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PubMed2005

Usefulness of an intraoperative electrophysiological navigator system for subthalamic nucleus surgery in Parkinson's disease.

OBJECTS: The characteristics and benefits are presented of an intraoperative neurophysiological navigator computerized system developed in our center (Columbus-Track 1.0) that helps the surgical team in neuronal identification and in strategy processes in subthalamic nucleus surgery for Parkinson's disease (PD). METHODS: The navigator consists of three assembled parts: (1) neuronal identification, based on wavelet processing, filtering and gaussian characteristics of the signal; (2) track identification, based on anatomical coincidence, somatomotor response and microstimulation quotient, and (3) strategy, coordinating correction for the next track. A retrospective comparative study was performed with 15 consecutive PD patients (30 targets) operated without the system and the next 15 consecutive patients operated with the aid of the system. With the aid of the computerized navigation system, a significant reduction in the number of tracks was observed (t = -2.503, p = 0.0015), with a mean difference of 1.2 tracks per hemisphere. A non-significant reduction in the total intervention time was also observed, with a mean difference of 20 min per hemisphere (t = -1.418, p = 0.161). CONCLUSIONS: The intraoperative computerized navigation system can aid the surgical team in better identifying the neuronal signal and in defining the optimal track to achieve the target.

Humans↗
PubMed2002

Localization of clinically effective stimulating electrodes in the human subthalamic nucleus on magnetic resonance imaging.

OBJECT: The authors sought to determine the location of deep brain stimulation (DBS) electrodes that were most effective in treating Parkinson disease (PD). METHODS: Fifty-four DBS electrodes were localized in and adjacent to the subthalamic nucleus (STN) postoperatively by using magnetic resonance (MR) imaging in a series of 29 patients in whom electrodes were implanted for the treatment of medically refractory PD, and for whom quantitative clinical assessments were available both pre- and postoperatively. A novel MR imaging sequence was developed that optimized visualization of the STN. The coordinates of the tips of these electrodes were calculated three dimensionally and the results were normalized and corrected for individual differences by using intraoperative neurophysiological data (mean 5.13 mm caudal to the midcommissural point [MCP], 8.46 mm inferior to the anterior commissure-posterior commissure [AC-PC], and 10.2 mm lateral to the midline). Despite reported concerns about distortion on the MR image, reconstructions provided consistent data for the localization of electrodes. The neurosurgical procedures used, which were guided by combined neuroimaging and neurophysiological methods, resulted in the consistent placement of DBS electrodes in the subthalamus and mesencephalon such that the electrode contacts passed through the STN and dorsally adjacent fields of Forel (FF) and zona incerta (ZI). The mean location of the clinically effective contacts was in the anterodorsal STN (mean 1.62 mm posterior to the MCP, 2.47 mm inferior to the AC-PC, and 11.72 mm lateral to the midline). Clinically effective stimulation was most commonly directed at the anterodorsal STN, with the current spreading into the dorsally adjacent FF and ZI. CONCLUSIONS: The anatomical localization of clinically effective electrode contacts provided in this study yields useful information for the postoperative programming of DBS electrodes.

Adult↗
PubMed2001

Deep brain stimulation for the treatment of Parkinson's disease: subthalamic nucleus versus globus pallidus internus.

OBJECTIVES: Deep brain stimulation of the basal ganglia has become a promising treatment option for patients with Parkinson's disease who have side effects from drugs. Which is the best target-globus pallidus internus (GPi) or subthalamic nucleus (STN)-is still a matter of discussion. The aim of this prospective study is to compare the long term effects of GPi and STN stimulation in patients with severe Parkinson's disease. PATIENTS AND METHODS: Bilateral deep brain stimulators were implanted in the GPi in six patients and in the STN in 12 patients with severe Parkinson's disease. Presurgery and 3, 6, and 12 months postsurgery patients were scored according to the CAPIT protocol. RESULTS: Stimulation of the STN increased best Schwab and England scale score significantly from 62 before surgery to 81 at 12 months after surgery; GPi stimulation did not have an effect on the Schwab and England scale. Stimulation of the GPi reduced dyskinesias directly whereas STN stimulation seemed to reduce dyskinesias by a reduction of medication. Whereas STN stimulation increased the unified Parkinson's disease rating scale (UPDRS) motor score, GPi stimulation did not have a significant effect. Fluctuations were reduced only by STN stimulation and STN stimulation suppressed tremor very effectively. CONCLUSION: Stimulation of the GPi reduces medication side effects, which leads to a better drug tolerance. There was no direct improvement of bradykinesia or tremor by GPi stimulation. Stimulation of the STN ameliorated all parkinsonian symptoms. Daily drug intake was reduced by STN stimulation. The STN is the target of choice for treating patients with severe Parkinson's disease who have side effects from drugs.

