Annapoorna Kuppuswamy

Action of 5 Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in human spinal cord injury

OBJECTIVE To assess the effectiveness of physiological outcome measures in detecting functional change in the degree of impairment of spinal cord injury (SCI) following repetitive transcranial magnetic stimulation (rTMS) of the sensorimotor cortex. METHODS Subjects with complete or incomplete cervical (or T1) SCI received real and sham rTMS in a randomised placebo-controlled single-blinded cross-over trial. rTMS at sub-threshold intensity for upper-limb muscles was applied (5 Hz, 900 stimuli) on 5 consecutive days. Assessments made before and for 2 weeks after treatment comprised the ASIA (American Spinal Injuries Association) impairment scale (AIS), the Action Research Arm Test (ARAT), a peg-board test, electrical perceptual test (EPT), motor evoked potentials, cortical silent period, cardiovascular and sympathetic skin responses. RESULTS There were no significant differences in AIS outcomes between real and sham rTMS. The ARAT was increased at 1h after real rTMS compared to baseline. Active motor threshold for the most caudally innervated hand muscle was increased at 72 and 120 h compared to baseline. Persistent reductions in EPT to rTMS occurred in two individuals. CONCLUSIONS Changes in cortical motor threshold measures may accompany functional gains to rTMS in SCI subjects. SIGNIFICANCE Electrophysiological measures may provide a useful adjunct to ASIA impairment scales.

Development of quantitative and sensitive assessments of physiological and functional outcome during recovery from spinal cord injury: a clinical initiative

The ability to detect physiological changes associated with treatments to effect axonal regeneration, or novel rehabilitation strategies, for spinal cord injury will be challenging using the widely employed American Spinal Injuries Association (ASIA) impairment scales (AIS) for sensory and motor function. Despite many revisions to the AIS standard neurological assessment, there remains a perceived need for more sensitive, quantitative and objective outcome measures. The purpose of Stage 1 of the Clinical Initiative was to develop these tools and then, in Stage 2 to test them for reliability against natural recovery and treatments expected to produce functional improvements in those with complete or incomplete spinal cord injury (SCI). Here we review aspects of the progress made by four teams involved in Stage 2. The strategies employed by the individual teams were (1) application of repetitive transcranial magnetic stimulation (rTMS) to the motor cortex in stable (chronic) SCI with intent to induce functional improvement of upper limb function, (2) a tele-rehabilitation approach using functional electrical stimulation to provide hand opening and grip allowing incomplete SCI subjects to deploy an instrumented manipulandum for hand and arm exercises and to play computer games, (3) weight-assisted treadmill walking therapy (WAT) comparing outcomes in acute and chronic groups of incomplete SCI patients receiving robotic assisted treadmill therapy, and (4) longitudinal monitoring of the natural progress of recovery in incomplete SCI subjects using motor tests for the lower extremity to investigate strength and coordination.

Review of physiological motor outcome measures in spinal cord injury using transcranial magnetic stimulation and spinal reflexes

This article reviews methods that have been developed as part of a clinical initiative on improving outcome measures for motor function assessment in subjects with spinal cord injury (SCI). Physiological motor outcome measures originally developed for limbs-transcranial magnetic stimulation (TMS) of the motor cortex to elicit motor-evoked potentials (MEPs) and mechanical stimulation to elicit spinal reflexes-have been extended to muscles of the trunk. The impetus for this development is the lack of a motor component in the American Spinal Injury Association clinical assessment for the thoracic myotomes. The application of TMS to the assessment of limb muscles is reviewed, followed by consideration of its application to the assessment of paravertebral and intercostal muscles. Spinal reflex testing of paravertebral muscles is also described. The principal markers for the thoracic SCI motor level that have emerged from this clinical initiative are (1) the threshold of MEPs in paravertebral muscles in response to TMS of the motor cortex, (2) the facilitation pattern and latency of MEPs in intercostal muscles during voluntary expiratory effort, and (3) the absence of long-latency reflex responses and the exaggeration of short-latency reflex responses in paravertebral muscles.

