1. Introduction
Cerebrovascular accidents (stroke) are the second leading cause of death and the third leading cause of disability worldwide (Global Health Estimates. Geneva, Switzerland: World Health Organization; 2012). Worldwide, 70% of strokes and 87% of both stroke-related deaths and disability-adjusted life years occur in low- and middle-income countries (LMIC) [
1]. While the incidence of stroke is decreasing in the developed world [
1], the incidence is increasing in India, an LMIC, due to demographic transition and a rapid shift in the socio-economic milieu. The estimated adjusted prevalence rate of stroke ranges from 84–262/100,000 in rural and 334–424/100,000 in urban India, and the incidence rate is 119–145/100,000 based on the recent population-based studies [
2]. Thus, stroke constitutes a substantial socioeconomic burden on the patients, caregivers, and society in India [
3,
4]. The scarcity of trained rehabilitation clinicians, as well as the cost of clinic-based rehabilitation programs, can deter stroke survivors from undergoing regular post-stroke rehabilitation leading to further decline in their health conditions. Given the high prevalence and incidence of stroke in India, there is a need to investigate low-cost neurotechnologies to facilitate early post-stroke rehabilitation.
Early task-specific rehabilitation after stroke may drive functionally relevant beneficial neuroplastic changes in the brain where neuroplasticity is the ability of the central nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function, and connections. Recent clinical studies in the USA on invasive deep brain stimulation of the cerebellum for post-stroke motor rehabilitation are based on the extensive reciprocal connectivity between the dentate nucleus and the wide swaths of cerebral cortex via the dentatothalamocortical and corticopontocerebellar tracts [
5]. Dentate is a promising target for brain stimulation since it remains mostly unaffected by lesions [
6], and deep brain stimulation of the cerebellum is proposed to ameliorate the known limitations to motor rehabilitation imposed by crossed cerebellar diaschisis. Here, the improvements in motor function are found paralleled by increased expression of markers of synaptic plasticity, synaptogenesis, and neurogenesis in the perilesional cortex. In this study, we investigated a low-cost non-invasive brain stimulation (NIBS) approach to the cerebellum [
7,
8] based on cerebellar transcranial direct current stimulation (ctDCS). ctDCS has been found to be a promising method to facilitate cerebellar functions [
9] where it can improve locomotor adaptation [
10] as well as postural recovery from disturbance by Achilles tendon vibration [
11]. The conventional ctDCS electrode montages [
12] most likely produce their effects by polarizing Purkinje cells [
13], and its therapeutic effects are an adjunct to motor training [
8]. In this study, we aimed to directly target the dentate nucleus with ctDCS which is the largest and most lateral of the four deep cerebellar nuclei and is known to be involved in planning and executing voluntary movements [
14]. In fact, the dentate nucleus can affect motor as well as cognitive function [
12] due to extensive reciprocal connectivity between the dentate nucleus and the wide swaths of the cerebral cortex. Since dentate receives proprioceptive information from the spinocerebellar tract via the inferior cerebellar peduncle and also receives planning and initiating voluntary movement-related information from the premotor and supplementary motor cortices so it can perform error computations (comparator function) relevant to maintain timing, balance, and equilibrium. Therefore, we postulate that subthreshold stimulation of the dentate nucleus can help generate appropriately timed burst activity [
15] during standing balance functional reach tasks (FRT) using a human-machine interface (HMI) [
16]. Our prior work on ctDCS optimization [
7] showed that highly conductive cerebrospinal fluid can provide a path for the stimulation current to reach the depths of the vermis, and since the dentate nucleus is directly adjacent to the vermis and the roof of the fourth ventricle bilaterally so we aimed to directly target dentate nucleus with ctDCS to facilitate cued weight-shifting in chronic stroke survivors. Here, patient selection may be crucial for ctDCS as an adjunct to post-stroke balance rehabilitation, e.g., in patients where the cerebellum is without lesion and the cerebello-cerebral connectivity is intact, since stroke is a heterogeneous disease with different mechanisms and etiologies.