Aged↗
PubMed2002

Visualisation of the subthalamic nucleus: a multiple sequential image fusion (MuSIF) technique for direct stereotaxic localisation and postoperative control.

A novel multiple, sequential image fusion (MuSIF) procedure merging stereotaxic CT with frameless magnetic resonance imaging (MRI) is used since June 2000 to visualise and directly localise the subthalamic nucleus (STN) on T2 images. In 13 consecutive Parkinson's cases, intraoperative recording and stimulation verified bilateral electrode implantation guided by fused T2 images. In 85% of sides, final implantation opted for visualised target track. Implanted electrode position on postoperative T2 images matched planned target. Clinical follow-up reproduces literature's best results. This MuSIF technique, effective for direct STN targeting, has practical advantages: MRI can be performed regardless of surgery time; regular MR scanning to correct real image distortion is unneeded; and the need for multiple localising tracks is reduced by enabling us to account for each patient's STN anatomy.

Electrodes, Implanted↗
PubMed2006

Quantification and visualization of the three-dimensional inconsistency of the subthalamic nucleus in the Schaltenbrand-Wahren brain atlas.

The Schaltenbrand-Wahren (SW) brain atlas has many limitations: the major two are three-dimensional (3D) inconsistency and spatial sparseness. In this work, we quantify and visualize the 3D inconsistency of the subthalamic nucleus (STN). The STN 3D models, 3D-A, 3D-C and 3D-S, are reconstructed from the SW axial, coronal, and sagittal microseries, respectively, by using a shape-based (NURBS) approach. All three models are placed in the SW coordinate system and compared quantitatively in terms of location (centroids), size (volumes), shape (normalized eigenvalues), orientation (eigenvectors), and mutual spatial relationships (overlaps and inclusions). Analysis is done in 3D within each orientation and across them. A dedicated tool is developed for quantitative validation of 3D modeling. The average error achieved is 0.088 mm, which is at the resolution limit of the digital SW atlas. The reconstructed 3D STN models differ in location, size, shape, orientation, overlap size, and inclusion rate. The 3D-S volume is 1.27 times larger than that of 3D-A and 1.38 times larger than that of 3D-C. The highest overlap size is found between 3D-A and 3D-S. The highest inclusion rates of 52.5 and 66.6% are for 3D-A and 3D-S. 3D-C has the lowest overlap size and results in the lowest inclusion rates (around 20-30%), meaning that 3D-C is substantially displaced in comparison to 3D-A and 3D-S. The lateral centroid coordinate of 3D-C is 9.18 mm while that of 3D-S is 12.17 mm. Each of the 3D models has some limitation: 3D-A in orientation, 3D-C in location, and 3D-S in shape realism. The STN in comparison to the actual almond is smaller, and relatively (i.e. normalized to the same height) 2.2-2.4 times wider and 3.7-5.5 times longer. 3D-C becomes more similar to 3D-S by scaling the SW coronal microseries laterally by 1.3257. Then the lateral coordinates of their centroids coincide, the difference between them in orientation is 0.11 mm, and 3D-S is only 1.06 times larger than the scaled 3D-C. This operation substantially improves registration of the SW atlas with the probabilistic functional atlas. However, 3D visualization shows that both 3D-S and scaled 3D-C models are heavily interwoven resulting in low inclusion rates of about 60%. The STN in the SW atlas shows severe 3D inaccuracy within each orientation and across them, and it has to be employed with great care and understanding of its limitations.

Anatomy, Artistic↗
PubMed1981

Connections of the subthalamic nucleus in the monkey.

