William DeVries

What goes up, can come down: Novel brain stimulation paradigms may attenuate craving and craving-related neural circuitry in substance dependent individuals

Vulnerability to drug related cues is one of the leading causes for continued use and relapse among substance dependent individuals. Using drugs in the face of cues may be associated with dysfunction in at least two frontal-striatal neural circuits: (1) elevated activity in medial and ventral areas that govern limbic arousal (including the medial prefrontal cortex (MPFC) and ventral striatum) or (2) depressed activity in dorsal and lateral areas that govern cognitive control (including the dorsolateral prefrontal cortex (DLPFC) and dorsal striatum). Transcranial magnetic stimulation (TMS) is emerging as a promising new tool for the attenuation of craving among multiple substance dependent populations. To date however, nearly all repetitive TMS studies in addiction have focused on amplifying activity in frontal-striatal circuits that govern cognitive control. This manuscript reviews recent work using TMS as a tool to decrease craving for multiple substances and provides a theoretical model for how clinical researchers might approach target and frequency selection for TMS of addiction. To buttress this model, preliminary data from a single-blind, sham-controlled, crossover study of 11 cocaine-dependent individuals is also presented. These results suggest that attenuating MPFC activity through theta burst stimulation decreases activity in the striatum and anterior insula. It is also more likely to attenuate craving than sham TMS. Hence, while many TMS studies are focused on applying LTP-like stimulation to the DLPFC, the MPFC might be a new, efficacious, and treatable target for craving in cocaine dependent individuals.

Probing the Frontostriatal Loops Involved in Executive and Limbic Processing via Interleaved TMS and Functional MRI at Two Prefrontal Locations: A Pilot Study

Background The prefrontal cortex (PFC) is an anatomically and functionally heterogeneous area which influences cognitive and limbic processing through connectivity to subcortical targets. As proposed by Alexander et al. (1986) the lateral and medial aspects of the PFC project to distinct areas of the striatum in parallel but functionally distinct circuits. The purpose of this preliminary study was to determine if we could differentially and consistently activate these lateral and medial cortical-subcortical circuits involved in executive and limbic processing though interleaved transcranial magnetic stimulation (TMS) in the MR environment. Methods Seventeen healthy individuals received interleaved TMS-BOLD imaging with the coil positioned over the dorsolateral (EEG: F3) and ventromedial PFC (EEG: FP1). BOLD signal change was calculated in the areas directly stimulated by the coil and in subcortical regions with afferent and efferent connectivity to the TMS target areas. Additionally, five individuals were tested on two occasions to determine test-retest reliability. Results Region of interest analysis revealed that TMS at both prefrontal sites led to significant BOLD signal increases in the cortex under the coil, in the striatum, and the thalamus, but not in the visual cortex (negative control region). There was a significantly larger BOLD signal change in the caudate following medial PFC TMS, relative to lateral TMS. The hippocampus in contrast was significantly more activated by lateral TMS. Post-hoc voxel-based analysis revealed that within the caudate the location of peak activity was in the ventral caudate following medial TMS and the dorsal caudate following lateral TMS. Test-retest reliability data revealed consistent BOLD responses to TMS within each individual but a large variation between individuals. Conclusion These data demonstrate that, through an optimized TMS/BOLD sequence over two unique prefrontal targets, it is possible to selectively interrogate the patency of these established cortical-subcortical networks in healthy individuals, and potentially patient populations.

The Efficacy of Daily Prefrontal Repetitive Transcranial Magnetic Stimulation (rTMS) for Burning Mouth Syndrome (BMS): A Randomized Controlled Single-blind Study

BACKGROUND Burning mouth syndrome (BMS) is a burning oral sensation without any corresponding abnormal findings. In some cases, BMS is refractory to pharmacologic treatments. Repetitive transcranial magnetic stimulation (rTMS) over left prefrontal cortex induces analgesic effect in both acute and chronic pain. However, its effect for BMS has not been evaluated. OBJECTIVE The aim of this randomized, controlled, single-blind study was to assess the efficacy of prefrontal rTMS for BMS. METHOD Twenty patients with BMS were recruited and randomized to receive 30,000 pulses in total at 10 Hz TMS (n = 12) or sham TMS (n = 8). We assessed the change of BMS pain condition, functional status and mood until 2 months after the beginning of treatment. RESULTS In the real group, the BMS pain intensity decreased 67%, and 75% of the patients reported >50% pain decrease on final assessment compared to baseline, without heavy side effects. There was significant pain reduction in subjects in the real group immediately after 1 week of treatment, whereas there was none in those in the sham group. Similar tendency was confirmed in change of functional status. Mood and the affective aspect of pain were not changed in this study. CONCLUSION BMS pain was significantly improved with 2 weeks of treatment of high frequency rTMS over left DLPFC compared to sham stimulation. Further study is needed to refine and improve TMS as a potential treatment of BMS.

