Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

Defining a role for the subthalamic nucleus within operative theoretical models of subcortical participation in language

Objective:To investigate the effects of bilateral, surgically induced functional inhibition of the subthalamic nucleus (STN) on general language, high level linguistic abilities, and semantic processing skills in a group of patients with Parkinson’s disease. Methods:Comprehensive linguistic profiles were obtained up to one month before and three months after bilateral implantation of electrodes in the STN during active deep brain stimulation (DBS) in five subjects with Parkinson’s disease (mean age, 63.2 years). Equivalent linguistic profiles were generated over a three month period for a non-surgical control cohort of 16 subjects with Parkinson’s disease (NSPD) (mean age, 64.4 years). Education and disease duration were similar in the two groups. Initial assessment and three month follow up performance profiles were compared within subjects by paired t tests. Reliability change indices (RCI), representing clinically significant alterations in performance over time, were calculated for each of the assessment scores achieved by the five STN-DBS cases and the 16 NSPD controls, relative to performance variability within a group of 16 non-neurologically impaired adults (mean age, 61.9 years). Proportions of reliable change were then compared between the STN-DBS and NSPD groups. Results:Paired comparisons within the STN-DBS group showed prolonged postoperative semantic processing reaction times for a range of word types coded for meanings and meaning relatedness. Case by case analyses of reliable change across language assessments and groups revealed differences in proportions of change over time within the STN-DBS and NSPD groups in the domains of high level linguistics and semantic processing. Specifically, when compared with the NSPD group, the STN-DBS group showed a proportionally significant (p

Confirmation of functional zones within the human subthalamic nucleus: patterns of connectivity and sub-parcellation using diffusion weighted imaging.

The subthalamic nucleus (STN) is a small, glutamatergic nucleus situated in the diencephalon. A critical component of normal motor function, it has become a key target for deep brain stimulation in the treatment of Parkinson's disease. Animal studies have demonstrated the existence of three functional sub-zones but these have never been shown conclusively in humans. In this work, a data driven method with diffusion weighted imaging demonstrated that three distinct clusters exist within the human STN based on brain connectivity profiles. The STN was successfully sub-parcellated into these regions, demonstrating good correspondence with that described in the animal literature. The local connectivity of each sub-region supported the hypothesis of bilateral limbic, associative and motor regions occupying the anterior, mid and posterior portions of the nucleus respectively. This study is the first to achieve in-vivo, non-invasive anatomical parcellation of the human STN into three anatomical zones within normal diagnostic scan times, which has important future implications for deep brain stimulation surgery.

Prévalence des troubles de l'humeur dans la maladie de Parkinson traitée par stimulation cérébrale profonde [Prevalence of mood disorders in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation].

Subthalamic nucleus deep brain stimulation (STN-DBS) is a recognized treatment for advanced and severe forms of Parkinson's Disease. The procedure improves motor signs and often allows a reduction of the medication. The impact of the procedure on cognitive and neuropsychiatric signs of the disease is more debated and there is an international consensus for the need of a multidisciplinary evaluation of patients undergoing such programs, including a neuropsychiatric assessment. We present a review of the literature as well as the experience at our centre focused on the short and long term outcome on mood following STN-DBS.

Structural and Resting State Functional Connectivity of the Subthalamic Nucleus: Identification of Motor STN Parts and the Hyperdirect Pathway.

Deep brain stimulation (DBS) for Parkinson's disease often alleviates the motor symptoms, but causes cognitive and emotional side effects in a substantial number of cases. Identification of the motor part of the subthalamic nucleus (STN) as part of the presurgical workup could minimize these adverse effects. In this study, we assessed the STN's connectivity to motor, associative, and limbic brain areas, based on structural and functional connectivity analysis of volunteer data. For the structural connectivity, we used streamline counts derived from HARDI fiber tracking. The resulting tracks supported the existence of the so-called "hyperdirect" pathway in humans. Furthermore, we determined the connectivity of each STN voxel with the motor cortical areas. Functional connectivity was calculated based on functional MRI, as the correlation of the signal within a given brain voxel with the signal in the STN. Also, the signal per STN voxel was explained in terms of the correlation with motor or limbic brain seed ROI areas. Both right and left STN ROIs appeared to be structurally and functionally connected to brain areas that are part of the motor, associative, and limbic circuit. Furthermore, this study enabled us to assess the level of segregation of the STN motor part, which is relevant for the planning of STN DBS procedures.

Subthalamic nucleus deep brain stimulation for Parkinson's disease : "Are we where we think we are ?