Attempts were made to determine the afferent and efferent connections of the subthalamic nucleus (STN) in the monkey using retrograde and anterograde axoplasmic transport technics. Following HRP injections limited to the STN, label was transported to arrays of cells adjacent, and parallel, to the lateral medullary lamina in the rostral two thirds of the lateral pallidal segment (LPS). Only sparse label was transported to cells of the pedunculopontine nucleus (PPN) and the locus ceruleus (LC). No enzyme was transported across the midline, or to the striatum, medial pallidal segment (MPS), thalamus, substantia nigra (SN) or dorsal nucleus of the raphe (DNR). HRP injected into portions of both the STN and SN produced retrograde transport of the enzyme to cells in parallel arrays in the LPS related rostrocaudally to the injection site. Additional enzyme transport was seen in cells of the striatum, the DNR and the PPN. Only a few isolated cells were labeled in the sensorimotor cortex. Efferent connections of the STN were studied in monkeys in which [3H]amino acids were injected hydraulically or iontophoretically into the STN. Isotope traced in serial autoradiographs was distributed to: (1) both segments of the globus pallidus (GP) in arrays parallel to the medullary laminae, and (2) the pars reticulata of SN (SNpr). The greatest number of terminals was found in the MPS. Fibers from the rostral part of the STN descended along the dorsal border of the SN and projected ventrally to terminations in the SNpr. No isotope was transported across the midline, or to the striatum, thalamus, DNR or PPN. Isotope injected into both the STN and SN produced similar transport to the GP and transport via nigral efferent fibers to: (1) portions of the striatum, (2) specific thalamic nuclei (VAmc, VLm, DMpl), (3) deep and middle gray layers of the superior colliculus and (4) PPN. Control studies indicated that [3H]amino acids injected only into the SN were transported to PPN. HRP injected into PPN produced profuse retrograde transport in cells of the MPS and SNpr and distinct label in a few cells of the zona incerta and STN. These data suggest that the STN receives its major subcortical input from cell of the LPS arranged in arrays which have a rostrocaudal organization. No cells of the MPS or SN project to the STN. The output of the STN is to both segments of the GP and SNpr. Major subcortical projections to PPN arise from the MPS and SNpr, but afferents also arise from other sources. The major projection of PPN is to SN.

Animals↗
PubMed1993

Subthalamic nucleus lesion regularizes firing patterns in globus pallidus and substantia nigra pars reticulata neurons in rats.

Subthalamic nucleus lesion altered the statistical properties of the firing patterns of globus pallidus and substantia nigra pars reticulata neurons recorded in urethane anesthetized rats by increasing the proportion of cells in both structures that fired with a very highly regular pattern (from approximately 25% to approximately 50%). In all cases, the most regularly firing neurons fired at a higher mean rate than did more slowly firing neurons. In contrast, globus pallidus lesion shifted the pattern of substantia nigra neurons towards more irregular firing and induced a bursty pattern in two neurons.

Action Potentials↗
PubMed1999

Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms.

The purpose of the present study was to investigate whether the subthalamic nucleus (STN) was implicated in the glutamatergic compensatory mechanisms which have been shown to mask the parkinsonian motor abnormalities at the end of the presymptomatic period in experimental parkinsonism. Using multiunit electrophysiological recordings, we follow changes of activity occurring in the STN and in both the pars externalis and the pars internalis of the globus pallidus of monkeys chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), according to a protocol designed to mimic the gradual evolution of dopaminergic neuronal death. STN activity augmented significantly in the course of treatment, even before the first appearance of clinical signs (P < 0.01). This result would indicate that the STN, which increases its level of activity even before the end of the presymptomatic period, is principally responsible for the instigation of glutamatergic compensatory mechanisms which allow the maintenance of the striatal dopaminergic homeostasis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Long-term effect of electrostimulation of the subthalamic nucleus in bradykinetic-rigid Parkinson's disease.

The motor effects of unilateral stimulation of the subthalamic nucleus on hypokinesia were studied in two patients 58 and 52 years old, both modified Hoehn and Yahr 2.5, at 16 and 15 months after the implantation of a quadripolar electrode (Medtronic). Motor UPDRS, time in the pegboard test, walking time, tapping, and serial reaction times were recorded. Chronic unilateral stimulation was associated with reversible improvement of measures of reaction time and hypokinesia > 1 year after the stereotactic electrode implantation. The beneficial effect was mainly contralateral to the stimulation. However, improvement of axial functions was also observed (phonation, walking).

Dominance, Cerebral↗
PubMed1992

Excitotoxic acid lesions of the primate subthalamic nucleus result in transient dyskinesias of the contralateral limbs.

