Andrea A. Kühn

High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapy for patients with severe Parkinsons disease (PD), but its mechanism of action is unclear. Exaggerated oscillatory synchronization in the β (13–30 Hz) frequency band has been associated with bradykinesia in patients with PD. Accordingly, we tested the hypothesis that the clinical benefit exerted by STN HFS is accompanied by suppression of local β activity. To this end, we explored the after effects of STN HFS on the oscillatory local field potential (LFP) activity recorded from the STN immediately after the cessation of HFS in 11 PD patients. Only patients that demonstrated a temporary persistence of clinical benefit after cessation of HFS were analyzed. STN HFS led to a significant reduction in STN LFP β activity for 12 s after the end of stimulation and a decrease in motor cortical–STN coherence in the β band over the same time period. The reduction in LFP β activity correlated with the movement amplitude during a simple motor task, so that a smaller amount of β activity was associated with better task performance. These features were absent when power in the 5–12 Hz frequency band was considered. Our findings suggest that HFS may act by modulating pathological patterns of synchronized oscillations, specifically by reduction of pathological β activity in PD.

Reduction in subthalamic 8-35 Hz oscillatory activity correlates with clinical improvement in Parkinson's disease.

Strong synchronization of neuronal activity occurs in the 8–35 Hz band in the subthalamic nucleus (STN) of patients with Parkinsons disease (PD) and is evident as oscillatory local field potential (LFP) activity. To test whether such synchronization may contribute to bradykinesia and rigidity, we sought correlations between the suppression of synchronization at 8–35 Hz in STN and the reduction in Parkinsonism with levodopa. LFPs were recorded on and off medication from STN deep‐brain stimulation electrodes in nine PD patients. LFP power was calculated over the frequencies of the most prominent spectral peak within the 8–35 Hz frequency band on each of 17 sides (off medication), and over the frequencies of any peak in the 60–90 Hz band, if present (seven sides, on medication). Levodopa‐induced reduction of LFP power over these two frequency ranges was then correlated with improvement in motor impairment as assessed by the Unified Parkinsons Disease Rating Scale (UPDRS). The reduction in peak activity in the 8–35 Hz band with levodopa positively correlated with the improvement in the contralateral hemibody motor UPDRS score with levodopa (r = 0.811, P < 0.001) as well as with hemibody subscores of akinesia‐rigidity (r = 0.835, P < 0.001), but not tremor. A trend for negative correlations was found between peak 60–90 Hz LFP power and UPDRS hemibody score, suggesting that positive correlations were relatively frequency‐specific. Our results support a link between levodopa‐induced improvements in bradykinesia and rigidity and reductions in population synchrony at frequencies < 35 Hz in the region of the STN in patients with PD.

The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease

Depth recordings in patients with Parkinsons disease (PD) have demonstrated prominent oscillatory activity in the beta frequency (13-35 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesized to contribute to bradykinesia, it is unclear to what extent the LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded both LFPs and multi-neuronal activity from microelectrodes inserted into STN in six PD patients (8 sides) during functional neurosurgery. As microelectrodes passed from above STN into STN, there was a pronounced increase in beta frequency band LFP activity. Furthermore, spike-triggered averages of LFP activity suggested that the discharges of neurons in STN were locked to beta oscillations in the LFP. The LFP is therefore likely to represent synchronous activity in populations of neurons in the STN of patients with PD.

Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity

Parkinsons disease (PD) is associated with exaggerated oscillatory synchrony in the basal ganglia at frequencies over 8-35 Hz. Studies have demonstrated a suppression of local field potential (LFP) activity in the subthalamic nucleus (STN) upon treatment with the dopamine prodrug, levodopa, with the degree of suppression of power in the 8-35 Hz band correlating with the improvement in combined measures of bradykinesia and rigidity. However, these studies do not explicitly address the question of what is more important in predicting clinical change - synchronisation of neuronal activity or the specific frequency within the 8-35 Hz band over which the latter occurs. In addition, they have not demonstrated a relationship between treatment-induced changes in synchronisation and changes in bradykinesia or rigidity on their own. To this end, we collected and analysed LFP and clinical data in 30 patients with PD. We found significant correlations between levodopa-induced power suppression and rigidity and bradykinesia, when these clinical features were considered separately, but only when power suppression profiles were re-aligned to the frequency of peak synchronisation. Under these circumstances correlations with rigidity persisted despite partialising out the effect of bradykinesia and vice versa. These data suggest that levodopa-induced improvements in both rigidity and bradykinesia scale with the degree of suppression of oscillatory power in the STN LFP, and that this is true irrespective of the frequency at which synchronisation occurs across a broad band from 8-35 Hz.

