Markus Butz

Distinct oscillatory STN-cortical loops revealed by simultaneous MEG and local field potential recordings in patients with Parkinson's disease

Neuronal oscillations are assumed to play a pivotal role in the pathophysiology of Parkinsons disease (PD). Neurons in the subthalamic nucleus (STN) generate oscillations which are coupled to rhythmic population activity both in other basal ganglia nuclei and cortical areas. In order to localize these cortical areas, we recorded local field potentials (LFPs) and magnetoencephalography (MEG) simultaneously in PD patients undergoing surgery for deep brain stimulation (DBS). Patients were withdrawn from antiparkinsonian medication and recorded at rest. We scanned the entire brain for oscillations coherent with LFPs recorded from the STN with a frequency domain beamformer. Coherent activity in the low (12-20 Hz) and high (20-35 Hz) beta range was found in the ipsilateral sensorimotor and the premotor cortex. Coherence in the alpha range (7-12 Hz) was observed at various locations in the ipsilateral temporal lobe. In a subset of subjects, the superior temporal gyrus consistently showed coherent alpha oscillations. Our findings provide new insights into patterns of frequency-specific functional connectivity between basal ganglia and cortex and suggest that simultaneous inter-regional interactions may be segregated in the frequency domain. Furthermore, they demonstrate that simultaneous MEG-LFP recordings are a powerful tool to study interactions between brain areas in PD patients undergoing surgery for DBS.

Synchronized brain network associated with essential tremor as revealed by magnetoencephalography

Despite the fact that essential tremor (ET) is the most prevalent movement disorder, the underlying pathological mechanisms are not fully understood. There is accumulating evidence that this specific type of tremor is mainly of central origin, in particular involving inferior olive, cerebellum, thalamus, and primary motor cortex. We studied 8 patients with ET recording simultaneously neural activity with a whole‐scalp neuromagnetometer and tremor activity with surface electromyography (EMG). Subjects performed an isometric contraction of the left forearm. Tremor frequency of 5 to 7 Hz and its first harmonic were clearly evident in power spectra of EMG recordings. We used the localization technique dynamic imaging of coherent sources (DICS) to identify cerebral areas coherent to the EMG signal at tremor frequency and its first harmonic. All subjects showed coherence to the contralateral primary motor cortex. In a further step, DICS was used to identify areas of significant cerebro‐cerebral coherence. The analysis revealed a network of areas consisting of contralateral primary motor cortex, premotor cortex, thalamus, brainstem, and ipsilateral cerebellum. These results are consistent with the view that in ET, a network of cerebral areas including brainstem shows oscillatory interactions, which lead to a rhythmic modulation of muscle activity becoming apparent as tremor.

Task-dependent oscillations during unimanual and bimanual movements in the human primary motor cortex and SMA studied with magnetoencephalography

The neural mechanisms subserving uni- and bimanual control of movements are not well understood. Nevertheless, recent studies indicate a functional role of oscillatory activity in movement control and point towards a hemispheric asymmetry in motor control. This study specifically addresses the issues of (i) task-relatedness, (ii) hemispheric symmetry, and (iii) frequency specificity of the measures power, cerebro-muscular coherence, and cerebro-cerebral coherence in bilateral primary motor cortex and supplementary motor area (SMA). We have studied 10 right-handed subjects with simultaneous recordings of magnetoencephalography and surface electromyography during different unimanual and bimanual tasks. Using the analysis technique Dynamic Imaging of Coherent Sources (DICS), left and right primary motor cortex and SMA were functionally localized. Power, cerebro-musclar coherence, and cerebro-cerebral coherence between these areas were computed for four frequency bands in each condition and subjected to ANOVA. Results show a task-specific modulation of power and coherence, and further indicate a hemispheric asymmetry in the control of unimanual and bimanual movements. In addition, different frequency bands showed different task-dependent variations. The gamma band (26-40 Hz) showed strongest modulation for cerebro-muscular coherence and was strongest for the isometric contraction conditions. In contrast, the beta band (13-24 Hz) showed the strongest variations between static and dynamic conditions, and seems to play a particular role in movement control. In summary, our results indicate a differential functional role of oscillatory activity and coupling in the motor system.

High frequency oscillations in the subthalamic nucleus: a neurophysiological marker of the motor state in Parkinson's disease.

