Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial.

Theta burst stimulation (TBS) is approved and widely used in the treatment of treatment resistant-major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. Here, we examined the efficacy and safety of accelerated bilateral TBS in major depressive disorder (MDD). In this open label pilot study, 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least one antidepressant, received bilateral TBS, consisting of 5 sequential bilateral intermittent TBS (iTBS) (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treat treatment changes at day 5 and 2-weeks in Hamilton Depression Rating Scale (HDRS-17) scores and response (≥ 50% reduction from the baseline scores) and remission (≤ 7) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2-weeks post treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2-weeks post treatment suggesting delayed clinical effects. However, reduction in symptom scores between two post treatment endpoints was non-significant. 60% of patients could not tolerate the high intensity stimulation. No major adverse events occurred. Open label uncontrolled study with small sample size. These preliminary findings suggest that accelerated bilateral TBS may be clinically effective and safe for treatment resistant depression. Randomized sham-controlled trials are needed to establish the therapeutic role of accelerated bilateral TBS in depression.Trial registration: ClinicalTrials.gov, NCT10001858.

Modulating intrinsic functional connectivity with visual cortex using low-frequency repetitive transcranial magnetic stimulation.

INTRODUCTION: Intrinsic network connectivity becomes altered in pathophysiology. Noninvasive brain stimulation can modulate pathological functional networks in an attempt to restore the inherent response. To determine its usefulness for visual-related disorders, we developed procedures investigating repetitive transcranial magnetic stimulation (rTMS) protocols targeting the visual cortex on modulating connectivity associated with the visual network and default mode network (DMN). METHODS: We compared two low-frequency (1 Hz) rTMS protocols to the visual cortex (V1)-a single 20 min session and five successive 20 min sessions (accelerated/within-session rTMS)-using multi-echo resting-state functional magnetic resonance whole-brain imaging and resting-state functional connectivity (rsFC). We also explored the relationship between rsFC and rTMS-induced changes in key inhibitory and excitatory neurotransmitters, γ-aminobutyric acid (GABA) and glutamate. GABA (GABA+) and glutamate (Glx) concentrations were measured in vivo using magnetic resonance spectroscopy. RESULTS: Acute disruption with a single rTMS session caused widespread connectivity reconfiguration with nodes of interest. Changes were not evident immediately post-rTMS but were observed at 1 h post-rTMS. Accelerated sessions resulted in weak alterations in connectivity, producing a relatively homeostatic response. Changes in GABA+ and Glx concentrations with network connectivity were dependent on the rTMS protocol. CONCLUSIONS: This proof-of-concept study offers new perspectives to assess stimulation-induced neural processes involved in intrinsic functional connectivity and the potential for rTMS to modulate nodes interconnected with the visual cortex. The differential effects of single-session and accelerated rTMS on physiological markers are crucial for furthering the advancement of treatment modalities in visual cortex related disorders.

Current Updates on Newer Forms of Transcranial Magnetic Stimulation in Major Depression.

Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved technique for treating medication-resistant depression. Conventional rTMS includes high frequency (HF) to left dorsolateral prefrontal cortex (DLPFC) and low frequency to right DLPFC. However, not all depressed patients could benefit from standard rTMS protocols. Meta-analytical evidence indicated that there was an average response rate of 29.3% for patients receiving the most commonly adopted HF rTMS to the left DLPFC. Hence, newer forms of rTMS paradigms are warranted to improve antidepressant response and remission rate in patients with depression, especially those who are refractory to adequate antidepressant trials. In the current chapter, we review newer forms of rTMS paradigms and the content will cover standard theta burst stimulation (TBS), prolonged iTBS (piTBS), accelerated rTMS (aTMS), deep TMS (dTMS), priming TMS (pTMS), synchronized TMS (sTMS), and magnetic seizure therapy (MST).

Assessing differential effects of single and accelerated low-frequency rTMS to the visual cortex on GABA and glutamate concentrations.

