Premotor cortical beta synchronization and the network neuromodulation of externally paced finger tapping in Parkinson's disease.

Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13-30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance.

Subthalamic and nigral neurons are differentially modulated during parkinsonian gait.

The parkinsonian gait disorder and freezing of gait are therapeutically demanding symptoms with considerable impact on quality of life. The aim of this study was to assess the role of subthalamic and nigral neurons in the parkinsonian gait control using intraoperative microelectrode recordings of basal ganglia neurons during a supine stepping task. Twelve male patients (56 ± 7 years) suffering from moderate idiopathic Parkinson's disease (disease duration 10 ± 3 years, Hoehn and Yahr stage 2), undergoing awake neurosurgery for deep brain stimulation, participated in the study. After 10 s resting, stepping at self-paced speed for 35 s was followed by short intervals of stepping in response to random 'start' and 'stop' cues. Single- and multi-unit activity was analysed offline in relation to different aspects of the stepping task (attentional 'start' and 'stop' cues, heel strikes, stepping irregularities) in terms of firing frequency, firing pattern and oscillatory activity. Subthalamic nucleus and substantia nigra neurons responded to different aspects of the stepping task. Of the subthalamic nucleus neurons, 24% exhibited movement-related activity modulation as an increase of the firing rate, suggesting a predominant role of the subthalamic nucleus in motor aspects of the task, while 8% of subthalamic nucleus neurons showed a modulation in response to the attentional cues. In contrast, responsive substantia nigra neurons showed activity changes exclusively associated with attentional aspects of the stepping task (15%). The firing pattern of subthalamic nucleus neurons revealed gait-related firing regularization and a drop of beta oscillations during the stepping performance. During freezing episodes instead, there was a rise of beta oscillatory activity. This study shows for the first time specific, task-related subthalamic nucleus and substantia nigra single-unit activity changes during gait-like movements in humans with differential roles in motor and attentional control of gait. The emergence of perturbed firing patterns in the subthalamic nucleus indicates a disrupted information transfer within the gait network, resulting in freezing of gait.

Combined Short-Pulse and Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor.

OBJECTIVE: Novel deep brain stimulation (DBS) systems allow directional and short-pulse stimulation to potentially improve symptoms and reduce side effects. The aim of this study was to investigate the effect of short-pulse and directional stimulation, in addition to a combination of both, in the ventral intermediate thalamus (VIM)/posterior subthalamic area (PSA) on tremor and stimulation-induced side effects in patients with essential tremor. MATERIALS AND METHODS: We recruited 11 patients with essential tremor and VIM/PSA-DBS. Tremor severity (Fahn-Tolosa-Marin), ataxia (International Cooperative Ataxia Rating Scale), and paresthesia (visual analog scale) were assessed with conventional omnidirectional and directional stimulation with pulse width of 60 µs and 30 µs. RESULTS: All stimulation conditions reduced tremor. The best directional stimulation with 60 µs reduced more tremor than did most other stimulation settings. The best directional stimulation, regardless of pulse width, effectively reduced stimulation-induced ataxia compared with the conventional stimulation (ring 60 µs) or worst directional stimulation with 60 µs. All new stimulation modes reduced occurrence of paresthesia, but only the best directional stimulation with 30 µs attenuated paresthesia compared with the conventional stimulation (ring 60 µs) or worst directional stimulation with 60 µs. The best directional stimulation with 30 µs reduced tremor, ataxia, and paresthesia compared with conventional stimulation in most patients. Correlation analyses indicated that more anterior stimulation sites are associated with stronger ataxia reduction with directional 30 µs than with conventional 60 µs stimulation. CONCLUSION: Directional and short-pulse stimulation, and a combination of both, revealed beneficial effects on stimulation-induced adverse effects.

Face-induced gamma oscillations and event-related potentials in patients with epilepsy: an intracranial EEG study.

