rTMS In Treatment-resistant Depression Research Articles

Trajectory Modeling and Response Prediction in Transcranial Magnetic Stimulation for Depression.

Repetitive transcranial magnetic stimulation (rTMS) therapy could be improved by better and earlier prediction of response. Latent class mixture (LCMM) and non-linear mixed effects (NLME) modelling have been applied to model the trajectories of antidepressant response (or non-response) to TMS, but it is not known whether such models can predict clinical outcomes. We compared LCMM and NLME approaches to model the antidepressant response to TMS in a naturalistic sample of 238 patients receiving rTMS for treatment resistant depression (TRD), across multiple coils and protocols. We then compared the predictive power of those models. LCMM trajectories were influenced largely by baseline symptom severity, but baseline symptoms provided little predictive power for later antidepressant response. Rather, the optimal LCMM model was a nonlinear two-class model that accounted for baseline symptoms. This model accurately predicted patient response at 4 weeks of treatment (AUC = 0.70, 95% CI = [0.52-0.87]), but not before. NLME offered slightly improved predictive performance at 4 weeks of treatment (AUC = 0.76, 95% CI = [0.58 - 0.94], but likewise, not before. In showing the predictive validity of these approaches to model response trajectories to rTMS, we provided preliminary evidence that trajectory modeling could be used to guide future treatment decisions.

Trajectories of suicidal ideation during rTMS for treatment-resistant depression

BackgroundrTMS is a safe and effective intervention for treatment-resistant depression (TRD). However, there is limited data on its specific impact on suicidal ideation (SI), and the trajectory of SI over the treatment course. ObjectiveThis open-label clinical trial investigated SI outcomes and trajectories in patients with TRD receiving low-frequency rTMS (LFR) to the right dorsolateral prefrontal cortex (DLPFC; N = 55). MethodsA latent class mixed-effect model was used to identify response trajectories for SI as well as core mood symptoms. Logistic regression analyses investigated risk factors associated with identified trajectories. ResultsFor each symptom domain, we identified two distinct trajectories during LFR, one tracking improvement (SI: n = 35, 60 %; mood: n = 29, 53 %) and the other tracking no improvement (SI: n = 20, 40 %; mood: n = 26, 47 %). Male sex, higher baseline anxiety, and higher baseline SI were risk factors for no improvement of SI; while higher baseline anxiety and benzodiazepine use were risk factors for no improvement of mood. Mediation analyses showed that anxiety was a risk factor for no improvement of SI and mood independent of benzodiazepine treatment. ConclusionsThis is the first study to investigate trajectories of response to LFR to the right DLPFC. SI and mood improved with LFR in most patients but the severity of anxiety symptoms was a factor of poor prognosis for both. Nuanced characterization of SI response to rTMS may lead to critical insights for individualized targeting strategies.

The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Efficacy of repetitive transcranial magnetic stimulation (rTMS) adjunctive therapy for major depressive disorder (MDD) after two antidepressant treatment failures: meta-analysis of randomized sham-controlled trials

BackgroundSeveral meta-analyses demonstrated the efficacy of unilateral High-Frequency Left-sided (HFL) repetitive Transcranial Magnetic Stimulation (rTMS) for individuals with Major Depressive Disorder (MDD); however, results are contradictory due to heterogeneity of the included studies.MethodsA systematic literature review (SLR) of English language articles published since 2000 was performed in March 2022 on PubMed and Scopus databases. Empirical evidence on the relative efficacy of rTMS treatment compared with standard pharmacotherapy in Treatment-Resistant Depression (TRD) were extracted. Random effects models were used to assess the effects of rTMS on response and remission rates.Results19 randomized double-blinded sham-controlled studies were included for quantitative analysis for response (n = 854 patients) and 9 studies for remission (n = 551 patients). The risk ratio (RR) for response and remission are 2.25 and 2.78, respectively for patients after two treatment failures using rTMS as add-on treatment compared to standard pharmacotherapy. Cochrane’s Q test showed no significant heterogeneity. No publication bias was detected.ConclusionsrTMS is significantly more effective than sham rTMS in TRD in response and remission outcomes and may be beneficial as an adjunctive treatment in patients with MDD after two treatment failures. This finding is consistent with previous meta-analyses; however, the effect size was smaller than in the formerly published literature.