A comprehensive study of sensorimotor cortex excitability in chronic cocaine users: Integrating TMS and functional MRI data

BACKGROUND Disruptions in motor control are often overlooked features of chronic cocaine users. During a simple sensorimotor integration task, for example, cocaine users activate a larger area of cortex than controls but have lower functional connectivity between the cortex and dorsal striatum, which is further correlated with poor performance. The purpose of this study was to determine whether abnormal cortical excitability in cocaine users was related to disrupted inhibitory or excitatory mechanisms, as measured by transcranial magnetic stimulation (TMS). METHODS A battery of TMS measures were acquired from 87 individuals (50 cocaine dependent, 37 controls). Functional MRI data were acquired from a subset of 28 individuals who performed a block-design finger tapping task. RESULTS TMS measures revealed that cocaine users had significantly higher resting motor thresholds and higher intracortical cortical facilitation (ICF) than controls. There was no between-group difference in either measure of cortical inhibition. Task-evoked BOLD signal in the motor cortex was significantly correlated with ICF in the cocaine users. There was no significant difference in brain-skull distance between groups. CONCLUSION These data demonstrated that cocaine users have disrupted cortical facilitation (as measured with TMS), which is related to elevated BOLD signal. Cortical inhibition, however, is largely intact. Given the relationship between ICF and glutamatergic agents, this may be a potentially fruitful and treatable target in addiction. Finally, among controls the distance from the scalp to the cortex was correlated with the motor threshold which may be a useful parameter to integrate into therapeutic TMS protocols in the future.

Expanded Safety and Efficacy Data for a New Method of Performing Electroconvulsive Therapy: Focal Electrically Administered Seizure Therapy.

Objective Electroconvulsive therapy (ECT) is the most rapid and effective antidepressant treatment but with concerns about cognitive adverse effects. A new form of ECT, focal electrically administered seizure therapy (FEAST), was designed to increase the focality of stimulation and better match stimulus parameters with neurophysiology. We recently reported on the safety and feasibility of FEAST in a cohort (n = 17) of depressed patients. We now report on the safety, feasibility, preliminary efficacy, and cognitive effects of FEAST in a new cohort. Methods Open-label FEAST was administered to 20 depressed adults (6 men; 3 with bipolar disorder; age 49.1 ± 10.6 years). Clinical and cognitive assessments were obtained at baseline and end of course. Time to orientation recovery was assessed at each treatment. Nonresponders switched to conventional ECT. Results Participants tolerated the treatment well with no dropouts. Five patients (25%) transitioned from FEAST to conventional ECT due to inadequate response. After FEAST (mean, 9.3 ± 3.5 sessions; range, 4–14), there was a 58.1% ± 36.0% improvement in Hamilton Rating Scale for Depression scores compared with that in the baseline (P < 0.0001); 13 (65%) of 20 patients met response criteria, and 11 (55%) of 20 met remission criteria. Patients achieved reorientation (4 of 5 items) in 4.4 ± 3.0 minutes (median, 4.5 minutes), timed from eyes opening. There was no deterioration in neuropsychological measures. Conclusions These findings provide further support for the safety and efficacy of FEAST. The remission and response rates were in the range found using conventional ECT, and the time to reorientation may be quicker. However, without a randomized comparison group, conclusions are tentative.

