Sequential Bilateral Accelerated Theta Burst Stimulation in Adolescents With Suicidal Ideation Associated With Major Depressive Disorder: Protocol for a Randomized Controlled Trial
Deniz YurukCan ÖzgerJuan F. GarzonJarrod M. LefflerJulia ShekunovJennifer L. Vande VoortMichael J. ZaccarielloPaul A. NakoneznyPaul E. Croarkin
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Abstract Background Suicide is a leading cause of death in adolescents worldwide. Previous research findings suggest that suicidal adolescents with depression have pathophysiological dorsolateral prefrontal cortex (DLPFC) deficits in γ-aminobutyric acid neurotransmission. Interventions with transcranial magnetic stimulation (TMS) directly address these underlying pathophysiological deficits in the prefrontal cortex. Theta burst stimulation (TBS) is newer dosing approach for TMS. Accelerated TBS (aTBS) involves administering multiple sessions of TMS daily as this dosing may be more efficient, tolerable, and rapid acting than standard TMS. Methods: This is a randomized, double-blind, sham-controlled trial of sequential bilateral aTBS in adolescents with MDD and suicidal ideation. Three sessions are administered daily for 10 days. During each session, continuous TBS is administered first to the right DPFC, in which 1,800 pulses are delivered continuously over 120 seconds. Then intermittent TBS is applied to the left DPFC, in which 1,800 pulses are delivered in 2-second bursts and repeated every 10 seconds for 570 seconds. The TBS parameters were adopted from prior research, with 3-pulse, 50-Hz bursts given every 200 ms (at 5 Hz) with an intensity of 80% active motor threshold. The comparison group will receive 3 daily sessions of bilateral sham TBS treatment for 10 days. All participants will receive the standard of care for patients with depression and suicidal ideation including daily psychotherapeutic skill sessions. Long-interval intracortical inhibition (LICI) biomarkers will be measured before and after treatment. Exploratory measures will be collected with TMS and electroencephalography for biomarker development. Discussion This is the first known randomized controlled trial to examine the efficacy of sequential bilateral aTBS for treating suicidal ideation in adolescents with MDD. Results from this study will also provide opportunities to further understand the neurophysiological and molecular mechanisms of suicidal ideation in adolescents. Trial registration Investigational device exemption (IDE) Number: G200220, ClinicalTrials.gov (ID: NCT04701840 ). Registered August 6, 2020. https://clinicaltrials.gov/ct2/show/NCT04502758?term=NCT04701840&draw=2&rank=1Keywords:
Dorsolateral prefrontal cortex
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Numerous studies have implicated the role of the prefrontal cortex in the expression of aggressive behavior. However, the nature of this relationship remains poorly understood. As such, the purpose of this article is to review both the animal and human literature pertaining to prefrontal cortical functioning and aggression in an attempt to help clarify this relationship. Particular attention is paid to differentiating the functions of the dorsolateral and the orbital regions of the prefrontal cortex in the expression of aggression. Evidence was garnered from four different types of studies: 1) those examining aggressive behavior in animals following ablations to the prefrontal cortex; 2) those examining aggressive behavior in humans following surgical and accidental lesions to the prefrontal cortex; 3) those examining prefrontal cortical functioning in individuals with psychiatric disorders characterized by aggression; and 4) those relating prefrontal cortical functioning to human aggressive behavior in laboratory situations. The general conclusion of this article is that the dorsolateral region of the prefrontal cortex is more likely to be involved in the expression of physical aggression whereas the orbital region is more likely to be involved in the expression of what is termed herein “disinhibited-nonaggressive” behavior. © 1995 Wiley-Liss, Inc.
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During the last decade, repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has become established as a treatment for various mental diseases. The rational of prefrontal stimulation has been adapted from the mode of action known from rTMS using motor-evoked potentials though little is known about the precise effect of rTMS at prefrontal sites. The objective of the current study is to investigate the inhibitory effect of prefrontal 1 Hz rTMS by stimulating the generators of event-related potentials (ERP) which are located in the prefrontal cortex. Thus, 1 Hz rTMS was applied offline over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (MPFC) in 18 healthy subjects who subsequently underwent a GoNogo task. Both active conditions were compared to sham rTMS within a randomized and counterbalanced cross-over design in one day. ERPs were recorded during task performance and the N2 and the P3 were analysed. After 1 Hz rTMS of the left DLPFC (but not of the MPFC), an inhibitory effect on the N2 amplitude was observed, which was related to inhibitory control. In contrast, after 1 Hz rTMS of the MPFC (but not at the left DLPFC) a trend towards an increased P3 amplitude was found. There was no significant modulation of latencies and behavioural data. The results argue in favour of an inhibitory effect of 1 Hz rTMS on N2 amplitudes in a GoNogo task. Our findings suggest that rTMS may mildly modulate prefrontally generated ERP immediately after stimulation, even where behavioural effects are not measurable. Thus, combined rTMS-ERP approaches need to be further established in order to serve as paradigms in experimental neuroscience and clinical research.
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We reviewed the literature on transcranial magnetic stimulation and its uses and efficacy in schizophrenia. Multiple sources were examined on transcranial magnetic stimulation efficacy in relieving positive and negative symptoms of schizophrenia. Literature review was conducted via Ovid Medline and PubMed databases. We found multiple published studies and metaanalyses that give evidence that repetitive transcranial magnetic stimulation can have benefit in relieving positive and negative symptoms of schizophrenia, particularly auditory hallucinations. These findings should encourage the psychiatric community to expand research into other applications for which transcranial magnetic stimulation may be used to treat patients with psychiatric disability.
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反復経頭蓋磁気刺激（repetitive transcranial magnetic stimulation，以下rTMS）は大きな変動磁場を頭皮上から引き起こすことで生じる渦電流が大脳皮質を刺激することを利用し，大脳皮質興奮性を変化させる特徴を有する．このrTMSの性質を利用し脳卒中，パーキンソン病，慢性疼痛などの中枢性疾患に対する治療報告が相次いでいる．リハビリテーション（以下，リハ）分野においては運動訓練だけでなく，強制使用，ボトックス治療，神経筋刺激を組み合わせることで脳卒中後運動麻痺を改善させる報告を認め，さらには言語訓練との併用が失語症に試みられつつある．大脳皮質興奮性を変化させることが可能なrTMSをリハ手法に併用することで，適切な可塑性を誘導し機能改善を引き出すことが期待されている．
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Converging evidence from investigations of a structure in the prefrontal cortex, the dorsolateral prefrontal cortex, provides intriguing data showing abnormalities ranging from neuropathological to functional changes in schizophrenia. Brain-imaging studies demonstrate that the dorsolateral prefrontal cortex is critical to working memory. People with schizophrenia have difficulty performing tasks involving working memory, and brain-imaging studies of the dorsolateral prefrontal cortex show that, during test performances, dorsolateral prefrontal cortex activation is less than that of controls. Results of dorsolateral prefrontal cortex brain tissue studies in people with schizophrenia reveal abnormalities that could affect neuronal circuitry function. Preliminary findings with microarray analyses support findings of ‘faulty’ wiring of brain circuitries relevant to dorsolateral prefrontal cortex function. The neurodevelopmental hypothesis of schizophrenia suggests that defects in the dorsolateral prefrontal cortex may result from early errors in brain development due to genetic factors and/or environmental influences (e.g. trauma, viral causes). This paper reviews a convincing body of evidence implicating defects in the dorsolateral prefrontal cortex that might explain the prominent cognitive symptoms observed in schizophrenia.
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