Key points: Pairing motor cortex stimulation and spinal cord epidural stimulation produced large augmentation in motor cortex evoked potentials if they were timed to converge in the spinal cord. The modulation of cortical evoked potentials by spinal cord stimulation was largest when the spinal electrodes were placed over the dorsal root entry zone. Repeated pairing of motor cortex and spinal cord stimulation caused lasting increases in evoked potentials from both sites, but only if the time between the stimuli was optimal. Both immediate and lasting effects of paired stimulation are likely mediated by convergence of descending motor circuits and large diameter afferents onto common interneurons in the cervical spinal cord. Convergent activity in neural circuits can generate changes at their intersection. The rules of paired electrical stimulation are best understood for protocols that stimulate input circuits and their targets. We took a different approach by targeting the interaction of descending motor pathways and large diameter afferents in the spinal cord. We hypothesized that pairing stimulation of motor cortex and cervical spinal cord would strengthen motor responses through their convergence. We placed epidural electrodes over motor cortex and the dorsal cervical spinal cord in rats; motor evoked potentials (MEPs) were measured from biceps. MEPs evoked from motor cortex were robustly augmented with spinal epidural stimulation delivered at an intensity below the threshold for provoking an MEP. Augmentation was critically dependent on the timing and position of spinal stimulation. When the spinal stimulation was timed to coincide with the descending volley from motor cortex stimulation, MEPs were more than doubled. We then tested the effect of repeated pairing of motor cortex and spinal stimulation. Repetitive pairing caused strong augmentation of cortical MEPs and spinal excitability that lasted up to an hour after just 5 min of pairing. Additional physiology experiments support the hypothesis that paired stimulation is mediated by convergence of descending motor circuits and large diameter afferents in the spinal cord. The large effect size of this protocol and the conservation of the circuits being manipulated between rats and humans makes it worth pursuing for recovery of sensorimotor function after injury to the central nervous system.

Objective . We sought to develop a cervical spinal cord stimulator for the rat that is durable, stable, and does not perturb the underlying spinal cord. Approach . We created a softening spinal cord stimulation (SCS) array made from shape memory polymer (SMP)-based flexible electronics. We developed a new photolithographic process to pattern high surface area titanium nitride (TiN) electrodes onto gold (Au) interconnects. The thiol-ene acrylate polymers are stiff at room temperature and soften following implantation into the body. Durability was measured by the duration the devices produced effective stimulation and by accelerated aging in vitro . Stability was measured by the threshold to provoke an electromyogram (EMG) muscle response and by measuring impedance using electrochemical impedance spectroscopy (EIS). In addition, spinal cord modulation of motor cortex potentials was measured. The spinal column and implanted arrays were imaged with MRI ex vivo , and histology for astrogliosis and immune reaction was performed. Main results . For durability, the design of the arrays was modified over three generations to create an array that demonstrated activity up to 29 weeks. SCS arrays showed no significant degradation over a simulated 29 week period of accelerated aging. For stability, the threshold for provoking an EMG rose in the first few weeks and then remained stable out to 16 weeks; the impedance showed a similar rise early with stability thereafter. Spinal cord stimulation strongly enhanced motor cortex potentials throughout. Upon explantation, device performance returned to pre-implant levels, indicating that biotic rather than abiotic processes were the cause of changing metrics. MRI and histology showed that softening SCS produced less tissue deformation than Parylene-C arrays. There was no significant astrogliosis or immune reaction to either type of array. Significance . Softening SCS arrays meet the needs for research-grade devices in rats and could be developed into human devices in the future.

Autism spectrum disorder (ASD) is a heterogeneous category of developmental psychiatric disorders which is characterized by inadequate social interaction, less communication, and repetitive phenotype behavior. ASD is comorbid with various types of disorders. The reported prevalence is 1% in the United Kingdom, 1.5% in the United States, and ~0.2% in India at present. The natural anti-inflammatory agents on brain development are linked to interaction with many types of inflammatory pathways affected by genetic, epigenetic, and environmental variables. Inflammatory targeting pathways have already been linked to ASD. However, these routes are diluted, and new strategies are being developed in natural anti-inflammatory medicines to treat ASD. This review summarizes the numerous preclinical and clinical studies having potential protective effects and natural anti-inflammatory agents on the developing brain during pregnancy. Inflammation during pregnancy activates the maternal infection that likely leads to the development of neuropsychiatric disorders in the offspring. The inflammatory pathways have been an effective target for the subject of translational research studies on ASD.

