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Rehabilitation approaches for individuals with neurologic conditions have increasingly shifted toward promoting neuroplasticity for enhanced recovery and restoration of function. This review focuses on exercise strategies and non-invasive neuromodulation techniques that target neuroplasticity, including transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and peripheral nerve stimulation (PNS). We have chosen to focus on non-invasive neuromodulation techniques due to their greater potential for integration into routine clinical practice. We explore and discuss the application of these interventional strategies in four neurological conditions that are frequently encountered in rehabilitation settings: Parkinson's Disease (PD), Traumatic Brain Injury (TBI), stroke, and Spinal Cord Injury (SCI). Additionally, we discuss the potential benefits of combining non-invasive neuromodulation with rehabilitation, which has shown promise in accelerating recovery. Our review identifies studies that demonstrate enhanced recovery through combined exercise and non-invasive neuromodulation in the selected patient populations. We primarily focus on the motor aspects of rehabilitation, but also briefly address non-motor impacts of these conditions. Additionally, we identify the gaps in current literature and barriers to implementation of combined approaches into clinical practice. We highlight areas needing further research and suggest avenues for future investigation, aiming to enhance the personalization of the unique neuroplastic responses associated with each condition. This review serves as a resource for rehabilitation professionals and researchers seeking a comprehensive understanding of neuroplastic exercise interventions and noninvasive neuromodulation techniques tailored for specific diseases and diagnoses. [ABSTRACT FROM AUTHOR]

Vagus nerve stimulation (VNS) has been recognized as a useful neuromodulation tool to target the central nervous system by electrical stimulation of peripheral nerves. Activation of the nucleus of the solitary tract (NTS) in the brainstem by vagal afferent nerve fibers allows for modulation of various higher order brain regions, including limbic and cerebral cortex structures. Along with neurological and psychiatric indications, clinical and preclinical studies suggest that VNS can improve memory. While the underlying mechanisms to improve memory with VNS involve brain areas, such as the prefrontal cortex and processes including alertness and arousal, here we focus on VNS-induced memory improvements related to the hippocampus, the main area implicated in memory acquisition. In addition, we detail research demonstrating that a targeted approach to VNS can modify memory outcomes and delve into the molecular mechanisms associated with these changes. These findings indicate that a greater understanding of VNS mechanisms while also considering stimulation parameters, administration site, timing in relation to training, and sex-specific factors, may allow for optimal VNS application to enhance memory. [ABSTRACT FROM AUTHOR]

Rehabilitation approaches for individuals with neurologic conditions have increasingly shifted toward promoting neuroplasticity for enhanced recovery and restoration of function. This review focuses on exercise strategies and non-invasive neuromodulation techniques that target neuroplasticity, including transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and peripheral nerve stimulation (PNS). We have chosen to focus on non-invasive neuromodulation techniques due to their greater potential for integration into routine clinical practice. We explore and discuss the application of these interventional strategies in four neurological conditions that are frequently encountered in rehabilitation settings: Parkinson’s Disease (PD), Traumatic Brain Injury (TBI), stroke, and Spinal Cord Injury (SCI). Additionally, we discuss the potential benefits of combining non-invasive neuromodulation with rehabilitation, which has shown promise in accelerating recovery. Our review identifies studies that demonstrate enhanced recovery through combined exercise and non-invasive neuromodulation in the selected patient populations. We primarily focus on the motor aspects of rehabilitation, but also briefly address non-motor impacts of these conditions. Additionally, we identify the gaps in current literature and barriers to implementation of combined approaches into clinical practice. We highlight areas needing further research and suggest avenues for future investigation, aiming to enhance the personalization of the unique neuroplastic responses associated with each condition. This review serves as a resource for rehabilitation professionals and researchers seeking a comprehensive understanding of neuroplastic exercise interventions and non-invasive neuromodulation techniques tailored for specific diseases and diagnoses.

