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PubMed2003

Excitation by dopamine of rat subthalamic nucleus neurones in vitro-a direct action with unconventional pharmacology.

Recent anatomical and physiological studies have pointed to a functional innervation of the subthalamic nucleus by dopamine. This nucleus has a pivotal role in basal ganglia function and voluntary movement control and the possibility that dopamine, and dopaminergic medication used in Parkinson's disease, might directly influence its activity is of considerable interest. We have evaluated electrophysiologically the action and pharmacology of dopamine on single subthalamic neurones in rat brain slices. Dopamine increased firing rate to up to a mean of 60% in 98% of the 261 neurones tested when examined using extracellular single-unit recording. This excitation was unaffected by the GABA antagonist picrotoxin, and the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted in a low Ca(2+)/raised Mg(2+) solution, indicative of a direct action, independent of synaptic transmission. Of the 33 cells examined using whole patch-clamp recording, only 13 showed measurable increases in firing rate and/or depolarisations in response to dopamine. Dopamine-responsive cells displayed significantly greater access resistance, suggesting that an unidentified cytoplamic constituent, removed by whole-cell dialysis, was required for the response. Using extracellular recording, the D2-like dopamine receptor agonists quinpirole and bromocryptine, but not the D1-like receptor agonist 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, also consistently caused an excitation. This was mimicked by the catecholamine releaser amphetamine in 60% of cells tested. However, the dopamine excitation was not significantly reduced either by the D1-like receptor antagonist 7-chloro8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine or the D2-like receptor antagonists (-)-sulpiride, eticlopride and (+)-butaclamol, and the quinpirole excitation was also unaffected by (-)-sulpiride. In contrast, (-)-sulpiride, eticlopride and (+)-butaclamol all abolished the D2-like receptor-mediated inhibition by dopamine of substantia nigra pars compacta neurones. The alpha-adrenoceptor antagonist phentolamine was a weak antagonist of dopamine excitations, but not of those caused by quinpirole. Dopamine excitations also showed weak sensitivity to the 5-HT(2) antagonist ritanserin, but were unaffected by the alpha(1)-adrenoceptor antagonist prazocin and the beta-adrenoceptor antagonist propranolol. The pharmacology of this dopamine excitation is inconsistent with an action on any known catecholamine receptor. However, the effect of amphetamine indicates that an unidentified monamine--possibly dopamine--can be released within the subthalamic nucleus to cause an excitation. The anomalies of its pharmacological characterisation do not strongly support a physiologically relevant direct action of dopamine in the rat subthalamic nucleus.

Amphetamine↗

PubMed2000

[Chronic electric stimulation of the internal globus pallidus and subthalamic nucleus in Parkinson disease].

PATHOPHYSIOLOGY: In Parkinson's disease, the neurodegenerative process of the nigrostriatal dopaminergic pathways induces an increase in activity of the subthalamic nucleus and the medial globus pallidus, which cause inhibition of thalamo-cortical outputs explaining parkinsonism. HIGH-FREQUENCY DEEP BRAIN STIMULATION: The adverse effects induced by lesions of subcortical structures (thalamotomy, pallidotomy) have increased interest in chronic electrical stimulation proposed as a new therapy in Parkinson's disease. This technique is reversible and can be modulated with less adverse effects. TWO TARGETS: Two targets may be proposed in case of severe motor fluctuations: the medial globus pallidus and the subthalamic nucleus. Pallidial stimulation improves dramatically levodopa-induced dyskinesia and, with a variable degree, the parkinsonian triad. Subthalamic stimulation rapidly reverses akinesia, rigidity and tremor and also dyskinesias which progressively tend to diminish after decreasing L-dopa dosage. LONG-TERM EFFICACY: A follow-up period of a few years has confirmed that the beneficial effect is maintained. However, stimulation dose not prevent the development of certain symptoms (postural impairment, cognitive decline). LIMITED INDICATIONS: Chronic electrical stimulation of medial globus pallidus and subthalamic nucleus may be proposed for parkinsonian patients with severe motor fluctuations associated with abnormal involuntary movements which are not controlled by different medical therapies. Parkinsonian symptoms must still be levodopa responsive and cause severe clinical disability severely limiting daily living activities. Cognitive impairment and other severe pathologies are contraindications.