Increasing evidence suggests that abnormal oscillatory activity in basal ganglia and cortex plays a pivotal role in the pathophysiology of Parkinsons disease. Recordings of local field potentials from subthalamic nucleus of patients undergoing deep brain stimulation have focused on oscillations occurring at frequencies below 100 Hz in the alpha, beta and gamma range and suggested that, in particular, an increase of beta band oscillations underlies slowing of movement in Parkinsons disease. Recent findings showing that the amplitude of high frequency oscillations (>200 Hz) couples with the phase of beta activity have raised the important question about the role of subthalamic high frequency oscillations in Parkinsons disease. To investigate functional characteristics and clinical relevance of high frequency oscillations, we recorded local field potentials from 18 subthalamic nuclei of 9 akinetic-rigid Parkinsonian patients with implanted deep brain stimulation electrodes and still externalised leads before and after intake of levodopa. We identified two distinct bands of high frequency oscillations, one centred around 250 Hz and another one around 350 Hz that show characteristic levodopa dependent amplitude and coupling behaviours. Administration of levodopa changed the power ratio between the two high frequency bands towards the component centred around 350 Hz in all 18 nuclei under study (p<10(-4)). Moreover, this power ratio correlated significantly with the Unified Parkinsons Disease Rating Scale hemibody akinesia/rigidity subscore (r=0.3618, p=0.015), but interestingly not with beta peak power (p=0.1) suggesting that levodopa induced changes in high frequency and beta oscillations are at least potentially independent of each other. Accordingly, a combined parameter composed of power ratio of high frequency oscillations and beta peak power significantly increased the correlation with the motor state (r=0.45, p=0.004). These results indicate that a shift from slower to faster frequencies of the spectrum greater than 200 Hz represents a prokinetic neurophysiological marker underlying levodopa induced motor improvement in Parkinsons disease.

Perilesional pathological oscillatory activity in the magnetoencephalogram of patients with cortical brain lesions.

In the surrounding of focal ischemic brain lesions dysfunctional neuronal zones emerge often resulting in pathological oscillatory activity. Using whole-head magnetoencephalography we recorded brain activity during rest in 23 patients with ischemic cortical lesions to find out whether we can localise and characterise low-frequency oscillatory activity. We measured patients at different times after stroke and partly in a follow-up approach to determine the time course of slow-wave activity. Using the analysis tool Dynamic Imaging of Coherent Sources we computed tomographic maps of oscillatory power in the delta-band (0.5-3 Hz). Fifteen of 23 patients with cortical strokes showed delta-activity, which was localised in an area not more than 2 cm away from the lesion. We found this perilesional low-frequency activity in the acute as well as in the chronic stage of stroke. Follow-up measurements of individual patients revealed persistence of perilesional low-frequency activity for months and even years. No consistent relation between perilesional activity and clinical symptoms was observed. Our results indicate that perilesional delta activity is common after ischemic cortical stroke. However, the functional significance remains to be elucidated.

A direct relationship between oscillatory subthalamic nucleus–cortex coupling and rest tremor in Parkinson’s disease

Electrophysiological studies suggest that rest tremor in Parkinsons disease is associated with an alteration of oscillatory activity. Although it is well known that tremor depends on cortico-muscular coupling, it is unclear whether synchronization within and between brain areas is specifically related to the presence and severity of tremor. To tackle this longstanding issue, we took advantage of naturally occurring spontaneous tremor fluctuations and investigated cerebral synchronization in the presence and absence of rest tremor. We simultaneously recorded local field potentials from the subthalamic nucleus, the magnetoencephalogram and the electromyogram of forearm muscles in 11 patients with Parkinsons disease (all male, age: 52-74 years). Recordings took place the day after surgery for deep brain stimulation, after withdrawal of anti-parkinsonian medication. We selected epochs containing spontaneous rest tremor and tremor-free epochs, respectively, and compared power and coherence between subthalamic nucleus, cortex and muscle across conditions. Tremor-associated changes in cerebro-muscular coherence were localized by Dynamic Imaging of Coherent Sources. Subsequently, cortico-cortical coupling was analysed by computation of the imaginary part of coherency, a coupling measure insensitive to volume conduction. After tremor onset, local field potential power increased at individual tremor frequency and cortical power decreased in the beta band (13-30 Hz). Sensor level subthalamic nucleus-cortex, cortico-muscular and subthalamic nucleus-muscle coherence increased during tremor specifically at tremor frequency. The increase in subthalamic nucleus-cortex coherence correlated with the increase in electromyogram power. On the source level, we observed tremor-associated increases in cortico-muscular coherence in primary motor cortex, premotor cortex and posterior parietal cortex contralateral to the tremulous limb. Analysis of the imaginary part of coherency revealed tremor-dependent coupling between these cortical areas at tremor frequency and double tremor frequency. Our findings demonstrate a direct relationship between the synchronization of cerebral oscillations and tremor manifestation. Furthermore, they suggest the feasibility of tremor detection based on local field potentials and might thus become relevant for the design of closed-loop stimulation systems.

Modality specific functional interaction in sensorimotor synchronization.

