Posts Tagged functional recovery

[Abstract] High-Intensity Interval Training After Stroke: An Opportunity to Promote Functional Recovery, Cardiovascular Health, and Neuroplasticity.

Abstract

INTRODUCTION:

Stroke is the leading cause of adult disability. Individuals poststroke possess less than half of the cardiorespiratory fitness (CRF) as their nonstroke counterparts, leading to inactivity, deconditioning, and an increased risk of cardiovascular events. Preserving cardiovascular health is critical to lower stroke risk; however, stroke rehabilitation typically provides limited opportunity for cardiovascular exercise. Optimal cardiovascular training parameters to maximize recovery in stroke survivors also remains unknown. While stroke rehabilitation recommendations suggest the use of moderate-intensity continuous exercise (MICE) to improve CRF, neither is it routinely implemented in clinical practice, nor is the intensity always sufficient to elicit a training effect. High-intensity interval training (HIIT) has emerged as a potentially effective alternative that encompasses brief high-intensity bursts of exercise interspersed with bouts of recovery, aiming to maximize cardiovascular exercise intensity in a time-efficient manner. HIIT may provide an alternative exercise intervention and invoke more pronounced benefits poststroke.

OBJECTIVES:

To provide an updated review of HIIT poststroke through ( a) synthesizing current evidence; ( b) proposing preliminary considerations of HIIT parameters to optimize benefit; ( c) discussing potential mechanisms underlying changes in function, cardiovascular health, and neuroplasticity following HIIT; and ( d) discussing clinical implications and directions for future research.

RESULTS:

Preliminary evidence from 10 studies report HIIT-associated improvements in functional, cardiovascular, and neuroplastic outcomes poststroke; however, optimal HIIT parameters remain unknown.

CONCLUSION:

Larger randomized controlled trials are necessary to establish ( a) effectiveness, safety, and optimal training parameters within more heterogeneous poststroke populations; (b) potential mechanisms of HIIT-associated improvements; and ( c) adherence and psychosocial outcomes.

 

via High-Intensity Interval Training After Stroke: An Opportunity to Promote Functional Recovery, Cardiovascular Health, and Neuroplasticity. – PubMed – NCBI

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[WEB SITE] Neural works

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STROKE IS THE leading cause of disability in adults, and can affect many parts of the brain, causing multiple deficits including the ones in cognitive, behavioural, visual, speech, sensation, movement, muscle tone and sphincter functions. There are two types of recovery after stroke—spontaneous neurological recovery, which happens in the first three to six months owing to resolution of local injury and can be modified by newer interventions, and functional recovery, for which the time period is unlimited and that involves intensive training that triggers newer electrical circuits in the brain.

Similarly, there are two different approaches of neurological rehabilitation—compensation and remediation. In the compensatory approach, for example, if someone has difficulty in walking because of lack of movements in the leg, then we give him a stick to walk. In remediation, on the other hand, we try to minimise the impairment or improve power in the leg muscles and reduce the chances of using a stick. This ability of the brain to restore the function by minimising the impairment depends upon the formation of new or alternative circuits in the brain. This inherent but not widely known ability of the brain to change in response to a triggered stimulus is called neuroplasticity.

Neuroplasticity is the capacity of neurons and neural networks in the brain to change their connections and behaviour in response to new information, sensory stimulation, development, damage or dysfunction. In fact, for many years, it was believed that certain functions were hard-wired in specific, localised regions of the brain and that any incidents of brain change or recovery were mere exceptions to the rule—’brain cannot change’. However, since the 1970s and 1980s, neuroplasticity has gained wide acceptance in the scientific community as a complex, multifaceted, fundamental property of the brain. Remodelling of neural circuits through plasticity can occur spontaneously or can be triggered by intensive training (experience-dependent plasticity) and biological treatments (pharmacological agents and transcranial magnetic stimulation).

Dr Abhishek Srivastava

Dr Abhishek Srivastava

There are four different types of neuroplasticity: map expansion, homologous area adaptation, compensatory masquerade and cross-modal reassignment.

