Increased anti-correlation between the left dorsolateral prefrontal cortex and the default mode network following Stanford Neuromodulation Therapy (SNT): analysis of a double-blinded, randomized, sham-controlled trial.

SNT is a high-dose accelerated intermittent theta-burst stimulation (iTBS) protocol coupled with functional-connectivity-guided targeting that is an efficacious and rapid-acting therapy for treatment-resistant depression (TRD). We used resting-state functional MRI (fMRI) data from a double-blinded sham-controlled randomized controlled trial1 to reveal the neural correlates of SNT-based symptom improvement. Neurobehavioral data were acquired at baseline, post-treatment, and 1-month follow-up. Our primary analytic objective was to investigate changes in seed-based functional connectivity (FC) following SNT and hypothesized that FC changes between the treatment target and the sgACC, DMN, and CEN would ensue following active SNT but not sham. We also investigated the durability of post-treatment observed FC changes at a 1-month follow-up. Study participants included transcranial magnetic stimulation (TMS)-naive adults with a primary diagnosis of moderate-to-severe TRD. Fifty-four participants were screened, 32 were randomized, and 29 received active or sham SNT. An additional 5 participants were excluded due to imaging artifacts, resulting in 12 participants per group (Sham: 5F; SNT: 5F). Although we did not observe any significant group × time effects on the FC between the individualized stimulation target (L-DLPFC) and the CEN or sgACC, we report an increased magnitude of negative FC between the target site and the DMN post-treatment in the active as compared to sham SNT group. This change in FC was sustained at the 1-month follow-up. Further, the degree of change in FC was correlated with improvements in depressive symptoms. Our results provide initial evidence for the putative changes in the functional organization of the brain post-SNT.

Early differences in lassitude predicts outcomes in Stanford Neuromodulation Therapy for difficult to treat depression.

Stanford Neuromodulation Therapy (SNT), has recently shown rapid efficacy in difficult to treat (DTT) depression. We conducted an exploratory analysis of individual symptom improvements during treatment, correlated with fMRI, to investigate this rapid improvement in 23 DTT participants from an SNT RCT (12 active, 11 sham). Montgomery-Åsberg Depression Rating Scale item 7 (Lassitude) was the earliest to show improvements between active and sham, as early as treatment day 2. Lassitude score at treatment day 3 was predictive of response at 4 weeks post-treatment and response immediately after treatment. Participants with lower lassitude scores at treatment day 3 had different patterns of sgACC functional connectivity compared to participants with higher scores in both baseline and post-treatment minus baseline analyses. Further work will aim to first replicate these preliminary findings, and then to extend these findings and examine how SNT may affect lassitude and behavioral activation early in treatment.

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.

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.

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.

Resting-State Functional Connectivity: Signal Origins and Analytic Methods.

Resting state functional connectivity (RSFC) has been widely studied in functional magnetic resonance imaging (fMRI) and is observed by a significant temporal correlation of spontaneous low-frequency signal fluctuations (SLFs) both within and across hemispheres during rest. Different hypotheses of RSFC include the biophysical origin hypothesis and cognitive origin hypothesis, which show that the role of SLFs and RSFC is still not completely understood. Furthermore, RSFC and age studies have shown an "age-related compensation" phenomenon. RSFC data analysis methods include time domain analysis, seed-based correlation, regional homogeneity, and principal and independent component analyses. Despite advances in RSFC, the authors also discuss challenges and limitations, ranging from head motion to methodological limitations.

Disrupted focal white matter integrity in autism spectrum disorder: A voxel-based meta-analysis of diffusion tensor imaging studies.

BACKGROUND: Autism spectrum disorder (ASD) is a mental disorder that has long been considered to result from brain underconnectivity. However, volumetric analysis of structural MRI data has failed to find consistent white matter alterations in patients with ASD. The present study aims to examine whether there are consistent focal white matter alterations as measured by diffusion tensor imaging (DTI) in individuals with ASD compared with typically developing (TD) individuals. METHOD: Coordinate-based meta-analysis was performed on 14 studies that reported fractional anisotropy (FA) alterations between individuals with ASD and TD individuals. These studies have in total 297 subjects with ASD and 302 TD subjects. RESULTS: Activation likelihood estimation (ALE) analysis identified two clusters of white matter regions that showed consistent reduction of FA in individuals with ASD compared with TD individuals: the left splenium of corpus callosum and the right cerebral peduncle. CONCLUSIONS: Consistent focal white matter reductions in ASD could be identified by using FA, highlighting the cerebral peduncle which is usually overlooked in studies focusing on major white matter tracts. These focal reductions in the splenium and the cerebral peduncle may be associated with sensorimotor impairments seen in individuals with ASD.

A Review of Resting-State Analysis Methods.

Resting-state functional connectivity is the synchronization of brain regions with each another. Alterations are suggestive of neurologic or psychological disorders. This article discusses methods and approaches used to describe resting-state brain connectivity and the results in neurotypical and diseased brains.