Revisiting Hemispheric Asymmetry in Mood Regulation: Implications for rTMS for Major Depressive Disorder

Hemispheric differences in emotional processing have been observed for over half a century, leading to multiple theories classifying differing roles for the right and left hemisphere in emotional processing. Conventional acceptance of these theories has had lasting clinical implications for the treatment of mood disorders. The theory that the left hemisphere is broadly associated with positively valenced emotions, while the right hemisphere is broadly associated with negatively valenced emotions, drove the initial application of repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depressive disorder (MDD). Subsequent rTMS research has led to improved response rates while adhering to the same initial paradigm of administering excitatory rTMS to the left prefrontal cortex (PFC) and inhibitory rTMS to the right PFC. However, accumulating evidence points to greater similarities in emotional regulation between the hemispheres than previously theorized, with potential implications for how rTMS for MDD may be delivered and optimized in the near future. This review will catalog the range of measurement modalities that have been used to explore and describe hemispheric differences, and highlight evidence that updates and advances knowledge of TMS targeting and parameter selection. Future directions for research are proposed that may advance precision medicine and improve efficacy of TMS for MDD.

Repetitive Transcranial Magnetic Stimulation Modulates Frontal and Temporal Time-Varying EEG Network in Generalized Anxiety Disorder: A Pilot Study

Generalized Anxiety Disorder (GAD) is a highly prevalent yet poorly understood chronic mental disorder. Previous studies have associated GAD with excessive activation of the right dorsolateral prefrontal cortex (DLPFC). This study aimed to investigate the effect of low-frequency repetitive transcranial magnetic stimulation (repetitive TMS, rTMS) targeting the right DLPFC on clinical symptoms and TMS-evoked time-varying brain network connectivity in patients with GAD. Eleven patients with GAD received 1 Hz rTMS treatment targeting the right DLPFC for 10 days. The severity of the clinical symptoms was evaluated using the Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Scale (HAMD) at baseline, right after treatment, and at the one-month follow-up. Co-registration of single-pulse TMS (targeting the right DLPFC) and electroencephalography (TMS-EEG) was performed pre- and post-treatment in these patients and 11 healthy controls. Time-varying brain network connectivity was analyzed using the adaptive directed transfer function. The scores of HAMA and HAMD significantly decreased after low-frequency rTMS treatment, and these improvements in ratings remained at the one-month follow-up. Analyses of the time-varying EEG network in the healthy controls showed a continuous weakened connection information outflow in the left frontal and mid-temporal regions. Compared with the healthy controls, the patients with GAD showed weakened connection information outflow in the left frontal pole and the posterior temporal pole at baseline. After 10-day rTMS treatment, the network patterns showed weakened connection information outflow in the left frontal and temporal regions. The time-varying EEG network changes induced by TMS perturbation targeting right DLPFC in patients with GAD were characterized by insufficient information outflow in the left frontal and temporal regions. Low-frequency rTMS targeting the right DLPFC reversed these abnormalities and improved the clinical symptoms of GAD.

Low-Frequency vs. Theta Burst Transcranial Magnetic Stimulation for the Treatment of Chronic Non-fluent Aphasia in Stroke: A Proof-of-Concept Study

BackgroundAlthough low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) has shown promise in the treatment of poststroke aphasia, the efficacy of high-frequency rTMS (HF-rTMS) has yet to be determined.PurposeWe investigated the efficacy of intermittent theta burst stimulation (iTBS) in ameliorating chronic non-fluent aphasia and compared it with that of LF-rTMS.MethodsWe randomly assigned patients with poststroke non-fluent aphasia to an ipsilesional iTBS (n = 29), contralesional 1-Hz rTMS (n = 27), or sham (n = 29) group. Each group received the rTMS protocol executed in 10 daily sessions over 2 weeks. We evaluated language function before and after the intervention by using the Concise Chinese Aphasia Test (CCAT).ResultsCompared with the sham group, the iTBS group exhibited significant improvements in conversation, description, and expression scores (P = 0.0004–0.031), which characterize verbal production, as well as in auditory comprehension, reading comprehension, and matching scores (P < 0.01), which characterize language perception. The 1-Hz group exhibited superior improvements in expression, reading comprehension, and imitation writing scores compared with the sham group (P < 0.05). The iTBS group had significantly superior results in CCAT total score, matching and auditory comprehension (P < 0.05) relative to the 1-Hz group.ConclusionOur study findings contribute to a growing body of evidence that ipsilesional iTBS enhances the language recovery of patients with non-fluent aphasia after a chronic stroke. Auditory comprehension was more preferentially enhanced by iTBS compared with the 1-Hz protocol. Our findings highlight the importance of ipsilesional modulation through excitatory rTMS for the recovery of non-fluent aphasia in patients with chronic stroke.Clinical Trial Registration:[www.ClinicalTrials.gov], identifier [NCT03059225].

