The cortical representation of the sensory environment is continuously modified by experience. Changes in spatial (receptive field) and temporal response properties of cortical neurons underlie many forms of natural learning. The scale and direction of these changes appear to be determined by specific features of the behavioral tasks that evoke cortical plasticity. The neural mechanisms responsible for this differential plasticity remain unclear partly because important sensory and cognitive parameters differ among these tasks. In this report, we demonstrate that differential sensory experience directs differential plasticity using a single paradigm that eliminates the task-specific variables that have confounded direct comparison of previous studies. Electrical activation of the basal forebrain (BF) was used to gate cortical plasticity mechanisms. The auditory stimulus paired with BF stimulation was systematically varied to determine how several basic features of the sensory input direct plasticity in primary auditory cortex (A1) of adult rats. The distributed cortical response was reconstructed from a dense sampling of A1 neurons after 4 wk of BF-sound pairing. We have previously used this method to show that when a tone is paired with BF activation, the region of the cortical map responding to that tone frequency is specifically expanded. In this report, we demonstrate that receptive-field size is determined by features of the stimulus paired with BF activation. Specifically, receptive fields were narrowed or broadened as a systematic function of both carrier-frequency variability and the temporal modulation rate of paired acoustic stimuli. For example, the mean bandwidth of A1 neurons was increased (+60%) after pairing BF stimulation with a rapid train of tones and decreased (-25%) after pairing unmodulated tones of different frequencies. These effects are consistent with previous reports of receptive-field plasticity evoked by natural learning. The maximum cortical following rate and minimum response latency were also modified as a function of stimulus modulation rate and carrier-frequency variability. The cortical response to a rapid train of tones was nearly doubled if BF stimulation was paired with rapid trains of random carrier frequency, while no following rate plasticity was observed if a single carrier frequency was used. Finally, we observed significant increases in response strength and total area of functionally defined A1 following BF activation paired with certain classes of stimuli and not others. These results indicate that the degree and direction of cortical plasticity of temporal and receptive-field selectivity are specified by the structure and schedule of inputs that co-occur with basal forebrain activation and suggest that the rules of cortical plasticity do not operate on each elemental stimulus feature independently of others.

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Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.

ObjectiveSensory dysfunction is a common consequence of many forms of neurological injury, including stroke and nerve damage. Rehabilitative paradigms that incorporate sensory retraining can provide modest benefits, but the majority of patients are left with lasting sensory loss. We have developed a novel strategy that uses closed‐loop vagus nerve stimulation (VNS) paired with tactile rehabilitation to enhance synaptic plasticity and facilitate recovery of sensory function.MethodsA clinical case report provides initial evidence that a similar implementation of closed‐loop VNS paired with a tactile rehabilitation regimen could improve recovery of somatosensory function. Here, we sought to build on these promising initial clinical data and rigorously evaluate the ability of VNS paired with tactile rehabilitation to improve recovery in an animal model of chronic sensory loss. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection (https://osf.io/xsnj5/).ResultsVNS paired with tactile rehabilitation resulted in a significant and nearly complete recovery of mechanosensory withdrawal thresholds. Equivalent tactile rehabilitation without VNS failed to improve sensory function. This VNS‐dependent restoration of sensory thresholds was maintained for several months after the cessation of stimulation, illustrating long‐term benefits. Moreover, VNS paired with tactile rehabilitation resulted in significant generalized improvements in other measures of sensorimotor forepaw function.InterpretationGiven the safety and tolerability of VNS therapy, these findings suggest that incorporating VNS paired with sensory retraining into rehabilitative regimens may represent a fundamentally new method to increase recovery of sensory function after neurological injury. ANN NEUROL 2020;87:194–205