Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

DiMANI: diffusion MRI for anatomical nuclei imaging-Application for the direct visualization of thalamic subnuclei.

The thalamus is a centrally located and heterogeneous brain structure that plays a critical role in various sensory, motor, and cognitive processes. However, visualizing the individual subnuclei of the thalamus using conventional MRI techniques is challenging. This difficulty has posed obstacles in targeting specific subnuclei for clinical interventions such as deep brain stimulation (DBS). In this paper, we present DiMANI, a novel method for directly visualizing the thalamic subnuclei using diffusion MRI (dMRI). The DiMANI contrast is computed by averaging, voxelwise, diffusion-weighted volumes enabling the direct distinction of thalamic subnuclei in individuals. We evaluated the reproducibility of DiMANI through multiple approaches. First, we utilized a unique dataset comprising 8 scans of a single participant collected over a 3-year period. Secondly, we quantitatively assessed manual segmentations of thalamic subnuclei for both intra-rater and inter-rater reliability. Thirdly, we qualitatively correlated DiMANI imaging data from several patients with Essential Tremor with the localization of implanted DBS electrodes and clinical observations. Lastly, we demonstrated that DiMANI can provide similar features at 3T and 7T MRI, using varying numbers of diffusion directions. Our results establish that DiMANI is a reproducible and clinically relevant method to directly visualize thalamic subnuclei. This has significant implications for the development of new DBS targets and the optimization of DBS therapy.

Paradoxical Modulation of STN ß-Band Activity with Medication Compared to Deep Brain Stimulation.

BACKGROUND: Excessive subthalamic nucleus (STN) ß-band (13-35 Hz) synchronized oscillations has garnered interest as a biomarker for characterizing disease state and developing adaptive stimulation systems for Parkinson's disease (PD). OBJECTIVES: To report on a patient with abnormal treatment-responsive modulation in the ß-band. METHODS: We examined STN local field potentials from an externalized deep brain stimulation (DBS) lead while assessing PD motor signs in four conditions (OFF, MEDS, DBS, and MEDS+DBS). RESULTS: The patient presented here exhibited a paradoxical increase in ß power following administration of levodopa and pramipexole (MEDS), but an attenuation in ß power during DBS and MEDS+DBS despite clinical improvement of 50% or greater under all three therapeutic conditions. CONCLUSIONS: This case highlights the need for further study on the role of ß oscillations in the pathophysiology of PD and the importance of personalized approaches to the development of ß or other biomarker-based DBS closed loop algorithms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A workflow for predicting radiofrequency-induced heating around bilateral deep brain stimulation electrodes in MRI.

BACKGROUND: Heating around deep brain stimulation (DBS) in magnetic resonance imaging (MRI) occurs when the time-varying electromagnetic (EM) fields induce currents in the electrodes which can generate heat and potentially cause tissue damage. Predicting the heating around the electrode contacts is important to ensure the safety of patients with DBS implants undergoing an MRI scan. We previously proposed a workflow to predict heating around DBS contacts and introduced a parameter, equivalent transimpedance, that is independent of electrode trajectories, termination, and radiofrequency (RF) excitations. The workflow performance was validated in a unilateral DBS system. PURPOSE: To predict RF heating around the contacts of bilateral (DBS) electrodes during an MRI scan in an anthropomorphic head phantom. METHODS: Bilateral electrodes were fixed in a skull phantom filled with hydroxyethyl cellulose (HEC) gel. The electrode shafts were suspended extracranially, in a head and torso phantom filled with the same gel material. The current induced on the electrode shaft was experimentally measured using an MR-based technique 3 cm above the tip. A transimpedance value determined in a previous offline calibration was used to scale the shaft current and calculate the contact voltage. The voltage was assigned as a boundary condition on the electrical contacts of the electrode in a quasi-static (EM) simulation. The resulting specific absorption rate (SAR) distribution became the input for a transient thermal simulation and was used to predict the heating around the contacts. RF heating experiments were performed for eight different lead trajectories using circularly polarized (CP) excitation and two linear excitations for one trajectory. The measured temperatures for all experiments were compared with the simulated temperatures and the root-mean-squared errors (RMSE) were calculated. RESULTS: The RF heating around the contacts of both bilateral electrodes was predicted with ≤ 0.29°C of RMSE for 20 heating scenarios. CONCLUSION: The workflow successfully predicted the heating for different bilateral DBS trajectories and excitation patterns in an anthropomorphic head phantom.

