Sensing in Sacral Neuromodulation: A Feasibility Study in Subjects With Urinary Incontinence and Retention.

OBJECTIVES: Sacral neuromodulation (SNM) therapy standard of care relies on visual-motor responses and patient-reported sensory responses in deciding optimized lead placement and programming. Automatic detection of stimulation responses could offer a simple, consistent indicator for optimizing SNM. The purpose of this study was to measure and characterize sacral evoked responses (SERs) resulting from sacral nerve stimulation using a commercial, tined SNM lead. MATERIALS AND METHODS: A custom external research system with stimulation and sensing hardware was connected to the percutaneous extension of an implanted lead during a staged (tined lead) evaluation for SNM. The system collected SER recordings across a range of prespecified stimulation settings (electrode configuration combinations for bipolar stimulation and bipolar sensing) during intraoperative and postoperative sessions in 21 subjects with overactive bladder (OAB) and nonobstructive urinary retention (NOUR). Motor and sensory thresholds were collected during the same sessions. RESULTS: SERs were detected in all 21 subjects. SER morphology (number of peaks, magnitude, and timing) varied across electrode configurations within and across subjects. Among subjects and electrode configurations tested, recordings contained SERs at motor threshold and/or sensory threshold in 75% to 80% of subjects. CONCLUSIONS: This study confirmed that implanted SNM leads can be used to directly record SERs elicited by stimulation in subjects with OAB and NOUR. SERs were readily detectable at typical SNM stimulation settings and procedural time points. Using these SERs as possible objective measures of SNM response has the capability to automate patient-specific SNM therapy, potentially providing consistent lead placement, programming, and/or closed-loop therapy.

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.

Mapping Spinal Cord Stimulation-Evoked Muscle Responses in Patients With Chronic Spinal Cord Injury.

OBJECTIVES: Epidural spinal cord stimulation (eSCS) has shown promise for restoring some volitional motor control after spinal cord injury (SCI). Maximizing therapeutic response requires effective spatial stimulation generated through careful configuration of anodes and cathodes on the eSCS lead. By exploring the way the spatial distribution of low frequency stimulation affects muscle activation patterns, we investigated the spatial specificity of stimulation-evoked responses for targeted muscle groups for restoration after chronic SCI (cSCI) in participants in the Epidural Stimulation After Neurologic Damage (E-STAND) trial. MATERIALS AND METHODS: Fifteen participants with Abbreviated Injury Scale A cSCI from the E-STAND study were evaluated with a wide range of bipolar spatial patterns. Surface electromyography captured stimulation-evoked responses from the rectus abdominis (RA), intercostal, paraspinal, iliopsoas, rectus femoris (RF), tibialis anterior (TA), extensor hallucis longus (EHL), and gastrocnemius muscle groups bilaterally. Peak-to-peak amplitudes were analyzed for each pulse across muscles. Stimulation patterns with dipoles parallel (vertical configurations), perpendicular (horizontal configurations), and oblique (diagonal configurations) relative to the rostral-caudal axis were evaluated. RESULTS: Cathodic stimulation in the transverse plane indicated ipsilaterally biased activation in RA, intercostal, paraspinal, iliopsoas, RF, TA, EHL, and gastrocnemius muscles (p < 0.05). We found that caudal cathodic stimulation was significantly more activating only in the RF and EHL muscle groups than in the rostral (p < 0.037 and p < 0.006, respectively). Oblique stimulation was found to be more activating in the RA, intercostal, paraspinal, iliopsoas, and TA muscle groups than in the transverse (p < 0.05). CONCLUSIONS: Cathodic stimulation provides uniform specificity for targeting laterality. Few muscle groups responded specifically to variation in rostral/caudal stimulation, and oblique stimulation improved stimulation responses when compared with horizontal configurations. These relations may enable tailored targeting of muscle groups, but the surprising amount of variation observed suggests that monitoring these evoked muscle responses will play a key role in this tailoring process. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03026816.

Orientation-selective and directional deep brain stimulation in swine assessed by functional MRI at 3T.