BACKGROUND: To examine the pathological effect of a mesial temporal seizure onset zone (SOZ) on local and inter-regional response to faces in the amygdala and other structures of the temporal lobe. METHODS: Intracranial EEG data was obtained from the amygdala, hippocampus, fusiform gyrus and parahippocampal gyrus of nine patients with drug-refractory epilepsy during visual stimulation with faces and mosaics. We analyzed event-related potentials (ERP), gamma frequency power, phase-amplitude coupling and phase-slope-index and compared the results between patients with versus without a mesial temporal SOZ. RESULTS: In the amygdala and fusiform gyrus, faces triggered higher ERP amplitudes compared to mosaics in both patient groups and higher gamma power in patients without a mesial temporal SOZ. In the hippocampus, famous faces triggered higher gamma power for both groups combined but did not affect ERPs in either group. The differentiated ERP response to famous faces in the parahippocampal gyrus was more pronounced in patients without a mesial temporal SOZ. Phase-amplitude coupling and phase-slope-index results yielded bidirectional modulation between amygdala and fusiform gyrus, and predominately unidirectional modulation between parahippocampal gyrus and hippocampus. CONCLUSIONS: A mesial temporal SOZ was associated with an impaired response to faces in the amygdala, fusiform gyrus and parahippocampal gyrus in our patients. Compared to this, the response to faces in the hippocampus was impaired in patients with, as well as without, a mesial temporal SOZ. Our results support existing evidence for face processing deficits in patients with a mesial temporal SOZ and suggest the pathological effect of a mesial temporal SOZ on the amygdala to play a pivotal role in this matter in particular.

Temporal evolution of beta bursts in the parkinsonian cortical and basal ganglia network.

Beta frequency oscillations (15 to 35 Hz) in cortical and basal ganglia circuits become abnormally synchronized in Parkinson's disease (PD). How excessive beta oscillations emerge in these circuits is unclear. We addressed this issue by defining the firing properties of basal ganglia neurons around the emergence of cortical beta bursts (ß bursts), transient (50 to 350 ms) increases in the beta amplitude of cortical signals. In PD patients, the phase locking of background spiking activity in the subthalamic nucleus (STN) to frontal electroencephalograms preceded the onset and followed the temporal profile of cortical ß bursts, with conditions of synchronization consistent within and across bursts. Neuronal ensemble recordings in multiple basal ganglia structures of parkinsonian rats revealed that these dynamics were recapitulated in STN, but also in external globus pallidus and striatum. The onset of consistent phase-locking conditions was preceded by abrupt phase slips between cortical and basal ganglia ensemble signals. Single-unit recordings demonstrated that ensemble-level properties of synchronization were not underlain by changes in firing rate but, rather, by the timing of action potentials in relation to cortical oscillation phase. Notably, the preferred angle of phase-locked action potential firing in each basal ganglia structure was shifted during burst initiation, then maintained stable phase relations during the burst. Subthalamic, pallidal, and striatal neurons engaged and disengaged with cortical ß bursts to different extents and timings. The temporal evolution of cortical and basal ganglia synchronization is cell type-selective, which could be key for the generation/ maintenance of excessive beta oscillations in parkinsonism.

Phase-Dependent Suppression of Beta Oscillations in Parkinson's Disease Patients.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for "closed-loop" stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain.

Parkinson's disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input in vivo.

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35 Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

A New Stimulation Mode for Deep Brain Stimulation in Parkinson's Disease: Theta Burst Stimulation.

BACKGROUND AND OBJECTIVES: The purpose of this study was to assess efficacy and safety of a new patterned theta burst stimulation algorithm of DBS with the aim of expanding the therapeutic window and clinical benefit in PD. METHODS: In this single-center, randomized, double-blind, clinical short-term trial, unilateral conventional subthalamic DBS was compared with unilateral patterned stimulation algorithms with intraburst high- or low-frequency theta burst stimulation in 17 PD patients. RESULTS: There were no serious adverse events with theta burst stimulation. During monopolar review, conventional subthalamic DBS and high-frequency theta burst stimulation were comparable, but low-frequency theta burst stimulation differed by requiring higher stimulation amplitudes for symptom reduction, but a larger therapeutic window. High- and low-frequency theta burst stimulation with adapted stimulation amplitude were effective in PD symptom reduction with differential effects on akinesia and tremor, depending on the theta burst stimulation mode. CONCLUSIONS: Theta burst stimulation is a safe and effective stimulation mode with potential future application opportunities. © 2020 International Parkinson and Movement Disorder Society.

Decision-making in temporal lobe epilepsy surgery based on invasive stereo-electroencephalography (sEEG).

