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PubMed2001

Time-course of changes in firing rates and firing patterns of subthalamic nucleus neuronal activity after 6-OHDA-induced dopamine depletion in rats.

The subthalamic nucleus (STN) plays a key role in motor control. Disorganization of its neuronal activity is implicated in the manifestation of parkinsonian motor symptoms. The aim of the present work was to study the time-course of changes in the firing activity of STN neurons in a rat model of parkinsonism. Electrophysiological recordings were done in normal rats and four groups of rats at different time points after 6-hydroxydopamine (6-OHDA) microinjection into the pars compacta of substantia nigra (SNc). Results showed a significant decrease in firing rate during the first and second weeks post lesion (5.53+/-0.56 and 7.66+/-0.73 spikes/s, respectively) compared to normal rats (11.13+/-0.59 spikes/s). From the 3rd week after 6-OHDA injection the firing rates returned toward baseline, with an average of 9.71+/-0.51 spikes/s during the 3rd week and 11.13+/-0.71 spikes/s during the 4th week. With regard to firing pattern, the majority of STN cells (90%) discharged regularly or slightly irregularly in normal animals. Only 4% exhibited burst activity and 6% had mixed firing patterns. After SNc-lesion, the percentage of cells exhibiting burst and mixed patterns increased progressively from 35% during the first week to 56% at week 4 post-lesion. In sum, these experiments revealed that the firing rate of STN neurons was altered only transiently following nigral lesions, whereas a progressive and stable change in the firing pattern was observed up to 4 weeks post lesion, suggesting that the persistence of bursts firing more closely relates to the motor pathologies of this rat model of parkinsonism.

Action Potentials↗
PubMed2003

Stimulation of the subthalamic nucleus in Parkinson's disease does not produce striatal dopamine release.

OBJECTIVE: The subthalamic nucleus (STN) is a target in the surgical treatment of Parkinson's disease (PD). The mechanism by which electrical stimulation of the STN ameliorates symptoms of PD remains unknown. One consistent aspect of STN stimulation is the ability to reduce the dosage of dopaminergic medications; sometimes they can be eliminated altogether. Furthermore, nigrostriatal projection axons are apposed to the dorsal surface of the STN and are likely affected by the application of current in this region. We sought to determine whether STN stimulation could release endogenous striatal dopamine. METHODS: Five patients with PD, who had previously undergone surgical implantation of bilateral STN stimulators, underwent [(11)C]raclopride positron emission tomographic scanning. l-dopa was withheld for 12 hours, and both stimulators were turned off 9 hours before scanning. We assayed for striatal dopamine release by measuring radioligand displacement as a consequence of turning on the right STN stimulator after 45 minutes of a 90-minute [(11)C]raclopride infusion. Patients were evaluated with the motor section of the Unified Parkinson's Disease Rating Scale before and after the studies. RESULTS: Comparisons between the right and left striata, before and after right STN stimulation, demonstrated no significant differences in [(11)C]raclopride binding, despite significant improvements in Unified Parkinson's Disease Rating Scale motor scores with unilateral stimulation (mean improvement, 26.0 +/- 16.4%; P < 0.05). This finding was also noted when the striatum was partitioned into dorsal and ventral caudate and putamen and the four regions were analyzed separately. CONCLUSION: Our results suggest that STN stimulation does not mediate its anti-PD effects via the release of dopamine, as assessed with [(11)C]raclopride displacement.

Adult↗
PubMed2006

Operative techniques and morbidity with subthalamic nucleus deep brain stimulation in 100 consecutive patients with advanced Parkinson's disease.

OBJECTIVE: Subthalamic nucleus (STN) stimulation for patients with medically refractory Parkinson disease (PD) is expanding. Reported experience has provided some indication of techniques, efficacy, and morbidity, but few centres have reported more than 50 patients. To expand this knowledge, we reviewed our experience with a large series of consecutive patients. METHODS: From March 1999 to September 2003, 191 subthalamic stimulator devices (19 unilateral) were implanted in 100 patients with PD at New York Presbyterian Hospital/Columbia University Medical Center. Sixteen patients had undergone a prior surgery for PD (pallidotomy, thalamotomy, or fetal transplant). Microelectrode guided implantations were performed using techniques similar to those described previously. Electrode implantation occurred 1-2 weeks before outpatient pulse generator implantation. RESULTS: Reductions of dyskinesias and off severity/duration were similar to prior published reports. Morbidity included: 7 device infections (3.7%), 1 cerebral infarct, 1 intracerebral haematoma, 1 subdural haematoma, 1 air embolism, 2 wound haematomas requiring drainage (1.0%), 2 skin erosions over implanted hardware (1.0%), 3 periprocedural seizures (1.6%), 6 brain electrode revisions (3.1%), postoperative confusion in 13 patients (6.8%), and 16 battery failures (8.4%). Of the 100 patients, there were no surgical deaths or permanent new neurological deficits. The average hospital stay for all 100 patients was 3.1 days. CONCLUSION: Subthalamic stimulator implantation in a large consecutive series of patients with PD produced significant clinical improvement without mortality or major neurological morbidity. Morbidity primarily involved device infections and hardware/wound revisions.

