 1995 to July 2, 2019, citing the scale development report of a widely used anhedonia questionnaire, the Snaith-Hamilton Pleasure Scale (SHAPS). Searches were conducted from April 5 to 11, 2018, and on July 2, 2019.
Study Selection
Studies including healthy patients and those with a verified diagnosis, assessed at baseline or in a no-treatment condition with the complete 14-item SHAPS, were included in this preregistered meta-analysis.
Data Extraction and Synthesis
Random-effects models were used to calculate mean SHAPS scores and 95% CIs separately for healthy participants and patients with current major depressive disorder (MDD), past/remitted MDD, bipolar disorder, schizophrenia, substance use disorders, Parkinson disease, and chronic pain. SHAPS scores were compared between groups using meta-regression, and traditional effect size meta-analyses were conducted to estimate differences in SHAPS scores between healthy and patient samples. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.
Main Outcomes and Measures
Self-reported anhedonia as measured by 2 different formats of the SHAPS (possible ranges, 0-14 and 14-56 points), with higher values on both scales indicating greater anhedonia symptoms.
Results
In the available literature (168 articles; 16 494 participants; 8058 [49%] female participants; aged 13-72 years), patients with current MDD, schizophrenia, substance use disorder, Parkinson disease, and chronic pain scored higher on the SHAPS than healthy participants. Within the patient groups, those with current MDD scored considerably higher than all other groups. Patients with remitted MDD scored within the healthy range (g = 0.1). This pattern replicated across SHAPS scoring methods and was consistent across point estimate and effect size analyses.
Conclusions and Relevance
The findings of this meta-analysis indicate that the severity of anhedonia may differ across disorders associated with anhedonia. Whereas anhedonia in MDD affects multiple pleasure domains, patients with other conditions may experience decreased enjoyment of only a minority of life’s many rewards. These findings have implications for psychiatric taxonomy development, where dimensional approaches are gaining attention. Moreover, the SHAPS reference values presented herein may be useful for researchers and clinicians assessing the efficacy of anhedonia treatments.
Background
rumination, defined as repetitive thoughts about emotionally relevant experiences, has been linked extensively with mood disorders, especially major depressive disorder (MDD)¹. However, there is a growing body of evidence suggesting the importance of rumination in bipolar disorder (BD)² as well.
Methods
we searched for studies that investigated rumination in both BD and MDD in four databases. Our systematic search identified 12 studies with an overall sample size of 2071 clinical patients.
Results
results demonstrated no significant difference in the ruminative tendencies of the two patient groups when all rumination measures were included. We tested for the effect of rumination subtype, BD subgroups, and the current mood state of BD and MDD patients. There were no significant differences in terms of depressive rumination, however, BD patients reported more rumination on positive affect. This difference remained significant when examining in BD-I³ and BD-II⁴ patient groups, with similar effect sizes.
Limitations
due to the lack of sufficient data in the literature, only a few self-report studies qualified to be included in our analysis. Thus additional moderating factors, such as the current mood state of the two patient groups could not be analyzed.
Conclusions
this review demonstrates that rumination is a significant process in both MDD and BD, highlighting the importance of interventions to reduce rumination in mood disorders. The two patient groups share several commonalities in terms of rumination, however, rumination subtype was found to be an important moderating variable underlining a difference in positive rumination.
Introduction
Anhedonia is a transdiagnostic psychopathological dimension, consisting in the impaired ability to experience pleasure. In order to further our understanding of its neural correlates and to explore its potential relevance as a predictor of treatment response, in this article we systematically reviewed studies involving anhedonia and neuromodulation interventions, across different disorders.
Methods
We included seven studies fulfilling inclusion/exclusion criteria and involving different measures of anticipatory and consummatory anhedonia, as well as different noninvasive brain stimulation interventions (transcranial magnetic stimulation and transcranial direct current stimulation). Studies not exploring hedonic measures or not involving neuromodulation intervention were excluded.
Results
All the included studies entailed the use of rTMS protocols in one of the diverse prefrontal targets. The limited amount of studies and the heterogeneity of stimulation protocols did not allow to draw any conclusion with regard to the efficacy of rTMS in the treatment of transnosographic anhedonia. A potential for anhedonia in dissecting possible endophenotypes of different psychopathological conditions preliminarily emerged.
Conclusions
Anhedonia is an underexplored condition in neuromodulation trials. It may represent a valuable transdiagnostic dimension that requires further examination in order to discover new clinical predictors for treatment response.
While considerable experimental research has examined the impact of transcranial direct current stimulation (tDCS) on a range of cognitive processes associated with emotional pathology, the impact of tDCS on worry has been comparatively neglected. Given that anxiety pathology is characterised by motivated engagement in worry, and that frontal tDCS has the capacity to enhance goal-oriented cognition, it is important to examine whether tDCS would increase or ameliorate the cognitive and emotional effects of worry. In the current study we examined how tDCS influenced the anxiety response to worry, and the frequency of negative intrusive thoughts. We additionally examined whether stimulation delivered in isolation, or in combination with a mindful-focus task would augment the effects of tDCS. Ninety-seven (75 female) healthy participants received either active or sham anodal tDCS to the left dorsolateral prefrontal cortex, delivered either in isolation or concurrently with a mindful task (four conditions). The frequency of negative thought intrusions was assessed before and after a period of instructed worry, and state anxiety was assessed across the study. Active tDCS was associated with significantly greater elevation in anxiety in response to the worry induction. No effects were observed on the frequency of negative thought intrusions, and the combined delivery of tDCS with the concurrent mindful task did not alter the pattern of observed effects. While inviting replication in a high anxious sample, the present results highlight the possibility that tDCS may interact with motivated engagement in negative patterns of cognition, such as worry, to produce greater emotional reactivity.
We investigated whether repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (DLPFC) would reduce anhedonia in a sample of 19 depressed adults (Mage = 45.21, SD = 11.21, 63% women) randomized to either active or sham rTMS. To track anhedonia, patients completed the Snaith-Hamilton Pleasure Scale (SHAPS)1 and a novel behavioral task called “Happy Faces,” which required patients to interpret neutral versus various intensities of positively valenced human facial expressions. Patients had to indicate dichotomously whether any degree of positive emotion was expressed. We expected that more anhedonic patients would struggle most with low intensity happy faces; often incorrectly calling them neutral. Patients also completed a self-report measure of “empathic happiness”—i.e., vicarious joy. Measures were completed pre- to post-treatment. Results indicate rTMS to DLPFC related to improvement in interpretation of subtle forms of happiness in active rTMS patients relative to sham. Furthermore, empathic happiness and anhedonia score were significantly antagonistic across all patients.