Map expansion entails flexibility of local brain regions that are dedicated to performing one type of function or storing a particular form of information. The arrangement of these local regions in the cerebral cortex is referred to as a ‘map’. When one function is carried out frequently enough through repeated behaviour or stimulus, the region of the cortical map dedicated to this function grows and shrinks as an individual exercises this function. This phenomenon usually takes place during the learning and practising of a skill such as playing a musical instrument or in task-specific trainings in stroke patients to improve specific functions like arm or leg movements, speech, language, cognitive or swallow function. This is the most commonly used approach in neurorehab.

Homologous area adaptation occurs during the early critical period of development. If a particular brain module becomes damaged in early life, its normal operations have the ability to shift to brain areas that do not include the affected module. The function is often shifted to a module in the matching or homologous area of the opposite brain hemisphere. This concept can help improve speech and language function after stroke with involvement of the dominant lobe.

Compensatory masquerade can simply be described as the brain figuring out an alternative strategy for carrying out a task when the initial strategy cannot be followed due to impairment. One example is when a person attempts to navigate from one location to another. Most people have an intuitive sense of direction and distance that they employ for navigation. However, a person who suffers some form of brain injury or stroke and impaired spatial sense will resort to another strategy for spatial navigation, such as memorising landmarks. The only change that occurs in the brain is a reorganisation of preexisting neuronal networks. This is a simple and novel way by which stroke survivors who were not able to do a complex everyday task can be trained to do it themselves.

Cross-modal reassignment entails the introduction of new inputs into a brain area deprived of its main inputs. A classic example of this is the ability of an adult who has been blind since birth to have touch or somatosensory input redirected to the visual cortex in the occipital lobe of the brain—specifically, in an area known as V1. Sighted people, however, do not display any V1 activity when presented with similar touch-oriented experiments. This occurs because neurons communicate with one another in the same abstract language of electrochemical impulses regardless of sensory modality. This strategy is useful to improve visual or auditory functions after stroke.

Most of the recent rehabilitation approaches to improve sensory-motor recovery, including rehab robotics, virtual reality, mirror training, constraint induced therapy, task-specific training and intensive locomotor training, work on the principles of neuroplasticity. These help in improving most of the functions after stroke including cognitive, visual, behavioural, speech, language, swallow, movements, tone or sphincter functions. I have seen many stroke patients, thought to be in a vegetative state for life, now living independently, thanks to neurological rehabilitation.

Srivastava is a neurorehab specialist and director, centre for rehabilitation, Kokilaben Dhirubhai Ambani Hospital, Mumbai.

 

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[Abstract+References] Brain Plasticity and Modern Neurorehabilitation Technologies

Abstract

In recent decades, interest in studies on basic and applied aspects of how the nervous system functions has been growing rapidly around the world. The recovery of lost functions rests on processes of neuroplasticity, which is determined by the ability of the brain to transform its structures in response to injury. The effects of both routine and state-of-the-art neurorehabilitation technologies are ensured by synaptic plasticity— long-term potentiation and long-term depression, which influence learning and the preservation of new knowledge and skills obtained during rehabilitation. The introduction of new methods of neuroimaging, neurophysiology, and mathematical statistics have powerfully stimulated the development of the neuroplasticity doctrine. It has become clear that the main role in the recovery of injured functions is played by the reorganization of cortical nets and not by tissue reparation as such. The Research Center of Neurology has accumulated significant experience in the use of innovative treatment methods based on modern neurorehabilitation principles. Some of them are used for acute stroke; among other things, their effectiveness and safety have been shown with regard to patients in intensive care units (cyclic robotic mechanotherapy) and patients with severe motor deficit and an associated somatic pathology (stimulation of plantar support zones). Opportunities to assess neuroplasticity under various rehabilitation methods using fMRI and navigated transcranial magnetic stimulation (TMS) are revealed. The center also studies the fundamentals of consciousness using original neuroimaging and neurophysiological protocols for the sake of its recovery. The center is actively introducing its data into the practice of domestic clinics specializing in recovery medicine and neurorehabilitation.

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[Abstract] Pilot Study Combining Electrical Stimulation and a Dynamic Hand Orthosis for Functional Recovery in Chronic Stroke

Abstract

OBJECTIVE. We investigated the effect of a combined neuromuscular electrical stimulation (ES) and dynamic hand orthosis (DHO) regimen with a group of people with chronic stroke to improve performance on specific daily tasks.

