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doi: 10.1093/brain/123.8.1545pmid: 10908186
In recent years there has been increasing interest in oscillatory neural activity in the CNS and in the role that such activity may have in motor control. It is thought that physiological tremor may be a manifestation in the periphery of such central oscillatory activity and that some pathological tremors are the result of derangement of these oscillators. This review re-evaluates both early and recent studies on physiological and pathological tremors and other peripheral oscillations in order to gain a new perspective on the nature and function of their central progenitors. This approach, namely using tremor as a `window' into the function of central oscillations, is particularly suited to human investigations because of the obvious limitations of direct central recording. It is argued that physiological tremor is likely to be multifactorial in origin, with contributions not only from CNS 10-Hz range oscillatory activity, but also from motor unit firing properties, mechanical resonances and reflex loop resonances. Different origins are likely to dominate under different conditions. While some pathological tremors appear to arise as a distortion of central or peripheral components of physiological tremor, others arise de novo, such as the pathological oscillation of 3- to 6-Hz parkinsonian tremor. CNS oscillations outside the 10-Hz range are also found to modulate limb activity in normal individuals, and oscillatory activity exists in other motor systems such as eye movements. Finally, it is shown how studies of peripheral oscillations may help develop hypotheses on the role of CNS oscillations in motor control, including the proposed `binding' function of synchronized oscillations and the possibility that motor signals could be coded by frequency of modulating oscillation as well as by synaptic connectivity.
Deuschl, G.; Wenzelburger, R.; Löffler, K.; Raethjen, J.
doi: 10.1093/brain/123.8.1568pmid: 10908187
The cerebellum is assumed to play a major role in the pathophysiology of essential tremor (ET). As intention tremor is considered one of the classical features of cerebellar disease, we have assessed a large group of patients with ET for the semiology of the tremor and have performed objective quantitative analysis of a grasping movement in patients with ET, cerebellar disease and a normal control group. We found 25% of the patients to have a moderate or severe kinetic tremor with clear-cut features of a classical intention tremor. Another 33% of the patients had a mild intentional component of their kinetic tremor. Patients with intention tremor (ET IT ) did not differ from those with predominant postural tremor (ET PT ) with respect to alcohol sensitivity of the tremor and the frequency of a family history. ET IT patients were older and more often showed head and trunk involvement. The onset of this intention tremor has been assessed retrospectively. It was found to begin at a randomly distributed time interval after the onset of the postural tremor, but older patients had a shorter time to development of intention tremor. Quantitative accelerometry of postural tremor showed similar tremor frequencies in both patient groups, but ET IT patients had a slightly larger tremor amplitude. Quantitative analysis of a grasping movement using an infrared-camera system was performed in two subgroups of the patients with ET PT and ET IT and control groups with cerebellar disease or normal subjects. The intention tremor could be quantified objectively as an increased amplitude of curvature during the deceleration and target phase of the movement. The amplitude measurements of intention tremor were clearly abnormal and of comparable magnitude for ET PT and cerebellar disease. Additionally, the patients with ET IT had a significantly slowed grasping movement during the deceleration and target period. Hypermetria was significantly increased for the patients with ET IT and cerebellar disease. We conclude that intention tremor is a feature of ET. ET IT patients have abnormalities of their upper limb function compatible with cerebellar disease. This suggests that patients with more advanced ET show abnormalities of cerebellar functions.
Barnett, Susan C.; Alexander, Claire L.; Iwashita, Yasushi; Gilson, Jennifer M.; Crowther, John; Clark, Louise; Dunn, Laurence T.; Papanastassiou, Vakis; Kennedy, Peter G. E.
doi: 10.1093/brain/123.8.1581pmid: 10908188
Kaji, Ryuji; Bostock, Hugh; Kohara, Nobuo; Murase, Nagako; Kimura, Jun
doi: 10.1093/brain/123.8.1602pmid: 10908190
Patients with multifocal motor neuropathy may complain of muscle fatigue, even though the degree of conduction block assessed at rest has improved with treatment. To explore the mechanism involved, we examined changes in muscle force during maximum voluntary contraction (MVC) and monitored conduction block before and after MVC in five patients with multifocal motor neuropathy. The results were compared with those for the contralateral unaffected homonymous muscles. For one patient, who had bilateral involvement, a normal subject of a similar age and stature served as the control. Results of conduction studies were also compared with those from six patients with amyotrophic lateral sclerosis (ALS) with similar compound muscle action potential (CMAP) amplitudes after proximal stimulation. During MVC for 60 s, the affected muscles developed prominent fatigue; the force at the end of contraction compared with the initial force was significantly lower for the affected muscles (42 ± 19% (mean ± standard deviation) of the initial force) than for the control muscles (94 ± 9%; P = 0.01). After MVC, the amplitude ratio of CMAPs after proximal versus distal nerve stimulation transiently decreased to 19 ± 14% of that before MVC in the affected muscles, but not in the control muscles (94 ± 3.8% of that before MVC) and in patients with ALS (95 ± 6.7%). In one patient with a focal lesion in the forearm, nerve excitability was monitored at the lesion site before and after MVC for 120 s. There were significant increases in axonal threshold (~48%) and supernormality (~135%) immediately after MVC, suggesting that the axonal membrane had undergone hyperpolarization and, by extrapolation, that this had precipitated the conduction block. This study is the first to show that activity-dependent conduction block plays a role in human disease by causing muscle fatigue.