Background:
Rumination is a cognitive process that is implicated in the development and maintenance of various forms of psychopathology, including problematic substance use. Most studies on the role of rumination in substance use have been conducted among community samples or individuals with alcohol use disorders and have predominately focused on overall rumination rather than differentiating between its subtypes, ruminative brooding and ruminative reflection. The current study therefore aimed to investigate i) whether rumination subtypes are associated with problematic substance use among people with a long-term history of illicit drug use independently of related psychological disorders (depression and post-traumatic stress disorder [PTSD]), and ii) whether gender moderates these relationships.
Methods:
This cross-sectional study used data from the Australian Treatment Outcome Study (ATOS); a naturalistic prospective cohort study of people with heroin dependence. At the 11-year follow-up of ATOS, a total of 380 participants completed measures of rumination, depression, PTSD, and indices of problematic substance use.
Results:
Hierarchical logistic regression analyses indicated that higher brooding scores were associated with current heroin dependence (OR = 1.11, CI: 1.01-1.22), polydrug use (OR = 1.16, CI: 1.06-1.28) and experience of injection related health problems (OR = 1.08, CI: 1.00-1.17), independently of depression, PTSD, and other covariates. Reflection was not related to any of the substance use measures. These results were not moderated by gender.
Conclusions:
Findings indicate that ruminative brooding is related to a poorer substance use profile among people with long-term illicit drug use and highlight the potential benefits of targeting brooding during substance use treatment.
Transcranial direct current stimulation (tDCS) is a neuromodulation technique, which noninvasively alters cortical excitability via weak polarizing currents between two electrodes placed on the scalp. Since it is comparably easy to handle, cheap to use and relatively well tolerated, tDCS has gained increasing interest in recent years. Based on well-known behavioral effects, a number of clinical studies have been performed in populations including patients with major depressive disorder followed by schizophrenia and substance use disorders, in sum with heterogeneous results with respect to efficacy. Nevertheless, the potential of tDCS must not be underestimated since it could be further improved by systematically investigating the various stimulation parameters to eventually increase clinical efficacy. The present article briefly explains the underlying physiology of tDCS, summarizes typical stimulation protocols and then reviews clinical efficacy for various psychiatric disorders as well as prevalent adverse effects. Future developments include combined and more complex interactions of tDCS with pharmacological or psychotherapeutic interventions. In particular, using computational models to individualize stimulation protocols, considering state dependency and applying closed-loop technologies will pave the way for tDCS-based personalized interventions as well as the development of home treatment settings promoting the role of tDCS as an effective treatment option for patients with mental health problems.
Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants’ accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.
Background
Few studies focused on the relationship between psychological measures, major depressive disorder (MDD) and repetitive transcranial magnetic stimulation (rTMS) response. This study investigated several psychological measures as potential predictors for rTMS treatment response. Additionally, this study employed two approaches to evaluate the robustness of our findings by implementing immediate replication and full-sample exploration with strict p -thresholding.
Methods
This study is an open-label, multi-site study with a total of 196 MDD patients. The sample was subdivided in a Discovery (60% of total sample, n = 119) and Replication sample (40% of total sample, n = 77). Patients were treated with right low frequency (1 Hz) or left high frequency (10 Hz) rTMS at the dorsolateral prefrontal cortex. Clinical variables [Beck Depression Inventory (BDI), Neuroticism, Extraversion, Openness Five-Factor Inventory, and Depression, Anxiety, and Stress Scale, and BDI subscales] were obtained at baseline, post-treatment, and at follow-up. Predictors were analyzed in terms of statistical association, robustness (independent replication), as well as for their clinical relevance [positive predictive value (PPV) and negative predictive value (NPV)].
Results
Univariate analyses revealed that non-responders had higher baseline anhedonia scores. Anhedonia scores at baseline correlated negatively with total BDI percentage change over time. This finding was replicated. However, anhedonia scores showed to be marginally predictive of rTMS response, and neither PPV nor NPV reached the levels of clinical relevance.
Conclusions
This study suggests that non-responders to rTMS treatment have higher baseline anhedonia scores. However, anhedonia was only marginally predictive of rTMS response. Since all other psychological measures did not show predictive value, it is concluded that psychological measures cannot be used as clinically relevant predictors to rTMS response in MDD.
Pleasure and motivation are important factors for goal-directed behavior and well-being in both animals and humans. Intact hedonic capacity requires an undisturbed interplay between a number of different brain regions and transmitter systems. Concordantly, dysfunction of networks encoding for reward have been shown in depression and other psychiatric disorders. The development of technological possibilities to investigate connectivity on a functional level in humans and to directly influence networks in animals using optogenetics among other techniques has provided new important insights in this field of research.
In this review, we aim to provide an overview on the neurobiological substrates of anhedonia on a network level. For this purpose, definition of anhedonia and the involved reward components are described first, then current data on reward networks in healthy individuals and in depressed patients are summarized, and the roles of different neurotransmitter systems involved in reward processing are specified. Based on this information, the impact of different therapeutic approaches on reward processing is described with a particular focus on deep brain stimulation (DBS) as a possibility for a direct modulation of human brain structures in vivo.
Overall, results of current studies emphasize the importance of anhedonia in psychiatric disorders and the relevance of targeting this phenotype for a successful psychiatric treatment. However, more data incorporating these results for the refinement of methodological approaches are needed to be able to develop individually tailored therapeutic concepts based on both clinical and neurobiological profiles of patients.
A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward-motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS.
Background
Anhedonia, as a dysregulation of the reward circuit, is present in both Major Depressive Disorder (MDD) and schizophrenia (SZ).
Aims
To elucidate the clinical and neurobiological differences between schizophrenia (SZ) and depression (MDD) in regard to anhedonia, while reconciling the challenges and benefits of assessing anhedonia as a transdiagnostic feature under the Research Domain Criteria (RDoC) framework.
Methods
In this review, we summarize data from publications examining anhedonia or its underlying reward deficits in SZ and MDD. A literature search was conducted in OVID Medline, PsycINFO and EMBASE databases between 2000 and 2017.
