Showing papers by "Mark Hallett published in 1996"

Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) Report of the NINDS-SPSP International Workshop*

Abstract: To improve the specificity and sensitivity of the clinical diagnosis of progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome), the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for PSP, Inc. (SPSP) sponsored an international workshop to develop an accurate and universally accepted set of criteria for this disorder. The NINDS-SPSP criteria, which were formulated from an extensive review of the literature, comparison with other previously published sets of criteria, and the consensus of experts, were validated on a clinical data set from autopsy-confirmed cases of PSP. The criteria specify three degrees of diagnostic certainty: possible PSP, probable PSP, and definite PSP. Possible PSP requires the presence of a gradually progressive disorder with onset at age 40 or later, either vertical supranuclear gaze palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset, as well as no evidence of other diseases that could explain these features. Probable PSP requires vertical supranuclear gaze palsy, prominent postural instability, and falls in the first year of onset, as well as the other features of possible PSP. Definite PSP requires a history of probable or possible PSP and histopathologic evidence of typical PSP. Criteria that support the diagnosis of PSP, and that exclude diseases often confused with PSP, are presented. The criteria for probable PSP are highly specific, making them suitable for therapeutic, analytic epidemiologic, and biologic studies, but not very sensitive. The criteria for possible PSP are substantially sensitive, making them suitable for descriptive epidemiologic studies, but less specific. An appendix provides guidelines for diagnosing and monitoring clinical disability in PSP.

Activation of the primary visual cortex by Braille reading in blind subjects.

Abstract: Primary visual cortex receives visual input from the eyes through the lateral geniculate nuclei, but is not known to receive input from other sensory modalities. Its level of activity, both at rest and during auditory or tactile tasks, is higher in blind subjects than in normal controls, suggesting that it can subserve nonvisual functions; however, a direct effect of non-visual tasks on activation has not been demonstrated. To determine whether the visual cortex receives input from the somatosensory system we used positron emission tomography (PET) to measure activation during tactile discrimination tasks in normal subjects and in Braille readers blinded in early life. Blind subjects showed activation of primary and secondary visual cortical areas during tactile tasks, whereas normal controls showed deactivation. A simple tactile stimulus that did not require discrimination produced no activation of visual areas in either group. Thus in blind subjects, cortical areas normally reserved for vision may be activated by other sensory modalities.

Cerebral structures participating in motor preparation in humans: a positron emission tomography study.

Abstract: 1. Using positron emission tomography and measurement of regional cerebral blood flow (rCBF) as an index of cerebral activity we investigated the central processing of motor preparation in 13 healthy volunteers. 2. We used a motor reaction time paradigm with visual cues as preparatory and response signals. A preparatory stimulus (PS) provided either full, partial, or no information regarding two variables of a forthcoming right finger movement: finger type (index or little finger) and movement direction (abduction or elevation). After a variable delay period, a response stimulus (RS) prompted the movement. A condition was also tested in which the subject could freely select any of the four possible movements during the preparation period ("free" condition). The timing of events was designed to emphasize the motor preparation phase over the motor execution component during the scanning time of 1 min. 3. Distinct preparatory processes, which depended on the information contained in the PS, were demonstrated by significant differences in reaction time between conditions. The reaction time was shorter in the "full" and free conditions, intermediate in the two partial information conditions ("finger" and "direction"), and longer when no preparatory information was available ("none" condition). Conversely, movement time and movement amplitude were similar between conditions, establishing the constancy of the motor executive output. 4. In comparison with a "rest" condition, which had matched visual inputs, the different conditions of motor preparation were associated with increased rCBF in a common set of cerebral regions: the contralateral frontal cortex (sensorimotor, premotor, cingulate, and supplementary motor cortex), the contralateral parietal association cortex (anterior and posterior regions), the ipsilateral cerebellum, the contralateral basal ganglia, and the thalamus. This observation substantiates the participation of those cerebral structures in the preparation for movement. Furthermore, the similarity of the activated areas among the different conditions compared with the rest condition suggests a single anatomic substrate for motor preparation, independent of the movement information context. 5. Differing amounts of movement information contained in the PS affected rCBF changes in some cerebral regions. In particular, the rCBF in the anterior parietal cortex (Brodmann's area 40) was significantly larger in each of the full, finger, and direction conditions, individually, compared with the none condition. This observation supports the hypothesis that the anterior parietal association cortex plays a major role in the use of visual instructions contained in the PS for partial or complete preparation to perform a motor act. On the other hand, the posterior parietal association cortex (Brodmann's area 7) was more activated in the finger, direction, and none conditions than in the full condition. This increased activity with restricted advance information suggests that the posterior region of the parietal cortex is concerned with correct movement selection on the basis of enhanced spatial attention to the RS. 6. In contrast with the parietal cortex, the secondary motor areas (i.e, premotor cortex, cingulate cortex, and supplementary motor area) showed similar activity regardless of the degree of preparation allowed by the advance visual information. Thus the parietal cortex may play a more crucial role than the secondary motor areas in integrating visual information in preparation for movement. 7. The effect on brain activity of the internal (self-generated) versus the external (cued) mode of movement selection was assessed by comparing the free and full conditions, the preparatory component being matched in the two conditions. The anterior part of the supplementary motor area was the main area preferentially involved in the internal selection of movement, independently of motor preparation processes.

Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation (rTMS) of the prefrontal cortex.

Abstract: Rapid-rate transcranial magnetic stimulation (rTMS) was administered to 10 healthy volunteers on different days over the right or left prefrontal cortex, midfrontal cortex, occipital cortex, or cerebellum. Mood (self-rated), reaction time, and hormone levels were serially measured. Consistent with a previous study, comparison of hemispheres revealed significant associations with decreased happiness after left prefrontal rTMS and decreased sadness after right prefrontal rTMS. Stimulation of all three prefrontal regions, but not the occipital or cerebellar regions, was associated with increases in serum thyroid-stimulating hormone. There was no effect on serum prolactin. rTMS applied to prefrontal cortex is safe and well tolerated and produces regionally and laterally specific changes in mood and neuroendocrine measures in healthy adults. rTMS is a promising tool for investigating prefrontal cortex functions.

Complexity affects regional cerebral blood flow change during sequential finger movements

Abstract: Brain regions activated with complex sequential finger movements were localized by measuring regional cerebral blood flow (rCBF) with positron emission tomography. Whereas the total number and frequency of finger movements were kept constant, the complexity of auditory cued sequential finger movements of the right hand varied, with sequence length as the independent variable. In four conditions of differing complexity, the bilateral primary sensorimotor area, left ventral premotor cortex, posterior supplementary motor area, right superior part of the cerebellum, and left putamen were consistently and equally activated. This finding suggests an executive role in running sequences, regardless of their length. The right dorsal premotor cortex (Brodmann area 6) and the right precuneus (Brodmann area 7) showed a linear increase of rCBF as sequence complexity increased. This finding is consistent with the hypothesis that these areas function in the storage of motor sequences in spatial working memory and the production of ongoing sequential movement with reference to that of buffered memory. A similar increase in the cerebellar vermis and the left thalamus likewise suggests a role of these subcortical structures in complexity of sequential finger movements. Conversely, the left inferior parietal lobule showed a decrease of rCBF as complexity increased. Because short-term phonological storage is localized to this area, we suggest that the visuospatial working memory system may suppress other systems not in use. Our findings suggest that complex sequential finger movements recruit a discrete set of brain areas, in addition to areas underlying the execution of simple movement sequences.

Use and safety of a new repetitive transcranial magnetic stimulator.

Abstract: In order to test a new repetitive transcranial magnetic stimulator, the Dantec MagPro, we administered transcranial magnetic stimulation (TMS) at 1 Hz and 125% of motor threshold for an average of 204 s (until the coil temperature reached 40°C) and 20 Hz stimulation at 100% of motor threshold for 2 s every minute for 10 min, on different days to 10 healthy volunteers. We stimulated 6 scalp positions (primary motor area (M1) and sites 5 cm anterior and posterior on each hemisphere) with an 8-shaped coil. We tested immediate and delayed memory, verbal fluency, prolactin levels and EEG at the beginning of the study and after stimulation on each day. No abnormalities were found. Motor evoked potentials evoked with 1 Hz stimulation diminished progressively in amplitude, and 1 Hz stimulation of M1 caused inhibition lasting at least 1 min in 3 of 4 subjects who were tested with 0.1 Hz stimulation before and after the 1 Hz stimulation period. This did not occur with 20 Hz stimulation. Finger tapping frequency was tested at the beginning of the study and after TMS at each scalp site. Finger tapping rate data from 6 additional subjects who were stimulated in an identical fashion with a different stimulator were also analyzed. There was an increase in tapping rate after TMS which was independent of scalp site. This was most pronounced with 1 Hz stimulation at 125% of threshold and reached statistical significance in the hand contralateral to the stimulation. The results of this study indicate that rTMS with the MagPro stimulator is safe at specific combinations of intensity, frequency and train duration.

