Individualized closed-loop TMS synchronized with exoskeleton for modulation of cortical-excitability in patients with stroke: a proof-of-concept study.

Background: Repetitive TMS is used in stroke rehabilitation with predefined passive low and high-frequency stimulation. Brain State-Dependent Stimulation (BSDS)/Activity-Dependent Stimulation (ADS) using bio-signal has been observed to strengthen synaptic connections. Without the personalization of brain-stimulation protocols, we risk a one-size-fits-all approach. Methods: We attempted to close the ADS loop via intrinsic-proprioceptive (via exoskeleton-movement) and extrinsic-visual-feedback to the brain. We developed a patient-specific brain stimulation platform with a two-way feedback system, to synchronize single-pulse TMS with exoskeleton along with adaptive performance visual feedback, in real-time, for a focused neurorehabilitation strategy to voluntarily engage the patient in the brain stimulation process. Results: The novel TMS Synchronized Exoskeleton Feedback (TSEF) platform, controlled by the patient's residual Electromyogram, simultaneously triggered exoskeleton movement and single-pulse TMS, once in 10 s, implying 0.1 Hz frequency. The TSEF platform was tested for a demonstration on three patients (n = 3) with different spasticity on the Modified Ashworth Scale (MAS = 1, 1+, 2) for one session each. Three patients completed their session in their own timing; patients with (more) spasticity tend to take (more) inter-trial intervals. A proof-of-concept study on two groups-TSEF-group and a physiotherapy control-group was performed for 45 min/day for 20-sessions. Dose-matched Physiotherapy was given to control-group. Post 20 sessions, an increase in ipsilesional cortical-excitability was observed; Motor Evoked Potential increased by ~48.5 µV at a decreased Resting Motor Threshold by ~15.6%, with improvement in clinical scales relevant to the Fugl-Mayer Wrist/Hand joint (involved in training) by 2.6 units, an effect not found in control-group. This strategy could voluntarily engage the patient. Conclusion: A brain stimulation platform with a real-time two-way feedback system was developed to voluntarily engage the patients during the brain stimulation process and a proof-of-concept study on three patients indicates clinical gains with increased cortical excitability, an effect not observed in the control-group; and the encouraging results nudge for further investigations on a larger cohort.

Clinical potential and neuroplastic effect of targeted virtual reality based intervention for distal upper limb in post-stroke rehabilitation: a pilot observational study.

PURPOSE: A library of Virtual Reality (VR) tasks has been developed for targeted post-stroke rehabilitation of distal upper extremities. The objective of this pilot study was to evaluate the clinical potential of the targeted VR-based therapeutic intervention in a small cohort of patients specifically with chronic stroke. Furthermore, our aim was to explore the possible neuronal reorganizations in corticospinal pathways in response to the distal upper limb targeted VR-intervention. METHODOLOGY: Five patients with chronic stroke were enrolled in this study and were given VR-intervention of 20 sessions of 45 min each. Clinical Scales, cortical-excitability measures (using Transcranial Magnetic Stimulation): Resting Motor Threshold (RMT), and Motor Evoked Potential (MEP) amplitude, task-specific performance metrics i.e., Time taken to complete the task (TCT), smoothness of trajectory, relative % error were evaluated pre- and post-intervention to evaluate the intervention-induced improvements. RESULTS: Pre-to post-intervention improvements were observed in Fugl-Meyer Assessment (both total and wrist/hand component), Modified Barthel Index, Stroke Impact Scale, Motor Assessment Scale, active range of motion at wrist, and task-specific outcome metrics. Pre-to post-intervention ipsilesional RMT reduced (mean ∼9%) and MEP amplitude increased (mean ∼29µV), indicating increased cortical excitability at post-intervention. CONCLUSION: VR-training exhibited improved motor outcomes and cortical-excitability in patients with stroke. Neurophysiological changes observed in terms of improved cortical-excitability might be a consequence of plastic reorganization induced by VR-intervention.IMPLICATIONS FOR REHABILITATIONPost-stroke rehabilitation of distal upper extremities is crucial and needs targeted intervention to rehabilitate in the chronic phase of recovery.Virtual reality (VR) has emerged as a supplemental approach in post-stroke rehabilitation. However, its customization as per clinical need is still under research.This pilot study provides preliminary evidence of the clinical utility of the developed VR tasks targeted for distal upper extremities.

Post-Stroke Rehabilitation of Distal Upper Limb with New Perspective Technologies: Virtual Reality and Repetitive Transcranial Magnetic Stimulation-A Mini Review.