Vagus nerve stimulation (VNS) has been recognized as a useful neuromodulation tool to target the central nervous system by electrical stimulation of peripheral nerves. Activation of the nucleus of the solitary tract (NTS) in the brainstem by vagal afferent nerve fibers allows for modulation of various higher order brain regions, including limbic and cerebral cortex structures. Along with neurological and psychiatric indications, clinical and preclinical studies suggest that VNS can improve memory. While the underlying mechanisms to improve memory with VNS involve brain areas, such as the prefrontal cortex and processes including alertness and arousal, here we focus on VNS-induced memory improvements related to the hippocampus, the main area implicated in memory acquisition. In addition, we detail research demonstrating that a targeted approach to VNS can modify memory outcomes and delve into the molecular mechanisms associated with these changes. These findings indicate that a greater understanding of VNS mechanisms while also considering stimulation parameters, administration site, timing in relation to training, and sex-specific factors, may allow for optimal VNS application to enhance memory.

During contact, phasic and tonic responses provide feedback that is used for task performance and perceptual processes. These disparate temporal dynamics are carried in peripheral nerves, and produce overlapping signals in cortex. Using longitudinal intrafascicular electrodes inserted into the median nerve of a nonhuman primate, we delivered composite stimulation consisting of onset and release bursts to capture rapidly adapting responses and sustained stochastic stimulation to capture the ongoing response of slowly adapting receptors. To measure the stimulation's effectiveness in producing natural responses, we monitored the local field potential in somatosensory cortex. We compared the cortical responses to peripheral nerve stimulation and vibrotactile/punctate stimulation of the fingertip, with particular focus on gamma band (30-65 Hz) responses. We found that vibrotactile stimulation produces consistently phase locked gamma throughout the duration of the stimulation. By contrast, punctate stimulation responses were phase locked at the onset and release of stimulation, but activity maintained through the stimulation was not phase locked. Using these responses as guideposts for assessing the response to the peripheral nerve stimulation, we found that constant frequency stimulation produced continual phase locking, whereas composite stimulation produced gamma enhancement throughout the stimulus, phase locked only at the onset and release of the stimulus. We describe this response as an "Appropriate Response in the gamma band" (ARg), a trend seen in other sensory systems. Our demonstration is the first shown for intracortical somatosensory local field potentials. We argue that this stimulation paradigm produces a more biomimetic response in somatosensory cortex and is more likely to produce naturalistic sensations for readily usable neuroprosthetic feedback. [ABSTRACT FROM AUTHOR]

During contact, phasic and tonic responses provide feedback that is used for task performance and perceptual processes. These disparate temporal dynamics are carried in peripheral nerves, and produce overlapping signals in cortex. Using longitudinal intrafascicular electrodes inserted into the median nerve of a nonhuman primate, we delivered composite stimulation consisting of onset and release bursts to capture rapidly adapting responses and sustained stochastic stimulation to capture the ongoing response of slowly adapting receptors. To measure the stimulation’s effectiveness in producing natural responses, we monitored the local field potential in somatosensory cortex. We compared the cortical responses to peripheral nerve stimulation and vibrotactile/punctate stimulation of the fingertip, with particular focus on gamma band (30–65 Hz) responses. We found that vibrotactile stimulation produces consistently phase locked gamma throughout the duration of the stimulation. By contrast, punctate stimulation responses were phase locked at the onset and release of stimulation, but activity maintained through the stimulation was not phase locked. Using these responses as guideposts for assessing the response to the peripheral nerve stimulation, we found that constant frequency stimulation produced continual phase locking, whereas composite stimulation produced gamma enhancement throughout the stimulus, phase locked only at the onset and release of the stimulus. We describe this response as an “Appropriate Response in the gamma band” (ARγ), a trend seen in other sensory systems. Our demonstration is the first shown for intracortical somatosensory local field potentials. We argue that this stimulation paradigm produces a more biomimetic response in somatosensory cortex and is more likely to produce naturalistic sensations for readily usable neuroprosthetic feedback.