Adult↗
PubMed2003

Simultaneous use of bilateral subthalamic nucleus stimulators and an implantable cardiac defibrillator. Case report.

Bilateral electrical stimulation of the subthalamic nucleus is being used with increasing frequency as a treatment for severe Parkinson disease (PD). Implantable cardiac defibrillators improve survival in certain high-risk patients with coronary artery disease and ventricular arrhythmias. Because of concern about possible interaction between these devices, deep brain stimulation (DBS) systems are routinely disconnected before defibrillators are implanted in patients with PD and arrhythmia. The authors report on a patient with bilateral subthalamic stimulators who underwent successful placement of an implantable defibrillator. Testing of the devices over a wide range of settings revealed no interaction. The patient subsequently underwent multiple episodes of cardioversion when the ventricular lead became dislodged. There was no evidence of adverse neurological effects, and interrogation of the DBS devices after cardioversion revealed no changes in stimulus parameters. The outcome in this case indicates that DBS systems may be safely retained in selected patients who require implantable cardiac defibrillators.

Aged↗
PubMed2006

Unilateral lesion of the subthalamic nucleus enhances cortical fos expression associated with focally evoked seizures in the rat.

Reducing subthalamic nucleus (STN) activity has been proposed as an anti-epileptic procedure. Here we show that, on the contrary, a unilateral lesion of the STN causes slight (nonsignificant) increases in the severity of limbic seizures evoked by bicuculline infusion into the piriform cortex, associated with marked Fos expression throughout the cerebral cortex. Abolishing the STN control over the basal ganglia output may therefore play a facilitatory role on cortical activation associated with limbic seizures.

Animals↗
PubMed2006

Dopaminergic and GABAergic modulation of glutamate release from rat subthalamic nucleus efferents to the substantia nigra.

The regulation of the glutamatergic projection from the subthalamic nucleus (STN) to the substantia nigra (SN) was investigated using dual-probe microdialysis in the awake behaving rat. Reverse dialysis of the cholinergic receptor agonist carbachol (1 mM) into the STN caused an increase in the extracellular concentrations of glutamate and dopamine in the SN. The increase in glutamate was transient and returned toward basal values despite the continued perfusions of the STN with carbachol. Carbachol-stimulated glutamate release was prolonged by perfusion of the selective D2 dopamine receptor antagonist raclopride (100 microM) into the SN and was attenuated by the perfusion of the selective D2-like receptor agonist quinpirole (10 microM). In contrast, perfusion of the D1 dopamine receptor antagonist SCH-23390 (100 microM) did not alter the carbachol-stimulated glutamate release even though it increased basal glutamate concentrations. Perfusion of the GABAA receptor antagonist bicuculline (10 microM) into the SN prolonged the carbachol-stimulated glutamate release in similar fashion as raclopride. The present findings suggest that somatodendritically released dopamine in the SN regulates glutamate release from subthalamic axon terminals by differentially activating dopamine D2 and D1 receptors. Activation of D2 heteroreceptors, located on STN axon terminals, provides a negative feedback control on stimulated subthalamic glutamate release, while D1 receptor activation preferentially regulates basal glutamate concentrations. The findings of the present study also indicate that GABA exerts an inhibitory control on glutamate release in the SN through GABAA receptors.

Analysis of Variance↗
PubMed1986

Stimulation of the subthalamic nucleus enhances the release of dopamine in the rat substantia nigra.

The release of dopamine in the substantia nigra and striatum was investigated in halothane anaesthetized rats by means of the push-pull cannula method. Electrical stimulation of the subthalamic nucleus produced a marked enhancement of dopamine release in the ipsilateral substantia nigra. This effect is likely to be mediated by subthalamic efferent neurons since the application of acetylcholine in the subthalamic nucleus produced a similar effect. A later decrease of dopamine release was always observed in the ipsilateral striatum and was attributed to the autoregulation mechanisms of nigro-striatal dopaminergic neurons.

