Frank Steigerwald

Most effective stimulation site in subthalamic deep brain stimulation for Parkinson's disease

The optimal stimulation site in subthalamic deep brain stimulation (STN‐DBS) was evaluated by correlation of the stereotactic position of the stimulation electrode with the electrophysiologically specified dorsal STN border. In a series of 25 electrodes, best clinical results with least energy consumption were found in contacts located in the dorsolateral border zone, whereas contacts within the subthalamic white matter, e.g., zona incerta, were significantly less effective. We suggest that the dorsolateral STN border should be covered by STN‐DBS.

Neuronal Activity of the Human Subthalamic Nucleus in the Parkinsonian and Nonparkinsonian State

We recorded resting-state neuronal activity from the human subthalamic nucleus (STN) during functional stereotactic surgeries. By inserting up to five parallel microelectrodes for single- or multiunit recordings and applying statistical spike-sorting methods, we were able to isolate a total of 351 single units in 65 patients with Parkinsons disease (PD) and 33 single units in 9 patients suffering from essential tremor (ET). Among these were 93 pairs of simultaneously recorded neurons in PD and 17 in ET, which were detected either by the same (n = 30) or neighboring microelectrodes (n = 80). Essential tremor is a movement disorder without any known basal ganglia pathology and with normal dopaminergic brain function. By comparing the neuronal activity of the STN in patients suffering from PD and ET we intended to characterize, for the first time, changes of basal ganglia activity in the human disease state that had previously been described in animal models of Parkinsons disease. We found a significant increase in the mean firing rate of STN neurons in PD and a relatively larger fraction of neurons exhibiting burstlike activity compared with ET. The overall proportion of neurons exhibiting intrinsic oscillations or interneuronal synchronization as defined by significant spectral peaks in the auto- or cross-correlations functions did not differ between PD and ET when considering the entire frequency range of 1-100 Hz. The distribution of significant oscillations across the theta (1-8 Hz), alpha (8-12 Hz), beta (12-35 Hz), and gamma band (>35 Hz), however, was uneven in ET and PD, as indicated by a trend in Fishers exact test (P = 0.05). Oscillations and pairwise synchronizations within the 12- to 35-Hz band were a unique feature of PD. Our results confirm the predictions of the rate model of Parkinsons disease. In addition, they emphasize abnormalities in the patterning and dynamics of neuronal discharges in the parkinsonian STN, which support current concepts of abnormal motor loop oscillations in Parkinsons disease.

Stimulation site within the MRI-defined STN predicts postoperative motor outcome.

High‐frequency stimulation of the subthalamic nucleus (STN‐HFS) is highly effective in treating motor symptoms in Parkinsons disease (PD) and medication side effects as well as in improving quality of life. Despite preoperative screening for patients as eligible candidates for this treatment, electrode position may furthermore influence treatment quality. Here, we investigated the relationship between the anatomical site of stimulation within the MRI‐defined STN and the outcome of PD patients after STN‐HFS. In 30 PD patients with bilateral STN stimulation, we retrospectively defined the boundaries of the STN within the axial target plane of the stereotactic T2‐weighted MRI and determined the position of the active electrode contact in relation to the border of the STN. The position of the active contact within the STN was the only variable to predict the outcome of STN stimulation. In contrast, covariates such as age, disease duration, symptom severity, and response to levodopa had no effect. The lateral position of the stimulation contact within the STN led to significantly better clinical improvement, lower stimulation parameters, and less need for postoperative dopaminergic medication. The outcome of patients with stimulation contacts within the medial region of the STN was significantly worse. Precise targeting of the lateral region of the STN is essential for achieving sufficient stimulation efficacy. Preoperative T2‐weighted MRI might be a useful component of the targeting procedure to improve the outcome of PD patients.

Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia

Objectives: Deep brain stimulation of the internal pallidum (GPi-DBS) is an established therapeutic option in treatment-refractory dystonia, and the identification of factors predicting surgical outcome is needed to optimize patient selection. Methods: In this retrospective multicenter study, GPi-DBS outcome of 8 patients with DYT6, 9 with DYT1, and 38 with isolated dystonia without known monogenic cause (non-DYT) was assessed at early (1–16 months) and late (22–92 months) follow-up using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores. Results: At early follow-up, mean reduction of dystonia severity was greater in patients with DYT1 (BFMDRS score: −60%) and non-DYT dystonia (−52%) than in patients with DYT6 dystonia (−32%; p = 0.046). Accordingly, the rate of responders was considerably lower in the latter group (57% vs >90%; p = 0.017). At late follow-up, however, GPi-DBS resulted in comparable improvement in all 3 groups (DYT6, −42%; DYT1, −44; non-DYT, −61%). Additional DBS of the same or another brain target was performed in 3 of 8 patients with DYT6 dystonia with varying results. Regardless of the genotype, patients with a shorter duration from onset of dystonia to surgery had better control of dystonia postoperatively. Conclusions: Long-term GPi-DBS is effective in patients with DYT6, DYT1, and non-DYT dystonia. However, the effect of DBS appears to be less predictable in patients with DYT6, suggesting that pre-DBS genetic testing and counseling for known dystonia gene mutations may be indicated. GPi-DBS should probably be considered earlier in the disease course. Classification of evidence: This study provides Class IV evidence that long-term GPi-DBS improves dystonia in patients with DYT1, DYT6, and non-DYT dystonia.