While non-invasive brain stimulation (NIBS) techniques, including tDCS, are increasingly used for the modulation of corticospinal excitability in humans by passing low electric currents through the brain, its treatment effects are rather inconsistent across studies [
17,
18]. Besides usability issues, one of the important factors contributing to the inconsistency is the lack of expertise in individualizing tDCS [
17,
18]. For example, ctDCS has shown promise in improving standing balance performance in small studies with fifteen patients with chronic stroke (>6 months post-stroke) [
19] where exploration of optimal timing, dose, and the relation between qualitative parameters and clinical improvements are needed [
19]. A recent study [
20] showed that multiple sessions (three sessions of 20 min per week for two weeks) of simultaneous postural training with bilateral anodal ctDCS (not postural training or bilateral anodal ctDCS alone) was necessary to deliver therapeutic effects in older adults with high fall risk. However, due to heterogeneous brain lesions in stroke, subject-specific optimization of the ctDCS electric field using Magnetic Resonance Imaging (MRI) data and a computational pipeline [
7] is important. We have shown that different ctDCS electrode montages affect different parts or lobules of the cerebellum [
7,
21], however, the related behavioral effects could not be determined in our prior works in the absence of patient data. In the current pilot study, we tested the usability and feasibility of a bipolar bilateral ctDCS in chronic (>6 months) stroke survivors where a group-averaged optimal bipolar bilateral ctDCS montage was developed based on subject-specific optimization across post-stroke participant MRI as well as based on a healthy MRI template. Usability testing with well-defined neuroimaging based customization outside of laboratory setting is necessary for strengthening remote patient care and monitoring for chronic stroke conditions. Here, heterogeneously lesioned brain regions after stroke present a challenge because of the alterations of current flow, which may require the development of individualized ctDCS electrode montage based on neuroimaging [
7]. In this study, we selected stroke survivors with cerebral lesions but with an intact cerebellum so that the ctDCS electric field effects can be delivered via intact cerebellum [
8]. We first optimized ctDCS with a whole head electrode montage using an age-appropriate human brain MRI template for the age-group of 55 to 59 years (
https://jerlab.sc.edu/projects/neurodevelopmental-mri-database/) to select a reduced set of electrodes that were then used to optimize bipolar bilateral ctDCS montage based on the MRIs from our post-stroke participants.
Our computational modeling pipeline [
7] and FRT evaluated a bipolar bilateral ctDCS montage to maximally (with electric field strength) target bilateral dentate nuclei (postulated to affect motor as well as cognitive function [
12]) versus one optimized to uniformly target the leg area of the cerebellum (i.e., comparable electric field in X, Y, Z directions across lobules VII–IX) [
7]. User experience due to 2 mA bipolar ctDCS were monitored by asking participants whether they experienced any of the following symptoms since the preceding treatment: scalp pain, headache, neck pain, dental pain, tingling, nausea, itching, burning sensation, skin redness, open lesion on skin, abnormal sleep, anxiety, difficulty concentrating, dizziness, impaired memory, altered mood, altered balance, impaired use of the unaffected side, or any other problem [
22].
3. Results
Figure 2 shows the head model from the MRI template of 55-59 years age-group which was used to generate the whole head transfer matrices (429 electrodes—See
Appendix B:
Table A2) to optimize the bipolar ctDCS montage. The reduced set of 87 electrode locations to optimize bipolar ctDCS montage were selected for high L1 norm of the columns of the transfer matrices related to cerebellar brain, namely (shown in
