Christiane Reck

Characterisation of tremor-associated local field potentials in the subthalamic nucleus in Parkinson's disease.

We simultaneously recorded local field potentials (LFPs) in the subthalamic nucleus (STN) and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm in eight patients with idiopathic tremor‐dominant Parkinson’s disease (resting tremor) during the bilateral implantation of deep brain stimulation electrodes. Recordings were made at different heights (in 0.5‐ to 2.0‐mm steps beginning outside the STN) using up to five concentrically configured macroelectrodes (2 mm apart). The patients were instructed to relax their contralateral forearm (rest condition). We analysed the coherence between tremor EMGs and STN LFPs, which showed significant tremor‐associated coupling at single tremor and double tremor frequencies. Moreover, the EMG–LFP coherences were characterised by differences between antagonistic muscles (flexor, extensor) and by the spatial distribution of LFPs within the STN. Coherence at single and double tremor frequencies occurred significantly more frequently within STN than above STN (in the zona incerta). In this study, we were able to show that, within STN, tremor‐associated LFP activity varied with spatial distribution and with the contralateral antagonistic forearm muscles. These findings suggest the existence of distribution‐ and muscle‐specific tremor‐associated LFP activity at different tremor frequencies and an organisation of tremor‐related subloops within the STN.

Pathological cerebral oscillatory activity in Parkinson’s disease: a critical review on methods, data and hypotheses

Although well-known for more than a century, a sound pathophysiological mechanism for Parkinson’s disease (PD) was lacking for a long time. The recent availability of electrophysiological techniques, such as magnetoencephalography, high-resolution electroencephalography and intra- and post-operative recordings in PD patients undergoing deep brain stimulation, allowed new approaches to record neuronal activity. Furthermore, the new application of signal analysis tools, such as the fast Fourier transformation, coherence, phase shifts, as well as causality measures, gave tremendous new insights into mechanisms of frequency-dependent oscillatory coupling. This review highlights these new analysis approaches, reviews the noninvasive magnetoencephalography, electroencephalography and intra- and post-operative data on PD patients, and summarizes the modern hypothesis that PD results from pathological oscillatory synchronization in the human sensorimotor system.

Task-specific modulation of effective connectivity during two simple unimanual motor tasks: A 122-channel EEG study

Neural oscillations are thought to underlie coupling of spatially remote neurons and gating of information within the human sensorimotor system. Here we tested the hypothesis that different unimanual motor tasks are specifically associated with distinct patterns of oscillatory coupling in human sensorimotor cortical areas. In 13 healthy, right-handed subjects, we recorded task-induced neural activity with 122-channel electroencephalography (EEG) while subjects performed fast self-paced extension-flexion movements with the right index finger and an isometric contraction of the right forearm. Task-related modulations of inter-regional coupling within a core motor network comprising the left primary motor cortex (M1), lateral premotor cortex (lPM) and supplementary motor area (SMA) were then modeled using dynamic causal modeling (DCM). A network model postulating coupling both within and across frequencies best captured observed spectral responses according to Bayesian model selection. DCM revealed dominant coupling within the β-band (13-30 Hz) between M1 and SMA during isometric contraction of the forearm, whereas fast repetitive finger movements were characterized by strong coupling within the γ-band (31-48 Hz) and between the θ- (4-7 Hz) and the γ-band. This coupling pattern was mainly expressed in connections from lPM to SMA and from lPM to M1. We infer that human manual motor control involves task-specific modulation of inter-regional oscillatory coupling both within and across distinct frequency bands. The results highlight the potential of DCM to characterize context-specific changes in coupling within functional brain networks.

Clinical outcome of subthalamic stimulation in Parkinson's disease is improved by intraoperative multiple trajectories microelectrode recording.