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.

Levodopa-induced modulation of subthalamic beta oscillations during self-paced movements in patients with Parkinson's disease.

Excessive synchronization of neural activity in the beta frequency band (∼20 Hz) within basal ganglia circuits might contribute to the paucity and slowness of movement in Parkinsons disease (PD). Treatment with dopaminergic drugs reduces the background level of beta frequency band synchronization in the subthalamic nucleus (STN), but has not been shown to increase the proportion of beta activity that is suppressed before voluntary movement in PD. We assessed changes in the event‐related desynchronization (ERD) in the beta frequency band of local field potential signals from the region of the STN in 14 patients with PD as they performed self‐paced movements of a joystick before and after levodopa administration. The dopamine precursor, levodopa, increased the duration and magnitude of the premovement beta ERD, but did not alter postmovement synchronization in the beta band. Both the latency and magnitude of the beta ERD inversely correlated with the degree of motor impairment. These findings suggest that the beta ERD recorded in the STN area reflects motor‐preparative processes that are at least partly dependent on dopaminergic activity within the basal ganglia.

Combined 123I-FP-CIT and 123I-IBZM SPECT for the diagnosis of parkinsonian syndromes: study on 72 patients.

Summary.72 consecutive patients with suspected parkinsonian syndromes (PS) were studied by dopamine transporter (DAT) and D2 receptor SPECT in order to evaluate the accuracy of combined SPECT imaging. In the follow-up, the patients were diagnosed as having Parkinson’s disease (PD, n = 25), dementia with Lewy bodies (DLB, n = 6), multiple system atrophy (MSA, n = 13), progressive supranuclear palsy (PSP, n = 8), corticobasal degeneration (CBD, n = 9), and essential tremor (ET, n = 11). Using the iteratively estimated optimal cutoffs, DAT was reduced in 57/61 PS patients, whereas all ET patients were identified as “normal”. Reduced D2 receptor binding had 7/13 patients with MSA, 6/8 patients with PSP, 2/9 patients with CBD and no ET, PD or DLB patients. FP-CIT SPECT allows an accurate detection of nigrostriatal affection in neurodegenerative PS. IBZM SPECT is useful to approve the diagnosis of PSP and MSA although a normal finding cannot exclude an atypical PS. IBZM SPECT seems to be of restricted value in CBD.

Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial

BACKGROUND Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. METHODS In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). FINDINGS An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. INTERPRETATION 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. FUNDING Medtronic.

Treatment of severe tardive dystonia with pallidal deep brain stimulation

In five patients with medically refractory tardive dystonia, continuous bilateral high-frequency stimulation of the globus pallidus internus was associated with a rapid (within 12 to 72 hours) and substantial (mean 87%, 10.7 SD of the motor part of the Burke–Fahn–Marsden Dystonia Rating Scale) improvement of dystonia and functional disability without adverse events.

Myoclonus-dystonia syndrome : epsilon-sarcoglycan mutations and phenotype

Mutations in the gene for ε‐sarcoglycan (SGCE) have been found to cause myoclonus‐dystonia syndrome. We now report clinical and genetic findings in nine additional European families with myoclonus‐dystonia syndrome. The clinical presentation in 24 affecteds was homogeneous with myoclonus predominantly of neck and upper limbs in 23 of them and dystonia, presenting as cervical dystonia and/or writers cramp, in 13 cases. Six novel and one previously known heterozygous SGCE mutations were identified. SGCE deficiency seems to be the common pathogenetic mechanism in myoclonus‐dystonia syndrome.