In medical refractory temporal lobe epilepsy (TLE), the epileptogenic zone can be difficult to identify and therefore difficult to treat, especially in the absence of clear MRI pathologies and specific results from presurgical evaluation. Invasive monitoring with stereo-electroencephalography (sEEG) is a tool for a better determination of the epileptogenic zone. Here, we investigate the impact of sEEG on decision-making in temporal lobe epilepsy surgery. We reviewed patients with TLE who underwent further investigation with sEEG in our epilepsy unit. We examined specifically how sEEG findings influenced our decision regarding indication for a surgical procedure and resection volume. From 2013 to 2017, we performed 152 temporal resections in epilepsy patients. Twenty-one of these patients were designated for further preoperative investigation with sEEG due to incongruent findings in presurgical evaluation. Six patients were implanted bitemporally. In five cases, the hypothesis for the epileptogenic zone and localization had to be changed due to sEEG findings and resulted in a different tailored resection than intended. In three cases, sEEG findings led to the cancelation of the originally intended temporal resection as the epileptogenic zone was not definable or bilateral. In another three cases, the prognosis for reduction of seizures postoperatively had to be reduced due to the sEEG findings. However, the resection was performed after interdisciplinary discussion and informed consent of the patient. The examination by sEEG led to a change of plan for further treatment in 13 patients (61.9%) suffering TLE in total. Invasive monitoring with sEEG electrodes had a strong impact on decision-making for further treatment in patients suffering from temporal lobe epilepsy with incongruent findings in presurgical examination designated for epilepsy surgery. This applies to resection volumes as well as to prediction of seizure outcome.

Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson's disease patients.

Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinson's disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities, inter spike intervals and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Furthermore, inter spike interval frequencies peaked in the same frequencies for which PAC was observed. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinson's disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS. SIGNIFICANCE STATEMENT: Identifying biomarkers for closed-loop deep brain stimulation (DBS) has become an increasingly important issue in Parkinson's Disease (PD) research. Two such biomarkers, phase-amplitude coupling (PAC) and beta-bursts, recorded from the implanted electrodes in subthalamic nucleus in PD patients, correlate with motor impairment. However, the physiological basis of PAC, and it relationship to beta bursts, is unclear. We provide multiple lines of evidence that PAC in the human STN reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with the duration of beta-bursts. This suggests that beta-bursts capture increased subthalamic input/output synchronisation and provides new insights in PD pathology with direct implications for closed-loop DBS therapy strategies.

Electrical Stimulation of the Anterior Thalamus for Epilepsy: Clinical Outcome and Analysis of Efficient Target.

OBJECTIVE: Deep brain stimulation (DBS) of the anterior thalamic complex (ANT) is an adjunctive therapy for pharmacoresistant epilepsy. To define the most efficient target in DBS for epilepsy, we investigate clinical data, position of leads, usability of atlas data compared to electric field modeling based on programming parameters. METHODS: Data from ten consecutive patients who underwent ANT-DBS were analyzed. The mammillothalamic tract (MTT), an internal landmark for direct stereotactic targeting, was segmented from MRI. Centers of stimulation were determined and their positions relative to ventricles and the MTT were analyzed. Two 3D thalamus atlases were transformed to segmented patient's thalami and proportions of activated nuclei were calculated. RESULTS: Our data indicate higher response rates with a center of stimulation 5 mm lateral to the wall of the third ventricle (R2 for reduction of focal seizure frequency and distance to the wall of the third ventricle = 0.48, p = 0.026). For reduction of focal seizures, a strong positive correlation with the dorsal distance to the midcommissural plane was found (R2 = 0.66, p = 0.004). In one 3D atlas, stimulation of internal medullary lamina (IML) correlated strongly positive with response rates, which, however, did not reach statistical significance (R2 = 0.69, p = 0.17 for tonic-clonic seizures). All electrical fields covered the diameter of the MTT. The position of the MTT in the thalamus was highly variable (range: x-coordinate 4.0 to 7.3 mm, y-coordinate -1.3 to 5.1 mm in AC-PC space). CONCLUSIONS: The distance of the active contact to the lateral wall of the third ventricle, MTT and the ventrodorsal distance to midcommissural plane appear to be relevant for optimal target planning. For reduction of focal seizure frequency, we found best response rates with a center of stimulation 5 mm lateral to the wall of the third ventricle, and a lead tip 10 mm dorsal of the midcommissural plane.

Spatio-temporal dynamics of cortical drive to human subthalamic nucleus neurons in Parkinson's disease.

Pathological synchronisation of beta frequency (12-35Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement. STN neurons lagged cortical signals recorded over midline (over premotor cortices) and frontal (over prefrontal cortices) with stable time delays, consistent with strong corticosubthalamic drive, and many neurons maintained these dynamics during movement. In contrast, most STN neurons desynchronised from lateral EEG signals (over primary motor cortices) during movement and those that did not had altered phase relations to the cortical signals. The strength of synchronisation between STN units and midline EEG in the high beta range (25-35Hz) correlated positively with the severity of akinetic-rigid motor symptoms across patients. Together, these results suggest that sustained synchronisation of STN neurons to premotor-cortical beta oscillations play an important role in disrupting the normal coding of movement in PD.

