A Review of Neuromodulation in the Neurorehabilitation

For many years, invasive neuromodulation has been used in neurorehabilitation, mainly in treatment of movement disorders and various psychiatric conditions. Use of deep brain stimulation and other implanted electrical stimulators is being explored in other conditions, such as stroke, traumatic brain injury and spinal cord injury. This paper provides a review of the possible role of Neuromodulation in neurorehabilitation and highlights some of its applications for patients with various neurological conditions. Since most of the existing findings are based on animal studies, preliminary data, case reports and poor-controlled studies, further investigations including research and clinical trials are necessary to increase the applications of neurostimulation in the field of neurorehabilitation.


Introduction
Neurorehabilitation is a complicated medical process; its goal is to help patients to recover from injuries or abnormalities in the Central Nervous System [CNS], and to compensate for functional deficits if possible. Neurorehabilitation offers a series of therapies, including physical, occupational, speech, psychological therapies and so on with a focus on improving the patients' health. The field of neurorehabilitation is relatively new, and some cutting edge therapies, including neuromodulation, that may be potentially beneficial topatients withCNS injuries or other disorders, are currently being investigated. The brain operates through signal processing within neural networks [1,2]. The advances in the understanding of brain circuitry, together with the development of neurostimulation technologies have prompted us to explore the potential of electrical stimulation of the nervous system to promote functional recovery in patients with CNS disorders through activation of neuronal structures and alteration or inhibition of pathological pattern of neuronal activity. Over the past several decades, electrical neurostimulation of deep cerebral structures hasbeen proven a clinically effective therapy in the treatment of movement disorders with a remarkable safety profile [3,4]. Neurostimulation approach in patients with movement disorders has shed light on the possibility of correcting abnormal networks. The neurostimulation technology has been also applied to psychiatric disorders and chronic pain. The objective of this review is to explore the use of neurostimulation in treatment of stroke, traumatic brain injury, spinal cord injury and epilepsy. A thorough search of the literature was conducted in preparation of this review.

Neuromodulation for Brain Injury Caused By Stroke And Trauma
The incidence rate of Traumatic Brain Injury [TBI] is 558 per 100,000 people [5], and that of stroke is 67-70 per 100,000 [6]. Brain injury caused bytrauma and stroke remains a significant public health problem with devastating consequences, and is a leading cause of disability and death in the world. New therapeutic strategies are needed for treatment of neurological functional deficits followingtraumatic or ischemic brain injury. Neuromodulation approach has been employed to treat stroke and TBI in animal models [7][8][9][10][11] and clinical studies [12][13][14], with preliminary data showing that neurostimulation may lead to functional improvement in the setting of brain injuries. A few animal studies in non-human primates have observed thatcortical stimulationenhances functional recovery and cortical plasticity after neural injury induced by stroke [7-9]. Cortical stimulation during Abstract For many years, invasive neuromodulation has been used in neurorehabilitation, mainly in treatment of movement disorders and various psychiatric conditions. Use of deep brain stimulation and other implanted electrical stimulators is being explored in other conditions, such as stroke, traumatic brain injury and spinal cord injury. This paper provides a review of the possible role of Neuromodulation in neurorehabilitation and highlights some of its applications for patients with various neurological conditions. Since most of the existing findings are based on animal studies, preliminary data, case reports and poor-controlled studies, further investigations including research and clinical trials are necessary to increase the applications of neurostimulation in the field of neurorehabilitation.

Motor Cortex Stimulation
A small randomized clinical trial [n=24] found that Motor Cortex Stimulation [MCS] lead to motor and functional improvements [difference of Fugl-Meyer motor scores in estimated means = 3.8, p = .042] in stroke patients, and the effect was maintained during 6-month follow-up period [12]. In a multicenter safety and efficacy study, MCSresulted in improvementsin upper-extremity function during 3 weeks or 6 weeks [13,14] of the rehabilitation. MCS for 3 weeks during stroke rehabilitation also led to improvement inpincer movement of the previously paretic hand in a hemi-paretic stroke patient [13]. Moreover, MCS resulted in 40%-50% improvement of pain caused by brain injury in approximately 50% of patients [15]. Table 1 shows clinical data of different studies. However, the limitations of these studies on MCS include small sample size and short follow up. Overall, the long-term effect of MCS is uncertain, as no study has explored that.The mechanismsby which such improvements occur are not clear.The improvements may be a result of increased dendritic plasticity and decreased astrogliosis in the perilesional cortex and the contralesional anterior horn of the cervical spinal cord as shown by an immunohistochemical study [16]. Another study indicated motor cortex stimulation after pyramidotomy could increase the length of axons from theprimary motor cortex to the spinal cord, as well as to the red nucleus and cuneate nucleus [17]. Increased axonal outgrowthwith stimulation may be due to a release of neurotrophins, such as brain-derived neurotrophic factor, and increased motor activityof the subjects [7].

