The validity of a hyperventilation test for an investigation of autonomic failure: assessment in patients with multiple system atrophy and Parkinson's disease.

Although heart rate (HR) responses to hyperventilation (HV) have been used as a cardiovascular autonomic function test, autonomic involvement during HV remains uncertain. To clarify the relationship between autonomic activity and cardiovascular changes during HV, we compared cardiovascular responses during HV among subjects with different autonomic function, namely 16 patients with probable multiple system atrophy (MSA), 16 with possible MSA, 28 with Parkinson's disease (PD) and 28 healthy controls. Abnormalities of cardiovascular responses to head-up postural change and the Valsalva maneuver were definitely present in the order of probable MSA, possible MSA and PD, and abnormal HR and blood pressure (BP) responses during HV were observed in probable MSA and possible MSA, but not in PD. Unlike the significant difference in standard cardiovascular autonomic function tests, the HR and BP responses during HV were equivalent between probable and possible MSA. These findings suggest that cardiovascular control during HV may be affected not only by autonomic activity but also by other factors.

Abnormal baroreceptor-mediated vasopressin release as possible marker in early diagnosis of multiple system atrophy.

BACKGROUND: Although autonomic failure (AF) is a critical symptom of multiple system atrophy (MSA), it may not appear until late in the disease process. OBJECTIVES: To clarify whether a detailed investigation of the autonomic nervous system in patients with MSA without overt AF demonstrates latent lesions of central cardiovascular control circuits and facilitates the early diagnosis of MSA. METHODS: Autonomic function tests, and plasma noradrenaline (NA) and vasopressin (AVP) responses to head-up tilt (HUT), were studied in 12 patients with MSA with AF (probable MSA), 12 with MSA without overt AF (possible MSA), and 24 controls. RESULTS: Abnormalities of cardiovascular autonomic function tests were prominent in the first group but mild in the second. Plasma NA and AVP increments upon HUT differed significantly among all three groups. CONCLUSIONS: These results indicate that probable MSA involves diffuse degeneration of central cardiovascular control circuits. On the other hand, the discrepancies in possible MSA suggest a vulnerability of the noradrenergic (A1) neurones of the caudal ventrolateral medulla that are involved in AVP secretion. This finding also suggests that AVP increment may be useful as a diagnostic tool in the early stages of MSA.

Changes of middle latency somatosensory evoked potentials (SEPs) and alpha rythmicity associated with oculomotor processes.

OBJECTIVES: To evaluate median nerve somatosensory evoked potentials (SEPs) and alpha waves during different eye conditions. METHODS: Median SEPs and occipital electroencephalographs (EEG) were recorded in 6 eye conditions: eye-closed (EC), goggle (G), goggle+saccade (GS), saccade (S), eye-opened (EO) and pursuit (P), in 8 normal adults. Subjects saccaded their eyes reacting to auditory cues to watch a diode on the right or left side alternatively during the S condition, or imitated the same saccadic eye-movement as that in the S condition during the GS condition. In the P condition, subjects traced a small circle moving on a computer screen. RESULTS: Compared with the EC and G conditions, N30 (P25-N30 or P14-N30) amplitudes in C4' were significantly larger and the mean amplitude and power of the alpha band was significantly attenuated in the other 4 conditions. The amplitude and power of the alpha band differed significantly between the GS and S conditions, whereas N30 amplitudes were similar between the two conditions. N30-P45 or P45-N60 amplitudes in C4' were significantly larger in the P condition than in other conditions. CONCLUSIONS: Present findings suggest that different neural mechanisms cause alpha blocking and the modification of middle latency SEPs associated with oculomotor control.

Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses?