The Pioneering and Unknown Stereotactic Approach of Roeder and Orthner from Göttingen. Part II: Long-Term Outcome and Postmortem Analysis of Bilateral Pallidotomy in the Pre-Levodopa Era.

Before the advent of levodopa, pallidotomy was initially the most effective treatment for Parkinson disease, but it was soon superseded by thalamotomy. It is widely unknown that, similar to Leksell, 2 neurologists from Göttingen, Orthner and Roeder, perpetuated pallidotomy against the mainstream of their time. Postmortem studies demonstrated that true posterior and ventral pallidoansotomy sparing the overwhelming mass of the pallidum was accomplished. This was due to a unique and individually tailored stereotactic technique even allowing bilateral staged pallidotomies. In 1962, the long-term effects (3-year follow-up on average) of the first 18 out of 36 patients with staged bilateral pallidotomies were reported in great detail. Meticulous descriptions of each case indicate long-term improvements in parkinsonian rigidity and associated pain, as well as posture, gait, and akinesia (e.g., improved repetitive movements and arm swinging). Alleviation of tremor was found to require larger lesions than needed for suppression of rigidity. No improvement in speech, drooling, or seborrhea was observed. By 1962, the team had operated 13 patients with postencephalitic oculogyric crises with remarkable results (mean follow-up: 5 years). They also described alleviation of nonparkinsonian hyperkinetic disorders (e.g., hemiballism and chorea) with pallidotomy. The reported rates for surgical mortality and other complications had been remarkably low, even if compared to those reported after the revival of pallidotomy by Laitinen in the post-levodopa era. This applies also to bilateral pallidotomy performed with a positive risk-benefit ratio that has remained unparalleled to date. The intricate history of pallidotomy for movement disorders is incomplete without an appreciation of the achievements of the Göttingen group.

The Pioneering and Unknown Stereotactic Approach of Roeder and Orthner from Göttingen. Part I. Surgical Technique for Tailoring Individualized Stereotactic Lesions.

During the 1950s through the 1970s, Hans Orthner and Fritz Roeder, two German neurologists from Göttingen, developed a sophisticated technique to perform functional stereotactic surgery with outstanding accuracy. They introduced direct air ventriculography performed in the same surgical session as the ablative stereotactic procedure. For individualized surgical targeting, Orthner prepared a stereotactic atlas (>60 brains) with an ingenious brain-slicing device, the Göttinger macrotome. Brains were grouped based on similarity of six different head and ventricle measurements. A brain cluster representing the best match for a patient was selected for stereotactic targeting. Stereotactic lesions were tailored in an individual manner and shaped by stringing together multiple small coagulations following intraoperative test stimulation. This was achieved from a single probe trajectory by using well-engineered string electrodes with calibrated curving and involved laborious calculations. Only high-frequency thermocoagulation was regarded as appropriate for lesioning. With this meticulous technique, the most advanced stereotactic procedures were performed, including bilateral pallidotomy that ultimately could be restricted to the ansa lenticularis and ventromedial hypothalamotomy, the most delicate stereotactic operation performed to date. Outside Göttingen, this technique has only been used by Prof. Dieter Müller in Hamburg, Germany. This elaborate stereotactic approach is widely unknown and deserves to be discussed in a historical context.

Activity parameters of subthalamic nucleus neurons selectively predict motor symptom severity in Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, ≥ 10 single units and/or multi-units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinson's Disease Rating Scale subscores (OFF medication). The mean spectral power at sub-beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype.

Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients.

In view of the regulatory function of the thalamus in the sleep-wake cycle, the impact of deep brain stimulation (DBS) of the anterior nucleus thalami (ANT) on sleep was assessed in a small consecutive cohort of epilepsy patients with standardized polysomnography (PSG). In nine patients treated with ANT-DBS (voltage 5 V, frequency 145 Hz, cyclic mode), the number of arousals during stimulation and nonstimulation periods, neuropsychiatric symptoms (npS), and seizure frequency were determined. Electroclinical arousals were triggered in 14.0 to 67.0% (mean 42.4 ± SD 16.8%) of all deep brain stimuli. Six patients reported npS. Nocturnal DBS voltages were reduced in eight patients (one patient without npS refused) and PSGs were repeated. Electroclinical arousals occurred between 1.4 and 6.7 (mean 3.3 ± 1.7) times more frequently during stimulation periods compared to nonstimulation periods; the number of arousals positively correlated with the level of DBS voltage (range 1 V to 5 V) (Spearman's rank coefficient 0.53121; p < 0.05). No patient experienced seizure deterioration and four patients reported remission of npS. This case-cohort study provides evidence that ANT-DBS interrupts sleep in a voltage-dependent manner, thus putatively resulting in an increase of npS. Reduction of nocturnal DBS voltage seems to lead to improvement of npS without hampering efficacy of ANT-DBS.