Movement execution strongly relies on precise sensorimotor synchronization. In a finger‐tapping task that requires subjects to synchronize their finger taps to regular pacing signal synchronization accuracy varies with respect to pacing signals modality. This study aimed at elucidating functional brain dynamics associated with modality specific behavioral synchronization accuracy. To this end, 10 right‐handed subjects performed a finger‐tapping task with respect to regular auditory and visual pacing, respectively, whereas neuromagnetic activity was recorded using a 122‐channel whole‐head neuromagnetometer. Visual pacing was associated with significantly reduced tap‐to‐pacer asynchrony and increased intertap variability as compared to auditory pacing. The brain dynamics associated with task execution were analyzed using the frequency domain beamformer approach dynamic imaging of coherent sources (DICS). Both tasks were shown to be associated with comparable networks. However, during visual pacing involvement of the ventral premotor cortex (PMv) was shown, whereas during auditory pacing the dorsal premotor cortex (PMd) was concerned with task execution. Synchronization with respect to visual pacing was associated with significantly increased functional interaction between thalamus and PMv at beta frequency as compared to functional interplay between thalamus and PMd during auditory pacing. Auditory synchronization was associated with increased functional interaction between left superior temporal gyrus and PMd at alpha frequency. Furthermore, functional interaction between thalamus and premotor cortex at beta frequency was significantly correlated with synchronization accuracy. All in all the present data suggest that modality specific synchronization differences are associated with frequency and connectivity specific changes of functional interaction in distinct brain networks. Hum Brain Mapp, 2009.

Levodopa Affects Functional Brain Networks in Parkinsonian Resting Tremor

Resting tremor in idiopathic Parkinsons disease (PD) is associated with an oscillatory network comprising cortical as well as subcortical brain areas. To shed light on the effect of levodopa on these network interactions, we investigated 10 patients with tremor‐dominant PD and reanalyzed data in 11 healthy volunteers mimicking PD resting tremor. To this end, we recorded surface electromyograms of forearm muscles and neuromagnetic activity using a 122‐channel whole‐head magnetometer (MEG). Measurements were performed after overnight withdrawal of levodopa (OFF) and 30 min after oral application of fast‐acting levodopa (ON). During OFF, patients showed the typical antagonistic resting tremor. Using the analysis tool Dynamic Imaging of Coherent Sources, we identified the oscillatory network associated with tremor comprising contralateral primary sensorimotor cortex (S1/M1), supplementary motor area (SMA), contralateral premotor cortex (PMC), thalamus, secondary somatosensory cortex (S2), posterior parietal cortex (PPC), and ipsilateral cerebellum oscillating at 8 to 10 Hz. After intake of levodopa, we found a significant decrease of cerebro‐cerebral coupling between thalamus and motor cortical areas. Similarly, in healthy controls mimicking resting tremor, we found a significant decrease of functional interaction within a thalamus–premotor–motor network during rest. However, in patients with PD, decrease of functional interaction between thalamus and PMC was significantly stronger when compared with healthy controls. These data support the hypothesis that (1) in patients with PD the basal ganglia and motor cortical structures become more closely entrained and (2) levodopa is associated with normalization of the functional interaction between thalamus and motor cortical areas.

Oscillatory coupling in writing and writer's cramp.

Writing is a highly skilled and overlearned movement. In patients suffering from writers cramp, a focal task-induced dystonia, writing is impaired or even impossible due to involuntary muscle contractions and abnormal posture, which occur as soon as the person picks up a pen or within writing a few words. The underlying pathophysiological mechanisms of this movement disorder are not fully understood up to now. The aim of the present study was to unravel the oscillatory network underlying physiological writing in healthy subjects and dystonic writing in writers cramp patients. Using whole-head magnetoencephalography (MEG) and the analysis tool dynamic imaging of coherent sources (DICS) we studied oscillatory neural coupling during writing in eleven healthy subjects and eight patients suffering from writers cramp. Simultaneous recording of brain activity with MEG and activity of forearm and hand muscles with surface electromyography (EMG) was performed while subjects were writing for five minutes with their dominant right hand. Applying DICS sources of strongest cerebro-muscular coherence and cerebro-cerebral coherence during writing were identified, which consistently included six brain areas in both, the control subjects and the patients: contralateral and ipsilateral sensorimotor cortex, ipsilateral cerebellum, contralateral thalamus, contralateral premotor and posterior parietal cortex. Coherence between cortical sources and muscles appeared primarily in the frequency of writing movements (3-7 Hz) while coherence between cerebral sources occurred primarily around 10 Hz (8-13 Hz). Interestingly, consistent coupling between both sensorimotor cortices was observed in patients only, whereas coupling between ipsilateral cerebellum and the contralateral posterior parietal cortex was found in control subjects only. These results are consistent with the often described bilateral pathophysiology and impaired sensorimotor integration in writers cramp patients.

Motor impairment in liver cirrhosis without and with minimal hepatic encephalopathy.

Butz M, Timmermann L, Braun M, Groiss SJ, Wojtecki L, Ostrowski S, Krause H, Pollok B, Gross J, Südmeyer M, Kircheis G, Häussinger D, Schnitzler A. Motor impairment in liver cirrhosis without and with minimal hepatic encephalopathy.
Acta Neurol Scand: 2010: 122: 27–35.
© 2009 The Authors Journal compilation