Real world transcranial magnetic stimulation for major depression: A multisite, naturalistic, retrospective study

BackgroundIn 2008, the U.S. FDA approved rTMS as a treatment against medication-resistant depression. However, real-world rTMS outcomes remain understudied. This study investigates how rTMS for depression is delivered in routine clinical practice in France, and measures its effectiveness as well as its moderators. MethodsFive centers provided retrospective data on patients who were treated with rTMS for treatment-resistant depression from January 2015 to December 2020. Patients were assessed twice using a hetero-questionnaire, with baseline and immediate post-treatment assessments. We conducted univariate analyses to study which factors were significantly associated with rTMS effectiveness. We then included age, gender, and significant factors in a multivariate model. ResultsWe collected data from 435 patients with a mean age of 51.27 (14.91): 66 % were female, and 26 % suffered from bipolar depression. Stimulation was delivered using four different stimulation parameters: 1 Hz (7 % of the individuals), 10 Hz (43 %), 20 Hz (12 %), and 50 Hz (intermittent Theta Burst Stimulation, iTBS) (38 %). The mean improvement of depressive symptoms was 33 % (p < 0.001, effect-size: 0.79). Response and remission rates were of 31 % and 22.8 %, respectively. In the multivariate analysis, improvement in depressive symptoms was associated with higher baseline symptoms. ConclusionThis is one of the largest studies that investigates, with careful clinician-rated scales by trained psychiatrists, the effect of rTMS in naturalistic settings. Repetitive TMS appears to be effective in routine clinical practice, although its efficacy could be improved by analyzing predictors of response, as well as personalized targeting of specific brain areas.

Cognitive-affective processes and suicidality in response to repetitive transcranial magnetic stimulation for treatment resistant depression

BackgroundRepetitive transcranial magnetic stimulation (rTMS) can elicit 45–55 % response rates and may alleviate suicidality symptoms in treatment resistant depression (TRD). Blunted anticipatory reward sensitivity and negatively biased self-referential processing may predict trajectories of depressive and suicidality symptoms in rTMS for TRD and be modulated during treatment. MethodsFifty-five individuals with TRD received four weeks of low-frequency rTMS applied to the right dorsolateral prefrontal cortex (LFR-rTMS) and were followed until 17 weeks post-baseline. Participants completed behavioral measures of anticipatory reward sensitivity and self-referential processing at baseline and five weeks post-baseline (approximately one-week post-treatment). We examined whether baseline anticipatory reward sensitivity and self-referential processing predicted trajectories of depressive and suicidality symptoms from baseline to follow-up and whether these cognitive-affective variables showed change from baseline to week five. ResultsAnticipatory reward sensitivity and negative self-referential encoding at baseline were associated with higher overall depressive symptoms and suicidality from baseline to 17 weeks post-baseline. At week five, participants self-attributed a higher number of positive traits and a lower number of negative traits and had a lesser tendency to remember negative relative to positive traits they had self-attributed, compared to baseline. LimitationsThe specificity of these results to LFR-rTMS is unknown in the absence of a comparison group, and our relatively small sample size precluded the interpretation of null results. ConclusionsBaseline blunted anticipatory reward sensitivity and negative biases in self-referential processing may be risk factors for higher depressive symptoms and suicidality during and after LFR-rTMS, and LFR-rTMS may modulate self-referential processing.

Repetitive Transcranial Magnetic Stimulation for the Treatment of Resistant Depression: A Scoping Review.

Treatment-resistant depression (TRD) is associated with significant disability, and due to its high prevalence, it results in a substantive socio-economic burden at a global level. TRD is the inability to accomplish and/or achieve remission after an adequate trial of antidepressant treatments. Studies comparing repetitive transcranial magnetic stimulation (rTMS) with electroconvulsive therapy (ECT) and pharmacotherapy have revealed evidence of the therapeutic efficacy of rTMS in TRD. These findings suggest a crucial role for rTMS in the management of TRD. This article aims to conduct a comprehensive scoping review of the current literature concerning the use of rTMS and its therapeutic efficacy as a treatment modality for TRD. PubMed, PsycINFO, Medline, Embase, and Cinahl were used to identify important articles on rTMS for TRD. The search strategy was limited to English articles within the last five years of data publication. Articles were included if they reported on a completed randomized controlled trial (RCT) of rTMS intervention for TRD. The exclusion criteria involved studies with rTMS for the treatment of conditions other than TRD, and study and experimental protocols of rTMS on TRD. In total, 17 studies were eligible for inclusion in this review. The search strategy spanned studies published in the last five years, to the date of the data search (14 February 2022). The regional breakdown of the extracted studies was North American (n = 9), European (n = 5), Asian (n = 2) and Australian (n = 1). The applied frequencies of rTMS ranged from 5 Hz to 50 Hz, with stimulation intensities ranging from 80% MT to 120% MT. Overall, 16 out of the 17 studies suggested that rTMS treatment was effective, safe and tolerated in TRD. For patients with TRD, rTMS appears to provide significant benefits through the reduction of depressive symptoms, and while there is progressive evidence in support of the same, more research is needed in order to define standardized protocols of rTMS application in terms of localization, frequency, intensity, and pulse parameters.

