Subthalamic Neuronal Activity Research Articles

Optimized Propofol Anesthesia Increases Power of Subthalamic Neuronal Activity in Patients with Parkinson's Disease Undergoing Deep Brain Stimulation.

IntroductionPropofol is a general anesthetic option for deep brain stimulation (DBS) of the subthalamic nucleus (STN) of patients with Parkinson's disease (PD). However, its effects on STN activity and neuropsychological outcomes are controversial. The optimal propofol anesthesia for asleep DBS is unknown. This study investigated the safety and effectiveness of an optimized propofol anesthesia regimen in asleep DBS.MethodsThis retrospective study enrolled 68 PD patients undergoing bilateral STN-DBS surgery. All patients received local scalp anesthesia, with (asleep group, n = 35) or without (awake group, n = 33) propofol-remifentanil general anesthesia by target-controlled infusion under electroencephalogram monitoring. The primary outcome was subthalamic neuronal spiking characterization during microelectrode recording. The secondary outcomes were clinical outcomes including motor, cognition, mind, sleep, and quality of life at 6 months.ResultsSignificantly increased delta and theta power were obtained under propofol anesthesia (awake vs. asleep group, mean ± standard deviation; delta: 31.97 ± 9.87 vs. 39.77 ± 10.56, p < 0.01; theta: 21.09 ± 5.55 vs. 24.82 ± 6.63, p = 0.01). After excluding the influence of confounding factors of age and preoperative motor scores, there was a statistically significant influence on the delta, theta, and alpha power of STN neuronal activity under different anesthesia regimens (delta: β = 2.64, p < 0.01; theta: β = 2.11, p < 0.01; alpha: β = 1.42, p = 0.01). There were no differences in modified burst index, firing rate, tract numbers of microelectrode recording, and other clinical outcomes between the two groups.ConclusionOptimized propofol anesthesia enhanced the delta, theta, and alpha power in STN compared with the awake technique and likely contributed to target recognition under propofol anesthesia. These results demonstrate that propofol is suitable, but needs to be optimized, for asleep STN-DBS.Trial RegistrationChinese Clinical Trial Registry Identification number: ChiCTR2100045942. Registered 29 April 2021–Retrospectively registeredSupplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00259-y.

Cortical Control of Subthalamic Neuronal Activity through the Hyperdirect and Indirect Pathways in Monkeys.

The subthalamic nucleus (STN) plays a key role in the control of voluntary movements and basal ganglia disorders, such as Parkinson's disease and hemiballismus. The STN receives glutamatergic inputs directly from the cerebral cortex via the cortico-STN hyperdirect pathway and GABAergic inputs from the external segment of the globus pallidus (GPe) via the cortico-striato-GPe-STN indirect pathway. The STN then drives the internal segment of the globus pallidus, which is the output nucleus of the basal ganglia. Thus, clarifying how STN neuronal activity is controlled by the two inputs is crucial. Cortical stimulation evokes early excitation and late excitation in STN neurons, intervened by a short gap. Here, to examine the origin of each component of this biphasic response, we recorded neuronal activity in the STN, combined with electrical stimulation of the motor cortices and local drug application in two male monkeys (Macaca fuscata) in the awake state. Local application of glutamate receptor antagonists, a mixture of an AMPA/kainate receptor antagonist and an NMDA receptor antagonist, into the vicinity of recorded STN neurons specifically diminished early excitation. Blockade of the striatum (putamen) or GPe with local injection of a GABAA receptor agonist, muscimol, diminished late excitation in the STN. Blockade of striato-GPe transmission with local injection of a GABAA receptor antagonist, gabazine, into the GPe also abolished late excitation. These results indicate that cortically evoked early and late excitation in the STN is mediated by the cortico-STN glutamatergic hyperdirect and the cortico-striato-GPe-STN indirect pathways, respectively.SIGNIFICANCE STATEMENT Here we show that the subthalamic nucleus (STN), an input station of the basal ganglia, receives cortical inputs through the cortico-STN hyperdirect and cortico-striato-external pallido-STN indirect pathways. This knowledge is important for understanding not only the normal functions of the STN, but also the pathophysiology of STN-related disorders and therapy targeting the STN. Lesions or application of high-frequency stimulation in the STN ameliorates parkinsonian symptoms. These procedures could affect all components in the STN, such as afferent inputs through the hyperdirect and indirect pathways, and STN neuronal activity. If we can understand which component is most affected by such procedures, we may be able to identify more effective manipulation targets or methods to treat Parkinson's disease.