Short pulse width widens the therapeutic window of subthalamic neurostimulation

We explored the impact of pulse durations <60 μsec on the therapeutic window of subthalamic neurostimulation in Parkinsons disease. Current thresholds for full rigidity control and first muscle contractions were evaluated at pulse durations between 20 and 120 μsec during a monopolar review session in four patients. The average therapeutic window was 2.16 mA at 60 μsec, which proportionally increased by 182% at 30 μsec, while decreasing by 46% at 120 μsec. Measured chronaxies and model data suggest, that pulse durations <60 μsec lead to a focusing of the neurostimulation effect on smaller diameter axons close to the electrode while avoiding stimulation of distant pyramidal tract fibers.

Directional deep brain stimulation of the subthalamic nucleus: A pilot study using a novel neurostimulation device

A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation.

Stimulation of subthalamic fibre tracts reduces dyskinesias in STN-DBS.

Rarely, the postoperative management of patients with subthalamic deep brain stimulation (STN‐DBS) is complicated by pharmacologically intractable dyskinesias. Here we report that in three of these patients additional stimulation of a proximal contact located within the subthalamic white matter may lead to a significant reduction of dyskinesias associated with STN‐DBS. We propose that pallidofugal fiber tracts play a major role in the etiopathology of dyskinesias and their blockade through DBS may explain our observations.

Effect of propofol anesthesia on pallidal neuronal discharges in generalized dystonia

We present the results of continuous microelectrode recordings from individual pallidal neurons in patients with idiopathic torsion dystonia under different levels of propofol anesthesia. Neither the estimated plasma concentration of propofol nor the level of consciousness had a consistent effect on abnormally low neuronal firing rates. Our data support the pathophysiological model of a decreased basal ganglia output in dystonia and argue against a possible pharmacological artifact.

Electrode implantation for deep brain stimulation in dystonia: a fast spin-echo inversion-recovery sequence technique for direct stereotactic targeting of the GPI.

OBJECTIVE Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment for medically refractory primary dystonia. We present our technique for direct preoperative visualization of the target using a fast spin-echo inversion-recovery (FSE-IR) sequence. METHODS Twenty-three consecutive patients (mean age 41 years, range 9-68 years, male to female ratio 11:12) with severe dystonia were operated using a combination of FSE-IR imaging for direct visualization of the globus pallidus internus with stereotactic, gadolinium-enhanced T1-MPRage images. The complete procedure, including stereotactic MRI, was performed under general anesthesia with propofol and remifentanyl. We used multichannel microdrive systems (Medtronic; Alpha-Omega) to introduce up to five parallel microelectrodes for microelectrode recordings (MER) and test stimulation with the central trajectory directed at the anatomically predefined target. The initial standard coordinates in relation to the mid-commissural point (mid-AC-PC) were as follows: lateral 21 mm, anterior 3 mm, and inferior 2 mm, which were then adapted to the individual case based on direct visualization of the target area and further refined by the intraoperative neurophysiology. RESULTS In ten patients (43%) atlas-based standard coordinates were modified based on the direct visualization of the GPi in the FSE-IR images (bilaterally in seven patients, unilaterally in three). The modified targets ranged from 18.5 to 23.5 mm (mean 20.76 mm) laterally, 1-7 mm (mean 2.75 mm) anteriorly and 1-2 mm (mean 1.95 mm) inferiorly to the mid-AC-PC. We implanted the permanent electrode based on the results of MER and intraoperative stimulation performed to determine the threshold for pyramidal tract responses on the central trajectory in 67%, medially in 16%, anteriorly in 11%, laterally in 4%, dorsally in 2%. The procedure resulted in excellent clinical benefits (average reduction of the Burke-Fahn-Marsden Dystonia Rating Score (BFMDRS) or the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) were respectively 65.9%, range 20.9-91.4%) within the first year after surgery. Safety was demonstrated by the absence of intracranial bleeding or other surgical complications causing neurological morbidity. CONCLUSION Inversion recovery sequences are an excellent tool for direct visualization of the GPi. These images can be fused to stereotactic MRI or CCT and may help to improve anatomical targeting of the GPi for the implantation of DBS electrodes.

Subthalamic deep brain stimulation increases pallidal firing rate and regularity

While high-frequency stimulation of the subthalamic nucleus (STN-HFS) is highly effective in the treatment of Parkinsons disease (PD), the mechanisms underlying its therapeutic action remain unclear. Here, we report changes of single-neuron pallidal activity during STN-HFS in a parkinsonian patient. STN-HFS increased firing rate in both segments of the pallidum. Neurons displayed time-locked responses to stimulation pulses, with an early excitation followed by inhibition and late excitation. Finally, pallidal neurons fired more regularly during STN-HFS. The time-locked responses and increased firing regularity may override abnormally patterned pallidal activity, and thereby significantly contribute to the clinical efficacy of STN-HFS in PD.