The role of sex and age in the differential efficacy of 10 Hz and intermittent theta-burst (iTBS) repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD).

BACKGROUND: Sex- and age-dependent outcome differences have been observed in treatment of Major Depressive Disorder (MDD), including 10 Hz repetitive Transcranial Magnetic Stimulation (rTMS). We examined whether there are sex- and age-dependent differences in outcome with intermittent Theta Burst Stimulation (iTBS), another rTMS protocol. METHODS: The relationship between biological sex, age, and treatment outcome was retrospectively examined among 414 patients with MDD treated with 10 Hz or iTBS rTMS. Linear mixed-effects modeling was used to examine the association between treatment and change in the 30-item Inventory of Depressive Symptomatology Self-Report (IDS-SR30) score from baseline to treatments 10 and 30, with biological sex (M/F), protocol (iTBS/10 Hz), age (≥/<50 years old), and time (treatment 1/10/30) included as fixed effects. The three-way sex-protocol-time and age-protocol-time interactions were used to determine any differential relationships between protocol and outcome dependent on sex and age. Post-hoc t-tests were conducted to examine differences in improvement. RESULTS: There was a significant three-way sex-protocol-time interaction at treatments 10 (p = 0.016) and 30 (p = 0.031). Males showed significantly greater improvement with iTBS than females at treatments 10 (p = 0.041) and 30 (p = 0.035), while females showed numerically greater improvement with 10 Hz treatment. While there was not a significant three-way age-protocol-time interaction, there was a significant interaction between age (≥50 years old) and time at treatments 10 (p = 0.007) and 30 (p = 0.042), and among age, sex, and time at treatment 30 (p = 0.028). LIMITATIONS: Retrospective naturalistic treatment protocol. CONCLUSIONS: iTBS appeared less efficacious in females than in males, and rTMS overall was more efficacious in patients over fifty, particularly females.

Bilateral Cerebellar Repetitive Transcranial Magnetic Stimulation for Chronic Ataxia After Hemorrhagic Stroke: a Case Report.

There are insufficient treatment options available for recovery related to cerebellar ataxia. Limited data using repetitive transcranial magnetic stimulation (rTMS) have demonstrated reduction of symptom burden, though associated with nonuniform cerebellar ataxia etiologies and differing rTMS treatment protocols. Additionally, there are limited available data for use of rTMS in individuals suffering from stroke-related symptoms. We present the case of a patient with chronic cerebellar ataxia following a hemorrhagic stroke who underwent inhibitory rTMS to bilateral cerebellar targets with demonstrated improvement in symptoms.

Pretreatment pupillary reactivity is associated with differential early response to 10 Hz and intermittent theta-burst repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD).

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective treatment for Major Depressive Disorder (MDD). Two common rTMS protocols, 10 Hz and intermittent theta burst stimulation (iTBS), have comparable rates of efficacy in groups of patients. Recent evidence suggests that some individuals may be more likely to benefit from one form of stimulation than the other. The pretreatment pupillary light reflex (PLR) is significantly associated with response to a full course of rTMS using heterogeneous stimulation protocols. OBJECTIVE: To test whether the relationship between pretreatment PLR and early symptom improvement differed between subjects treated with iTBS or 10 Hz stimulation. METHODS: PLR was measured in 52 subjects who received solely 10 Hz (n = 35) or iTBS (n = 17) to left dorsolateral prefrontal cortex (DLPFC) for the first ten sessions of their treatment course. Primary outcome measure was the percent change of Inventory of Depressive Symptomatology - Self Report (IDS-SR) from session 1 to session 10. RESULTS: There was a positive association between normalized maximum constriction velocity (nMCV) and early improvement in subjects receiving 10 Hz stimulation (R = 0.48, p = 0.004) and a negative association in subjects receiving iTBS (R = -0.52, p = 0.03). ANOVA revealed a significant interaction between nMCV and the type of initial stimulation (p = 0.001). Among subjects with low nMCV, those initially treated with iTBS showed 2.6 times greater improvement after 10 sessions (p = 0.01) than subjects initially receiving 10 Hz stimulation. CONCLUSION: nMCV may detect physiologic differences between those likely to benefit from 10 Hz or iTBS treatment. Future studies should examine whether PLR could guide prospective treatment selection.

