The Effects of Focal Electrically Administered Seizure Therapy Compared With Ultrabrief Pulse Right Unilateral Electroconvulsive Therapy on Suicidal Ideation: A 2-Site Clinical Trial.

BACKGROUND: Preliminary data suggest that focal electrically administered seizure therapy (FEAST) has antidepressant effects and less adverse cognitive effects than traditional forms of electroconvulsive therapy (ECT). This study compared the impact of FEAST and ultrabrief pulse, right unilateral (UB-RUL) ECT on suicidal ideation. METHODS: At 2 sites, patients in a major depressive episode were treated openly with FEAST or UB-RUL ECT, depending on their preference. The primary outcome measure was scores on the Beck Scale for Suicide Ideation (SSI). Scores on the suicide item of the Hamilton Rating Scale for Depression (HRSD-SI) provided a secondary outcome measure. RESULTS: Thirty-nine patients were included in the intent-to-treat sample (FEAST, n = 20; UB-RUL ECT, n = 19). Scores on both the SSI and HRSD-SI were equivalently reduced with both interventions. Both responders and nonresponders to the interventions showed substantial reductions in SSI and HRSD-SI scores, although the magnitude of improvement was greater among treatment responders. CONCLUSIONS: Although limited by the open-label, nonrandomized design, FEAST showed comparable effects on suicidal ideation when compared with routine use of UB-RUL ECT. These results are encouraging and support the need for further research and a noninferiority trial.

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.

A model for a medical school surgery interest group.

The purpose of this report is to record some of the recent accomplishments of the Surgery Interest Group (SIG) at the Uniformed Services University of the Health Sciences, and to provide a framework for others to follow, with the goal of encouraging students to become interested in the exciting field of surgery. We will outline some of the events that our SIG planned and carried out in order to provide a quality experience to its members.

Neurophysiologic Effects of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) via Electrical Stimulation of the Tragus: A Concurrent taVNS/fMRI Study and Review.

(Appeared originally in Brain Stimulation 2018; 11:492-500) Reprinted with permission from Elsevier.

Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury.

Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC(+)) OLs, and CNTF significantly increased the percentage of APC(+) OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.

Dorsally-derived oligodendrocytes in the spinal cord contribute to axonal myelination during development and remyelination following focal demyelination.

In the developing spinal cord, the majority of oligodendrocytes are derived from the ventral ventricular zone. Several recent studies suggested that a small number of oligodendrocyte precursor cells (OPCs) can also be generated in the dorsal spinal cord. However, it is not clear whether these dorsal oligodendrocyte precursor cells participate in myelination and remyelination. To investigate the fate and potential function of these dorsally-derived oligodendrocytes (dOLs) in the adult spinal cord, Cre-lox genetic fate mapping in transgenic mice was employed. We used the Pax3(Cre) knock-in mouse to drive Cre expression in the entire dorsal epithelium and the Rosa26-lacZ or Z/EG reporter line to trace their spatial distribution and population dynamics in the spinal cord. The dorsal OPCs generated from the Pax3-expressing domains migrate into all regions of spinal cord and subsequently undergo terminal differentiation and axonal myelination. In response to a focal demyelination injury, a large number of newly differentiated oligodendrocytes originated from dOLs, suggesting that dOLs may provide an important source of OPCs for axonal remyelination in multiple sclerosis or spinal cord injury.

CD47 knockout mice exhibit improved recovery from spinal cord injury.

Recent data have implicated thrombospondin-1 (TSP-1) signaling in the acute neuropathological events that occur in microvascular endothelial cells (ECs) following spinal cord injury (SCI) (Benton et al., 2008b). We hypothesized that deletion of TSP-1 or its receptor CD47 would reduce these pathological events following SCI. CD47 is expressed in a variety of tissues, including vascular ECs and neutrophils. CD47 binds to TSP-1 and inhibits angiogenesis. CD47 also binds to the signal regulatory protein (SIRP)α and facilitates neutrophil diapedesis across ECs to sites of injury. After contusive SCI, TSP-1(-/-) mice did not show functional improvement compared to wildtype (WT) mice. CD47(-/-) mice, however, exhibited functional locomotor improvements and greater white matter sparing. Whereas targeted deletion of either CD47 or TSP-1 improved acute epicenter vascularity in contused mice, only CD47 deletion reduced neutrophil diapedesis and increased microvascular perfusion. An ex vivo model of the CNS microvasculature revealed that CD47(-/-)-derived microvessels (MVs) prominently exhibit adherent WT or CD47(-/-) neutrophils on the endothelial lumen, whereas WT-derived MVs do not. This implicates a defect in diapedesis mediated by the loss of CD47 expression on ECs. In vitro transmigration assays confirmed the role of SIRPα in neutrophil diapedesis through EC monolayers. We conclude that CD47 deletion modestly, but significantly, improves functional recovery from SCI via an increase in vascular patency and a reduction of SIRPα-mediated neutrophil diapedesis, rather than the abrogation of TSP-1-mediated anti-angiogenic signaling.

