James Robert McIntosh

Target engagement determines therapeutic efficacy. In spinal cord stimulation (SCS), efficacy depends on the attributes of the electrodes used to deliver stimulation, particularly their position, interelectrode distance, size, and current orientation. We tested the effects of these electrode parameters using cervical stimulation to elicit forelimb muscle responses in the rat. We implanted devices over the C6 dorsal root entry zone (DREZ) in eight rats and measured responses in six forelimb muscles. We used custom designed electrode arrays to systematically vary position, distance, and size with linear arrays, and current orientation with circular arrays. Stimulation consisted of biphasic and pseudomonophasic pulse shapes with bipolar or distant return, and a high-definition montage with four returns surrounding a central contact to increase local current density. Efficacy was calculated from the motor thresholds of recruitment curves, and parameters were compared using linear mixed models. For position, stimulation over the DREZ was most effective, reducing thresholds by 25.9% ( p = 0.0002) relative to the midline; efficacy decreased as the electrode was positioned medial or lateral to the DREZ. For distance, placing the electrodes farther apart significantly improved efficacy ( p = 0.0022). For size, large electrodes increased SCS efficacy, reducing thresholds by 21.5% ( p = 0.0026) relative to small electrodes. After accounting for position and distance, current orientation did not affect SCS efficacy. Lastly, the high-definition montage decreased efficacy, increasing thresholds by 16.7% ( p = 0.003) relative to monopolar stimulation with a distant return. In conclusion, electrode position, distance, and size had the greatest effect on SCS efficacy, with the optimal parameters combining large electrodes at the DREZ position with a distant return. These results have the potential to lower the current needed to engage cervical spinal circuitry and to inform the design of SCS systems to improve dexterity in people with neurological injury or disease.

Precise movement requires integrating descending motor control with sensory feedback. Sensory networks interact strongly with descending motor circuits within the spinal cord. We targeted this interaction by pairing stimulation of the motor cortex with coordinated stimulation of the cervical spinal cord. We used separate non-invasive and epidural experiments to test the hypothesis that the strongest muscle response would occur when paired brain and spinal cord stimuli simultaneously converge within the spinal cord. For non-invasive experiments, we measured arm and hand muscle motor evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS) and transcutaneous spinal cord stimulation (TSCS) in 16 individuals with chronic spinal cord injury (SCI) and 15 uninjured individuals. We compared this noninvasive approach to intraoperative paired stimulation experiments using dorsal epidural electrodes in 38 individuals undergoing surgery for cervical myelopathy. We observed augmented muscle responses to suprathreshold TMS when subthreshold TSCS stimuli were timed to converge synchronously in the spinal cord. At convergent timing, target muscle MEPs increased by 11.0% overall (13.3% in people with SCI, 6.2% in uninjured individuals) compared to non-convergent time intervals. Facilitation correlated with TSCS intensity, with intensity close to movement threshold being most effective. Facilitation did not correlate with SCI level or severity, indicating spared circuits were sufficient for this effect. Noninvasive pairing produced less facilitation compared to intraoperative (epidural) pairing. Thus, sensorimotor interactions in the cervical spinal spinal cord can be targeted with paired stimulation in health and after SCI. Highlights Electrical stimulation of spinal sensory circuits can augment cortical motor evoked potentials, but only when they are timed to arrive synchronously in the spinal cord. Facilitation was at least as large in people with spinal cord injury compared with uninjured controls, suggesting that the necessary circuits for this facilitation were spared by injury. The magnitude of facilitation with noninvasive facilitation was smaller than the facilitation effect observed with epidural stimulation during elective spinal surgery, but they both rely on precisely timed interactions. Facilitation of hand and arm muscle responses correlated with the transcutaneous spinal stimulation intensity, suggesting that the magnitude of the pairing effect can be improved. Pairing was effective both in uninjured participants and those with SCI, independently of injury level, severity, or chronicity.

Neural implantable devices serve as electronic interfaces facilitating communication between the body and external electronic systems. These bioelectronic systems ideally possess stable electrical conductivity, flexibility, and stretchability to accommodate dynamic movements within the body. However, achieving both high electrical conductivity and mechanical compatibility remains a challenge. Effective electrical conductors tend to be rigid and stiff, leading to a substantial mechanical mismatch with bodily tissues. On the other hand, highly stretchable polymers, while mechanically compatible, often suffer from limited compatibility with lithography techniques and reduced electrical stability. Therefore, there exists a pressing need to develop electromechanically stable neural interfaces that enable precise communication with biological tissues. In this study, a polymer that is softening, flexible, conformal, and compatible with lithography to microfabricate perforated thin‐film architectures is utilized. These architectures offer stretchability and improved mechanical compatibility. Three distinct geometries are evaluated both mechanically and electrically under in vitro conditions that simulate physiological environments. Notably, the Peano structure demonstrates minimal changes in resistance, varying less than 1.5× even when subjected to ≈150% strain. Furthermore, devices exhibit a maximum mechanical elongation before fracture, reaching 220%. Finally, the application of multi‐electrode spinal cord leads employing titanium nitride for neural stimulation in rat models is demonstrated.

Volitional movement requires descending input from the 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 posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation 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 was stimulated with epidural electrodes, with muscle responses being 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, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. image Key points: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain‐ or spinal‐only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients (i.e., less than 50%). Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders.

Electrical stimulation of the brain and spinal cord can strengthen sensorimotor circuits and improve movement through associative plasticity. Current paired stimulation paradigms target the motor system alone or sensorimotor connections in cortex. We developed a paired stimulation approach in rats that targets sensory and motor connections in the cervical spinal cord. Since the circuits necessary for paired stimulation are conserved between species, we hypothesized that paired stimulation of motor cortex and posterior cervical spinal cord in humans would produce synergistic muscle responses but only when stimulation is properly timed. In 59 individuals undergoing clinically indicated cervical spine 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 over either the posterior or anterior spinal cord, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and posterior, but not anterior, spinal cord stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred when descending motor and spinal afferent stimuli were timed to converge in the cervical 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. Significance Statement Pairs of stimuli that alter nervous system function typically target the motor system alone or the sensorimotor convergence in cortex. In humans undergoing clinically indicated surgery we tested a paired brain and spinal cord stimulation paradigm that we developed in rats to target sensorimotor convergence in the cervical spinal cord. Arm and hand muscle responses to paired stimulation were six times larger than brain or spinal cord stimulation alone and more selective to the targeted muscles when applied to the posterior but not anterior spinal cord. The paired stimulation effect was independent of the degree of myelopathy, suggesting that it could be applied as therapy in people affected by spinal cord injury.

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.