Electric Stimulation Therapy↗

PubMed2004

The functional organization of the sensorimotor region of the subthalamic nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is viewed by many as the ultimate therapy targeting severe advanced stages of Parkinson's disease (PD). A fundamental constituent of the mechanisms underlying the therapeutic effects of DBS is clearly the functional organization of the STN; however, there is limited understanding of the organization of this structure in humans. Data from primates suggest that different domains can be identified in the STN, including a sensorimotor area with a segregated body map, as well as nonmotor areas. Recent clinical studies have used microelectrode recording to investigate the presence of a body map in the sensorimotor STN of PD patients. This paper will review and compare experimental and clinical data regarding the functional organization of the STN and discuss the clinical implications for PD patients undergoing STN DBS.

Animals↗

PubMed2006

Protection of nigral cell death by bilateral subthalamic nucleus stimulation.

In Parkinson disease (PD), the subthalamic nucleus (STN) becomes hyperactive (disinhibited), which is reported to cause excitotoxic damage to midbrain dopaminergic neurons. Here, we examined whether silencing of the hyperactive STN by chronic bilateral deep brain stimulation (DBS) increased the survival of midbrain dopaminergic neurons in a rat model of PD. High-precision design-based stereologic examination of the total number of neurons and tyrosine tydroxylase (TH) immunoreactive neurons in the substantia nigra pars compacta revealed that STN DBS resulted in a significant survival of these neurons. These data provide the first evidence in vivo that bilateral STN DBS is useful for protecting midbrain dopaminergic neurons from cell death in PD.

Adrenergic Agents↗

PubMed2006

[Electrophysiology of subthalamic nucleus in normal and Parkinson's disease].

Subthalamic nucleus (STN) has been known to play an important role in the regulation of cortico-basal ganglia-thalamo-cortical loop. STN neurons have pacemaking activitiy and their firing pattern can switch from spike mode to bursting mode when membrane potential becomes hyperpolarized. Recent study has shown that STN neurons show marked increase in burst and oscillatory activity during the dopamine-depleting state of Parkinson's disease (PD). This electrophysiological change in activity is now considered as an characterstic pathophysiological feature of PD. High frequency stimulation of STN can modify and "normalize" the activity of STN neurons in the pathophysiologial state. This electrophysiological treatment applied to STN, known as deep brain stimulation (DBS) clinically, ameliorates the symptoms of PD effectively, and is becoming a standard treatment in patients with advanced PD. This article would review the basic researches concerning electrical activities of STN and try to extend the basic knowledge into clinical applications.

Basal Ganglia↗

PubMed2005

Use of sagittal images for localization of the subthalamic nucleus. Technical note.

Direct observation of the subthalamic nucleus (STN) is not always possible, and physicians at many centers rely on indirect methods that relate the position of the STN to more easily recognized structures such as the red nucleus (RN). In this paper the authors describe an indirect method of viewing the STN based on the anatomy depicted on sagittal magnetic resonance (MR) images. A review of sagittal slices appearing in standard stereotactic atlases showed that the STN lies within the angle formed by the descending internal capsule (IC) and the substantia nigra (SN). The authors' technique consists of marking the location of the STN in this nigrocapsular angle on each sagittal MR image between the RN and the lateral border of the brainstem, and transferring these points to axial MR images to build a locus of points used to describe the STN. A point is chosen in the center of this locus as the stereotactic target. Two hundred eighty-two sagittal images obtained from 71 MR imaging studies performed in 29 patients by using a fast-spin echo inversion-recovery technique were examined for the presence of the STN, the SN, and the IC. The descending IC could be detected in 97% of the slices, the SN in 95% of the slices, and the STN in 73% of the slices. This indirect method involving sagittal anatomy can be used to refine localization of the STN.

Humans↗

PubMed2003

Deep brain stimulation in Parkinson's disease: bilateral implantation of globus pallidus and subthalamic nucleus.