Brain stimulation in zero gravity: transcranial magnetic stimulation (TMS) motor threshold decreases during zero gravity induced by parabolic flight.

We are just beginning to understand how spaceflight may impact brain function. As NASA proceeds with plans to send astronauts to the Moon and commercial space travel interest increases, it is critical to understand how the human brain and peripheral nervous system respond to zero gravity. Here, we developed and refined head-worn transcranial magnetic stimulation (TMS) systems capable of reliably and quickly determining the amount of electromagnetism each individual needs to detect electromyographic (EMG) threshold levels in the thumb (called the resting motor threshold (rMT)). We then collected rMTs in 10 healthy adult participants in the laboratory at baseline, and subsequently at three time points onboard an airplane: (T1) pre-flight at Earth gravity, (T2) during zero gravity periods induced by parabolic flight and (T3) post-flight at Earth gravity. Overall, the subjects required 12.6% less electromagnetism applied to the brain to cause thumb muscle activation during weightlessness compared to Earth gravity, suggesting neurophysiological changes occur during brief periods of zero gravity. We discuss several candidate explanations for this finding, including upward shift of the brain within the skull, acute increases in cortical excitability, changes in intracranial pressure, and diffuse spinal or neuromuscular system effects. All of these possible explanations warrant further study. In summary, we documented neurophysiological changes during brief episodes of zero gravity and thus highlighting the need for further studies of human brain function in altered gravity conditions to optimally prepare for prolonged microgravity exposure during spaceflight.

Transcranial electrical stimulation motor threshold can estimate individualized tDCS dosage from reverse-calculation electric-field modeling.

BACKGROUND: Unique amongst brain stimulation tools, transcranial direct current stimulation (tDCS) currently lacks an easy or widely implemented method for individualizing dosage. OBJECTIVE: We developed a method of reverse-calculating electric-field (E-field) models based on Magnetic Resonance Imaging (MRI) scans that can estimate individualized tDCS dose. We also evaluated an MRI-free method of individualizing tDCS dose by measuring transcranial magnetic stimulation (TMS) motor threshold (MT) and single pulse, suprathreshold transcranial electrical stimulation (TES) MT and regressing it against E-field modeling. Key assumptions of reverse-calculation E-field modeling, including the size of region of interest (ROI) analysis and the linearity of multiple E-field models were also tested. METHODS: In 29 healthy adults, we acquired TMS MT, TES MT, and anatomical T1-weighted MPRAGE MRI scans with a fiducial marking the motor hotspot. We then computed a "reverse-calculated tDCS dose" of tDCS applied at the scalp needed to cause a 1.00 V/m E-field at the cortex. Finally, we examined whether the predicted E-field values correlated with each participant's measured TMS MT or TES MT. RESULTS: We were able to determine a reverse-calculated tDCS dose for each participant using a 5 × 5 x 5 voxel grid region of interest (ROI) approach (average = 6.03 mA, SD = 1.44 mA, range = 3.75-9.74 mA). The Transcranial Electrical Stimulation MT, but not the Transcranial Magnetic Stimulation MT, significantly correlated with the ROI-based reverse-calculated tDCS dose determined by E-field modeling (R2 = 0.45, p < 0.001). CONCLUSIONS: Reverse-calculation E-field modeling, alone or regressed against TES MT, shows promise as a method to individualize tDCS dose. The large range of the reverse-calculated tDCS doses between subjects underscores the likely need to individualize tDCS dose. Future research should further examine the use of TES MT to individually dose tDCS as an MRI-free method of dosing tDCS.

Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study.