DBS has been explored on patients with Persistent Vegetative State
[PVS] or minimally conscious state [MinCS] following traumatic brain injury.In the late 1960-s, Hassler et al described the concept of using DBS to treat disorder of consciousness [18], and then in early 1990s, two groups used this technique in a larger series of patients with vegetative state [19,20].In one case-series study, DBS of the midbrain reticular formation or central thalamus was conducted in patients with MinCS 4-8 months post-injury. They received continuous stimulation for 10 years. Eight of the 21 patients emerged from a vegetative state and were able to follow verbal instructions [21][22][23]. A case study observed improvements in the level of arousal, limb movement and verbalization after DBS to the central thalamus [24]. However, one has to be cautious to differentiate the effectiveness of DBS from spontaneous recovery following injury [25]. Sen et al also pointed out that differentiating between the PVS and MinCS may be important in determining the possible benefit of DBS therapy since either state may result from a traumatic brain injury and both have profound functional  [32][33][34][35][36][37][38][39]. The effect of SCS on increase in CBF in human brain was first reported in 1985 [40]. An interesting concept of "redistribution of CBF" rather than an absolute change in CBF during SCS was introduced in 1995 [41,42]. Further case series studies have shown cervical SCS could increase CBF, and improve upper-extremity motor function and communication skills in patients with MinCS resulted from TBI and stroke [7,43]. A singlegroup study reported improvements in awareness in 54% [109/201] of people with stroke or TBI after cervical SCS [44]. The treatment effect may be achieved by enhancing cerebral hemodynamics via autonomic nervous system and the release of hormonal factors [45]. Moreover, based on the thorough literature review, it has been proposed that SCS targeting the lower cervical segments may prevent Subarachnoid Hemorrhage [SAH]-related delayed vasospasm [46][47][48]. Furthermore, once the vasospasm is present,patients may still receive additional benefit and possibly improve clinical outcome by CBF augmentation and treatment of thevasospasm through stimulation of the cervical spinal cord.

Transcranial Magnetic Stimulation And Transcranial Direct-Current Stimulation
Transcranial Magnetic Stimulation [TMS] and transcranial Direct-Current Stimulation [tDCS] are two non-invasive neuromodulatory therapies, which can modulate neuroplasticity and cortical hyperexcitability [49][50][51].Their therapeutic value is unclear. Some studies, including randomized double-blind studyand sham stimulationcontrolled trial, have assessed their effects on motor function in people with stroke and TBI. The findings have been inconsistent [51-54].

Neuromodulation for Spinal Cord Injury
Traumatic Spinal Cord Injury[SCI] is estimated to affect approximately 300,000 individuals in the United States, and more than 2.5 million worldwide [55], with estimated cost over $9 billion annually in the United States alone [56]. SCI often leads to serious neurological sequelae and medical complications. Therefore, more efforts in medical practice development are needed to improve the quality of life of patients with SCI.It has been reported that SCS in lumbosacral segments helped restore voluntary control of locomotion in paralyzed rats after SCI [57].A study using closed-loop neuromodulation to treat rats with complete SCI found that it improved the locomotion and enabled animals to perform more than 1,000 successive steps without failure and to climb staircases of various heights and lengths with precision and fluidity [58]. Another similar study on rats, however, found no treatment effect [59]. A case study reported that SCS enabled a paraplegic man [C7-T1 subluxation] to produce some leg movements and to stand during stimulation [60]. The author pointed out that even after a severe low cervical SCI, the neural networks remaining within the lumbosacral segments can be reactivated into functional states so that they can recognize specific details of ensembles of sensory input delivered by SCS to the extent that it [SCS] may serve as the source of neural control [60]. While this suggests that SCS can activate spared neural circuits and promote plasticity, there is no evidence that it would lead to functional gains and physical improvements after SCS.

Neuromodulation for Epilepsy
Epilepsy affects 1% of population in the world, and 30-40% of cases are medically refractory [61][62][63][64][65]. Management of patients who have recurrent seizures and did not respond to medication or surgery is challenging. A number of double-blind randomized controlled trials have confirmed the therapeutic effects of Vagus Nerve Stimulation [VNS] for epilepsy [66][67][68][69]. A recent European long-term study [n=347] showed a 50% reduction in seizure frequency for up to 43.8% of patients [66]. Greater treatment effect has been observed with higher VNS settings [66]. A review study also found DBS effective in reducing seizure frequency [70]. The target areas of DBS for treatment of epilepsy include Anterior Nucleus [AN] of thalamus [71][72][73], centro median nucleus [CM] of thalamus [74,75], Sub Thalamic Nucleus [STN] [76,77], Caudate Nucleus [75], cerebellum [78]and hippocampus [79]. Closed loop brain stimulation has recently been used for treatment of epilepsy. One type of this stimulation is a Responsive Neurostimulation System [RNS][Responsive Neurostimulation System, Neuropace, Mountain view, CA] that delivers stimuli only when abnormal electrocortico graphic activity of a seizure is detected [80]. Another type is a recording pulse generator unit [Medtronic, Minneapolis, MN] [81] that deliver bidirectional stimulation. The RNS is approved by FDA for clinical use in the USA [82,83], and the DBS -by the regulatory agencies in Canada, Europe, Australia, and elsewhere [61]. However,DBS is still in its early stage as a therapy for epilepsy.

Discussion
Overall, advances in neuromodulation may offer new therapeutic interventions for patients with stroke, traumatic brain injury, spinal cord injury and epilepsy by counteract the abnormal network in the brain. The emerging neuromodulation therapy for patients with these conditions is still facing great challenges. Since most of the existing findings are based on animal studies, preliminary data, case reports andpoor-controlled studies, and short follow up, further investigations including research and clinical trials are necessary to increase the applications of neurostimulation in the field of neurorehabilitation.