Functional MRI (fMRI) has become an important tool for probing network-level effects of deep brain stimulation (DBS). Previous DBS-fMRI studies have shown that electrical stimulation of the ventrolateral (VL) thalamus can modulate sensorimotor cortices in a frequency and amplitude dependent manner. Here, we investigated, using a swine animal model, how the direction and orientation of the electric field, induced by VL-thalamus DBS, affects activity in the sensorimotor cortex. Adult swine underwent implantation of a novel 16-electrode (4 rows x 4 columns) directional DBS lead in the VL thalamus. A within-subject design was used to compare fMRI responses for (1) directional stimulation consisting of monopolar stimulation in four radial directions around the DBS lead, and (2) orientation-selective stimulation where an electric field dipole was rotated 0°-360° around a quadrangle of electrodes. Functional responses were quantified in the premotor, primary motor, and somatosensory cortices. High frequency electrical stimulation through leads implanted in the VL thalamus induced directional tuning in cortical response patterns to varying degrees depending on DBS lead position. Orientation-selective stimulation showed maximal functional response when the electric field was oriented approximately parallel to the DBS lead, which is consistent with known axonal orientations of the cortico-thalamocortical pathway. These results demonstrate that directional and orientation-selective stimulation paradigms in the VL thalamus can tune network-level modulation patterns in the sensorimotor cortex, which may have translational utility in improving functional outcomes of DBS therapy.

Clinical deep brain stimulation strategies for orientation-selective pathway activation.

OBJECTIVE: This study investigated stimulation strategies to increase the selectivity of activating axonal pathways within the brain based on their orientations relative to clinical deep brain stimulation (DBS) lead implants. APPROACH: Previous work has shown how varying electrode shape and controlling the primary electric field direction through preclinical electrode arrays can produce orientation-selective axonal stimulation. Here, we significantly extend those results using computational models to evaluate the degree to which clinical DBS leads can direct stimulus-induced electric fields and generate orientation-selective activation of fiber pathways in the brain. Orientation-selective pulse paradigms were evaluated in conceptual models and in patient-specific models of subthalamic nucleus (STN)-DBS for treating Parkinson's disease. MAIN RESULTS: Single-contact monopolar or two-contact bipolar stimulation through clinical DBS leads with cylindrical electrodes primarily activated axons orientated parallel to the lead. Conversely, multi-contact monopolar stimulation with a cathode-leading pulse waveform selectively activated axons perpendicular to the DBS lead. Clinical DBS leads with segmented rows of electrodes and a single current source provided additional angular resolution for activating axons oriented 0°, ±22.5°, ±45°, ±67.5°, or 90° relative to the lead shaft. Employing multiple independent current sources to deliver unequal amounts of current through these leads further increased the angular resolution of activation relative to the lead shaft. The patient-specific models indicated that multi-contact cathode configurations, which are rarely used in clinical practice, could increase activation of the hyperdirect pathway collaterals projecting into STN (a putative therapeutic target), while minimizing direct activation of the corticospinal tract of internal capsule, which can elicit sensorimotor side-effects when stimulated. SIGNIFICANCE: When combined with patient-specific tissue anisotropy and patient-specific anatomical morphologies of neural pathways responsible for therapy and side effects, orientation-selective DBS approaches show potential to significantly improve clinical outcomes of DBS therapy for a range of existing and investigational clinical indications.

A model of motor and sensory axon activation in the median nerve using surface electrical stimulation.

Surface electrical stimulation has the potential to be a powerful and non-invasive treatment for a variety of medical conditions but currently it is difficult to obtain consistent evoked responses. A viable clinical system must be able to adapt to variations in individuals to produce repeatable results. To more fully study the effect of these variations without performing exhaustive testing on human subjects, a system of computer models was created to predict motor and sensory axon activation in the median nerve due to surface electrical stimulation at the elbow. An anatomically-based finite element model of the arm was built to accurately predict voltages resulting from surface electrical stimulation. In addition, two axon models were developed based on previously published models to incorporate physiological differences between sensory and motor axons. This resulted in axon models that could reproduce experimental results for conduction velocity, strength-duration curves and activation threshold. Differences in experimentally obtained action potential shape between the motor and sensory axons were reflected in the models. The models predicted a lower threshold for sensory axons than motor axons of the same diameter, allowing a range of sensory axons to be activated before any motor axons. This system of models will be a useful tool for development of surface electrical stimulation as a method to target specific neural functions.

Natural Sensations Evoked in Distal Extremities Using Surface Electrical Stimulation.