Results
While certain subgroups share commonalities, there are also important differences. SZ may be characterized by a disorganization, rather than a deficiency, in reward processing and cognitive function, including inappropriate energy expenditure and focus on irrelevant cues. In contrast, MDD has been characterized by deficits in anticipatory pleasure, development of reward associations, and integration of information from past experience. Understanding the roles of neurotransmitters and aberrant brain circuitry is necessary to appreciate differences in reward function in SZ and MDD.
Conclusion
Anhedonia as a clinical presentation of reward circuit dysregulation is an important and relatively undertreated symptom of both SZ and MDD. In order to improve patient outcomes and quality of life, it is important to consider how anhedonia fits into both diagnoses.
Background
Rumination increases vulnerability to depression, exacerbates and perpetuates negative moods. This study was aimed to examine the psychometric properties of the Chinese version of the 10-item Ruminative Response Scale (RRS-10) in a large undergraduate sample. MethodsA sample of 5,236 university students finished the RRS and the Center for Epidemiological Studies Depression Scale (CES-D). Confirmatory Factor Analysis (CFA) was performed to examine the two-factor structure and the measurement equivalence of the RRS-10 across gender. The internal consistency, test-retest reliability, correlations among RRS, RRS-10 and CES-D were also explored. In addition, gender difference on rumination and the relationship between rumination and depression were further investigated. ResultsThe two-factor model of RRS-10 fit the data reasonably and had acceptable internal consistency and test-retest reliability in Chinese undergraduates sample. And the measurement equivalence of the RRS-10 was acceptable across gender in Chinese university students. Findings in respect of latent means and manifest means revealed non-significant gender difference in RRS-10. Besides, participants with high-level rumination had more depressive symptoms than those with low-level rumination. Conclusions
The Chinese version of the RRS-10 showed good psychometric properties and was measurement invariant across gender in undergraduates.
A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson’s disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer’s disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10-24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients.
Prescribing of antidepressant treatment (ADT) for major depressive disorder (MDD) has increased in quantity and popularity over the last two decades. This is likely due to the approval of safer medications, better education of clinicians and their patients, direct-to-consumer marketing practices, and less stigma associated with those taking ADT. This trend has also been met with some controversy, however, as the ongoing safety and effectiveness of these treatments have at times been called into question. This paper discusses the differing levels of evidence that support the use of ADT based on (A) Food and Drug Administration approvals, (B) data from randomized controlled trials or meta-analyses and, where these are not available, the authors discuss and apply, (C) theoretical pharmacodynamic principles to justify antidepressant choice in the treatment of MDD patients. The final section discusses standard psychopharmacology guideline approaches to better alert the reader as to which practices are commonplace compared with those which are more outside of the standard of care.
Anhedonia is a prominent symptom in neuropsychiatric disorders, most markedly in major depressive disorder (MDD) and schizophrenia (SZ). Emerging evidence indicates an overlap in the neural substrates of anhedonia between MDD and SZ, which supported a transdiagnostic approach. Therefore, we used activation likelihood estimation (ALE) meta-analysis of functional magnetic resonance imaging studies in MDD and SZ to examine the neural bases of three subdomains of anhedonia: consummatory anhedonia, anticipatory anhedonia and emotional processing. ALE analysis focused specifically on MDD or SZ was used later to dissociate specific anhedonia-related neurobiological impairments from potential disease general impairments. ALE results revealed that consummatory anhedonia was associated with decreased activation in ventral basal ganglia areas, while anticipatory anhedonia was associated with more substrates in frontal-striatal networks except the ventral striatum, which included the dorsal anterior cingulate, middle frontal gyrus and medial frontal gyrus. MDD and SZ patients showed similar neurobiological impairments in anticipatory and consummatory anhedonia, but differences in the emotional experience task, which may also involve affective/mood general processing. These results support that anhedonia is characterized by alterations in reward processing and relies on frontal-striatal brain circuitry. The transdiagnostic approach is a promising way to reveal the overall neurobiological framework that contributes to anhedonia and could help to improve targeted treatment strategies.
Cognitive behavioural therapy is an effective treatment for depression. However, one third of the patients do not respond satisfactorily, and relapse rates of around 30 % within the first post-treatment year were reported in a recent meta-analysis. In total, 30-50 % of remitted patients present with residual symptoms by the end of treatment. A common residual symptom is rumination, a process of recurrent negative thinking and dwelling on negative affect. Rumination has been demonstrated as a major factor in vulnerability to depression, predicting the onset, severity, and duration of future depression. Rumination-focused cognitive behavioural therapy is a psychotherapeutic treatment targeting rumination. Because rumination plays a major role in the initiation and maintenance of depression, targeting rumination with rumination-focused cognitive behavioural therapy may be more effective in treating depression and reducing relapse than standard cognitive behavioural therapy.
This study is a two-arm pragmatic randomised controlled superiority trial comparing the effectiveness of group-based rumination-focused cognitive behaviour therapy with the effectiveness of group-based cognitive behavioural therapy for treatment of depression. One hundred twenty-eight patients with depression will be recruited from and given treatment in an outpatient service at a psychiatric hospital in Denmark. Our primary outcome will be severity of depressive symptoms (Hamilton Rating Scale for Depression) at completion of treatment. Secondary outcomes will be level of rumination, worry, anxiety, quality of life, behavioural activation, experimental measures of cognitive flexibility, and emotional attentional bias. A 6-month follow-up is planned and will include the primary outcome measure and assessment of relapse.
The clinical outcome of this trial may guide clinicians to decide on the merits of including rumination-focused cognitive behavioural therapy in the treatment of depression in outpatient services.
ClinicalTrials.gov Identifier: NCT02278224 , registered 28 Oct. 2014.
Transcranial direct current stimulation (tDCS) is a non-invasive technique that has been experimentally tested for a number of psychiatric and neurological conditions. Preliminary observations suggest that this approach can indeed influencea number of cellular and molecular pathways which may bedisease-relevant. However, the mechanisms of actionunderlying its beneficial effects are largely unknown and need to be better understood in order to allow thistherapy to be used optimally. In this review, we summarizethephysiological responses observed in vitro and in vivo, with a particular emphasis oncellular and molecular cascades associated withinflammation, angiogenesis, neurogenesis and neuroplasticityrecruited by DCS; a topic which has been largely neglected in the literature. A better understanding of the neural responses to tDCS is criticalif this therapy is to be used in large-scale clinical trials with a view of being routinely offered to patients suffering from various conditions affecting the central nervous system.
© The Author 2014. Published by Oxford University Press on behalf of CINP.
