Dongming Gao

Acute and Long-Term Effects of Subthalamic Nucleus Stimulation in Parkinson's Disease

In animal models of Parkinsons disease (PD), it is postulated that the excessive output from the subthalamic nucleus (STN) plays a critical role. Selective lesions or high frequency electrical stimulation of the STN can alleviate parkinsonian symptoms in MPTP-treated monkeys. We decided to carry out STN stimulation in patients suffering from severe akinetic forms of PD. After approval of the institutional ethical committee, we operated on a parkinsonian patient aged 51, suffering for 8 years from a strongly disabling akinetorigid form of PD, complicated by an on-off effect (Hoehn and Yahr stage 5 in the worst-off motor phase). Stereotactic surgery was done on one side under local anesthesia. The theoretical target was chosen according to stereotactic atlases, based on ventriculographic landmarks such as anterior and posterior commissures (AC and PC). The final position of the chronic electrodes was optimized using electrophysiological recording and stimulation along with clinical assessment and surface EMG of agonist and antagonist muscles of the examined limbs. A spontaneous increase in neuronal activity was recorded in an area located 2-4 mm under the level of the intercommissural plane, 10 mm from the midline, at mid-distance between AC and PC. Within the same place, a 130-Hz stimulation induced acute and reversible akinesia alleviation mainly on the contralateral limbs, comparable to that obtained with dopaminergic drugs. No dyskinesia, such as hemiballism, was induced by introduction of electrodes or by stimulation. Then a long-term quadripolar DBS Medtronic electrode was inserted in this area. Studies of the effects of chronic stimulation were extensively performed to determine the best spatiotemporal and electrical stimulation variables.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Changes in the firing pattern of globus pallidus neurons after the degeneration of nigrostriatal pathway are mediated by the subthalamic nucleus in the rat

Changes in the neuronal activity of globus pallidus (GP) have been shown in animal models of parkinsonism. In order to study the implication of the subthalamic nucleus (STN) in these changes, the effects of STN lesions alone or in combination with 6‐hydroxydopamine (6‐OHDA) ‐induced damage to the substantia nigra compacta (SNc) were examined in rats using electrophysiological recordings of GP cells. In normal rats, the firing rate was 22.1 ± 1.4 spikes/s. The pattern was regular in 45%, irregular in 49% and bursty in 6% of the cases. In rats with STN lesions, the firing rate of GP units (20.15 ± 1.25 spikes/s) did not differ from that of normal rats and only regular (46%) and irregular (54%) cells were found; a bursty pattern was not observed. 6‐OHDA lesions of the SNc induced no change in the firing rate of GP neurons (21.5 ± 1.4 spikes/s, P > 0.05) but a significant decrease in the percentage of regular cells (27%, P < 0.001), a significant increase in burst cells (21%, P < 0.001) with no change in the percentage of irregular units (52%) were observed. In rats with combined SNc and STN lesions, the firing pattern did not change from that of normal rats. The present results show that STN lesions induced the disappearance of bursts in normal rats and normalization of firing pattern in the GP units of rats with 6‐OHDA lesions suggesting that the STN plays an important role in the modulation of the pattern of activity of GP neurons which may account for the therapeutic effect of STN lesions in Parkinsons disease.

High frequency stimulation of the STN influences the activity of dopamine neurons in the rat

&NA; The effect of high frequency stimulation (HFS) of the subthalamic nucleus (STN) on the spontaneous activity of substantia nigra pars compacta (SNc) dopaminergic neurons was investigated in normal rats and in rats with globus pallidus (GP) lesions. In normal rats, the spontaneous activity of SNc neurons did not significantly differ from that of rats with GP lesions (4.2 ± 2.2 versus 4.4 ± 2.6 spikes/s). STN‐HFS induced an increase of firing rate in the majority of tested cells in normal (76%) and GP‐lesioned rats (73%) with an after‐effect of 34.4 ± 3.4 and 33.2 ± 3.1 s, respectively. These results demonstrate that STN‐HFS influences the activity of the SNc dopaminergic neurons by increasing their firing rate and that this increase of activity is independent of the globus pallidus.