Upper extremity motor impairment is the most common sequelae in patients with stroke. Moreover, its continual nature limits the optimal functioning of patients in the activities of daily living. Because of the intrinsic limitations in the conventional form of rehabilitation, the rehabilitation applications have been expanded to technology-driven solutions, such as Virtual Reality and Repetitive Transcranial Magnetic Stimulation (rTMS). The motor relearning processes are influenced by variables, such as task specificity, motivation, and feedback provision, and a VR environment in the form of interactive games could provide novel and motivating customized training solutions for better post-stroke upper limb motor improvement. rTMS being a precise non-invasive brain stimulation method with good control of stimulation parameters, has the potential to facilitate neuroplasticity and hence a good recovery. Although several studies have discussed these forms of approaches and their underlying mechanisms, only a few of them have specifically summarized the synergistic applications of these paradigms. To bridge the gaps, this mini review presents recent research and focuses precisely on the applications of VR and rTMS in distal upper limb rehabilitation. It is anticipated that this article will provide a better representation of the role of VR and rTMS in distal joint upper limb rehabilitation in patients with stroke.

A novel perspective of associativity of upper limb motor impairment and cortical excitability in sub-acute and chronic stroke.

Background: The global inclination of stroke onset in earlier years of life and increased lifespan have resulted in an increased chronic post-stroke-related disability. The precise and simplistic approach such as the correlation of Fugl-Meyer Assessment (FMA) with Transcranial Magnetic Stimulation (TMS) parameters, Resting Motor Threshold (RMT) and Motor Evoked Potential (MEP), in patients with stroke might play a critical role, given the prognostic value of MEP, a measure of cortical excitability, and might be the key point in prescribing appropriate therapeutic strategies. Objective: The study aimed to determine the correlation of FMA-based impairment in the upper extremity function specifically of the wrist and hand with respect to the neurophysiological parameters of corticospinal tract integrity. Materials and methods: The Institutional Review Board approved the study and 67 (n) patients with stroke were enrolled in the Department of Neurology, AIIMS, New Delhi, India. The motor assessment was performed on patients by the upper extremity subset of Fugl-Meyer Assessment (FMA) and the clinical history was obtained. RMT and MEP of Extensor Digitorum Communis (EDC) muscle were measured via TMS. Results: A significant positive correlation was observed between Fugl-Meyer Assessment Wrist/Hand (FMA W/H) and MEP scores (r = 0.560, <0.001). Also, Fugl-Meyer Assessment Upper Extremity (FMA UE) scores demonstrated a moderate positive association with MEP responsiveness (r = 0.421, <0.001). Conclusion: MEP of the EDC muscle was found to be associated with sensorimotor control as measured by FMA. Moreover, FMA W/H score values might be a better prognostic indicator of EDC MEP responsiveness. Interestingly, a novel element comprising the range of FMA UE and FMA W/H components was observed to be a potential indicator of MEP responsiveness and could also indicate establishing FMA as a surrogate for TMS in resource-limited settings for prognostification.

Preclinical safety of tetrahydrocurcumin loaded lipidic nanoparticles incorporated into tacrolimus ointment: In vitro and in vivo evaluation.

Preclinical safety and proof of concept studies for a topical ointment comprising of concentrated tetrahydrocurcumin loaded lipidic nanoparticles (THC-LNs) and tacrolimus ointment (TTO) is proposed in the present investigation. The skin irritation potential and acute dermal toxicity were performed in rats in compliance with the Organization for Economic Cooperation and Development (OECD) guidelines (402, 404 and 410) while the cytotoxic potential was performed in HaCaT cells. Finally, in vivo evaluation was performed in Imiquimod mice model of psoriasis. In primary skin irritation assessment, TTO formulation, marketed formulation (Tacroz® Forte), THC-LNs, and blank LNs were topically applied on intact skin sites in rats while another group served as a negative control group for 72 h. TTO did not induce any adverse reactions. Repeated 28 days dermal toxicity followed by biochemical and histopathological assessment showed negligible alternations and skin lesions. THC-LNs revealed negligible cytotoxic potential in HaCaT cells. TTO showed significantly high anti-psoriatic activity in comparison to marketed ointment. This was also confirmed via histopathological evaluation. Based on these findings, it can be ascertained that TTO showed minimal toxicity and has ample potential for further clinical analysis. The above studies affirm the potential of TTO as an alternative for psoriasis.

Design and Validation of Virtual Reality Task for Neuro-Rehabilitation of Distal Upper Extremities.