1. To examine the role of the subthalamic nucleus (STN) in the pathogenesis of dyskinesias, the STN was experimentally lesioned with fiber-sparing excitotoxins in two awake monkeys. 2. A combined recording-injection device was used to locate and lesion the STN accurately under physiological guidance. A small amount (1 microliters) of ibotenic acid (10 micrograms/microliters) or kainic acid (1 micrograms/microliters) was injected into each of four to seven target sites in the STN. Postmortem histology confirmed that lesions were confined to the STN, and the volume of each lesion at each site was 4-11% of the total volume of the nucleus. 3. Approximately 20 min after the end of each injection, the frequency of movements increased in the distal portions of the upper and lower limbs contralateral to the injection site. Severe dyskinesias, involving the proximal joints to a greater degree than the distal, developed in the contralateral limbs after 60-80 min and lasted < or = 4 h. The pattern of involvement and time course were similar after each lesion. In the days after the lesioning, only rare dyskinesias were observed in the contralateral hands and feet, typically occurring when the animals were stimulated. 4. Despite the severe dyskinesias, there was no obvious effect on voluntary movements such as grooming or reaching. 5. These results suggest that reduction of STN activity plays a role in the production of dyskinesias.

Animals↗
PubMed1995

In a rat model of parkinsonism, lesions of the subthalamic nucleus reverse increases of reaction time but induce a dramatic premature responding deficit.

Lesions of the subthalamic nucleus (STN) have been found to reduce the severe akinetic motor symptom produced in animal models of Parkinson's disease, such as in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or in monoamine-depleted rats. However, little is known about the effect of STN exclusion on subtle motor deficits induced by moderate dopaminergic lesions in complex motor tasks. The present study was thus performed on rats trained in a reaction time (RT) task known to be extremely sensitive to variations of dopamine transmission in the striatum. Animals were trained to release a lever after the onset of a visual stimulus within a time limit to obtain a food reward. Discrete dopamine depletion produced by infusing the neurotoxin 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal part of the striatum, produced motor initiation deficits which were revealed by an increase in the number of delayed responses (lever release after the time limit) and a lengthening of RTs. In contrast, bilateral excitotoxic lesion of the STN with ibotenic acid induced severe behavioral deficits which were opposite to those produced by the dopaminergic lesion, as shown by an increase in the number of premature responses (lever release before the onset of the visual stimulus) and a decrease of RTs. Surprisingly, the performance of the animals bearing a double lesion (striatal dopaminergic lesion followed 14 d later by STN ibotenic lesion) was still impaired 40 d after the ibotenic lesion. As expected, the 6-OHDA-induced motor initiation deficits were reversed by a subsequent STN lesion. However, the dramatic increase of premature responses contributing to major behavioral deficits induced by the STN lesion remained unchanged. Thus, the bilateral lesion of the STN was found to alleviate the motor deficits in this model of parkinsonism, but essentially produced over time, long lasting deficits that might be related to dyskinesia or cognitive impairment. The present results strongly support the recent concept of a predominant control of the STN on basal ganglia output structures.

Animals↗
PubMed2004

Very fast oscillations evoked by median nerve stimulation in the human thalamus and subthalamic nucleus.

Very fast oscillations (VFOs; 500-1,500 Hz) are associated with sensory-evoked potentials (SEPs), but their origin is unknown. To characterize the origins of VFOs, we studied 35 patients with deep brain stimulation (DBS) electrodes [15 with thalamic and 20 with the subthalamic nucleus (STN) electrodes]. We recorded median nerve stimulation-evoked SEPs from the thalamus and STN with microelectrodes during stereotactic surgery and from the contacts of the DBS electrodes postoperatively. We also examined the firing of individual neurons in thalamus in relation to the VFOs. In the thalamus, VFOs with frequencies around 1,000 Hz were superimposed on slow potentials. Both slow and fast SEP components showed phase reversals in the somatosensory thalamus [ventralis caudalis (Vc)]. Median nerve poststimulus time histograms showed that single thalamic neurons fired at preferred times at intervals between 0.8 to 1.2 ms that were synchronous with the VFOs, although the neurons fired only once or a few times per trial. In the STN, low-amplitude SEPs with VFOs were observed at a latency similar to the thalamic SEPs. The VFOs from STN probably represent volume conduction, possibly from the medial lemniscus. We conclude that the thalamic VFOs are generated within Vc and that they induce time-locked firing in a network of neurons.

Adult↗
PubMed2003

Variability in position of the subthalamic nucleus targeted by magnetic resonance imaging and microelectrode recordings as compared to atlas co-ordinates.

