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Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's disease.

The aim of this study was to examine possible neuropsychological changes in patients with advanced idiopathic Parkinson's disease treated with bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). Eleven patients (age = 67 +/- 8 years, years with Parkinson's disease = 15 +/- 3, verbal IQ = 114 +/- 12) were evaluated (in their best 'on state') with tests assessing processes reliant on the functional integrity of frontal striatal circuitry, prior to the procedure (n = 11), at 3-6 months (n = 11) and at 9-12 months (n =10) post-operatively. Six of these patients were older than 69 years. Despite clinical motor benefits at 3-6 months post-operative, significant declines were noted in working memory, speed of mental processing, bimanual motor speed and co-ordination, set switching, phonemic fluency, long-term consolidation of verbal material and the encoding of visuospatial material. Declines were more consistently observed in patients who were older than 69 years, leading to a mental state comparable with progressive supranuclear palsy. 'Frontal' behavioural dyscontrol without the benefit of insight was also reported by half (three of six) of the caregivers of the elderly subgroup. At 9-12 months postoperative, only learning based on multiple trials had recovered. Tasks reliant on the integrity of frontal striatal circuitry either did not recover or gradually worsened over time. Bilateral STN DBS can have a negative impact on various aspects of frontal executive functioning, especially in patients older than 69 years. Future studies will evaluate a larger group of patients and examine the possible reversibility of these effects by turning the DBS off.

Affect↗

Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease.

OBJECT: The authors compared the effects of deep brain stimulation (DBS) in the globus pallidus internus (GPi) with those in the subthalamic nucleus (STN) in patients with Parkinson disease (PD) in whom electrodes had been bilaterally implanted in both targets. METHODS: Eight of 14 patients with advanced PD in whom electrodes had been implanted bilaterally in both the GPi and STN for DBS were selected on the basis of optimal DBS effects and were studied 2 months postsurgery in off- and on-stimulus conditions and after at least 1 month of pharmacological withdrawal. Subcutaneous administration of an apomorphine test dose (0.04 mg/kg) was also performed in both conditions. Compared with the off status, the results showed less reduction in the Unified PD Rating Scale Section III scores during DBS in the GPi (43.1%) than during DBS of the STN (54.5%) or DBS of both the STN and GPi (57.1%). The difference between the effects of DBS in the GPi compared with that in the STN or simultaneous DBS was statistically significant (p < 0.01). In contrast, no statistical difference was found between DBS in the STN and simultaneous DBS in the STN and GPi (p < 0.9). The improvement induced by adding apomorphine administration to DBS was similar in all three stimulus modalities. The abnormal involuntary movements (AIMs) induced by apomorphine were almost abolished by DBS of the GPi, but were not affected by stimulation of the STN. The simultaneous stimulation of STN and GPi produced both antiparkinsonian and anti-AIM effects. CONCLUSIONS: The improvement of parkinsonian symptoms during stimulation of the GPi, STN, and both nuclei simultaneously may indicate a similar DBS mechanism for both nuclei in inducing antiparkinsonian effects, although STN is more effective. The antidyskinetic effects produced only by DBS of the GPi, with or without STN, may indicate different mechanisms for the antidyskinetic and antiparkinsonian activity related to DBS of the GPi or an additional mechanism in the GPi. These findings indicate that implantation of double electrodes for DBS should not be proposed as a routine procedure, but could be considered as a possible subsequent choice if electrode implantation for DBS of the STN does not control AIMs.

Adult↗

OFF-off rebound dyskinesia in subthalamic nucleus deep brain stimulation of Parkinson's disease.

A 61-year-old man with Parkinson's disease (PD), motor fluctuations, and dyskinesias underwent bilateral implantation of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN). One month after surgery, DBS was optimized to bilateral monopolar settings at the most proximal electrode just superior to the STN, which improved motor fluctuations and dyskinesias. At several postoperative evaluations off medications overnight, both stimulators were turned off and within 60 seconds he developed severe dyskinesias. When the stimulators were turned back on, the dyskinesias soon resolved. This article is a first report of a unique pattern of rebound-type dyskinesia that occurred in the off medication state produced by stopping STN DBS.