BACKGROUND: The application of repetitive transcranial magnetic stimulation (rTMS) for therapeutic use in visual-related disorders and its underlying mechanisms in the visual cortex is under-investigated. Additionally, there is little examination of rTMS adverse effects particularly with regards to visual and cognitive function. Neural plasticity is key in rehabilitation and recovery of function; thus, effective therapeutic strategies must be capable of modulating plasticity. Glutamate and γ-aminobutyric acid (GABA)-mediated changes in the balance between excitation and inhibition are prominent features in visual cortical plasticity. OBJECTIVES AND METHOD: We investigated the effects of low-frequency (1 Hz) rTMS to the visual cortex on levels of neurotransmitters GABA and glutamate to determine the therapeutic potential of 1 Hz rTMS for visual-related disorders. Two rTMS regimes commonly used in clinical applications were investigated: participants received rTMS to the visual cortex either in a single 20-min session or five accelerated 20-min sessions (not previously investigated at the visual cortex). Proton (1H) magnetic resonance spectroscopy for in vivo quantification of GABA (assessed via GABA+) and glutamate (assessed via Glx) concentrations was performed pre- and post-rTMS. RESULTS: GABA+ and Glx concentrations were unaltered following a single session of rTMS to the visual cortex. One day of accelerated rTMS significantly reduced GABA+ concentration for up to 24 hr, with levels returning to baseline by 1-week post-rTMS. Basic visual and cognitive function remained largely unchanged. CONCLUSION: Accelerated 1 Hz rTMS to the visual cortex has greater potential for approaches targeting plasticity or in cases with altered GABAergic responses in visual disorders. Notably, these results provide preliminary insight into a critical window of plasticity with accelerated rTMS (e.g., 24 hr) in which adjunct therapies may offer better functional outcome. We describe detailed procedures to enable further exploration of these protocols.

Accelerated rTMS: A Potential Treatment to Alleviate Refractory Depression.

Three decades of clinical research on repetitive transcranial magnetic stimulation (rTMS) has yielded one clear treatment indication in psychiatry for major depression disorder (MDD). Although the clinical response equals the standard treatment algorithms, the effect sizes on the beneficial outcome remain rather modest. Over the last couple of years, to improve the efficacy in resistant depression, two new avenues have been developed: personalization and intensifying rTMS treatment. For the latter, we retrospectively compared accelerated high-frequency rTMS (arTMS) with accelerated intermittent theta burst stimulation (aiTBS) in the refractory depressed state. Although the clinical efficacy was not significantly different between both protocols, our observations substantiate the potential of the accelerated stimulation to shorten the treatment duration from the depressed state to the response state. Any time gain from the depressed state to the recovered state is in the patients' interest.

Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: A fast road to remission?

Although accelerated repetitive Transcranial Magnetic Stimulation (rTMS) paradigms and intermittent Theta-burst Stimulation (iTBS) may have the potency to result in superior clinical outcomes in Treatment Resistant Depression (TRD), accelerated iTBS treatment has not yet been studied. In this registered randomized double-blind sham-controlled crossover study, spread over four successive days, 50 TRD patients received 20 iTBS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). The accelerated iTBS treatment procedure was found to be safe and resulted in immediate statistically significant decreases in depressive symptoms regardless of order/type of stimulation (real/sham). While only 28% of the patients showed a 50% reduction of their initial Hamilton Depression Rating Scale score at the end of the two-week procedure, this response rate increased to 38% when assessed two weeks after the end of the sham-controlled iTBS protocol, indicating delayed clinical effects. Importantly, 30% of the responders were considered in clinical remission. We found no demographic predictors for response. Our findings indicate that only four days of accelerated iTBS treatment applied to the left DLPFC in TRD may lead to meaningful clinical responses within two weeks post stimulation.

Effectiveness and acceptability of accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open label trial.

BACKGROUND: Major depressive disorder (MDD) is a significant cause of worldwide disability and treatment resistance is common. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has emerged as a treatment for MDD, and while efficacious, the daily commitment for typical 4-6 weeks of treatment poses a significant challenge. We aimed to determine the effectiveness and acceptability of an accelerated rTMS protocol for MDD. METHODS: In this naturalistic trial, 27 patients with moderate to severe chronic and treatment-resistant MDD were treated with twice-daily HF-rTMS (10 Hz) applied over the left dorsolateral prefrontal cortex for 2 consecutive weeks (60,000 pulses). The primary outcomes were rates of clinical remission and response (16-item Quick Inventory of Depressive Symptomatology post-treatment score ≤ 6, and ≥ 50% reduction, respectively). Secondary outcomes were self-reported anxious symptoms, depressive symptoms and quality of life, and dropout rates as a proxy for acceptability. RESULTS: Ten (37.0%) patients met criteria for clinical remission and 15 (55.6%) were classified as responders, with comparable outcomes for both moderate and severe MDD. Clinician-rated improvements in depressive symptoms were paralleled in self-reported depressive and anxious symptoms, as well as quality of life. No patient discontinued treatment. LIMITATIONS: This study is limited by short treatment duration that might be lengthened with corresponding improvements in effectiveness, limited duration of follow-up, small sample size, and an open-label design requiring randomized controlled replication. CONCLUSION: An accelerated protocol involving twice-daily sessions of HF-rTMS over the left DLPFC for 2 weeks was effective in treatment-resistant MDD, and had excellent acceptability. Additional research is required to optimize accelerated rTMS treatment protocols and determine efficacy using sham-controlled trials.