Robert L. Rennaker

Knockdown of the Dyslexia-Associated Gene Kiaa0319 Impairs Temporal Responses to Speech Stimuli in Rat Primary Auditory Cortex

One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319. It is not known whether reduced expression of KIAA0319 can degrade the brains ability to process phonemes. In the current study, we used RNA interference (RNAi) to reduce expression of Kiaa0319 (the rat homolog of the human gene KIAA0319) and evaluate the effect in a rat model of phoneme discrimination. Speech discrimination thresholds in normal rats are nearly identical to human thresholds. We recorded multiunit neural responses to isolated speech sounds in primary auditory cortex (A1) of rats that received in utero RNAi of Kiaa0319. Reduced expression of Kiaa0319 increased the trial-by-trial variability of speech responses and reduced the neural discrimination ability of speech sounds. Intracellular recordings from affected neurons revealed that reduced expression of Kiaa0319 increased neural excitability and input resistance. These results provide the first evidence that decreased expression of the dyslexia-associated gene Kiaa0319 can alter cortical responses and impair phoneme processing in auditory cortex.

Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex.

Although sensory and motor systems support different functions, both systems exhibit experience-dependent cortical plasticity under similar conditions. If mechanisms regulating cortical plasticity are common to sensory and motor cortices, then methods generating plasticity in sensory cortex should be effective in motor cortex. Repeatedly pairing a tone with a brief period of vagus nerve stimulation (VNS) increases the proportion of primary auditory cortex responding to the paired tone (Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake J, Sudanagunta SP, Borland MS, Kilgard MP. 2011. Reversing pathological neural activity using targeted plasticity. Nature. 470:101-104). In this study, we predicted that repeatedly pairing VNS with a specific movement would result in an increased representation of that movement in primary motor cortex. To test this hypothesis, we paired VNS with movements of the distal or proximal forelimb in 2 groups of rats. After 5 days of VNS movement pairing, intracranial microstimulation was used to quantify the organization of primary motor cortex. Larger cortical areas were associated with movements paired with VNS. Rats receiving identical motor training without VNS pairing did not exhibit motor cortex map plasticity. These results suggest that pairing VNS with specific events may act as a general method for increasing cortical representations of those events. VNS movement pairing could provide a new approach for treating disorders associated with abnormal movement representations.

Thiol-ene/acrylate substrates for softening intracortical electrodes

Neural interfaces have traditionally been fabricated on rigid and planar substrates, including silicon and engineering thermoplastics. However, the neural tissue with which these devices interact is both 3D and highly compliant. The mechanical mismatch at the biotic-abiotic interface is expected to contribute to the tissue response that limits chronic signal recording and stimulation. In this work, novel ternary thiol-ene/acrylate polymer networks are used to create softening substrates for neural recording electrodes. Thermomechanical properties of the substrates are studied through differential scanning calorimetry and dynamic mechanical analysis both before and after exposure physiological conditions. This substrate system softens from more than 1 GPa to 18 MPa on exposure to physiological conditions: reaching body temperature and taking up less than 3% fluid. The impedance of 177 µm(2) gold electrodes electroplated with platinum black fabricated on these substrates is measured to be 206 kΩ at 1 kHz. Specifically, intracortical electrodes are fabricated, implanted, and used to record driven neural activity. This work describes the first substrate system that can use the full capabilities of photolithography, respond to physiological conditions by softening markedly after insertion, and record driven neural activity for 4 weeks.

Targeting Plasticity with Vagus Nerve Stimulation to Treat Neurological Disease

Pathological neural activity in a variety of neurological disorders could be treated by directing plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal function. Brief bursts of acetylcholine and norepinephrine can enhance the neural plasticity associated with coincident events. Vagus nerve stimulation (VNS) represents a safe and effective means to trigger the release of these neuromodulators with a high degree of temporal control. VNS-event pairing can generate highly specific and long-lasting plasticity in sensory and motor cortex. Based on the capacity to drive specific changes in neural circuitry, VNS paired with experience has been successful in effectively ameliorating animal models of chronic tinnitus, stroke, and posttraumatic stress disorder. Targeted plasticity therapy utilizing VNS is currently being translated to humans to treat chronic tinnitus and improve motor recovery after stroke. This chapter will discuss the current progress of VNS paired with experience to drive specific plasticity to treat these neurological disorders and will evaluate additional future applications of targeted plasticity therapy.

Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke

Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement. We have recently developed a novel method that uses vagus nerve stimulation (VNS) paired with forelimb movements to drive specific, long-lasting map plasticity in rat primary motor cortex. Here we report that VNS paired with rehabilitative training can enhance recovery of forelimb force generation following infarction of primary motor cortex in rats. Quantitative measures of forelimb function returned to pre-lesion levels when VNS was delivered during rehab training. Intensive rehab training without VNS failed to restore function back to pre-lesion levels. Animals that received VNS during rehab improved twice as much as rats that received the same rehabilitation without VNS. VNS delivered during physical rehabilitation represents a novel method that may provide long-lasting benefits towards stroke recovery.