Antiparkinson Agents↗

EEG and evoked potential recording from the subthalamic nucleus for deep brain stimulation of intractable epilepsy.

OBJECTIVES: The substantia nigra in the animal model has been implicated in the control of epilepsy. The substantia nigra pars reticulata (SNpr) receives afferents from the subthalamic nucleus (STN), which thus may have an effect on the control of epilepsy. There is evidence in the animal model of a direct connection from the cortex to the STN. High-frequency STN stimulation is being used in experimental trial for the management of intractable epilepsy. Our primary objective in this study was to determine if there was epileptiform activity recorded from the STN in association with scalp recorded epileptiform activity to support the presence of a pathway from the cortex to the STN in humans as described in animals that may be important for the management of epilepsy. This article describes the interictal and ictal electroencephalographic (EEG) findings as well as evoked potential recordings from the STN in these patients with intractable epilepsy. METHODS: Four patients (3 males) ranging from 19 to 45 years with intractable focal epilepsy refractory to anti-epileptic drugs were studied. Two patients failed vagal nerve stimulation and one patient had previous epilepsy surgery. Depth electrodes were implanted stereotactically in the STN bilaterally. A comparative analysis of the interictal and ictal activities recorded from the scalp and STN electrodes was performed. Median nerve somatosensory evoked potentials (SEPs) and auditory evoked potentials (AEPs) were also recorded. RESULTS: Interictal sharp waves recorded in the scalp EEG were always negative in polarity. These sharp waves were always associated with sharp waves recorded at the ipsilateral STN electrode contacts that were always positive in polarity. In addition repetitive spikes were recorded independently at the left or right STN electrode contacts, with no reflection at the scalp. These spikes were extremely stereotyped, of high amplitude and short duration, and were positive or negative in polarity. Focal scalp EEG seizures were also recorded at the ipsilateral STN electrodes. In 3 patients SEPs were recorded from the contralateral STN electrodes corresponding to the P14/N18 far-field complex. In two patients AEPs were recorded, and wave V (near-field) and wave VII (far-field) from the contralateral STN electrodes. CONCLUSIONS: This study demonstrates that scalp recorded epileptiform activity is reflected at the ipsilateral STN either following or preceding the scalp sharp waves. The STN sharp waves are most probably an expression of the direct cortico-STN glutamatergic pathways that have been demonstrated previously in animals. This pathway in man may be important with regard to a possible mechanism for the treatment of epilepsy with STN stimulation.

Action Potentials↗

Subthalamic nucleus stimulation in patients with a prior pallidotomy.

OBJECT: A substantial number of patients with Parkinson disease (PD) who have undergone unilateral stereotactic pallidotomy ultimately develop symptom progression, becoming potential candidates for further surgical treatment. Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been shown to be effective in the treatment of a subset of patients with refractory PD. Microelectrode recording is performed to help localize the STN and guide final placement of the electrode. Potential alterations in physiological features of the STN after pallidotomy may complicate localization of this structure in this group of patients. METHODS: Bilateral STN DBS surgery guided by microelectrode recording was performed in six patients who had undergone previous unilateral pallidotomies. Physiologically obtained parameters of the STN, including trajectory length, mean firing rate, cell number, and cell density were calculated. These data were compared with those from the side without prior pallidotomy within each patient, as well as with those from our series of 49 subthalamic nuclei explored in 26 patients who had not undergone prior pallidotomy but who underwent bilateral STN stimulator placement. In all patients, analysis of STN cellular activity on the side ipsilateral to the pallidotomy demonstrated a lower mean firing frequency than on the contralateral, intact side. The physiological features on the intact side were not significantly different from those found in our series of patients who had not undergone prior pallidotomy. CONCLUSIONS: Physicians who perform STN surgery in patients with prior pallidotomy should be aware of the electrophysiological differences between the STN that had undergone pallidotomy and the one that had not, to avoid prolonging recording time to search for the typical STN. The implications of these findings for the current models of information processing in the basal ganglia are discussed.