Animals↗
PubMed2007

Subthalamic nucleus stimulation is efficacious in patients with Parkinsonism and LRRK2 mutations.

Stimulation of the subthalamic nucleus (STN) improves motor signs in patients with levodopa-responsive Parkinson's disease (PD). Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause Parkinsonism. We assessed 69 patients under STN stimulation and found heterozygous LRRK2 mutations in 9 (G2019S in 8 and T2031S in 1). The age at onset of PD, the clinical characteristics before or after neurosurgery, and the clinical response to STN stimulation were similar in both groups. Two patients with the G2019S LRRK2 mutation still benefited from STN stimulation, 9 and 10 years after surgery. Patients with LRRK2 mutations are, therefore, good candidates for STN stimulation.

Adult↗
PubMed2004

Sodium currents in subthalamic nucleus neurons from Nav1.6-null mice.

In some central neurons, including cerebellar Purkinje neurons and subthalamic nucleus (STN) neurons, TTX-sensitive sodium channels show unusual gating behavior whereby some channels open transiently during recovery from inactivation. This "resurgent" sodium current is effectively activated immediately after action potential-like waveforms. Earlier work using Purkinje neurons suggested that the great majority of resurgent current originates from Na(v)1.6 sodium channels. Here we used a mouse mutant lacking Na(v)1.6 to explore the contribution of these channels to resurgent, transient, and persistent components of TTX-sensitive sodium current in STN neurons. The resurgent current of STN neurons from Na(v)1.6(-/-) mice was reduced by 63% relative to wild-type littermates, a less dramatic reduction than that observed in Purkinje neurons recorded under identical conditions. The transient and persistent currents of Na(v)1.6(-/-) STN neurons were reduced by approximately 40 and 55%, respectively. The resurgent current present in Na(v)1.6(-/-) null STN neurons was similar in voltage dependence to that in wild-type STN and Purkinje neurons, differing only in having somewhat slower decay kinetics. These results show that sodium channels other than Na(v)1.6 can make resurgent sodium current much like that from Na(v)1.6 channels.

Animals↗
PubMed2003

Effects of subthalamic nucleus stimulation on the micturation reflex in cats.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) has been performed to reverse motor dysfunction in severe parkinsonian patients. Recent studies suggested that neural circuitry in the basal ganglia might regulate micturition function as well. In 15 adult male cats under ketamine anesthesia, in which spontaneous isovolumetric micturition reflex had been generated, we performed electrical stimulation and extracellular single unit recording in the STN. Electrical stimulation applied in the STN elicited inhibition of the micturition reflex. None of the responses was facilitatory. Effective amplitude of the electrical stimulation for evoking inhibitory responses was less than 50 microA, which gradually increased and exceeded 250 microA as the location of the stimulation exceeded an area of the STN. Effective frequency of the electrical stimulation with given stimulus intensity was 50 Hz and higher. Total 10 neurons were recorded in the STN that were related to urinary storage/micturition cycles. All neurons were tonically active throughout storage/micturition cycles with storage phase predominance, with almost constant firing activities during the storage phase. In conclusion, our results showed that HFS-STN inhibited the micturition reflex and there were micturition-related neuronal firings in the STN in cats, suggesting the STN may be involved in neural control of micturition. The results also provide an implication that clinical HFS-STN may alter urinary function in parkinsonian patients.

Animals↗
PubMed2006

Real-time refinement of subthalamic nucleus targeting using Bayesian decision-making on the root mean square measure.

The subthalamic nucleus (STN) is a major target for treatment of advanced Parkinson's disease patients undergoing deep brain stimulation surgery. Microelectrode recording (MER) is used in many cases to identify the target nucleus. A real-time procedure for identifying the entry and exit points of the STN would improve the outcome of this targeting procedure. We used the normalized root mean square (NRMS) of a short (5 seconds) MER sampled signal and the estimated anatomical distance to target (EDT) as the basis for this procedure. Electrode tip location was defined intraoperatively by an expert neurophysiologist to be before, within, or after the STN. Data from 46 trajectories of 27 patients were used to calculate the Bayesian posterior probability of being in each of these locations, given RMS-EDT pair values. We tested our predictions on each trajectory using a bootstrapping technique, with the rest of the trajectories serving as a training set and found the error in predicting the STN entry to be (mean +/- SD) 0.18 +/- 0.84, and 0.50 +/- 0.59 mm for STN exit point, which yields a 0.30 +/- 0.28 mm deviation from the expert's target center. The simplicity and computational ease of RMS calculation, its spike sorting-independent nature and tolerance to electrode parameters of this Bayesian predictor, can lead directly to the development of a fully automated intraoperative physiological procedure for the refinement of imaging estimates of STN borders.

