Sorin Breit

Intraoperative microrecordings of the subthalamic nucleus in Parkinson's disease

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 Parkinsons 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.

Deep brain stimulation

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.

Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat

The role of the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinsons 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.

Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial

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.

Effects of 6-hydroxydopamine-induced severe or partial lesion of the nigrostriatal pathway on the neuronal activity of pallido-subthalamic network in the rat.

The origin of changes in the neuronal activity of the globus pallidus (GP) and the subthalamic nucleus (STN) in animal models of Parkinsons disease (PD) is still controversial. The aim of the study was to investigate the neuronal activity of STN and GP neurons under urethane anesthesia in an early and in an advanced stage PD rat model. 6-Hydroxydopamine (6-OHDA) injection into the striatum induced a partial lesion of dopamine cells in the substantia nigra pars compacta (SNc) and fibers in the striatum. The GP firing rate decreased significantly with no significant change of the pattern. 6-OHDA injection into the SNc induced a total or subtotal lesion without any change in the firing rate and patterns of GP neurons. Concerning the STN, after partial lesion, the firing rate remained unchanged but the firing pattern significantly changed towards a more irregular and bursty pattern. In rats with total or subtotal lesion of the SNc the firing rate increased significantly and the relative amount of tonic neurons significantly decreased. Our results demonstrate that neuronal reactivity in the basal ganglia network considerably differs in the early versus late stage model of PD. We showed that the pathological activity of STN neurons after severe lesion is not mediated by the GP. Moreover, the unchanged activity of GP neurons is likely to be a consequence of the STN hyperactivity. These data suggest that in the GP-STN-GP network, the excitatory influence of the STN-GP pathway overrides that of the GABAergic GP-STN pathway, questioning the classical model of basal ganglia organization.

Lesion of the pedunculopontine nucleus reverses hyperactivity of the subthalamic nucleus and substantia nigra pars reticulata in a 6-hydroxydopamine rat model

The pedunculopontine nucleus (PPN) and the subthalamic nucleus (STN) are reciprocally connected by excitatory projections. In the 6‐hydroxydopamine (6‐OHDA) rat model the PPN was found to be hyperactive. Similarly, the STN and the substantia nigra pars reticulata (SNr) showed increased activity in Parkinsons disease (PD) animal models. A lesion of the STN was shown to restore increased activity levels in the SNr of 6‐OHDA‐treated rats. As the STN and the PPN were reciprocally connected by excitatory projections and both structures were shown to be hyperactive in PD animal models, the present study was performed in order to investigate the changes in neuronal activity of the STN and SNr under urethane anesthesia after unilateral ibotenic acid lesioning of the PPN in animals with previous unilateral 6‐OHDA lesions of the substantia nigra pars compacta (SNc). The firing rate of STN neurons significantly increased from 10.3 ± 0.6 spikes/s (mean ± SEM) to 17.8 ± 1.8 spikes/s after SNc lesion and returned to normal levels of 10.8 ± 0.7 spikes/s after additional lesion of the PPN. Similarly, the firing rate of SNr neurons significantly increased from 19.0 ± 1.1 to 25.9 ± 1.4 spikes/s after SNc lesion, the hyperactivity being reversed after additional PPN lesion to 16.8 ± 1.2 spikes/s. The reversal of STN and SNr hyperactivity of 6‐OHDA‐treated rats by additional PPN lesion suggests an important modulatory influence of the PPN on STN activity. Moreover, these findings could indicate a new therapeutic strategy in PD by interventional modulation of the PPN.

Pretargeting for the implantation of stimulation electrodes into the subthalamic nucleus: a comparative study of magnetic resonance imaging and ventriculography.

OBJECTIVE: The optimal imaging modality for preoperative targeting of the subthalamic nucleus (STN) for high-frequency stimulation is controversially discussed. Commonly used methods were stereotactic magnetic resonance imaging (MRI), stereotactic ventriculography, and fusion between MRI and stereotactic computer tomography. All of these techniques not only have their own advantages but also specific limitations and drawbacks. The purpose of this study was to evaluate the accuracy of the preoperative MRI targeting as compared with ventriculography in terms of both the STN target as well as the internal landmarks. METHODS: Thirty patients with Parkinson’s disease who underwent bilateral surgery for STN–high-frequency stimulation received both stereotactic ventriculography and stereotactic MRI. The theoretical target was determined by each of these two imaging modalities. The final electrode placement was performed after extensive electrophysiological evaluation using microrecording and microstimulation. The real target was assumed to be given by the electrode contact with the best clinical result assessed by the United Parkinson’s Disease Rating Scale in the postoperative follow-up. In addition, the coordinates of the two landmarks, anterior commissure and posterior commissure, were determined using both imaging methods. RESULTS: The mean targeting error was 4.1 ± 1.7 mm (mean ± standard deviation) for MRI and 2.4 ± 1.1 mm for ventriculography (P < 0.0001). The mean target mismatch between the two imaging methods was 2.9 ± 1.2 mm. The length of the anterior commissure-posterior commissure distance differed significantly (P < 0.0001) between MRI (27.6 ± 1.6 mm) and ventriculography (25.0 ± 1.3 mm). The mismatch was mainly induced by an anterior diplacement of the anterior commissure by 1.9 ± 2.2 mm (P < 0.0001) in MRI determination, as compared with ventriculography. CONCLUSION: Our findings show that the indirect targeting of the STN using coordinates based on radiological landmarks is more accurate than the direct targeting using anatomic visualization of the target structure. Regardless of the imaging procedure, electrophysiological mapping is required for optimal electrode placement, although in 20% of cases, the target determined by MRI falls out of the radius explored by electrophysiology.