Figure 3), “E145”, “E146”, “E156”, “E165”, “Ex1”, “Ex2”, “Ex3”, “Ex4”, “Ex5”, “Ex6”, “Ex7”, “Ex8”, “Exx10”, “Exx11”, “Exx12”, “Exx1”, “Exx2”, “Exx3”, “Exx4”, “Exx5”, “Exx6”, “Exx7”, “Exx8”, “Exx9”, “Exxz”, “Exz”, “I1h”, “I2h”, “Iz”, “NkB”, “NkL”, “NkR”, “O1”, “O1h”, “O2”, “O2h”, “OI1”, “OI1h”, “OI2”, “OI2h”, “OIz”, “Oz”, “P10”, “P10h”, “P7”, “P7h”, “P8”, “P8h”, “P9”, “P9h”, “PO10”, “PO10h”, “PO7”, “PO7h”, “PO8”, “PO8h”, “PO9”, “PO9h”, “POO10”, “POO10h”, “POO1h”, “POO2”, “POO2h”, “POO3h”, “POO8”, “POO9”, “POO9h”, “POOz”, “PPO10”, “PPO10h”, “PPO7”, “PPO7h”, “PPO8”, “PPO8h”, “PPO9”, “PPO9h”, “T5”, “T6”, “TPP10h”, “TPP7”, “TPP8”, “TPP8h”, “TPP9h”, “Z1”, “Z2”, “Z7”, “Z9”. In this study, we also wanted a low L1 norm of the columns of the transfer matrices (L1 norm < 0.01 selected—see
Appendix C) for the non-cerebellar brain (i.e., row 35—see
Appendix C) to avoid spillover to lesional cerebral areas in stroke subjects which limited the available electrode locations to “E145”, “E146”, “E156”, “E165”,”Ex1”, “Ex2”, “Ex3”, “Ex4”, “Ex6”, “Exx1”, “Exx2”, “Exx3”, “Exx4”, “Exx5”, “Exx6”, “Exx7”, “Exx8”, “Exxz”, “Exz”, “I1h”, “I2h”, “Iz”, “NkB”, “NkL”, “NkR”, “O2h”, “OI1h”, “OI2h”, “OIz”, “Oz”, “POO1h”, “POO2”, “POO2h”, “POOz”, “Z1”, “Z2”, “Z7”, “Z9”. This provided a reduced set of scalp electrode locations (primarily overlying the cerebellum) for stroke subjects.
The optimal bipolar montage found for the head model from the MRI template of 55-59 years age- group were Z7–POO2 for case 4 (optimization for dentate nuclei) and Exx5–Ex6 for case 5 (optimization for bilateral lobules VII–IX). For the post-stroke subjects undergoing ctDCS, we selected PO9h–PO10h for case 1 and Exx7–Exx8 for case 2 based on group-analysis of the subject-specific optimization since the lesional brain areas were primarily in the frontal lobe (occipital and parietal lobes were free from lesions) in the five post-stroke participants who volunteered for the ctDCS FRT study.
Figure 4 shows the boxplot of the electric field (EF) strength for different ctDCS montages for the head model from the MRI template of 55-59 years age-group across 24 cerebellar regions, occipital and parietal lobes where
Figure 4a shows the EF distribution for the Celnik montage,
Figure 4b shows the EF distribution for the Manto montage,
Figure 4c shows the EF distribution for the Extracephalic montage,
Figure 4d shows the EF distribution for the PO9h–PO10h montage for case 1 (optimization for dentate nuclei),
Figure 4e shows the EF distribution for the Exx7–Exx8 montage for case 2 (optimization for bilateral lobules VII–IX). Here, the electric field strength at the dentate nuclei was found to be high across all montages including the conventional Celnik and Manto ctDCS montages where the Manto montage from conventional ctDCS montages was found to be the best to stimulate the dentate nuclei in addition to the lower limb representations in the cerebellum. Also, the EF strength at the non-cerebellar occipital and parietal regions was found to be high (comparable to the Manto montage) for our PO9h–PO10h montage. However, the EF strength at the non-cerebellar occipital and parietal regions was found to be low (comparable to the Extracephalic montage) for the Exx7–Exx8 montage. Nevertheless, the median of the EF strength at the non-cerebellar occipital and parietal regions was low (<0.02 V/m), and most of the boxplot consisted of the outliers which are plotted individually using the + symbol. Here,
Figure 4f shows two-way ANOVA results for the factors of interest–brain regions, montages, and their interactions (brain region*montage) which were all significant.
Figure 5 and
Figure 6 present the boxplot of the electric field distribution for the 10 post-stroke patients for the PO9h–PO10h montage for case 1 (optimization for dentate nuclei) and for the Exx7–Exx8 montage for case 2 (optimization for bilateral lobules VII–IX) respectively. PO9h–PO10h montage for case 1 was optimized for the dentate nuclei which led to a higher electric field strength at the dentate nuclei as expected. However, PO9h–PO10h montage also led to an overall higher electric field strength at the bilateral leg lobules VII-IX when compared to the Exx7–Exx8 montage for the same stimulation current (2 mA). PO9h–PO10h montage also led to electric field spillover to the non-cerebellar occipital and parietal regions.
