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

Electrophysiological studies suggest that rest tremor in Parkinson's 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 Parkinson's 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

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 trial

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

Longitudinal Deformation-Based Morphometry Reveals Spatio-Temporal Dynamics of Brain Volume Changes in Patients with Corticobasal Syndrome

Corticobasal syndrome (CBS) is a rare neurodegenerative disorder characterized by a progressive and asymmetric manifestation of cortical and basal-ganglia symptoms of different origin. The spatio-temporal dynamics of cerebral atrophy in CBS is barely known. This study aimed to longitudinally quantify the individual dynamics of brain volume changes in patients with CBS as compared to healthy controls.We used deformation-field-based morphometry (DFM) to study volumetric changes of each individual brain in short intervals of a few months. DFM enabled the quantitative analysis of local volume changes without predefining regions of interest in MR images of 6 patients with CBS and 11 matched healthy controls. A total of 64 whole brain 3D-MR-scans were acquired two to eight times over periods of 14 to 26 months. Based on repeated registrations of MR observations to the initial scan, maps of local volume ratio changes were computed.Compared to controls patients showed significant and increasing volume loss over time in premotor and primary-motor-cortices, somatosensory area 3a, superior parietal areas BA 5/7, and corticospinal tract. Furthermore, significant and asymmetric atrophy was identified in the caudate nucleus head, putamen, pallidum, motor-thalamus and substantia nigra. Temporal lobe was affected in those patients who presented progressive cognitive impairment.The analysis revealed localized, pathological changes in brains of patients with CBS, which differed significantly from those occurring during aging in healthy controls. As compared to age- and sex-matched controls, brains of CBS patients showed a common degenerating neural network comprising the motor circuit with basal ganglia and motor thalamic nuclei as well as the premotor and primary-motor-cortex

The treatment of Parkinson′s disease with deep brain stimulation: current issues

Deep brain stimulation has become a well-established symptomatic treatment for Parkinson′s disease during the last 25 years. Besides improving motor symptoms and long-term motor complications, positive effects on patients′ mobility, activities of daily living, emotional well-being and health-related quality of life have been recognized. Apart from that, numerous clinical trials analyzed effects on non-motor symptoms and side effects of deep brain stimulation. Several technical issues and stimulation paradigms have been and are still being developed to optimize the therapeutic effects, minimize the side effects and facilitate handling. This review summarizes current therapeutic issues, i.e., patient and target selection, surgical procedure and programming paradigms. In addition it focuses on neuropsychological effects and side effects of deep brain stimulation

Deep brain stimulation of the subthalamic nucleus transiently enhances loss-chasing behaviour in patients with Parkinson's disease

Dopaminergic treatments are associated with impulse control disorders such as pathological gambling in a subset of patients with Parkinson's Disease. While deep brain stimulation of the subthalamic nucleus has been reported to reduce symptoms of impulse control disorders in some Parkinson's Disease patients, little is known about its specific effects on gambling behaviour. In this experiment, we investigated the effects of deep brain stimulation of the subthalamic nucleus on one of the central features of pathological gambling: the tendency to chase losses. Loss-chasing is associated with impaired control over gambling behaviour and it is one of the most salient features of pathological gambling as it presents in the clinic. Twenty two patients with advanced idiopathic Parkinson's Disease and chronically implanted subthalamic nucleus electrodes for deep brain stimulation completed a simple laboratory model of loss-chasing behaviour twice: once with and once without stimulation. Exploratory analysis indicated that deep brain stimulation of the subthalamic nucleus increased the value of losses chased by patients with Parkinson's Disease when shifting from off- to on-stimulation. These effects were not attributable to changes in state affect or to the motor impairments produced by the withdrawal of deep brain stimulation of the subthalamic nucleus. The effects of the stimulation on the value of losses chased were more pronounced in female than in male patients and reduced in patients taking dopamine receptor agonists. Collectively, these results suggest that deep brain stimulation of the subthalamic nucleus can transiently alter the evaluation of accumulated losses during gambling episodes in idiopathic Parkinson's Disease

Deep Brain Stimulation in Huntington’s Disease—Preliminary Evidence on Pathophysiology, Efficacy and Safety

Huntington’s disease (HD) is one of the most disabling degenerative movement disorders, as it not only affects the motor system but also leads to cognitive disabilities and psychiatric symptoms. Deep brain stimulation (DBS) of the pallidum is a promising symptomatic treatment targeting the core motor symptom: chorea. This article gives an overview of preliminary evidence on pathophysiology, safety and efficacy of DBS in HD

Modulation of central thalamic oscillations during emotional-cognitive processing in chronic disorder of consciousness

We report on thalamic recordings in a patient with chronic disorder of consciousness (DOC). Implantation of central thalamic deep brain stimulation (CT-DBS) electrodes was chosen, as this treatment has been reported to display beneficial effects with respect to behavioural responsiveness in DOC. Local field potential (LFP) oscillations were recorded from central thalamic electrodes and their changes elicited by speech stimuli consisting either of familiar voices addressing the patient or unfamiliar non-addressing phrases were studied. In response to familiar-addressing speech we observed modulation of oscillatory activity in the beta and theta band within the central thalamus accompanied by an increase in thalamocortical coherence in the theta band. Furthermore, the theta phase was coupled to the amplitude of gamma locally in the thalamus. These findings indicate a local and long-range cross-frequency response which is not only indicative of the principle involvement of the central thalamus in processing emotional and cognitive information, but also point towards intact physiological functions that may serve as a marker in diagnosing DOC patients and determining novel targets and parameters concerning therapeutic efforts

Screening for Cognitive Impairment in Parkinson's Disease: Improving the Diagnostic Utility of the MoCA through Subtest Weighting

Background Given the high prevalence of cognitive impairment in Parkinson's disease (PD), cognitive screening is important in clinical practice. The Montreal Cognitive Assessment (MoCA) is a frequently used screening test in PD to detect mild cognitive impairment (PD-MCI) and Parkinson's disease dementia (PD-D). However, the proportion in which the subtests are represented in the MoCA total score does not seem reasonable. We present the development and preliminary evaluation of an empirically based alternative scoring system of the MoCA which aims at increasing the overall diagnostic accuracy. Methods In study 1, the MoCA was administered to 40 patients with PD without cognitive impairment (PD-N), PD-MCI, or PD-D, as defined by a comprehensive neuropsychological test battery. The new MoCA scoring algorithm was developed by defining Areas under the Curve (AUC) for MoCA subtests in a Receiver Operating Characteristic (ROC) and by weighting the sub-tests according to their sensitivities and specificities. In study 2, an independent sample of 24 PD patients (PD-N, PD-MCI, or PD-D) was tested with the MoCA. In both studies, diagnostic accuracy of the original and the new scoring procedure was calculated. Results Diagnostic accuracy increased with the new MoCA scoring algorithm. In study 1, the sensitivity to detect cognitive impairment increased from 62.5% to 92%, while specificity decreased only slightly from 77.7% to 73%; in study 2, sensitivity increased from 68.8% to 81.3%, while specificity stayed stable at 75%. Conclusion This pilot study demonstrates that the sensitivity of the MoCA can be enhanced substantially by an empirically based weighting procedure and that the proposed scoring algorithm may serve the MoCA's actual purpose as a screening tool in the detection of cognitive dysfunction in PD patients better than the original scoring of the MoCA. Further research with larger sample sizes is necessary to establish efficacy of the alternate scoring system