BACKGROUND AND STUDY AIMS The use of multiple trajectories microelectrode recording (MER) during implantation of deep brain stimulation (DBS) electrodes into the subthalamic nucleus (STN) in patients with Parkinsons disease (PD) is discussed controversially because of possible risks and unclear benefits. The aim of the study is to investigate whether MER combined with intraoperative evaluation of stimulation effects improve clinical outcome in PD patients undergoing STN DBS surgery. MATERIAL AND METHODS Prior to final DBS electrode implantation, we performed multiple trajectories MER and intraoperative test stimulations after magnetic resonance imaging (MRI)-guided planning in 32 PD patients. In further 10 patients no MER (only intraoperative test stimulation) was used. RESULTS We found a significantly better clinical outcome (Unified Parkinsons Disease Rating Scale [UPDRS] III) in patients undergoing MER compared with non-MER patients. In MER patients, DBS electrode placement was performed using the central trajectory in 73%. Another than the central trajectory was taken in 27% of the patients. No difference in clinical outcome between DBS electrodes implanted on the central or a decentral trajectory was observed. CONCLUSIONS DBS surgery based on intraoperative multiple trajectories MER and test stimulation improves clinical outcome if compared with intraoperative test stimulation alone. The data suggest that DBS surgery solely based on MRI and intraoperative test stimulation without MER may lead to nonoptimal placement of DBS electrodes and consequently poorer clinical outcome.

Dopamine Replacement Modulates Oscillatory Coupling Between Premotor and Motor Cortical Areas in Parkinson's Disease

Efficient neural communication between premotor and motor cortical areas is critical for manual motor control. Here, we used high-density electroencephalography to study cortical connectivity in patients with Parkinsons disease (PD) and age-matched healthy controls while they performed repetitive movements of the right index finger at maximal repetition rate. Multiple source beamformer analysis and dynamic causal modeling were used to assess oscillatory coupling between the lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1) in the contralateral hemisphere. Elderly healthy controls showed task-related modulation in connections from lPM to SMA and M1, mainly within the γ-band (>30 Hz). Nonmedicated PD patients also showed task-related γ-γ coupling from lPM to M1, but γ coupling from lPM to SMA was absent. Levodopa reinstated physiological γ-γ coupling from lPM to SMA and significantly strengthened coupling in the feedback connection from M1 to lPM expressed as β-β as well as θ-β coupling. Enhancement in cross-frequency θ-β coupling from M1 to lPM was correlated with levodopa-induced improvement in motor function. The results show that PD is associated with an altered neural communication between premotor and motor cortical areas, which can be modulated by dopamine replacement.

Coherence analysis of local field potentials in the subthalamic nucleus: differences in parkinsonian rest and postural tremor

Implantation of electrodes in the subthalamic nucleus (STN) for deep brain stimulation is a well‐established method to ameliorate motor symptoms in patients suffering from Parkinson’s disease (PD). This study investigated the pathophysiology of rest and postural tremor in PD. In 14 patients with PD, we recorded intraoperatively local field potentials (LFPs) in the STN (at different recording depths) and electromyographic signals (EMGs) of the contralateral forearm. Using coherence analysis we analysed tremor epochs both at rest and hold conditions in patients of the akinetic‐rigid or of the tremor‐dominant PD subtype. Data analysis revealed significant LFP–EMG coherence during periods of rest and postural tremor. However, strong differences between both tremor types were observed: local maxima (cluster) of rest and postural tremor did not match. Additionally, during rest tremor coherence occurred significantly more frequently at single tremor frequency than at double tremor frequency in tremor‐dominant as well as in akinetic‐rigid patients. In contrast, during postural tremor in patients with akinetic‐rigid PD coherence was predominantly at double tremor frequency. The data suggest a specific topography of ‘tremor clusters’ for rest and postural tremor. Furthermore, we presume that the same tremor mechanisms exist in patients with tremor‐dominant and akinetic‐rigid PD, but to different degrees.

Ten Hertz thalamus stimulation increases tremor activity in the subthalamic nucleus in a patient with Parkinson’s disease

OBJECTIVE In patients with Parkinsons disease (PD) the effect of thalamic stimulation on tremor pathophysiology remains largely unclear. By recording local field potentials (LFPs) in the subthalamic nucleus (STN) while stimulating the nucleus ventralis intermedius thalami (VIM), information of the stimulation effects should be gained. METHODS We had the unique opportunity to intraoperatively record LFPs of the STN in a patient with PD while stimulating the VIM. VIM electrodes had been implanted 9 years previously because of tremor. Due to worsening of clinical symptoms an implantation of STN electrodes had become necessary. RESULTS High frequency stimulation in the VIM lowered the power of the tremor frequency band (4-7Hz) in the STN. In contrast, 10Hz VIM stimulation elevated the power of the tremor frequency band as well as STN-EMG coupling. CONCLUSIONS The effect of high frequency stimulation may explain the improvement of tremor in patients who are treated with VIM deep brain stimulation. The power elevation during 10Hz stimulation suggests that the pathological cerebral and cerebral-muscular communication in PD is mainly driven at 10Hz. SIGNIFICANCE The direct cerebral recordings support the view that a 10Hz network is a pathophysiological key mechanism in the generation of motor deficits in PD.

