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Background: The efficacy of repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (dlPFC) has been established in patients with treatment-resistant depression (TRD), suggesting that alterations in signal propagation from the left dlPFC to other brain regions may be linked to the pathophysiology of TRD. Alterations at the cellular level, including dysfunction of oligodendrocytes, may contribute to these network abnormalities. The objectives of the present study were to compare signal propagation from the left dlPFC to other neural networks in patients with TRD and healthy controls. We used TMS combined with electroencephalography to explore links between cell-specific gene expression and signal propagation in TRD using a virtual-histology approach. Methods: We examined source-level estimated signal propagation from the left dlPFC to the 7 neural networks in 60 patients with TRD and 30 healthy controls. We also calculated correlations between the interregional profiles of altered signal propagation and gene expression for 9 neural cell types derived from the Allen Human Brain Atlas data set. Results: Signal propagation from the left dlPFC to the salience network was reduced in the θ and α bands in patients with TRD (p = 0.0055). Furthermore, this decreased signal propagation was correlated with cellspecific gene expression of oligodendrocytes (p < 0.000001). Limitations: These results show only part of the pathophysiology of TRD, because stimulation was limited to the left dlPFC. Conclusion: Reduced signal propagation from the left dlPFC to the salience network may represent a pathophysiological endophenotype of TRD; this finding may be associated with reduced expression of oligodendrocytes. [ABSTRACT FROM AUTHOR]

Background: Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown. Methods: Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment (n = 23) and after approximately 12 weeks of treatment. Results: Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology. Limitations: The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex. Conclusion: These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in latelife depression, and that venlafaxine treatment does not target these abnormalities. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant bipolar depression can be treated effectively using electroconvulsive therapy, but its use is limited because of stigma and cognitive adverse effects. Magnetic seizure therapy is a new convulsive therapy with promising early evidence of antidepressant effects and minimal cognitive adverse effects. However, there are no clinical trials of the efficacy and safety of magnetic seizure therapy for treatment-resistant bipolar depression. Methods: Participants with treatment-resistant bipolar depression were treated with magnetic seizure therapy for up to 24 sessions or until remission. Magnetic seizure therapy was applied over the prefrontal cortex at high (100 Hz; n = 8), medium (50 or 60 Hz; n = 9) or low (25 Hz; n = 3) frequency, or over the vertex at high frequency (n = 6). The primary outcome measure was the 24-item Hamilton Rating Scale for Depression. Participants completed a comprehensive battery of neurocognitive tests. Results: Twenty-six participants completed a minimally adequate trial of magnetic seizure therapy (i.e., ≥ 8 sessions), and 20 completed full treatment per protocol. Participants showed a significant reduction in scores on the Hamilton Rating Scale for Depression. Adequate trial completers had a remission rate of 23.1% and a response rate of 38.5%. Per-protocol completers had a remission rate of 30% and a response rate of 50%. Almost all cognitive measures remained stable, except for significantly worsened recall consistency on the autobiographical memory inventory. Limitations: The open-label study design and modest sample size did not allow for comparisons between stimulation parameters. Conclusion: In treatment-resistant bipolar depression, magnetic seizure therapy produced significant improvements in depression symptoms with minimal effects on cognitive performance. These promising results warrant further investigation with larger randomized clinical trials comparing magnetic seizure therapy to electroconvulsive therapy. Clinical trial registration: NCT01596608; clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Background: Approximately 35% of people with depression do not respond to 2 courses of antidepressant medications of adequate dosage, and treatment-resistant depression (TRD) is still a major clinical concern with a great impact on patients, their families, society and the health system. The present meta-analysis evaluates antidepressant efficacy of unilateral and bilateral repetitive transcranial magnetic stimulation (rTMS) in patients with unipolar TRD. Methods: We searched for randomized controlled trials that compared rTMS with sham treatment and were published by Apr. 3, 2017. The primary outcome was improvement in depression scores measured using the Hamilton Rating Scale for Depression. The secondary outcomes were remission and response rates. Two independent review authors screened the studies and extracted the data. Results: Twenty-three studies met the inclusion criteria. Meta-analysis of the depression scores showed a weighted mean difference (WMD) of 3.36 (95% confidence interval [CI] 1.85–4.88) between unilateral rTMS and sham treatment. Stratified data showed that the effect was relatively higher when rTMS was used as an add-on to antidepressant medications (WMD 3.64, 95% CI 1.52–5.76) than when it was used as a stand-alone treatment (WMD 2.47, 95% CI 0.90–4.05). The WMD between bilateral rTMS and sham was 2.67 (95% CI 0.83–4.51), and all studies that contributed to this outcome used rTMS while participants were taking antidepressant medications. The pooled remission and response rates for unilateral rTMS versus sham treatment were 16.0% and 25.1% for rTMS and 5.7% and 11.0% for sham treatment, respectively. The pooled remission and response rates for bilateral rTMS versus sham treatment were 16.6% and 25.4% for rTMS and 2.0% and 6.8% for sham treatment, respectively. Conclusion: This study suggests that rTMS has moderate antidepressant effects and appears to be promising in the short-term treatment of patients with unipolar TRD. [ABSTRACT FROM AUTHOR]

Background: Several factors may mitigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) over sham rTMS in patients with treatment-resistant depression (TRD). These factors include unilateral stimulation (i.e., treatment of only the left dorsolateral prefrontal cortex [DLPFC]), suboptimal methods of targeting the DLPFC and insufficient stimulation intensity (based on coil-to-cortex distance). Methods: We recruited patients with TRD between the ages of 18 and 85 years from a university hospital, and participants were randomized to receive sequential bilateral rTMS (600 pulses at 1 Hz followed by 1500 pulses at 10 Hz), unilateral high-frequency left (HFL)-rTMS (2100 pulses at 10 Hz) or sham rTMS for 3 or 6 weeks depending on treatment response. Stimulation was targeted with MRI localization over the junction of the middle and anterior thirds of the middle frontal gyrus, using 120% of the coil-to-cortex adjusted motor threshold. Our primary outcome of interest was the remission rate. Results: A total of 121 patients participated in this study. The remission rate was significantly higher in the bilateral group than the sham group. The remission rate in the HFL-rTMS group was intermediate and did not differ statistically from the rate in the 2 other groups. There were no significant differences in reduction of depression scores among the 3 groups. Limitations: The number of pulses used per session in the unilateral group was somewhat lower in our trial than in more recent trials, and the sham condition did not involve active stimulation. Conclusion: Our findings suggest that sequential bilateral rTMS is superior to sham rTMS; however, adjusting for coil-to-cortex distance did not yield enhanced efficacy rates. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission are implicated in the pathophysiology of schizophrenia, bipolar disorder, major depressive disorder and obsessive-compulsive disorder. Cortical inhibition refers to a neurophysiological process, whereby GABA inhibitory interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to measure cortical inhibition, excitability and plasticity in the cortex. These measures were traditionally specific to the motor cortex, which is an important limitation when nonmotor neurophysiological processes are of primary interest. Recently, TMS has been combined with electro encephalography (EEG) to derive such measurements directly from the cortex. This review focuses on neurophysiological studies related to inhibitory and excitatory TMS paradigms, linking dysfunctional GABAergic neurotransmission to disease states. We review evidence that suggests cortical inhibition deficits among psychiatric populations and demonstrate how each disorder has a specific neurophysiological response to treatment. We conclude by discussing the future directions of TMS combined with EEG, demonstrating the potential to identify biological markers of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]