Yasushi Shimo

A rotarod test for evaluation of motor skill learning.

The rotarod test is widely used to evaluate the motor coordination of rodents, and is especially sensitive in detecting cerebellar dysfunction. However, mice with striatal dopamine depletion show only mild or no motor deficit on the typical accelerating rotarod. This suggests that dopamine-depleted mice are useful as animal models for non-motor symptoms, because the influence of motor deficit is minimum and easy to discriminate from cognitive aspects of the behavioral change. The typical accelerating rotarod test is designed to evaluate maximal motor performance and is not optimized to detect motor skill learning. In an attempt to make the test more selective to motor skill learning rather than maximal gait performance, we modified the rotarod test by using a slowly rotating large drum to obtain a steep learning curve. Furthermore, administration of nomifensine, a dopamine uptake inhibitor, improved the learning. On the other hand, apomorphine, an agonist of dopamine autoreceptor, a dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) impaired the learning. These pharmacological profiles fit the involvement of the so-called phasic dopamine neurotransmission. Using our modified procedure, we found impaired learning of Parkin-deficit mice, which has not been detected in typical accelerating rotarod. The modified rotarod test would be useful for evaluation of dopamine involvement in the acquisition of motor skill learning.

Motor and non-motor symptoms of 1453 patients with Parkinson's disease: Prevalence and risks

PURPOSE We examined the prevalence and risk of clinical symptoms in a large number of Japanese patients with Parkinsons disease (PD) (n = 1453; 650 males). METHODS Events were analyzed using Kaplan-Meier survival curves, logistic regression, and Cox proportional-hazards models. RESULTS The mean age (SD) was 67.7 (10.0), age of onset was 58.0 (11.5), and disease duration was 9.7 (6.6) years. The mean modified Hoehn and Yahr stage was 2.8 (1.2). Most patients (88.9%) received levodopa (547.7 (257.6) mg/day). A large proportion (81.3%) received dopamine agonists (136.2 (140.7) mg/day). About 23.4% received pain treatment 6.9 (5.1) years after the onset; females (p < 0.05) and patients with late-onset PD (≥60 years, p < 0.001) were more likely to be affected. About 44.7% of patients had wearing-off 7.5 (4.7) years after the onset, and it was more common in females (p < 0.001) and patients with early-onset PD (p < 0.001). Camptocormia was found in 9.5% of patients 8.1 (6.2) years after the onset, and it was more common in females (p < 0.05) and patients with late-onset PD (p < 0.05). About 28.6% of patients developed psychosis 9.0 (5.4) years after the onset, and it was more likely to occur in patients with late-onset PD (p < 0.001). Late-onset PD and cerebrovascular disease were also associated with increased risk of pneumonia. CONCLUSIONS Considering that very few studies have assessed numerous clinical symptoms in the same report, these data provide a useful reference for the clinical course of PD.

Impaired in vivo dopamine release in parkin knockout mice

parkin is the most frequent causative gene among familial Parkinsons disease (PD). Although parkin deficiency induces autosomal recessive juvenile parkinsonism (AR-JP, PARK2) in humans, parkin knockout (PKO) mice consistently show few signs of dopaminergic degeneration. We aimed to directly measure evoked extracellular dopamine (DA) overflow in the striatum with in vivo voltammetry. The amplitude of evoked DA overflow was low in PKO mice. The half-life time of evoked DA overflow was long in PKO mice suggesting lower release and uptake of dopamine. Facilitation of DA overflow by repetitive stimulation enhanced in the older PKO mice. Decreased dopamine release and uptake in young PKO mice suggest early pre-symptomatic changes in dopamine neurotransmission, while the enhanced facilitation in the older PKO mice may reflect a compensatory adaptation in dopamine function during the late pre-symptomatic phase of Parkinsons disease. Our results showed parkin deficiency may affect DA release in PKO mice, although it does not cause massive nigral degeneration or parkinsonian symptoms as in humans.

Familial cortical tremor with epilepsy

We report here on a Japanese family in which five members in three generations developed non-progressive adult onset cortical tremor and epilepsy. Other than tremulous movements resembling essential tremor, the neurologic findings were unremarkable. Electrophysiologic studies revealed giant somatosensory evoked potentials (SEPs), enhanced long latency reflexes (C-reflex), and positive premovement cortical potentials, recorded by jerk-locked averaging, indicating cortical reflex myoclonus. The seizures were sporadic in nature and easily controlled by the anticonvulsants. The tremor also responded well to anticonvulsants such as clonazepam or sodium valproate, but not to beta-blockers. This dominantly inherited disorder should be considered in the differential diagnosis of essential tremor.

Lewy body pathology in a patient with a homozygous Parkin deletion

We report neuropathologic findings in a patient with homozygous deletions of exons 2 to 4 of parkin.

