Wolf-Julian Neumann

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.

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.

Cortico-pallidal oscillatory connectivity in patients with dystonia

Primary dystonia has been associated with an underlying dysfunction of a wide network of brain regions including the motor cortex, basal ganglia, cerebellum, brainstem and spinal cord. Dystonia can be effectively treated by pallidal deep brain stimulation although the mechanism of this effect is not well understood. Here, we sought to characterize cortico-basal ganglia functional connectivity using a frequency-specific measure of connectivity-coherence. We recorded direct local field potentials from the human pallidum simultaneously with whole head magnetoencephalography to characterize functional connectivity in the cortico-pallidal oscillatory network in nine patients with idiopathic dystonia. Three-dimensional cortico-pallidal coherence images were compared to surrogate images of phase shuffled data across patients to reveal clusters of significant coherence (family-wise error P < 0.01, voxel extent 1000). Three frequency-specific, spatially-distinct cortico-pallidal networks have been identified: a pallido-temporal source of theta band (4-8 Hz) coherence, a pallido-cerebellar source of alpha band (7-13 Hz) coherence and a cortico-pallidal source of beta band (13-30 Hz) coherence over sensorimotor areas. Granger-based directionality analysis revealed directional coupling with the pallidal local field potentials leading in the theta and alpha band and the magnetoencephalographic cortical source leading in the beta band. The degree of pallido-cerebellar coupling showed an inverse correlation with dystonic symptom severity. Our data extend previous findings in patients with Parkinsons disease describing motor cortex-basal ganglia oscillatory connectivity in the beta band to patients with dystonia. Source coherence analysis revealed two additional frequency-specific networks involving the temporal cortex and the cerebellum. Pallido-cerebellar oscillatory connectivity and its association with dystonic symptoms provides further confirmation of cerebellar involvement in dystonia that has been recently reported using functional magnetic resonance imaging and fibre tracking.

Deep Brain Recordings Using an Implanted Pulse Generator in Parkinson's Disease

Recent studies suggest that oscillatory beta activity could be used as a state biomarker in patients with Parkinsons disease for subthalamic closed‐loop stimulation with the intention of improving clinical benefit. Here we investigate the feasibility of subthalamic recordings via a novel chronically implanted pulse generator.

Different patterns of local field potentials from limbic DBS targets in patients with major depressive and obsessive compulsive disorder

The role of distinct limbic areas in emotion regulation has been largely inferred from neuroimaging studies. Recently, the opportunity for intracranial recordings from limbic areas has arisen in patients undergoing deep brain stimulation (DBS) for neuropsychiatric disorders including major depressive disorder (MDD) and obsessive compulsive disorder (OCD). Here we test the hypothesis that distinct temporal patterns of local field potential (LFP) activity in the human limbic system reflect disease state and symptom severity in MDD and OCD patients. To this end, we recorded LFPs via implanted DBS electrodes from the bed nucleus of stria terminalis (BNST area) in 12 patients (5 OCD, 7 MDD) and from the subgenual cingulate cortex in 7 MDD patients (CG25 area). We found a distinct pattern of oscillatory activity with significantly higher α-power in MDD compared with OCD in the BNST area (broad α-band 8–14 Hz; P<0.01) and a similar level of α-activity in the CG25 area as in the BNST area in MDD patients. The mean α-power correlated with severity of depressive symptoms as assessed by the Beck depression inventory in MDD (n=14, r=0.55, P=0.042) but not with severity of obsessive compulsive symptoms in OCD. Here we show larger α-band activity in MDD patients compared with OCD recorded from intracranial DBS targets. Our results suggest that α-activity in the limbic system may be a signature of symptom severity in MDD and may serve as a potential state biomarker for closed loop DBS in MDD.

Subthalamic synchronized oscillatory activity correlates with motor impairment in patients with Parkinson's disease.

Beta band oscillations in the subthalamic nucleus (STN) have been proposed as a pathophysiological signature in patients with Parkinsons disease (PD). The aim of this study was to investigate the potential association between oscillatory activity in the STN and symptom severity in PD.

Toward an electrophysiological “sweet spot” for deep brain stimulation in the subthalamic nucleus

Enhanced beta‐band activity recorded in patients suffering from Parkinson‘s Disease (PD) has been described as a potential physiomarker for disease severity. Beta power is suppressed by Levodopa intake and STN deep brain stimulation (DBS) and correlates with disease severity across patients. The aim of the present study was to explore the promising signature of the physiomarker in the spatial domain. Based on local field potential data acquired from 54 patients undergoing STN‐DBS, power values within alpha, beta, low beta, and high beta bands were calculated. Values were projected into common stereotactic space after DBS lead localization. Recorded beta power values were significantly higher at posterior and dorsal lead positions, as well as in active compared with inactive pairs. The peak of activity in the beta band was situated within the sensorimotor functional zone of the nucleus. In contrast, higher alpha activity was found in a more ventromedial region, potentially corresponding to associative or premotor functional zones of the STN. Beta‐ and alpha‐power peaks were then used as seeds in a fiber tracking experiment. Here, the beta‐site received more input from primary motor cortex whereas the alpha‐site was more strongly connected to premotor and prefrontal areas. The results summarize predominant spatial locations of frequency signatures recorded in STN‐DBS patients in a probabilistic fashion. The site of predominant beta‐activity may serve as an electrophysiologically determined target for optimal outcome in STN‐DBS for PD in the future. Hum Brain Mapp 38:3377–3390, 2017.

Enhanced low-frequency oscillatory activity of the subthalamic nucleus in a patient with dystonia.

Local field potentials were recorded from the subthalamic nucleus (STN) in a patient with dystonia to further elucidate disease‐specific aspects of basal ganglia oscillatory activity.

A localized pallidal physiomarker in cervical dystonia

Deep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinsons disease, a disease‐specific physiomarker was identified that is now used to investigate adaptive closed‐loop stimulation in first studies. In dystonia, such a physiomarker is missing.

Long term correlation of subthalamic beta band activity with motor impairment in patients with Parkinson’s disease

OBJECTIVES To investigate the long term association of subthalamic beta activity with parkinsonian motor signs. METHODS We recruited 15 patients with Parkinsons disease undergoing subthalamic DBS for local field potential recordings after electrode implantation, and at 3 and 8months post-operatively using the implantable sensing enabled Activa PC+S (Medtronic). Three patients dropped out leaving 12 patients. Recordings were conducted ON and OFF levodopa at rest. Beta (13-35Hz) peak amplitudes were extracted, compared across time points and correlated with UPDRS-III hemibody scores. RESULTS Peaks in the beta frequency band (13-35Hz) in the OFF medication state were found in all hemispheres. Mean beta activity was significantly suppressed by levodopa at all recorded time points (P<0.007) and individual beta power amplitude correlated with parkinsonian motor impairment across time points and dopaminergic states (pooled data; ρ=0.25, P<0.001). CONCLUSIONS Our results indicate that beta-activity is correlated with parkinsonian motor signs over a time period of 8months. SIGNIFICANCE Beta-activity may be a chronically detectable biomarker of symptom severity in PD that should be further evaluated under ongoing DBS.