The study demonstrated clinical and neurophysiological-changes in response to the robotic-exoskeleton (19) training compared to the conventional-rehabilitation. The clinical-scales showed improved changes in both RG and CG, however, increased cortical-excitability in the ipsilesional-hemisphere was shown only in RG. Five patients in RG, with the absence of MEPs at the pre-therapy measurements, showed the appearance of MEPs in the ipsilesional-hemisphere post-therapy. The improvement in RMT in ipsilesional-hemisphere showed a trend of normalization over the intervention and were also correlated with sensorimotor-functional improvement.
4.1 Comparison of Clinical-scales of Robotic-therapy group with control-group
The robotic-therapy was effective at releasing spasticity at the wrist-joint with ~ 26% (p = 0.03) improvement over ~ 14% in CG. The regaining normal muscle-tone is considered as a predictor of recovery or the first-step in recovery (22) followed by an increase in muscle-strength and improvement in functional movements or ADL, finally leading to muscle-strength. In this study, AROM and Barthel-Index have been measured as the indicators of ADL (Table-2). Both groups showed significant improvement of AROM, however, RG showed significantly higher improvement of 130% over 47% in CG (p = 0.02). AROM is one of an important parameters in evaluating ADL and increase in AROM of wrist could lead to greater participation in ADL (23). For Barthel-Index, both groups showed similar (~ 20%) improvement (p = 0.82). BI, non-specific crude discrete measure of ADL, measuring discretely for independence, partial-dependence and fully-dependence, and hence, even minimal improvement counts and increases the score by 5. A significant improvement in BI was observed for both the groups (RG & CG). BI is not much reliable as scores might get affected depending on dominant/non-dominant side, thus, is not alone predictor for therapeutic-outcomes (24). Both groups showed significant improvement for BS, however, RG showed ~ 32% improvements over ~ 20% in CG (intergroup p = 0.31) (Table-2). As BS measure the synergy pattern of joints, it depends mainly on various factors e.g. proximal and/or distal-joint condition of recovery, MAS and chronicity etc.
FMU/L, stroke-specific scale, is most reliable measure of sensorimotor-functionalities of the whole-arm (25). RG established significantly higher improvements of ~ 40% over ~ 21% in CG (p = 0.039). In FMS/E, RG showed ~ 28% improvement over ~ 15% in CG. RG did not show significantly different results (p = 0.13) as expected as the intervention was not focused on proximal-component. However, for FMW/H distal-component, both groups showed significant improvement but RG showed significantly higher improvement of ~ 72% over 32% in CG (p = 0.012) because of intensive and repetitive-training of wrist and MCP. Similar improvement has also been reflected in proximal-joints in along with distal-joints robotic-training possibly because of compensatory muscle-activities from proximal-joints (12).
Thus, RG shows an overall increase in sensorimotor-ability and functionality evidenced by increase in FM, AROM and decrease in spasticity (MAS). Patients in RG showed more participation in ADL, reflected by an increase in BI and AROM of the wrist (23). Among the available wrist rehabilitative-devices and dose-matched conventional-intervention for rehabilitation of wrist in stroke, the reported gain in FMW/H is < 4 on a scale of 24 (12),(8),(26–28). In our study, the improvement in the FM score was ~ 14.25 (W/H ~ 7). Any direct comparison with literature is, however, inappropriate considering different factors like chronicity of patients, lesion site, age of the patients, etc. in this study. HWARD(29) also showed improvement in FMW/H (~ 3.8), indicating the usefulness of synchronizing both wrist and MCP-joint movement in grasp and release.
4.2 Comparison of Cortical-excitability of Robotic-therapy with the control-group
Cortical-excitability in pre-therapy measurements was found to be lower in patients with stroke as observed by higher RMT and lower MEP (30),(31),(32),(33),(34). In some patients due to low cortical-excitability, MEP is not recordable even after delivering TMS-stimuli at the highest possible intensity (Maximum Stimulator Output at 100%) (30),(31),(32),(33),(34). In those patients with no MEP recorded, RMT is taken as value of 100, as suggested in literature (35),(36). This study investigated specific impact of therapeutic-interventions on TMS neurophysiological-parameters for cortical-pathways in the context of functional-gains of the hand motor-function.
4.2.1 Ipsilesional and Contralesional-hemisphere changes
At pre-therapy measures in the ipsilesional-hemisphere, only ~ 39% of the total patients’ cohort in the study evoked MEP (Table-2). In RG, 67% of patients (8/12) did not evoke MEP. Out of these 8 (67%) patients, 5 (62%) patients later evoked MEP showing the therapeutic-effectiveness of the exoskeleton in RG. RG showed a significant decrease in RMT (p = 0.0039) from pre-to-post-therapy-sessions which was not observed in CG (p = 0.12). RG showed ~ 16% improvement as compared to ~ 4% improvement in CG (p = 0.037). Interestingly, RG showed significantly higher increase in MEP-amplitude (p = 0.048) post-therapy with increase of ~ 140% (mean = 54.9 µv), whereas CG showed no such improvement. In the contralesional-hemisphere, MEP-amplitude showed a considerable decrease in both groups, though not significant, RG evidencing a considerable decrease of ~ 30% (mean = 151.03 µv) and CG a decrease of only ~ 7% (mean = 14.8 µv) with no significant differences (p = 0.51) (Table-2).