Estimation of cortical silent period following transcranial magnetic stimulation using a computerised cumulative sum method.

The cortical silent period (CSP) following transcranial magnetic stimulation (TMS) of the motor cortex can be used to measure intra-cortical inhibition and changes in a number of important pathologies affecting the central nervous system. The main drawback of this technique has been the difficulty in accurately identifying the onset and offset of the cortical silent period leading to inter-observer variability. We developed an automated method based on the cumulative sum (Cusum) technique to improve the determination of the duration and area of the cortical silent period. This was compared with experienced raters and two other automated methods. We showed that the automated Cusum method reliably correlated with the experienced raters for both duration and area of CSP. Compared with the automated methods, the Cusum also showed the strongest correlation with the experienced raters. Our results show the Cusum method to be a simple, graphical and powerful method of detecting low-intensity CSP that can be easily automated using standard software.

The effect of an energy drink containing glucose and caffeine on human corticospinal excitability

Glucose- and caffeine-containing energy drinks are said to influence the cognitive and cellular function within the brain. In this study, we have used the size of motor-evoked potentials (MEPs) produced in response to transcranial magnetic stimulation (TMS) of the motor cortex as an index of corticospinal excitability after ingestion of Lucozade and control drinks of glucose-containing or caffeine-containing carbonated water or carbonated water alone. With local ethical approval and informed consent, 10 healthy volunteers took part; surface electromyographic (EMG) recordings were taken from the thenar muscles of the dominant hand. In each assessment, 15 TMS stimuli were delivered over the motor cortex at an intensity of 1.1 T. Six subjects ingested a 380-ml bottle of carbonated Lucozade drink containing 68 g of glucose and 46 mg caffeine. Four subjects took part in three control trials drinking: (A) carbonated water with caffeine, (B) carbonated water with glucose and (C) carbonated water alone. Assessments were made before and at 30-min intervals after each drink. Mean fasting blood glucose concentrations and mean areas of MEPs rose after the Lucozade, remaining elevated for 90 min. Similar rises in MEP areas were seen in trials after drinking carbonated water with caffeine or with glucose, but not after drinking carbonated water alone. No change was seen in the M-wave evoked by electrical stimulation of the ulnar nerve. We conclude that Lucozade can affect the size of MEPs to activation of the motor cortex with fixed-intensity TMS. The underlying mechanism is likely to relate to the combined effects of caffeine and glucose on the brain.

Post-stroke fatigue: a deficit in corticomotor excitability?

The pathophysiology of post-stroke fatigue is poorly understood although it is thought to be a consequence of central nervous system pathophysiology. In this study we investigate the relationship between corticomotor excitability and self-reported non-exercise related fatigue in chronic stroke population. Seventy first-time non-depressed stroke survivors (60.36 ± 12.4 years, 20 females, 56.81 ± 63 months post-stroke) with minimal motor and cognitive impairment were included in the cross-sectional observational study. Fatigue was measured using two validated questionnaires: Fatigue Severity Scale 7 and Neurological Fatigue Index - Stroke. Perception of effort was measured using a 0-10 numerical rating scale in an isometric biceps hold-task and was used as a secondary measure of fatigue. Neurophysiological measures of corticomotor excitability were performed using transcranial magnetic stimulation. Corticospinal excitability was quantified using resting and active motor thresholds and stimulus-response curves of the first dorsal interosseous muscle. Intracortical M1 excitability was measured using paired pulse paradigms: short and long interval intracortical inhibition in the same hand muscle as above. Excitability of cortical and subcortical inputs that drive M1 output was measured in the biceps muscle using a modified twitch interpolation technique to provide an index of central activation failure. Stepwise regression was performed to determine the explanatory variables that significantly accounted for variance in the fatigue and perception scores. Resting motor threshold (R = 0.384; 95% confidence interval = 0.071; P = 0.036) accounted for 14.7% (R(2)) of the variation in Fatigue Severity Scale 7. Central activation failure (R = 0.416; 95% confidence interval = -1.618; P = 0.003) accounted for 17.3% (R(2)) of the variation in perceived effort score. Thus chronic stroke survivors with high fatigue exhibit high motor thresholds and those who perceive high effort have low excitability of inputs that drive motor cortex output. We suggest that low excitability of both corticospinal output and its facilitatory synaptic inputs from cortical and sub-cortical sites contribute to high levels of fatigue after stroke.

