Microelectrode recordings of single unit neuronal activity were used during stereotactic surgery to define the subthalamic nucleus for chronic deep brain stimulation in the treatment of Parkinson's disease. By using five parallel trajectories, often two to three microelectrodes allow us to recognize subthalamic nucleus (STN) neuronal activity. STN neurons were easily distinguished from cells of the overlying zona incerta and the underlying substantia nigra. During a typical exploratory track, we can observe a very low background noise in the zona incerta and almost complete absence of single cell recording. Penetration of the electrode tip into the STN is characterized by a sudden increase in background activity and single cell activity of spontaneously active neurons. The exit of electrode tip out of the STN corresponds to a decrease in background noise and a loss of single cell activity. Spontaneous neuronal activity increases again when the electrode tips enters the substantia nigra pars reticulata (SNr); however, the activity is less rich than in the STN, indicating a more cell-sparse nucleus. STN neurons are characterized by a mean firing rate of 42.30 +/- 22.00 spikes/sec (mean +/- SD). The STN cells exhibited irregular or bursty discharge pattern. The pattern of single cell activity in the SNr is a more regular tonic activity that can easily be distinguished from the bursting pattern in the STN. The most useful criteria to select a trajectory are (1) the length of an individual trajectory displaying typical STN activity, (2) the bursting pattern of activity, and (3) motor responses typical of the sensorimotor part of the nucleus. In conclusion, microelectrode recording of the subthalamic area improves the accuracy of targeting the STN.

Gait and balance disturbances typically emerge in advanced Parkinson’s disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson’s Disease Rating Scale score (Scale II items 13–15, Scale III items 27–31) at ‘3-week follow-up’. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the ‘3-week follow-up’. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no ‘global’ effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial.

During the last decade deep brain stimulation (DBS) has become a routine method for the treatment of advanced Parkinson's disease (PD), leading to striking improvements in motor function and quality of life of PD patients. It is associated with minimal morbidity. The rationale of targeting specific structures within basal ganglia such as the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is strongly supported by the current knowledge of the basal ganglia pathophysiology, which is derived from extensive experimental work and which provides the theoretical basis for surgical therapy in PD. In particular, the STN has advanced to the worldwide most used target for DBS in the treatment of PD, due to the marked improvement of all cardinal symptoms of the disease. Moreover on-period dyskinesias are reduced in parallel with a marked reduction of the equivalent daily levodopa dose following STN-DBS. The success of the therapy largely depends on the selection of the appropriate candidate patients and on the precise implantation of the stimulation electrode, which necessitates careful imaging-based pre-targeting and extensive electrophysiological exploration of the target area. Despite the clinical success of the therapy, the fundamental mechanisms of high-frequency stimulation are still not fully elucidated. There is a large amount of evidence from experimental and clinical data that stimulation frequency represents a key factor with respect to clinical effect of DBS. Interestingly, high-frequency stimulation mimics the functional effects of ablation in various brain structures. The main hypotheses for the mechanism of high-frequency stimulation are: (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion-channels, (2) jamming of information by imposing an efferent stimulation-driven high-frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, (4) synaptic failure by stimulation-induced neurotransmitter depletion. As the hyperactivity of the STN is considered a functional hallmark of PD and as there is experimental evidence for STN-mediated glutamatergic excitotoxicity on neurons of the substantia nigra pars compacta (SNc), STN-DBS might reduce glutamatergic drive, leading to neuroprotection. Further studies will be needed to elucidate if STN-DBS indeed provides a slow-down of disease progression.

The role of the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinson's disease is still unclear. Using microrecordings, we investigated the changes occurring in PPN neurons after lesions of the substantia nigra compacta (SNc) and the role of the subthalamic nucleus (STN) in these changes. In normal rats the firing rate of PPN neurons was 10.6 +/- 1.4 spikes/s, the majority of neurons (91%) having a regular firing pattern, 6% irregular and 3% in bursts. In rats with 6-hydroxydopamine lesions of the SNc, the firing rate increased significantly to 18.3 +/- 3.0 spikes/s compared with normal rats. In addition, the firing pattern changed significantly: 70% of the neurons discharged regularly, 27% irregularly and 3% in bursts. In rats with ibotenic acid lesions of the STN, the firing rate decreased significantly to 7.2 +/- 0.9 spikes/s and the firing pattern changed significantly: 50% of the neurons discharged regularly, 43% irregularly and 7% in bursts. The rats with combined SNc and STN lesions showed no change in the firing rate (8.5 +/- 1.0 spikes/s) compared to normal rats. The firing pattern changed significantly: 69% of the cells discharged regularly, 26% irregularly and 5% in bursts. These findings demonstrate that PPN neurons are overactive and more irregular in the 6-hydroxydopamine-lesioned rats, suggesting the implication of this nucleus in the pathophysiology of parkinsonism. Moreover, the fact that STN lesions induced a reduction in the firing rate of the PPN in normal rats and a normalization of the firing rate in rats with 6-hydroxydopamine lesions suggests that this nucleus is under major control of the STN.

