Daniel W. Moran

BACKGROUND: Loss of hand control is a major source of poststroke disability, particularly when infarcts involve subcortical white matter. Yet, most preclinical models target the cortex and infer recovery from task performance without quantifying whether improvements reflect restoration or adaptation. To address this, we developed a novel nonhuman primate model of focal internal capsule infarct. This study is exploratory and hypothesis-testing, including prespecified hypotheses regarding motor impairment and adaptation. METHODS: Three adult male rhesus macaques ( Macaca mulatta , 5–10 years) received stereotactically guided ET-1 (endothelin-1) injections (0.5 µg/µL; 9–10 µL total) into the left posterior limb of the internal capsule in a within-subject pre-infarct versus post-infarct design. Infarcts were characterized by magnetic resonance imaging and postmortem histology. Motor function was tested with a center-out joystick task and a Klüver board task using standard behavioral metrics; hand posture was additionally scored by blinded raters to quantify adaptation. Pre-infarct versus post-infarct comparisons used generalized linear mixed models with per-session random effects; adaptation covariates were evaluated using likelihood-ratio tests. RESULTS: Magnetic resonance imaging and histology confirmed focal infarcts centered on the posterior limb of the internal capsule, with variable volumes. All animals significantly reduced contralesional hand use post-infarct (Fisher exact test; all P P P =0.0015). Pooled generalized linear mixed models showed significant post-infarct increases in retrieval time (estimate=0.73 s; P P P <0.0001). CONCLUSIONS: This model recapitulates key features of human subcortical stroke, including persistent distal motor deficits, shifts in hand preference, systematic motor adaptation, and interindividual variability, establishing a translationally oriented platform for studying stroke mechanisms and evaluating recovery-promoting interventions.

Loss of distal hand and finger control is among the most disabling consequences of stroke. Functional outcomes are typically worse when infarcts involve subcortical white matter tracts, particularly the internal capsule, yet most preclinical stroke models target cortical regions. To address this gap, we developed a non-human primate model of internal capsule infarct using stereotactically guided endothelin-1 injections to disrupt descending fibers from the primary motor cortex hand area. Serial structural and diffusion MRI, along with histology, confirmed subcortical infarcts centered on the targeted white matter region with no apparent cortical involvement. Motor function was assessed pre- and post-infarct using a joystick-based center-out task (proximal forelimb control) and a Klüver board task (distal forelimb control). Animals exhibited variable impairments in proximal function and consistent post-infarct deficits in distal function, including reduced contralesional hand use, longer retrieval time, and increased in-well digit flexions. One animal showed mild post-infarct impairment and the smallest lesion, highlighting that this model reflects inter-individual differences in infarct size and functional outcome as seen in human subcortical stroke. In contrast, the other two animals developed a compensatory wrist-extended posture on the Klüver board task by 4 weeks post-infarct, which stabilized the hand and enabled improved digit flexion. Incorporating this behavioral adaptation into statistical models improved prediction of motor performance. The observed adaptation may have drawn on spared corticospinal output pathways, allowing animals to re-engage pre-existing motor routines to perform the retrieval. While future studies may benefit from ethologically relevant tasks to further elucidate such adaptations, findings from this study recapitulate key features of human subcortical stroke, including persistent distal motor deficits and emergence of adaptive motor strategies. By combining precise lesioning, longitudinal imaging, and detailed behavioral analysis, this model provides a translationally oriented platform for studying white matter stroke mechanisms and evaluating interventions that promote functional recovery.

Motor action after auditory stimulus elicits high gamma responses in sensory-motor and auditory cortex, respectively. We show that high gamma coherence reliably and greatly increased during motor response, but not after auditory stimulus. Underlying high gamma power could not explain high gamma coherence. Our results indicate that high gamma coherence is a physiologically distinct sensory-motor phenomenon that may serve as an indicator of increased synaptic communication on short timescales (∼1 s).

Objective. Peripheral nerve interfaces seek to restore nervous system function through electrical stimulation of peripheral nerves. In clinical use, these devices should function reliably for years or decades. In this study, we assessed evoked sensations from multi-channel cuff electrode stimulation in macaque monkeys up to 711 d post-implantation. Approach. Three trained macaque monkeys received multi-channel cuff electrode implants at the median or ulnar nerves in the upper arm. Electrical stimuli from the cuff interfaces evoked sensations, which we measured via standard psychophysical tasks. We adjusted pulse amplitude or pulse width for each block with various electrode channel configurations to examine the effects of stimulus parameterization on sensation. We measured detection thresholds and just-noticeable differences (JNDs) at irregular, near-daily intervals for several months using Bayesian inferencing from trial data. We examined data trends using classical models such as Weber’s Law and the strength-duration relationship using linear regression. Main results. Detection thresholds were similar between blocks with pulse width modulation and blocks with pulse amplitude modulation when represented as charge per pulse, the product of the amplitude and the pulse width. Conversely, Weber fractions—calculated as the slope of the regression between JND charge values and reference stimulus charge—were significantly different between pulse width and pulse amplitude modulation blocks for the discrimination task. Significance. Weber fractions were lower in blocks with amplitude modulation than in blocks with pulse width modulation, suggesting that pulse amplitude modulation allows finer resolution of sensory encoding above threshold. Consequently, amplitude modulation may enable a greater dynamic range for sensory perception with neuroprosthetic devices.