Stroke, affecting approximately 15 million people worldwide, has long been a global cause of death and disability. Virtual Reality (VR) has shown its potential as an assistive tool for post-stroke rehabilitation. The objective of this pilot study was to define the task-specific performance metrics of VR tasks to assess the performance level of healthy subjects and patients quantitatively and to obtain their feedback for improving the developed framework. A pilot prospective study was designed. We tested the designed VR tasks on forty healthy right-handed subjects to evaluate its potential. Qualitative trajectory plots and three quantitative performance metrics-time taken to complete the task, percentage relative error, and trajectory smoothness-were computed from the recorded data of forty healthy subjects. Two patients with stroke were also enrolled to compare their performance with healthy subjects. Each participant received one VR session of 90 min. No adverse effects were noticed throughout the study. Performance metrics obtained from healthy subjects were used as a reference for patients. Relatively higher values of task completion time and trajectory smoothness and lower values of relative % error was observed for the affected hands w.r.t the unaffected hands of both the patients. For the unaffected hands of both the patients, the performance levels were found objectively closer to that of healthy subjects. A library of VR tasks for wrist and fingers were designed, and task-specific performance metrics were defined in this study. The evaluation of the VR exercises using these performance metrics will help the clinicians to assess the patient's progress quantitatively and to design the rehabilitation framework for a future clinical study.

Clinical Effectiveness of Non-Immersive Virtual Reality Tasks for Post-Stroke Neuro-Rehabilitation of Distal Upper-Extremities: A Case Report.

A library of non-immersive Virtual Reality (VR) tasks were developed for post-stroke rehabilitation of distal upper extremities. The objective was to evaluate the rehabilitation impact of the developed VR-tasks on a patient with chronic stroke. The study involved a 50-year-old male patient with chronic (13 month) stroke. Twenty VR therapy sessions of 45 min each were given. Clinical scales, cortical-excitability measures, functional MRI (fMRI), and diffusion tensor imaging (DTI) data were acquired pre-and post-therapy to evaluate the motor recovery. Increase in Fugl-Meyer Assessment (wrist/hand) by 2 units, Barthel Index by 5 units, Brunnstrom Stage by 1 unit, Addenbrooke's Cognitive Examination by 3 units, Wrist Active Range of Motion by 5° and decrease in Modified Ashworth Scale by 1 unit were observed. Ipsilesional Motor Evoked Potential (MEP) amplitude (obtained using Transcranial Magnetic Stimulation) was increased by 60.9µV with a decrease in Resting Motor Threshold (RMT) by 7%, and contralesional MEP amplitude was increased by 56.2µV with a decrease in RMT by 7%. The fMRI-derived Laterality Index of Sensorimotor Cortex increased in precentral-gyrus (from 0.28 to 0.33) and in postcentral-gyrus (from 0.07 to 0.3). The DTI-derived FA-asymmetry decreased in precentral-gyrus (from 0.029 to 0.024) and in postcentral-gyrus (from 0.027 to 0.017). Relative reduction in task-specific performance metrics, i.e., time taken to complete the task (31.6%), smoothness of trajectory (76.7%), and relative percentage error (80.7%), were observed from day 1 to day 20 of the VR therapy. VR therapy resulted in improvement in clinical outcomes in a patient with chronic stroke. The research also gives insights to further improve the overall system of rehabilitation.

A Case Report: Effect of Robotic Exoskeleton Based Therapy on Neurological and Functional Recovery of a Patient With Chronic Stroke.

Background: In this study, a novel electromechanical robotic exoskeleton was developed for the rehabilitation of distal joints. The objective was to explore the functional MRI and the neurophysiological changes in cortical-excitability in response to exoskeleton training for a 9-year chronic stroke patient. Case-Report: The study involved a 52-year old female patient with a 9-year chronic stroke of the right hemisphere, who underwent 20 therapy sessions of 45 min each. Cortical-excitability and clinical-scales: Fugl-Mayer (FM), Modified Ashworth Scale (MAS), Brunnstrom-Stage (BS), Barthel-Index (BI), Range of Motion (ROM), were assessed pre-and post-therapy to quantitatively assess the motor recovery. Clinical Rehabilitation Impact: Increase in FM wrist/hand by 6, BI by 10, and decrease in MAS by 1 were reported. Ipsilesional Motor Evoked Potential (MEP) (obtained using Transcranial Magnetic Stimulation) was increased by 98 µV with a decrease in RMT by 6% and contralesional MEP was increased by 43 µV with a decrease in RMT by 4%. Laterality Index of Sensorimotor Cortex (SMC) reduced in precentral- gyrus (from 0.152 to -0.707) and in postcentral-gyrus (from 0.203 to -0.632). Conclusion: The novel exoskeleton-based training showed improved motor outcomes, cortical excitability, and neuronal activation. The research encourages the further investigation of the potential of exoskeleton training.