OBJECTIVES: To investigate the mechanisms responsible for suppressing the amplitude of electromyogram (EMG) responses to a standard transcranial magnetic stimulus (TMS) after prior conditioning of the motor cortex with repetitive subthreshold TMS (rTMS) at a frequency of 1 Hz. METHODS: EMG responses from the first dorsal interosseous, abductor pollicis brevis and flexor carpi radialis (FCR) muscles were recorded after suprathreshold TMS of the motor cortex. In some experiments, H-reflexes were also obtained in the FCR. The amplitude of these responses was compared before and after applying from 150 to 1500 rTMS pulses to motor cortex at an intensity of 95% resting motor threshold through the same figure-of-8 coil. RESULTS: When tested with subjects relaxed, rTMS conditioning reduced the amplitude of motor evoked potentials (MEPs) to approximately 60% of pre-conditioning values for 2-10 min after the end of the conditioning train, depending on the number of pulses in the train. There was more suppression with 1500 rTMS pulses than with 150 pulses. There was no effect on H-reflexes. There was no effect on MEPs if the test stimuli were given during active contraction of the target muscle. CONCLUSIONS: The findings confirm previous observations that low-frequency, low-intensity rTMS to motor cortex can produce transient depression of MEP excitability. Since there was no effect on spinal H-reflexes, this is consistent with the idea that some of the suppression occurs because of an effect on the motor cortex itself. The lack of any conditioning effect on MEPs evoked in actively contracting muscle is not readily consistent with the idea that rTMS depresses transmission in synaptic connections to pyramidal cells activated by the test TMS pulse. An alternative explanation is that rTMS reduces the excitability of cortical neurones in relaxed subjects, so that responses to a given input are smaller than before conditioning. Voluntary contraction normalises excitability levels so that the effect is no longer seen.

Impaired novelty P3 potentials in multiple system atrophy--correlation with orthostatic hypotension.

Although neuropsychological tests demonstrate frontal lobe dysfunction in multiple system atrophy (MSA), assessment of frontal function using event-related brain potentials (ERPs) has not been sufficiently performed in MSA. The correlation between frontal lobe dysfunction and orthostatic hypotension (OH), which is known to cause frontal hypoperfusion, remains unclear. Our objectives were to assess frontal lobe dysfunction in MSA patients using ERPs and to elucidate the relevance of OH to changes in ERPs. Nine consecutive patients with MSA and nine age- and gender-matched healthy controls were compared by performance in the Wisconsin Card Sorting Test (WCST) and somatosensory ERPs to target and novel stimuli, namely, parietal maximal P3 (target P3) and fronto-central P3 (novelty P3), respectively. The correlation between novelty P3 and OH was evaluated in the MSA group. The MSA group showed a poorer performance in categories achieved (CA), total errors (TE) and perseverative errors by Nelson's (PEN) method in the WCST compared with the control group (CA and PEN: p<0.01; TE: p<0.02). Novelty and target P3s in the MSA group showed significantly prolonged latency (novelty: p<0.05; target: p<0.01) and reduced amplitude (novelty: p<0.02; target: p<0.01) compared with the control group. There was a significant negative correlation between novelty P3 latency and a drop in systolic blood pressure (r=0.76; p<0.02). Abnormalities of novelty P3 in the MSA group might reflect frontal lobe dysfunction, namely failure of attentional set-shifting, that was identified by the WCST. OH may play a role in the development of frontal lobe dysfunction in MSA.

Transient spinal inhibition induced by electrical stimulation of the rat brain.

Intracortical electrical stimulation of the rat brain using single pulse induced motor evoked potentials (MEPs) with shorter onset latencies in the bilateral extremity muscles. The MEPs appeared in the stimulation of cortical areas outside the motor cortex (MI) and subcortical areas. Train-pulse stimulation of the MI at a stimulus intensity just above the threshold induced MEPs with longer onset latency in muscles corresponding to the somatotopy of the MI stimulated. This implies that the potential characterizing shorter onset latency is equal to responses induced via the extrapyramidal tract, and responses with longer onset latency originate in the pyramidal tract. Corresponding to MEPs, we recorded two types of spinal potentials (SPs) via extrapyramidal and pyramidal tracts. In paired-pulse stimulation of the extrapyramidal tract, second MEPs showed a long-lasting inhibition up to 3 s after the first MEPs, while the changes in second SPs were not remarkable. Extrapyramidal tract stimulation inhibited H-reflex in the same manner as MEPs. These results suggest that the electrical stimulation of rat brain has a long-lasting effect in inhibiting lower motoneuron excitabilities. Our method may be a useful experimental model to induce the transient inhibition of spinal motoneuron excitabilities caused by supraspinal structures.