AIM: Deep brain stimulation (DBS) of subthalamic nucleus (STN) and of the pars interna of globus pallidus (GPi) is used to improve Parkinsonian symptoms and attenuate levodopa-induced motor complications in Parkinson's disease (PD). What are the physiological effect of DBS and the best anatomical structure to stimulate are still not completely clear. In this way we could evaluate the clinical effects of simultaneous stimulation of STN and GPi as well as the isolated stimulation of each target. METHODS: The stereotactic methods used to localise STN and GPi were based on non-telemetric ventriculography, with 3P Maranello or Leksell Stereotactic System. The effects of DBS have been assessed in 13 cases of PD, immediately after (30 minutes) the stimulation has turned on and during chronic stimulation (weeks or months). RESULTS: Most of the studies have been conducted on patients with STN implantation, and these studies reported relevant improvement in motor function and relatively low rate of complication. CONCLUSION: The large experience of ablative surgery associate with the DBS experience of some group worldwide indicate that GPi is a possible and very promising target for the management of Parkinsonian symptoms. Our patients demonstrate in acute and chronic evaluation, the best clinical results with contemporary activation of DBS in both targets.

Antiparkinson Agents↗

PubMed2004

Premature responding following bilateral stimulation of the rat subthalamic nucleus is amplitude and frequency dependent.

The subthalamic nucleus (STN), a key component of the basal ganglia circuitry, functions as an internal clock that regulates the correct sequence of movements in a motor response. The importance of the STN in motor function is evidenced by its involvement in Parkinson disease (PD). This nucleus has also been associated with the attentional and emotional aspects of motor behavior through its connections with the limbic and prefrontal areas of the brain. As lesions of the STN have been shown to increase premature responding in a serial reaction time task in rats, indicative of its involvement in cognitive performance, the present study aimed to investigate whether bilateral deep brain stimulation (DBS) of the STN, in non-lesioned rats, affects cognitive functions and whether these are dependent on certain stimulation parameters. Rats were trained in a choice reaction time task and implanted bilaterally with electrodes. Stimulation parameters (amplitude, frequency and pulse width) were varied during the test procedure, after which rats were sacrificed and the brains processed for histochemical staining. Results show no change in reaction times or motor times during stimulation. However, a linear decrease in premature responses was observed with decreasing amplitudes and at high frequencies only. These results are the first to demonstrate that bilateral STN HFS has a positive effect on cognition in freely moving rats. This latter result is in contrast to findings following lesions of the STN, and suggests that current strength and frequency of stimulation are parameters that are integral to the mediation of stimulation effects. Furthermore, the overall effects of DBS on neuronal cells cannot be classified simply as being "inhibitory" and evidently mediates its effects by more complex mechanisms than lesions of the same brain area.

Animals↗

PubMed2002

MRI-directed subthalamic nucleus surgery for Parkinson's disease.

The subthalamic nucleus (STN) is now regarded as the optimal surgical target for the treatment of medically refractory idiopathic Parkinson's disease. In our center, a predominantly MRI-directed method has been developed for targeting the STN. The STN is localized on T2-weighted images from a 1.5-T MRI scanner. Long acquisition, high-resolution images are acquired in both the axial and coronal planes under strict stereotactic conditions with the patient under general anesthesia. The boundary of STN is co-registered in both planes to give optimal 3-dimensional target definition. Stereotactic coordinates of the dorsolateral STN are recorded and the trajectory is planned down the axis of the nucleus in the coronal plane. Initially, per-operative macrostimulation was used for adjustment at the target prior to unilateral subthalamotomy in 26 patients. Five patients were lost to follow-up. Assessments of the lesions in post-operative images confirmed successful localisation of the lesions within the dorsolateral STN in all of the remaining 21 cases. In a subsequent series of 19 patients treated by deep brain stimulation (DBS), unilateral in 1 patient and bilateral in 18, the STN was targeted using the same MRI-directed method, guide tubes and radio-opaque stylettes were implanted, and target verification was entirely MRI-based. Following implantation of the guide tubes and stylettes, assessments of the per-operative MRI images for the 37 STN targetings confirmed a mean target error, between the stylette and the desired target in the axial plane, of 0.3 mm mediolaterally (SD = 0.4) and 0.4 mm anteroposteriorly (SD = 0.4), with median errors of 0.5 mm. This study demonstrates that MRI-directed targeting of the STN through guide tubes is accurate, and allows direct verification and corrections as necessary. Cumulative frequencies predict that the majority of DBS electrodes placed in this manner will be within 0.5 mm of the planned target. Because physiological methods are not required, the whole procedure can be performed under general anesthesia. We feel that planning with reference to a standard atlas is unreliable and not significantly helped by the addition of microelectrode recording, the accuracy of which in the axial plane is dependent upon the distance between the recording trajectories, which is typically 2 mm.