Adult↗

The effect of unilateral electrostimulation of the subthalamic nucleus on respiratory/phonatory subsystems of speech production in Parkinson's disease--a preliminary report.

This paper reports findings on the respiratory/phonatory subsystems from an on-going study investigating the effect of unilateral electrostimulation of the subthalamic nucleus (STN) on different speech subsystems in people with Parkinson's disease (PD). Speech recordings were made in the medication-off state at baseline, three months post surgery with stimulation-on, and with stimulation-off, in six right-handed PD patients. Subjects completed several speech tasks. Acoustic analyses of the maximally sustained vowel phonation were reported. The results were compared to the scores of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III) obtained under the same conditions. Results showed that stimulation-on improved UPDRS-III scores in all six subjects. While mild improvement was observed for all subjects in the Stimulation-on condition, three subjects received left-STN stimulation showed a significant decline in vocal intensity and vowel duration from their baseline indicating the speech function was very susceptible to micro lesions due to the surgical procedure itself when the surgical site was in the dominant hemisphere.

Acoustics↗

Cortical and subcortical contributions to Stop signal response inhibition: role of the subthalamic nucleus.

Suppressing an already initiated manual response depends critically on the right inferior frontal cortex (IFC), yet it is unclear how this inhibitory function is implemented in the motor system. It has been suggested that the subthalamic nucleus (STN), which is a part of the basal ganglia, may play a role because it is well placed to suppress the "direct" fronto-striatal pathway that is activated by response initiation. In two experiments, we investigated this hypothesis with functional magnetic resonance imaging and a Stop-signal task. Subjects responded to Go signals and attempted to inhibit the initiated response to occasional Stop signals. In experiment 1, Going significantly activated frontal, striatal, pallidal, and motor cortical regions, consistent with the direct pathway, whereas Stopping significantly activated right IFC and STN. In addition, Stopping-related activation was significantly greater for fast inhibitors than slow ones in both IFC and STN, and activity in these regions was correlated across subjects. In experiment 2, high-resolution functional and structural imaging confirmed the location of Stopping activation within the vicinity of the STN. We propose that the role of the STN is to suppress thalamocortical output, thereby blocking Go response execution. These results provide convergent data for a role for the STN in Stop-signal response inhibition. They also suggest that the speed of Go and Stop processes could relate to the relative activation of different neural pathways. Future research is required to establish whether Stop-signal inhibition could be implemented via a direct functional neuroanatomic projection between IFC and STN (a "hyperdirect" pathway).

Adult↗

Influence of chronic bilateral stimulation of the subthalamic nucleus on cognitive function in Parkinson's disease.

BACKGROUND: The clinical efficacy of chronic deep brain stimulation in the treatment of parkinsonian patients with severe levodopa-related motor adverse effects has been repeatedly shown. Bilateral subthalamic nucleus (STN) stimulation has been shown to present an advantage over pallidal stimulation as it induces a higher antiakinetic effect and has positive effects on all parkinsonian symptoms. The morbidity of such surgery is usually considered to be very low. However, few studies have extensively examined the effects of chronic STN stimulation on cognitive function. OBJECTIVE: The aim of the present study was to assess the effects of chronic bilateral STN stimulation on performance in an extensive battery of neuropsychological tests, three months and one year after surgery. METHODS: Nine patients with Parkinson's disease were selected for STN electrodes implantation. They underwent a neuropsychological evaluation at one month before and at three months after surgery. Six of them were examined again at one year after surgery. RESULTS: Before surgery, no patient showed cognitive decline. At three months after surgery, no modification was observed for most tasks. The information processing speed tended to improve. There was a significant reduction of the performance in a delayed free recall test and a trend toward a significant reduction of categorial word fluency. At one year after surgery, most task measures did not change. Slight impairment was observed for tasks evaluating executive function. Examination of individual results showed that some patients (30% at 3 months after surgery) showed an overall cognitive decline. Behavioural changes were also observed in 4 patients with overall cognitive decline in one of them. CONCLUSION: In general, STN deep brain stimulation can be considered as a significant contribution to the treatment of severe Parkinson's disease However, in some patients it can induce overall cognitive decline or behavioural changes.