Figure 7a shows three-way ANOVA results for the factors of interest–subjects, brain regions, montages, and their interactions which were all significant.
Figure 7b shows the multiple comparisons of the population marginal means between the PO9h–PO10h montage and the Exx7–Exx8 montage which was found to be significantly (alpha = 0.05) different from each other.
Figure 7c shows the multiple comparison test of the population marginal means of different brain regions (X2) where the dentate nuclei were exposed to a significantly (alpha = 0.05) higher electric field strength (>0.12 V/m) when compared to other brain regions across montages (X1) and subjects (X3).
Figure 7d shows the multiple comparison test of the population marginal means of different subjects (X3) where the subjects P8-P10 were exposed to the significantly (alpha = 0.05) higher electric field strength when compared to other subjects across montages (X1) and brain regions (X2). Pre-intervention baseline equivalence of the FRT success rate (%) between the two repeated-measure counter-balanced crossover study groups was confirmed by the Wilcoxon rank-sum test that gave a p-value of 0.5216 so there was not enough evidence (5% significance level) to reject the null hypothesis of equal medians. The post-intervention FRT success rate (%) between the two repeated-measure counter-balanced crossover study groups gave a
p-value of 4.6635 × e
−5 so the null hypothesis of equal medians was rejected. Since the electric field,
, distribution, as well as the post-intervention FRT success rate (%), significantly varied so a GLM model (with probit link) was fitted to the independent variable, FRT success rate (%), as the
p × 1 behavioral outcome matrix, B, from the FRT study.
Figure 8 shows that a probit fit is comparable to a linear fit along with its linear regression residuals. The top panel of
Figure 8 shows the GLM model (with probit link) results where the lobular maximum electric field strength is the predictor in
Figure 8a and the lobular median electric field strength is the predictor in
Figure 8b. FRT success rate (%) was found to be more sensitive to the lobular median electric field strength than the lobular maximum electric field strength, slope 0.17 versus 0.09. Also, the bottom panel of
Figure 8 shows the GLM model (with probit link) results where the median electric field strength in the dentate nuclei is the predictor in the
Figure 8c and the lower-limb area lobular median electric field strength is the predictor in the
Figure 8d. Here, the FRT success rate (%) was found to be more sensitive to the lower-limb representations lobular median electric field strength than the dentate nuclei median electric field strength, slope 0.34 versus 0.27.
4. Discussion
In this pilot study on 5 stroke survivors, ctDCS of the dentate nuclei facilitated greater target reaches during FRT when compared to bilateral cerebellar lower-limb representations ctDCS. Inter-subject variability in the electric field strength at the cerebellum, as shown in
Figure 7d, is expected due to the “one-size-fits-all” approach taken in this preliminary study. Nevertheless,
Figure 8 shows that the FRT success rate (%) was positively related to the electric field strength at the cerebellum. Here, the FRT success rate (%) was found to be more sensitive to the lower-limb representations lobular median electric field strength than the dentate nuclei median electric field strength. Therefore, a higher electric field strength at the lower-limb representations of the cerebellum is postulated to be responsible for the improvements found during our VR-based based target reaching task where ctDCS montage for the dentate nuclei (PO9h–PO10h) resulted in a significantly (alpha = 0.05) higher electric field strength when compared to the ctDCS montage for the bilateral lower-limb representation of the cerebellum (Exx7–Exx8) for the same stimulation current (2 mA) as shown in the
Figure 7b. Electric field strength due to ctDCS montage for the dentate nuclei (PO9h–PO10h) reached not only the dentate nuclei but also reached lobules Crus I and Crus II (see
Figure 4d ,e), and even resulted in a higher electric field strength at the cerebellar lower-limb representations when compared to the ctDCS montage for the bilateral lower-limb representations of the cerebellum (Exx7–Exx8) for the same stimulation current (2 mA)—see
Figure 4,
Figure 5 and
Figure 6. This is due to a different objective function used to optimize ctDCS montage for the dentate nuclei versus that for the bilateral lower-limb representations of the cerebellum. The optimal ctDCS montage for the bilateral lower-limb representations of the cerebellum aimed for the uniform electric field in the bilateral cerebellar lobules VII-IX whereas the optimal ctDCS montage for the dentate nuclei aimed for maximum electric field strength. Here, the ctDCS montage for the bilateral lower-limb representations of the cerebellum (Exx7–Exx8) will require a higher stimulation current to reach comparable electric field strength at the lower-limb representations of the cerebellum. Also, this pilot study was limited by “one-size-fits-all” ctDCS montage for the dentate nuclei as well as the bilateral lower-limb representations of the cerebellum. In future clinical studies, subject-specific ctDCS montages need to be tested for post-stroke balance training.