METHOD. Four people with chronic stroke participated in an ES–DHO regimen using the affected upper extremity 5×/wk for 6 wk. Outcome measures included grip strength, range of motion (ROM), and analysis of muscle activation–deactivation during release of grasp through electromyography. Ability to perform specific daily living tasks was assessed using the Assessment of Motor and Process Skills (AMPS).

RESULTS. Results suggested that improvements in strength, ROM, and grasp deactivation are possible with the combined ES–DHO regimen. All participants’ AMPS motor scores improved.

CONCLUSIONS. An ES–DHO regimen may improve motor skills needed for functional task performance in people with chronic stroke. Results should be interpreted cautiously because of the pilot nature of the study and the small sample size.

via Pilot Study Combining Electrical Stimulation and a Dynamic Hand Orthosis for Functional Recovery in Chronic Stroke | American Journal of Occupational Therapy

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[Abstract] Improving Cognitive Function in Patients with Stroke: Can Computerized Training Be the Future?

Background

Cognitive impairment after stroke is common and can cause disability with a high impact on quality of life and independence. Cognitive rehabilitation is a therapeutic approach designed to improve cognitive functioning after central nervous system’s injuries. Computerized cognitive rehabilitation (CCR) uses multimedia and informatics resources to optimize cognitive compromised performances. The aim of this study is to evaluate the effects of pc cognitive training with Erica software in patients with stroke.

Methods

We studied 35 subjects (randomly divided into 2 groups), affected by either ischemic or hemorrhagic stroke, having attended from January 2013 to May 2015 the Laboratory of Robotic and Cognitive Rehabilitation of Istituto di Ricerca e Cura a Carattere Scientifico Neurolesi in Messina. Cognitive dysfunctions were investigated through a complete neuropsychological battery, administered before (T0) and after (T1) each different training.

Results

At T0, all the patients showed language and cognitive deficits, especially in attention process and memory abilities, with mood alterations. After the rehabilitation program (T1), we noted a global cognitive improvement in both groups, but a more significant increase in the scores of the different clinical scales we administered was found after CCR.

Conclusions

Our data suggest that cognitive pc training by using the Erica software may be a useful methodology to increase the post-stroke cognitive recovery.

 

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[Abstract] Improving Cognitive Function in Patients with Stroke: Can Computerized Training Be the Future?

Background

Cognitive impairment after stroke is common and can cause disability with a high impact on quality of life and independence. Cognitive rehabilitation is a therapeutic approach designed to improve cognitive functioning after central nervous system’s injuries. Computerized cognitive rehabilitation (CCR) uses multimedia and informatics resources to optimize cognitive compromised performances. The aim of this study is to evaluate the effects of pc cognitive training with Erica software in patients with stroke.

Methods

We studied 35 subjects (randomly divided into 2 groups), affected by either ischemic or hemorrhagic stroke, having attended from January 2013 to May 2015 the Laboratory of Robotic and Cognitive Rehabilitation of Istituto di Ricerca e Cura a Carattere Scientifico Neurolesi in Messina. Cognitive dysfunctions were investigated through a complete neuropsychological battery, administered before (T0) and after (T1) each different training.

Results

At T0, all the patients showed language and cognitive deficits, especially in attention process and memory abilities, with mood alterations. After the rehabilitation program (T1), we noted a global cognitive improvement in both groups, but a more significant increase in the scores of the different clinical scales we administered was found after CCR.

Conclusions

Our data suggest that cognitive pc training by using the Erica software may be a useful methodology to increase the post-stroke cognitive recovery.

 

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[Abstract] Effects of Transcranial direct current stimulation with sensory modulation on stroke motor rehabilitation: A randomized controlled trial  

 

Abstract

Objective

To test whether a multi-strategy intervention enhanced recovery immediately and longitudinally in patients with severe to moderate upper extremity (UE) paresis.

Design

Double-blind randomized controlled trial with placebo control.

Setting

An outpatient department of a local medical center.

Participants

People (n = 25) with chronic stroke were randomly assigned to 2 groups. Participants in the transcranial direct current stimulation with sensory modulation (tDCS-SM) and in the control group were 55.3±11.5 (n=14) and 56.9±13.5 (n=11) years old, respectively.

Interventions

8-week intervention. The tDCS-SM group received bilateral tDCS, bilateral cutaneous anesthesia, and high repetitions of passive movements on the paretic hand. The control group received the same passive movements but with sham tDCS and sham anesthesia. During the experiment, all participants continued their regular rehabilitation.

