Andreas Horn

Lead-DBS: a toolbox for deep brain stimulation electrode localizations and visualizations.

To determine placement of electrodes after deep brain stimulation (DBS) surgery, a novel toolbox that facilitates both reconstruction of the lead electrode trajectory and the contact placement is introduced. Using the toolbox, electrode placement can be reconstructed and visualized based on the electrode-induced artifacts on post-operative magnetic resonance (MR) or computed tomography (CT) images. Correct electrode placement is essential for efficacious treatment with DBS. Post-operative knowledge about the placement of DBS electrode contacts and trajectories is a promising tool for clinical evaluation of DBS effects and adverse effects. It may help clinicians in identifying the best stimulation contacts based on anatomical target areas and may even shorten test stimulation protocols in the future. Fifty patients that underwent DBS surgery were analyzed in this study. After normalizing the post-operative MR/CT volumes into standard Montreal Neurological Institute (MNI)-stereotactic space, electrode leads (n=104) were detected by a novel algorithm that iteratively thresholds each axial slice and isolates the centroids of the electrode artifacts within the MR/CT-images (MR only n=32, CT only n=10, MR and CT n=8). Two patients received four, the others received two quadripolar DBS leads bilaterally, summing up to a total of 120 lead localizations. In a second reconstruction step, electrode contacts along the lead trajectories were reconstructed by using templates of electrode tips that had been manually created beforehand. Reconstructions that were made by the algorithm were finally compared to manual surveys of contact localizations. The algorithm was able to robustly accomplish lead reconstructions in an automated manner in 98% of electrodes and contact reconstructions in 69% of electrodes. Using additional subsequent manual refinement of the reconstructed contact positions, 118 of 120 electrode lead and contact reconstructions could be localized using the toolbox. Taken together, the toolbox presented here allows for a precise and fast reconstruction of DBS contacts by proposing a semi-automated procedure. Reconstruction results can be directly exported to two- and three-dimensional views that show the relationship between DBS contacts and anatomical target regions. The toolbox is made available to the public in form of an open-source MATLAB repository.

Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements.

Deep brain stimulation of the globus pallidus internus alleviates involuntary movements in patients with dystonia. However, the mechanism is still not entirely understood. One hypothesis is that deep brain stimulation suppresses abnormally enhanced synchronized oscillatory activity within the motor cortico-basal ganglia network. Here, we explore deep brain stimulation-induced modulation of pathological low frequency (4-12 Hz) pallidal activity that has been described in local field potential recordings in patients with dystonia. Therefore, local field potentials were recorded from 16 hemispheres in 12 patients undergoing deep brain stimulation for severe dystonia using a specially designed amplifier allowing simultaneous high frequency stimulation at therapeutic parameter settings and local field potential recordings. For coherence analysis electroencephalographic activity (EEG) over motor areas and electromyographic activity (EMG) from affected neck muscles were recorded before and immediately after cessation of high frequency stimulation. High frequency stimulation led to a significant reduction of mean power in the 4-12 Hz band by 24.8 ± 7.0% in patients with predominantly phasic dystonia. A significant decrease of coherence between cortical EEG and pallidal local field potential activity in the 4-12 Hz range was revealed for the time period of 30 s after switching off high frequency stimulation. Coherence between EMG activity and pallidal activity was mainly found in patients with phasic dystonic movements where it was suppressed after high frequency stimulation. Our findings suggest that high frequency stimulation may suppress pathologically enhanced low frequency activity in patients with phasic dystonia. These dystonic features are the quickest to respond to high frequency stimulation and may thus directly relate to modulation of pathological basal ganglia activity, whereas improvement in tonic features may depend on long-term plastic changes within the motor network.

Cortico-pallidal oscillatory connectivity in patients with dystonia

Primary dystonia has been associated with an underlying dysfunction of a wide network of brain regions including the motor cortex, basal ganglia, cerebellum, brainstem and spinal cord. Dystonia can be effectively treated by pallidal deep brain stimulation although the mechanism of this effect is not well understood. Here, we sought to characterize cortico-basal ganglia functional connectivity using a frequency-specific measure of connectivity-coherence. We recorded direct local field potentials from the human pallidum simultaneously with whole head magnetoencephalography to characterize functional connectivity in the cortico-pallidal oscillatory network in nine patients with idiopathic dystonia. Three-dimensional cortico-pallidal coherence images were compared to surrogate images of phase shuffled data across patients to reveal clusters of significant coherence (family-wise error P < 0.01, voxel extent 1000). Three frequency-specific, spatially-distinct cortico-pallidal networks have been identified: a pallido-temporal source of theta band (4-8 Hz) coherence, a pallido-cerebellar source of alpha band (7-13 Hz) coherence and a cortico-pallidal source of beta band (13-30 Hz) coherence over sensorimotor areas. Granger-based directionality analysis revealed directional coupling with the pallidal local field potentials leading in the theta and alpha band and the magnetoencephalographic cortical source leading in the beta band. The degree of pallido-cerebellar coupling showed an inverse correlation with dystonic symptom severity. Our data extend previous findings in patients with Parkinsons disease describing motor cortex-basal ganglia oscillatory connectivity in the beta band to patients with dystonia. Source coherence analysis revealed two additional frequency-specific networks involving the temporal cortex and the cerebellum. Pallido-cerebellar oscillatory connectivity and its association with dystonic symptoms provides further confirmation of cerebellar involvement in dystonia that has been recently reported using functional magnetic resonance imaging and fibre tracking.

