Stefan Jun Groiss

Non-invasive Cerebellar Stimulation—a Consensus Paper

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.

Deep brain stimulation in Parkinson's disease

During the last 15 years deep brain stimulation (DBS) has been established as a highly-effective therapy for advanced Parkinson’s disease (PD). Patient selection, stereotactic implantation, postoperative stimulator programming and patient care requires a multi-disciplinary team including movement disorders specialists in neurology and functional neurosurgery. To treat medically refractory levodopa-induced motor complications or resistant tremor the preferred target for high-frequency DBS is the subthalamic nucleus (STN). STN-DBS results in significant reduction of dyskinesias and dopaminergic medication, improvement of all cardinal motor symptoms with sustained long-term benefits, and significant improvement of quality of life when compared with best medical treatment. These benefits have to be weighed against potential surgery-related adverse events, device-related complications, and stimulus-induced side effects. The mean disease duration before initiating DBS in PD is currently about 13 years. It is presently investigated whether the optimal timing for implantation may be at an earlier disease-stage to prevent psychosocial decline and to maintain quality of life for a longer period of time.

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.

Differential effects of levodopa and subthalamic nucleus deep brain stimulation on bradykinesia in Parkinson's disease

Cardinal symptoms of Parkinsons disease (PD) respond well to treatment with levodopa and deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, it has remained unclear whether levodopa and STN‐DBS have differential effects on bradykinesia. We investigated 8 PD‐patients with STN‐electrodes in four conditions: STN‐DBS and levodopa (ONMED/ONSTIM), STN‐DBS only (OFFMED/ONSTIM), levodopa only (ONMED/OFFSTIM), without STN‐DBS/levodopa (OFFMED/OFFSTIM). Fourteen volunteers served as controls. Subjects performed fastest possible (1) pronation/supination of the forearm (diadochokinesia) and (2) flexion and extension of the index finger (finger movements). Movements were recorded using a 3D‐ultrasound‐system. Maximum frequency, amplitude, and smoothness of movements were determined. During OFFMED/OFFSTIM, all parameters were worser than in all other conditions. In proximal diadochokinesia, OFFMED/ONSTIM significantly improved the amplitude and frequency, whereas ONMED/OFFSTIM had no significant effect. In contrast, we found a stronger effect of levodopa (ONMED/OFFSTIM) on amplitudes of distal finger movement than on amplitudes of diadochokinesia. Combination of treatments during ONMED/ONSTIM further improved both movements. However, maximum frequency remained lower in PD‐patients during ONMED/ONSTIM compared with controls. This study demonstrates a better effect of levodopa on distal finger movements and STN‐DBS on proximal diadochokinesia. Furthermore, a complementary effect of both therapies on brain areas involved in bradykinesia can be assumed.

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

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.

Cerebellar Stimulation in Ataxia

The cerebellum plays an important role in movement execution and motor control by modulation of the primary motor cortex (M1) through cerebello-thalamo-cortical connections. Transcranial magnetic stimulation (TMS) allows direct investigations of neural networks by stimulating neural structures in humans noninvasively. The motor evoked potential to single-pulse TMS of M1 is used to measure the motor cortical excitability. A conditioning stimulus over the cerebellum preceding a test stimulus of the contralateral M1 enables us to study the cerebellar regulatory functions on M1. In this brief review, we describe this cerebellar stimulation method and its usefulness as a diagnostic tool in clinical neurophysiology.

A prospective pilot trial for pallidal deep brain stimulation in Huntington´s disease

Background Movement disorders in Huntington’s disease are often medically refractive. The aim of the trial was assessment of procedure safety of deep brain stimulation, equality of internal- and external-pallidal stimulation and efficacy followed-up for 6 months in a prospective pilot trial. Methods In a controlled double-blind phase six patients (four chorea-dominant, two Westphal-variant) with predominant movement disorder were randomly assigned to either the sequence of 6-week internal- or 6-week external-pallidal stimulation, or vice versa, followed by further 3 months chronic pallidal stimulation at the target with best effect-side-effect ratio. Primary endpoints were changes in the Unified Huntington’s Disease Rating Scale motor-score, chorea subscore, and total motor-score 4 (blinded-video ratings), comparing internal- versus external-pallidal stimulation, and 6 months versus baseline. Secondary endpoints assessed scores on dystonia, hypokinesia, cognition, mood, functionality/disability, and quality-of-life. Results Intention-to-treat analysis of all patients (n = 3 in each treatment sequence): Both targets were equal in terms of efficacy. Chorea subscores decreased significantly over 6 months (−5.3 (60.2%), p = 0.037). Effects on dystonia were not significant over the group due to it consisting of three responders (>50% improvement) and three non-responders. Westphal patients did not improve. Cognition was stable. Mood and some functionality/disability and quality-of-life scores improved significantly. Eight adverse events and two additional serious adverse events – mostly internal-pallidal stimulation-related – resolved without sequalae. No procedure-related complications occurred. Conclusion Pallidal deep brain stimulation was demonstrated to be a safe treatment option for the reduction of chorea in Huntington’s disease. Their effects on chorea and dystonia and on quality-of-life should be examined in larger controlled trials.

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. Parkinsońs 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.

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.