Cognition Disorders↗

Results of chronic subthalamic nucleus stimulation for Parkinson's disease: a 1-year follow-up study.

BACKGROUND: Deep brain stimulation (DBS) has been established as an alternative approach for the treatment of advanced Parkinson's disease (PD). Recently, the subthalamic nucleus (STN) has been identified as the optimal target for DBS. METHODS: Thirty-eight patients have undergone surgery for advanced PD since 1996. They include 12 females and 26 males with a mean age of 55.6 years. The mean stage on the Hoehn and Yahr Scale was 3.5 (off condition). Electrodes (Medtronic DBS 31389) were stereotactically implanted into the STN bilaterally. Targeting was performed using computerized tomography (CT) scans and ventriculography (VG). After 4 days of external stimulation, permanent neurostimulators were implanted. Patients were evaluated preoperatively and 1, 6, and 12 months postoperatively. Evaluations were performed in defined on and off states using the Unified Parkinson's Disease Rating Scale (UPDRS) as well as the Hoehn and Yahr Scale, the dyskinesia scale, and the Activities of Daily Living (ADL) Scale. RESULTS: Significant improvement of all motor symptoms was found in all patients (UPDRS motor score 32/48 preoperatively versus 15/30 at 12-month follow-up, p < 0.001). Daily off-times were reduced by 35%. Dyskinesias also improved markedly (UPDRS IV: 3.2/3.1 [on/off] vs. 0.9/1.3 at 12 months follow-up). Postoperative L-dopa medication was adjusted (mean reduction: 53%). Complications occurred in two patients (5%) who developed infections, leading to system removal. Systems were replaced after 6 months. Two patients (5%) had a permanent worsening of a previously known depressive state and developed progressive dementia. CONCLUSIONS: TN stimulation is a relatively safe procedure for treating advanced PD. The possibility of readjusting the stimulation parameters postoperatively improves the therapeutic outcome and reduces side effects in comparison to ablative methods.

Electric Stimulation Therapy↗

Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysiological data.

By selective chemical stimulation of the subthalamic nucleus (STh) with the gamma-aminobutyric acid (GABA) antagonist bicuculline, we have studied the effect of its projections to the target nuclei. Results show that bicuculline (0.39 mM) produced a mean activation of 358% in subthalamic neurons. Most of the cells recorded in the substantia nigra pars reticulata (SNpr), the entopenduncular nucleus (EP), and the globus pallidus (GP) were also significantly activated. In the substantia nigra pars compacta (SNpc), slight and opposite changes were produced: half of the cells were activated and half were inhibited. In the striatum, 3 types of responses were recorded: activation, inhibition, and biphasic effect. Inhibition of subthalamic neurons by local microinjection of muscimol (0.95 mM), produced reductions in the neuronal activity of cells in the SNpr, the EP, and the GP. These results suggest that the STh conveys an important and permanent excitatory influence onto its target nuclei. In another set of experiments, in order to investigate whether or not the STh utilizes glutamate for neurotransmission in the SNpr, we injected the glutamate receptor antagonist kynurenic acid (2.6 mM) into the SNpr, later followed by an injection of bicuculline in the STh. Kynurenic acid alone produced a mean inhibition of 30% in non-dopaminergic nigral cells, and antagonized the subsequent bicuculline-induced activating effect of the STh. These results further confirm recent data showing that the STh exerts an excitatory action on its efferent structures, and provide new evidence for glutamatergic transmission in subthalamic projections.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Cocaine-induced psychomotor activity is associated with its ability to induce c-fos mRNA expression in the subthalamic nucleus: effects of dose and repeated treatment.

