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.

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.

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.

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.

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.

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.

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.

Sildenafil improves epicenter vascular perfusion but not hindlimb functional recovery after contusive spinal cord injury in mice.

Nitric oxide (NO) is an important regulator of vasodilation and angiogenesis in the central nervous system (CNS). Signaling initiated by the membrane receptor CD47 antagonizes vasodilation and angiogenesis by inhibiting synthesis of cyclic guanosine monophosphate (cGMP). We recently found that deletion of CD47 led to significant functional locomotor improvements, enhanced angiogenesis, and increased epicenter microvascular perfusion in mice after moderate contusive spinal cord injury (SCI). We tested the hypothesis that improving NO/cGMP signaling within the spinal cord immediately after injury would increase microvascular perfusion, angiogenesis, and functional recovery, with an acute, 7-day administration of the cGMP phosphodiesterase 5 (PDE5) inhibitor sildenafil. PDE5 expression is localized within spinal cord microvascular endothelial cells and smooth muscle cells. While PDE5 antagonism has been shown to increase angiogenesis in a rat embolic stroke model, sildenafil had no significant effect on angiogenesis at 7 days post-injury after murine contusive SCI. Sildenafil treatment increased cGMP concentrations within the spinal cord and improved epicenter microvascular perfusion. Basso Mouse Scale (BMS) and Treadscan analyses revealed that sildenafil treatment had no functional consequence on hindlimb locomotor recovery. These data support the hypothesis that acutely improving microvascular perfusion within the injury epicenter by itself is an insufficient strategy for improving functional deficits following contusive 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.