The proposed deep ctDCS targeting the dentate nuclei were found to be painless by all the 5 subjects where a weak direct current (= 2 mA) was delivered through a 2 cm diameter saline-soaked sponge electrode overlying the cerebellum. Skin irritation was found in one subject which can be due to a relatively high current density of 0.635 mA/cm
2. Larger electrode size can ameliorate this issue in subjects with sensitive skin. Overall, bipolar bilateral ctDCS of the dentate nuclei performed better than the bipolar bilateral ctDCS of the cerebellar lower-limb representations for the same 2mA stimulation current where extensive reciprocal connectivity between the dentate nucleus and the wide swaths of cerebral cortex can affect motor as well as cognitive function [
12].
Figure 4 shows that conventional ctDCS montages, e.g., Celnik, Manto, and Extracephalic, all affected the dentate nuclei so the functional effects due to these conventional ctDCS montages should be investigated not only based on its effects by polarizing Purkinje cells [
13] but also based on its effects on the dentate nuclei. Also, the electric field effects of the Manto ctDCS montage were primarily focused on the cerebellar lower-limb representations which were found to be comparable to our ctDCS montage (Exx7–Exx8 montage)—see
Figure 4b,e. We also found that electric field effects of our ctDCS montage for the dentate nuclei (PO9h–PO10h) reached lobules Crus I and Crus II (see
Figure 4d) which can have beneficial cognitive effects by polarizing Purkinje cells. Nevertheless, the effectiveness of ctDCS of dentate nuclei needs to be tested as an adjuvant treatment to VR-based balance/weight-shifting training since the final goal is to improve functional outcomes. This pilot study was limited by a heterogeneous small sample size due to convenience sampling which consisted of 10 males within a large age range from 28 years to 59 years. Therefore, a larger clinical study is necessary to statistically confirm the effectiveness of ctDCS of the dentate nuclei with objective balance assessments.
During balance rehabilitation, an objective assessment of the balance and posture during functional reach tasks (FRT) or cued weight-shifting will require optical motion analysis technology that can provide a sensitive measure. However, marker-based systems (e.g., VICON, UK) are too expensive for monitoring in a community setting not only in developing countries but also in developed countries including the USA. Therefore, we developed marker-less time-of-flight systems [
16,
26,
63,
64], including the low-cost (<
$150) Microsoft Kinect sensor (developed for video gaming), that are increasingly used for motion capture due to its lower costs [
65]. Also, postural sway based on the center of pressure (CoP) is important for balance assessment; and the Wii Balance Board (WiiBB) has demonstrated good test-retest reliability (ICC = 0.66–0.94) and construct validity when benchmarked against laboratory-grade force platforms (ICC = 0.77–0.89) [
66]. In principal accordance, we used low-cost (<
$150) WiiBB for standing balance tests where cursor tracking in the virtual reality (VR) using CoP has been implemented and tested for usability [
23]. This HMI has also been tested under an operant conditioning paradigm for balance training [
67] where the cursor (a VR object) controller is designed such that it is less challenging to control using paretic leg to reach the cued VR targets, and this innovative approach can ameliorate learned non-use of the paretic leg by encouraging its increased use during adaptive VR-based weight-shifting tasks [
67]. We postulate that operant conditioning can lead to learned internal representations and response to stimuli that can be facilitated with adjuvant treatment with ctDCS [
68,
69]. Here, VR-environment for FRT is postulated to be motivating thereby improving the therapy effects (Gil-Gómez et al., 2011). Indeed, systematic review and meta-analysis based on forty-three randomized controlled trials have shown that balance capacities can be improved by well-targeted exercise therapy programs, specifically, balance and/or weight-shifting training, in the chronic phase after stroke [
70]. Furthermore, another systematic review and meta-analysis based on literature searches in databases including PubMed, Embase, MEDLINE, and Cochrane Library by de Rooij et al. [
71] showed that VR training is more effective than balance training without VR for improving balance ability in patients with stroke. Also, a systematic review on feasibility and effectiveness based on literature searches in five databases including PubMed and the Cochrane Library [
72] showed that VR can increase motivation allowing longer and more training sessions in community-dwelling stroke survivors. Nevertheless, there exists very little evidence about interventions other than exercises, e.g., ctDCS, that can improve post-stroke standing balance function [
73].