Abnormal cortical motor excitability in dystonia

Abstract: To assess the excitability of the motor system, we studied 11 patients with task-specific dystonia and 11 age-matched normal subjects. The dominant side was affected in nine of the patients. We delivered transcranial magnetic stimuli at different stimulus intensities and with different levels of muscle facilitation to the side contralateral to the side of electromyographic recording, and recorded motor evoked potentials (MEPs) from the flexor carpi radialis muscles bilaterally. The threshold intensity for eliciting MEPs at rest did not differ between patients and normal subjects. We compared the affected side in patients with the dominant side in normal subjects. With facilitation, the percentage of the area of the MEP to the M wave (MEP area%) was similar in both groups at low stimulus intensities, but with increasing stimulus intensity the increase in the MEP area% was greater in patients than in normal subjects (ANOVA, p < 0.001). The increase in MEP area% was similar in both groups with increasing facilitation levels. The duration of the silent period was similar in patients and normal subjects. We conclude that cortical motor excitability is increased in dystonia.

Single–joint rapid arm movements in normal subjects and in patients with motor disorders

Abstract: In normal subjects the execution of single rapid one-joint movements is characterized by an electromyographic (EMG) pattern composed of three discrete bursts of activity; two bursts (first and second agonist bursts, or AG1 and AG2) are present in the agonist muscle separated by an almost complete period of electrical silence. During this pause, another burst (antagonist burst, or ANT) occurs in the antagonist muscle. If a rapid movement is executed during tonic activation of the agonist muscle, tonic activity is inhibited just prior to AG1 onset (agonist inhibition). Similarly, if the movement is performed during tonic activation of the antagonist muscle, such activity is also inhibited prior to AG1 onset (antagonist inhibition). Antagonist inhibition also starts prior to AG1 onset and lasts until ANT onset. A general descriptor of the kinematic features related to the EMG pattern described above is a symmetrical and unimodal velocity profile that is bell-shaped and shows an acceleration time roughly equal to the deceleration time. This holds true for movements performed under low accuracy constraints; as accuracy demands become stricter and stricter, the peak velocity decreases but, as long as the movement is made with one continuous trajectory, the velocity profile remains roughly symmetrical. In general terms, the function of AG1 is to provide the impulsive force to start the movement; the function of ANT is to halt the movement at the desired end-point; and the function of AG2 is to dampen out the oscillations which might occur at the end of the movement. The timing and size of the bursts vary according to the speed and amplitude of the movement. The origin of the EMG pattern is a central programme, but afferent inputs can modulate the voluntary activity. In this paper, we also review the EMG and kinematic abnormalities that are present during the execution of single-joint, rapid arm movements in patients with Parkinson's disease, Huntington's disease, Sydenham's chorea, dystonia, athetosis, cerebellar deficits, upper motor neuron syndrome, essential tremor and large-fibre sensory neuropathy. The data from these studies lead us to the following conclusions: (i) the basal ganglia have a role in scaling the size of AG1, reinforcing the voluntary command and inhibiting inappropriate EMG activity; (ii) the cerebellum has a role in timing the voluntary bursts and probably in implementing muscle force phasically; (iii) the corticospinal tract has a role in determining spatial and temporal recruitment of motor units; (iv) proprioceptive feedback is not necessary to produce the triphasic pattern but it contributes to the accuracy of both the trajectory and the end-point of rapid movements.