Electric Stimulation Therapy↗

PubMed2005

Pallidal origin of GABA release within the substantia nigra pars reticulata during high-frequency stimulation of the subthalamic nucleus.

High-frequency stimulation of the subthalamic nucleus (HFS-STN) is an effective treatment for alleviating the motor symptoms of parkinsonian patients. However, the neurochemical basis of its effects remains unknown. We showed previously that 1 h of HFS-STN in normal rats increases extracellular glutamate (Glu) level in the output nuclei of the STN, the globus pallidus (GP), and the substantia nigra pars reticulata (SNr), consistent with an increase in the activity of STN neurons. HFS-STN also increases GABA levels in the SNr, but the origin of this increase is unclear. We investigated the effectiveness of HFS-STN for improving Parkinson's disease symptoms, using intracerebral microdialysis to determine the extracellular Glu and GABA levels of the GP and SNr in response to HFS-STN in anesthetized hemiparkinsonian rats [6-hydroxydopamine lesion of the substantia nigra pars compacta (SNc)]. Basal levels of Glu and GABA in the GP and SNr were significantly higher in hemiparkinsonian than in intact rats. HFS-STN did not affect extracellular Glu level in the SNr of hemiparkinsonian rats but doubled the level of GABA. Ibotenic acid lesion of the GP abolished the increase in GABA levels in the SNr induced by HFS-STN in SNc-lesioned rats. These results provide neurochemical confirmation of the hyperactivity of the STN after dopaminergic denervation and suggest that the therapeutic effects of HFS-STN may result partly from the stimulation of pallidonigral fibers, thereby revealing a potential role for pallidal GABA in the inhibition of basal ganglial output structures during HFS-STN.

Animals↗

PubMed2000

Levodopa withdrawal after bilateral subthalamic nucleus stimulation in advanced Parkinson disease.

CONTEXT: Subthalamic nucleus (STN) stimulation may be effective in ameliorating parkinsonian symptoms even to the extent to permit levodopa withdrawal. OBJECTIVES: To analyze the efficacy of STN stimulation in patients with Parkinson disease (PD) and to determine if levodopa may be withdrawn after surgery. DESIGN: Before-after trial. SETTING: Referral center, hospitalized care. PATIENTS: Fifteen patients with advanced PD. INTERVENTIONS: Microelectrode-guided bilateral STN high-frequency stimulation. OUTCOME MEASURES: Before surgery patients were evaluated in off-medication and on-medication conditions. Dopaminergic drug dosages were reduced after surgery, aiming for complete withdrawal. Six months after surgery, patients were reeavaluated in off- and on-medication conditions, with the stimulation turned on and off. RESULTS: Total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the off-medication condition improved by 65.9%; and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively. UPDRS part II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. Levodopa was withdrawn in 8 patients and the overall levodopa dose was reduced 80.4%. "Off" time was reduced 89.7% and the severity of dyskinesias decreased 80.6% after surgery. All results reached significance (P<.001). Stimulation of the STN achieved antiparkinsonian effect similar to that of treatment with levodopa. No life-threatening adverse effects occurred. CONCLUSIONS: Bilateral STN stimulation safely improves all parkinsonian symptoms, decreases or eliminates the need for levodopa, and ameliorates motor fluctuations and dyskinesias. Complete withdrawal of levodopa is feasible with this technique and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.