Transcutaneous Spinal Cord Stimulation to Stabilize Seated Systolic Blood Pressure in Persons With Chronic Spinal Cord Injury: Protocol Development.

Transcutaneous spinal cord stimulation (tSCS) is an emerging therapeutic strategy to target spinal autonomic circuitry to normalize and stabilize blood pressure (BP) in hypotensive persons living with chronic spinal cord injury (SCI). Our aim is to describe our current methodological approach to identify individual tSCS parameters that result in the maintenance of seated systolic blood pressure (SBP) within a pre-defined target range. The parent study is a prospective, randomized clinical trial in which eligible participants will undergo multiple mapping sessions to optimize tSCS parameter settings to promote stable SBP within a target range of 110-120 mm Hg for males and 100-120 mm Hg for females. Parameter mapping includes cathode electrode placement site (T7/8, T9/10, T11/12, and L1/2), stimulation frequency (30, 60 Hz), current amplitudes (0-120 mA), waveform (mono- and biphasic), pulse width (1000 µs), and use of carrier frequency (0, 10 kHz). Each participant will undergo up to 10 mapping sessions involving different electrode placement sites and parameter settings. BP will be continuously monitored throughout each mapping session. Stimulation amplitude (mA) will be increased at intervals of between 2 and 10 mA until one of the following occurs: 1) seated SBP reaches the target range; 2) tSCS intensity reaches 120 mA; or 3) the participant requests to stop. Secondary outcomes recorded include 1) symptoms related to autonomic dysreflexia and orthostatic hypotension, 2) Likert pain scale, and 3) skin appearance after removal of the tSCS electrode. Clinical Trials Registration: NCT05180227.

Active contact proximity to the cerebellothalamic tract predicts initial therapeutic current requirement with DBS for ET: an application of 7T MRI.

Objective: To characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET). Background: DBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely. Methods: A retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores. Results: The therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58). Conclusion: Active DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

Ultra-high-field 7T MRI in Parkinson's disease: ready for clinical use?-a narrative review.

Background and Objective: The maturation of ultra-high-field magnetic resonance imaging (MRI) [≥7 Tesla (7T)] has improved our capability to depict and characterise brain structures efficiently, with better signal-to-noise ratio (SNR) and spatial resolution. We evaluated whether these improvements benefit the clinical detection and management of Parkinson's disease (PD). Methods: We performed a literature search in March 2023 in PubMed (MEDLINE), EMBASE and Google Scholar for articles on "7T MRI" AND "Parkinson*", written in English, published between inception and 1st March, 2023, which we synthesised in narrative form. Key Content and Findings: In deep-brain stimulation (DBS) surgical planning, early studies show that 7T MRI can distinguish anatomical substructures, and that this results in reduced adverse effects. In other areas, while there is strong evidence for improved accuracy and precision of 7T MRI-based measurements for PD, there is limited evidence for meaningful clinical translation. In particular, neuromelanin-iron complex quantification and visualisation in midbrain nuclei is enhanced, enabling depiction of nigrosomes 1-5, improved morphometry and vastly improved radiological assessments; however, studies on the related clinical outcomes, diagnosis, subtyping, differentiation of atypical parkinsonisms, and monitoring of treatment response using 7T MRI are lacking. Moreover, improvements in clinical utility must be great enough to justify the additional costs. Conclusions: Together, current evidence supports feasible future clinical implementation of 7T MRI for PD. Future impacts to clinical decision making for diagnosis, differentiation, and monitoring of progression or treatment response are likely; however, to achieve this, further longitudinal studies using 7T MRI are needed in prodromal, early-stage PD and parkinsonism cohorts focusing on clinical translational potential.

Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Introduction: Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. Methods: We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Results: Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Discussion: Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.