Frequency-Dependent Changes of Regional Cerebral Blood Flow during Finger Movements

Abstract: To study the effect of the repetition rate of a simple movement on the distribution and magnitude of neuronal recruitment, we measured regional CBF (rCBF) in eight normal volunteers, using positron emission tomography and 15O-labeled water. An auditory-cued, repetitive flexion movement of the right index finger against the thumb was performed at very slow (0.25 and 0.5 Hz), slow (0.75 and 1 Hz), fast (2 and 2.5 Hz), and very fast (3 and 4 Hz) rates. The increase of rCBF during movement relative to the resting condition was calculated for each pair of movement conditions. Left primary sensorimotor cortex showed no significant activation at the very slow rates. There was a rapid rise of rCBF between the slow and the fast rates, but no further increase at the very fast rates. The right cerebellum showed similar changes. Changes in the left primary sensorimotor cortex and the cerebellum likely reflect the effect of the movement rate. The posterior supplementary motor area (SMA) showed its highest activation at the very slow rates but no significant activation at the very fast rates. Changes correlating with those in the SMA were found in the anterior cingulate gyrus, right prefrontal area, and right thalamus. The decreases in CBF may reflect a progressive change in performance from reactive to predictive.

The role of the dorsolateral prefrontal cortex in implicit procedural learning

Abstract: We studied the role of the dorsolateral prefrontal cortex in procedural learning. Normal subjects completed several blocks of a serial reaction time task using only one hand without or with concurrent non-invasive repetitive transcranial magnetic stimulation. To disrupt their function transiently, stimulation was applied at low intensity over the supplementary motor area or over the dorsolateral prefrontal cortex contralateral or ipsilateral to the hand used for the test. Stimulation to the contralateral dorsolateral prefrontal cortex markedly impaired procedural implicit learning, as documented by the lack of significant change in response times during the task. Stimulation over the other areas did not interfere with learning. These results support the notion of a critical role of contralateral dorsolateral prefrontal structures in learning of motor sequences.

Responses to paired transcranial magnetic stimuli in resting, active, and recently activated muscles

Abstract: Transcranial magnetic stimulation (TMS) causes the corticospinal system to become refractory to subsequent stimuli for up to 200 ms. We examined the phenomenon of paired pulse inhibition with TMS under conditions of rest, ongoing voluntary activation (isometric force generation), and at variable delays following activation (postactivation) of the wrist extensors of seven normal subjects. Paired stimuli were delivered to the motor cortex with a circular coil at 1.1 times motor evoked potential (MEP) threshold, with various interstimulus intervals. Voluntary activation caused a marked decrease in the variability of the ratio of the amplitude of the MEP evoked by the test pulse to that of the MEP evoked by the conditioning pulse. Marked inhibition of the MEP evoked by the test pulse was still present. Postactivation, however, caused a dramatic reversal of the inhibitory effect of the conditioning pulse in all subjects at interstimulus intervals ranging from 40 to 120 ms. This effect lasted for up to 10 s following the cessation of activation. MEPs to transcranial electrical stimulation were also inhibited by conditioning TMS, but postactivation did not reverse this inhibition, indicating that the reversal of paired pulse inhibition is intracortical. We conjecture that paired pulse inhibition reflects activity of inhibitory interneurons or inhibitory connections between cortical output cells that are inactivated in the postactivation state.

Characterization of postexercise facilitation and depression of motor evoked potentials to transcranial magnetic stimulation

Abstract: We studied the effects of exercise on motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES). Subjects performed 30-second periods of isometric exercise of the extensor carpi radialis until fatigue, which was defined as the inability to maintain half maximum force. The amplitude of MEPs to TMS recorded from the resting muscle after each exercise period was on average more than twice the pre-exercise value (postexercise MEP facilitation). After fatigue occurred, the MEP amplitudes were approximately 60% of the pre-exercise value (postexercise MEP depression). There was a gradual recovery of the depressed MEPs to pre-exercise values over several minutes of rest. Postexercise MEP facilitation was constant when exercise intensity ranged from 10 to 50% of maximum voluntary contraction and it decayed to baseline over several minutes after the end of exercise. There was no postexercise MEP facilitation to TES. We hypothesize that both postexercise MEP facilitation and MEP depression are due to intracortical mechanisms.