Bayes Theorem↗
PubMed2004

Single pulse stimulation of the human subthalamic nucleus facilitates the motor cortex at short intervals.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). The mechanism is poorly understood. High-frequency STN DBS has been reported to affect motor cortex excitability in a complex way, but the timing between STN stimuli and changes in motor cortical (M1) excitability has not been investigated. We examined the time course of changes in motor cortical excitability following single pulse STN DBS. We studied 14 PD patients with implanted DBS electrodes in the STN, 2 patients with electrodes in internal globus pallidus (GPi), and 1 patient with an electrode in the sensory thalamus. Transcranial magnetic stimulation (TMS) was delivered to the M1 ipsilateral to the DBS with induced currents either in the anterior-posterior direction in the brain to evoke indirect (I) waves or in the lateral-medial direction to activate corticospinal axons directly. Single pulse stimulation through the DBS contacts preceded the TMS by 0-10 ms. Surface EMG was recorded from the contralateral first dorsal interosseous muscle. Three milliseconds after STN stimulation, the motor evoked potential (MEP) amplitudes produced by anterior-posterior current were significantly larger than control responses, while the responses to lateral-medial currents were unchanged. Similar facilitation also occurred after GPi stimulation, but not with thalamic stimulation. Single pulse STN stimulation facilitates the M1 at short latencies. The possible mechanisms include antidromic excitation of the cortico-STN fibers or transmission through the basal ganglia-thalamocortical pathway.

Adult↗
PubMed2005

Suppression of secondary generalization of limbic seizures by stimulation of subthalamic nucleus in rats.

OBJECT: Deep brain stimulation (DBS) of subcortical nuclei such as the subthalamic nucleus (STN) or the substantia nigra pars reticulata (SNR) may provide an alternative therapy for intractable epilepsy. The authors attempted to evaluate the antiepileptic effects of DBS to these structures in an experimental seizure model. METHODS: Three groups of rats were prepared. In the first two groups, the rats underwent unilateral implantation of stimulation electrodes in the STN (six rats) or the SNR (six rats). A control group received no electrodes (six rats). Kainic acid (KA) was systemically administered to induce limbic seizures, which started with focal seizures and became generalized secondarily. High-frequency electrical stimulation of the STN or SNR was begun immediately after KA administration, and changes on electroencephalography (EEG) and the magnitude of clinical seizures were evaluated. Results showed that STN stimulation significantly reduced the duration of generalized seizures on EEG, although the total duration of seizures (generalized plus focal seizures) was unchanged. The duration of focal seizures on EEG was prolonged by STN DBS, a result possibly due to the suppression of secondary generalization. In addition, STN DBS reduced the severity of clinical seizures. On the other hand, stimulation of the SNR demonstrated no effect. CONCLUSIONS: Unilateral STN DBS showed significant suppression of the secondary generalization of limbic seizures. Note, however, that SNR DBS was less effective, which implies that in addition to the nigral control of the epilepsy system, another antiepileptic mechanism such as antidromic stimulation of the corticosubthalamic pathway should be considered.

Animals↗
PubMed2006

MEP latency shift after implantation of deep brain stimulation systems in the subthalamic nucleus in patients with advanced Parkinson's disease.

Deep brain stimulation (DBS) into the subthalamic nucleus (STN) is a highly effective treatment for advanced Parkinson's disease (PD). The consequences of STN stimulation on intracortical and corticospinal excitability have been addressed in a few studies using transcranial magnetic stimulation (TMS). Although excitability measurements were compared between the STN stimulation OFF and ON condition, in these experiments, there are no longitudinal studies examining the impact of electrode implantation per se on motor excitability. Here, we explored the effects of STN electrode implantation on resting motor thresholds (RMT), motor evoked potential (MEP) recruitment curves, and MEP onset latencies on 2 consecutive days before and shortly after STN surgery with the stimulator switched off, thus avoiding the effects of chronic DBS on the motor system, in 8 PD patients not taking any dopaminergic medication. After surgery, RMT and MEP recruitment curves were unchanged. In contrast, MEP onset latencies were significantly shorter when examined in relaxed muscles but were unchanged under preactivation. We hypothesize that postoperatively TMS pulses induced small currents in scalp leads underneath the TMS coil connecting the external stimulator with STN electrodes leading to inadvertent stimulation of fast-conducting descending neural elements in the vicinity of the STN, thereby producing submotor threshold descending volleys. These "conditioning" volleys probably preactivated spinal motor neurons leading to earlier suprathreshold activation by the multiple corticospinal volleys produced by TMS of the motor cortex. These TMS effects need to be considered when interpreting results of excitability measurements in PD patients after implantation of STN electrodes.