Peripheral electrical stimulation (PES), which encompasses several techniques with heterogeneous physiological responses, has shown in some cases remarkable outcomes for pain treatment and clinical rehabilitation. However, results are still mixed, mainly because there is a lack of understanding regarding its neural mechanisms of action. In this study, we aimed to assess its effects by measuring cortical activation as indexed by functional near infrared spectroscopy (fNIRS). fNIRS is a functional optical imaging method to evaluate hemodynamic changes in oxygenated (HbO) and de-oxygenated (HbR) blood hemoglobin concentrations in cortical capillary networks that can be related to cortical activity. We hypothesized that non-painful PES of accessory spinal nerve (ASN) can promote cortical activation of sensorimotor cortex (SMC) and dorsolateral prefrontal cortex (DLPFC) pain processing cortical areas. Fifteen healthy volunteers received both active and sham ASN electrical stimulation in a crossover study. The hemodynamic cortical response to unilateral right ASN burst electrical stimulation with 10 Hz was measured by a 40-channel fNIRS system. The effect of ASN electrical stimulation over HbO concentration in cortical areas of interest (CAI) was observed through the activation of right-DLPFC (p = 0.025) and left-SMC (p = 0.042) in the active group but not in sham group. Regarding left-DLPFC (p = 0.610) and right-SMC (p = 0.174) there was no statistical difference between groups. As in non-invasive brain stimulation (NIBS) top-down modulation, bottom-up electrical stimulation to the ASN seems to activate the same critical cortical areas on pain pathways related to sensory-discriminative and affective-motivational pain dimensions. These results provide additional mechanistic evidence to develop and optimize the use of peripheral nerve electrical stimulation as a neuromodulatory tool (NCT 03295370— www.clinicaltrials.gov).

Peripheral electrical stimulation (PES), which encompasses several techniques with heterogeneous physiological responses, has shown in some cases remarkable outcomes for pain treatment and clinical rehabilitation. However, results are still mixed, mainly because there is a lack of understanding regarding its neural mechanisms of action. In this study, we aimed to assess its effects by measuring cortical activation as indexed by functional near infrared spectroscopy (fNIRS). fNIRS is a functional optical imaging method to evaluate hemodynamic changes in oxygenated (HbO) and de-oxygenated (HbR) blood hemoglobin concentrations in cortical capillary networks that can be related to cortical activity. We hypothesized that non-painful PES of accessory spinal nerve (ASN) can promote cortical activation of sensorimotor cortex (SMC) and dorsolateral prefrontal cortex (DLPFC) pain processing cortical areas. Fifteen healthy volunteers received both active and sham ASN electrical stimulation in a crossover study. The hemodynamic cortical response to unilateral right ASN burst electrical stimulation with 10 Hz was measured by a 40-channel fNIRS system. The effect of ASN electrical stimulation over HbO concentration in cortical areas of interest (CAI) was observed through the activation of right-DLPFC (p = 0.025) and left-SMC (p = 0.042) in the active group but not in sham group. Regarding left-DLPFC (p = 0.610) and right-SMC (p = 0.174) there was no statistical difference between groups. As in non-invasive brain stimulation (NIBS) top-down modulation, bottom-up electrical stimulation to the ASN seems to activate the same critical cortical areas on pain pathways related to sensory-discriminative and affective-motivational pain dimensions. These results provide additional mechanistic evidence to develop and optimize the use of peripheral nerve electrical stimulation as a neuromodulatory tool (NCT 03295370— www.clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

For clinical application of transcranial static magnetic stimulation (tSMS), it is important to achieve a focal target cortical stimulation. Previous study suggested that the associative stimulation combining non-invasive stimulation of the motor cortex (M1) and the peripheral nerve stimulation (PNS) may be useful to produce cortical excitability change. To test this hypothesis, we measured the M1 excitability and intracortical circuits by using transcranial magnetic stimulation (TMS) before and after the tSMS of short duration (5 min) combined with PNS. Thirty-three normal volunteers were participated; tSMS+PNS (n=11), sham+PNS (n=11) and tSMS alone (n=11). We found the transient suppression of the motor-evoked potential (MEP) of the right abductor pollicis brevis (APB) muscle, but not of the abductor digiti minimi (ADM) muscle, when combining tSMS with PNS over median nerve at the wrist. The lack of suppressive effect on APB in tSMS alone with short duration is in accord with the previous observation. In addition, the tendency of transient enhancement of the short-latency intracortical inhibition was observed immediately after intervention in the tSMS+PNS group. These findings show that the combination of tSMS and PNS can induce the cortical excitability change in target cortical motor area and potentiate the suppression effect.