Pretreatment pupillary reactivity is associated with outcome of Repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD).

BACKGROUND: Pre-treatment biomarkers for outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD) have proven elusive. One promising family of biomarkers involves the autonomic nervous system (ANS), which is dysregulated in individuals with MDD. METHODS: We examined the relationship between the pre-treatment pupillary light reflex (PLR) and rTMS outcome in 51 MDD patients. Outcome was measured as the percent change in the 30-item Inventory of Depressive Symptomatology Self Rated (IDS-SR) score from baseline to treatment 30. RESULTS: Patients showed significant improvement with rTMS treatment. There was a significant correlation between baseline pupillary Constriction Amplitude (CA) and clinical improvement over the treatment course (R = 0.41, p = 0.003). LIMITATIONS: We examined a limited number of subjects who received heterogeneous treatment protocols. Almost all patients in the study received psychotropic medications concomitant with rTMS treatment. CONCLUSION: PLR measured before treatment may be a predictive biomarker for clinical improvement from rTMS in subjects with MDD.

Novel method for identification of individualized resonant frequencies for treatment of Major Depressive Disorder (MDD) using repetitive Transcranial Magnetic Stimulation (rTMS): A proof-of-concept study.

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective treatment for Major Depressive Disorder (MDD), but therapeutic benefit is highly variable. Clinical improvement is related to changes in brain circuits, which have preferred resonant frequencies (RFs) and vary across individuals. OBJECTIVE: We developed a novel rTMS-electroencephalography (rTMS-EEG) interrogation paradigm to identify RFs using the association of power/connectivity measures with symptom severity and treatment outcome. METHODS: 35 subjects underwent rTMS interrogation at 71 frequencies ranging from 3 to 17 Hz administered to left dorsolateral prefrontal cortex (DLPFC). rTMS-EEG was used to assess resonance in oscillatory power/connectivity changes (phase coherence [PC], envelope correlation [EC], and spectral correlation coefficient [SCC]) after each frequency. Multiple regression was used to detect relationships between 10 Hz resonance and baseline symptoms as well as clinical improvement after 10 sessions of 10 Hz rTMS treatment. RESULTS: Baseline symptom severity was significantly associated with SCC resonance in left sensorimotor (SM; p < 0.0004), PC resonance in fronto-parietal (p = 0.001), and EC resonance in centro-posterior channels (p = 0.002). Subjects significantly improved with 10 sessions of rTMS treatment. Only decreased SCC SM resonance was significantly associated with clinical improvement (r = 0.35, p = 0.04). Subjects for whom 10 Hz SM SCC was highly ranked as an RF among all stimulation frequencies had better outcomes from 10 Hz treatment. CONCLUSIONS: Resonance of 10 Hz stimulation measured using SCC correlated with both symptom severity and improvement with 10 Hz rTMS treatment. Research should determine whether this interrogation paradigm can identify individualized rTMS treatment frequencies.

Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC). Methods: In 26 adults with TRD, we used Mescher­Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents. Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment. Limitations: This study had an open-label design in a population receiving naturalistic treatment. Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.

Changes in Functional Connectivity Predict Outcome of Repetitive Transcranial Magnetic Stimulation Treatment of Major Depressive Disorder.

Repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD) is associated with changes in brain functional connectivity (FC). These changes may be related to the mechanism of action of rTMS and explain the variability in clinical outcome. We examined changes in electroencephalographic FC during the first rTMS treatment in 109 subjects treated with 10 Hz stimulation to left dorsolateral prefrontal cortex. All subjects subsequently received 30 treatments and clinical response was defined as ≥40% improvement in the inventory of depressive symptomatology-30 SR score at treatment 30. Connectivity change was assessed with coherence, envelope correlation, and a novel measure, alpha spectral correlation (αSC). Machine learning was used to develop predictive models of outcome for each connectivity measure, which were compared with prediction based upon early clinical improvement. Significant connectivity changes were associated with clinical outcome (P < 0.001). Machine learning models based on αSC yielded the most accurate prediction (area under the curve, AUC = 0.83), and performance improved when combined with early clinical improvement measures (AUC = 0.91). The initial rTMS treatment session produced robust changes in FC, which were significant predictors of clinical outcome of a full course of treatment for MDD.