PURPOSE OF REVIEW: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC. RECENT FINDINGS: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis. SUMMARY: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy.

Implant-friendly MRI of deep brain stimulation electrodes at 7 T.

PURPOSE: The purpose of this study is to present a strategy to calculate the implant-friendly (IF) excitation modes-which mitigate the RF heating at the contacts of deep brain stimulation (DBS) electrodes-of multichannel RF coils at 7 T. METHODS: An induced RF current on an implantable electrode generates a scattered magnetic field whose left-handed circularly polarizing component ( B 1 + $$ B{1}^{+} $$ ) is approximated using a B 1 + $$ B{1}^{+} $$ -mapping technique and subsequently used as a gauge for the electrode's induced current. Using this approach, the relative induced currents resulting from each channel of a multichannel RF coil on the DBS electrode were calculated. The IF modes of the corresponding multichannel coil were determined by calculating the null space of the relative induced currents. The proposed strategy was tested and validated for unilateral and bilateral commercial DBS electrodes (directional lead; Infinity DBS system, Abbott Laboratories) placed inside a uniform phantom by performing heating and imaging studies on a 7T MRI scanner using a 16-channel transceive RF coil. RESULTS: Neither individual IF modes nor shim solutions obtained from IF modes induced significant temperature increase when used for a high-power turbo spin-echo sequence. In contrast, shimming with the scanner's toolbox (i.e., based on per-channel B 1 + $$ B{1}^{+} $$ fields) resulted in a more than 2°C temperature increase for the same amount of input power. CONCLUSION: A strategy for calculating the IF modes of a multichannel RF coil is presented. This strategy was validated using a 16-channel RF coil at 7 T for unilateral and bilateral commercial DBS electrodes inside a uniform phantom.

Timing dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans it is not known whether dorsal epidural SCS targeted at the sensorimotor interface or anterior epidural SCS targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord with epidural electrodes while muscle responses were recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation.

Widening the care gap? An international comparison of care leaving in the time of COVID-19.

Following COVID-19, young people who transitioned to adulthood from different types of alternative care (care leavers) experienced an exacerbation of the challenges they had before the pandemic. The purpose of this international survey was to explore the range of policy and service responses that have or have not been implemented around the world to support care leavers during COVID-19. Responses were collected from care-leaving researchers from 19 countries toward the end of 2020. Half of the participating countries reported that the state had issued directives about measures that should be taken to support care leavers following COVID-19 outbreak, but only three reported actual changes in legislation. Additionally, nongovernmental organizations (NGOs) in various countries took steps to guide and support care leavers, while two thirds reported on special initiatives that were mounted. The most common change in practices during COVID-19 was the postponement of exits from care, and the second was an increase in contact from workers. These findings are critically discussed in relation to the impact of policy changes on an already vulnerable group. In particular, we indicate that there appears to be a widening care gap: Some countries with stronger leaving care legal and policy frameworks pre-COVID-19 were more inclined to introduce additional supportive measures during the pandemic, whereas some with underdeveloped services tended not to increase the support. By contrast, other countries used this crisis to develop services that were not available before. The creativity and flexibility in the services provided during the COVID-19 outbreak are required on an ongoing basis and thus should be implemented overall. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Use of a Commercial 7-T MRI Scanner for Clinical Brain Imaging: Indications, Protocols, Challenges, and Solutions-A Single-Center Experience.

The first commercially available 7-T MRI scanner (Magnetom Terra) was approved by the FDA in 2017 for clinical imaging of the brain and knee. After initial protocol development and sequence optimization efforts in volunteers, the 7-T system, in combination with an FDA-approved 1-channel transmit/32-channel receive array head coil, can now be routinely used for clinical brain MRI examinations. The ultrahigh field strength of 7-T MRI has the advantages of improved spatial resolution, increased SNR, and increased CNR but also introduces an array of new technical challenges. The purpose of this article is to describe an institutional experience with the use of the commercially available 7-T MRI scanner for routine clinical brain imaging. Specific clinical indications for which 7-T MRI may be useful for brain imaging include brain tumor evaluation with possible perfusion imaging and/or spectroscopy, radiotherapy planning; evaluation of multiple sclerosis and other demyelinating diseases, evaluation of Parkinson disease and guidance of deep brain stimulator placement, high-detail intracranial MRA and vessel wall imaging, evaluation of pituitary pathology, and evaluation of epilepsy. Detailed protocols, including sequence parameters, for these various indications are presented, and implementation challenges (including artifacts, safety, and side effects) and potential solutions are explored.