Auer-Grumbach, Michaela; Löscher, Wolfgang N.; Wagner, Klaus; Petek, Erwin; Körner, Eva; Offenbacher, Hans
doi: 10.1093/brain/123.8.1612pmid: 10908191
We report on a large four-generation Austrian family with autosomal dominant distal hereditary motor neuronopathy type V (distal HMN V). Forty-seven at-risk family members, of whom 21 were definitely affected, underwent detailed clinical, electrophysiological and genetic studies. The age at onset was in the second decade of life in most affected individuals, but clinical presentation was rather variable. While the majority of patients were primarily disabled by progressive asymmetrical wasting of the thenar and the first dorsal interosseus muscles, others had marked foot deformity and gait disturbance with the occasional absence of hand involvement. Sensation sense was normal except for the reduced response to vibration. Many individuals showed brisk tendon reflexes and some elevated muscle tone in the lower limbs, but extensor plantar responses were rarely observed. Electrophysiological evaluation revealed normal or reduced motor nerve conduction velocities, normal or prolonged distal motor latencies, and low compound motor action potentials, depending on the degree of muscle wasting. Sensory nerve studies were usually within the normal range or slightly to moderately abnormal in older or severely affected persons. Electromyography showed high-amplitude motor unit potentials and reduced recruitment compatible with anterior horn cell degeneration. Central motor conduction times were prolonged in two-thirds of the patients. Molecular genetic studies excluded Charcot–Marie–Tooth 1A syndrome and proximal spinal muscular atrophy linked to chromosome 5q as well as the known gene loci for distal HMN II on chromosome 12q, HMN V on chromosome 7p and juvenile amyotrophic lateral sclerosis on chromosome 9q. The findings in this family thus provide detailed clinical and electrophysiological information on HMN V and demonstrate broad phenotypic variability in this disorder. Hallmark features are discussed that appear to be most reliable to differentiate this type of HMN V from other variants of hereditary neuropathies, and a set of diagnostic criteria is proposed. Furthermore, this is the first report of prolonged central motor conduction times in HMN V, which indicates additional involvement of the central motor pathways in this disease. Finally, molecular genetic studies demonstrate genetic heterogeneity, suggesting the existence of at least a second genetic subtype in HMN V.
Rees, Geraint; Wojciulik, Ewa; Clarke, Karen; Husain, Masud; Frith, Chris
doi: 10.1093/brain/123.8.1624pmid: 10908192
Visual extinction is a sign classically associated with right parietal damage. The patient can see a single stimulus presented in the ipsilesional or contralesional visual field, but is characteristically unaware of the same contralesional stimulus during simultaneous stimulation of both fields. The ipsilesional stimulus is said to `extinguish' the contralesional stimulus from awareness during bilateral stimulation, perhaps due to a pathological bias in attention towards the ipsilesional side. Recent psychophysical evidence suggests that, although extinguished stimuli are not consciously seen, they may undergo residual processing and exert implicit effects on performance. However, the neural structures mediating such residual processing for extinguished stimuli remain unknown. Here we studied the neural activity evoked by an extinguished visual stimulus, using event-related functional MRI (fMRI), in a patient with circumscribed right inferior parietal damage and profound left-sided extinction. Monochrome objects (faces or houses) were presented in the left or right field, either unilaterally or bilaterally on each trial, with the patient indicating by button press whether he saw an object on the left, the right or on both sides. He usually saw only the right object on bilateral trials, yet the fMRI data showed activation of visual cortex contralateral to the extinguished left stimulus on these trials (compared with right-only stimulation), in both striate and early extrastriate areas of the right hemisphere. This activity had a similar location and time-course to that resulting from a single stimulus in the left versus right visual field. Cortical pathways involved in the normal processing of a single seen stimulus can thus still be activated by an unseen, extinguished stimulus after right parietal damage. Comparison of fMRI responses for faces versus houses revealed some category-specific activation for extinguished stimuli in right fusiform regions, but only at low statistical threshold. These results are discussed in terms of theoretical accounts for parietal extinction and, more generally, for the neural substrates of visual awareness.