Main outcome measures

Voluntary UE movement, spasticity, UE function, and basic activities of daily living. Outcomes were assessed at baseline, at post-intervention, and at 3- and 6-month follow-ups.

Results

No significant differences were found between groups. However, there was a trend that the voluntary UE movement improved more in the tDCS-SM group than in the control group, with a moderate immediate effect (partial η2, ηp2 = 0.14, p = 0.07) and moderate long-term effects (ηp2 =0.17, p = 0.05 and ηp2 = 0.12, p = 0.10). Compared with the control group, the tDCS-SM group had a trend of a small immediate effect (ηp2 = 0.02 – 0.04) on reducing spasticity but no long-term effect. A trend of small immediate and long-term effects in favor of tDCS-SM was found on UE function and daily function recovery (ηp2= 0.02 – 0.09).

Conclusions

Accompanied with traditional rehabilitation, tDCS-SM had a non-significant trend of having immediate and longitudinal effects on voluntary UE movement recovery in patients with severe to moderate UE paresis after stroke, but its effects on spasticity reduction and functional recovery may be limited. (NCT01847157)

Source: Effects of Transcranial direct current stimulation with sensory modulation on stroke motor rehabilitation: A randomized controlled trial – Archives of Physical Medicine and Rehabilitation

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[ARTICLE] Cognitive and functional outcomes following inpatient rehabilitation in patients with acquired brain injury: A prospective follow-up study – Full Text

Abstract

Objectives: To study the effects of cognitive retraining and inpatient rehabilitation to study the effects of cognitive retraining and inpatient rehabilitation in patients with acquired brain injury (ABI).

Design and Setting: This was a prospective follow-up study in a neurological rehabilitation department of quaternary research hospital.

Patients and Methods: Thirty patients with ABI, mean age 36.43 years (standard deviation [SD] 12.6, range 18–60), mean duration of illness 77.87 days (SD 91.78, range 21–300 days) with cognitive, physical, and motor-sensory deficits underwent inpatient rehabilitation for minimum of 14 sessions over a period of 3 weeks. Nineteen patients (63%) reported in the follow-up of minimum 3 months after discharge. Type of ABI, cognitive status (using Montreal Cognitive assessment scale [MoCA] and cognitive Functional Independence Measure [Cog FIM]®), and functional status (motor FIM®) were noted at admission, discharge, and follow-up and scores were compared.

Results: Patients received inpatient rehabilitation addressing cognitive and functional impairments. Baseline MoCA, motor FIM, and Cog FIM scores were 15.27 (SD = 7.2, range 3–30), 31.57 (SD = 15.6, range 12–63), and 23.47 (SD = 9.7, range 5–35), respectively. All the parameters improved significantly at the time of discharge (MoCA = 19.6 ± 7.4 range 3–30, motor FIM® = 61.33 ± 18.7 range 12–89, Cog FIM® =27.23 ± 8.10 range 9–35). Patients were discharged with home-based programs. Nineteen patients reported in follow-up and observed to have maintained cognition on MoCA (18.8 ± 6.8 range 6–27), significantly improved (P < 0.01) on Cog FIM® (28.0 ± 7.7 range 14–35) and motor FIM® =72.89 ± 16.2 range 40–96) as compare to discharge scores.

Conclusions: Cognitive and functional outcomes improve significantly with dedicated and specialized inpatient rehabilitation in ABI patients, which is sustainable over a period.

 Introduction

Acquired brain injury (ABI) is defined as “damage to the brain, which occurs after birth and is not related to a congenital or a degenerative disease.” “These impairments may be temporary or permanent and cause physical, functional disability, or psychosocial maladjustment.”[1],[2] By this definition, ABI encompasses a wide variety of disorders of varying etiologies such as vascular, hypoxic, malignant, and traumatic. There are often long-lasting effects on domains of cognition, motor, behavior, and personality in affected individuals.[3] Cognitive impairment is common sequelae and important marker for prediction of rehabilitation outcomes, and cognitive outcome can be modified through targeted interventions.[4]