BACKGROUND: Electrical stimulation is increasingly relevant in a variety of medical treatments. In this study, surface electrical stimulation was evaluated as a method to non-invasively target a neural function, specifically natural sensation in the distal limbs. METHOD: Electrodes were placed over the median and ulnar nerves at the elbow and the common peroneal and lateral sural cutaneous nerves at the knee. Strength-duration curves for sensation were compared between nerves. The location, modality, and intensity of each sensation were also analyzed. In an effort to evoke natural sensations, several patterned waveforms were evaluated. RESULTS: Distal sensation was obtained in all but one of the 48 nerves tested in able-bodied subjects and in the two nerves from subjects with an amputation. Increasing the pulse amplitude of the stimulus caused an increase in the area and magnitude of the sensation in a majority of subjects. A low frequency waveform evoked a tapping or tapping-like sensation in 29 out of the 31 able-bodied subjects and a sensation that could be considered natural in two subjects with an amputation. This waveform performed better than other patterned waveforms that had proven effective during implanted extra-neural stimulation. CONCLUSION: Surface electrical stimulation has the potential to be a powerful, non-invasive tool for activation of the nervous system. These results suggest that a tapping sensation in the distal extremity can be evoked in most able-bodied individuals and that targeting the nerve trunk from the surface is a valid method to evoke sensation in the phantom limb of individuals with an amputation for short term applications.

Tuning Neuromodulation Effects by Orientation Selective Deep Brain Stimulation in the Rat Medial Frontal Cortex.

Previous studies that focused on treating major depressive disorder with conventional deep brain stimulation (DBS) paradigms produced inconsistent results. In this proof-of-concept preclinical study in rats (n = 8), we used novel paradigms of orientation selective DBS for stimulating the complex circuitry crossing the infralimbic cortex, an area considered analogous to human subgenual cingulate cortex. Using functional MRI at 9.4 T, we monitored whole brain responses to varying the electrical field orientation of DBS within the infralimbic cortex. Substantial alterations of functional MRI responses in the amygdala, a major node connected to the infralimbic cortex implicated in the pathophysiology of depression, were observed. As expected, the activation cluster near the electrode was insensitive to the changes of the stimulation orientation. Hence, our findings substantiate the ability of orientation selective stimulation (OSS) to recruit neuronal pathways of distinct orientations relative to the position of the electrode, even in complex circuits such as those involved in major depressive disorder. We conclude that OSS is a promising approach for stimulating brain areas that inherently require individualisation of the treatment approach.

Orientation selective deep brain stimulation.

OBJECTIVE: Target selectivity of deep brain stimulation (DBS) therapy is critical, as the precise locus and pattern of the stimulation dictates the degree to which desired treatment responses are achieved and adverse side effects are avoided. There is a clear clinical need to improve DBS technology beyond currently available stimulation steering and shaping approaches. We introduce orientation selective neural stimulation as a concept to increase the specificity of target selection in DBS. APPROACH: This concept, which involves orienting the electric field along an axonal pathway, was tested in the corpus callosum of the rat brain by freely controlling the direction of the electric field on a plane using a three-electrode bundle, and monitoring the response of the neurons using functional magnetic resonance imaging (fMRI). Computational models were developed to further analyze axonal excitability for varied electric field orientation. MAIN RESULTS: Our results demonstrated that the strongest fMRI response was observed when the electric field was oriented parallel to the axons, while almost no response was detected with the perpendicular orientation of the electric field relative to the primary fiber tract. These results were confirmed by computational models of the experimental paradigm quantifying the activation of radially distributed axons while varying the primary direction of the electric field. SIGNIFICANCE: The described strategies identify a new course for selective neuromodulation paradigms in DBS based on axonal fiber orientation.

Surface electrical stimulation to evoke referred sensation.

Surface electrical stimulation (SES) is being investigated as a noninvasive method to evoke natural sensations distal to electrode location. This may improve treatment for phantom limb pain as well as provide an alternative method to deliver sensory feedback. The median and/or ulnar nerves of 35 subjects were stimulated at the elbow using surface electrodes. Strength-duration curves of hand sensation were found for each subject. All subjects experienced sensation in their hand, which was mostly described as a paresthesia-like sensation. The rheobase and chronaxie values were found to be lower for the median nerve than the ulnar nerve, with no significant difference between sexes. Repeated sessions with the same subject resulted in sufficient variability to suggest that recalculating the strength-duration curve for each electrode placement is necessary. Most of the recruitment curves in this study were generated with 28 to 36 data points. To quickly reproduce these curves with limited increase in error, we recommend 10 data points. Future studies will focus on obtaining different sensations using SES with the strength-duration curve defining the threshold of the effective parameter space.