Changes in the metabolites of cerebrospinal fluid induced by rTMS in treatment-resistant depression: A pilot study

Repetitive transcranial magnetic stimulation (rTMS) improves depressive symptoms in treatment-resistant depression (TRD). This study aimed to analyze changes in cerebrospinal fluid (CSF) metabolites in patients with TRD after rTMS. Five patients with TRD were enrolled in a high frequency (10-Hz) rTMS study. The concentration of 72 CSF metabolites were measured at baseline and at the end of the 6-week rTMS treatment. rTMS significantly increased CSF niacinamide, kynurenine, and creatinine levels and significantly decreased CSF cystine levels, but not the levels of the other 68 CSF metabolites. This is the first CSF metabolomics study on patients with TRD who underwent rTMS.

Treatment of anxiety symptoms in patients receiving rTMS for treatment resistant depression

This retrospective analysis examined the effects of left-sided dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) on comorbid anxiety symptoms patients with treatment resistant depression (TRD). Response rates, remission rates, reliable change index (RCI), and clinically significant change (CSC) were assessed using the 7-item Generalized Anxiety Disorder Scale (GAD-7) and the 17-item Hamilton Rating Scale for Depression (HAMD-17) Anxiety subscale at over an average of 32.9 treatments ( SD ​= ​9.2). Fifty-seven TRD patients showed statistically and clinically significant improvement in all anxiety measurements with left DLPFC rTMS. This retrospective study had no sham control and allowed for medication changes during the rTMS treatment course. Left DLPFC rTMS may be an important tool in reducing anxiety in TRD patients, improving overall treatment resistant symptoms and suicide risk. • Anxious depression is associated with more suicide risk and treatment resistance. • Transcranial Magnetic Stimulation (TMS) may be a treatment option. • TMS improved anxiety in patients with treatment resistant depression and anxiety.

Simultaneous aerobic exercise and rTMS for treatment-resistant depression – a case report

Simultaneous aerobic exercise and rTMS for treatment-resistant depression – a case report

The changes in kynurenine metabolites induced by rTMS in treatment-resistant depression: A pilot study

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is considered a valuable and promising technique for improving depressive symptoms in treatment-resistant depression (TRD). However, the exact mechanism by which rTMS ameliorates depressive symptoms remains to be clarified. ObjectiveThe aim of the present study was to analyzed the changes in metabolites of patients with TRD in the rTMS treatment, especially focusing on the kynurenine (KYN) pathway. MethodsThirteen participants with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and the concentration of plasma tryptophan (TRP) metabolites were measured at baseline and at the endpoint of rTMS treatment. ResultsrTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that rTMS treatment significantly increased plasma TRP levels and significantly decreased plasma serotonin levels, while plasma KYN and kynurenic acid level as well as KYN/TRP ratio remained unchanged. ConclusionsThis is the first metabolomic study of patients with TRD undergoing rTMS treatment. To validate the present results, it is necessary to increase the number of cases including controls, use a sample of cerebrospinal fluid, and measure blood concentration over time in the course of rTMS treatment.

Functional connectivity of the anterior cingulate cortex predicts treatment outcome for rTMS in treatment-resistant depression at 3-month follow-up

Background and objectiveRepetitive transcranial magnetic stimulation (rTMS) is a first-line treatment for treatment-resistant depression (TRD). The mechanisms of action of rTMS are not fully understood, and no biomarkers are available to assist in clinical practice to predict response to rTMS. This study aimed to demonstrate that after-rTMS clinical improvement is associated with functional connectivity (FC) changes of the subgenual cingulate cortex (sgACC) and rostral anterior cingulate (rACC), and FC of sgACC and rACC might serve as potential predictors for treatment response. MethodsResting-state functional magnetic resonance imaging (rs-fMRI) data were collected within 1 week before rTMS initiation in 50 TRD patients to predict subsequent response to rTMS on the left dorsolateral prefrontal cortex (DLPFC). Follow-up rs-fMRI was obtained 12 weeks after completion of rTMS and neural correlates of rTMS in sgACC- and rACC-related FC patterns were compared to before rTMS data and with rs-fMRI from healthy participants. ResultsTreatment response was associated with lower FC of sgACC to right DLPFC and higher FC of rACC to left lateral parietal cortex (IPL) measured at baseline. Using sgACC-DLPFC and rACC-IPL connectivity as features, responder-nonresponder classification accuracies of 84% and 76% (end-of-treatment), 88% and 81% (3-month follow-up), respectively were achieved. Longitudinal rs-fMRI data analyses revealed that the hyperconnectivity between sgACC and visual cortex was normalized to a level which was comparable to that of healthy participants. ConclusionsBrain activity patterns in depression are predictive of treatment response to rTMS, and longitudinal change of brain activity in relevant brain circuits after rTMS is associated with treatment response in depression. Target engagement paradigms may offer opportunities to increase the efficacy of rTMS in TRD by optimal selection of patients for treatment. Trial registrationClinicalTrials.gov Identifiers: NCT01887782 and NCT02800226.