Cortical-excitability measures are used as an objective investigative tool to measure the treatment responsiveness as it provide insights into membrane-excitability of neurons, conduction, and functional-integrity of corticospinal-tract and neuromuscular-junctions (37). The significant decrease in RMT and increase in MEP-amplitude in the ipsilesional-hemisphere demonstrates significant amount of increase in cortical-excitability (38), as was demonstrated in the RG versus CG. It can be interpreted that recovery of motor-function could most likely be a consequence of plastic-reorganization and use-dependent plasticity (38). Cortical-excitability and corticospinal-tract integrity have also been shown to be correlated with functional recovery potential in patients with chronic stroke (31) and exoskeleton-training appears to be beneficial in activating the ipsilesional-hemisphere for chronic patients (13.8 ± 9.1 months). Activation of ipsilesional-hemisphere could indicate either vicariation of the loss of neural circuits or unmasking of pre-existing synapses or recruitment of perilesional areas in ipsilesional-hemisphere or exploitation of the preserved functional recovery reservoir in ipsilesional-hemisphere (35),(39),(40),(41). Further, a ~ 30% decrease in MEP-amplitude in contralesional-hemisphere over the duration of intervention might indicate a decrease in cortical-excitability, evidencing a trend towards restoring the Inter-Hemisphere Inhibition (IHI) balance in the motor-network between the two hemispheres(39),(40), however, it needs to be further evaluated in a larger cohort.
The cortical-excitability measures, usually, are acquired in pre and post-intervention mostly involving brain-stimulation studies. Examples are repetitive TMS, Transcranial Direct-Current Stimulation (tDCS)(42),(43), etc. or in a combination of brain-stimulation with other neuro-rehabilitation strategies like Constrain Induced Movement-Therapy (CIMT) (44) or mirror-therapy (45) or training(46),(47). However, studies evaluating the therapeutic-changes in the cortical-excitability using robotic-training intervention are very rare. To best of our knowledge, only two studies attempt to evaluate the effect of active robotic-training on changes in cortical-excitability, using commercially available devices, such as Lokomat-robot (lower-limb) (48) and ARMEO (upper-limb) (49).
4.2.2 Specific five-patients in RG
A very critical outcome of the therapy was that in RG, MEP was evoked in ipsilesional-hemisphere only for 4/12 patients at the pre-therapy measurements, however, MEP was later evoked for 9/12 patients after robotic-therapy. However, in CG, MEP was evoked only for 5/11 patients and was later evoked for 6/11 patients at post-therapy. Five specific patients in RG who did not evoke MEP at pre-therapy (0 µv) and later evoked MEP (mean = 136.6 ± 38.48 µv), showed a decrease of RMT in ipsilesional-hemisphere (mean = 27 ± 9.64), relative change RMT-ratio (mean = 0.22 ± 0.13) and mean increase in clinical-scales (FMW/H: 7.8 ± 2.38, BI: 22 ± 11.72, AROM: 22 ± 2.73). These changes were relatively much higher than the changes in patients who had MEP evoked at pre-therapy measures. The appearance of MEP in five patients indicates that the robotic-therapy (of just four-weeks with 20 therapy-sessions) has an immense potential of training and reorganization of brain based on use-dependent plasticity, for patients with chronic stroke. The increase in cortical-excitability and normalization of TMS neurophysiological-makers on the ipsilesional-side are also accompanied by greater recovery of hand-function, indexed by sensorimotor and functional recovery (by clinical-scales FMW/H, BI & AROM). Indeed, the appearance of MEPs in ipsilesional-side could be a critical recovery marker in stroke recovery.
4.2.3 Inter-hemispheric differences and asymmetries
The diaschisis between ipsilesional-areas and intact neuronal-networks of contralesional-areas may disturb the cortical-excitability and connectivity-patterns of connected, remote, or primary-motor areas of contralesional-hemisphere (via transcallosal-fibers). The effect of robotic-exoskeleton training on cortical-excitability of both hemisphere shows remodelling of the bilateral primary-motor areas in RG (time*sides p = 0.049, F = 4.08) which is not shown in CG (time*sides p = 0.06, F = 3.68). The effect of exoskeleton-training shows the potential of the exoskeleton to accelerate the cortical-plasticity phenomena in favour of functional-restoration with changes in both ipsilesional and contralesional-hemispheres.