Factors that modulate the psychomotor activating effects of amphetamine and cocaine, such as environmental novelty and dose, also regulate the ability of these drugs to induce c-fos mRNA expression in the subthalamic nucleus (STN). We hypothesized therefore that engagement of the STN may be important for stimulant-induced psychomotor activation. To further test this hypothesis we examined whether repeated treatment with cocaine, which enhances its psychomotor activating effects (i.e. produces behavioural sensitization), also enhances its ability to induce c-fos expression in the STN. In addition, given that STN activity is thought to be influenced by preproenkephalin mRNA-containing (ENK+) neurons in the caudate-putamen, we also examined whether repeated cocaine treatment alters c-fos expression in ENK+ cells. We report that: (i) cocaine pretreatment enhances the ability of a cocaine challenge to induce c-fos mRNA expression in the STN, and this effect is most robust at challenge doses where behavioural sensitization is observed; (ii) the ability of cocaine to induce c-fos in the STN is independent of the ability of cocaine to engage ENK+ cells. These results support the idea that the STN is involved in stimulant-induced psychomotor activation and sensitization, but suggest that stimulant-induced engagement of the STN is not dependent on ENK+ cells in the caudate-putamen. These findings may have implications concerning the neurobiological mechanisms underlying the behavioural effects of psychostimulant drugs.

Animals↗

Morphological organization of the globus pallidus-subthalamic nucleus system studied in organotypic cultures.

The morphological organization of the globus pallidus (GP), the subthalamic nucleus (STN), and the pallidosubthalamic projection was studied in organotypic cultures. Coronal slices from the GP, the STN, the striatum (CPu), and the cortex (Cx) were taken from the rat after postnatal days 0-2 and grown for 2 or 5-6 weeks. For analysis, immunocytochemistry against glutamate (GLU), parvalbumin (PV), and calretinin (CR) was combined with confocal microscopy. After 2 weeks in vitro, the STN showed a densely packed, homogeneous GLU-immunoreactive (ir) cell population. Pallidal GLU-ir neurons were heterogeneous, consisting of large-sized weakly GLU-ir neurons and small-sized intensively GLU-ir neurons. After 5-6 weeks in vitro, pallidal axons had radiated from numerous large-sized PV-ir cells and selectively innervated the STN, where they heavily ramified. Cultured STN neurons were not stained for PV; however, multipolar intensely PV-ir neurons were located at the border of the STN with their dendrites oriented towards the STN. Double labeling for PV and CR in both mature cultures and in the adult rat revealed that the culture CR-ir neurons from the GP, the Cpu, and from areas adjacent to the STN were different from cultured PV-ir neurons and their morphologies and distribution corresponded to that in vivo. These results demonstrate that 1) cultured CP and STN neurons display similar morphologies found in in vivo, 2) PV-ir pallidal neurons heavily and selectively innervate the STN; 3) there is a specific class of STN border neurons; and 4) in contrast to the in vivo situation, most cultured STN neurons are PV-negative.

Animals↗

Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease.

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37+/-17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement-related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71+/-23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1-2 seconds) of electrical microstimulation of STN could produce tremor arrest but were not found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.

Adult↗

Topographical projections from the thalamus, subthalamic nucleus and pedunculopontine tegmental nucleus to the striatum in the Japanese monkey, Macaca fuscata.

