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.

Neural correlates of age-related changes in cortical neurophysiology.

Functional imaging studies of cortical motor systems in humans have demonstrated age-related reorganisation often attributed to anatomical and physiological changes. In this study we investigated whether aspects of brain activity during a motor task were influenced not only by age, but also by neurophysiological parameters of the motor cortex contralateral to the moving hand. Twenty seven right-handed volunteers underwent functional magnetic resonance imaging whilst performing repetitive isometric right hand grips in which the target force was parametrically varied between 15 and 55% of each subject's own maximum grip force. For each subject we characterised two orthogonal parameters, B(G) (average task-related activity for all hand grips) and B(F) (the degree to which task-related activity co-varied with peak grip force). We used transcranial magnetic stimulation (TMS) to assess task-related changes in interhemispheric inhibition from left to right motor cortex (IHIc) and to perform measures relating to left motor cortex excitability during activation of the right hand. Firstly, we found that B(G) in right (ipsilateral) motor cortex was greater with increasing values of age(2) and IHIc. Secondly, B(F) in left ventral premotor cortex was greater in older subjects and in those in whom contralateral M1 was less responsive to TMS stimulation. In both cases, neurophysiological parameters accounted for variability in brain responses over and above that explained by ageing. These results indicate that neurophysiological markers may be better indicators of biological ageing than chronological age and point towards the mechanisms by which reconfiguration of distributed brain networks occurs in the face of degenerative changes.

The effect of age on task-related modulation of interhemispheric balance.

Normal aging is associated with less lateralised task-related activation of the primary motor cortices. It has been hypothesized, but not tested, that this phenomenon is mediated transcallosaly. We have used Transcranial Magnetic Stimulation to look for age-related changes in interhemispheric inhibition (IHI). Thirty healthy individuals (aged 19-78 years) were studied using a paired-pulse protocol at rest and during a low-strength isometric contraction with the right hand. The IHI targeting the right motor cortex was assessed at two intervals, 10 ms (IHI10) and 40 ms (IHI40). The corticospinal excitability of the left hemisphere was assessed by means of input-output curves constructed during voluntary construction. Age was not correlated with IHI10 or IHI40 at rest. During muscle contraction IHI tended to increase at both intervals. However, this increase in IHI during the active condition (changeIHI) was less evident with advancing age for the 40 ms interval (r = 0.444, P = 0.02); in fact a degree of disinhibition was often present. There was no correlation between age and changeIHI10. Age was negatively correlated with the area under the recruitment curve (r = -0.585, P = 0.001) and the size of the maximum MEP collected (r = -0.485, P = 0.007). ChangeIHI and measures of corticospinal excitability were not intercorrelated. In conclusion, task-related increases in interhemispheric inhibition seem to diminish with advancing age. This phenomenon is specific for long-latency IHI and may underlie the age-related bihemispheric activation seen in functional imaging studies. The mechanism underlying changes in IHI with advancing age and the association with changes in corticospinal excitability need further investigation.

Future perspectives in functional neuroimaging in stroke recovery.

Neurological damage and stroke in particular is the leading cause of long-term disability worldwide. Recovery of function after stroke is a consequence of many factors including resolution of oedema and survival of the ischaemic penumbra. In addition, there is a growing interest in how reorganisation of the surviving tissue might subserve the improvements in function that are commonly seen over weeks, months, and sometimes years after stroke. Noninvasive techniques such as functional magnetic resonance imaging, electroencephalography, magnetoencephalography and transcranial magnetic stimulation allow the study of this reorganisation in humans. Currently, results suggest that functionally relevant reorganisation does occur in cerebral networks in human stroke patients. This reorganisation can only occur in structurally and functionally intact brain regions. Because these vary depending on the location of the infarction, it is likely that different therapeutic strategies will be required to promote reorganisation depending on residual functional anatomy. This review maps out the attempts to describe functionally relevant adaptive changes in the human brain following focal damage. A greater understanding of how these changes are related to the recovery process will facilitate the development of novel therapeutic techniques designed to minimise impairment based on neurobiological principles and how to target these treatments to individual patients.

Mechanisms underlying recovery of motor function after stroke.

Neurological damage, and stroke in particular, is the leading cause of long term disability worldwide. There is growing interest in the part that central nervous system reorganisation plays in recovery of function. Techniques such as functional magnetic resonance imaging and transcranial magnetic stimulation permit the non-invasive study of the working human brain, and suggest that functionally relevant adaptive changes occur in the human brain after focal damage. An understanding of how these changes are related to recovery will facilitate the development of novel therapeutic techniques that are based on neurobiological principles and that are designed to minimise impairment in appropriately targeted patients suffering from stroke.