To investigate post-stroke standing balance function, CoP trajectories during cued weight shifts in different directions during FRT [
23] can elucidate ideomotor apraxia (IMA) found in our subjects, which may contribute to patients overall day-to-day motor disability [
74]. IMA of lower limbs has rarely been investigated systematically [
75] even though it has high relevance for maintaining independence in daily life activities [
76]. Furthermore, IMA is one the earliest disturbances in Alzheimer′s disease [
77] where disruption of the cerebrocerebellar network has been hypothesized based on the executive cluster of the cerebellar cognitive affective syndrome (CCAS) [
59]. We recently presented ctDCS for healthy aging [
78] where bipolar bilateral ctDCS can be a low-cost intervention that needs to be validated using a prospective, randomized, placebo-controlled, double-blinded, clinical study. Also, according to the majority of studies in the literature, limb apraxia in right-handed stroke patients is a disorder that typically occurs in 30–50% of the patients with left hemisphere damage and 0 to 30% in patients with right hemisphere damage [
76]. Here, post-stroke IMA patients with left posterior parietal and/or premotor cortex lesions but intact cerebellum can be suitable for ctDCS. Therefore, we are investigating the feasibility of our mobile VR-based balance training in conjunction with bilateral ctDCS in the right lower limb post-stroke IMA with left hemisphere damage [
75]. IMA is also an area of scientific significance for our operant conditioning approach to balance training [
67] where one can learn how the normal human praxis system improves in IMA during adaptive balance training [
67]. This is postulated due to IMA’s cerebellar component related to cardinal motor deficits which are thought to arise from damage to the cerebrocerebellar network communicating internal representations for actions. Here, an early operant conditioning approach to balance training [
67] in a community setting after stroke may be crucial for recovery through learning and experience [
79]. Recovery through balance training [
67] is crucial since falls are more likely in the apraxias [
80], and the severity of apraxia predicts the rehabilitation success for patients with hemiplegia [
76]. In principal accordance, an augmented mobile VR interface can allow remote delivery of new VR balance training games to keep the motivation for home-based intervention. To address usability issues with individualized ctDCS montage, we have developed an innovative low-cost washable neoprene cap with subject-specific stitched saline-soaked electrodes that can be worn during balance training [
20]. Such a home-based upper-limb training approach has also been proposed by de Winckel and colleagues [
22], however, our approach is novel for lower limb balance training.
Our optimization approach for a minimal set of electrodes for home-based tDCS is based on an open-source computational pipeline [
7] that aimed to keep the bilateral ctDCS electric field limited to the cerebellum and away from the cerebral areas that were lesioned in our stroke subjects. Here, first, a reduced set of electrodes (see
Figure 3) relevant for focal stimulation of the cerebellum were identified in the stroke subjects for the optimization of a “one-size-fits-all” bipolar electrode montage for ctDCS, as discussed in the Methods section. This two-step process to identify a “one-size-fits-all” bipolar electrode montage to target cerebellar lobules and nuclei is postulated to be more practical in low-resource home-based or community-based settings constrained by a lack of computing power and high-quality neuroimaging data. However, our innovation in optimizing the lobular electric field for patient-relevant functional outcome and neuroplastic effects in stroke survivors is also important for patient-specific dosing based on MRI data that may reduce inter-individual variability [
81]. Here, optimization based on the relevant component of the electric field [
81] needs to be verified for different cerebellar lobular targets, including the molecular layer, the granule cell layer and the Purkinje cell layer, since different ctDCS electrode montages can affect different parts of the cerebellum (and cerebellar circuit) [
7] leading to different functional outcomes and neuroplastic effects. For example, anodal ctDCS using Celnik montage [
13] affected the adaptation rate of spatial but not temporal elements of walking where the spatial adaptation was postulated to be related to pontocerebellum stimulation [
10]. Our open-source computational modeling pipeline [
7] confirmed that the magnitude of the electric field for Celnik montage [
13] primarily targeted the pontocerebellum as postulated in the experimental paper by Jayaram et al. [
10]. The innovation lies not only in the ability to optimize the lobular electric field in the cerebellum [
7] but also in the augmented approach to address functional heterogeneity [
58] based on the outcomes from a task battery. Here, post-stroke deficits can cover multiple task domains that can be elucidated with multi-domain behavioral experiments (e.g., FRT balance function, hand function, gait function, cognitive function) to develop an appropriate objective function for ctDCS optimization that addresses cerebellar multiple functionalities [
58]. Here, optimization of the lobular electric field in the cerebellum [
7] is challenging without subject-specific neuroimaging guided head modeling due to the extreme folding of the cerebellar cortex. We also postulate for future studies that ctDCS optimization needs to be based on the mapping to universal cerebellar computations (e.g., comparator function) [
58] that can ameliorate deficits in multiple task domains [
58].