Simple motor tics may be preceded by a premotor potential

Abstract: Obeso et al reported that simple motor tics in Tourette's syndrome were not associated with premotor potentials, which were present when patients mimicked their tics voluntarily, suggesting that spontaneous tics were not generated in the same manner as voluntary movements. Five patients with simple motor tics were studied using a similar paradigm. Premotor potentials were examined during spontaneous tics and during voluntary imitation of the tics. All patients had premotor negativity with the voluntary movements. As in the study of Obeso et al, spontaneous tics were not preceded by premotor potentials in three patients. However, premotor negativity was present with spontaneous tics in two patients and resembled the NS' segment of the premotor potential seen with self paced, voluntary movements. A similar premotor potential pattern has been reported with voluntary movements performed in response to external triggering stimuli. In patients with Tourette's syndrome, the eliciting signals could be internal sensations.

Decreased postexercise facilitation of motor evoked potentials in patients with chronic fatigue syndrome or depression

Abstract: We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 18 normal (control) subjects, 12 patients with chronic fatigue syndrome, and 10 depressed patients. Subjects performed repeated sets of isometric exercise of the extensor carpi radialis muscle until they were unable to maintain half maximal force. MEPs were recorded before and after each exercise set and for up to 30 minutes after the last set. The mean amplitude of MEPs recorded from the resting muscle immediately after each exercise set was 218% of the mean pre-exercise MEP amplitude in normal subjects, 126% in chronic fatigue patients, and 155% in depressed patients, indicating postexercise MEP facilitation in all three groups. The increases in the patient groups, however, were significantly lower than normal. The mean amplitudes of MEPs recorded within the first few minutes after the last exercise sets in all three groups were approximately half their mean pre-exercise MEP amplitudes. This postexercise MEP depression was similar in all groups. We conclude that postexercise cortical excitability is significantly reduced in patients with chronic fatigue syndrome and in depressed patients compared with that of normal subjects.

Reliability of the NINDS Myotatic Reflex Scale

Abstract: The assessment of deep tendon reflexes is useful for localization and diagnosis of neurologic disorders, but only a few studies have evaluated their reliability. We assessed the reliability of four neurologists, instructed in two different countries, in using the National Institute of Neurological Disorders and Stroke (NINDS) Myotatic Reflex Scale. To evaluate the role of training in using the scale, the neurologists randomly and blindly evaluated a total of 80 patients, 40 before and 40 after a training session. Inter- and intraobserver reliability were measured with kappa statistics. Our results showed substantial to near-perfect intraobserver reliability, and moderate-to-substantial interobserver reliability of the NINDS Myotatic Reflex Scale. The reproducibility was better for reflexes in the lower than in the upper extremities. Neither educational background nor the training session influenced the reliability of our results. The NINDS Myotatic Reflex Scale has sufficient reliability to be adopted as a universal scale.

Adaptation motor learning of arm movements in patients with cerebellar disease.

Abstract: OBJECTIVE--To design a test of motor learning using arm movements in normal subjects and patients with cerebellar disease. METHODS--Elbow angle was continuously displayed as a cursor (a dot) on a computer screen, and subjects made ballistic elbow flexion and extension movements to try to move the cursor between two targets on the screen. The relation between the arm movement and its visual feedback was changed, and the subjects reacted by adapting the amplitude of their movements in subsequent trials. RESULTS--The consecutive errors showed exponential learning curves during adaptation, which were quantified by their steepness. Ten patients with isolated cerebellar or olivopontocerebellar degeneration had less steep learning curves than normal subjects, indicating a failure of adaptation motor learning in cerebellar disease. The results show that this test may be useful for the analysis of motor learning.

Cortical modulation of spinal excitability: an F-wave study.