ABSTRACT High frequency electrical deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a worldwide recognized therapy for the motor symptoms of Parkinson's disease in fluctuating patients who are progressively disabled despite medical treatment adjustments. However, such improvements emerge despite a lack of understanding of either the precise role of STN in human motor control or the mechanism(s) of action of DBS. Through the question "are we where we think we are", this thesis is first dedicated to the control of the position of the preoperatively defined target and of the implanted electrodes on magnetic resonance imaging (MRI). This anatomical approach will provide a way to identify more precisely the structure(s) involved by electrical stimulation. Then, a study of the correlation existing between the position of the preoperative target and the position of the electrode is performed. In this part, a unique opportunity is given to identify factors that may affect these correlation results. Finally, the whole work represents a « quality assessment » of the crucial steps of STN DBS: first, the target and the implanted electrode localisation procedures that have been developed in collaboration with the Radiological department; second the implantation procedure that has been performed nowadays on more than 50 parkinsonian patients in the Neurosurgical department of the Centre Hospitalier Universitaire Vaudois in collaboration with the Neurological department. This work is especially addressed to the multidisciplinary medical team involved in the surgical treatment of movement disorders, including also neurophysiologists, neuropsychologists and psychiatrists. RESUME La stimulation électrique à haute fréquence du noyau sous-thalamique est à ce jour mondialement reconnue pour le traitement des symptômes moteurs de la maladie de Parkinson chez des patients sévèrement atteints et chez qui la réponse fluctuante au traitement médicamenteux ne peut être améliorée de façon satisfaisante. Cependant, les résultats observés surviennent malgré une compréhension approximative et controversée du rôle réel du noyau sous-thalamique dans le contrôle du mouvement volontaire aussi bien que des mécanismes d'action de la stimulation cérébrale profonde. A travers la question « sommes-nous où nous pensons être », cette thèse est tout d'abord consacrée à l'étude du contrôle de la position de la cible définie avant l'intervention et de la position des électrodes implantées sur l'imagerie par résonance magnétique (IRM). Cette approche anatomique permettra d'identifier plus précisément la (les) structure(s) influencées par la stimulation électrique. Ensuite, une étude de la corrélation existant entre la position de la cible préopératoire et la position des électrodes implantées est effectuée. Elle a pour but de mettre en évidence les facteurs influençant les résultats de cette corrélation. Enfin, le travail dans son ensemble est un « contrôle de qualité » des étapes cruciales de la stimulation du noyau sous-thalamique : premièrement, des méthodes de localisation de la cible et des électrodes implantées effectuées sur IRM, développées en collaboration avec le service de Radiologie ; deuxièmement, de la méthode d'implantation utilisée à ce jour chez plus de 50 patients dans le service de Neurochirurgie du Centre Hospitalier Universitaire Vaudois en collaboration avec le service de Neurologie. Ce travail s'adresse spécialement aux équipes médicales pluridisciplinaires impliquées dans le traitement chirurgical des mouvements anormaux, incluant également des neurophysiologistes, des neuropsychologues et des psychiatres.

An active contour-based atlas registration model applied to automatic subthalamic nucleus targeting on MRI: method and validation.

This paper presents a new non parametric atlas registration framework, derived from the optical flow model and the active contour theory, applied to automatic subthalamic nucleus (STN) targeting in deep brain stimulation (DBS) surgery. In a previous work, we demonstrated that the STN position can be predicted based on the position of surrounding visible structures, namely the lateral and third ventricles. A STN targeting process can thus be obtained by registering these structures of interest between a brain atlas and the patient image. Here we aim to improve the results of the state of the art targeting methods and at the same time to reduce the computational time. Our simultaneous segmentation and registration model shows mean STN localization errors statistically similar to the most performing registration algorithms tested so far and to the targeting expert's variability. Moreover, the computational time of our registration method is much lower, which is a worthwhile improvement from a clinical point of view.

Do we need to revise the tripartite subdivision hypothesis of the human subthalamic nucleus (STN)? Response to Alkemade and Forstmann.

Recently in this journal, Alkemade and Forstmann again challenged the evidence for a tripartite organisation to the subthalamic nucleus (STN) (Alkemade & Forstmann 2014). Additionally, they raised specific issues with the earlier published results using 3T MRI to perform in vivo diffusion weighted imaging (DWI) based segmentation of the STN (Lambert et al. 2012). Their comments reveal a common misconception related to the underlying methodologies used, which we clarify in this reply, in addition to highlighting how their current conclusions are synonymous with our original paper. The ongoing debate, instigated by the controversies surrounding STN parcellation, raises important implications for the assumptions and methodologies employed in mapping functional brain anatomy, both in vivo and ex vivo, and reveals a fundamental emergent problem with the current techniques. These issues are reviewed, and potential strategies that could be developed to manage them in the future are discussed further.