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review

BACKGROUND Electrical stimulation of the auricular branch of the vagus nerve (ABVN) via transcutaneous auricular vagus nerve stimulation (taVNS) may influence afferent vagal networks. There have been 5 prior taVNS/fMRI studies, with inconsistent findings due to variability in stimulation targets and parameters. OBJECTIVE We developed a taVNS/fMRI system to enable concurrent electrical stimulation and fMRI acquisition to compare the effects of taVNS in relation to control stimulation. METHODS We enrolled 17 healthy adults in this single-blind, crossover taVNS/fMRI trial. Based on parameters shown to affect heart rate in healthy volunteers, participants received either left tragus (active) or earlobe (control) stimulation at 500 μs 25 HZ for 60 s (repeated 3 times over 6 min). Whole brain fMRI analysis was performed exploring the effect of: active stimulation, control stimulation, and the comparison. Region of interest analysis of the midbrain and brainstem was also conducted. RESULTS Active stimulation produced significant increased BOLD signal in the contralateral postcentral gyrus, bilateral insula, frontal cortex, right operculum, and left cerebellum. Control stimulation produced BOLD signal activation in the contralateral postcentral gyrus. In the active vs. control contrast, tragus stimulation produced significantly greater BOLD increases in the right caudate, bilateral anterior cingulate, cerebellum, left prefrontal cortex, and mid-cingulate. CONCLUSION Stimulation of the tragus activates the cerebral afferents of the vagal pathway and combined with our review of the literature suggest that taVNS is a promising form of VNS. Future taVNS/fMRI studies should systematically explore various parameters and alternative stimulation targets aimed to optimize this novel form of neuromodulation.

A Double-Blind, Sham-Controlled Pilot Trial of Pre-Supplementary Motor Area (Pre-SMA) 1 Hz rTMS to Treat Essential Tremor.

Please cite this article as: Bashar W. Badran, Chloe E. Glusman, Chris W. Austelle, Shonna Jenkins, William H. DeVries, Virginia Galbraith, Tiffani Thomas, Thomas G. Adams Jr, Mark S. George, Gonzalo J Revuelta, A Double-Blind, Sham-Controlled Pilot Trial of Pre-Supplementary Motor Area (Pre-SMA) 1Hz rTMS to Treat Essential Tremor, Brain Stimulation (2016), http://dx.doi.org/doi: 10.1016/j.brs.2016.08.003.

The effect of task difficulty on motor performance and frontal-striatal connectivity in cocaine users

BACKGROUND There is growing recognition that chronic cocaine users have alterations in sensorimotor control that are positively related to low frontal-striatal connectivity within the motor system. These frontal-striatal motor circuits however, are modulated by circuits governing attention, which are also disrupted in cocaine users. This studys aim was to determine if sensorimotor control deficits are positively related to the difficulty of a motor task or exist independent of the increasing cognitive demand. METHODS Functional MRI data was collected from 40 individuals (20 non-treatment seeking chronic cocaine users, 20 age and gender matched non-drug using controls) as they mimicked an unpredictable finger-tapping sequence at various speeds. Dependent measures included task accuracy, percent BOLD signal change in sensorimotor regions of interest (ROIs), and functional connectivity (temporal correlations) between ROIs. RESULTS In both groups, as speed increased, the BOLD signal change increased in the primary motor cortex, supplementary motor area (SMA), cerebellum, and anterior cingulate cortex. Compared to controls, cocaine user SMA-Caudate and ACC-Putamen connectivity was lower at all speeds in the contralateral hemisphere. Furthermore, as speed increased there was a decrease in connectivity between additional ROI pairs among users. CONCLUSIONS These data support previous observations of sensorimotor performance deficits and dorsal frontal-striatal connectivity impairments among cocaine users. While previous studies demonstrate these deficits when performing a finger-tapping task at a single speed, we show that these same impairments exist at multiple levels of task difficulty. These data suggest that previously observed frontal-striatal connectivity in cocaine users during sensorimotor task performance are stable and not directly related to cognitive demands of the task.

Continuous theta burst stimulation to the medial prefrontal cortex decreases frontal-striatal circuitry involved in drug craving

Continuous theta burst stimulation to the medial prefrontal cortex decreases frontal-striatal circuitry involved in drug craving Colleen A. Hanlon , Logan T. Dowdle , Oliver Mithofer , Christopher W. Austelle , William DeVries , Bashar Badran , Mark S. George a,b,c,d Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina Department of Neurosciences, Medical University of South Carolina Center for Biomedical Imaging, Medical University of South Carolina Ralph H Johnson Veterans Affairs Medical Center Department of Biology, College of Charleston

Tragus or cymba conchae? Investigating the anatomical foundation of transcutaneous auricular vagus nerve stimulation (taVNS)

a Brain Stimulation Lab, Medical University of South Carolina, Charleston, SC, USA b Department of Biomedical Engineering, City College of New York, New York, NY, USA c U.S. Army Research Lab, Aberdeen Proving Ground, MD, USA d College of Charleston, Charleston, SC, USA e Center for Biomedical Imaging, Medical University of South Carolina, Charleston, SC, USA f Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA g Department of Neurology, Medical University of South Carolina, Charleston, SC, USA h Ralph H. Johnson VA Medical Center, Charleston, SC, USA