Thalamomuscular coherence in essential tremor: hen or egg in the emergence of tremor?

Thalamomuscular coherence in essential tremor (ET) has consistently been detected in numerous neurophysiological studies. Thereby, spatial properties of coherence indicate a differentiated, somatotopic organization; so far, however, little attention has been paid to temporal aspects of this interdependency. Further insight into the relationship between tremor onset and the onset of coherence could pave the way to more efficient deep brain stimulation (DBS) algorithms for tremor. We studied 10 severely affected ET patients (six females, four males) during surgery for DBS-electrode implantation and simultaneously recorded local field potentials (LFPs) and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm during its elevation. The temporal relationship between the onset of significant wavelet cross spectrum (WCS) and tremor onset was determined. Moreover, we examined the influence of electrode location within one recording depth on this latency and the coincidence of coherence and tremor for depths with strong overall coherence ("tremor clusters") and those without. Data analysis revealed tremor onset occurring 220 ± 460 ms before the start of significant LFP-EMG coherence. Furthermore, we could detect an anterolateral gradient of WCS onset within one recording depth. Finally, the coincidence of tremor and coherence was significantly higher in tremor clusters. We conclude that tremor onset precedes the beginning of coherence. Besides, within one recording depth there is a spread of the tremor signal. This reflects the importance of somatosensory feedback for ET and questions the suitability of thalamomuscular coherence as a biomarker for "closed-loop" DBS systems to prevent tremor emergence.

Decision-making under risk is improved by both dopaminergic medication and subthalamic stimulation in Parkinson's disease.

Inconsistent findings regarding the effects of dopaminergic medication (MED) and deep brain stimulation (DBS) of the subthalamic nucleus (STN) on decision making processes and impulsivity in Parkinson's disease (PD) patients have been reported. This study investigated the influence of MED and STN-DBS on decision-making under risk. Eighteen non-demented PD patients, treated with both MED and STN-DBS (64.3±10.2years, UPDRS III MED off, DBS off 45.5±17.1) were tested with the Game of Dice Task (GDT) which probes decision-making under risk during four conditions: MED on/DBS on, MED on/DBS off, MED off/DBS on, and MED off/DBS off. Task performance across conditions was compared analyzing two GDT-parameters: (i) the "net score" indicating advantageous decisions, and (ii) the patient's ability to use negative feedback. Significantly higher GDT net scores were observed in Med on in contrast to Med off conditions as well as in DBS on versus DBS off conditions. However, no effect of therapy for the patient's ability to make use of negative feedback could be detected. The data suggest a positive influence of both MED and STN-DBS on making decisions under risk in PD patients, an effect which seems to be mediated by mechanisms other than the use of negative feedback.

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 Parkinson's 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 ß-ß as well as θ-ß coupling. Enhancement in cross-frequency θ-ß 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.

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 Parkinson's 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 Parkinson's 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.

Essential tremor and tremor in Parkinson's disease are associated with distinct 'tremor clusters' in the ventral thalamus.

Different tremor entities such as Essential Tremor (ET) or tremor in Parkinson's disease (PD) can be ameliorated by the implantation of electrodes in the ventral thalamus for Deep Brain Stimulation (DBS). The exact neural mechanisms underlying this treatment, as well as the specific pathophysiology of the tremor in both diseases to date remain elusive. Since tremor-related local field potentials (LFP) have been shown to cluster with a somatotopic representation in the subthalamic nucleus, we here investigated the neurophysiological correlates of tremor in the ventral thalamus in ET and PD using power and coherence analysis. Local field potentials (LFPs) at different recording depths and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm were recorded simultaneously in twelve ET and five PD patients. Data analysis revealed individual electrophysiological patterns of LFP-EMG coherence at single and double tremor frequency for each patient. Patterns observed varied in their spatial distribution within the Ventral lateral posterior nucleus of the thalamus (VLp), revealing a specific topography of 'tremor clusters' for PD and ET. The data strongly suggest that within VLp individual tremor-related electrophysiological signatures exist in ET and PD tremor.

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 ß-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.

Modulation of human time processing by subthalamic deep brain stimulation.

Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG) oscillatory loops are involved in time interval recognition. Parkinsons disease (PD) is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ≥ 130-Hz-STN-DBS compared to healthy controls. We found under(re-)production of the 15-second interval and a significant enhancement of this under(re-)production by 10-Hz-stimulation compared to no stimulation, ≥ 130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds.

Long-term time course of affective lability after subthalamic deep brain stimulation electrode implantation.

The mechanism and time course of emotional side effects of subthalamic deep brain stimulation in Parkinson's disease are a matter for discussion. We report a 53-month follow-up of a patient with affective lability. Postoperative lesion plus bilateral stimulation strongly influenced mood in the first week in terms of laughing behavior, while voltage changes had only minor long-term impact up to 37 months on negative emotion, possibly caused by the right electrode stimulating the subthalamic nucleus and adjacent fiber tracts involving the internal capsule. Thus we conclude that affective lability can occur with different temporal dynamics of microlesion, and early and chronic stimulation.

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.

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.

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 Parkinson's 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 Parkinson's 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.

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.

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

OBJECTIVE: In patients with Parkinson's 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.

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.