Background: Iron oxide nanoparticles (IONPs) can attenuate oxidative stress in a neutral pH environment in vitro. In combination with an external electromagnetic field, they can also facilitate axon regeneration. The present study demonstrates the in vivo potential of IONPs to recover functional deficits in rats with complete spinal cord injury. Methods: The spinal cord was completely transected at the T11 vertebra in male albino Wistar rats. Iron oxide nanoparticle solution (25 µg/mL) embedded in 3% agarose gel was implanted at the site of transection, which was subsequently exposed to an electromagnetic field (50 Hz, 17.96 µT for two hours daily for five weeks). Results: Locomotor and sensorimotor assessment as well as histological analysis demonstrated significant functional recovery and a reduction in lesion volume in rats with IONP implantation and exposure to an electromagnetic field. No collagenous scar was observed and IONPs were localized intracellularly in the immediate vicinity of the lesion. Further, in vitro experiments to explore the cytotoxic effects of IONPs showed no effect on cell survival. However, a significant decrease in H₂O₂-mediated oxidative stress was evident in the medium containing IONPs, indicating their free radical scavenging properties. Conclusion: These novel findings indicate a therapeutic role for IONPs in spinal cord injury and other neurodegenerative disorders mediated by reactive oxygen species.

Associative plasticity occurs when two stimuli converge on a common neural target. Previous efforts to promote associative plasticity have targeted cortex, with variable and moderate effects. In addition, the targeted circuits are inferred, rather than tested directly. In contrast, we sought to target the strong convergence between motor and sensory systems in the spinal cord.We developed spinal cord associative plasticity, precisely timed pairing of motor cortex and dorsal spinal cord stimulations, to target this interaction. We tested the hypothesis that properly timed paired stimulation would strengthen the sensorimotor connections in the spinal cord and improve recovery after spinal cord injury. We tested physiological effects of paired stimulation, the pathways that mediate it, and its function in a preclinical trial.Subthreshold spinal cord stimulation strongly augmented motor cortex evoked muscle potentials at the time they were paired, but only when they arrived synchronously in the spinal cord. This paired stimulation effect depended on both cortical descending motor and spinal cord proprioceptive afferents; selective inactivation of either of these pathways fully abrogated the paired stimulation effect. Spinal cord associative plasticity, repetitive pairing of these pathways for 5 or 30 min in awake rats, increased spinal excitability for hours after pairing ended. To apply spinal cord associative plasticity as therapy, we optimized the parameters to promote strong and long-lasting effects. This effect was just as strong in rats with cervical spinal cord injury as in uninjured rats, demonstrating that spared connections after moderate spinal cord injury were sufficient to support plasticity. In a blinded trial, rats received a moderate C4 contusive spinal cord injury. Ten days after injury, they were randomized to 30 min of spinal cord associative plasticity each day for 10 days or sham stimulation. Rats with spinal cord associative plasticity had significantly improved function on the primary outcome measure, a test of dexterity during manipulation of food, at 50 days after spinal cord injury. In addition, rats with spinal cord associative plasticity had persistently stronger responses to cortical and spinal stimulation than sham stimulation rats, indicating a spinal locus of plasticity. After spinal cord associative plasticity, rats had near normalization of H-reflex modulation. The groups had no difference in the rat grimace scale, a measure of pain.We conclude that spinal cord associative plasticity strengthens sensorimotor connections within the spinal cord, resulting in partial recovery of reflex modulation and forelimb function after moderate spinal cord injury. Since both motor cortex and spinal cord stimulation are performed routinely in humans, this approach can be trialled in people with spinal cord injury or other disorders that damage sensorimotor connections and impair dexterity.