Background:
The medial forebrain bundle (MFB) is an important pathway of the reward system. Two branches have been described using diffusion magnetic resonance imaging (MRI)-based tractography: the infero-medial MFB (imMFB) and the supero-lateral MFB (slMFB). Previous studies point to white-matter microstructural alterations of the slMFB in major depressive disorder (MDD) during acute episodes. To extend this finding, this study investigates whether white-matter microstructure is also altered in MDD patients that are in remission. Further, we explore associations between diffusion MRI-based metrics of white-matter microstructure of imMFB, slMFB and hedonic tone, the ability to derive pleasure.
Method:
Eighteen remitted depressed (RD) and 22 never depressed (ND) participants underwent high angular resolution diffusion-weighted imaging (HARDI) scans. To reconstruct the two pathways of the MFB (imMFB and slMFB) we used the damped Richardson-Lucy (dRL) algorithm. Mean fractional anisotropy (FA) was sampled along the tracts.
Results:
Mean FA of imMFB, slMFB and a comparison tract (the middle cerebellar peduncle) did not differ between ND and RD participants. Hedonic capacity correlated negatively with mean FA of the left slMFB, explaining 21% of the variance.
Conclusions:
Diffusion MRI-based metrics of white-matter microstructure of the MFB in RD do not differ from ND. Hedonic capacity is associated with altered white-matter microstructure of the slMFB.
Transcranial direct current stimulation (tDCS) of the prefrontal cortex is known as a promising intervention in major depression disorder (MDD). However, limited information on predictors of therapeutic response to tDCS are available. This study aimed to investigate clinical and demographic predictors of therapeutic response in patients taking no medications. For this purpose, the required data were collected from 2 independent tDCS trials on 116 MDD patients. Accordingly, 84 patients underwent 10 sessions of 2 mA tDCS daily each one lasted for 20 min and 32 patients received 10 twice sessions of 2 mA tDCS daily each one lasted for 20 min. Anodal electrode was located over the left dorsolateral prefrontal cortex (DLPFC), and cathode was over the right supraorbital region. Depression symptoms and the underlying clinical dimensions were assessed using the Beck Depression Inventory (BDI-II) at baseline and after the tDCS treatment. Of the included 116 patients, 47.4% showed an antidepressant response. Results of logistic regression analysis showed that the reduction in BDI-II scores after tDCS was associated with the baseline values of cognitive-affective symptoms factor, loss of pleasure, loss of interest, and sleep problems. Pronounced sleep disturbances and cognitive-affective symptoms were identified as the potential clinical predictors of response to tDCS. However, more prospective tDCS studies are necessary to validate the predictive value of the derived model.
Anhedonia is one of the core symptoms of major depressive disorder (MDD), which is often inadequately treated by traditional antidepressants. The modern framework of anhedonia extends the definition from impaired consummatory pleasure or interest in rewards to a broad spectrum of deficits that impact functions such as reward anticipation, approach motivation, effort expenditure, reward valuation, expectation, and reward-cue association learning. Substantial preclinical and clinical research has explored the neural basis of reward deficits in the context of depression, and has implicated mesocorticolimbic reward circuitry comprising the nucleus accumbens, ventral pallidum, ventral tegmental area, amygdala, hippocampus, anterior cingulate, insula, orbitofrontal cortex, and other prefrontal cortex regions. Dopamine modulates several reward facets including anticipation, motivation, effort, and learning. As well, serotonin, norepinephrine, opioids, glutamate, Gamma aminobutyric acid (GABA), and acetylcholine are also involved in anhedonia, and medications targeting these systems may also potentially normalize reward processing in depression. Unfortunately, whereas reward anticipation and reward outcome are extensively explored by both preclinical and clinical studies, translational gaps remain in reward motivation, effort, valuation, and learning, where clinical neuroimaging studies are in the early stages. This review aims to synthesize the neurobiological mechanisms underlying anhedonia in MDD uncovered by preclinical and clinical research. The translational difficulties in studying the neural basis of reward are also discussed.
Increasing research has implicated rumination in the development and maintenance in many types of psychopathology, including anxiety-related disorders. A few studies have explored the impact of rumination during cognitive-behavioral therapy (CBT) for anxiety-related disorders (which rely heavily on exposure-based interventions), with mixed results. The present study assessed levels of (trait) rumination before starting treatment for predicting outcomes in 147 adults seeking CBT for anxiety-related disorders in an open treatment clinic. Results revealed that pretreatment levels of rumination significantly predicted (lower) quality of life at the end of treatment, after accounting for baseline variance in quality of life. This finding remained robust when also accounting for demographics, depression, general anxiety, and diagnosis. This result was not observed for self-reflection (a construct related to, but distinguishable from, rumination). Nevertheless, a follow-up (receiver-operator characteristic) analysis showed that pretreatment rumination did not reliably distinguish participants who showed clinically meaningful gains in quality of life during treatment from those who did not. Theoretical and clinical implications of these findings are discussed. We propose that rumination may impede emotional processing during CBT for anxiety, and warrants further attention and treatment. However, more advanced methods (e.g., multivariate modeling) are needed to improve the prognostic utility of rumination.
We evaluated the efficacy and acceptability of transcranial direct current stimulation (tDCS) for treating acute depressive episodes using individual patient data that provide more precise estimates than aggregate data meta-analysis. A systematic review of placebo-controlled trials on tDCS as only intervention was conducted until December-2018. Data from each study was collated to estimate odds ratio (OR) and number needed to treat (NNT) of response and remission, and depression improvement. Endpoints were pre-determined. Nine eligible studies (572 participants), presenting moderate/high certainty of evidence, were included. Active tDCS was significantly superior to sham for response (30.9% vs. 18.9% respectively; OR = 1.96, 95%CI [1.30-2.95], NNT = 9), remission (19.9% vs. 11.7%, OR = 1.94 [1.19-3.16], NNT = 13) and depression improvement (effect size of β = 0.31, [0.15-0.47]). Moreover, continuous clinical improvement was observed even after the end of acute tDCS treatment. There were no differences in all-cause discontinuation rates and no predictors of response were identified. To conclude, active tDCS was statistically superior to sham in all outcomes, although its clinical effects were moderate.