Aged↗

PubMed2002

Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata.

Excitatory glutamatergic inputs to the subthalamic nucleus (STN), and subthalamic afferents to the substantia nigra pars reticulata (SNr) are believed to play a key role in the pathophysiology of Parkinson's disease (PD). Previously, we have shown that activation of the group I mGlus in the STN and SNr induces a direct depolarization of the neurons in these nuclei. Surprisingly, although both group I mGlus were present in the STN and SNr, mGlu5 alone mediated the DHPG-induced depolarization of the STN, and mGlu1 alone mediated the DHPG-induced depolarization of the SNr. We now report that both mGlu1 and mGlu5 are coexpressed in the same cells in both of these brain regions, and that both receptors play a role in mediating the DHPG-induced increase in intracellular calcium. Furthermore, we demonstrate that the induction of an acute PD-like state using a 16 h haloperidol treatment produces an alteration in the coupling of the group I receptors, such that post-haloperidol, DHPG-induced depolarizations are mediated by both mGlu1 and mGlu5 in the STN and SNr. Therefore, the pharmacology of the group I mGlu-mediated depolarization depends on the state of the system, and alterations in receptor coupling may be evident in pathological states such as PD.

Animals↗

PubMedDate not supplied

[Subthalamic nucleus targeting and spatial variability].

AIM: The effectiveness of anatomic localization of the subthalamic nucleus (EAL) was assessed and the mapping method is described here. The symmetry of contralateral nuclei (SCN) was analyzed on 11 parkinsonian patients submitted to bilateral subthalamotomy with ablative lesioning. PATIENTS AND METHODS: To assess EAL the percentage so much of first trajectory (p1) as the total of trajectories (pt) that hit the target and the rest of subthalamic nucleus average distance (d) was calculated. The anatomic localization error (epsilon) is determined as a difference between first trajectory coordinates with those of medial determined nucleus point, through electrophysiological data as to the statistical significance of this error. SCN is analyzed by contrasting equality hypothesis at the nucleus maximum height alongside a trajectory, average electrophysiological position center and spatial distribution of all intranuclear recordings found in each hemisphere in all patients. RESULTS: The pi, pt and d obtained values were 86.36%, 86.13% and 1.41 +/- 1.01 mm respectively. The epsilon value was greater in anteroposterior direction of 1.11 +/- 0.83 mm without statistical significance. The average number of recorded trajectories for the first procedure was 6.45 and 6 for the second. The asymmetry of contralateral nucleus was not significant. CONCLUSIONS: An indirect method with CT brain images and a new electrophysiological mapping method with a multiunitary recording for first and second nucleus is safe enough and it yields a high effectiveness in anatomofunctional nucleus localization. The nucleus of a same patient are symmetrical. There is little space variability among patient non related to the differences in the intercommissural distance.

Aged↗

PubMed2003

Presynaptic inhibition of synaptic transmission by adenosine in rat subthalamic nucleus in vitro.

Whole-cell patch clamp recordings were made from the subthalamic nucleus in rat brain slice preparations to examine the effect of adenosine on inhibitory and excitatory synaptic transmission. Adenosine reversibly inhibited both GABA-mediated inhibitory and glutamate-mediated excitatory postsynaptic currents. Adenosine at 100 microM reduced the amplitude of inhibitory and excitatory postsynaptic currents by 42+/-5% and 34+/-6%, respectively. Reductions in the amplitude of both inhibitory and excitatory postsynaptic currents were accompanied by increases in paired-pulse ratios. In addition, adenosine decreased the frequency of spontaneous miniature excitatory postsynaptic currents but had no effect on their amplitude. These results are consistent with a presynaptic site of action. The adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine completely reversed the adenosine-induced attenuation of inhibitory and excitatory postsynaptic currents, but 8-cyclopentyl-1,3-dipropylxanthine alone had no effect on synaptic currents evoked at 0.1 Hz. However, 8-cyclopentyl-1,3-dipropylxanthine inhibited a time-dependent depression of excitatory postsynaptic currents that was normally observed in response to a 5 Hz train of stimuli, suggesting that endogenous adenosine could be released during higher frequencies of stimulation. These results suggest that adenosine inhibits synaptic release of GABA and glutamate by stimulation of presynaptic A(1) receptors in the subthalamic nucleus.