Afferent and efferent excitabilities of the transcortical loop in patients with dentatorubral-pallidoluysian atrophy.

To evaluate the excitabilities of the transcortical loop in patients with dentatorubral-pallidoluysian atrophy (DRPLA), we studied somatosensory evoked potentials (SEPs) and evoked EMG responses (V1 and V2) in 10 patients and age-matched controls. In addition, the facilitatory effects of somatosensory inputs on motor evoked potentials (MEPs) were studied in four patients and controls. We observed attenuated or prolonged cervical and subcortical potentials and prolonged middle latency components of SEPs. The amplitudes of V2 in patients were significantly lowered compared to those in the controls, while the amplitudes and latencies of V1 were similar between the two groups. Since V2 was considered as a transcortical reflex, our results suggest reduced excitabilities of the afferent pathway of the transcortical loop in patients with DRPLA. Median nerve stimulation (MNS) 25 to 30 ms preceding transcranial magnetic stimulation (TMS) facilitated MEPs in the thenar muscle in two of the four patients and in the controls. The facilitation of MEPs by MNS tended to be independent of the reduction in V2. Such a result suggests that different neural mechanisms elicit V2 and facilitate MEPs following peripheral nerve stimulation, although further studies are needed. The combination of SEPs, evoked EMG responses and MEPs may be a useful technique to detect abnormalities of input and output coordinations of the transcortical loop.

[An assessment of dysphagia using videofluorography in Parkinson's disease and progressive supranuclear palsy].

We assessed the oropharyngeal swallowing ability in 8 patients with Parkinson's disease (PD), 8 patients with progressive supranuclear palsy (PSP), and 10 age-matched healthy controls (CTL) using videofluorography (VF). In VF studies, PD and PSP patients demonstrated food pooling on the tongue, difficulty in bolus formation, and bolus falling into pharynx before swallow. PSP patients had a significantly longer delay in the pharyngeal phase and showed food falling into larynx more often than PD patients (p < 0.05). On measurement of swallowing time periods as proposed by Robbins et al., both patient groups showed significantly longer periods during many swallowing phases (P < 0.05) compared to those in the control group, but there were no significant differences between the PD and PSP groups. However, in PSP patients, the time for "transferring the food bolus from the oral cavity to pharynx" which we defined as a distinct stage was significantly longer (p < 0.05) than that in the PD group. We think that the difference in dysphagia characteristics between the two diseases arises from the variations in pathological changes in PSP, including those in the cerebral cortex, cerebellum, pons and medulla tegmentum in addition to the basal ganglia. Dystonia in the neck muscle also plays a role in dysphagia in PSP patients. Levodopa medication, changing the form of foods and training in rehabilitation techniques such as the chin down posture, supraglottic swallowing and ice-massage of the oral region are probably effective for dysphagia in PD patients. In patients with PSP, there are few research reports about the treatment of dysphagia. However, several dysphagia treatments seem to be useful depending on the abnormal patterns in the VF. Further studies are necessary to establish more effective treatments for dysphagia in PD and PSP.

Reduction in terminal excitability of nigrostriatal dopaminergic neurons in rats following chronic L-dopa administration.

The effects of chronic L-dopa administration on antidromic excitability and the firing rate of nigrostriatal dopaminergic neurons were investigated in urethane-anesthetized rats. Rats that received daily L-dopa (100 mg/kg) and carbidopa (25 mg/kg) for 60 days showed a marked decrease in terminal excitability compared with the controls. There were no significant differences in the firing rates between the two groups. This finding may be related to impaired striatal dopamine release from exogenous L-dopa subsequent to chronic L-dopa treatment.

["Painful legs and moving toes" and muscle cramps spreading to the bilateral legs in a patient with alcoholic polyneuropathy].