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Severe gait disturbances in idiopathic Parkinson's disease (PD) are observed in up to 80% of all patients in advanced disease stages [1,2] with an important impact on quality of life [3][4][5]. While segmental symptoms generally respond well to dopaminergic medication and high-frequent deep brain stimulation of the subthalamic nucleus (STN-DBS), treatment of gait disturbances often remains unsatisfactory [5][6][7]. DBS of the pedunculopontine area is currently under investigation to treat gait disturbances and imbalance in PD; however, appropriate targeting and patient selection remain controversial [8][9][10]. Here, we describe a novel stimulation paradigm of simultaneous stimulation on distant electrode contacts located in the STN and the caudal border zone between the STN and substantia nigra pars reticulata (SNr) in a patient with a severe hypokinetic gait disturbance.A 72-year-old female patient with PD (Hoehn & Yahr IV, disease duration 20 years) with severe dopaminergic motor fluctuations including wearing off, peak-dose dyskinesias since 2007, and severe hypokinetic gait disturbance was referred to our center for deep brain stimulation and, therefore, considered for STN-DBS. A quadripolar electrode (type 3389, Medtronic, Minneapolis, MN, USA) was inserted into each STN and connected to an implantable pulse stimulator (Activa PC, Medtronic, Minneapolis, MN, USA). Localizations of the active electrode contacts were determined from the postoperative MR imaging and co-registration between pre-and postoperative imaging.Stimulation pulses can be delivered more selectively on distant contacts of a lead using a novel paradigm of the socalled 'interleaved pulses', i.e., impulses are delivered simultaneously on two different contacts in alternating order (e.g., 125 Hz on each contact). Importantly, each of the contacts can be programmed with specific parameters (e.g., amplitude, pulse width). Short-term effects of three different stimulator settings on a timed walking test [11] were tested 6 months after DBS surgery after 30 minutes of constant settings: (1) stimulation off [StimOff], (2) conventional stimulation on proximal STN contacts [STNmono], and (3) combined [STN ? SNr] using interleaving pulses on contacts located in both the STN area and the caudal border zone of STN and SNr (detailed parameters in Table 1). Dopaminergic medications were withdrawn overnight. In order to limit the patient's knowledge of the current stimulator settings, DBS was switched on and off several times before the final parameters were maintained. Further follow-up examinations on both [STNmono] and [STN ? SNr] were performed after 2 weeks of constant stimulation on either setting. The freezing of gait questionnaire (FOG-Q) [12], PD-Q 39, and axial UPDRS subscores (UPDRS II, items 13-15 and Electronic supplementary material The online version of this article (

The differential diagnosis of tremor is mainly based on clinical criteria.Nevertheless, these criteria are in some cases not sufficient to differentiate between different tremor forms. Long-term EMG has proven to be a valid and reliable method for the quantification of pathological tremors. The aim of the study was to develop a long-term EMG-based automated analysis procedure that separates parkinsonian tremor from essential tremor. Using longterm EMG tremor was recorded in 45 consecutive patients, 26 with Parkinson's disease (PD) and 19 with essential tremor (ET). Eight tremor parameters were generated automatically. By stepwise backward regression a subset of these criteria was extracted to achieve an automated classification of the tremor by a mathematical model. The obtained model was then tested on a new group of 13 patients in early stages of the disease. Significant differences between groups were found for tremor occurrence, tremor asymmetry, mean tremor frequency and standard deviation of phase of antagonistic muscles. Due to data overlap a classification of the two tremor forms was not possible based on a single tremor parameter. Using logistic regression, a linear formula based on the three parameters tremor occurrence, mean tremor frequency and standard deviation of phase was established and predicted the correct diagnosis in 93% of patients. The validation of the model on the new group of patients in early stages of the tremor disease yielded a correct diagnosis in 100% of cases. We conclude that long-term EMG recording allows a rater-independent classification of parkinsonian versus essential tremor.