Adenosine↗

PubMed2003

Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease.

OBJECTIVE: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson's disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. METHODS: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson's disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. RESULTS: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. CONCLUSIONS: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson's disease and may alleviate the postoperative decline in verbal fluency.

Aged↗

PubMed1995

Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation.

In monkeys rendered parkinsonian, lesions and electrical stimulation of the subthalamic nucleus reduce all major motor disturbances. The effect of electrical stimulation of the subthalamic nucleus was assessed in three patients with disabling akinetic-rigid Parkinson's disease and severe motor fluctuations. Quadripolar electrodes connected to a pulse generator were implanted in the subthalamic nuclei on both sides. Patients were evaluated with the unified Parkinson's disease rating scale and timed motor tests. 3 months after surgery, activities of daily living scores had improved by 58-88% and motor scores by 42-84%. This improvement was maintained for up to 8 months in the first patient operated upon. One patient was confused for 2 weeks after surgery, and another developed neuropsychological impairment related to a thalamic infarction which improved over 3 months. In one patient, stimulation could induce ballism that was stopped by reduction of stimulation. This is the first demonstration in human beings of the part played by the subthalamic nuclei in the pathophysiology of Parkinson's disease.

Electric Stimulation Therapy↗

PubMed2003

Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion.

Intermittent oral doses of levodopa (L-DOPA) are routinely used to treat Parkinson's disease, but with prolonged use can result in adverse motor complications, such as dyskinesia. Continuous administration of L-DOPA achieves therapeutic efficacy without producing this effect, yet the molecular mechanisms are unclear. This study examined, by in situ hybridization histochemistry, the effects of continuous or intermittent L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Results were compared to 6-OHDA-treated rats receiving vehicle. Our results provide original evidence that continuous L-DOPA normalizes the 6-OHDA-lesion-induced increase in mRNA levels encoding for the 67 kDa isoform of glutamate decarboxylase in neurons of the globus pallidus and cytochrome oxidase subunit I mRNA levels in the subthalamic nucleus. The extent of normalization did not differ between the continuous and intermittent groups. In addition, intermittent L-DOPA induced an increase in the mRNA levels encoding for the 65 kDa isoform of glutamate decarboxylase in globus pallidus neurons ipsilateral to the lesion and a bilateral increase in c-fos mRNA expression in the subthalamic nucleus. These results suggest that continuous L-DOPA tends to normalize the 6-OHDA-lesion-induced alterations in cell signaling in the pallido-subthalamic loop. On the other hand, we propose that chronic intermittent L-DOPA exerts a dual effect by normalizing cell signaling in a subpopulation of neurons in the globus pallidus and subthalamic nucleus while inducing abnormal signaling in another subpopulation.

Animals↗

PubMed2000

Lesion of the subthalamic nucleus or globus pallidus does not cause chaotic firing patterns in basal ganglia neurons in rats.

The basal ganglia appears to play an important role in behavioral selection. One model (Berns and Sejnowski's) of basal ganglia function argues that the subthalamic nucleus plays a critical role in this selection process and predicts that the subthalamic nucleus prevents the basal ganglia and its re-entrant circuits with the thalamus and cerebral cortex from developing chaotic oscillations. We tested this prediction by generating three-dimensional sequential interval state space plots of the spike trains from 684 globus pallidus, substantia nigra pars reticulata and subthalamic neurons recorded in intact, subthalamic lesioned and globus pallidus lesioned rats, neurons which had previously been analyzed with more standard statistical methods. Only 1 neuron (a globus pallidus neuron in a subthalamic lesioned rat) of the 684 showed a chaotic attractor. In no case did subthalamic nucleus lesion induce a chaotic firing pattern elsewhere in the basal ganglia.

Action Potentials↗