Evidence of neuroplasticity with robotic hand exoskeleton for post-stroke rehabilitation: a randomized controlled trial.

BACKGROUND: A novel electromechanical robotic-exoskeleton was designed in-house for the rehabilitation of wrist joint and Metacarpophalangeal (MCP) joint. OBJECTIVE: The objective was to compare the rehabilitation effectiveness (clinical-scales and neurophysiological-measures) of robotic-therapy training sessions with dose-matched conventional therapy in patients with stroke. METHODS: A pilot prospective parallel randomized controlled study at clinical settings was designed for patients with stroke within 2 years of chronicity. Patients were randomly assigned to receive an intervention of 20 sessions of 45 min each, five days a week for four weeks, in Robotic-therapy Group (RG) (n = 12) and conventional upper-limb rehabilitation in Control-Group (CG) (n = 11). We intended to evaluate the effects of a novel exoskeleton based therapy on the functional rehabilitation outcomes of upper-limb and cortical-excitability in patients with stroke as compared to the conventional-rehabilitation. Clinical-scales- Modified Ashworth Scale, Active Range of Motion, Barthel-Index, Brunnstrom-stage and Fugl-Meyer (FM) scale and neurophysiological measures of cortical-excitability (using Transcranial Magnetic Stimulation) -Motor Evoked Potential and Resting Motor threshold, were acquired pre- and post-therapy. RESULTS: No side effects were noticed in any of the patients. Both RG and CG showed significant (p < 0.05) improvement in all clinical motor-outcomes except Modified Ashworth Scale in CG. RG showed significantly (p < 0.05) higher improvement over CG in Modified Ashworth Scale, Active Range of Motion and Fugl-Meyer scale and FM Wrist-/Hand component. An increase in cortical-excitability in ipsilesional-hemisphere was found to be statistically significant (p < 0.05) in RG over CG, as indexed by a decrease in Resting Motor Threshold and increase in the amplitude of Motor Evoked Potential. No significant changes were shown by the contralesional-hemisphere. Interhemispheric RMT-asymmetry evidenced significant (p < 0.05) changes in RG over CG indicating increased cortical-excitability in ipsilesional-hemisphere along with interhemispheric changes. CONCLUSION: Robotic-exoskeleton training showed improvement in motor outcomes and cortical-excitability in patients with stroke. Neurophysiological changes in RG could most likely be a consequence of plastic reorganization and use-dependent plasticity. Trial registry number: ISRCTN95291802.

Assay and Dermatokinetics of Tetrahydrocurcumin Lipidic Nanostructures Using Reverse Phase-high Performance Liquid Chromatography.

BACKGROUND: Envisaging the poor solubility (56 ngml1) and permeability of tetrahydrocurcumin (THCC), it was formulated into lipidic nanostructures to enhance its bioavailability upon topical application to promote the healing process for skin inflammatory disorders. Lack of literature on a suitable method for determining THCC per se and nanoformulations prompted us to develop an RP-HPLC method to detect the drug in its nanostructures and in pig ear skin post dermatokinetics. OBJECTIVE: The present investigation aimed to develop a simple, precise and RP-HPLC method for the quantitative estimation of THCC in prepared lipidic nanostructures, its ointment, and in skin homogenate obtained post dermatokinetic study. METHODS: THCC encapsulated nanostructures and ointment were formulated using a modified emulsification method and embedded into an ointment base to enhance its spreadability and improve patient compliance. A fast and sensitive reverse-phase high-performance liquid chromatography method was developed using a Hypersil BDS reverse phase C18 column (4.6 mm × 250 mm, 5 µm) with mobile phase comprising tetrahydrofuran (THF) and 1 mgmL-1 citric acid (4:6), at a flow rate of 1.0 mLmin-1 with a run time of 20 min. RESULTS: THCC nanostructures were successfully prepared using the spontaneous microemulsification method. THCC was detected at 282 nm and revealed two peaks which were attributed to the keto-enol tautomerism in the molecule with retention times of 6.23 min and 11.06 min, respectively. The assay of THCC in nanostructures and ointment was found to be 98.30 % and 99.98 %, with an entrapment efficiency 77.00±2.74 %. The dermatokinetic studies revealed sufficient release of THCC from its ointment up to 24 hr with a concentration of 1382 µgcm-2, for causing a therapeutic effect. CONCLUSION: The method was found to be reproducible and robust, as shown by the low coefficient of variation and a constant analyte/IS ratio. It was successfully employed for the estimation of THCC assay in nanostructures and its ointment and dermatokinetic analysis in the skin.