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study.

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Priming locomotor training with transspinal stimulation in people with spinal cord injury: study protocol of a randomized clinical trial.

Background: The seemingly simple tasks of standing and walking require continuous integration of complex spinal reflex circuits between descending motor commands and ascending sensory inputs. Spinal cord injury greatly impairs standing and walking ability, but both improve with locomotor training. However, even after multiple locomotor training sessions, abnormal muscle activity and coordination persist. Thus, locomotor training alone cannot fully optimize the neuronal plasticity required to strengthen the synapses connecting the brain, spinal cord, and local circuits and potentiate neuronal activity based on need. Transcutaneous spinal cord (transspinal) stimulation alters motoneuron excitability over multiple segments by bringing motoneurons closer to threshold, a prerequisite for effectively promoting spinal locomotor network neuromodulation and strengthening neural connectivity of the injured human spinal cord. Importantly, whether concurrent treatment with transspinal stimulation and locomotor training maximizes motor recovery after spinal cord injury is unknown. Methods: Forty-five individuals with chronic spinal cord injury are receiving 40 sessions of robotic gait training primed with 30 Hz transspinal stimulation at the Thoracic 10 vertebral level. Participants are randomized to receive 30-minutes of active or sham transspinal stimulation during standing or active transspinal stimulation while supine followed by 30-minutes of robotic gait training. Over the course of locomotor training, the body weight support, treadmill speed, and leg guidance force are adjusted as needed for each participant based on absence of knee buckling during the stance phase and toe dragging during the swing phase. At baseline and after completion of all therapeutic sessions, neurophysiological recordings registering corticospinal and spinal neural excitability changes along with clinical assessment measures of standing and walking, and autonomic function via questionnaires regarding bowel, bladder and sexual function are taken. Discussion: The results of this mechanistic randomized clinical trial will demonstrate that tonic transspinal stimulation strengthens corticomotoneuronal connectivity and dynamic neuromodulation through posture-dependent corticospinal and spinal neuroplasticity. We anticipate that this mechanistic clinical trial will greatly impact clinical practice because in real-world clinical settings, noninvasive transspinal stimulation can be more easily and widely implemented than invasive epidural stimulation. Additionally, by applying multiple interventions to accelerate motor recovery, we are employing a treatment regimen that reflects a true clinical approach. Trial registration: ClinicalTrials.gov: NCT04807764; Registered on March 19, 2021.

Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor.

BACKGROUND: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. METHODS: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. RESULTS: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). CONCLUSIONS: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.

Priming locomotor training with transspinal stimulation in people with spinal cord injury: study protocol of a randomized clinical trial.