Deep Brain Recordings Using an Implanted Pulse Generator in Parkinson's Disease

Recent studies suggest that oscillatory beta activity could be used as a state biomarker in patients with Parkinsons disease for subthalamic closed‐loop stimulation with the intention of improving clinical benefit. Here we investigate the feasibility of subthalamic recordings via a novel chronically implanted pulse generator.

A single dual-stream framework for syntactic computations in music and language

This study is the first to compare in the same subjects the specific spatial distribution and the functional and anatomical connectivity of the neuronal resources that activate and integrate syntactic representations during music and language processing. Combining functional magnetic resonance imaging with functional connectivity and diffusion tensor imaging-based probabilistic tractography, we examined the brain network involved in the recognition and integration of words and chords that were not hierarchically related to the preceding syntax; that is, those deviating from the universal principles of grammar and tonal relatedness. This kind of syntactic processing in both domains was found to rely on a shared network in the left hemisphere centered on the inferior part of the inferior frontal gyrus (IFG), including pars opercularis and pars triangularis, and on dorsal and ventral long association tracts connecting this brain area with temporo-parietal regions. Language processing utilized some adjacent left hemispheric IFG and middle temporal regions more than music processing, and music processing also involved right hemisphere regions not activated in language processing. Our data indicate that a dual-stream system with dorsal and ventral long association tracts centered on a functionally and structurally highly differentiated left IFG is pivotal for domain-general syntactic competence over a broad range of elements including words and chords.

A localized pallidal physiomarker in cervical dystonia

Deep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinsons disease, a disease‐specific physiomarker was identified that is now used to investigate adaptive closed‐loop stimulation in first studies. In dystonia, such a physiomarker is missing.

Long term correlation of subthalamic beta band activity with motor impairment in patients with Parkinson’s disease

OBJECTIVES To investigate the long term association of subthalamic beta activity with parkinsonian motor signs. METHODS We recruited 15 patients with Parkinsons disease undergoing subthalamic DBS for local field potential recordings after electrode implantation, and at 3 and 8months post-operatively using the implantable sensing enabled Activa PC+S (Medtronic). Three patients dropped out leaving 12 patients. Recordings were conducted ON and OFF levodopa at rest. Beta (13-35Hz) peak amplitudes were extracted, compared across time points and correlated with UPDRS-III hemibody scores. RESULTS Peaks in the beta frequency band (13-35Hz) in the OFF medication state were found in all hemispheres. Mean beta activity was significantly suppressed by levodopa at all recorded time points (P<0.007) and individual beta power amplitude correlated with parkinsonian motor impairment across time points and dopaminergic states (pooled data; ρ=0.25, P<0.001). CONCLUSIONS Our results indicate that beta-activity is correlated with parkinsonian motor signs over a time period of 8months. SIGNIFICANCE Beta-activity may be a chronically detectable biomarker of symptom severity in PD that should be further evaluated under ongoing DBS.

Failure of Pallidal Deep Brain Stimulation in a Case of Rapid‐Onset Dystonia Parkinsonism (DYT12)