Aged↗
PubMed2006

Impact of subthalamic nucleus stimulation on the initiation of gait in Parkinson's disease.

The effects of subthalamic nucleus (STN) stimulation on the anticipatory postural actions associated with the initiation of gait were studied in ten patients with idiopathic Parkinson's disease undergoing therapeutic deep brain stimulation. Kinematic, dynamic and electromyographic analysis was performed before and while subjects were starting gait in response to an external cue. Effects of STN stimulation on the standing posture preceding the go signal included significant improvement of the vertical alignment of the trunk and shank, decrease of the hip joint moment, backward shift of the center of pressure (CoP) and reduction of abnormal tonic and/or rhythmic activity in the thigh and leg muscles. Responses to bilateral STN stimulation were more consistent than those evoked by unilateral stimulation. Moreover, comparison between postural changes induced by STN stimulation applied prior to the gait initiation cue and during simple quiet standing revealed more significant responses in the former condition. Effects on the actual gait initiation process included shortening of the imbalance phase, larger backward/lateral displacement of CoP and more physiological expression of the underlying anticipatory muscular synergy. Additional changes were shortening of the unloading phase, shortening of the first-swing phase and increase in the length of the first step. Results demonstrate substantial influence of STN stimulation on functionally basic motor control mechanisms. In particular, the evidence of more significant responses upon attention-demanding conditions and the remarkable effects on postural programmes sub-serving feed-forward regulation of the onset of complex multijoint movements, suggests a consistent action on postural sub-systems relying on cognitive data processing and internal models of body mechanics.

Aged↗
PubMed2006

Basal ganglia neural responses during behaviorally effective deep brain stimulation of the subthalamic nucleus in rats performing a treadmill locomotion test.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). In spite of proven therapeutic success, the mechanism underlying the benefits of DBS has not been resolved. A multiple-channel single-unit recording technique was used in the present study to investigate basal ganglia (BG) neural responses during behaviorally effective DBS of the STN in a rat model of PD. Rats underwent unilateral dopamine (DA) depletion by injection of 6-hydroxyDA (6-OHDA) into one side of the medial forebrain bundle and subsequently developed a partial akinesia, which was assessed during the treadmill locomotion task. High frequency stimulation (HFS) of the STN restored normal treadmill locomotion behavior. Simultaneous recording of single unit activity in the striatum (STR), globus pallidus (GP), substantia nigra pars reticulata (SNr), and STN revealed a variety of neural responses during behaviorally effective HFS of the STN. Predominant inhibitory responses appeared in the STN stimulation site. Nearly equal numbers of excitatory and inhibitory responses were found in the GP and SNr, whereas more rebound excitatory responses were found in the STR. Mean firing rate did not change significantly in the STR, GP, and SNr, but significantly decreased in both sides of STN during DBS. A decrease in firing rate in the contralateral side of STN provides neural substrate for the clinical observation that unilateral DBS produces bilateral benefits in patients with PD. In addition to the firing rate changes, a decrease in burst firing was observed in the GP and STN. The present study indicates that DBS induces complex modulations of the BG circuit and further suggests that BG network reorganization, rather than a simple excitation or inhibition, may underlie the therapeutic effects of DBS in patients with PD.

Adrenergic Agents↗
PubMed1978

Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey.

Corticofugal projections were examined by means of the autoradiographic tracer method in 21 macaca fascicularis. The labeled material was injected into the main body representation areas of the precentral motor cortex and into various regions of Brodmann's areas 6, 8 and 9 of the frontal lobe. The ipsilateral subthalamic nucleus receives a moderately strong and somato-topically organized projection from Woolsey's precentral motor cortex. This projection is mainly restricted to the lateral moiety. The remaining nucleus is occupied by less intensive projections from premotor and prefrontal areas. It is concluded that the subthalamic nucleus is a convergence site of pallidal and corticomotor and frontal projections. Cortical afferents may exert an influence on the pallido-subthalamic-pallidal inhibitory feedback loop.

Animals↗