Neonates born premature or who suffer brain injury at birth often have oral feeding dysfunction and do not meet oral intake requirements needed for discharge. Low oral intake volumes result in extended stays in the hospital (>2 months) and can lead to surgical implant and explant of a gastrostomy tube (G-tube). Prior work suggests pairing vagus nerve stimulation (VNS) with motor activity accelerates functional improvements after stroke, and transcutaneous auricular VNS (taVNS) has emerged as promising noninvasive form of VNS. Pairing taVNS with bottle-feeding rehabilitation may improve oromotor coordination and lead to improved oral intake volumes, ultimately avoiding the need for G-tube placement. We investigated whether taVNS paired with oromotor rehabilitation is tolerable and safe and facilitates motor learning in infants who have failed oral feeding. We enrolled 14 infants [11 premature and 3 hypoxic-ischemic encephalopathy (HIE)] who were slated for G-tube placement in a prospective, open-label study of taVNS-paired rehabilitation to increase feeding volumes. Once-daily taVNS was delivered to the left tragus during bottle feeding for 2 weeks, with optional extension. The primary outcome was attainment of oral feeding volumes and weight gain adequate for discharge without G-tube while also monitoring discomfort and heart rate (HR) as safety outcomes. We observed no adverse events related to stimulation, and stimulation-induced HR reductions were transient and safe and likely confirmed vagal engagement. Eight of 14 participants (57%) achieved adequate feeding volumes for discharge without G-tube (mean treatment length: 16 ± 6 days). We observed significant increases in feeding volume trajectories in responders compared with pre-stimulation (p < 0.05). taVNS-paired feeding rehabilitation appears safe and may improve oral feeding in infants with oromotor dyscoordination, increasing the rate of discharge without G-tube, warranting larger controlled trials.

State-Dependent Effects of Ventromedial Prefrontal Cortex Continuous Thetaburst Stimulation on Cocaine Cue Reactivity in Chronic Cocaine Users.

Cue-induced craving is a significant barrier to obtaining abstinence from cocaine. Neuroimaging research has shown that cocaine cue exposure evokes elevated activity in a network of frontal-striatal brain regions involved in drug craving and drug seeking. Prior research from our laboratory has demonstrated that when targeted at the medial prefrontal cortex (mPFC), continuous theta burst stimulation (cTBS), an inhibitory form of non-invasive brain stimulation, can decrease drug cue-related activity in the striatum in cocaine users and alcohol users. However, it is known that there are individual differences in response to repetitive transcranial magnetic stimulation (rTMS), with some individuals being responders and others non-responders. There is some evidence that state-dependent effects influence response to rTMS, with baseline neural state predicting rTMS treatment outcomes. In this single-blind, active sham-controlled crossover study, we assess the striatum as a biomarker of treatment response by determining if baseline drug cue reactivity in the striatum influences striatal response to mPFC cTBS. The brain response to cocaine cues was measured in 19 cocaine-dependent individuals immediately before and after real and sham cTBS (110% resting motor threshold, 3600 total pulses). Group independent component analysis (ICA) revealed a prominent striatum network comprised of bilateral caudate, putamen, and nucleus accumbens, which was modulated by the cocaine cue reactivity task. Baseline drug cue reactivity in this striatal network was inversely related to change in striatum reactivity after real (vs. sham) cTBS treatment (ρ = -.79; p < .001; R 2 Adj = .58). Specifically, individuals with a high striatal response to cocaine cues at baseline had significantly attenuated striatal activity after real but not sham cTBS (t 9 = -3.76; p ≤ .005). These data demonstrate that the effects of mPFC cTBS on the neural circuitry of craving are not uniform and may depend on an individual's baseline frontal-striatal reactivity to cues. This underscores the importance of assessing individual variability as we develop brain stimulation treatments for addiction.

Elevated Brain Iron in Cocaine Use Disorder as Indexed by Magnetic Field Correlation Imaging.

BACKGROUND: Iron homeostasis is a critical biological process that may be disrupted in cocaine use disorder (CUD). In the brain, iron is required for neural processes involved in addiction and can be lethal to cells if unbound, especially in excess. Moreover, recent studies have implicated elevated brain iron in conditions of prolonged psychostimulant exposure. Thus, the purpose of this study was to examine iron in basal ganglia reward regions of individuals with CUD using an advanced imaging method called magnetic field correlation (MFC) imaging. METHODS: MFC imaging was acquired in 19 non-treatment-seeking individuals with CUD and 19 healthy control individuals (both male and female). Region-of-interest analyses for MFC group differences and within-group correlations with age and years of cocaine use were conducted in the globus pallidus internal segment (GPi), globus pallidus external segment, putamen, caudate nucleus, thalamus, and red nucleus. RESULTS: Individuals with CUD had significantly elevated MFC compared with control individuals within the GPi. In control individuals, MFC significantly increased with age in the GPi, globus pallidus external segment, putamen, and caudate nucleus. Conversely, there were no significant MFC within-group correlations in the CUD group. CONCLUSIONS: Individuals with CUD have excess iron in the GPi, as indexed by MFC, and lack the age-related gradual iron deposition seen in normal aging. Because the globus pallidus is critical for the transition of goal-directed behavior to compulsive behavior, significantly elevated iron in the GPi may contribute to the persistence of CUD. These findings implicate dysregulation of brain iron homeostasis in CUD and support pursuing this new line of research.

