Chin Song Lu

Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease.

Excessive synchronization of neuronal activity at around 20 Hz is a common finding in the basal ganglia of patients with untreated Parkinsons disease (PD). Correlative evidence suggests, but does not prove, that this spontaneous activity may contribute to slowness of movement in this condition. Here we investigate whether externally imposed synchronization through direct stimulation of the region of the subthalamic nucleus at 20 Hz can slow motor performance in a simple unimanual tapping task and whether this effect is frequency selective. Tapping rates were recorded on 42 sides in 22 patients with PD after overnight withdrawal of medication. Tapping was performed without stimulation and during bilateral stimulation at 20 Hz, 50 Hz and 130 Hz. We found that tapping rates were slowed by 8.2+/-3.2% (p=0.014) during 20-Hz stimulation in subjects with relatively preserved baseline function in the task. This effect was frequency selective. The current data provide proof of the principle that excessive beta synchrony within the basal ganglia-cortical loop may contribute to the slowing of movements in Parkinsons disease.

Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson's disease.

Excessive synchronization of basal ganglia neural activity at low frequencies is considered a hallmark of Parkinsons disease (PD). However, few studies have unambiguously linked this activity to movement impairment through direct stimulation of basal ganglia targets at low frequency. Furthermore, these studies have varied in their methodology and findings, so it remains unclear whether stimulation at any or all frequencies ≤ 20 Hz impairs movement and if so, whether effects are identical across this broad frequency band. To address these issues, 18 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both subthalamic nuclei were stimulated bilaterally at 5, 10 and 20 Hz after overnight withdrawal of their medication and the effects of the DBS on a finger tapping task were compared to performance without DBS (0 Hz). Tapping rate decreased at 5 and 20 Hz compared to 0 Hz (by 11.8 ± 4.9%, p = 0.022 and 7.4 ± 2.6%, p = 0.009, respectively) on those sides with relatively preserved baseline task performance. Moreover, the coefficient of variation of tap intervals increased at 5 and 10 Hz compared to 0 Hz (by 70.4 ± 35.8%, p = 0.038 and 81.5 ± 48.2%, p = 0.043, respectively). These data suggest that the susceptibility of basal ganglia networks to the effects of excessive synchronization may be elevated across a broad low-frequency band in parkinsonian patients, although the nature of the consequent motor impairment may depend on the precise frequencies at which synchronization occurs.

Complexity of subthalamic 13-35 Hz oscillatory activity directly correlates with clinical impairment in patients with Parkinson's disease.

Excessive synchronization of the basal ganglia neuronal activity in the 13- to 35-Hz frequency band, so-called beta activity, has been associated with the motor deficits of Parkinsons disease (PD). Studies have demonstrated that beta activity may be suppressed by treatment with dopaminergic medication and high-frequency stimulation of the subthalamic nucleus (STN), with the degree of suppression correlating with clinical improvement. However, these studies failed to demonstrate any correlation between beta activity of parkinsonism in the resting, untreated state. This argues against a significant relationship between beta activity and motor impairment. Here we use an advanced nonlinear dynamical analysis method based on the Lempel-Ziv estimator to show frequency band and symptom-subset specific correlations between STN local field potential (LFP) complexity and motor impairment in PD patients. Oscillatory activity has a reduced complexity, and we found a strong negative correlation between the complexity of the STN LFP over the 13- to 35-Hz frequency range and akinesia-rigidity. There was no such correlation with tremor. Furthermore, there was no correlation between LFP Lempel-Ziv complexity (LZC) over the 0- to 12-Hz frequency band and any parkinsonian motor impairment. The results strengthen the association between the dynamic structure of synchonised (LFP) activity in the beta frequency band in the STN and akinesia-rigidity.

Deep brain stimulation of the subthalamic nucleus: A two-edged sword

Document S1. Supplemental Experimental ProceduresxDownload (.09 MB ) Document S1. Supplemental Experimental Procedures

Stimulation of the subthalamic region at 20Hz slows the development of grip force in Parkinson's disease

Excessive synchronization of basal ganglia neuronal activity at ~20 Hz is characteristic of patients with untreated Parkinsons disease (PD). Correlative evidence suggests that this activity may contribute to bradykinesia. Attempts to demonstrate causality through stimulation imposed synchronization at 20 Hz in the region of the subthalamic nucleus (STN) have had limited success. Finger-tapping is slowed by about 8% and only in those PD patients that have a relatively normal baseline performance in this task. Here we investigate whether greater performance decrements might be seen in a reaction time grip task. We studied 32 sides in 16 patients with PD after overnight withdrawal of medication. Patients were asked to grip as hard and as fast as possible without STN stimulation and during bilateral stimulation at 5 Hz, 10 Hz, 20 Hz, 50 Hz and 130 Hz. Stimulation at 20 Hz slowed the development of force by 14.7±8.3% (P=0.044) across all patients. Slowing increased by 22±7% (P=0.005) in those patients with the best performance in the task without stimulation. The effect was frequency specific. These data provide direct interventional evidence of a mechanistic link between excessive neuronal synchronization in the beta range and motor impairment in PD.