Biomarker-guided rTMS for Treatment Resistant Depression

Biomarker-guided rTMS for Treatment Resistant Depression

Baseline effective connectivity predicts response to repetitive transcranial magnetic stimulation in patients with treatment-resistant depression

Repetitive transcranial magnetic stimulation (rTMS) has become a popular treatment option for treatment-resistant depression (TRD). However, suboptimal response rates highlight the need for improved efficacy through optimisation of treatment protocol and patient selection. We investigate whether the limbic salience network and its connectivity with prefrontal stimulation sites predict immediate and longer-term responsiveness to rTMS. Twenty-seven patients with TRD were randomly allocated to receive 16 sessions of either conventional rTMS or intermittent theta-burst (iTBS) over 4 weeks; delivered using connectivity profiling and neuronavigation to target person-specific dorsolateral prefrontal cortex (DLPFC). At baseline and 3-month follow-up, patients underwent clinical assessment and scanning session, and 1-month clinical follow-up. Resting-state fMRI data were entered into seed-based functional and effective connectivity analyses between right anterior insula (rAI) and DLPFC target, and independent components analysis to extract resting-state networks. Cerebral blood flow (CBF) was also assessed in the rAI. All brain measures were compared between baseline and follow-up, and related to treatment response at 1- and 3-months. Baseline fronto-insular effective connectivity and salience network connectivity were significantly positively correlated, while baseline rAI CBF was negatively correlated, with early (1-month) response to rTMS treatment but not sustained response (3-months), suggesting persistence of therapeutic response is not associated with baseline features. Connectivity or CBF measures did not change between the two time points. We demonstrate that fronto-insular and salience-network interactions can predict early response to rTMS in TRD, suggesting that these network nodes may be key regions toward developing rTMS response biomarkers.

Structural network integrity of the central executive network is associated with the therapeutic effect of rTMS in treatment resistant depression

Repetitive transcranial magnetic stimulation (rTMS) is a first-line option for treatment-resistant depression (TRD), but prediction of treatment outcome remains a clinical challenge. The present study aimed to compare structural and functional covariance networks (SCNs and FCNs) between remitters and nonremitters. We determined the predictive capacities of SCNs and FCNs to discriminate the two groups. Fifty TRD patients underwent a course of rTMS to the left dorsolateral prefrontal cortex. They were categorized into remitters (n = 22) and nonremitters (n = 28) based on HDRS≤7 at the end of treatment. Baseline structural and functional magnetic imaging (sMRI and fMRI) of the patients and 42 healthy controls were collected. SCNs and FCNs were defined based on structural and functional covariance of gray mater volume (GMV) and fractional amplitude of low-frequency fluctuations (fALFF) from sMRI and fMRI, respectively. Structural/functional network integrity of these networks (default mode network [DMN], central executive network [CEN] and salience network [SN]) were compared between the three groups. In patients, associations between SCNs and FCNs with clinical improvements were studied using linear correlation analysis. Receiver-operating characteristic (ROC) analysis was conducted to confirm the utility of the SCNs and FCNs in classifying clinical sub-groups. Nonremitters exhibited lower structural integrity in CEN than remitters and controls. Higher structural integrity of CEN was related to clinical improvement (r = 0.423, p = .002), and structural integrity distinguished remitters and nonremitters with a fairly high accuracy (AUC = 0.71, p = .008). No group differences or correlation with clinical changes were found in FCNs. Results suggest the CEN may play a role mediating clinical improvement in rTMS for depression. Structural covariance networks may be features to consider in prediction of clinical improvement.

