ABSTRACT
Extinction of traumatic memory, a primary treatment approach (termed exposure therapy) in posttraumatic stress disorder (PTSD), occurs through relearning and may be subserved at the molecular level by long-term potentiation of relevant circuits. In parallel, repetitive transcranial magnetic stimulation (TMS) is thought to work through long-term potentiation-like mechanisms and may provide a novel, safe, and effective treatment for PTSD. In a recent failed randomized controlled trial we emphasized the necessity of correctly identifying cortical targets, the directionality of TMS protocols, and the role of memory activation. Here, we provide a systematic review of TMS for PTSD to further identify how, where, and when TMS treatment should be delivered to alleviate PTSD symptoms. We conducted a systematic review of the literature by searching for repetitive TMS clinical trials involving patients with PTSD and outcomes. We searched MEDLINE through October 25, 2023, for "TMS and PTSD" and "transcranial magnetic stimulation and posttraumatic stress disorder." Thirty-one publications met our inclusion criteria (k = 17 randomized controlled trials, k = 14 open label). Randomized controlled trial protocols were varied in terms of TMS protocols, cortical TMS targets, and memory activation protocols. There was no clear superiority of low-frequency (k = 5) versus high-frequency (k = 6) protocols or by stimulation location. Memory provocation or exposure protocols (k = 7) appear to enhance response. Overall, TMS appears to be effective in treating PTSD symptoms across a variety of TMS frequencies, hemispheric target differences, and exposure protocols. Disparate protocols may be conceptually harmonized when viewed as potentiating proposed anxiolytic networks or suppressing anxiogenic networks.
ABSTRACT
BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation modality that has been used to study human synaptic plasticity. Leveraging work in ex vivo preparations, mechanistically informed pharmacological adjuncts to TMS have been used to improve our fundamental understanding of TMS-induced synaptic plasticity. METHODS: We systematically reviewed the literature pairing pharmacological adjuncts with TMS plasticity-induction protocols in humans. We searched MEDLINE, PsycINFO, and Embase from 2013 to Mar. 10, 2023. Studies published before 2013 were extracted from a previous systematic review. We included studies using repetitive TMS, theta-burst stimulation, paired associative stimulation, and quadripulse stimulation paradigms in healthy and clinical populations. RESULTS: Thirty-six studies met our inclusion criteria (28 in healthy and 8 in clinical populations). Most pharmacological agents have targeted the glutamatergic N-methyl-d-aspartate (NMDA; 15 studies) or dopamine receptors (13 studies). The NMDA receptor is necessary for TMS-induced plasticity; however, sufficiency has not been shown across protocols. Dopaminergic modulation of TMS-induced plasticity appears to be dose-dependent. The GABAergic, cholinergic, noradrenergic, and serotonergic neurotransmitter systems have small evidence bases supporting modulation of TMS-induced plasticity, as do voltage-gated calcium and sodium channels. Studies in clinical populations suggest that pharmacological adjuncts to TMS may rescue motor cortex plasticity, with implications for therapeutic applications of TMS and a promising clinical trial in depression. LIMITATIONS: This review is limited by the predominance in the literature of studies with small sample sizes and crossover designs. CONCLUSION: Pharmacologically enhanced TMS largely parallels findings from ex vivo preparations. As this area expands and novel targets are tested, adequately powered samples in healthy and clinical populations will inform the mechanisms of TMS-induced plasticity in health and disease.
Subject(s)
Neuronal Plasticity , Transcranial Magnetic Stimulation , Transcranial Magnetic Stimulation/methods , Humans , Neuronal Plasticity/physiology , Neuronal Plasticity/drug effects , Receptors, N-Methyl-D-AspartateABSTRACT
Background: Caffeine is a widely used psychostimulant. In the brain, caffeine acts as a competitive, non-selective adenosine receptor antagonist of A1 and A2A, both known to modulate long-term potentiation (LTP), the cellular basis of learning and memory. Repetitive transcranial magnetic stimulation (rTMS) is theorized to work through LTP induction and can modulate cortical excitability as measured by motor evoked potentials (MEPs). The acute effects of single caffeine doses diminish rTMS-induced corticomotor plasticity. However, plasticity in chronic daily caffeine users has not been examined. Method: We conducted a post hoc secondary covariate analysis from two previously published plasticity-inducing pharmaco-rTMS studies combining 10 Hz rTMS and D-cycloserine (DCS) in twenty healthy subjects. Results: In this hypothesis-generating pilot study, we observed enhanced MEP facilitation in non-caffeine users compared to caffeine users and placebo. Conclusion: These preliminary data highlight a need to directly test the effects of caffeine in prospective well-powered studies, because in theory, they suggest that chronic caffeine use could limit learning or plasticity, including rTMS effectiveness.
ABSTRACT
INTRODUCTION: Genomic and morphologic heterogeneity in clear cell renal cell carcinoma (ccRCC) presents a barrier to prognostication and treatment decisions. Data from pathology are used with clinical markers to predict disease progression after nephrectomy. However, determining the risk of cancer recurrence, and survival with metastatic cancer remains challenging. Recently, analysis of histologic growth patterns (HGP) in ccRCC revealed promising associations with survival outcomes. METHODS: To investigate whether HGPs can be used to predict overall survival (OS) after nephrectomy, we examined 24 HGPs in primary tumors of 147 patients that included 107 patients with metastatic disease. RESULTS: The median number of HGPs per case was 5 and was greater in metastatic and larger tumors. After adjustment for 6 pathologic and demographic variables, HGPs were significantly associated with OS post nephrectomy. Small nests, expansile nests and nests with high nuclear to cytoplasmic ratio were associated with favorable outcomes; while spindled low grade, fused nests/solid sheets, rhabdoid, and sarcomatoid patterns were associated with unfavorable outcomes. A 3-tiered and a 2-tiered risk model were developed based on combinations of HGPs. The models performed equally well as WHO/ISUP nucleolar plus necrosis grade (necrosis grade), and better than WHO/ISUP nucleolar grade alone in predicting OS at the median OS of 6 years. Pairwise correlations between HGPs revealed 2 tumor evolutionary branches that differed in risk of metastatic disease: one with mesenchymal differentiation, and other with epithelial tubulopapillary differentiation. While 44 of 107 (41%) patients with metastatic ccRCC displayed evidence of mesenchymal differentiation, mesenchymal features were only observed in 1 of 40 (3%) patients without evidence of metastatic disease. CONCLUSION: These findings suggest that HGPs may provide a novel path to refine the estimation of OS after nephrectomy and to determine the molecular basis of tumor evolution.