Deep brain stimulation of the ventrolateral thalamic base and posterior subthalamic area in dystonic head tremor.

Dystonic head tremor (DHT) is characterized by head tremor associated with cervical dystonia (CD). Deep brain stimulation (DBS) can be considered when local treatment with botulinum toxin or oral medication has failed. However, there is lack of data regarding the optimal target structure for surgery in DHT.DBS of the ventrolateral (VL) thalamus is an established treatment option for medically refractory tremor. Tremor suppression is described as being most effective when stimulating at the inferior thalamic base and within the posterior subthalamic area (PSA). Moreover, there is surgical evidence from the pre-DBS era that both lesions and high-frequency stimulation of the PSA improve CD. Based on these observations, we performed DBS in three patients with DHT, placing the proximal contacts of the electrodes into the inferior base of VL thalamic nuclei and the distal contacts into the adjacent PSA. Chronic stimulation improved not only head tremor but also CD. These findings suggest that DBS at the base of VL thalamus and the adjacent PSA should undergo further investigation as a potential target for patients with DHT.

STN stimulation in general anaesthesia: evidence beyond 'evidence-based medicine'.

Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson's disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient.

Incomplete tumour control following DNA vaccination against rat gliomas expressing a model antigen.

BACKGROUND: Vaccination against tumour-associated antigens is one approach to elicit anti-tumour responses. We investigated the effect of polynucleotide (DNA) vaccination using a model antigen (E. coli lacZ) in a syngeneic gliosarcoma model (9L). METHODS: Fisher 344 rats were vaccinated thrice by intramuscular injection of a lacZ-encoding or a control plasmid in weekly intervals. One week after the last vaccination, lacZ-expressing 9L cells were implanted into the striatum. RESULTS: After 3 weeks, in lacZ-vaccinated animals the tumours were significantly smaller than in control-vaccinated animals. In cytotoxic T cell assays lysis rates of >50 % could only be observed in a few of the lacZ-vaccinated animals. This response was directed against lacZ-expressing and parental 9L cells but not against syngeneic MADB 106 adenocarcinoma cells. In Elispot assays interferon-γ production was observed upon stimulation with 9LlacZ and 9L wild-type but not MADB 106 cells. This response was higher for lacZ-immunized animals. All animals revealed dense infiltrates with CD8+ lymphocytes and, to a lesser extent, with NK cells. CD25-staining indicated cells possibly associated with the maintenance of peripheral tolerance to self-antigens. All tumours were densely infiltrated by microglia consisting mostly of ramified cells. Only focal accumulation of macrophage-like cells expressing ED1, a marker for phagocytic activity, was observed. CONCLUSION: Prophylactic DNA vaccination resulted in effective but incomplete suppression of brain tumour formation. Mechanisms other than cytotoxic T cell responses as measured in the generally used in vitro assays appear to play a role in tumour suppression.

Comparison of subthalamic unilateral and bilateral theta burst deep brain stimulation in Parkinson's disease.

High-frequency, conventional deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) is usually applied bilaterally under the assumption of additive effects due to interhemispheric crosstalk. Theta burst stimulation (TBS-DBS) represents a new patterned stimulation mode with 5 Hz interburst and 200 Hz intraburst frequency, whose stimulation effects in a bilateral mode compared to unilateral are unknown. This single-center study evaluated acute motor effects of the most affected, contralateral body side in 17 PD patients with unilateral subthalamic TBS-DBS and 11 PD patients with bilateral TBS-DBS. Compared to therapy absence, both unilateral and bilateral TBS-DBS significantly improved (p < 0.05) lateralized Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) scores. Bilateral TBS-DBS revealed only slight, but not significant additional effects in comparison to unilateral TBS-DBS on total lateralized motor scores, but on the subitem lower limb rigidity. These results indicate that bilateral TBS-DBS has limited additive beneficial effects compared to unilateral TBS-DBS in the short term.