Neurorehabilitation service delivery at homes and in the community settings can incorporate mobile-health based approaches to low-cost neurotechnologies that are tailored to an individual health condition as identified based on WHO International Classification of Functioning (ICF) [
82]. Here, functional optimization of ctDCS will require a large patient outcome dataset possible using big data mobile-health (mHealth) approaches that also requires sustainable and multi-professional rehabilitation systems, including the provision of services to the rural population. This was investigated by a randomized controlled trial on family-led rehabilitation after stroke in India (ATTEND) [
83]. In the ATTEND trial, regular stroke rehabilitation services provided by family caregivers were found not effective even after structured training including information provision, joint goal setting, carer training, and task-specific training [
83]. ATTEND trial suggested investigation of the effects of task shifting to health-care assistants or team-based community care that necessitated telerehabilitation strategies due to the scarcity of trained professionals in India. Furthermore, telestroke model in India for thrombolysis in acute ischemic stroke showed that smartphone-based telestroke services may be a much cheaper alternative to video-conferencing-based telestroke services and are more portable with less technical glitches [
84]. India is ripe for the assessment of the feasibility and usability of telemedicine approaches not only in acute stroke [
84] but also in chronic stroke. Tele-rehabilitation is also justified since functional improvements have been found to be equal for telerehabilitation and virtual reality (VR)-based training when compared to a similar intervention with therapist-supervision in the clinic [
72]. Therefore, we propose testing of the effectiveness of a low-cost neurotechnology platform [
23] for remote (smartphone-based) patient care and monitoring through the hub and spoke model (HSM) of telemedicine that is not only necessary to create a large patient outcome dataset but is also crucial to meet the growing needs of stroke survivors in India [
85,
86]. In the HSM of neurorehabilitation, the service delivery assets into a network consist of an anchor establishment (hub) which will offer a full array of services, complemented by secondary community-based establishments (spokes) that can offer local neurorehabilitation service arrays, routing patients needing more intensive services to the hub for treatment. Here, the feasibility of an online assessment document called ‘Rehabilitation Problem-Solving Form’ (RPS-Form) [
87] was shown by us in a preliminary study in India to monitor patient’s response to a short-duration moderate-intensity neurostimulation therapy by assessing all the ICF components. Here, our innovative online RPS-Form captures patients’ perspective that has been shown in our preliminary study [
87] to facilitate communications between the patient (at the spoke in HSM) and his/her multi-disciplinary rehabilitation team (at the hub in HSM) consisting of physiotherapists, occupational therapists, medical doctors, and rehabilitation engineers. Such multi-session neurotechnology intervention may be necessary for a community setting where post-stroke remote tDCS plus target tracking training has been shown feasible and usable for upper limb [
22], however, the feasibility of remote delivery of ctDCS in conjunction with mobile VR-based balance training in a low resource community setting is unknown. Here, the feasibility and usability testing of remote delivery of ctDCS are crucial since usability issues could lead to user error that has the potential to compromise patient safety and negatively impact the quality of therapy and outcomes.