Boatman, Dana; Gordon, Barry; Hart, John; Selnes, Ola; Miglioretti, Diana
doi: 10.1093/brain/123.8.1634pmid: 10908193
Transcortical sensory aphasia (TSA) is characterized by impaired auditory comprehension with intact repetition and fluent speech. We induced TSA transiently by electrical interference during routine cortical function mapping in six adult seizure patients. For each patient, TSA was associated with multiple posterior cortical sites, including the posterior superior and middle temporal gyri, in classical Wernicke's area. A number of TSA sites were immediately adjacent to sites where Wernicke's aphasia was elicited in the same patients. Phonological decoding of speech sounds was assessed by auditory syllable discrimination and found to be intact at all sites where TSA was induced. At a subset of electrode sites where the pattern of language deficits otherwise resembled TSA, naming and word reading remained intact. Language lateralization testing by intracarotid amobarbital injection showed no evidence of independent right hemisphere language. These results suggest that TSA may result from a one-way disruption between left hemisphere phonology and lexical–semantic processing.
Husain, Masud; Mattingley, Jason B.; Rorden, Chris; Kennard, Christopher
doi: 10.1093/brain/123.8.1643pmid: 10908194
Left neglect after right-hemisphere damage may involve perceptual and/or motor impairments. Here we discuss the limitations of previous attempts to separate these components, and introduce a new method. Six neglect patients (three with right inferior parietal lesions and three with right inferior frontal lesions) moved their right hand to a target light, which appeared unpredictably on either the left or the right of central fixation. The target appeared alone or with a distractor light in the opposite hemifield. Any directional motoric bias was measured by comparing reaches from a central start position with those for the same visual displays, but starting from the left of both possible targets (thus requiring only rightward reaches) or from the right (requiring only leftward reaches). All patients were slower to initiate reaches to left than right targets from a central start, which could reflect perceptual and/or motor biases. Critically, in the parietal neglect group only, initiation speed for left targets improved when a rightward reach was required to these (from a left start) rather than a leftward reach. This suggests a deficit in programming leftward movements into left hemispace, in addition to any visual impairment, for parietal neglect. A control task confirmed that this effect of start position was due to the associated change in reach direction and not to afferent inputs from the hand as it rested at the start position. Frontal neglect patients were slow to execute reaches to left targets, regardless of movement direction. Right visual distractors slowed visual reaction times to left targets more than vice versa in frontal neglect patients, and likewise for reach execution times in parietal neglect patients, suggesting that visual distractors on the neglected side have less impact. Distractor effects were unaffected by start position in the frontal neglect group (suggesting a perceptual basis), but distractors slowed reach initiation in the parietal neglect group only from left and central starts. Taken together, these findings demonstrate a directional motor component to parietal but not frontal neglect, and suggest that in man the inferior parietal lobe plays a role not only in perception but also in the programming of selective reaches. These conclusions are related to recent single-unit data from the monkey parietal lobe.
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The olfactory ensheathing cell (OEC) has attracted much interest recently because of its potential for transplantation-based therapy of CNS disease. Rat OECs are able to remyelinate demyelinated axons and support regeneration of damaged axons. Although OECs can be grown readily from the rat, a macrosmatic species, it has been uncertain whether it would be similarly straightforward to obtain these cells from the human, a microsmatic species with a relatively poorly developed olfactory system. In this study, we have identified a human OEC which shares many properties with its rat counterpart, including expression of the low-affinity nerve growth factor receptor (L-NGFr) and similar growth factor requirements. Purified populations of human OECs obtained by selection with L-NGFr antibodies have extremely high viability in tissue culture, and are capable of remyelinating persistently demyelinated CNS axons following transplantation into experimentally induced demyelinating lesions in the rat spinal cord. Thus, the human OEC represents an important new cell for the development of transplant therapy of CNS diseases.
H 2 15 O-PET was used to investigate changes in regional cerebral blood flow in response to auditory stimulation in patients in the vegetative state. Five patients in a vegetative state of hypoxic origin were compared with 18 age-matched controls. In addition, the cerebral metabolism of these patients and 53 age-matched controls was studied using ( 18 F)fluorodeoxyglucose. In control subjects, auditory click stimuli activated bilateral auditory cortices (Brodmann areas (BA) 41 and 42) and the contralateral auditory association cortices (BA 22). In the patients, although resting metabolism was decreased to 61% of normal values, bilateral auditory areas 41 and 42 showed activation as seen in the controls, but the temporoparietal junction cortex (BA 22) failed to be activated. Moreover, the auditory association cortex was functionally disconnected from the posterior parietal association area (BA 40), the anterior cingulate cortex (BA 24) and the hippocampus, as revealed by psychophysiological interaction analysis. Thus, despite altered resting metabolism, the auditory primary cortices were still activated during external stimulation, whereas hierarchically higher-order multi- modal association areas were not. Such a cascade of functional disconnections along the auditory cortical pathways, from the primary auditory areas to multimodal and limbic areas, suggests that the residual cortical processing observed in the vegetative state cannot lead to the integrative processes that are thought to be necessary for the attainment of the normal level of awareness.