A 37-year-old man with alcoholic polyneuropathy showed involuntary movement as intermittent flexion-extension or abduction-adduction of his toes identical to "painful legs and moving toes (PLMT)" and muscle cramps. Regarding the sequential spreading of PLMT and cramps from unilateral to contralateral leg muscles and phasic discharges observed by a needle EMG in the foot muscles during PLMT, we suppose that a spinal or supraspinal mechanism was responsible for the production of those movements. This case showed novel aspects of PLMT which was induced by sensory stimulation of the left lower leg and subsequently initiated cramps. The destruction of the lumbar sympathetic ganglion remarkably ameliorated the spontaneous PLMT and cramps, whereas sensory stimulation of the left lower leg still induced those movements. Therefore, we think that sensory inputs from peripheral nerves played a critical role in the generation of PLMT and cramps, and abnormal activities of spinal sympathetic nerves exacerbated those involuntary movements. Sensory induced PLMT may be a subgroup of this movement disorder.

Reduced excitability of the cortico-spinal system during the warning period of a reaction time task.

Seven subjects made a wrist flexion movement as rapidly as possible in response to a cutaneous shock on the opposite hand. In some trials, an auditory warning signal was given 0.5 s beforehand. In random trials, transcranial magnetic stimulation (TMS) was used to elicit EMG responses (MEPs) in forearm flexor and extensor muscles 0-500 ms before the cutaneous shock. H-reflexes were elicited in flexor muscles at the same intervals. The warning stimulus reduced reaction time from about 400 ms to 200 ms. MEPs in the flexor muscles were significantly suppressed from 125 ms after the warning stimulus until the time of the cutaneous shock whilst MEPs in the extensors, and H-reflexes in the flexor were either unaffected, or reduced by a smaller amount at a later time. Responses in relaxed contralateral muscles were unchanged. If the task was changed to a choice reaction, in which the imperative stimulus (but not the warning signal) indicated whether to flex or extend the wrist, then there was no change in the MEPs or H-reflex in the warning period. A similar effect was seen if the duration of the warning period was extended from 0.5 to 2 s in a simple reaction (flexion) task. We conclude that increased excitability of the corticospinal output is not required to speed up reaction times. The time taken to discharge cortical output elements is relatively unimportant compared with the time needed to process the sensory input and link it to the motor output.

Enhanced amplitude reduction of somatosensory evoked potentials by voluntary movement in the elderly.

We studied the effects of aging on modification of the median nerve somatosensory evoked potentials (SEPs) by voluntary movement in 17 aged (66.5 +/- 8.9 years, mean +/- SD) and 12 young normal humans (27.5 +/- 5.0 years). The amplitudes of cortical SEP components were generally larger in the aged group than in the young group. Following isometric contraction of the thenar muscle, the aged group showed significant attenuation of the prerolandic P22-N28-P45 and the postrolandic P24-N30-P45, while the young group only demonstrated significant reduction of the prerolandic P22-N28 amplitude. In the prerolandic N28-P45 and the postrolandic P24-N30 and N30-P45, amplitudes reduced by voluntary movement (gated amplitude) significantly correlated with amplitudes at rest (resting amplitude) and with the age of subjects. The effects of stimulus intensity and frequency on gating supported the correlative changes between gated and resting amplitudes. These results suggest that the magnitude of gating depends on SEP amplitudes at rest, and that augmented gating in the aged group is a result of enlarged SEPs. Since the cervical and Erb's potentials were not changed by movement, and passive movement did not significantly affect the SEPs, a centrifugal mechanism is probably responsible for gating in this study.

Significance of cognitive function in the elicitation of sympathetic skin response in healthy humans.