994. A Randomized Comparison of 1 Hz Vs. 20 Hz Vs. Sham Dorsomedial Prefrontal rTMS for Treatment-Resistant Depression: Preliminary Clinical Results

994. A Randomized Comparison of 1 Hz Vs. 20 Hz Vs. Sham Dorsomedial Prefrontal rTMS for Treatment-Resistant Depression: Preliminary Clinical Results

Open label trial of rTMS for treatment resistant depression in youth

Open label trial of rTMS for treatment resistant depression in youth

Changes in dorsolateral prefrontal connectivity after rTMS in treatment-resistant depression: a brain perfusion SPECT study.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and safe alternative to electroconvulsive therapy for treatment-resistant depression (TRD). After rTMS, changes in brain SPECT perfusion have been remotely identified within medial temporal limbic areas, while no local effects have been found within the left dorsolateral prefrontal cortex (DLPFC)-i.e. under the coil. Functional changes in connectivity may underlie these remote effects. Interestingly, functional connectivity has been recently investigated using perfusion SPECT, and abnormalities identified in TRD patients. The aim of the present study is to evaluate perfusion and connectivity SPECT changes in TRD patients after rTMS of the left DLPFC. We hypothesize that changes in DLPFC networks may explain remote hypoperfusions found after rTMS. Fifty-eight TRD patients underwent a brain SPECT before and after high-frequency rTMS of the left DLPFC. Whole-brain voxel-based changes in perfusion were evaluated with SPM8, and inter-regional correlation analysis performed to study left DLPFC functional connectivity (p < 0.005, corrected for cluster volume). After rTMS, patients were significantly improved on Beck Depression Inventory score (p < 0.0001). Considering a 50% reduction threshold, 27 patients were identified as responders (47%). After rTMS, perfusion changes were not found locally within the left DLPFC, but remotely within the bilateral temporal lobes, including limbic areas. Inter-regional correlation SPECT analysis brings out a decrease of connectivity between the left DLPFC and both the cingulate/medial frontal cortex and bilateral medial temporal limbic areas, in relation with the clinical response. rTMS of DLPFC in TRD patients leads to remote temporal hypoperfusions in relation with changes in functional connectivity between the DLPFC and the default mode network, especially including medial temporal limbic areas.

Cognitive safety of dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression

The most widely used target for repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD) is the dorsolateral prefrontal cortex (DLPFC). Despite convergent evidence that the dorsomedial prefrontal cortex (DMPFC) may be a promising alternative target for rTMS in TRD, its cognitive safety profile has not previously been assessed. Here, we applied 20 sessions of rTMS to the DMPFC in 21 TRD patients. Before and after treatment, a battery of neuropsychological tasks was administered to evaluate changes in cognition across three general cognitive domains: learning and memory, attention and processing speed, and cognitive flexibility. Subjects also completed the 17-item Hamilton Rating Scale for Depression (HamD17) prior to and following treatment to measure changes in severity of depressive symptoms, and to assess the relationship between mood and cognitive performance over the course of treatment. No serious adverse effects or significant deterioration in cognitive performance were observed. Overall, subjects improved significantly on Stroop Inhibition/Switching and on Trails B, and this improvement was independent of the degree of improvement in depression symptoms. No domains or items significantly predicted clinical outcome, with the exception of baseline performance on Visual Elevator Accuracy. Clinical improvement correlated to improved performance in the overall domain of attention and processing speed, although this effect was not evident following covariate adjustment. DMPFC-rTMS did not produce any detectable cognitive adverse effects during treatment of TRD. Performance did not deteriorate significantly on any measures. Taken together, the present findings support the tolerability and cognitive safety of DMPFC-rTMS in refractory depression.

Intermittent theta-burst versus 10 Hz left dorsolateral prefrontal rTMS for treatment resistant depression: preliminary results from a two-site, randomized, single blind non-inferiority trial

s / Brain Stimulation 8 (2015) 326e342 329 factors of SITE (vertex or occiput) and TIME (pre/post rTMS).we found a significant SITE x TIME interaction( F(1,9)1⁄45.595, df1⁄41, P1⁄40.042) in the visual short term memory task(DMS) which was due to the fact that performance improved after V1 stimulation (p1⁄40.048) but not after vertex stimulation. In contrast there was no significant interaction effect in the spatial recognition task, indicating that the effect of V1 stimulation was the same as vertex stimulation. There was a significant main effect of TIME (F (1,9)1⁄4 5.795, df1⁄41, P1⁄40.039), due to the fact that performance of both groups declined after rTMS. These findings provide evidence for the significant role of the V1 in visual short-term memory and that rTMS can affect visual shortterm memory and could be use as a tool for improving cognition function and achievement of peak performance in sport.