Differential distribution of coherence between beta-band subthalamic oscillations and forearm muscles in Parkinson's disease during isometric contraction

OBJECTIVE Under rest condition, beta-band (13-30Hz) activity in patients with Parkinsons disease (PD) is prominent in the subthalamic nucleus (STN). However, the beta-band coupling between STN and muscle activity, its distribution and relation to motor symptoms remains unclear. METHODS Using up to five electrodes, we recorded local field potentials (LFPs) above (zona incerta, ZI) and within the STN at different recording heights in 20 PD patients during isometric contraction. Simultaneously, we registered activity of the contralateral flexor and extensor muscle. We analysed LFP-EMG coherence to estimate coupling in the frequency domain. RESULTS Coherence analysis showed beta-associated coupling in the ZI and STN with more significant LFP-EMG coherences in the STN. Coherence varied depending on the localisation of the LFP and muscles. We found significant difference between coherence of the extensor and the flexor muscle to the same LFP (p=0.045). CONCLUSIONS We demonstrated that coherence between beta-band oscillations and forearm muscles are differentially distributed in the subthalamic region and between the forearm muscles in Parkinsons disease during isometric contraction. However, the significant LFP-EMG coupling did not associate with motor deficits in PD patients. SIGNIFICANCE The differential distribution of beta-band activity in the STN highlights the importance of a topographically distinct therapeutic modulation.

Causality between local field potentials of the subthalamic nucleus and electromyograms of forearm muscles in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson’s disease, although its precise mechanisms remain poorly understood. To gain further insight into the mechanisms underlying deep brain stimulation, we analysed the causal relationship between forearm muscle activity and local field potentials derived from the subthalamic nucleus. In 19 patients suffering from Parkinson’s disease of the akinetic‐rigid subtype, we calculated the squared partial directed coherence between muscles of the contralateral forearm and the subthalamic nucleus or zona incerta during both a rest and a hold condition of the arm. For both recording regions, data analysis revealed that, during the rest condition, electromyographic activity was significantly more often ‘Granger‐causal’ for the local field potentials than the opposite causation. In contrast, during the hold condition, no significant difference was found in the occurrence of causalities. Contrary to the existing basal ganglia model and the current concept of Parkinson’s disease pathophysiology, we found the subthalamic nucleus to receive more ‘afferences’ than it emitted ‘efferences’, suggesting that its role is more complex than a simple driving nucleus in the basal ganglia loop. Therefore, the effect of deep brain stimulation in the subthalamic nucleus could, at least in part, result from a blockade of pathological afferent input.

Modulation of local field potential power of the subthalamic nucleus during isometric force generation in patients with Parkinson’s disease

Investigations of local field potentials of the subthalamic nucleus of patients with Parkinsons disease have provided evidence for pathologically exaggerated oscillatory beta-band activity (13-30 Hz) which is amenable to physiological modulation by, e.g., voluntary movement. Previous functional magnetic resonance imaging studies in healthy controls have provided evidence for an increase of subthalamic nucleus blood-oxygenation-level-dependant signal in incremental force generation tasks. However, the modulation of neuronal activity by force generation and its relationship to peripheral feedback remain to be elucidated. We hypothesised that beta-band activity in the subthalamic nucleus is modulated by incremental force generation. Subthalamic nucleus local field potentials were recorded intraoperatively in 13 patients with Parkinsons disease (37 recording sites) during rest and five incremental isometric force generation conditions of the arm with applied loads of 0-400 g (in 100-g increments). Repeated measures analysis of variance (ANOVA) revealed a modulation of local field potential (LFP) power in the upper beta-band (in 24-30 Hz; F(₃.₀₄₂)=4.693, p=0.036) and the gamma-band (in 70-76 Hz; F(₄)=4.116, p=0.036). Granger-causality was computed with the squared partial directed coherence and showed no significant modulation during incremental isometric force generation. Our findings indicate that the upper beta- and gamma-band power of subthalamic nucleus local field potentials are modulated by the physiological task of force generation in patients with Parkinsons disease. This modulation seems to be not an effect of a modulation of peripheral feedback.