The sympathetic skin response (SSR) is used as an index of sudomotor sympathetic function. However, the central processing of this response is not fully understood. To clarify this point, we assessed the relevance of cognitive function in the elicitation of SSR in 14 healthy subjects by recording simultaneously the somatosensory event-related potential (ERP) and SSR evoked by electric stimuli. The ERP paradigm consisted of three types of stimuli, task-relevant target, task-irrelevant electric shock which is equivalent to the common stimulus for eliciting SSR, and task-irrelevant standard stimuli. ERPs were recorded at Fz, Cz, and Pz on the scalp, SSRs were recorded in both palms and soles of the subject after each stimulus in the ERP paradigm. Target stimuli generated a P300 (P3b) and elicited a variety of SSRs from subject to subject. Electric shock stimuli generated a novelty P300 with a shorter peak latency and a higher amplitude than the P3b, with stable elicitation of SSR in the four limbs of all subjects. P300 amplitude showed a significant positive correlation with SSR amplitude with electric shock stimuli. This correlation predominated in the frontal region (Fz), as compared with the parietal region (Pz). A negative correlation between P300 latency and SSR amplitude with electric shock stimuli was also observed. These findings indicate that the elicitation of SSR is influenced by the generation of novelty P300, that is, cognitive function. The frontal region may play a key role in the elicitation of SSR. We believe that the assessment of novelty P300 is required for a precise interpretation of the SSR.

[Non-paralytic pontine exotropia with alternating exotropia].

We report a patient with pontine infarction who showed non-paralytic pontine exotropia (NPPE) with alternating exotropia. An 81-year old woman developed diplopia and gait disturbance. On the fourth day, she was admitted to our hospital. Oculomotor findings on admission showed that the ocular position of the left eye on forward gaze was fixed at the midline, while the right eye was abducted. When she was instructed to use the right eye for forward gaze, the left eye deviated outward. On right gaze, the left eye was not abducted and monocular nystagmus was noted in the abducted right eye. Upper gaze was limited in the right eye and convergence was not possible. The remaining ocular movements were intact. On cranial CT performed on eye closure, the left eye was abducted and the right eye was fixed at the midline. Brain MRI showed cerebral infarction located in the left paramedian portion of the middle pontine tegmentum with involvement of the medial longitudinum fasciculus (MLF) and in the ventral site of the upper pons. On the 16th day, right exotropia disappeared on eye opening without forward gaze, but forward gaze easily induced outward deviation of the right eye. On the 39th day, right exotropia on forward gaze had almost disappeared. However, left MLF syndrome and abnormal convergence were persistent when she discharged on the 76th day. In conjunction with oculomotor and neuroradiological findings, the NPPE with alternating exotropia in our patient may be due to severe MLF damage and secondary hyperactivity of the contralateral paramedian pontine reticular formation.

[A case of mitochondrial encephalomyopathy with peripheral neuropathy and autonomic symptoms].

We report a 28-year-old man with mitochondrial encephalomyopathy with peripheral neuropathy and autonomic symptoms. Muscle biopsy from the quadriceps femoris muscle showed myopathic changes with ragged-red fibers and abnormal mitochondria. He experienced recurrent and acute weakness in his bilateral lower limbs. Needle electromyogram revealed neurogenic changes, and the amplitude of muscle action potential was low in the right posterior tibial nerve. Sural nerve biopsy showed a marked loss of both large and small myelinated fibers, and moderate to severe axonal degeneration was diagnosed. He experienced autonomic symptoms (nausea, constipation, hypoidosis and urinary retention) along with the weakness in his lower limbs which is considered to be a very rare situation. We hypothesized that autonomic symptoms in this case were due to the axonal degeneration that included unmyelinated fibers.

Movement-related cortical potentials preceding repetitive and random-choice hand movements in Parkinson's disease.

The movement-related cortical electroencephalographic potential was recorded from scalp electrodes in 8 patients with idiopathic Parkinson's disease studied at least 12 hours after withdrawal of their normal drug therapy, and compared with the results from a group of 8 age-matched control subjects. Two types of self-paced voluntary arm movements were examined: repetitive forward movement of a joystick, and random-choice movements of the same joystick in which subjects had to choose freely the direction in which they were to move the stick (forward, backward, left, or right). In normal subjects, the movement-related cortical potential was larger prior to random-choice movements, whereas in the patients, the amplitude was the same in both tasks. The implication is that processes involved in self-selection of movement are abnormal in Parkinson's disease. This may contribute to the difficulty that patients have in initiating voluntary movement in the absence of any external cues.

[Crossed cerebello-cerebral diaschisis in olivopontocerebellar atrophy].