Two core features of depression include depressed mood (heightened distress) and anhedonia (reduced pleasure). Despite their centrality to depression, studies have not examined their contribution to treatment outcomes in a randomized clinical trial providing mainstream treatments like antidepressant medications (ADM) and cognitive therapy (CT). We used baseline distress and anhedonia derived from a factor analysis of the Mood and Anxiety Symptom Questionnaire to predict remission and recovery in 433 individuals with recurrent/chronic major depressive disorder. Patients were provided with only ADM or both ADM and CT. Overall, higher baseline distress and anhedonia predicted longer times to remission within one year and recovery within three years. When controlling for treatment condition, distress improved prediction of outcomes over and above anhedonia, while anhedonia did not improve prediction of outcomes over and above distress. Interactions with treatment condition demonstrated that individuals with higher distress and anhedonia benefited from receiving CT in addition to ADM, whereas there was no added benefit of CT for individuals with lower distress and anhedonia. Assessing distress and anhedonia prior to treatment may help select patients who will benefit most from CT in addition to ADM. For the treatments and outcome measures tested, utilizing distress to guide treatment planning may yield the greatest benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00057577.
Currently, there is not definitive information regarding the efficacy of transcranial direct current stimulation (tDCS) for Post-traumatic stress disorder (PTSD). This study aimed to examine the efficacy of tDCS for PTSD and its sub-symptoms. In a double-blind, controlled randomized clinical trial, 40 participants with PTSD were randomly assigned to receive either 10 tDCS sessions delivered at 2 mA to the right (cathode) and left (anode) dorsolateral prefrontal cortex (DLPFC) or 10 sham tDCS sessions to the same area. A blinded rater assessed PTSD, depressive, and anxiety symptoms before treatment, following it, and after a 1-month follow-up period. According to the results: i) PTSD patients demonstrated a significant reduction in PTSD symptoms, hyper-arousal and negative alterations in cognition and mood sub-symptoms as well as depressive and anxiety symptoms in the active stimulation compared to the sham stimulation at post-treatment and follow-up; ii) active stimulation when compared to sham stimulation revealed greater reductions in re-experiencing sub-symptoms from baseline to post-test. However, follow-up differences did not reach significance; iii) With respect to avoidance sub-symptoms, there were no significant differences between the active and sham stimulation at post-test and follow-up. This study supported the efficacy of 10 sessions of bilateral DLPFC tCDS delivered at 2 mA for the treatment of PTSD symptoms. Taken together, these findings suggest that although tDCS can reduce PTSD symptoms, researchers should consider the different types of PTSD and use strategies to ensure sufficient power to detect a potential effect of tDCS on various types of PTSD.
No studies have examined the efficacy of bi-anodal transcranial direct current stimulation (tDCS) over bilateral dorsolateral prefrontal cortex (DLPFC) coupled with bilateral extracephalic references in treating negative symptoms of non-acute schizophrenia patients. This study aimed to investigate the therapeutic effects of the new approach of tDCS on negative symptoms, other schizophrenia symptoms, cognitive deficits and psychosocial functioning in a double-blind, randomized, sham-controlled trial. Patients with non-acute schizophrenia (N = 60) in randomized order received sham treatment or bilaterally provided tDCS (2 mA, twice-daily sessions for five consecutive days) with the anode over the DLPFC and the reference (cathode) over the ipsilateral forearm. The negative symptoms as measured by a dimensional approach of Positive and Negative Syndrome Scale (PANSS) were rapidly reduced by bimodal tDCS relative to sham stimulation (F = 24.86, Cohen's d = 0.661, p = 6.11 × 10-6). The beneficial effect on negative symptoms lasted for up to 3 months. The authors also observed improvement with tDCS of psychosocial functioning as measured by the global score of Personal and Social Performance scale (PSP) and psychopathological symptoms especially for disorganization and cognitive symptoms as measured by the PANSS. No effects were observed on other schizophrenia symptom dimensions and the performance on a series of neurocognitive tests. Our results show promise for bi-anodal tDCS over bilateral DLPFC using bilateral extracephalic references in treating negative symptoms and other selected manifestations of schizophrenia. Further studies with electrophysiological or imaging evaluation help unravel the exact mechanism of action of this novel stimulation parameter of tDCS in schizophrenia patients. (ClinicalTrials.gov ID:NCT03701100).
Depressive brooding following a stressful event predicts negative affect and neuroendocrine responses related to psychological stress. The dorsolateral prefrontal cortex (DLPFC) has been associated with the top-down regulation of thoughts and emotions, and abnormal neural activity within this region has been associated with increased psychological stress and ruminative thinking. The aim of this study was to investigate whether the modulation of the DLPFC could have beneficial effects on ruminative thoughts and the endocrine response following a self-relevant stressor. Using a sham-controlled within-subjects crossover-design, two sessions of intermittent theta-burst stimulation (iTBS) were administered over the left DLPFC to thirty-eight healthy-volunteers after they were confronted with a social-evaluative stressor, the Trier Social Stress Test. To assess stress recovery, momentary rumination was measured before and after a resting period subsequent to the encounter with the stressor. In addition, cortisol levels were measured between and after the two iTBS sessions that were applied during the stress recovery phase. Overall, iTBS did not significantly influence ruminative thinking and cortisol secretion during the stress recovery phase. However, taking into account participants ruminative tendencies, our results revealed that for participants with higher levels of brooding ruminative thinking remained stable after iTBS, whereas in the sham condition there was a marginal significant increase in ruminative thinking. Moreover, only after iTBS, there was a significant reduction in cortisol secretion (i.e. a faster return to baseline as compared to sham) for high brooders during the recovery from the stressor. These results show that the prefrontal cortex plays a role in stress recovery mechanisms in individuals who are more vulnerable for psychopathology.
Transcranial direct current stimulation (tDCS) is a low intensity neuromodulation technique shown to elicit therapeutic effects in a number of neuropsychological conditions. Independent randomized sham-controlled trials and meta- and mega-analyses demonstrate that tDCS targeted to the left dorsolateral prefrontal cortex can produce a clinically meaningful response in patients with major depressive disorder (MDD), but effects are small to moderate in size. However, the heterogeneous presentation, and the neurobiology underlying particular features of depression suggest clinical outcomes might benefit from empirically informed patient selection. In this review, we summarize the status of tDCS research in MDD with focus on the clinical, biological, and intrinsic and extrinsic factors shown to enhance or predict antidepressant response. We also discuss research strategies for optimizing tDCS to improve patient-specific clinical outcomes. TDCS appears suited for both bipolar and unipolar depression, but is less effective in treatment resistant depression. TDCS may also better target core aspects of depressed mood over vegetative symptoms, while pretreatment patient characteristics might inform subsequent response. Peripheral blood markers of gene and immune system function have not yet proven useful as predictors or correlates of tDCS response. Though further research is needed, several lines of evidence suggest that tDCS administered in combination with pharmacological and cognitive behavioral interventions can improve outcomes. Tailoring stimulation to the functional and structural anatomy and/or connectivity of individual patients can maximize physiological response in targeted networks, which in turn could translate to therapeutic benefits.