Studies suggest that traumatic brain injury (TBI) and stroke are the two main causes of ABI and regarded as important public health problem.[5] The incidence of TBI from 23 reports was found to vary greatly among European countries. Most rates were in the range 150–300/100,000 people per year.[6] The prevalence of stroke In western developed world ranges from 500 to 600/100,000. Rates per 100,000 from developing countries are also variable and range from 58 in India and 76 in the United Republic of Tanzania to 620 in China and 690 in Thailand.[7] Between 1.5 and 2 million persons are injured and 1 million die every year in India following TBI.[8] Cardiovascular diseases including stroke caused 19% of deaths in India between 2001 and 2003 and this is estimated to rise to 36% by 2030.[9] According to disease burden in India report September 2005, central nervous system malignancies (included in ABI) comprise 2% of the total cancer burden.[10] Other causes of ABI such as meningoencephalitis and stroke mimics also contribute to this pool of patients.

The majority of ABI survivors continue to live with disabilities without access to comprehensive rehabilitation services and remain a burden on caregivers and society.[11],[12] Physical and cognitive deficits are most commonly observed in these patients but are not adequately addressed due to lack of approachable rehabilitation services and awareness.[13],[14] Many of these patients opt for complementary and alternative medicine, which are popular in India but demonstrate questionable benefits.[15]

It is evident, both clinically and scientifically, that the improvement in motor control after ABI is training dependent, responding best to repetitive task training with continuous modification of the program to keep training tasks challenging to the patients (activity-based recovery and neural plasticity).[16],[17] Single or multiple domains of cognition can be affected in these patients depending on the site (s) and severity of injury. Disturbances in memory, attention, and/or executive functions are commonly involved. Deficits in language and speech, learning, abstract thinking, and orientation occur in severe cases. It is well established that cognitive deficits interfere with rehabilitation efforts and also result in a greater negative impact on quality of life.[18] Cognitive rehabilitation (CR) is a specialized treatment procedure designed to improve the cognition affected by internal or external injury to the brain. There are two types of CR: restorative and compensatory rehabilitation.[19],[20],[21] Restorative rehabilitation enables the patient to develop lost functions through specialized computerized and manual cognitive exercises. Compensatory rehabilitation helps the patient to train and use aids and tools to overcome the impairment. The objective of the present study was to rehabilitate ABI patients in all affected domains including cognitive, physical, sensory-motor, and behavior with customized inpatient programs. Another objective was to observe the effect of inpatient rehabilitation in improving cognition and functionality of the patients (by comparing admission and discharge scores). We also tried to observe whether the benefits of inpatient rehabilitation are sustainable by assessing the patients in follow-up examination a minimum of 3 months after discharge.[…]

Continue —>  Cognitive and functional outcomes following inpatient rehabilitation in patients with acquired brain injury: A prospective follow-up study Patil M, Gupta A, Khanna M, Taly AB, Soni A, Kumar J K, Thennarasu K – J Neurosci Rural Pract

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[Abstract] “A CLINICAL FRAMEWORK FOR FUNCTIONAL RECOVERY IN A PERSON WITH CHRONIC TRAUMATIC BRAIN INJURY: A CASE REPORT” |

Provisional Abstract:
Background and Purpose: This case report describes a task-specific program for gait and functional recovery in a young man with severe chronic traumatic brain injury (TBI).

Case Description: The individual was a 26-year-old man 4 years post TBI with severe motor impairments who had not walked outside of therapy since his injury. He had received extensive gait training prior to initiation of services. His goal was to recover the ability to walk.

Intervention: The primary focus of the interventions was the restoration of gait. A variety of interventions were used, including locomotor treadmill training, electrical stimulation, orthoses and specialized assistive devices. A total of 79 treatments were delivered over a period of 62 weeks.

Outcomes: At the conclusion of therapy, the client was able to walk independently with a gait trainer for over 3000 feet and walked in the community with the assistance of his mother using a rocker bottom crutch for distances of up to 350 feet.

Discussion: Given the chronicity of this individual’s injury, the magnitude of his functional improvements were unexpected. However, very intentional interventions were selected in the development of his treatment plan. His potential was realized by structuring practice of the salient task, i.e. walking, with adequate intensity and frequency.

