Chiung Chu Chen

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.

Intra-operative recordings of local field potentials can help localize the subthalamic nucleus in Parkinson's disease surgery

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be a highly effective treatment for Parkinsons disease (PD). However, therapeutic efficacy is limited by difficulties in consistently and correctly targeting this nucleus. Increasing evidence suggests that there is abnormal synchronization of beta frequency band activity (approximately 20 Hz) in the STN of PD patients, as reflected in the oscillatory nature of the local field potential (LFP). We hypothesized that an increase in the power of the LFP beta activity may provide intra-operative confirmation of STN targeting in patients undergoing STN implantation for the treatment of advanced PD. Accordingly, we recorded LFPs from the four contacts of DBS electrodes as the latter were advanced in 2 mm steps from a point 4-6 mm above the intended surgical target point in the STN, to a point 4 mm below this. Contacts were configured to give three bipolar recordings of LFPs. These were analyzed on 16 sides in 9 patients. The power in the 13-35 Hz band recorded at the lowest contact pair underwent a steep but focal increase during electrode descent. The depth of the peak beta activity showed excellent agreement with the level of the intra-operative clinical stun effect (k coefficient = 0.792). The depth of peak beta activity also showed 100% specificity and 100% sensitivity for placement within STN in comparison to pre- and Post-operative stereotactic MRI. Functional physiological localization of STN by the on-line spectral analysis of LFPs is quick to perform and may provide information directly relevant to the position of the electrode contact actually used for DBS.

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.

Parkinsonian impairment correlates with spatially extensive subthalamic oscillatory synchronization.

The local strength of pathological synchronization in the region of the subthalamic nucleus (STN) is emerging as a possible factor in the motor impairment of Parkinsons Disease (PD). In particular, correlations have been repeatedly demonstrated between treatment-induced suppressions of local oscillatory activity in the beta frequency band and improvements in motor performance. However, a mechanistic role for beta activity is brought into question by the difficulty in showing a correlation between such activity at rest and the motor deficit in patients withdrawn from medication. Here we recorded local field potential (LFP) activity from 36 subthalamic regions in 18 patients undergoing functional neurosurgery for the treatment of PD. We recorded directly from the contacts of the deep brain stimulation (DBS) electrodes as they were introduced in successive 2 mm steps, and assessed phase coherence as a measure of spatially extended, rather than local, oscillatory synchronization. We found that phase coherence in the beta frequency band correlated with the severity of Parkinsonian bradykinesia and rigidity, both in the limbs and axial body. Such correlations were frequency and site specific in so far as they were reduced when the lowermost contact of the DBS electrode was above the dorsal STN. Correlations with limb tremor occurred at sub-beta band frequencies and were more lateralized than those between beta activity and limb bradykinesia and rigidity. Phase coherence could account for up to ∼25% of the variance in motor scores between sides and patients. These new data suggest that the strength of spatially extended oscillatory synchronization, as well as the strength of local synchronization, may be worthwhile incorporating into modelling studies designed to inform surgical targeting, post-operative stimulation parameter selection and closed-loop stimulation regimes in PD. In addition, they strengthen the link between pathological synchronization and the different motor features of Parkinsonism.

The subthalamic region is activated during valence-related emotional processing in patients with Parkinson's disease

Visual stimuli are judged for their emotional significance based on two fundamental dimensions, valence and arousal, and may lead to changes in neural and body functions like attention, affect, memory and heart rate. Alterations in behaviour and mood have been encountered in patients with Parkinsons disease (PD) undergoing functional neurosurgery, suggesting that electrical high‐frequency stimulation of the subthalamic nucleus (STN) may interfere with emotional information processing. Here, we use the opportunity to directly record neuronal activity from the STN macroelectrodes in patients with PD during presentation of emotionally laden and neutral pictures taken from the International Affective Picture System (IAPS) to further elucidate the role of the STN in emotional processing. We found a significant event‐related desynchronization of STN alpha activity with pleasant stimuli that correlated with the individual valence rating of the pictures. Our findings suggest involvement of the human STN in valence‐related emotional information processing that can potentially be altered during high‐frequency stimulation of the STN in PD leading to behavioural complications.

Neuronal activity in globus pallidus interna can be synchronized to local field potential activity over 3-12 Hz in patients with dystonia

Pallidal recordings of local field potentials (LFPs) in patients with dystonia have demonstrated semi-oscillatory activity over 3-12 Hz. Although this activity has been hypothesized to contribute to dystonia, it is unclear to what extent these LFP oscillations arise in the globus pallidus interna (GPi) and are synchronous with local neuronal discharge. We therefore recorded LFPs and neuronal activity from microelectrodes inserted into the pallidum on nine sides in six awake patients with primary dystonia during functional neurosurgery. Mean normalized LFP power over 3-12 Hz was higher in GPi than globus pallidus externa. Spike triggered averages were computed, and 11 exhibited significant features in the 3-12 Hz band, indicating that the discharges of local neurons were locked to 3-12 Hz oscillations in the LFP. All but two of these STAs were in GPi. We conclude that pallidal oscillations at 3-12 Hz are maximal in GPi, the surgical target, in patients with dystonia and that they can be synchronized to activity in local neurons. This lends support to a pathophysiological relationship between LFP activity at 3-12 Hz and dystonia.

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

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

Value of subthalamic nucleus local field potentials recordings in predicting stimulation parameters for deep brain stimulation in Parkinson's disease

Objectives Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be a highly effective treatment for Parkinsons disease. However, therapeutic efficacy can be limited by inconsistent targeting of this nucleus. It was shown previously that an increase in local field potential (LFP) power over the beta frequency band may provide intraoperative confirmation of STN targeting. Whether the depth of this focal increase also helps predict the depth and voltage chosen for chronic stimulation is tested here. Methods LFPs were recorded from the contacts of 57 DBS electrodes as the latter were advanced in 2 mm steps from above to below the intended surgical target point in STN. Results A spectral peak in the bipolar LFP was recorded in the 11–35 Hz band at the lowest contact pair that underwent a steep but focal change during electrode descent in all but three sides. The depth of the initial intraoperative step increase in beta correlated with the depth of the contact independently chosen for chronic DBS (Spearmans rho=0.35, p=0.01). In addition, the absolute difference between the depths of the initial increase in beta and the contact chosen for chronic DBS correlated with the voltage used for chronic stimulation (rho=0.322, p=0.017). Thus more voltage had to be employed if a depth was selected for chronic stimulation that differed from that of the beta generator. Conclusions Online spectral analysis of LFPs recorded from the DBS electrode may help identify the optimal therapeutic target in the STN region for DBS.

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.