Anhedonia is defined as a diminished ability to experience interest or pleasure, and is a critical psychopathological dimension of major depressive disorder (MDD). The purpose of the current systematic review is to evaluate the therapeutic efficacy of pharmacological treatments on measures of anhedonia in adults with MDD. Electronic databases Cochrane Library (CENTRAL), Ovid MEDLINE, PubMed, PsycINFO, and Google Scholar were searched from inception to June 1, 2018 for longitudinal studies utilizing pharmacotherapy for the treatment of anhedonia in patients with MDD. A total of 17 eligible studies were identified (i.e., evaluated the effects of pharmacotherapy on a measure of anhedonia). Among the identified studies, the efficacy of 14 different pharmacotherapies on measures of anhedonia were evaluated, including melatonergic agents (i.e. agomelatine), monoaminergic agents (i.e. moclobemide, clomipramine, bupropion, venlafaxine, fluoxetine, amitifadine and levomilnacipran, escitalopram, and sertraline), glutamatergic agents (i.e., ketamine and riluzole), stimulants (i.e., methylphenidate), and psychedelics (i.e., psilocybin). Based on the available evidence, most antidepressants demonstrated beneficial effects on measures of anhedonia as well as the other depressive symptoms. Only escitalopram/riluzole combination treatment was ineffective in treating symptoms of anhedonia in MDD. Continued research is warranted to further support the efficacy of mechanistically-distinct antidepressants in treating symptoms of anhedonia in MDD. Future research should also aim to parse out the heterogeneous effects of different pharmacotherapies on anhedonic symptoms.
Background:
A growing body of literature indicates a correlation between asymmetrical activity of frontal brain sites and approach versus withdrawal motivation. Yet the causal status of this relationship is presently unclear. Here we examined the effect of anodal tDCS applied over the left dorsolateral prefrontal cortex (dlPFC) on approach motivation, operationalized as effort allocation during the Effort-Expenditure for Reward Task (EEfRT).
Hypothesis:
We expected left frontal anodal transcranial direct current simulation (tDCS) to increase participants' willingness to allocate more effort during the EEfRT. Based on previous research, we expected this effect to be strongest on trials with low probability of reward attainment.
Methods:
60 right-handed neurologically and psychologically healthy participants (63% female) aged 18 - 35 were tested in a counterbalanced within-subject design. Participants were invited to our lab twice to complete two 15-minute blocks of the EEfRT on each study day, randomly assigned to either an anodal tDCS or a SHAM condition.
Results:
No main effect of stimulation condition was found, however the interactions of stimulation condition and both probability of reward attainment and reward magnitude reached significance. These interactions indicated that left frontal anodal tDCS specifically increased the percentage of hard task choices (HTC) in trials with low probability of reward attainment and in trials with high reward magnitude.
Discussion:
The observation of an increasing effect of left frontal anodal tDCS on effort expenditure for reward as indicated by HTC supports the idea of a causal relationship between asymmetric activity of frontal brain sites and approach motivation and hints at moderating effects of task-features on the effects of tDCS.
Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been gaining favor as a viable tool in Psychiatry. The purpose of this review is to summarize the evidence of tDCS as a treatment of disorders such as depression, schizophrenia, and obsessive-compulsive disorder (OCD). Current findings indicate that tDCS is probably effective in non-treatment-resistant depressive patients. Regarding schizophrenia and OCD, present evidence is not robust enough, although preliminary results indicate that tDCS is a promising technique. Therefore, more trials are needed before using tDCS in a clinical setting.
Background:
Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, but only some individuals respond. Predicting response could reduce patient and clinical burden. Neural activity related to working memory (WM) has been related to mood improvements, so may represent a biomarker for response prediction.
Primary hypotheses:
We expected higher theta and alpha activity in responders compared to non-responders to rTMS.
Methods:
Fifty patients with treatment resistant depression and twenty controls performed a WM task while electroencephalography (EEG) was recorded. Patients underwent 5-8 weeks of rTMS treatment, repeating the EEG at week 1 (W1). Of the 39 participants with valid WM-related EEG data from baseline and W1, 10 were responders. Comparisons between responders and non-responders were made at baseline and W1 for measures of theta (4-8 Hz), upper alpha (10-12.5 Hz), and gamma (30-45 Hz) power, connectivity, and theta-gamma coupling. The control group's measures were compared to the depression group's baseline measures separately.
Results:
Responders showed higher levels of WM-related fronto-midline theta power and theta connectivity compared to non-responders at baseline and W1. Responder's fronto-midline theta power and connectivity was similar to controls. Responders also showed an increase in gamma connectivity from baseline to W1, with a concurrent improvement in mood and WM reaction times. An unbiased combination of all measures provided mean sensitivity of 0.90 at predicting responders and specificity of 0.92 in a predictive machine learning algorithm.
Conclusion:
Baseline and W1 fronto-midline theta power and theta connectivity show good potential for predicting response to rTMS treatment for depression.
It has been proposed that a crucial link between cognitive (i.e., self-schemas) and biological vulnerability is prefrontal control. This is because decreased control leads to impaired ability to inhibit ruminative thinking after the activation of negative self-schemas. However, current evidence is mainly correlational. In the current experimental study we tested whether the effect of neurostimulation of the dorsolateral prefrontal cortex (DLPFC) on self-esteem is mediated by momentary ruminative self-referential thinking (MRST) after the induction of negative self-schemas by criticism. We used a single, sham-controlled crossover session of anodal transcranial Direct Current Stimulation (tDCS) applied to the left DLPFC (cathode over the right supraorbital region) in healthy female individuals. After receiving tDCS/sham stimulation, we measured MRST and exposed the participants to critical audio scripts, followed by another MRST measurement. Subsequently, all participants completed two Implicit Relational Assessment Procedures to implicitly measure actual and ideal self-esteem. Our behavioral data indicated a significant decrease in MRST after real but not sham tDCS. Moreover, although there was no immediate effect of tDCS on implicit self-esteem, an indirect effect was found through double mediation, with the difference in MRST from baseline to after stimulation and from baseline to after criticism as our two mediators. The larger the decrease of criticism induced MRST after real tDCS, the higher the level of actual self-esteem. Our results show that tDCS can influence cognitive processes such as rumination, and subsequently self-esteem, but only after the activation of negative self-schemas. Rumination and negative self-esteem characterize different forms of psychopathology, and these data expand our knowledge of the role of the prefrontal cortex in controlling these self-referential processes, and the mechanisms of action of tDCS.
