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.

Real-Time Semi-Automated and Automated Voxel Placement using fMRI Targets for Repeated Acquisition Magnetic Resonance Spectroscopy.

BACKGROUND: Currently, magnetic resonance spectroscopy (MRS) is dependent on the investigative team to manually prescribe, or demarcate, the desired tissue volume-of-interest. The need for a new method to automate precise voxel placements is warranted to improve the utility and interpretability of MRS data. NEW METHOD: We propose and validate robust and real-time methods to automate MRS voxel placement using functionally defined coordinates within the prefrontal cortex. Data were collected and analyzed using two independent prospective studies: 1) two independent imaging days with each consisting of a multi-session sandwich design (MRS data only collected on one of the days determined based on scan time) and 2) a longitudinal design. Participants with fibromyalgia syndrome (N = 50) and major depressive disorder (N = 35) underwent neuroimaging. MRS acquisitions were acquired at 3-tesla. Evaluation of the reproducibility of spatial location and tissue segmentation was assessed for: 1) manual, 2) semi-automated, and 3) automated voxel prescription approaches RESULTS: Variability of voxel grey and white matter tissue composition was reduced using automated placement protocols. Spatially, post- to pre-voxel center-of-gravity distance was reduced and voxel overlap increased significantly across datasets using automated compared to manual procedures COMPARISON WITH EXISTING METHODS: Manual prescription, the current standard in the field, can produce inconsistent data across repeated acquisitions. Using automated voxel placement, we found reduced variability and more consistent voxel placement across multiple acquisitions CONCLUSIONS: These results demonstrate the within subject reliability and reproducibility of a method for reducing variability introduced by spatial inconsistencies during MRS acquisitions. The proposed method is a meaningful advance toward improved consistency of MRS data in neuroscience and can be utilized for multi-session and longitudinal studies.

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.

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression.

OBJECTIVE: New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression. METHODS: Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT. RESULTS: One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects. CONCLUSIONS: SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

Altered structural brain network topology in chronic migraine.

Despite its prevalence and high disease burden, the pathophysiological mechanisms underlying chronic migraine (CM) are not well understood. As CM is a complex disorder associated with a range of sensory, cognitive, and affective comorbidities, examining structural network disruption may provide additional insights into CM symptomology beyond studies of focal brain regions. Here, we compared structural interconnections in patients with CM (n = 52) and healthy controls (HC) (n = 48) using MRI measures of cortical thickness and subcortical volume combined with graph theoretical network analyses. The analysis focused on both local (nodal) and global measures of topology to examine network integration, efficiency, centrality, and segregation. Our results indicated that patients with CM had altered global network properties that were characterized as less integrated and efficient (lower global and local efficiency) and more highly segregated (higher transitivity). Patients also demonstrated aberrant local network topology that was less integrated (higher path length), less central (lower closeness centrality), less efficient (lower local efficiency) and less segregated (lower clustering). These network differences not only were most prominent in the limbic and insular cortices but also occurred in frontal, temporal, and brainstem regions, and occurred in the absence of group differences in focal brain regions. Taken together, examining structural correlations between brain areas may be a more sensitive means to detect altered brain structure and understand CM symptomology at the network level. These findings contribute to an increased understanding of structural connectivity in CM and provide a novel approach to potentially track and predict the progression of migraine disorders.This study is registered on ClinicalTrials.gov (Identifier: NCT03304886).

Structural network differences in chronic muskuloskeletal pain: Beyond fractional anisotropy.