Rapid-onset dystonia parkinsonism (RDP) is a rare disorder characterized by a sudden onset of dystonic and parkinsonian symptoms. It is caused by a loss-of-function mutation in the a3-isoform gene, ATP1A3, which encodes the Na/K-ATPase a3-subunit (DYT12, OMIM 128235). The pathophysiological mechanism leading to abrupt onset of the extrapyramidal syndrome is unknown, and no treatment is available thus far. In a recent postmortem study, brains of DYT12 patients showed marked neuronal loss and gliosis throughout multiple nuclei of the basal ganglia, brainstem, and cerebellum, compared to nonaffected siblings. Here, we report on the results of bilateral pallidal DBS in a young man with sporadic RDP. A 22-year-old young male of European descent of nonconsanguineous parents with genetically proven heterozygote mutation of the ATP1A3 gene was admitted for further treatment options. He presented with generalized bradykinesia, more pronounced on the upper limbs, dystonic posturing of both hands, severe dysarthrophonia, and sardonic smiling (see Video 1) that had developed over 4 weeks at the age of 17. After the initial period of deterioration that had been preceded by a slight dystonic impairment of the fine motor skills of the right hand for 2 to 3 months, the clinical symptoms have remained stable over a 6-year follow-up period. An alcoholic binge might have been a triggering event for symptom onset. Neuropsychological testing and psychiatric evaluation were normal. Cranial MRI, cerebrospinal fluid, copper, slit lamp, EEG, and nerve conduction velocity were unremarkable. There was no family history for movement disorders. The patient was born at term with normal development of motor and cognitive milestones. At the ages of 11 and 13, he experienced a seizure, but no further treatment was started. At that time, he also presented with moderate learning problems at school. Treatment with levodopa (up to 600 mg/day over 2 months) and anticholinergic medication (30 mg/day of trihexyphenidyl over 3–4 months) did not improve motor symptoms. Because of severe motor impairment and after education of the patient and relatives about the experimental character of the procedure, DBS was offered for further treatment. Bilateral DBS electrodes (3389; Medtronic, Minneapolis, MN) were implanted into the internal part of the globus pallidus (GPi). Postoperative MRI confirmed correct placement of the distal two contacts in GPi. Monopolar pallidal stimulation was used with standard parameters (90 ls, 130 Hz, up to 2.8 V) at distal contacts for at least 3 months without significant effect on motor symptoms (preoperative BurkeFahn-Marsden Dystonia Rating Scale: 28/120; postoperative best setting at 1-year follow-up: 26/120; UPDRS-III preoperative: 25/108; postoperative best score: 23/108). Minor reduction in dystonic symptoms during DBS had no functional significance. Further testing of different stimulation parameters included modulation of stimulation frequency (30, 60, and 180 Hz) and pulse width (210 and 450 ls) as well as bipolar stimulation and stimulation at two contacts per electrode and interleaving stimulation for at least 24 hours each (up to 4 weeks), which revealed no beneficial effects on motor symptoms. Stimulation at proximal contacts (probably located in the external part of the globus pallidus) increased bradykinesia (UPDRS-III OFF-DBS: 24/108; ON-DBS: 28/108) without improvement of dystonia. At 1and 2-year follow-up, the patient reported no functional improvement and no change of subjective well-being on the 39-item Parkinson’s Disease Questionnaire. Eighteen months after implantation of the DBS system, the patient experienced another seizure and anticonvulsant therapy with lamotrigine was started. We present a case of pallidal DBS in a patient with genetically proven DYT12. Pallidal DBS is an effective therapy for primary dystonia and idiopathic Parkinson’s disease. However, the clinical response is far more limited in patients with symptomatic dystonia (such as cerebral palsy) or hereditary neurodegenerative disease with dystonia. In our patient, the GPi target was chosen because of dystonic involvement of the arms and hands and its potential benefit on bradykinesia. Two cases

Neuroanatomical Characteristics Associated With Response to Deep Brain Stimulation of the Nucleus Basalis of Meynert for Alzheimer's Disease

First reports on the application of deep brain stimulation (DBS) of the Nucleus basalis of Meynert (NBM) showed feasibility and safety of the intervention in patients with Alzheimer´s disease. However, clinical effects vary and the mechanisms of actions are still not well understood. The aim of this study was to characterize neuroimaging changes that are associated with the responsiveness to the treatment.

Dopamine-dependent scaling of subthalamic gamma bursts with movement velocity in patients with Parkinson's disease

Gamma synchronization increases during movement and scales with kinematic parameters. Here, disease-specific characteristics of this synchronization and the dopamine-dependence of its scaling in Parkinson’s disease are investigated. In 16 patients undergoing deep brain stimulation surgery, movements of different velocities revealed that subthalamic gamma power peaked in the sensorimotor part of the subthalamic nucleus, correlated positively with maximal velocity and negatively with symptom severity. These effects relied on movement-related bursts of transient synchrony in the gamma band. The gamma burst rate highly correlated with averaged power, increased gradually with larger movements and correlated with symptom severity. In the dopamine-depleted state, gamma power and burst rate significantly decreased, particularly when peak velocity was slower than ON medication. Burst amplitude and duration were unaffected by the medication state. We propose that insufficient recruitment of fast gamma bursts during movement may underlie bradykinesia as one of the cardinal symptoms in Parkinson’s disease.