Hemiballism after subthalamotomy in patients with Parkinson's disease: Report of 2 cases

The occurrence of persistent hemiballism after subthalamotomy for Parkinsons disease (PD) has not been described as frequently as mild or transient dyskinesia. We report on 2 patients with advanced PD who developed hemiballism and/or dyskinesia after subthalamotomy. One patient with a small lesion confined to the subthalamic nucleus (STN) developed persistent hemiballism; the other with a larger lesion involving the STN and also the zona incerta presented with a transient dyskinesia in a single limb. We conclude that a precise STN lesion might bear a potential risk of persistent hemiballism.

Clinical and magnetic resonance imaging manifestations of Holmes tremor.

Holmes tremor is a rare symptomatic slow tremor in the proximal parts of the limbs. It may be present at rest or maintenance of a posture, or during the movement of the affected limb. We describe herein three patients of Holmes tremor with possible etiologies of brainstem infarction and head injury. The intervals between the causal events and the appearance of tremor range from 1 month to 12 months. Magnetic resonance imaging studies reveal hypertrophy of the inferior olivary nucleus in all of the three patients, although only one of them has palatal myoclonus. The surface electromyographic recordings reveal characteristic slow oscillation with frequencies of 3.5 to 4.2 Hz. These features suggest that perturbation of the dentato-rubral-olivary circuitry may play a pivotal role for the generation of Holmes tremor. However, no tight correlation is observed between the presence of inferior olivary nuclear hypertrophy and the appearance of symptomatic palatal myoclonus in the current report.

The impact of low-frequency stimulation of subthalamic region on self-generated isometric contraction in patients with Parkinson’s disease

Growing evidence suggests that spontaneous oscillatory low-frequency synchronization in the subthalamic nuclei (STN) may modulate motor performance in patients with Parkinson’s disease (PD). To explore this in more detail, 15 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both STN were stimulated bilaterally at 5, 10, 20, 50 and 130xa0Hz and the effects of the DBS on self-initiated isometric elbow flexion (FLEX) and finger pinch (PINCH) were compared to performance without DBS. Baseline performance was very much impaired. Peak force was significantly greater during 130 and 10xa0Hz stimulation when compared to no stimulation in both tasks. Cumulative sums of the changes in mean rising force and peak force in the two tasks upon stimulation at 10 and 20xa0Hz demonstrated that patients improved their performance on stimulation, except for those with the best performance off stimulation who deteriorated with stimulation at 20xa0Hz. Thus, no effect was detected with 20xa0Hz stimulation at the group level. The current study highlights the need to consider the baseline performance of a subject in a given task when determining the effects of low-frequency STN stimulation in PD patients. It also demonstrates that stimulation at 10xa0Hz can improve motor function in subjects with poor baseline function.

A novel missense mutation of the GTP cyclohydrolase 1 gene in a Taiwanese family with dopa-responsive dystonia: A case report

BACKGROUNDnDopa-responsive dystonia (DRD) is a clinical syndrome characterized by early onset dystonia and a dramatic response to relatively low doses of levodopa. The autosomal dominant DRD is caused by mutations in the gene coding GTP cyclohydrolase 1 (GCH1), the enzyme that catalyzes the first step in the biosynthesis of tetrahydrobiopterin. We herein report a novel gene mutation causally links to DRD.nnnSUBJECT AND METHODSnA 23-year-old woman, presented with a history of gait abnormality and leg dystonia at age 15. Her symptoms were worsened especially in recent 2 years prior to visiting neurological clinic. In view of typical diurnal variation of dystonia, a therapeutic trial with levodopa was given and there was a dramatic response. Hence, a diagnosis of DRD was tentatively made. In addition, her father has leg dystonia since his 14 years old with leg tremor. Her 2 uncles and probably her 2 grandaunts also have limbs tremor. Genetic analysis by using PCR-direct sequencing revealed a novel point mutation (c.263G>T: p. Arg88Leu) in GCH1, including her father and asymptomatic eldest sister.nnnCONCLUSIONnWe here report a Taiwanese family afflicted with DRD due to a novel missense mutation of the GCH1. The clinical features are considerably variable within the family. The findings extend the genotypic and clinical spectrum of DRD.