BACKGROUND: Traditional methods for localisation of target nuclei for deep brain stimulation (DBS) have used brain atlas co-ordinates for initial targeting. It is now possible to visualise the subthalamic nucleus (STN) on magnetic resonance imaging (MRI) and determine the individual variability of its position. METHODS: The present study was performed in patients undergoing STN DBS for Parkinson's disease. The STN was directly targeted from axially obtained MRI and verified with microelectrode recordings. Postoperatively, the most effective contact was identified for each patient, and its position was calculated. RESULTS: Fifty electrodes were inserted in 25 patients. The target position varied considerably in relation to the mid-commissural point. The mean effective contact position lies just dorsal to the location of the STN in a standard brain atlas. CONCLUSION: The STN varies in position, and can be accurately targeted from MRI alone.

Adult↗
PubMed2004

Subthalamic nucleus deep brain stimulation for parkinson's disease after successful pallidotomy: clinical and electrophysiological observations.

Unilateral pallidotomy is an effective treatment for contralateral parkinsonism and dyskinesia, yet symptoms progress in many patients. Little is known about whether such patients obtain a useful response to subsequent bilateral subthalamic nucleus deep brain stimulation (STN DBS). Changes in Unified Parkinson's Disease Rating Scale (UPDRS) Motor and Activities of Daily Living (ADL) scores, medication requirements, and dyskinesias were measured. Clinical outcomes were compared to patients with de novo STN DBS. Neuronal recordings were performed. STN DBS resulted in a significant reduction in UPDRS Motor scores (42.1%; 95% confidence interval [CI], 26.9-57.4; P = 0.03), comparable with de novo STN DBS surgery (41%; 95% CI, 26-46%; P < 0.001). There was also less change in dyskinesia duration and disability scores (P = 0.017, 0.005). There were no side-to-side differences clinically or in the STN neuronal firing rates and patterns. Bilateral STN DBS is safe and efficacious in improving motor symptoms in patients with prior pallidotomy.

Activities of Daily Living↗
PubMed2003

Bilateral subthalamic nucleus stimulation after bilateral pallidotomies in a patient with advanced Parkinson's disease.

A 54-year-old man with advanced Parkinson's disease (PD) presented to our institution in early 2000. He had undergone a right pallidotomy in 1994, a left pallidotomy in 1996, and bilateral subthalamic nucleus (STN) electrode implants in 1999. The patient had cervical myelopathy for which he had undergone neck surgery in 1998. We used the Unified Parkinson's Disease Rating Scale (UPDRS) to evaluate motor performance in four states: combinations of stimulation OFF or ON and medication OFF or ON. There was no significant change in motor UPDRS scores with STN stimulation or with medications. Multiple attempts to optimize stimulation parameters and medication dosages did not result in significant and sustained improvement in activities of daily living or motor performance. To our knowledge, this is the first reported case of bilateral STN stimulation after bilateral pallidotomies. The presence of cervical myelopathy and the limited response to anti-Parkinson medications in this patient underscores the importance of patient selection for functional neurosurgery in PD.

Electric Stimulation Therapy↗
PubMed2006

Chronic deep brain stimulation of the subthalamic nucleus for Parkinson's disease: effects on cognition, mood, anxiety and personality traits.

OBJECTIVE: To evaluate modifications occurring in cognitive functions and behavioural aspects in a group of 72 consecutive patients with Parkinson's disease (PD) 15 months after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: 72 consecutive PD patients bilaterally implanted for DBS of the STN were evaluated before and after surgery with a mean follow-up of 15 months. A neuropsychological assessment was performed to evaluate reasoning (Raven Colour Matrices), memory (Bisyllabic Word Repetition Test, Corsi's Block-Tapping Test, Paired-Associate Learning) and frontal executive functions (Trail Making Test Part B, Nelson Modified Card Sorting Test, phonemic and category verbal fluency tasks). Mood and suicidal ideation were evaluated using the Beck Depression Inventory (BDI). Anxiety was measured by means of the State-Trait Anxiety Inventory and personality traits were evaluated with the Structured Clinical Interview for the DSM-III-R Axis II Disorders (SCID-II). Assessment of thought disorders and apathy was based on subitems of the Unified Parkinson's Disease Rating Scale. RESULTS: The comparisons between pre- and postoperative neuropsychological test scores showed a significant worsening only in phonemic and semantic verbal fluency tasks, while fewer errors were found in the Nelson Modified Card Sorting Test. Globally, behavioural assessment evidenced a small improvement in mood, as assessed by the BDI, in obsessive-compulsive and paranoid personality traits (SCID-II). Thought disorders worsened while suicidal ideation, anxiety and apathy showed no postoperative modifications. The analysis of individual outcomes (+/-1 SD criterion) evidenced a relevant postoperative cognitive decline in 3 patients out of 65 (4.5%). Moreover, following implantation, 1 patients exhibited psychosis (1.5%), 2 patients experienced a clinically relevant worsening of depressive symptoms (3%), 7 patients showed an increase in anxiety (12%) and 3 patients a worsening in depression and anxiety symptoms (3%). On the contrary, 12 patients (20%) showed a relevant improvement in mood and 14 patients (23%) a relevant reduction of anxiety symptoms after the surgery. CONCLUSIONS: The present study confirms that STN DBS is cognitively safe since the only relevant change observed was a mild decrease in verbal fluency tasks. Globally, a small postoperative improvement was found in the BDI, and in two SCID-II subscales concerning obsessive-compulsive and paranoid personality traits, even though postoperative behavioural disturbances can occur in individual patients.