Vagus Nerve Stimulation Delivered During Motor Rehabilitation Improves Recovery in a Rat Model of Stroke

Neural plasticity is widely believed to support functional recovery following brain damage. Vagus nerve stimulation paired with different forelimb movements causes long-lasting map plasticity in rat primary motor cortex that is specific to the paired movement. We tested the hypothesis that repeatedly pairing vagus nerve stimulation with upper forelimb movements would improve recovery of motor function in a rat model of stroke. Rats were separated into 3 groups: vagus nerve stimulation during rehabilitation (rehab), vagus nerve stimulation after rehab, and rehab alone. Animals underwent 4 training stages: shaping (motor skill learning), prelesion training, postlesion training, and therapeutic training. Rats were given a unilateral ischemic lesion within motor cortex and implanted with a left vagus nerve cuff. Animals were allowed 1 week of recovery before postlesion baseline training. During the therapeutic training stage, rats received vagus nerve stimulation paired with each successful trial. All 17 trained rats demonstrated significant contralateral forelimb impairment when performing a bradykinesia assessment task. Forelimb function was recovered completely to prelesion levels when vagus nerve stimulation was delivered during rehab training. Alternatively, intensive rehab training alone (without stimulation) failed to restore function to prelesion levels. Delivering the same amount of stimulation after rehab training did not yield improvements compared with rehab alone. These results demonstrate that vagus nerve stimulation repeatedly paired with successful forelimb movements can improve recovery after motor cortex ischemia and may be a viable option for stroke rehabilitation.

Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke

Background and Purpose— Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke. Methods— Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl–Meyer Assessment-Upper Extremity). Results— Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl–Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, −0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl–Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6). Conclusions— This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01669161.

Vagus Nerve Stimulation During Rehabilitative Training Improves Functional Recovery After Intracerebral Hemorrhage

Background and Purpose— Vagus nerve stimulation (VNS) delivered during rehabilitative training enhances neuroplasticity and improves recovery in models of cortical ischemic stroke. However, VNS therapy has not been applied in a model of subcortical intracerebral hemorrhage (ICH). We hypothesized that VNS paired with rehabilitative training after ICH would enhance recovery of forelimb motor function beyond rehabilitative training alone. Methods— Rats were trained to perform an automated, quantitative measure of forelimb function. Once proficient, rats received an intrastriatal injection of bacterial collagenase to induce ICH. Rats then underwent VNS paired with rehabilitative training (VNS+Rehab; n=14) or rehabilitative training without VNS (Rehab; n=12). Rehabilitative training began ≥9 days after ICH and continued for 6 weeks. Results— VNS paired with rehabilitative training significantly improved recovery of forelimb function when compared with rehabilitative training without VNS. The VNS+Rehab group displayed a 77% recovery of function, whereas the Rehab group only exhibited 29% recovery. Recovery was sustained after cessation of stimulation. Both groups performed similar amounts of trials during rehabilitative, and lesion size was not different between groups. Conclusions— VNS paired with rehabilitative training confers significantly improved forelimb recovery after ICH compared to rehabilitative training without VNS.

Smart Polymers for Neural Interfaces

Thermomechanical properties of smart polymers can be specifically tuned to address critical problems in neural interfaces. A compilation of materials and approaches is presented from each of three often overlapping research communities: shape memory polymers, hydrogels, and neural interfaces. The path toward chronically implantable devices for neural recording and stimulation relies on careful control of mechanical, chemical, electronic and geometric properties of next generation devices. These phenomena are described and put into a context of modulus changing materials, as opposed to the current focus on shape changing materials, as a paradigm that may lead to new discoveries addressing unmet clinical needs.

The isometric pull task: A novel automated method for quantifying forelimb force generation in rats

Reach-to-grasp tasks are commonly used to assess forelimb function in rodent models. While these tasks have been useful for investigating several facets of forelimb function, they are typically labor-intensive and do not directly quantify physiological parameters. Here we describe the isometric pull task, a novel method to measure forelimb strength and function in rats. Animals were trained to reach outside the cage, grasp a handle attached to a stationary force transducer, and pull with a predetermined amount of force to receive a food reward. This task provides quantitative data on operant forelimb force generation. Multiple parameters can be measured with a high degree of accuracy, including force, success rate, pull attempts, and latency to maximal force. The task is fully automated, allowing a single experimenter to test multiple animals simultaneously with usually more than 300 trials per day, providing more statistical power than most other forelimb motor tasks. We demonstrate that an ischemic lesion in primary motor cortex yields robust deficits in all forelimb function parameters measured with this method. The isometric pull task is a significant advance in operant conditioning systems designed to automate the measurement of multiple facets of forelimb function and assess deficits in rodent models of brain damage and motor dysfunction.