High-frequency alternating current (HFAC) can yield a rapid-acting and reversible nerve conduction block. The present study aimed to demonstrate the successful implementation of HFAC block delivery via regenerative macro-sieve electrodes (MSEs). Dual-electrode assemblies in two configurations [dual macro-sieve electrode-1 (DMSE-I), DMSE-II] were fabricated from pairs of MSEs and implanted in the transected and subsequently repaired sciatic nerves of two male Lewis rats. After four months of postoperative nerve regeneration through the MSEs' transit zones, the efficacy of acute HFAC block was tested for both configurations. Frequencies ranging from 10 kHz to 42 kHz, and stimulus amplitudes with peak-to-peak voltages ranging from 2 V to 20 V were tested. Evoked muscle force measurement was used to quantify the nerve conduction block. HFAC stimulation delivered via DMSE assemblies obtained a complete block at frequencies of 14 to 26 kHz and stimulus amplitudes of 12 to 20 V p-p. The threshold voltage for the complete block showed an approximately linear dependence on frequency. The threshold voltage for the partial conduction block was also approximately linear. For those frequencies that displayed both partial and complete block, the partial block thresholds were consistently lower. This study provides a proof of concept that regenerative MSEs can achieve complete and reversible conduction block via HFAC stimulation of regenerated nerve tissue. A chronically interfaced DMSE assembly may thereby facilitate the inactivation of targeted nerves in cases wherein pathologic neuronal hyperactivity is involved.

Objective . Successful use of a prosthetic limb by an amputee is facilitated by haptic feedback—both a sense of touch and proprioception. Stimulating afferent fibers within peripheral nerves has been shown to provide somatosensation enabling amputees to modulate the control of prosthetic limbs. Peripheral nerve interfaces (PNIs) have also been used to decode patients’ motor intentions. It seems ideal to use PNIs to record efferent fibers for motor control while stimulating afferent fibers to create concurrent sensory feedback. However, while many PNIs claim to be bi-directional, few can both stimulate and record at the same time due to stimulation artifacts which are orders of magnitude larger than the recorded motor signals. This study uses computational modelling to compare the stimulation artifact at threshold levels of stimulation for thin-film transverse intrafascicular multichannel electrodes (tfTIMEs) with micro-channel sieve electrodes . Approach . Finite element models of micro-channel sieves and tfTIMESs were used to solve for electric fields generated during peripheral nerve stimulation. Electrophysiological responses were simulated using axon models. Stimulation artifacts were calculated for stimuli eliciting axonal action potentials. Simulations were carried out for multiple micro-channel geometries and electrode configurations. Main results . Stimulation artifacts generated for threshold stimulation currents are lower for micro-channel devices compared to tfTIMEs. Consequently, stimulus artifacts at threshold currents were substantially higher for the tfTIME. Micro-channel width has a moderate impact on recruitment thresholds and stimulus artifacts. Using the micro-channel sieve in bipolar and tripolar stimulation configurations greatly decreases stimulation artifacts particularly for optimized contact placements (CPs). Electroneurogram (ENG) signals from the companion paper were incorporated showing a great improvement in signal-to-artifact ratio for the micro-channel electrode compared to tfTIMEs. Significance . Stimulating regenerated nerve tissue using micro-channel sieve electrodes can decrease stimulation artifacts and elicit neuronal responses at low stimulation amplitudes. Further analysis provides clues to optimal implementations of micro-channel devices. Finally, stimulation artifacts for simulated tfTIME devices were 2–3 orders of magnitude larger than ENG levels. In contrast, for some micro-channel configurations stimulation artifacts were 3–4 orders of magnitude smaller than ENG levels.

Objective . Advancement in prosthetic limb technology requires corresponding improvements in the capability of the amputee to naturally control the device via original motor pathways while simultaneously receiving haptic feedback via sensory pathways. Recording efferent axonal activity using a peripheral neural interface (PNI) allows a good tradeoff between invasiveness and selectivity while possibly preserving the phenomenology of controlling the original limb. One such PNI, the thin-film transverse intrafascicular multichannel electrode (tfTIME), has been shown to be successful in controlling powered prosthetics. However, the tfTIME is highly susceptible to stimulation artifact; thus, using such a PNI to both record efferent motor signals while concurrently stimulating afferent sensory axons in the same nerve is problematic. The micro-channel sieve electrode could also provide a stable, selective, neural interface with larger signal-to-noise levels that are less susceptible to concurrent stimulation artifact or other external noise effects. Approach . This study uses a computational model to compare recording levels of simulated ENGs across neural drive levels as well as basic control signals derived from the ENGs in both tfTIME and micro-channel sieve PNIs. A motor neuron pool model generated axon firing rates at a given neural drive. The time course of the corresponding extracellular currents of the myelinated motor axons were determined using core conductor axon models. Finite element models determined the contribution of the extracellular current from nodes of Ranvier on potentials recorded using each interface. Contributions from each node were combined to create the final ENG. Main results . ENGs recorded using the micro-channel sieves were shown to have much higher amplitudes compared to ENGs recorded using the tfTIMEs. Signal amplitudes also varied less as a function of axonal placement and spike timing, resulting in more consistent signals with amplitudes determined predominantly by neural drive. Significance . Simulation results suggest that the micro-channel sieve provides higher quality control signals over tfTIME PNIs in decoding ENGs. Coupling these results with concurrent stimulation results of the companion paper (Part B: stimulation) suggests that the micro-channel sieve is an optimal bidirectional PNI.