Topographical projections from the thalamus, subthalamic nucleus (STN) and pedunculopontine tegmental nucleus (PPN) to the striatum were examined in the Japanese monkey (Macaca fuscata) by using the retrograde axonal transport technique of WGA-HRP (wheat germ agglutinin-conjugated horseradish peroxidase). After WGA-HRP injection in the head of the caudate nucleus (CN) or putamen (Put), labeled neuronal cell bodies in the thalamus were distributed mainly in the nucleus ventralis anterior (VA)-nucleus ventralis lateralis (VL) complex and the nucleus centrum medianum (CM)-nucleus parafascicularis (Pf) complex, and additionally in the paraventricular, parataenial, rhomboid, reuniens, centrodorsal, centrolateral, paracentral, and centromedial nuclei. The data indicated that the pars principalis of VA (VApc) projected mainly to CN and additionally to Put, and that the pars magnocellularis of VA (VAmc) or pars oralis of VL (VLo) projected selectively to CN or Put, respectively. It was also indicated that CM projected to the middle and caudal parts of Put, while Pf projected to CN and the rostral part of the Put. The data further indicated that the dorsomedial, ventromedial, or lateral part of CM projected respectively to the dorsolateral, ventromedial, or intermediate part of Put, and that the medial or lateral part of Pf projected respectively to the medial or lateral part of the head of CN. Direct projections from STN and PPN to the striatum were confirmed. The subthalamostriatal projections showed a mediolateral topography. The PPN was shown to project bilaterally to the striatum with an ipsilateral predominance.

Animals↗

D1 dopamine receptors influence Fos immunoreactivity in the globus pallidus and subthalamic nucleus of intact and nigrostriatal-lesioned rats.

Studies of the globus pallidus (GP) and subthalamic nucleus (STN) have emphasized the role of D2 dopamine receptors, although effects of D1 receptor activation on GP firing rate and STN metabolism have been reported, especially in rats with nigrostriatal lesions. This study systematically investigated the effects of D1 and D2 receptor activation on the activity of the GP and STN in intact and 6-OHDA-lesioned rats using immunostaining for the immediate-early gene Fos. In intact rats, the D1 agonist SKF 38393 (20.0 mg/kg) produced a five-fold potentiation of the GP Fos expression due to the D2 agonist quinpirole produced significant Fos expression. In rats with prior nigrostriatal lesions, SKF 38393 (4.0 or 20.0 mg/kg) increased Fos immunostaining in both the GP and STN, while quinpirole increased it only in the GP. SKF 38393 effects in the GP and STN of nigrostriatal-lesioned rats were blocked completely by SCH 23390, and unaffected by eticlopride. These results are a novel demonstration of control of Fos expression by dopaminergic drugs in the STN and by D1 agonists in the GP.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Subthalamic nucleus deep brain stimulation in Parkinson disease patients over age 70 years.

The effects of subthalamic nucleus deep brain stimulation were studied in 52 consecutive patients (13 over age 70, 15 under age 60, 24 age 60 to 70). All groups had improvement of motor fluctuations and dyskinesia. Patients over age 70 had worsening of Unified Parkinson's Disease Rating Scale motor scores on medication, despite less medication reduction. Their activities of daily living and axial subscores worsened, particularly in those with preoperative gait difficulties.

Age Factors↗

The fine structure of the subthalamic nucleus in the cat. I. Neuronal perikarya.

The fine structure of the neurons in the subthalamic nucleus (Sth) of the cat has been studied. On the basis of the following criteria: the size and the shape of the neuronal perikarya, the ultrastructural characteristics of their organelles, the presence and quantity of somatic spines and their afferentation, three categories of neuronal perikarya were discriminated: large, medium and small neurons. The large neurons have a diameter above 18 microns and nucleocytoplasmic ratio above 1:1,8. These neurons are the richest in organelles, possess the most numerous spines, and are most afferented. According to their shape, the large neurons were subdivided in multipolar, fusiform, and irregular types. The medium sized neurons have a mean diameter between 16 and 13 microns and nucleocytoplasmic ratio 1:1,5-1:1,3. Their cytoplasm contains a lesser number of organelles that are more loosely distributed. The medium neurons possess a small number of somatic spines and are less afferented. The small neurons have a mean diameter below 12 microns and their nucleocytoplasmic ratio is below 1:1,2. Their cytoplasm is poor in organelles and they usually lack spines. The small neurons are remarkably oligoafferented. The large neurons constitute approximately 25%, the medium sized - about 50%, and the small neurons - less than 5% of the neuronal population. The remaining neuronal perikarya do not offer reliable electron microscopical criteria that could allow an unequivocal discrimination.

Animals↗