Neural correlates of motor recovery after stroke: a longitudinal fMRI study.

Recovery of motor function after stroke may occur over weeks or months and is often attributed to cerebral reorganization. We have investigated the longitudinal relationship between recovery after stroke and task-related brain activation during a motor task as measured using functional MRI (fMRI). Eight first-ever stroke patients presenting with hemiparesis resulting from cerebral infarction sparing the primary motor cortex, and four control subjects were recruited. Subjects were scanned on a number of occasions whilst performing an isometric dynamic visually paced hand grip task. Recovery in the patient group was assessed using a battery of outcome measures at each time point. Task-related brain activations decreased over sessions as a function of recovery in a number of primary and non-primary motor regions in all patients, but no session effects were seen in the controls. Furthermore, consistent decreases across sessions correlating with recovery were seen across the whole patient group independent of rate of recovery or initial severity, in primary motor cortex, premotor and prefrontal cortex, supplementary motor areas, cingulate sulcus, temporal lobe, striate cortex, cerebellum, thalamus and basal ganglia. Although recovery-related increases were seen in different brain regions in four patients, there were no consistent effects across the group. These results further our understanding of the recovery process by demonstrating for the first time a clear temporal relationship between recovery and task-related activation of the motor system after stroke.

Neural correlates of outcome after stroke: a cross-sectional fMRI study.

Recovery of motor function after stroke may occur over weeks or months and is often attributed to neuronal reorganization. Functional imaging studies investigating patients who have made a good recovery after stroke have suggested that recruitment of other motor-related networks underlies this recovery. However, patients with less complete recovery have rarely been studied, or else the degree of recovery has not been taken into account. We set out to investigate the relationship between the degree of recovery after stroke and the pattern of recruitment of brain regions during a motor task as measured using functional MRI. We recruited 20 patients who were at least 3 months after their first ever stroke, and 26 right-handed age-matched control subjects. None of our patients had infarcts involving the hand region of the primary motor cortex. All subjects were scanned whilst performing an isometric, dynamic visually paced handgrip task. The degree of functional recovery of each patient was assessed using a battery of outcome measures. Single-patient versus control group analysis revealed that patients with poor recovery were more likely to recruit a number of motor-related brain regions over and above those seen in the control group during the motor task, whereas patients with more complete recovery were more likely to have 'normal' task-related brain activation. Across the whole patient group and across stroke subtypes, we were able to demonstrate a negative correlation between outcome and the degree of task-related activation in regions such as the supplementary motor area, cingulate motor areas, premotor cortex, posterior parietal cortex, and cerebellum. This negative correlation was also seen in parts of both contralateral and ipsilateral primary motor cortex. These results further our understanding of the recovery process by demonstrating for the first time a clear relationship between task-related activation of the motor system and outcome after stroke.

Age-related changes in the neural correlates of motor performance.

Age-related neurodegenerative and neurochemical changes are thought to underlie decline in motor and cognitive functions, but compensatory processes in cortical and subcortical function may allow maintenance of performance level in some people. Our objective was to investigate age-related changes in the motor system of the human brain using functional MRI. Twenty six right handed volunteers were scanned whilst performing an isometric, dynamic, visually paced hand grip task, using dominant (right) and non-dominant (left) hands in separate sessions. Hand grip with visual feedback activated a network of cortical and subcortical regions known to be involved in the generation of simple motor acts. In addition, activation was seen in a putative human 'grasping circuit', involving rostral ventral premotor cortex (Brodmann area 44) and intraparietal sulcus. Within this network, a number of regions were more likely to be activated the older the subject. In particular, age-related changes in task- specific activations were demonstrated in left deep anterior central sulcus when using the dominant or non-dominant hand. Additional age-related increases were seen in caudal dorsal premotor cortex, caudal cingulate sulcus, intraparietal sulcus, insula, frontal operculum and cerebellar vermis. We have demonstrated a clear age-related effect in the neural correlates of motor performance, and furthermore suggest that these changes are non-linear. These results support the notion that an adaptable and plastic motor network is able to respond to age-related degenerative changes in order to maintain performance levels.

Differential brain activations during intentionally simulated and subjectively experienced paralysis.

