Christof Brücke

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.

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.

Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements.

Deep brain stimulation of the globus pallidus internus alleviates involuntary movements in patients with dystonia. However, the mechanism is still not entirely understood. One hypothesis is that deep brain stimulation suppresses abnormally enhanced synchronized oscillatory activity within the motor cortico-basal ganglia network. Here, we explore deep brain stimulation-induced modulation of pathological low frequency (4-12 Hz) pallidal activity that has been described in local field potential recordings in patients with dystonia. Therefore, local field potentials were recorded from 16 hemispheres in 12 patients undergoing deep brain stimulation for severe dystonia using a specially designed amplifier allowing simultaneous high frequency stimulation at therapeutic parameter settings and local field potential recordings. For coherence analysis electroencephalographic activity (EEG) over motor areas and electromyographic activity (EMG) from affected neck muscles were recorded before and immediately after cessation of high frequency stimulation. High frequency stimulation led to a significant reduction of mean power in the 4-12 Hz band by 24.8 ± 7.0% in patients with predominantly phasic dystonia. A significant decrease of coherence between cortical EEG and pallidal local field potential activity in the 4-12 Hz range was revealed for the time period of 30 s after switching off high frequency stimulation. Coherence between EMG activity and pallidal activity was mainly found in patients with phasic dystonic movements where it was suppressed after high frequency stimulation. Our findings suggest that high frequency stimulation may suppress pathologically enhanced low frequency activity in patients with phasic dystonia. These dystonic features are the quickest to respond to high frequency stimulation and may thus directly relate to modulation of pathological basal ganglia activity, whereas improvement in tonic features may depend on long-term plastic changes within the motor network.

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.

Gamma activity and reactivity in human thalamic local field potentials

Depth recordings in patients with Parkinson’s disease on dopaminergic therapy have revealed a tendency for oscillatory activity in the basal ganglia that is sharply tuned to frequencies of ∼70 Hz and increases with voluntary movement. It is unclear whether this activity is essentially physiological and whether it might be involved in arousal processes. Here we demonstrate an oscillatory activity with similar spectral characteristics and motor reactivity in the human thalamus. Depth signals were recorded in 29 patients in whom the ventral intermediate or centromedian nucleus were surgically targeted for deep brain stimulation. Thirteen patients with four different pathologies showed sharply tuned activity centred at ∼70 Hz in spectra of thalamic local field potential (LFP) recordings. This activity was modulated by movement and, critically, varied over the sleep–wake cycle, being suppressed during slow wave sleep and re‐emergent during rapid eye movement sleep, which physiologically bears strong similarities with the waking state. It was enhanced by startle‐eliciting stimuli, also consistent with modulation by arousal state. The link between this pattern of thalamic activity and that of similar frequency in the basal ganglia was strengthened by the finding that fast thalamic oscillations were lost in untreated parkinsonian patients, paralleling the behaviour of this activity in the basal ganglia. Furthermore, there was sharply tuned coherence between thalamic and pallidal LFP activity at ∼70 Hz in eight out of the 11 patients in whom globus pallidus and thalamus were simultaneously implanted. Subcortical oscillatory activity at ∼70 Hz may be involved in movement and arousal.

Scaling of Movement Is Related to Pallidal γ Oscillations in Patients with Dystonia

Neuronal synchronization in the gamma (γ) band is considered important for information processing through functional integration of neuronal assemblies across different brain areas. Movement-related γ synchronization occurs in the human basal ganglia where it is centered at ∼70 Hz and more pronounced contralateral to the moved hand. However, its functional significance in motor performance is not yet well understood. Here, we assessed whether event-related γ synchronization (ERS) recorded from the globus pallidus internus in patients undergoing deep brain stimulation for medically intractable primary focal and segmental dystonia might code specific motor parameters. Pallidal local field potentials were recorded in 22 patients during performance of a choice-reaction-time task. Movement amplitude of the forearm pronation-supination movements was parametrically modulated with an angular degree of 30°, 60°, and 90°. Only patients with limbs not affected by dystonia were tested. A broad contralateral γ band (35–105 Hz) ERS occurred at movement onset with a maximum reached at peak velocity of the movement. The pallidal oscillatory γ activity correlated with movement parameters: the larger and faster the movement, the stronger was the synchronization in the γ band. In contrast, the event-related decrease in beta band activity was similar for all movements. Gamma band activity did not change with movement direction and did not occur during passive movements. The stepwise increase of γ activity with movement size and velocity suggests a role of neuronal synchronization in this frequency range in basal ganglia control of the scaling of ongoing movements.

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

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

Premovement activities in the subthalamic area of patients with Parkinson's disease and their dependence on task.

Movement preparation and execution are associated with a reduction in oscillatory synchrony over 6–35 Hz (event‐related desynchronization; ERD) and increases in oscillatory synchrony at higher frequencies (event‐related synchronization; ERS) in the human parkinsonian subthalamic nucleus (STN). The timing of the ERD < 35 Hz in STN correlates with, but precedes, the timing of voluntary movement, in line with a role in motor processing. Here, we explore how directly the synchrony manifest in local field potential (LFP) activities depends on the details of motor processing. To this end, we recorded local field potentials from the STN area of parkinsonian subjects while they performed internally paced single movements or double movements with one hand. Analysis was limited to time periods that were unequivocally premovement, so as to avoid the confounding effects of sensory afferance during movement. LFP power differed from baseline activity as early as 2.1–1.1 s prior to movement over 6–18 Hz and 56–70 Hz. However, only the early changes in LFP power in the 56–70 Hz band depended on task type. Later on, within 0.5 s of the forthcoming movement, the behaviour of both the 6–18 and 56–70 Hz bands differed according to movement type. In addition, a change was seen in LFP activity over 23–35 Hz, although the ERD in this band remained similar across movement types. The findings further implicate the human STN in the feedforward organization of movement in premotor circuits. Different aspects of this organization may be preferentially reflected in changes in synchrony at different frequencies.

Modulation of subthalamic alpha activity to emotional stimuli correlates with depressive symptoms in Parkinson's disease1

Background: Deep brain stimulation of the subthalamic nucleus is an effective treatment for patients with advanced Parkinsons disease. However, affective side effects following subthalamic deep brain stimulation have been reported. Here, we aim to elucidate the influence of affective state on emotional processing as indexed by local field potential activity and to identify neurophysiological markers in patients at risk of developing depressive symptoms during subthalamic deep brain stimulation.

Increased beta activity in dystonia patients after drug-induced dopamine deficiency.

Several studies have confirmed that subthalamic and pallidal local field potential activity in the beta frequency band (13-30 Hz) is exaggerated in untreated patients with Parkinsons disease (PD) and is suppressed by dopaminergic treatment. This particular spectral pattern differs from that in patients with dystonia in whom pallidal activity is prominent at low frequencies (<12 Hz). Here we demonstrate that tetrabenazine induced monoamine depletion and dopamine blockade is associated with increased activity in the low beta band (13-20 Hz) in the internal pallidum of patients with dystonia. Beta activity was elevated in six patients treated with tetrabenazine compared to six patients in whom this drug was not used. Our findings suggest that beta activity is enhanced in the chronically dopamine-depleted and blocked state irrespective of the underlying pathology, consistent with the idea that excessive synchrony in the beta band is directly related to dopaminergic hypofunction, rather than some degenerative disease-specific attribute of Parkinsons disease.