Affect↗
PubMed2006

Delayed synchronization of activity in cortex and subthalamic nucleus following cortical stimulation in the rat.

Oscillations may play a role in the functional organization of cortico-basal ganglia-thalamocortical circuits, and it is important to understand their underlying mechanisms. The cortex often drives basal ganglia (BG) activity, and particularly, oscillatory activity in the subthalamic nucleus (STN). However, the STN may also indirectly influence cortex. The aim of this study was to characterize the delayed (>200 ms) responses of STN neurons to synchronized cortical inputs, focusing on their relationship with oscillatory cortical activity. We recorded the short-latency and delayed responses of STN units and frontal electrocorticogram (ECoG) to cortical stimulation in anaesthetized rats. Similar to previous studies, stimulation of ipsilateral frontal cortex, but not temporal cortex, evoked a short-latency triphasic response, followed by a sustained reduction or pause in firing, in rostral STN units. Caudal STN units did not show the short-latency triphasic response but often displayed a prolonged firing reduction. Oscillations in STN unit activity and ECoG were common after this sustained firing reduction, particularly between 200 and 600 ms after frontal cortical stimulation. These delayed oscillations were significantly coherent in a broad frequency band of 5-30 Hz. Coherence with ECoG at 5-15 Hz was observed throughout STN, though coherence at 15-30 Hz was largely restricted to rostral STN. Furthermore, oscillatory responses at 5-30 Hz in rostral STN predominantly led those in cortex (mean latency of 29 ms) after frontal cortical stimulation. These findings suggest that STN neurons responding to corticosubthalamic inputs may provide a delayed input to cortex, via BG output nuclei, and thence, thalamocortical pathways.

Action Potentials↗
PubMed2006

Subthalamic nucleus lesioning inhibits expression and phosphorylation of c-Jun in nigral neurons in the rat's 6-OHDA model of Parkinson's disease.

Parkinson's Disease (PD) is characterized by a loss of nigral dopamine (DA) neurons, followed by a striatal DA deficit. Inhibition of the subthalamic nucleus (STN) reverses L-DOPA sensitive motor symptoms and improves efficacy of pharmacotherapy in PD-patients. The underlying mechanism of these effects, however, remains largely unknown. Previously, we could show in the rat's 6-hydroxyDA (6-OHDA) model of PD that ablative STN-lesioning exerts functionally neuroprotective effects on the DAergic nigrostriatal pathway against 6-OHDA toxicity, in terms of elevating the number of tyrosine hydroxylase (TH)-expressing neurons rather than enhancing the total number of cells surviving 2 and 6 weeks post lesioning, as assessed via fluorogold staining. These data were correlated with increased functional recovery of 6-OHDA-lesioned rats with preceding STN-lesioning. Here, we extend the previous study design to observation periods of up to 12 weeks to assess long-term effects. Furthermore, to elucidate cellular mechanisms underlying potential neuroprotective effects, we explore the regulation of cellular markers involved in neurodegenerative cascades via immunocytochemistry. We show that preceding STN-lesioning significantly inhibits 6-OHDA induced expression/phosphorylation of the transcription factor c-Jun in surviving nigral neurons in comparison with controls. However, we also demonstrate that functionally neuroprotective effects of preceding STN-lesioning subside after 12 weeks, as assessed with TH immunostaining. We therefore conclude that c-Jun induction/phosphorylation is involved in 6-OHDA toxicity and that STN-lesioning transiently preserves of dopaminergic phenotype of nigral neurons partially via delaying the induction and attenuating the expression and phosphorylation of c-Jun.

Adrenergic Agents↗