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations.

Non-invasive vagus nerve stimulation (VNS) may be administered via a novel, emerging neuromodulatory technique known as transcutaneous auricular vagus nerve stimulation (taVNS). Unlike cervically-implanted VNS, taVNS is an inexpensive and non-surgical method used to modulate the vagus system. taVNS is appealing as it allows for rapid translation of basic VNS research and serves as a safe, inexpensive, and portable neurostimulation system for the future treatment of central and peripheral disease. The background and rationale for taVNS is described, along with electrical and parametric considerations, proper ear targeting and attachment of stimulation electrodes, individual dosing via determination of perception threshold (PT), and safe administration of taVNS.

Spinal cord contusion based on precise vertebral stabilization and tissue displacement measured by combined assessment to discriminate small functional differences.

Contusive spinal cord injury (SCI) is the most common type of spinal injury seen clinically. Several rat contusion SCI models have been described, and all have strengths and weaknesses with respect to sensitivity, reproducibility, and clinical relevance. We developed the Louisville Injury System Apparatus (LISA), which contains a novel spine-stabilizing device that enables precise and stable spine fixation, and is based on tissue displacement to determine the severity of injury. Injuries graded from mild to moderately severe were produced using 0.2-, 0.4-, 0.6-, 0.8-, 1.0-, and 1.2-mm spinal cord displacement in rats. Basso, Beattie, and Bresnahan (BBB) and Louisville Swim Score (LSS) could not significantly distinguish between 0.2-mm lesion severities, except those of 0.6- and 0.8-mm BBB scores, but could between 0.4-mm injury differences or if the data were grouped (0.2-0.4, 0.6-0.8, and 1.0-1.2). Transcranial magnetic motor evoked potential (tcMMEP) response amplitudes were decreased 10-fold at 0.2-mm displacement, barely detected at 0.4-mm displacement, and absent with greater displacement injuries. In contrast, somatosensory evoked potentials (SSEPs) were recorded at 0.2- and 0.4-mm displacements with normal amplitudes and latencies but were detected at lower amplitudes at 0.6-mm displacement and absent with more severe injuries. Analyzing combined BBB, tcMMEP, and SSEP results enabled statistically significant discrimination between 0.2-, 0.4-, 0.6-, and 0.8-mm displacement injuries but not the more severe injuries. Present data document that the LISA produces reliable and reproducible SCI whose parameters of injury can be adjusted to more accurately reflect clinical SCI. Moreover, multiple outcome measures are necessary to accurately detect small differences in functional deficits and/or recovery. This is of crucial importance when trying to detect functional improvement after therapeutic intervention to treat SCI.

Transdiagnostic Effects of Ventromedial Prefrontal Cortex Transcranial Magnetic Stimulation on Cue Reactivity.

BACKGROUND: Elevated frontal and striatal reactivity to drug cues is a transdiagnostic hallmark of substance use disorders. The goal of these experiments was to determine if it is possible to decrease frontal and striatal reactivity to drug cues in both cocaine users and heavy alcohol users through continuous theta burst stimulation (cTBS) to the left ventromedial prefrontal cortex (VMPFC). METHODS: Two single-blinded, within-subject, active sham-controlled experiments were performed wherein neural reactivity to drug/alcohol cues versus neutral cues was evaluated immediately before and after receiving real or sham cTBS (110% resting motor threshold, 3600 pulses, Fp1 location; N = 49: 25 cocaine users [experiment 1], 24 alcohol users [experiment 2]; 196 total functional magnetic resonance imaging scans). Generalized psychophysiological interaction and three-way repeated-measures analysis of variance were used to evaluate cTBS-induced changes in drug cue-associated functional connectivity between the left VMPFC and eight regions of interest: ventral striatum, left and right caudate, left and right putamen, left and right insula, and anterior cingulate cortex. RESULTS: In both experiments, there was a significant interaction between treatment (real/sham) and time (pre/post). In both experiments, cue-related functional connectivity was significantly attenuated following real cTBS versus sham cTBS. There was no significant interaction with region of interest for either experiment. CONCLUSIONS: This is the first sham-controlled investigation to demonstrate, in two populations, that VMPFC cTBS can attenuate neural reactivity to drug and alcohol cues in frontostriatal circuits. These results provide an empirical foundation for future clinical trials that may evaluate the efficacy, durability, and clinical implications of VMPFC cTBS to treat addictions.