Asymmetric cortico‐cortical inhibition in patients with progressive limb‐kinetic apraxia

Objectives– To evaluate the activity of cortico‐cortical (intracortical) inhibitory circuits within the motor cortex in patients with progressive asymmetric limb‐kinetic apraxia. Materials and methods– We studied 4 patients with progressive limb‐kinetic apraxia whose clinical diagnosis was corticobasal degeneration (CBD) and 7 control subjects. Cortico‐cortical inhibition was measured using the technique of double pulse transcranial magnetic stimulation over the motor cortex. The effects of conditioning stimuli on the test responses were examined. Results– In the normal control subjects, the conditioning magnetic stimulus suppressed motor evoked responses to the test stimulus at interstimulus intervals of 1 to 5 ms. This inhibition was significantly diminished on the affected side of the patients, but it was normal on the less affected side. Conclusion– Disruption of intracortical inhibitory circuits in the motor cortex may, at least in part, be related to severe limb clumsiness in the patients with progressive limb‐kinetic apraxia.

Unmet Needs of Patients with Parkinson's Disease: Interview Survey of Patients and Caregivers

We performed a 20-item questionnaire-based interview of 132 patients with Parkinsons disease (PD): 81 patients with Hoehn & Yahr (H&Y) stage I–III PD, and 51 caregivers of patients with H&Y stage IV–V PD, to evaluate patient and caregiver satisfaction with PD treatment. The survey revealed that PD patients often experience non-motor symptoms, which are not adequately alleviated by antiparkinsonian agents. Furthermore, PD patients want their physicians to listen to them and take their concerns seriously, to explain their disease comprehensively, and to provide the latest information on PD and its treatment. Both patients and caregivers agreed on anxiety toward the future, communication difficulties, and their different movement pace; however, there were differences in their relative perceptions of various aspects of daily care. The evaluation revealed that PD patients have unmet needs in their treatment and standards of care. Areas for future improvement as highlighted in this study include: the development of better treatment for motor symptoms, the development of new treatments for non-motor symptoms and improved two-way communication between patient and physician.

Subsecond reward-related dopamine release in the mouse dorsal striatum.

Reward presentation is known to induce transient bursts of midbrain dopamine neurons in monkeys and rats, and the reward-induced dopamine overflow has been detected in the rat ventral striatum. To detect reward-related dopamine release in the dorsal striatum of behaving mice (C57BL/6), we used voltammetry with carbon-fiber microelectrodes implanted into the dorsal striatum. Dopamine signals increased transiently after food delivery with a peak at 0.6 s after the delivery onset. The success in detecting transient reward-response of dopamine in behaving mice opens a wide range of application to studies in mutant mice.

Validity of single tract microelectrode recording in subthalamic nucleus stimulation.

In surgery for subthalamic nucleus (STN) deep brain stimulation (DBS), precise implantation of the lead into the STN is essential. Physiological refinement with microelectrode recording (MER) is the gold standard for identifying STN. We studied single tract MER findings and surgical outcomes and verified our surgical method using single tract MER. The number of trajectories in MER and the final position of lead placement were retrospectively analyzed in 440 sides of STN DBS in 221 patients. Bilateral STN DBS yielded marked improvement in the motor score, dyskinesia/fluctuation score, and reduced requirement of dopaminergic medication in this series. The number of trajectories required to obtain sufficient activity of the STN was one in 79.0%, two in 18.2%, and three or more in 2.5% of 440 sides. In 92 sides requiring altered trajectory, the final direction of trajectory movement was posterior in 73.9%, anterior in 13.0%, lateral in 5.4%, and medial in 4.3%. In 18 patients, posterior moves were required due to significant brain shift with intracranial air caused by outflow of CSF during the second side procedure. Sufficient STN activity is obtained with minimum trajectories by proper targeting and precise interpretation of MER findings even in the single tract method. Anterior–posterior moves rather than medial–lateral moves should be attempted first in cases with insufficient recording of STN activity.

Effects of aging and idiopathic Parkinson's disease on tactile temporal order judgment.

It is generally accepted that the basal ganglia play an important role in interval timing that requires the measurement of temporal durations. By contrast, it remains controversial whether the basal ganglia play an essential role in temporal order judgment (TOJ) of successive stimuli, a behavior that does not necessarily require the measurement of durations in time. To address this issue, we compared the effects of idiopathic Parkinson’s disease (PD) on the TOJ of two successive taps delivered to each hand, with the arms uncrossed in one condition and crossed in another. In addition to age-matched elderly participants without PD (non-PD), we examined young healthy participants so that the effect of aging could serve as a control for evaluating the effects of PD. There was no significant difference between PD and non-PD participants in any parameter of TOJ under either arm posture, although reaction time was significantly longer in PD compared with non-PD participants. By contrast, the effect of aging was apparent in both conditions. With their arms uncrossed, the temporal resolution (the interstimulus interval that yielded 84% correct responses) in elderly participants was significantly worse compared with young participants. With their arms crossed, elderly participants made more errors at longer intervals (~1 s) than young participants, although both age groups showed similar judgment reversal at moderately short intervals (~200 ms). These results indicate that the basal ganglia and dopaminergic systems do not play essential roles in tactile TOJ involving both hands and that the effect of aging on TOJ is mostly independent of the dopaminergic systems.