The effects of repetitive transcranial magnetic stimulation (rTMS) and sensory cueing (SC) on unilateral neglect and hemiplegic upper limb functions in patients after stroke

Abstract

Unilateral neglect (UN) is a complicated disorder which occurs most commonly after right hemispheric stroke. Approximately one-third to one-half of patients have UN during the acute stage of stroke; nearly one-third of them have symptoms that persist for up to one year after stroke onset. The symptoms are heterogeneous and their underlying mechanism is not well understood. UN is an obstacle to satisfactory stroke recovery during rehabilitation as the patient may respond poorly to most conventional rehabilitative interventions. UN has been proved to be a negative predictor of functional independence. The disorder has not previously received much attention in clinical practice; however, within the last two decades, considerable research has been conducted to investigate the underlying mechanism, assessment tools, and treatment procedures. To date, a variety of theories and models have been proposed to explain UN, and a series of rehabilitation treatments have been developed, based on these and related hypotheses. Determining which of these treatments provides the optimal effect has been difficult owing to the heterogeneous symptoms and severities. This difficulty has been compounded by the poor understanding of the underlying reason for the clinical manifestations. It is essential in future that more effective treatments should be developed to remedy UN and hence improve the functional performance and quality of life of patients with stroke. The current research explored potentially effective UN rehabilitative interventions based on an in-depth search of published evidence. This study consisted of a systematic review and meta-analysis of rehabilitative interventions for UN, a pilot study exploring the use of low frequency repetitive transcranial magnetic stimulation (rTMS) and sensory cueing (SC) for UN rehabilitation, and a randomized controlled trial (RCT) examining the combined effect of rTMS and SC for UN rehabilitation in stroke patients with right brain lesion. This research would illuminate the possibility of specific attention network modulation for treating UN. This report starts with an overview of strokes, followed by a comprehensive literature review on progress related to post-stroke UN rehabilitation (including a definition and classification of UN, an indication of its incidence, and the advancement of assessment and rehabilitative interventions), a systematic review and meta-analysis, 2 pilot studies involving rTMS and SC respectively for UN rehabilitation, and concludes with the main study examining the combined effects of low frequency rTMS and SC on UN in subacute, right hemispheric post-stroke patients. The research-related materials (informed consent form, assessment tools and published papers) are listed in the Appendix. At the beginning of the study, a systematic review on the effectiveness of rehabilitation for persons with post-stroke UN was conducted by searching computerized databases from 1997 through 2012. RCTs involving UN treatment strategies for stroke patients, using the Behavioral Inattention Test (BIT) as the primary outcome measure, were eligible to be included. Out of 201 studies identified, we included 12 RCTs, involving 277 patients. All studies faced the same weaknesses of having reduced statistical power due to small sample sizes and limited blinding in the design. Prism adaptation (PA) was the most common intervention, and continuous theta-burst stimulation-a new kind of rTMS- appeared promising. The meta-analysis showed that for immediate effects, the BIT-conventional (BIT-C) subscore had a large mean effect size (ES, 0.76; 95% confidence interval [CI], 0.28-1.23; p = 0.002) whereas the BIT total score showed a modest mean effect size (ES, 0.55; 95% CI, 0.16-0.94; p = 0.006). No significant mean effect size was found for long-lasting effects for any of the BIT outcomes. PA appeared to be the more effective of the various interventions, based on the pooled analysis results. However, more rigorous rTMS studies are needed before concluding that it is a promising UN treatment. The first pilot study, which hypothesized that UN results in an imbalanced pathophysiological excitability between the 2 brain hemispheres, after stroke, was performed using 3 chronic stroke patients in a convalescent hospital in Hong Kong. Each patient demonstrated a hyperactive state in the contralesional hemisphere, but a hypoactive state in the ipsilesional hemisphere. Low frequency rTMS was used on the contralesional side of the brain cortex to reduce excitability and help rebalance the interhemispheric excitability, using a top-down approach. The rTMS study protocol involved in stimulating the normal posterior parietal cortex (corresponding to P5, according to the 10/20 electroencephalography system) in the left hemesphere. The results of rTMS, in the 3 chronic stroke patients, varied; however, the results generally indicated that rTMS might improve attention on the ipsilesional side by inhibiting the hyperactivity of the contralesional hemisphere. This was reflected by improvements in the BIT-C cancellation subtest. During the pilot study period, no adverse effects were reported during and after rTMS. The second pilot study investigated the effects of a 2-week programme of sensory cueing (SC) treatment alone conducted in inpatients with UN after following subacute stroke. A single-group, single-case design study was applied; 5 post-stroke UN patients with unilateral spatial neglect underwent a tailored sensory cueing treatment, in addition to conventional rehabilitation, for 2 weeks. Significant changes in the BIT-C scores were found between the baseline and post-interventional testing. Further analysis of the BITC test items in the BIT-C showed that the significant improvement was mostly found mostly in the cancellation subtest; the m. More severe the impairment in UN the patient had, the more significant was the increase in the BIT-C results was found. SC treatment, alone, may be useful and feasible in reducing neglect by improving attention to the contralesional body side of the body, in this neglect patient populations; with subacute stroke, however, a randomized controlled trial (RCT), with proper sample sizes, larger treatment intensitiesy, and longer term of follow-up would beare necessary to prove the effects. In the main study, we compared the effects of low frequency rTMS combined with SC, rTMS alone, and conventional rehabilitation in an RCT that focused on reducing UN and improving hemiplegic arm functions and the performance of activities of daily living (ADL). Sixty subacute patients with left UN, after right hemispheric stroke, were randomly assigned to 1 of the 3 groups. Low frequency (1 Hz) rTMS was applied over P5 of the contralesional hemisphere while vibrational SC was emitted (3 h/day, 5 days/week) using a wristwatch device attached to the hemiplegic arm for 2 weeks. The 3 groups received the same amount of conventional rehabilitation on top of their experimental interventions. Blinded assessments were administered at baseline, 2 weeks postintervention, and 4-weeks after completing the training. As a result, the patients receiving combined low frequency rTMS and SC or rTMS alone demonstrated significantly reduced UN, when measured using the BIT-C; the combination was more effective than rTMS alone. Hemiplegic arm functions and ADL improved in all patients, across the 3 groups, with no significant differences found among the groups. In conclusion, rTMS combined with SC, was better than either rTMS alone, or conventional rehabilitation in producing immediate and long-lasting improvements. The combination treatment might assist in restoring the interhemispheric balance of spatial attention in these types of patients with UN, but the improvements are not associated with arm functions or ADL. This study shows that brain stimulation combined with rehabilitation intervention can assist in restoring the interhemispheric balance of spatial attention after subacute stroke and hence reduce the symptoms of UN. The findings of this thesis would contribute to the scientific evidence and neuroscience, and assist in the design of theorybased treatment in rehabilitation for UN in stroke worldwide.