Sweat production and the sympathetic skin response: Improving the clinical assessment of autonomic function

The aim of this project was to establish the relationship between sweat production and the electrodermal events comprising the sympathetic skin response to arousal stimuli. A series of randomly timed magnetic stimuli were applied to the neck of healthy human volunteers. Sympathetic skin responses and the associated sweat responses were recorded from the palms of both hands. Sympathetic skin responses typically had a biphasic shape consisting of a negative initial potential (palm relative to dorsum of hand) followed by a positive deflection. Sweat production was positively correlated with amplitude of the second positive deflection of the sympathetic skin response and negatively correlated with the amplitude of the initial negative deflection. For subjects showing only an initial negative sympathetic skin response, sweat release was low or not detectable. During habituation, the negative initial wave increased relative to the second positive wave, and sweat production fell. The strong correlation between the positive wave of the sympathetic skin response and sweat production suggests that the former may provide a quantitative functional measure of sudomotor activity in situations when it is impractical to measure the amount of sweat produced in the startle response. Thus, the positive component of the biphasic sympathetic skin response may be employed in clinical assessment of the functional efficacy of the sympathetic sudomotor system.

Differential effects of endurance and resistance training on central fatigue

Abstract The effect of long-term endurance and resistance training on central fatigue has been studied using transcranial magnetic stimulation by exercising the biceps brachii to exhaustion and recording motor-evoked potentials from the non-exercised homologous biceps. Three groups of eight healthy individuals took part: two groups of individuals who had more than 8 years of athletic training in either an endurance or resistance sport, and a group of controls. The size of a motor-evoked potential (area of averaged rectified response) was significantly depressed in all three groups in the non-exercised arm after exhaustive exercise of the opposite arm. Recovery of motor-evoked potentials occurred earlier in endurance athletes (20 min) than in control participants (30 min) and resistance athletes (>30 min). Dexterity and maximum voluntary contraction of the biceps for the non-exercised arm were not depressed in any group. In a separate session, the limit of endurance time for the biceps was reduced significantly following exhaustive exercise of the biceps of the other arm for resistance athletes and control participants, whereas there was no change in the endurance athletes. Our findings suggest that athletic training has an effect on the mechanism of central fatigue that may be specific to the nature of training.

The fatigue conundrum

Fatigue is a major affective symptom in neurological disease, but its basis is poorly understood. Kuppuswamy describes the defining features of fatigue and its relationship to perceived effort, before proposing that pathological fatigue is a consequence of impaired sensory attenuation.

Post-stroke fatigue: a problem of altered corticomotor control?

Objectives We recently showed that diminished motor cortical excitability is associated with high levels of post-stroke fatigue. Motor cortex excitability impacts movement parameters such as reaction and movement times. We predicted that one or both would be influenced by the presence of post-stroke fatigue. Methods 41 first-time stroke survivors (high fatigue n=21, Fatigue Severity Scale 7 (FSS-7) score >5; low fatigue n=20, FSS-7 score <3) participated in the study. Movement times, choice and simple reaction times were measured in all participants. Results A three way ANOVA with fatigue (high and low), task (movement time, simple reaction time and choice reaction time) and hand (affected and unaffected) as the three factors, revealed a significant difference between affected (but not unaffected) hand movement times in the high compared to low fatigue groups. Reaction times, however, were not different between the high-fatigue and low-fatigue groups in either the affected or unaffected hand. Conclusions Previously, we showed that motor cortex excitability is lower in patients with high post-stroke fatigue. Our current findings suggest that post-stroke fatigue (1) is a problem of movement speed (possibly a consequence of diminished motor cortex excitability) and not movement preparation, and (2) may have a focal origin confined to the lesioned hemisphere. We suggest that low motor cortex excitability in the lesioned hemisphere is a viable therapeutic target in post-stroke fatigue.