A Retrospective Naturalistic Study Comparing the Efficacy of Ketamine and Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression

Depression is a common mental disorder that affects many people worldwide, while a significant proportion of patients remain non-responsive to antidepressant medications. Alternative treatment options such as ketamine therapy and repetitive transcranial magnetic stimulation (rTMS) therapy are offered nowadays. This study aims to describe and compare the acute antidepressive efficacy of both, intramuscular ketamine and rTMS in depression patients seeking help in a naturalistic clinical mental health setting. The clinical records of 24 patients with treatment resistant depression were collected from the clinical base of a real life clinic. Twelve patients were treated with intramuscular ketamine, twice weekly for 8 sessions, and twelve patients were treated with 30 sessions of left dorsolateral prefrontal cortex – intermittent theta-burst stimulation (DLPFC-iTBS). Using three clinical assessments (HDRS, HAM-A, BDI-II), our data reveal that both therapies led to significant improvement in symptoms from pre- to post- treatment, as well as that the two experimental groups did not differ significantly with respect to pre- to post- depressive and anxiety symptoms, indicating that the effect of both experimental groups in our sample was equally effective. Furthermore, our results showed high remission and response rates in both groups, with no statistical differences between the patients of ketamine group and rTMS group in remission and response rates. We show a significant pre- to post- treatment reduction in depressive and anxiety symptoms, with no significant differences between the two experimental groups, indicating that the effect of both therapies was equally effective in our limited sample.

Efficacy of repetitive transcranial magnetic stimulation (rTMS) for reducing consumption in patients with alcohol use disorders (ALCOSTIM): study protocol for a randomized controlled trial

Background The number of people with an alcohol use disorder (AUD) was recently estimated to be 63.5 million worldwide. The global burden of disease and injury attributable to alcohol is considerable: about 3 million deaths, namely one in 20, were caused by alcohol in 2015. At the same time, AUD remains seriously undertreated. In this context, alternative or adjunctive therapies such as brain stimulation could play an important role. The early results of studies using repetitive transcranial magnetic stimulation (rTMS) suggest that stimulations delivered to the dorsolateral prefrontal cortex significantly reduce cravings and improve decision-making processes in various addictive disorders. We therefore hypothesize that rTMS could lead to a decrease in alcohol consumption in patients with AUD. Methods/design We report the protocol of a randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy of rTMS on alcohol reduction in individuals diagnosed with AUD. The study will be conducted in 2 centers in France. Altogether, 144 subjects older than 18 years and diagnosed with AUD will be randomized to receive 5 consecutive twice-daily sessions of either active or sham rTMS (10 Hz over the right DLPFC, 2000 pulses per day). The main outcomes of the study will be changes in alcohol consumption within the 4 weeks after the rTMS sessions. Secondary outcome measures will include changes in alcohol consumption within the 24 weeks, alcohol cravings, clinical and biological improvements, effects on mood and quality of life, and cognitive and safety assessments, and, for smokers, an assessment of the effects of rTMS on tobacco consumption. Discussion Several studies have observed a beneficial effect of rTMS on substance use disorders by reducing craving, impulsivity, and risk-taking behavior and suggest that rTMS may be a promising treatment in addiction. However, to date, no studies have included sufficiently large samples and sufficient follow-up to confirm this hypothesis. The results from this large randomized controlled trial will give a better overview of the therapeutic potential of rTMS in AUD. Trial registration ClinicalTrials.gov NCT04773691. Registered on 26 February 2021 https://clinicaltrials.gov/ct2/show/NCT04773691?term=trojak&draw=2&rank=5.

Effects of repetitive transcranial magnetic stimulation combined with cognitive training on resting-state brain activity in Alzheimer’s disease

Objectives Repetitive transcranial magnetic stimulation (rTMS) is a promising tool to modulate brain plasticity, but the neural basis has been little addressed. The purpose was to investigate the effects of rTMS on resting-state brain activity in patients with Alzheimer’s disease (AD). Methods Seventeen patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS combined with cognitive training (real group, n = 9); (2) sham rTMS with cognitive training (sham group, n = 8). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex and then the left lateral temporal lobe for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment and resting-state functional magnetic resonance imaging (rsfMRI) before and after treatment. The fractional amplitude of low frequency fluctuation (fALFF) of rsfMRI data in real group were: (1) compared to sham; (2) correlated with rTMS-induced cognitive alterations. Results Significantly increased fALFF in right cerebellum/declive, left lingual/cuneus and left cingulate gyrus, as well as decreased fALFF in left middle frontal gyrus were found after 10 Hz rTMS, but not after sham stimulation. Using these suprathreshold regions, we found that rTMS increased functional connectivity between the right cerebellum/declive and left precentral/postcentral gyrus. The fALFF increase in left lingual/cuneus and right cerebellum/declive was associated with significant improvement in cognitive function. Conclusions rTMS combined with cognitive training induced increased low frequency fluctuation neural oscillations and functional connectivity in brain regions subserving cognition, suggesting a possible neuronal mechanism of the beneficial effects of rTMS.