Exercise-induced fatigue affects the motor control and the ability to generate a given force or power. Surface electroencephalography allows researchers to investigate movement-related cortical potentials (MRCP), which reflect preparatory brain activity 1.5 seconds before movement onset. Although the MRCP amplitude appears to increase after repetitive single-joint contractions, the effects of large-muscle group dynamic exercise on such pre-motor potential remain to be described. Sixteen volunteers exercised 30 minutes at 60% of the maximal aerobic power on a cycle ergometer, followed by a 10-km all-out time trial. Before and after each of these tasks, knee extensor neuromuscular function was investigated using maximal voluntary contractions (MVC) combined with electrical stimulations of the femoral nerve. MRCP was recorded during 60 knee extensions after each neuromuscular sequence.The exercise resulted in a significant decrease in the knee extensor MVC force after the 30-min exercise (-10±8%) and the time trial (-21±9%)). The voluntary activation level (VAL) (-6±8% and -12±10%), peak twitch (Pt) (-21±16% and -32±17%) and paired stimuli (P100Hz) (-7±11% and -12±13%) were also significantly reduced after the 30-min exercise and the time trial. The first exercise was followed by a decrease in the MRCP, mainly above the mean activity measured at electrodes FC1-FC2, whereas the reduction observed after the time trial was related to the FC1-FC2 and C2 electrodes. After both exercises, the reduction in the late MRCP component above FC1-FC2 was significantly correlated with the reduction in P100Hz (r=0.61), and the reduction in the same component above C2 was significantly correlated with the reduction in VAL (r=0.64).In conclusion, large-muscle group exercise induced a reduction in pre-motor potential, which was related to muscle alterations and resulted in the inability to produce a maximal voluntary contraction.

For clinical application of transcranial static magnetic stimulation (tSMS), it is important to achieve a focal target cortical stimulation. Previous study suggested that the associative stimulation combining non-invasive stimulation of the motor cortex (M1) and the peripheral nerve stimulation (PNS) may be useful to produce cortical excitability change. To test this hypothesis, we measured the M1 excitability and intracortical circuits by using transcranial magnetic stimulation (TMS) before and after the tSMS of short duration (5 min) combined with PNS. Thirty-three normal volunteers were participated; tSMS+PNS (n = 11), sham+PNS (n = 11), and tSMS alone (n = 11). We found the transient suppression of the motor-evoked potential (MEP) of the right abductor pollicis brevis (APB) muscle, but not of the abductor digiti minimi (ADM) muscle, when combining tSMS with PNS over median nerve at the wrist. The lack of suppressive effect on APB in tSMS alone with short duration is in accord with the previous observation. In addition, the tendency of transient enhancement of the short-latency intracortical inhibition was observed immediately after intervention in the tSMS±PNS group. These findings show that the combination of tSMS and PNS can induce the cortical excitability change in target cortical motor area and potentiate the suppression effect. [ABSTRACT FROM AUTHOR]

Exercise-induced fatigue affects the motor control and the ability to generate a given force or power. Surface electroencephalography allows researchers to investigate movement-related cortical potentials (MRCP), which reflect preparatory brain activity 1.5 s before movement onset. Although the MRCP amplitude appears to increase after repetitive single-joint contractions, the effects of large-muscle group dynamic exercise on such pre-motor potential remain to be described. Sixteen volunteers exercised 30 min at 60% of the maximal aerobic power on a cycle ergometer, followed by a 10-km all-out time trial. Before and after each of these tasks, knee extensor neuromuscular function was investigated using maximal voluntary contractions (MVC) combined with electrical stimulations of the femoral nerve. MRCP was recorded during 60 knee extensions after each neuromuscular sequence. The exercise resulted in a significant decrease in the knee extensor MVC force after the 30-min exercise (-10 ± 8%) and the time trial (-21 ± 9%). The voluntary activation level (VAL; -6 ± 8 and -12 ± 10%), peak twitch (Pt; -21 ± 16 and -32 ± 17%), and paired stimuli (P100 Hz; -7 ± 11 and -12 ± 13%) were also significantly reduced after the 30-min exercise and the time trial. The first exercise was followed by a decrease in the MRCP, mainly above the mean activity measured at electrodes FC1-FC2, whereas the reduction observed after the time trial was related to the FC1-FC2 and C2 electrodes. After both exercises, the reduction in the late MRCP component above FC1-FC2 was significantly correlated with the reduction in P100 Hz (r = 0.61), and the reduction in the same component above C2 was significantly correlated with the reduction in VAL (r = 0.64). In conclusion, large-muscle group exercise induced a reduction in pre-motor potential, which was related to muscle alterations and resulted in the inability to produce a maximal voluntary contraction. [ABSTRACT FROM AUTHOR]

Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation. [ABSTRACT FROM AUTHOR]