Background:
Transcranial direct current stimulation (tDCS) is a non-invasive electrical stimulation technique, assumed to influence cognition and emotional processing.
Objective:
However, it is unclear how tDCS influences spontaneous cognitive processes such as momentary self-referential thoughts on the neuronal level.
Methods:
Forty healthy female volunteers participated in a single session sham-controlled crossover tDCS study while being in the MRI scanner. We measured brain perfusion (arterial spin labeling) just before and just after tDCS. Before and after the stimulation procedure, participants were scored on mood (visual analogue scales) and on the Momentary Ruminative Self-focus Inventory (MRSI). We performed a 1.5 mA, 20-min, anodal left dorsolateral prefrontal cortex, cathodal right supraorbital stimulation.
Results:
One sham-controlled tDCS session did not result in subjective mood changes. However, as compared to before, MRSI scores significantly decreased only after active tDCS. Regression analysis revealed that this reduction in momentary ruminative self-referential thoughts was related to tDCS-related increases in left prefrontal cortical perfusion. tDCS decreased momentary self-referential thoughts, which was associated with increasing perfusion in the left prefrontal cortex.
Conclusion:
Our findings are in line with the hypothesis that tDCS of the DLPFC attenuates ruminative processes.
Objectives: Accelerated intermittent theta-burst stimulation (aiTBS) anti-depressive working mechanisms are still unclear. Because aiTBS may work through modulating the reward system and the level of anhedonia may influence this modulation, we investigated the effect of aiTBS on reward responsiveness in high and low anhedonic MDD patients.
Methods: In this registered RCT (NCT01832805), 50 MDD patients were randomised to a sham-controlled cross-over aiTBS treatment protocol over the left dorsolateral prefrontal cortex (DLPFC). Patients performed a probabilistic learning task in fMRI before and after each week of stimulation.
Results: Task performance analyses did not show any significant effects of aiTBS on reward responsiveness, nor differences between both groups of MDD patients. However, at baseline, low anhedonic patients displayed higher neural activity in the caudate and putamen. After the first week of aiTBS treatment, in low anhedonic patients we found a decreased neural activity within the reward system, in contrast to an increased activity observed in high anhedonic patients. No changes were observed in reward related neural regions after the first week of sham stimulation.
Conclusions: Although both MDD groups showed no differences in task performance, our brain imaging findings suggest that left DLPFC aiTBS treatment modulates the reward system differently according to anhedonia severity.
Objective
Previous studies investigated predictors of repetitive transcranial magnetic stimulation (rTMS) response in depressive disorders but there is still limited knowledge about clinical predictors. Moreover, predictors of rTMS response in bipolar depression (BDD) are less studied than unipolar depression (UDD).
Methods
We performed a binary logistic regression analysis in 248 patients with depressive disorders (unipolar N = 102, bipolar N = 146) who received 20 sessions of DLPFC rTMS (High-frequency rTMS, low-frequency rTMS, bilateral rTMS) to investigate significant clinical and demographic predictors of rTMS response. We also investigated effects of depression type, response (yes, no) and time on reducing somatic and cognitive-affective symptoms of patients.
Results
Depression type (unipolar vs. bipolar) did not have a significant effect on rTMS response. 45% of all patients, 51.5% of UDD patients and 41% of BDD patients, responded to rTMS treatment. Age was the only significant demographic predictor of treatment response in all patients. Cognitive-affective symptoms, compared to somatic symptoms were significant predictors for treatment response to rTMS. Common and unique clinical predictor for UDD and BDD were identified.
Conclusions
Younger patients and those with cognitive-affective rather than somatic symptoms benefit more from DLPFC rTMS treatment. rTMS is effective in UDD and BDD patients. Patients should be selected based on clinical and demographic profile.
Significance
Findings are based on the largest thus far reported sample of patients with depressive disorders that received DLPFC rTMS.
Keywords
Unipolar depressive disorderBipolar depressive disorderRepetitive transcranial magnetic stimulation (rTMS)Clinical predictorsDemographic predictorsDorsolateral prefrontal cortex (DLPFC)
Background:
Transcranial direct current stimulation (tDCS) is a promising neuromodulation intervention for poor-responding or refractory depressed patients. However, little is known about predictors of response to this therapy. The present study aimed to analyze clinical predictors of response to tDCS in depressed patients.
Methods:
Clinical data from 3 independent tDCS trials on 171 depressed patients (including unipolar and bipolar depression), were pooled and analyzed to assess predictors of response. Depression severity and the underlying clinical dimensions were measured using the Hamilton Depression Rating Scale (HDRS) at baseline and after the tDCS treatment. Age, gender and diagnosis (bipolar/unipolar depression) were also investigated as predictors of response. Linear mixed models were fitted in order to ascertain which HDRS factors were associated with response to tDCS.
Results:
Age, gender and diagnosis did not show any association with response to treatment. The reduction in HDRS scores after tDCS was strongly associated with the baseline values of "Cognitive Disturbances" and "Retardation" factors, whilst the "Anxiety/Somatization" factor showed a mild association with the response.
Limitations:
Open-label design, the lack of control group, and minor differences in stimulation protocols.
Conclusions:
No differences in response to tDCS were found between unipolar and bipolar patients, suggesting that tDCS is effective for both conditions. "Cognitive disturbance", "Retardation", and "Anxiety/Somatization", were identified as potential clinical predictors of response to tDCS. These findings point to the pre-selection of the potential responders to tDCS, therefore optimizing the clinical use of this technique and the overall cost-effectiveness of the psychiatric intervention for depressed patients.