Chronic musculoskeletal pain is a condition that influences central nervous system structure. In this study, we combined novel structural neuroimaging techniques, using well-validated software packages including FSL, Mrtrix3, and DSI Studio, to characterize brain grey (GM) and white matter (WM) differences in chronic musculoskeletal pain participants (n = 74), compared to age-matched pain-free controls (n = 31). In participants with chronic pain, we identified significantly higher volume in subcortical GM structures using voxel-based morphometry (FSLVBM). These differences were most prominent in the caudate, amygdala, and the hippocampus. At the same time, volume was lower in the dorsolateral prefrontal cortex, as well as the primary motor and sensory regions in patients with chronic pain. To delineate WM microstructural differences of neuronal (e.g., activity-dependent myelin remodeling) and non-neuronal (e.g., neuroinflammation) origins, we utilized Mrtrix3 software pipelines to investigate WM fiber complexity, density, and cross-section. Whole-brain analyses revealed lower WM fiber complexity within the corpus callosum and the anterior limb of the left internal capsule. Whole brain and region of interest analyses revealed fiber complexity differences within the salience and the sensorimotor networks. In contrast, we detected non-neuronal white matter density differences within the dorsal attention network: density was lower in the inferior fronto-occipital fasciculus and the splenium of the corpus callosum in chronic musculoskeletal pain. Consistent with the involvement of the dorsal attention network, WM tractography analysis, conducted with DSI Studio and Network Based Statistics, revealed higher connectivity from the superior parietal lobule to the hippocampus in patients with chronic pain. No differences were detected in measures of fiber cross-section, suggesting the absence of neuronal degeneration in chronic pain. The combination of multiple neuroimaging techniques in this study offers a unique window into the structural differences within the chronic pain brain and provides the first evidence of microstructural variations in fiber complexity and density.

Diffusion Capillary Phantom vs. Human Data: Outcomes for Reconstruction Methods Depend on Evaluation Medium.

PURPOSE: Diffusion MRI provides a non-invasive way of estimating structural connectivity in the brain. Many studies have used diffusion phantoms as benchmarks to assess the performance of different tractography reconstruction algorithms and assumed that the results can be applied to in vivo studies. Here we examined whether quality metrics derived from a common, publically available, diffusion phantom can reliably predict tractography performance in human white matter tissue. MATERIALS AND METHODS: We compared estimates of fiber length and fiber crossing among a simple tensor model (diffusion tensor imaging), a more complicated model (ball-and-sticks) and model-free (diffusion spectrum imaging, generalized q-sampling imaging) reconstruction methods using a capillary phantom and in vivo human data (N = 14). RESULTS: Our analysis showed that evaluation outcomes differ depending on whether they were obtained from phantom or human data. Specifically, the diffusion phantom favored a more complicated model over a simple tensor model or model-free methods for resolving crossing fibers. On the other hand, the human studies showed the opposite pattern of results, with the model-free methods being more advantageous than model-based methods or simple tensor models. This performance difference was consistent across several metrics, including estimating fiber length and resolving fiber crossings in established white matter pathways. CONCLUSIONS: These findings indicate that the construction of current capillary diffusion phantoms tends to favor complicated reconstruction models over a simple tensor model or model-free methods, whereas the in vivo data tends to produce opposite results. This brings into question the previous phantom-based evaluation approaches and suggests that a more realistic phantom or simulation is necessary to accurately predict the relative performance of different tractography reconstruction methods.

Ultrasound Evaluation of the Combined Effects of Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model.

The persistence of back pain following acute back "sprains" is a serious public health problem with poorly understood pathophysiology. The recent finding that human subjects with chronic low back pain (LBP) have increased thickness and decreased mobility of the thoracolumbar fascia measured with ultrasound suggest that the fasciae of the back may be involved in LBP pathophysiology. This study used a porcine model to test the hypothesis that similar ultrasound findings can be produced experimentally in a porcine model by combining a local injury of fascia with movement restriction using a "hobble" device linking one foot to a chest harness for 8 weeks. Ultrasound measurements of thoracolumbar fascia thickness and shear plane mobility (shear strain) during passive hip flexion were made at the 8 week time point on the non-intervention side (injury and/or hobble). Injury alone caused both an increase in fascia thickness (p = .007) and a decrease in fascia shear strain on the non-injured side (p = .027). Movement restriction alone did not change fascia thickness but did decrease shear strain on the non-hobble side (p = .024). The combination of injury plus movement restriction had additive effects on reducing fascia mobility with a 52% reduction in shear strain compared with controls and a 28% reduction compared to movement restriction alone. These results suggest that a back injury involving fascia, even when healed, can affect the relative mobility of fascia layers away from the injured area, especially when movement is also restricted.