For cortical excitability to be increased in ipsilesional-hemisphere for patients with stroke, the ipsilesional-RMT should be decreased from pre-to-post-therapy and hence, RMTasymm (RMT Ipsilesional/RMT contralesional) should decrease/approach normalization (35). Significant differences were observed between the groups when TMS-neurophysiological changes over the intervention was expressed in terms of the interhemispheric-asymmetry ratio RMTasymm indicating a significantly greater trend towards the normalization of asymmetry of TMS-measures in RG in response to exoskeleton-training than CG (p = 0.028). Also, the extent of normalization i.e. ∆RMTasymm-ratio showed a mean increase of 0.12 ± 0.14 in RG and CG an increase of mean 0.011 ± 0.1 (Table-3). Normalization might indicate the recruitment of peri-lesional areas in the ipsilesional-hemisphere or exploitation of the preserved functional-recovery reservoir in the ipsilesional-hemisphere (35),(39),(40),(41). Normalization in response to therapy, in terms of TMS measures on the ipsilesional-side, has been shown to have a greater recovery of arm and hand function in acute, sub-acute and chronic stages (35).
4.3 TMS neurophysiological improvement correlating the motor-outcome of both groups
The amount of change in TMS neurophysiological-measures of corticomotor-pathways (∆RMTipsi and ∆RMTasymm-ratio) were found to be associated with the amount of improvement in functional motor-outcome during rehabilitation of the distal-part of upper-limb (∆FMW/H) (Figure-3). These parameters were significantly different for RG and CG (∆RMTipsi p = 0.0235, ∆RMTasymm-ratio p = 0.028 and ∆FMW/H p = 0.012). Greater improvement (decrease) in motor-threshold tend to show greater increases with clinical-outcome and was found to have strong positive statistical correlation with ∆FMW/H in RG (∆RMTipsi r = 0.64, p = 0.022 and not in CG r = 0.47, p = 0.13 and ∆RMTasymm-ratio r = 0.6, p = 0.03 and not in CG (r = 0.29, p = 0.38) (Figure-3). The improvement in RMT were most likely due to increased cortical-excitability of preserved motor-pathways with earlier studies in sub-acute and chronic stroke demonstrating correlation of improvement in TMS neurophysiological-measures (improvement in RMT and normalization) with functional improvement (35),(50),(51). This also suggests the usefulness of TMS-measures as an index of recovery in the ipsilesional-hemisphere (35). These neurophysiological-measures were obtained specifically from cortical-representation of EDC muscle, a clinically affected muscle, with a specific function which was involved in training with a robotic-exoskeleton, whereas most clinical-measures do not necessarily require a particular muscle-group and measures motor-function in a broader sense.
Also, these neurophysiological-parameters individually establishes as a significant predictor (∆RMTipsi r = 0.64, F = 7.24, p = 0.022 and ∆RMTasymm-ratio r = 0.6, F = 5.77, p = 0.03) of functional rehabilitation-outcome of hand (∆FMW/H) in RG, indicating that changes in cortical-excitability of ipsilesional-hemisphere could be used to predict the clinical-outcome, hence, emerging as critical recovery parameters to be considered and evaluated in larger data-samples. This might possibly be the plasticity markers predicting the responsiveness of chronic post-stroke patients(49). Hence, the correlation and prediction of improvement in ∆FMW/H component by these muscle-specific neurophysiological-measures comes as an evidence of task-specific rehabilitation of specific-muscle.
4.4 Changes due to the device
The exoskeleton training in RG induced an evident modulation in ipsilesional and contralesional-hemispheres. However, (significant) changes in CG were found to be limited only to the clinical-scales, and the changes in brain was specifically found only in the RG. An increase in cortical-excitability in the ipsilesional-hemisphere along with interhemispheric-normalization of RMTasymm could point towards the recruitment of peri-lesional areas in ipsilesional-hemisphere or exploitation of the preserved functional recovery reservoir in the ipsilesional-hemisphere (35),(39),(40),(41). The decrease of RMT and change in RMT asymmetry from distal-muscle was also accompanied by functional markers-FMW/H evidencing sensorimotor-plasticity, functional recovery along with task-dependent rehabilitation. Greater magnitude of the neurophysiological-changes observed in RG, as compared to CG, may be attributed to the unique features of the device e.g. easy donning and doffing of the device for repositioning of hand, maximum finger-extension at baseline position to provide maximum stretch to reduce spasticity; and diverse attributes of device e.g bio-triggered, real-time adaptive performance-feedback, counteracting flexor-hypertonia against gravity, mimicking functional motion, user-friendly, simple design and patient-specific customizable features with different amount of sensory inputs (proprioceptive, visual, tactile) (19). In combination with the above features, the other unique feature of the device is that it allows the facilitation of a specific-pattern of movements mirroring complex inter-joint coordination of hand with a patient-specific impairment, currently not integrated in the available other devices with isolated-joint movements (52). The devices were able to simulate the movement pattern maintaining joint-coordination, especially at the distal-joints which could aid in translating the motor-improvements into ADL.
Even though data are promising, the study had few limitations such as small sample-size and no long term follow-up of patients. As most of the patients at our quaternary hospital came from far places across India and it was not possible to follow-up with them once they have left New-Delhi.