Healthy individuals reporting higher (as compared to lower) levels of trait rumination recruit more neural activity in dorso-cortical regions (mostly in the right hemisphere) when inhibiting negative information, possibly to compensate their difficulty to disengage from it. In the present study, we investigated whether these latter neural correlates are causally implicated in cognitive control in these individuals. We administered the Cued Emotional Control Task, a measure of cognitive control indexed by cognitive costs for inhibiting versus providing a habitual response for emotional information, in thirty-five healthy volunteers reporting a broad range of trait rumination levels. Participants completed the task after receiving both real and sham-placebo (counterbalanced order) anodal transcranial Direct Current Stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC). Results reveal that the tDCS induced effects on cognitive costs for emotional information were associated with individual differences in trait rumination: the higher the trait rumination level, the less cognitive costs following real neuromodulation of the right DLPFC. Interestingly, these effects were observed for both positive and negative stimuli, and not only negative information as hypothesized. Overall, the data suggest that the right DLPFC is causally involved in the alteration of cognitive control in healthy individuals who tend to ruminate, possibly by helping them to disengage from emotional material.
Up to one third of patients adequately treated for Major Depressive Disorder (MDD) do not respond to multiple interventions. Many studies investigated predictors in MDD outcome, but no study focused on predictors of non-response or non-remission to antidepressants in subjects with treatment resistant depression (TRD). The present study aimed to evaluate possible socio-demographic and clinical predictors of non-response and non-remission in MDD patients who failed to benefit from at least one antidepressant trial. A total of 51 papers were included. A number of severity indicators, such as longer duration of depressive episode, moderate-high suicidal risk, anxious comorbidity, higher number of hospitalizations and higher dosage of antidepressants, were associated with non-response as well as age. Interestingly, severity of illness, as well as comorbid personality disorders and anxiety symptoms, had also a predictive value in non-remission with the addition of marital status.
Considering limitations, selected studies were observational or randomized non controlled/ controlled trials and different TRD definitions and outcome measures were used. Overall, predictors of outcome were similar to MDD, but specific socio-demographic and clinical factors should be considered in clinical practice to formulate a more focused treatment in TRD patients.
The resurgence of interest in anhedonia within major depression has been fuelled by clinical trials demonstrating its utility in predicting antidepressant response as well as recent conceptualizations focused on the role and manifestation of anhedonia in depression. Historically, anhedonia has been conceptualized as a "loss of pleasure", yet neuropsychological and neurobiological studies reveal a multifaceted reconceptualization that emphasizes different facets of hedonic function, including desire, effort/motivation, anticipation and consummatory pleasure. To ensure generalizability across studies, evaluation of the available subjective and objective methods to assess anhedonia is necessary. The majority of research regarding anhedonia and its neurobiological underpinnings comes from preclinical research, which uses primary reward (e.g. food) to probe hedonic responding. In contrast, behavioural studies in humans primarily use secondary reward (e.g. money) to measure many aspects of reward responding, including delay discounting, response bias, prediction error, probabilistic reversal learning, effort, anticipation and consummatory pleasure. The development of subjective scales to measure anhedonia has also increased in the last decade. This review will assess the current methodology to measure anhedonia, with a focus on scales and behavioural tasks in humans. Limitations of current work and recommendations for future studies are discussed.
Objective
Parkinson's disease is associated with high rates of depression. There is growing interest in non-pharmacological management including psychological approaches such as Cognitive Behaviour Therapy. To date, little research has investigated whether processes that underpin cognitive models of depression, on which such treatment is based, apply in patients with Parkinson's disease. The study aimed to investigate the contribution of core psychological factors to the presence and degree of depressive symptoms.
Methods
104 participants completed questionnaires measuring mood, motor disability and core psychological variables, including maladaptive assumptions, rumination, cognitive-behavioural avoidance, illness representations and cognitive-behavioural responses to symptoms.
Results
Regression analyses revealed that a small number of psychological factors accounted for the majority of depression variance, over and above that explained by overall disability. Participants reporting high levels of rumination, avoidance and symptom focusing experienced more severe depressive symptoms. In contrast, pervasive negative dysfunctional beliefs did not independently contribute to depression variance.
Conclusion
Specific cognitive (rumination and symptom focusing) and behavioural (avoidance) processes may be key psychological markers of depression in Parkinson's disease and therefore offer important targets for tailored psychological interventions.
Over the last 15-years, transcranial direct current stimulation (tDCS), a relatively novel form of neuromodulation, has seen a surge of popularity in both clinical and academic settings. Despite numerous claims suggesting that a single session of tDCS can modulate cognition in healthy adult populations (especially working memory and language production), the paradigms utilized and results reported in the literature are extremely variable. To address this, we conduct the largest quantitative review of the cognitive data to date.
Single-session tDCS data in healthy adults (18-50) from every cognitive outcome measure reported by at least two different research groups in the literature was collected. Outcome measures were divided into 4 broad categories: executive function, language, memory, and miscellaneous. To account for the paradigmatic variability in the literature, we undertook a three-tier analysis system; each with less-stringent inclusion criteria than the prior. Standard mean difference values with 95% CIs were generated for included studies and pooled for each analysis.
Of the 59 analyses conducted, tDCS was found to not have a significant effect on any - regardless of inclusion laxity. This includes no effect on any working memory outcome or language production task.
Our quantitative review does not support the idea that tDCS generates a reliable effect on cognition in healthy adults. Reasons for and limitations of this finding are discussed. This work raises important questions regarding the efficacy of tDCS, state-dependency effects, and future directions for this tool in cognitive research.
Copyright © 2015 Elsevier Inc. All rights reserved.
Based on findings that major depressive disorder (MDD) is associated to decreased dorsolateral prefrontal cortical (DLPFC) activity; interventions that increase DLPFC activity might theoretically present antidepressant effects. Two of them are cognitive control therapy (CCT), a neurocognitive intervention that uses computer-based working memory exercises, and transcranial direct current stimulation (tDCS), which delivers weak, electric direct currents over the scalp.
We investigated whether tDCS enhanced the effects of CCT in a double-blind trial, in which participants were randomized to sham tDCS and CCT (n=17) vs. active tDCS and CCT (n=20). CCT and tDCS were applied for 10 consecutive workdays. Clinicaltrials.gov identifier: NCT01434836.
Both CCT alone and combined with tDCS ameliorated depressive symptoms after the acute treatment period and at follow-up, with a response rate of approximately 25%. Older patients and those who presented better performance in the task throughout the trial (possibly indicating greater engagement and activation of the DLPFC) had greater depression improvement in the combined treatment group.
Our exploratory findings should be further confirmed in prospective controlled trials.
CCT and tDCS combined might be beneficial for older depressed patients, particularly for those who have cognitive resources to adequately learn and improve task performance over time. This combined therapy might be specifically relevant in this subgroup that is more prone to present cognitive decline and prefrontal cortical atrophy.
Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes.
Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode.
Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region.
The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.