Unilateral lesion of the pedunculopontine nucleus induces hyperactivity in the subthalamic nucleus and substantia nigra in the rat

Recent data suggest a role for the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinsons disease. Although there is anatomical evidence that the PPN and the basal ganglia are reciprocally connected, the functional importance of these connections is poorly understood. Lesioning of the PPN was shown to induce akinesia in primates, whereas in the 6‐hydroxydopamine rat model the PPN was found to be hyperactive. As both nigrostriatal dopamine depletion and lesioning of the PPN were shown to induce akinesia and parkinsonism, the present study was performed in order to investigate the changes in neuronal activity of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) after unilateral ibotenic acid lesioning of the PPN and after unilateral 6‐hydroxydopamine lesioning of the substantia nigra pars compacta (SNc). The firing rate of STN neurones significantly increased from 10.2 ± 6.2 (mean ± SD) to 14.6 ± 11.7 spikes/s after lesion of the PPN and to 18.6 ± 14.5 spikes/s after lesion of the SNc. The activity of the SNr significantly increased from 19.6 ± 10.5 to 28.7 ± 13.4 spikes/s after PPN lesioning and to 23.5 ± 10.8 spikes/s after SNc lesioning. Furthermore, PPN lesion decreased the number of spontaneously firing dopaminergic SNc cells, while having no effect on their firing rate. The results of our study show that lesion of the PPN leads to hyperactivity of the STN and SNr, similar to the changes induced by lesion of the SNc. Moreover, the decreased activity of SNc cells observed after PPN lesion might be at the origin of activity changes in the STN and SNr.

Sustained improvement of obsessive–compulsive disorder by deep brain stimulation in a woman with residual schizophrenia

Co-occurrence of obsessive–compulsive disorder (OCD) and schizophrenia is not rare (Eisen et al., 1997). Given that the obsessional content is not related to psychotic subject matter, both disorders can be regarded as delimitable diagnostic entities (Bottas et al., 2005). Recently, a number of case reports and small case series have demonstrated that deep brain stimulation (DBS) targeting the fronto-striato-thalamic circuit can have beneficial effects on OCD (Abelson et al., 2005; Greenberg et al., 2006; Sturm et al., 2003). DBS treatment of patients with current or past psychotic disorders has not yet been reported. Here, we present a comprehensive clinical evaluation of a woman with intractable OCD and residual symptoms of schizophrenia that were treated with unilateral DBS of the right nucleus accumbens (NAc), including neuropsychological long-term follow-up, neurophysiological measurements and functional brain imaging. This 51-yr-old right-handed woman suffered from a severely disabling, chronic and intractable form of OCD with excessive hand washing, cleaning, rearrangement of objects and compulsory praying [Yale–Brown Obsessive Compulsive Scale (YBOCS) score 32/40, 1 month prior to treatment]. Psychosocial functioning as measured by the GAF (Global Assessment of Functioning) scale was severely impaired (31/100). The symptoms started during childhood and accumulated during her early twenties. Obsession consisted of preoccupation with thoughts about guilt and purgation. Later in the course of the disease, psychotic symptoms (delusions, hallucinations, disorganized behaviour) meeting DSM-IV criteria for schizophrenia occurred transiently. The remaining presence of a few odd beliefs, minor paranoid ideation and disorganized behaviour in an attenuated form that were unrelated to the obsessions and compulsions led to the diagnosis of residual schizophrenia according to DSM-IV using SCID (Structured Clinical …

Bilateral Changes in Neuronal Activity of the Basal Ganglia in the Unilateral 6-Hydroxydopamine Rat Model

The functional significance of the interhemispheric projections on the basal ganglia level is poorly understood. Insofar as the anatomical evidence for crossing projections between basal ganglia nuclei is sparse, whereas tracing studies demonstrated important crossing projections from the pedunculopontine nucleus (PPN) to the basal ganglia, it is suggested that the PPN might play a key role in interhemispheric regulation of basal ganglia activity. The present study was performed to assess changes in neuronal activity of ipsilateral and contralateral subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and PPN in the unilateral 6‐hydroxydopamine (6‐OHDA) rat model of advanced PD under urethane anesthesia. After unilateral lesioning of the SNc, the firing rate of contralateral STN neurons significantly increased from 10.9 ± 1.0 spikes/sec (mean ± SEM) to 16.3 ± 1.5 spikes/sec. Similarly, the firing rate of contralateral SNr neurons significantly increased from 19.4 ± 1.2 to 25.7 ± 1.9 spikes/sec, and the firing rate of contralateral PPN neurons significantly increased from 10.6 ± 0.8 to 13.9 ± 1.1 spikes/sec. The observed activity changes in contralateral STN, SNr, and PPN are similar to those induced in the corresponding nuclei of the hemisphere ipsilateral to the nigrostriatal degeneration. Based on previous, predominantly anatomical data, the results of the present study suggest that the PPN on the lesioned side is at the origin of changes in the activity of STN and SNr on the contralateral hemisphere, because of its crossing efferent projections.