BACKGROUND: The seemingly simple tasks of standing and walking require continuous integration of complex spinal reflex circuits between descending motor commands and ascending sensory inputs. Spinal cord injury greatly impairs standing and walking ability, but both improve with locomotor training. However, even after multiple locomotor training sessions, abnormal muscle activity and coordination persist. Thus, locomotor training alone cannot fully optimize the neuronal plasticity required to strengthen the synapses connecting the brain, spinal cord, and local circuits and potentiate neuronal activity based on need. Transcutaneous spinal cord (transspinal) stimulation alters motoneuron excitability over multiple segments by bringing motoneurons closer to threshold, a prerequisite for effectively promoting spinal locomotor network neuromodulation and strengthening neural connectivity of the injured human spinal cord. Importantly, whether concurrent treatment with transspinal stimulation and locomotor training maximizes motor recovery after spinal cord injury is unknown. METHODS: Forty-five individuals with chronic spinal cord injury are receiving 40 sessions of robotic gait training primed with 30 Hz transspinal stimulation at the Thoracic 10 vertebral level. Participants are randomized to receive 30 min of active or sham transspinal stimulation during standing or active transspinal stimulation while supine followed by 30 min of robotic gait training. Over the course of locomotor training, the body weight support, treadmill speed, and leg guidance force are adjusted as needed for each participant based on absence of knee buckling during the stance phase and toe dragging during the swing phase. At baseline and after completion of all therapeutic sessions, neurophysiological recordings registering corticospinal and spinal neural excitability changes along with clinical assessment measures of standing and walking, and autonomic function via questionnaires regarding bowel, bladder, and sexual function are taken. DISCUSSION: The results of this mechanistic randomized clinical trial will demonstrate that tonic transspinal stimulation strengthens corticomotoneuronal connectivity and dynamic neuromodulation through posture-dependent corticospinal and spinal neuroplasticity. We anticipate that this mechanistic clinical trial will greatly impact clinical practice because, in real-world clinical settings, noninvasive transspinal stimulation can be more easily and widely implemented than invasive epidural stimulation. Additionally, by applying multiple interventions to accelerate motor recovery, we are employing a treatment regimen that reflects a true clinical approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT04807764 . Registered on March 19, 2021.

Intraoperative electrical stimulation of the human dorsal spinal cord reveals a map of arm and hand muscle responses.

Although epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective and responses would be strongest in the muscles innervated by the stimulated segment. Twenty-six people undergoing clinically indicated cervical spine surgery consented to mapping of motor responses. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; six arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline despite similar latency and shape of responses. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in response sizes to stimulation of adjacent cervical segments argue for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function.NEW & NOTEWORTHY A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline and revealed differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally, indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively.

Motion robust magnetic resonance imaging via efficient Fourier aggregation.

We present a method for suppressing motion artifacts in anatomical magnetic resonance acquisitions. Our proposed technique, termed MOTOR-MRI, can recover and salvage images which are otherwise heavily corrupted by motion induced artifacts and blur which renders them unusable. Contrary to other techniques, MOTOR-MRI operates on the reconstructed images and not on k-space data. It relies on breaking the standard acquisition protocol into several shorter ones (while maintaining the same total acquisition time) and subsequent efficient aggregation in Fourier space of locally sharp and consistent information among them, producing a sharp and motion mitigated image. We demonstrate the efficacy of the technique on T2-weighted turbo spin echo magnetic resonance brain scans with severe motion corruption from both 3 T and 7 T scanners and show significant qualitative and quantitative improvement in image quality. MOTOR-MRI can operate independently, or in conjunction with additional motion correction methods.

Lead location as a determinant of motor benefit in subthalamic nucleus deep brain stimulation for Parkinson's disease.

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) is regarded as an effective treatment for patients with advanced Parkinson's disease (PD). Clinical benefit, however, varies significantly across patients. Lead location has been hypothesized to play a critical role in determining motor outcome and may account for much of the observed variability reported among patients. Objective: To retrospectively evaluate the relationship of lead location to motor outcomes in patients who had been implanted previously at another center by employing a novel visualization technology that more precisely determines the location of the DBS lead and its contacts with respect to each patient's individually defined STN. Methods: Anatomical models were generated using novel imaging in 40 PD patients who had undergone bilateral STN DBS (80 electrodes) at another center. Patient-specific models of each STN were evaluated to determine DBS electrode contact locations with respect to anterior to posterior and medial to lateral regions of the individualized STNs and compared to the change in the contralateral hemi-body Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) motor score. Results: The greatest improvement in hemi-body motor function was found when active contacts were located within the posterolateral portion of the STN (71.5%). Motor benefit was 52 and 36% for central and anterior segments, respectively. Active contacts within the posterolateral portion also demonstrated the greatest reduction in levodopa dosage (77%). Conclusion: The degree of motor benefit was dependent on the location of the stimulating contact within the STN. Although other factors may play a role, we provide further evidence in support of the hypothesis that lead location is a critical factor in determining clinical outcomes in STN DBS.