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

Bilateral high-frequency stimulation of the subthalamic nucleus on attentional performance: transient deleterious effects and enhanced motivation in both intact and parkinsonian rats.

It is now well established that subthalamic nucleus high-frequency stimulation (STN HFS) alleviates motor problems in Parkinson's disease. However, its efficacy for cognitive function remains a matter of debate. The aim of this study was to assess the effects of STN HFS in rats performing a visual attentional task. Bilateral STN HFS was applied in intact and in bilaterally dopamine (DA)-depleted rats. In all animals, STN HFS had a transient debilitating effect on all the variables measured in the task. In DA-depleted rats, STN HFS did not alleviate the deficits induced by the DA lesion such as omissions and latency to make correct responses, but induced perseverative approaches to the food magazine, an indicator of enhanced motivation. In sham-operated controls, STN HFS significantly reduced accuracy and induced perseverative behaviour, mimicking partially the effects of bilateral STN lesions in the same task. These results are in line with the hypothesis that STN HFS only partially mimics inactivation of STN produced by lesioning and confirm the motivational exacerbation induced by STN inactivation.

Features for detection of Parkinson's disease tremor from local field potentials of the subthalamic nucleus

Deep Brain Stimulation (DBS) is a treatment routinely used to alleviate the symptoms of Parkinson's disease (PD). In this type of treatment, electrical pulses are applied through electrodes implanted into the basal ganglia of the patient. As the symptoms are not permanent in most patients, it is desirable to develop an on-demand stimulator, applying pulses only when onset of the symptoms is detected. This study evaluates a feature set created for the detection of tremor - a cardinal symptom of PD. The designed feature set was based on standard signal features and researched properties of the electrical signals recorded from subthalamic nucleus (STN) within the basal ganglia, which together included temporal, spectral, statistical, autocorrelation and fractal properties. The most characterized tremor related features were selected using statistical testing and backward algorithms then used for classification on unseen patient signals. The spectral features were among the most efficient at detecting tremor, notably spectral bands 3.5-5.5 Hz and 0-1 Hz proved to be highly significant. The classification results for determination of tremor achieved 94% sensitivity with specificity equaling one.

Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knock-out mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

Bilateral subthalamic nucleus stimulation for generalized dystonia after bilateral pallidotomy

Background: Thalamotomies and pallidotomies were commonly performed before the deep brain stimulation (DBS) era. Although ablative procedures can lead to significant dystonia improvement, longer periods of analysis reveal disease progression and functional deterioration. Today, the same patients seek additional treatment possibilities. Methods: Four patients with generalized dystonia who previously had undergone bilateral pallidotomy came to our service seeking additional treatment because of dystonic symptom progression. Bilateral subthalamic nucleus DBS (B-STN-DBS) was the treatment of choice. The patients were evaluated with the BurkeFahnMarsden Dystonia Rating Scale (BFMDRS) and the Unified Dystonia Rating Scale (UDRS) before and 2 years after surgery. Results: All patients showed significant functional improvement, averaging 65.3% in BFMDRS (P = .014) and 69.2% in UDRS (P = .025). Conclusions: These results suggest that B-STN-DBS may be an interesting treatment option for generalized dystonia, even for patients who have already undergone bilateral pallidotomy. (c) 2012 Movement Disorder Society

Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease: Concept and standards of the EARLYSTIM-study

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for advanced Parkinson's disease (PD) with disabling motor complications. However, stimulation may be beneficial at an earlier stage of PD when motor fluctuations and dyskinesia are only mild and psychosocial competence is still maintained. The EARLYSTIM trial was conducted in patients with recent onset of levodopa-induced motor complications (<3 years) whose social and occupational functioning remained preserved. This is called 'early' here. The study was a randomized, multicenter, bi-national pivotal trial with a 2 year observation period. Quality of life was the main outcome measure, and a video-based motor score was a blinded secondary outcome of the study. Motor, neuropsychological, psychiatric and psychosocial aspects were captured by established scales and questionnaires. The patient group randomized here is the earliest in the disease course and the youngest recruited in controlled DBS trials so far. The methodological innovation for DBS-studies of this study lies in novel procedures developed and used for monitoring best medical treatment, neurosurgical consistency, best management of stimulation programming, blinded video assessment of motor disability, and prevention of suicidal behaviors.