Effect of microiontophoretic application of dopamine on subthalamic nucleus neuronal activity in normal rats and in rats with unilateral lesion of the nigrostriatal pathway

The subthalamic nucleus (STN) receives dopamine inputs from the substantia nigra but their implication in the pathophysiology of parkinsonism is still debated. Extracellular microrecordings were used to study the effect of microiontophoretic injection of dopamine and the D1 receptor agonist SKF 38393 on the activity of STN neurons in normal and 6‐hydroxydopamine‐lesioned rats under urethane anaesthesia. Dopamine and SKF induced an increase in the firing rate of the majority of STN neurons in both normal and 6‐OHDA rats. In rats with 6‐OHDA lesions, the percentage of firing rate increase did not differ from that of controls. When GABA, glutamate and dopamine were all applied to the same individual STN neurons, GABA induced an inhibitory effect and glutamate and dopamine caused an excitatory effect in both groups. This excitatory response was suppressed by the application of GABA. Systemic administration of apomorphine provoked a decrease in the firing rate of STN neurons in rats with 6‐OHDA lesions. These results show that dopamine exerts an excitatory influence on STN neurons, suggesting that the inhibitory effect induced by the systemic injection of apomorphine is due to the GABAergic inputs from the globus pallidus as predicted by the current model of basal ganglia organization. In addition, we show that dopamine, GABA and glutamate can act on the same STN neuron and that GABA can reverse the excitatory effect of dopamine and glutamate, suggesting the predominant influence of GABAergic inputs to the subthalamic nucleus.

Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus and of other nuclei as a treatment for Parkinson's disease

Abstract:During stereotaxy in nonanesthetized patients with Parkinsons disease or essential tremor, tremor was suppressed by test stimulation of the thalamic ventralis intermedius nucleus (Vim) at high frequency (130 Hz). Based on this finding, the authors have used chronic stimulation of the Vim a

Intensity-dependent nociceptive responses from presumed dopaminergic neurons of the substantia nigra, pars compacta in the rat and their modification by lateral habenula inputs

The characteristics of nociceptive responses from presumed dopaminergic (DAergic) neurons in the SN were investigated in the anesthetized rat with extracellular recordings. 194 presumed DAergic neurons were recorded. A majority of these neurons (78%) were inhibited by intensive electrical stimulation performed at the tail (PNS) and 15% were excited. Both inhibitory and excitatory responses were intensity-dependent. Single shock stimulation of the lateral habenula (LHb) inhibited 89% of the tested DAergic neurons, most of which (83.8%) were also inhibited by PNS. LHb stimulation increased PNS-induced inhibition of DAergic neurons and electrical destruction of ipsilateral LHb depressed their nociceptive responses. Our results strongly suggest that DAergic neurons encode the nociceptive stimulation intensity and that the LHb shares a step in nociceptive projection to the SN.

Roles of GABA, glutamate, acetylcholine and STN stimulation on thalamic VM in rats.

THE effects of high frequency stimulation of the subthalamic nucleus (STN) and of iontophoretic application of different neurotransmitters on neuronal activities of the ventromedial thalamic nucleus (VM) were investigated in rats. GABA, when applied iontophoretically, inhibited VM neuronal activity while bicuculline, L-glutamic acid and acetylcholine enhanced the firing rates of the same VM neurons. High frequency stimulation of the STN increased VM neuronal activity in a frequency-dependent manner, which could be blocked by MK801. These results suggest that GABAergic, cholinergic and glutamatergic input information converge in the same VM neurons and that an increase in the delivery of glutamatergic neurotransmitter activities in the VM is involved in the process of high frequency stimulation of the STN.

PHYSIOLOGY OF SUBTHALAMIC NUCLEUS NEURONS IN ANIMAL MODELS OF PARKINSON'S DISEASE

The subthalamic nucleus (STN) has been reported to play an important role in the control of movement. It is described as a “driving force of the basal ganglia” because it exerts a glutamatergic excitatory influence on the output structures of the system: the pars reticulata of substantia nigra (SNr) and the internal part of globus pallidus (GPi, the equivalent of the entopeduncular nucleus (EP) in rodents) (Kitai and Kita, 1987; Robledo and Feger, 1990). From the review of Parent and Hazrati (1995), it appears that the STN, like the striatum, is a major structure through which cortical signals are transmitted to the output nuclei of the basal ganglia. Moreover, in addition to the direct cortico-STN pathway, the cortex influences the STN through an indirect pathway involving the striatum and the external part of globus pallidus (GPe, an equivalent of GP in rodents).