Abstract: F-waves are known to be highly sensitive to changes in the excitatory state of the spinal cord. This paper describes the effects of subthreshold transcranial magnetic stimulation on the F-waves evoked in hand and foot muscles. In the abductor pollicis brevis muscle, the F-wave was significantly enhanced when the cortical stimulus was given with a delay corresponding approximately to the expected time of collision, i.e., the difference between the mean latency of the F-wave and the mean latency of the motor evoked potential. A second, usually larger facilitatory phase follows the first phase after 2-3 msec, and later peaks of enhancement often occurred. After the enhancement periods, a significant inhibition of the F-wave was usually observed. In the extensor digitorum brevis muscle, the first facilitatory phase was observed some milliseconds earlier than expected in 4 of 5 subjects, and the inhibitory phase was less pronounced. We argue that the sequential arrival of I-waves at the spinal segment could be responsible for the changes observed in the F-wave recorded from the small hand muscle. In the foot muscle, anatomical and technical factors could contribute to the generation of a D-wave. The strong inhibition observed in the F-wave recorded from the hand muscle is likely to be due to the arrival on alpha-motoneurons of inhibitory postsynaptic potentials (IPSPs) generated by the cortical stimulus. Our data show that the F-wave ia a probe for changes in the spinal cord excitatory state.

Kinematics of initiating a two-joint arm movement in patients with cerebellar ataxia.

Abstract: OBJECTIVE To characterize kinematically any systematic aberration in multi-joint movements in cerebellar ataxia. METHODS Nine patients with cerebellar degeneration and nine normal subjects, mobile only at the shoulder and elbow of the right arm, were required to produce left-to-right cross-body linear hand trajectories on the horizontal surface of a digitizing tablet. Nonlinearity indicated failure of precise coordination of the two joints. A wide range of hand speeds was studied. Data analysis was restricted primarily to the first 130 ms of movement. RESULTS As hand velocities increased, normal subjects and, especially, patients produced misdirected, curved paths. Normal subjects had significant curvature when peak speeds exceeded 100 cm/s and a trend toward significant bi-directional angular deviation at velocities greater than 300 cm/s. In patients, peak path curvature was significantly greater than normal at peak velocities of 50 to 200 cm/s. By 3.3 cm, their paths deviated significantly outward at all but the slowest speeds. Overall, patients' maximal hand velocities and shoulder angular velocities, as well as maximal angular accelerations at both joints, were significantly lower than normal. CONCLUSIONS The patients' trajectory aberrations were attributed to a deficient rate of rotation at the shoulder relative to that at the elbow. Relative to task requirements, their rate of torque development was apparently deficient at both joints. but to a greater degree at the shoulder. Joint torque-rate impairment may contribute to the ataxia in both multi- and single-joint movements of patients with cerebellar disorders. A similar, but smaller impairment may produce milder nonlinearity in high-velocity movements of normal subjects.

Blepharospasm: Report of a workshop

Abstract: Blepharospasm refers to excessive involuntary closure of the eyelids. It is generally (but not always) due to spasm of the orbicularis oculi (OO) muscles and occurs in a variety of disorders of the CNS, or may occur secondarily to ocular disorders. The most common form of blepharospasm, benign essential blepharospasm (BEB), is of unknown origin and is generally considered a form of focal dystonia. Before a full discussion of the clinical and pathophysiologic aspects of blepharospasm, we review the normal anatomy and physiology of eyelid control. The movements of the eyelids are controlled by two muscles. The OO muscle closes the eyelid, and the levator palpebrae opens the eyelid by elevating the upper lid. The OO muscle is composed of three portions. The deepest (closest to the eyeball) is the pretarsal portion that covers the tarsus (the eyelid proper). Next is the preseptal portion, and the most superficial is the orbital portion. With normal blinking, the pretarsal portion is primarily recruited. The preseptal and orbital regions are recruited with more forced voluntary closure of the eyelids. The muscle fibers of the OO muscle do not run the full length of the muscle, and interdigitate. 1 In the rabbit eyelid, fiber length averages 36% of the length of the entire muscle. The motor units of the OO are small, with approximately 25 muscle fibers per unit. Anatomically, 90% of the muscle fibers is fast or type II. Physiologic observations of the time to peak tension and half relaxation times are consistent with this, but the muscle appears to be more fatigue resistant than would be expected. 2 Hence, the character of the muscle is unique compared with skeletal muscle. There are occasional muscle spindles in OO muscle, but these are sparse and are not well studied. The kinematics of blinks has …

Electrophysiological tests of autonomic function in patients with idiopathic autonomic failure syndromes