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Source: JUST ACCEPTED: “A CLINICAL FRAMEWORK FOR FUNCTIONAL RECOVERY IN A PERSON WITH CHRONIC TRAUMATIC BRAIN INJURY: A CASE REPORT” |

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[ARTICLE] Eclectic/mixed model method for upper extremity functional recovery in stroke rehabilitation: A pilot study

Abstract

Background: Eclectic treatment method is a flexible approach that uses techniques drawn from various schools of thought involving several treatment methods and allows the therapist to adapt to each client’s individual needs. Wider application for eclectic approach is however limited in stroke rehabilitation. Aim: The objective is to find out whether eclectic approach improves upper extremity (UE) functional recovery in acute stroke rehabilitation. Methodology: Twenty-five postacute unilateral supratentorial stroke subjects recruited from tertiary care hospitals recovered with Stage 2–5 in Brunnstorm stage of UE motor recovery (BRS-UE) underwent 45 min of eclectic approach for UE every day involving seven different treatment methods (5 min for each method) for 6 days consecutively. The outcome was UE subscale of the Fugl-Meyer Motor test (UE-FM), UE subscale of the Stroke Rehabilitation Assessment of Movement (UE-STREAM), Wolf Motor Function test (WMFT-FAS), and Stroke Impact Scale-16 (SIS-16) was collected at the end of the sixth session. Results: All the participants showed significant improvement in all the outcome measures. The Stage 2 and 3 subjects showed UE-STREAM (P = 0.007) WMFT-FAS (P < 0.001), SIS (P = 0.023) respectively and for Stage 4 and 5 the subjects have shown UE FM (P < 0.001), WMFT-FAS (P < 0.001), SIS (P = 0.004) with large magnitude of treatment effect for all stages of BRS-UE. Conclusion: Our study findings are in favor of integrating eclectic approach than single intervention/approach in clinical practice to improve the UE functional recovery for motor rehabilitation when the stroke occurs.

Introduction

Globally, stroke is the third major cause of mortality and a major health issue in low- and middle-income countries like India.[1]Eighty percent of stroke survivors experience motor impairments (hemiparesis) typically affecting movement of the face, arm, trunk, and leg of one side of the body often persistent and disabling them. These residual impairments limit their functional independence and predisposing them to restrict their participation in community and social roles.[2],[3]

Upper limb hemiparesis is one of the primary impairments following the stroke. It is often reported to be incomplete in functional recovery and to restore the motor skills. The studies on recovery of voluntary arm movements have also shown that 5–20% of stroke survivors achieved complete functional recovery and 30–60% of paretic arm can never have complete recovery during the first 6 months after the stroke.[4],[5] Common upper extremity (UE) impairments after the stroke include paresis, loss of fractionated movement, abnormal muscle tone and/or changes in somatosensation, shoulder pain, and subluxation which prevents the functional use of the arm, bimanual tasks and also for fine motor skills.[6],[7] Post stroke, persistent arm motor impairment (a period of 1 year or above) can be associated with anxiety and poorer perception of health-related quality of life and subjective well-being.[8],[9]

One of the primary aims of the stroke rehabilitation is to improve the arm functions and to regain the gross and fine motor skills. Currently, the existing rehabilitation protocols that are designed to improve UE functions include the various treatment methods/interventions such as Roods, Brunnstorm, proprioceptive neuromuscular facilitation, neuro-developmental therapy techniques, repetitive/task-specific training, strength training, sensorimotor interventions, constraint-induced movement therapy, virtual reality, spasticity treatment, electromyographic/biofeedback, transcutaneous electrical nerve stimulation, neuromuscular electrical stimulation, functional electric stimulation, motor imagery, mirror therapy, and bilateral arm training.[10] However, recent systematic reviews have concluded that there is insufficient evidence observed for any intervention or approach that can currently be used in routine practice to improve the paretic upper limb functions.[11]

An eclectic therapy is a therapeutic approach that incorporates a variety of therapeutic principles and philosophies to create the ideal treatment program to meet the specific needs of the patient or client. The intervention of an eclectic approach is based on the stable principles of the classic traditional methods but is open to refining and can be used in conjunction with the elements of other various new methods, thus providing a framework for designing an optimal neurorehabilitation protocol.[12],[13] The studies have shown that the eclectic approach is suitable for a diverse and complex set of patients.[14],[15],[16] However, wider application of eclectic approach in stroke rehabilitation is limited in literature.

Continue —> Eclectic/mixed model method for upper extremity functional recovery in stroke rehabilitation: A pilot study Kumar K V, Joshua AM, Kedambadi R, Mithra P P – J Nat Sc Biol Med

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