INTRODUCTION: Distinguishing conversion disorder from malingering presents a significant challenge as the diagnosis ultimately depends on the patient's subjective report and the clinician's suspicion of an intention to deceive. Using hypnosis to manipulate the intentionality of movement inhibition in the same subjects, we used positron emission tomography (PET) to determine whether failure to move during intentionally simulated and subjectively experienced paralysis is mediated by different neural structures. METHODS: Using a within-subject design, 12 normal, hypnotised subjects were tested under two paralysis conditions during the same scanning session. Half of the scans were performed with the suggestion that the left leg was paralysed (subjectively experienced paralysis condition) and half with the leg normal but with the instruction that paralysis should be feigned (intentionally simulated paralysis condition). RESULTS: Relative increases in brain activation were seen in the right orbitofrontal cortex, right cerebellum, left thalamus, and left putamen during subjectively experienced paralysis compared to intentionally simulated paralysis, although a previously reported activation of the right anterior cingulate cortex was not seen. During intentionally simulated paralysis compared to subjectively experienced paralysis relative increases in brain activation were seen in the left ventrolateral prefrontal cortex, and a number of right posterior cortical structures. CONCLUSIONS: Our results suggest that subjectively experienced paralysis has a different neural basis to intentionally simulated paralysis. These findings have theoretical and clinical implications for malingering and related attempts to unravel the neuropsychological basis for conversion hysteria.

Functional imaging in stroke.

Recent advances in magnetic resonance techniques make it possible to image physiological parameters such as molecular diffusion, tissue perfusion and cortical activation. These techniques greatly contribute to the early detection and to the understanding of the pathophysiological evolution and recovery from ischaemic stroke.

Isolated familial hypomagnesaemia with novel neurological features: causal link or chance concurrence?

We report a patient with isolated familial hypomagnesaemia with hypocalciuria, a rare congenital disorder of magnesium metabolism. During adolescence the patient developed neurological and ophthalmological features not hitherto reported in this condition, including seizures, myoclonus, and retinal pigmentary degeneration. These suggested the phenotype of mitochondrial disease, which has been occasionally reported in association with hypomagnesaemia, but subsequent investigations of mitochondrial function were normal. The pathogenesis of this unusual neurological and ophthalmological syndrome therefore remains uncertain.

How broad is the phenotype of Hallervorden-Spatz disease?

Magnetic resonance imaging (MRI) has enabled ante mortem diagnosis of Hallervorden Spatz disease (HSD). Childhood-onset cases are the most common type and usually present with progressive dystonia and dementia. The duration of illness is 15 to 20 years, leading to death. Presentation in adulthood and infancy have also been reported, however again the progression is usually inexorable. We present a 30-year-old woman who developed cognitive and motor developmental delay from the age of 8 months. There was further cognitive decline in her late teenage years with seizures and then more recent motor decline with dystonia. The imaging appearance was of iron deposition in the globus pallidus and substantia nigra leading to a diagnosis of HSD. The increased availability of MRI has allowed more cases of HSD to be diagnosed in life but as our case illustrates classification of the disease may need to be further examined.

Pulmonary function testing in neuromuscular disease.

Pulmonary function testing is useful in the diagnosis and management of patients with neuromuscular disease. It is important, however, to keep in mind that certain tests commonly used to assess these patients, such as MIPs and MEPs, although useful, are fraught with potential error and rigorous attention should be paid to technical details when performing them. In addition, many studies have shown that pulmonary impairment does not always parallel generalized muscle impairment and thorough testing therefore should be done in any patient with neuromuscular disease to assess the level of respiratory compromise accurately. In addition, the clinician should be aware that the pattern of involvement-bulbar versus inspiratory, versus expiratory muscle weakness-may vary markedly among patients, even with the same diagnosis, so testing should be tailored to detect these patterns. Furthermore, serial follow-up examinations should be performed to track the rate of deterioration so that therapeutic interventions can be initiated before respiratory crises occur.

Interleukin-6-induced protection in hyperoxic acute lung injury.

Hyperoxic lung injury is commonly encountered in patients who require treatment with high concentrations of inspired oxygen. To determine whether interleukin (IL)-6 is protective in oxygen toxicity, we compared the effects of 100% O(2) in transgenic mice that overexpress IL-6 in the lung and transgene (-) controls. IL-6 markedly enhanced survival, with 100% of transgene (-) animals dying within 72 to 96 h, 100% of transgene (+) animals living for more than 8 d and more than 90% of transgene (+) animals living longer than 12 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, and lung lipid peroxidation. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-6 markedly diminished this cytopathic response. The protective effects of IL-6 were not associated with significant alterations in the activities of copper/ zinc superoxide dismutase (SOD) or manganese SOD. They were, however, associated with the enhanced accumulation of the cell-death inhibitor Bcl-2, but not the cell-death stimulator BAX, and with the heightened accumulation of the cell-death regulator tissue inhibitor of metalloproteinase-1 (TIMP-1). These studies demonstrate that IL-6 markedly diminishes hyperoxic lung injury and that this protection is associated with a marked diminution in hyperoxia-induced cell death and DNA fragmentation. They also demonstrate that this protection is not associated with significant alterations in SOD activity, but is associated with the induction of Bcl-2 and TIMP-1.