Abstract: Three electrophysiological tests of autonomic function were performed in patients with autonomic nervous system dysfunction to define test sensitivities and specificities. The skin sympathetic response, Valsalva ratio, and heart rate variation with deep breathing were studied in 10 patients with multiple system atrophy (MSA) and in 7 patients with pure (also called progressive or primary) autonomic failure (PAF); control subjects were 17 normal individuals of similar age. Thirteen patients had abnormal skin sympathetic responses, and 16 had abnormal Valsalva ratios. Fourteen patients had an abnormal variation of the heart rate with deep breathing. Taking the three tests together, binary logistic regression for distinguishing between patients and normal subjects correctly classified 91% of the 33 individuals for whom there were complete data with sensitivity of 88% and specificity of 94%. However, only 69% of the patients could be correctly classified by a logistic regression for discriminating between MSA and PAF. Electromyography (EMG) studies showed that 7 of 8 patients with MSA but only 2 of 7 patients with PAF (both multiparous women) had denervation of the rectal sphincter muscle. The EMG study is, therefore, valuable in men, but has a high false positive rate in women, probably because of pudendal nerve injury from parturition.

Proton magnetic resonance spectroscopic imaging in patients with cerebellar degeneration

Abstract: Using proton magnetic resonance spectroscopic imaging, we studied the cerebellum of 9 patients with cerebellar degeneration and of 9 age-matched normal control subjects. This technique permits the simultaneous measurement of N-acetylaspartate, choline-containing compounds, creatine/phosphocreatine, and lactate signal intensities from four 15-mm slices divided into 0.84-ml single-volume elements. Because patients with cerebellar degeneration often show substantial atrophy on magnetic resonance imaging (MRI), we specifically chose to analyze the spectroscopic signals only from tissue that did not have an atrophic appearance on the MRI. The spectroscopic findings showed a significant reduction of N-acetylaspartate in all parts of the cerebellum, a significant correlation with MRI scores of cerebellar atrophy, and a significant correlation with clinical rating scores of cerebellar disturbance. Our method of analysis suggests the presence of a neurodegenerative process in cerebellar areas that do not appear to be atrophic on the MRI. Some limitations of proton magnetic resonance spectroscopic imaging in the present study were related to the partial field inhomogeneity characteristics of the posterior fossa, the anatomical location of the cerebellum, and the particularly severe cerebellar atrophy in some of the patients.

Haplotype analysis at the DYT1 Locus in ashkenazi jewish patients with occupational hand dystonia

Abstract: Genetic haplotypes at five marker loci that are closely linked to the DYT1 gene on chromosome 9q were determined in 10 Ashkenazi Jewish patients with focal hand dystonia (eight with musician's cramp, two with writer's cramp). The founder haplotype associated with >90% of cases of generalized dystonia in the Ashkenazi Jewish population could not be constructed from any of the twenty chromosomes. Potential haplotypes were determined, and no common haplotype was discerned in these patients. These findings argue against a role for the founder mutation in the DYT1 gene in the etiology of occupational hand dystonia in this ethnic group. Further, if the DYT1 gene is involved in these later onset dystonias, there is no evidence for a common mutation in the Ashkenazic Jewish population. It appears that excessive, repetitive use, possibly in combination with ulnar neuropathy, may serve as the inciting cause of some focal dystonias.

Physiological studies of spinal inhibitory pathways in patients with hereditary hyperekplexia

Abstract: Because hereditary hyperekplexia results from a defect in the glycine receptor, we studied in five patients several spinal inhibitory pathways that are thought to use either glycine or gamma-aminobutyric acid as a neurotransmitter. Three patients had a mutation in the alpha1 subunit of the glycine receptor, whereas two sisters with the same clinical syndrome did not have this mutation. Compared with normal subjects, reciprocal inhibition between flexor and extensor muscles of the forearm was diminished during the first period of inhibition and preserved during the second period of inhibition in all three patients tested. Facilitation after the early period of inhibition was prominent. Recurrent inhibition of the soleus H reflex was normal in four patients, as was inhibition of the H reflex produced by Achilles' tendon vibration. There was no significant difference in nonreciprocal (Ib) inhibition between patients and normal individuals, The findings suggest that disynaptic reciprocal inhibition in humans is mediated through glycinergic interneurons, but that recurrent inhibition may have a contribution from nonglycinergic mechanisms.