Accelerated Theta Burst Stimulation: Safety, Efficacy, and Future Advancements.

Theta burst stimulation (TBS) is a noninvasive brain stimulation technique that can be used to modulate neural networks underlying psychiatric and neurological disorders. TBS can be delivered intermittently or continuously. The conventional intermittent TBS protocol is approved by the U.S. Food and Drug Administration to treat otherwise treatment-resistant depression, but the 6-week duration limits the applicability of this therapy. Accelerated TBS protocols present an opportunity to deliver higher pulse doses in shorter periods of time, thus resulting in faster and potentially more clinically effective treatment. However, the acceleration of TBS delivery raises questions regarding the relative safety, efficacy, and durability compared with conventional TBS protocols. In this review paper, we present the data from accelerated TBS trials to date that support the safety and effectiveness of accelerated protocols while acknowledging the need for more durability data. We discuss the stimulation parameters that seem to be important for the efficacy of accelerated TBS protocols and possible avenues for further optimization.

Magnesium-ibogaine therapy in veterans with traumatic brain injuries.

Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (Pcorrected < 0.001, Cohen's d = 0.74) and 1 month (Pcorrected < 0.001, d = 2.20) after treatment and in PTSD (Pcorrected < 0.001, d = 2.54), depression (Pcorrected < 0.001, d = 2.80) and anxiety (Pcorrected < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 .

A preliminary randomized controlled trial of repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex in treatment seeking participants with cannabis use disorder.

BACKGROUND: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have therapeutic clinical effects when applied in serial-sessions. The present study sought to preliminarily determine whether serial-sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. METHODS: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, two-sessions-per-visit, two-visits-per-week, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. RESULTS: There were no significant differences in craving between conditions. Participants who received active-rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham-rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active-rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period than those receiving sham-rTMS (Active vs. Sham: -0.72; Z=-2.33, p=0.02). CONCLUSIONS: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Responsive deep brain stimulation guided by ventral striatal electrophysiology of obsession durably ameliorates compulsion.

Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD.

Network effects of Stanford Neuromodulation Therapy (SNT) in treatment-resistant major depressive disorder: a randomized, controlled trial.

Here, we investigated the brain functional connectivity (FC) changes following a novel accelerated theta burst stimulation protocol known as Stanford Neuromodulation Therapy (SNT) which demonstrated significant antidepressant efficacy in treatment-resistant depression (TRD). In a sample of 24 patients (12 active and 12 sham), active stimulation was associated with significant pre- and post-treatment modulation of three FC pairs, involving the default mode network (DMN), amygdala, salience network (SN) and striatum. The most robust finding was the SNT effect on amygdala-DMN FC (group*time interaction F(1,22) = 14.89, p < 0.001). This FC change correlated with improvement in depressive symptoms (rho (Spearman) = -0.45, df = 22, p = 0.026). The post-treatment FC pattern showed a change in the direction of the healthy control group and was sustained at the one-month follow-up. These results are consistent with amygdala-DMN connectivity dysfunction as an underlying mechanism of TRD and bring us closer to the goal of developing imaging biomarkers for TMS treatment optimization.Trial registration: ClinicalTrials.gov NCT03068715.

A Preliminary Investigation Of Repetitive Transcranial Magnetic Stimulation Applied To The Left Dorsolateral Prefrontal Cortex In Treatment Seeking Participants With Cannabis Use Disorder.

Background: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have a therapeutic clinical effect when applied in serial sessions. The present study sought to preliminarily determine whether serial sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. Methods: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post-treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. Results: There were no significant differences in craving between conditions. Participants who received active rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period (Active vs. Sham: -0.72; Z=-2.33, p=0.02). Conclusions: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Targeted neurostimulation reverses a spatiotemporal biomarker of treatment-resistant depression.

Major depressive disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet, prior resting-state-functional MRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to investigate the relationship between directed rs-fMRI activity, MDD, and treatment response to FDA-approved neurostimulation paradigm termed Stanford neuromodulation therapy (SNT). We find that SNT over the left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pretreatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD.

Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and evidence-based therapy for treatment-resistant major depressive disorder. A conventional course of rTMS applies 20-30 daily sessions over 4-6 weeks. The schedule of rTMS delivery can be accelerated by applying multiple stimulation sessions per day, which reduces the duration of a treatment course with a predefined number of sessions. Accelerated rTMS reduces time demands, improves clinical efficiency, and potentially induces faster onset of antidepressant effects. However, considerable heterogeneity exists across study designs. Stimulation protocols vary in parameters such as the stimulation target, frequency, intensity, number of pulses applied per session or over a course of treatment, and duration of intersession intervals. In this article, clinician-researchers and neuroscientists who have extensive research experience in accelerated rTMS synthesize a consensus based on two decades of investigation and development, from early studies ("Past") to contemporaneous theta burst stimulation, a time-efficient form of rTMS gaining acceptance in clinical settings ("Present"). We propose descriptive nomenclature for accelerated rTMS, recommend avenues to optimize therapeutic and efficiency potential, and suggest using neuroimaging and electrophysiological biomarkers to individualize treatment protocols ("Future"). Overall, empirical studies show that accelerated rTMS protocols are well tolerated and not associated with serious adverse effects. Importantly, the antidepressant efficacy of accelerated rTMS appears comparable to conventional, once daily rTMS protocols. Whether accelerated rTMS induces antidepressant effects more quickly remains uncertain. On present evidence, treatment protocols incorporating high pulse dose and multiple treatments per day show promise and improved efficacy.

Taking modern psychiatry into the metaverse: Integrating augmented, virtual, and mixed reality technologies into psychiatric care.

The landscape of psychiatry is ever evolving and has recently begun to be influenced more heavily by new technologies. One novel technology which may have particular application to psychiatry is the metaverse, a three-dimensional digital social platform accessed via augmented, virtual, and mixed reality (AR/VR/MR). The metaverse allows the interaction of users in a virtual world which can be measured and manipulated, posing at once exciting new possibilities and significant potential challenges and risks. While the final form of the nascent metaverse is not yet clear, the immersive simulation and holographic mixed reality-based worlds made possible by the metaverse have the potential to redefine neuropsychiatric care for both patients and their providers. While a number of applications for this technology can be envisioned, this article will focus on leveraging the metaverse in three specific domains: medical education, brain stimulation, and biofeedback. Within medical education, the metaverse could allow for more precise feedback to students performing patient interviews as well as the ability to more easily disseminate highly specialized technical skills, such as those used in advanced neurostimulation paradigms. Examples of potential applications in brain stimulation and biofeedback range from using AR to improve precision targeting of non-invasive neuromodulation modalities to more innovative practices, such as using physiological and behavioral measures derived from interactions in VR environments to directly inform and personalize treatment parameters for patients. Along with promising future applications, we also discuss ethical implications and data security concerns that arise when considering the introduction of the metaverse and related AR/VR technologies to psychiatric research and care.

Time for Brain Medicine.

Unprecedented knowledge of the brain is inevitably contributing to the convergence of neurology and psychiatry. However, clinical training continues to follow a divergent approach established in the 19th century. An etiological approach will continue to shift more psychiatric patients to the care of neurologists who are untrained in psychiatric management. At the same time, this new era of diagnostic biomarkers and neuroscience-based precision treatments requires skills not readily available to those trained in psychiatry. The challenges in training the next generation of doctors include establishing competence involving aspects of the whole brain, fostering the subspecialized expertise needed to remain current, and developing programs that are feasible in duration and practical in implementation. A new 4-year residency training program proposed in this article could replace existing residency programs. The program includes 2 years of common and urgent training in various aspects of neurology and psychiatry followed by 2 years of elective subspecialty tracks. The concept is similar to internal medicine residencies and fellowships. No changes to existing departmental structures are necessary. In concert with the emerging biological approach to the brain, "brain medicine" is proposed as a new name to denote this practice in the simplest terms: a focus on all aspects of the brain.

Aberrant impulse control circuitry in obesity.

The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial.

OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression. METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment. RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group. CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

Hypnotic predictors of agency: Responsiveness to specific suggestions in hypnosis is associated with involuntariness in fibromyalgia.

Hypnosis is associated with alterations in the sense of agency which can play a role in its utilization as a nonpharmacological option for pain management. The goal of the current study was to examine the relationships between responsiveness to suggestions in hypnosis and alterations of the sense of agency among patients with fibromyalgia. Ninety-eight participants with fibromyalgia underwent two hypnotizability assessments followed by the Sense of Agency Rating Scale. Clinical pain measures were also collected. Involuntariness was predicted by responsiveness to control, ideomotor, and dissociation suggestions. Effortlessness was predicted by responsiveness to control and ideomotor suggestions, and age. Hypnotizability was associated with main clinical pain outcomes, but agency alterations were not. Results suggest a shared mechanism between responsiveness to specific suggestions and the sense of agency in hypnosis. We discuss theoretical and clinical implications for pain management and the need for further research.