Robotic Exoskeleton for Wrist and Fingers Joint in Post-Stroke Neuro-Rehabilitation for Low-Resource Settings.

Robots have the potential to help provide exercise therapy in a repeatable and reproducible manner for stroke survivors. To facilitate rehabilitation of the wrist and fingers joint, an electromechanical exoskeleton was developed that simultaneously moves the wrist and metacarpophalangeal joints. The device was designed for the ease of manufacturing and maintenance, with specific considerations for countries with limited resources. Active participation of the user is ensured by the implementation of electromyographic control and visual feedback of performance. Muscle activity requirements, movement parameters, range of motion and speed, of the device can all be customized to meet the needs of the user. Twelve stroke survivors, ranging from the subacute to chronic phases of recovery (mean 10.6 months post-stroke) participated in a pilot study with the device. Participants completed 20 sessions, each lasting 45 minutes. Overall, subjects exhibited statistically significant changes (p < 0.05) in clinical outcome measures following the treatment, with the Fugl-Meyer Stroke Assessment score for the upper extremity increasing from 36 to 50 and the Barthel Index increasing from 74 to 89. Active range of wrist motion increased by 19° while spasticity decreased from 1.75 to 1.29 on the Modified Ashworth Scale. Thus, this device shows promise for improving rehabilitation outcomes, especially for patients in countries with limited resources.

Formulation and evaluation of curcumin microsponges for oral and topical drug delivery.

The aim of the present study was to improve the release rate of curcumin by microsponges prepared through quasi-emulsion solvent diffusion technique using ethylcellulose and PVA as carriers. The microsponges were characterized by FTIR, DSC, XRD and SEM studies followed by determination of total drug content and entrapment efficiency. The prepared microsponges were further filled in hard gelatin capsule shell and then loaded in carbopol gel to evaluate its potential in oral and topical drug delivery. Further, it was observed from the studies on release rate that microsponges filled in hard gelatin capsule shells (batch MS4) showed 93.2% release of curcumin whereas pure curcumin filled in capsule showed only 11.7% release in 8 h study. Furthermore, the microsponges loaded in carbopol gel were evaluated for ex vivo drug deposition studies and it was found that 77.5% of the curcumin was released within 24 h. The estimated drug remained in the skin was 207.61 ± 5.03 µg/cm2 as determined by a Franz diffusion cell. The drug release profile data were found to be fitted best into the zero-order model with anomalous transport mechanism of drug release in both cases.

Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment.

Cancer remains a global health problem and approximately 1.7 million new cancer cases are diagnosed every year worldwide. Although diverse molecules are currently being explored as targets for cancer therapy the tumor treatment and therapy is highly tricky. Secondary messengers are important for hormone-mediated signaling pathway. Cyclic AMP (cAMP), a secondary messenger responsible for various physiological processes regulates cell metabolism by activating Protein kinase A (PKA) and by targeting exchange protein directly activated by cAMP (EPAC). EPAC is present in two isoforms EPAC1 and EPAC2, which exhibit different tissue distribution and is involved in GDP/GTP exchange along with activating Rap1- and Rap2-mediated signaling pathways. EPAC is also known for its dual role in cancer as pro- and anti-proliferative in addition to metastasis. Results after perturbing EPAC activity suggests its involvement in cancer cell migration, proliferation, and cytoskeleton remodeling which makes it a potential therapeutic target for cancer treatments.

Insight into buffalo (Bubalus bubalis) RIG1 and MDA5 receptors: a comparative study on dsRNA recognition and in-vitro antiviral response.

RIG1 and MDA5 have emerged as important intracellular innate pattern recognition receptors that recognize viral RNA and mediate cellular signals controlling Type I interferon (IFN-I) response. Buffalo RIG1 and MDA5 genes were investigated to understand the mechanism of receptor induced antiviral response. Sequence analysis revealed that RIG1 and MDA5 maintain a domain arrangement that is common in mammals. Critical binding site residues of the receptors are evolutionary conserved among mammals. Molecular dynamics simulations suggested that RIG1 and MDA5 follow a similar, if not identical, dsRNA binding pattern that has been previously reported in human. Moreover, binding free energy calculation revealed that MDA5 had a greater affinity towards dsRNA compared to RIG1. Constitutive expressions of RLR genes were ubiquitous in different tissues without being specific to immune organs. Poly I:C stimulation induced elevated expressions of IFN-ß and IFN-stimulated genes (ISGs) through interferon regulatory factors (IRFs) mediated pathway in buffalo foetal fibroblast cells. The present study provides crucial insights into the structure and function of RIG1 and MDA5 receptors in buffalo.