We reported a case of crossed cerebello-cerebral diaschisis (CCCD) in olivopontocerebellar atrophy (OPCA). A 49-year-old male was admitted with complaints of titubation, dysarthria and tremor. Examination on admission revealed exaggerated triceps, patella and achilles tendon reflexes on both sides and rigidity in left wrist. Ocular movements were slightly saccadic and speech was scanning or explosive. Finger-nose and heel-knee coordination was poor on both sides (left dominant). Cardiovascular reflex tests showed abnormal findings, suggesting insidious autonomic dysfunction. Brain CT and magnetic resonance imaging (MRI) revealed mild atrophy of the pons and cerebellum. Brain single photon emission computed tomography (SPECT) showed reduced cerebellar N-isopropyl-P-(123I) iodoamphetamine (IMP) uptake more prominent on the left than on the right side. A reduction of 123I-IMP uptake was more striking in the right thalamus, basal ganglia and frontal lobe than on the left side. The cerebellar sign which was left dominant and the left extrapyramidal sign were consistent with the side where reduction of 123I-IMP uptake was more prominent. We suggest that CCCD in our case resulted from transneuronal deactivation in the classic anatomical (cerebello-thalamo-cortical) pathway and dopaminergic (cerebello-basal ganglia-cortical) pathway. There is a possibility that CCCD reflects the development of pathological changes in OPCA.

[Pure sensory stroke due to pontine lacunar infarction].

A 72-year-old woman presented a sudden onset isolated sensory deficit of medial lemniscal type in the right half of the body. MRI showed a small lacune in the left paramedian pontine tegmentum corresponding to the location of the medial lemniscus. MRI appeared to be most valuable in the topographic delineation of lacunar infarctions which were responsible for pure sensory stroke.

Electrophysiological comparison between catechol- and urea-induced myoclonus models in the rat.

Catechol- and urea-induced myoclonus models in the rat were electrophysiologically compared to clarify pathophysiological differences. Catechol-induced myoclonus had various similarities with cortical reflex myoclonus in that there were electroencephalogram (EEG) discharges prior to myoclonic discharges, a spread of myoclonic discharges from the rostral to the caudal site, and a high amplitude somatosensory evoked potential (SEP). In urea-induced myoclonus, there were no EEG discharges related to myoclonic discharges and no enlarged SEP components as in reticular reflex myoclonus. Catechol-induced myoclonus had two evoked EMG responses of the biceps femoris at mean onsets of 8.0(C1) and 13.4 (C2) ms, and urea-induced myoclonus had a response (U1) at the mean onset of 10.2 ms. A study of the effects of various lesions in the central nervous system on these evoked EMG responses suggests that C1 is a monosynaptic spinal reflex. C2 which disappeared when the bilateral sensorimotor cortex for the hind limb had been resected and the lesion cooled is generated by the deep cerebral structures, such as the thalamus or basal ganglia, and U1 originates in the brain stem reticular formation. These results imply definitive differences of the pathophysiological mechanisms between catechol- and urea-induced myoclonus.

[Event-related potentials in progressive supranuclear palsy].

Abnormal event-related potential (ERP) has been reported in several types of dementing illness including Parkinson's disease (PD) and progressive supranuclear palsy (PSP). In this paper we report the result of EPR recordings obtained in normal control subjects (14 cases) and in patients with PSP (6 cases) and PD (32 cases). ERPs were recorded from 13 scalp electrodes, using the acoustic odd-ball paradigm. All PD patients were in early stage (Yahr stage 1 to 2), and all PSP patients were in the mild-to-moderate state. In control subjects and PD patients P3 was normal. In PSP patients, only one subject (17%) showed a normal P3 component, three cases (50%) demonstrated low amplitude and normal latency P3, and two cases (33%) featured lack of normal P3 sequence. The P3 abnormalities in PSP patients were not related with dementia, but with low amplitude P3 being observed in 2 of 3 non-demented patients, and abolished P3 in a patient with only mild dementia. The result suggests that the P3 changes in PSP patients develop earlier than the cognitive dysfunction, and they are related to the underlying subcortical lesion rather than dementia.