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.

Emergency Resuscitative Thoracotomy in the Combat or Operational Environment.

Resuscitative thoracotomy has been extensively described in the civilian trauma literature and has a high mortality rate, due largely to the nature of the injuries leading to arrest. The survival rates are generally highest (10-30%) for penetrating truncal injuries and patients who arrive with vital signs and proceed to arrest or who have impending arrest. They are significantly lower (less than 5%) for blunt trauma victims, particularly those who arrest in the field or during transport (1% or less). In addition, the likelihood of survival with intact neurologic function is significantly lower than the overall survival rates, particularly for blunt trauma victims and for prehospital arrest.

Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate.

BACKGROUND: Optimal parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are still undetermined. Given the vagus nerve's role in regulating heart rate (HR), it is important to determine safety and HR effects of various taVNS parameters. OBJECTIVE: We conducted two sequential trials to systematically test the effects of various taVNS parameters on HR. METHODS: 15 healthy individuals participated in the initial two-visit, crossover exploratory trial, receiving either tragus (active) or earlobe (control) stimulation each visit. Nine stimulation blocks of varying parameters (pulse width: 100 µs, 200 µs, 500 µs; frequency: 1 Hz, 10 Hz, 25 Hz) were administered each visit. HR was recorded and analyzed for stimulation-induced changes. Using similar methods and the two best parameters from trial 1 (500µs 10 Hz and 500µs 25 Hz), 20 healthy individuals then participated in a follow-up confirmatory study. RESULTS: Trial 1- There was no overall effect of the nine conditions on HR during stimulation. However multivariate analysis revealed two parameters that significantly decreased HR during active stimulation compared to control (500µs 10 Hz and 500µs 25 Hz; p < 0.01). Additionally, active taVNS significantly attenuated overall sympathetic HR rebound (post-stimulation) compared to control (p < 0.001). Trial 2-For these two conditions, active taVNS significantly decreased HR compared to control (p = 0.02), with the strongest effects at 500µs 10 Hz (p = 0.032). CONCLUSION: These studies suggest that 60s blocks of tragus stimulation are safe, and some specific parameters modulate HR. Of the nine parameters studied, 500µs 10 Hz induced the greatest HR effects.

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 study's 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.

Developing Repetitive Transcranial Magnetic Stimulation (rTMS) as a Treatment Tool for Cocaine Use Disorder: a Series of Six Translational Studies.

PURPOSE OF THE REVIEW: Cocaine dependence is a chronic and relapsing disorder which is particularly resistant to behavioral or pharmacologic treatment, and likely involves multiple dysfunctional frontal-striatal circuits. Through advances in preclinical research in the last decade, we now have an unprecedented understanding of the neural control of drug-taking behavior. In both rodent models and human clinical neuroimaging studies, it is apparent that medial frontal-striatal limbic circuits regulate drug cue-triggered behavior. While non-human preclinical studies can use invasive stimulation techniques to inhibit drug cue-evoked behavior, in human clinical neuroscience, we are pursuing non-invasive theta burst stimulation (TBS) as a novel therapeutic tool to inhibit drug cue-associated behavior. RECENT FINDINGS: Our laboratory and others have spent the last 7 years systematically and empirically developing a non-invasive, neural circuit-based intervention for cocaine use disorder. Utilizing a multimodal approach of functional brain imaging and brain stimulation, we have attempted to design and optimize a repetitive transcranial magnetic stimulation treatment protocol for cocaine use disorder. This manuscript will briefly review the data largely from our own lab that motivated our selection of candidate neural circuits, and then summarize the results of six studies, culminating in the first double-blinded, sham-controlled clinical trial of TMS as a treatment adjuvant for treatment-engaged cocaine users (10 sessions, medial prefrontal cortex, 110% resting motor threshold, continuous theta burst stimulation, 3600 pulses/session). SUMMARY: The intent of this review is to highlight one example of a systematic path for TMS treatment development in patients. This path is not necessarily optimal, exclusive, or appropriate for every neurologic or psychiatric disease. Rather, it is one example of a reasoned, empirically derived pathway which we hope will serve as scaffolding for future investigators seeking to develop TMS treatment protocols.