Subthalamic Nucleus Neurons Differentially Encode Early and Late Aspects of Speech Production.

Basal ganglia-thalamocortical loops mediate all motor behavior, yet little detail is known about the role of basal ganglia nuclei in speech production. Using intracranial recording during deep brain stimulation surgery in humans with Parkinson's disease, we tested the hypothesis that the firing rate of subthalamic nucleus neurons is modulated in sync with motor execution aspects of speech. Nearly half of 79 unit recordings exhibited firing-rate modulation during a syllable reading task across 12 subjects (male and female). Trial-to-trial timing of changes in subthalamic neuronal activity, relative to cue onset versus production onset, revealed that locking to cue presentation was associated more with units that decreased firing rate, whereas locking to speech onset was associated more with units that increased firing rate. These unique data indicate that subthalamic activity is dynamic during the production of speech, reflecting temporally-dependent inhibition and excitation of separate populations of subthalamic neurons.SIGNIFICANCE STATEMENT The basal ganglia are widely assumed to participate in speech production, yet no prior studies have reported detailed examination of speech-related activity in basal ganglia nuclei. Using microelectrode recordings from the subthalamic nucleus during a single-syllable reading task, in awake humans undergoing deep brain stimulation implantation surgery, we show that the firing rate of subthalamic nucleus neurons is modulated in response to motor execution aspects of speech. These results are the first to establish a role for subthalamic nucleus neurons in encoding of aspects of speech production, and they lay the groundwork for launching a modern subfield to explore basal ganglia function in human speech.

Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation

Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease. To support a potential link between LRRK2 and α-synuclein in the pathophysiological mechanisms underlying PD, the effect of LRRK2 ablation or LRRK2 kinase pharmacological inhibition were studied in rats with adeno-associated virus-induced (AAV) α-synuclein overexpression in the nigrostriatal pathway. We first report that viral overexpression of α-synuclein induced increased burst firing in subthalamic neurons. Aberrant firing pattern of subthalamic neurons has also been reported in PD patients and neurotoxin-based animal models, and is hypothesized to play a key role in the appearance of motor dysfunction. We further report that genetic LRRK2 ablation, as well as pharmacological inhibition of LRRK2 kinase activity with PFE-360, reversed the aberrant firing pattern of subthalamic neurons induced by AAV-α-synuclein overexpression. This effect of LRRK2 modulation was not associated with any neuroprotective effect or motor improvement. Nonetheless, our findings may indicate a potential therapeutic benefit of LRRK2 kinase inhibition by normalizing the aberrant neuronal activity of subthalamic neurons induced by AAV-α-synuclein, a neurophysiological trait recapitulating observations in PD.

GABAA and GABAB receptor subunit localization on neurochemically identified neurons of the human subthalamic nucleus.

The subthalamic nucleus (STN) is a critical excitatory signaling center within the basal ganglia circuitry. The activity of subthalamic neurons is tightly controlled by upstream inhibitory signaling centers in the basal ganglia. In this study, we used immunohistochemical techniques to firstly, visualize and quantify the STN neurochemical organization based on neuronal markers including parvalbumin (PV), calretinin (CR), SMI-32, and GAD65/67 . Secondly, we characterized the detailed regional, cellular and subcellular expression of GABAA (α1 , α2 , α3 , β2/3 , and γ2 ) and GABAB (R1 and R2) receptor subunits within the normal human STN. Overall, we found seven neurochemically distinct populations of principal neurons in the human STN. The three main populations detected were: (a) triple-labeled PV+ /CR+ /SMI32+ ; (b) double-labeled PV+ /CR+ ; and (c) single-labeled CR+ neurons. Subthalamic principal neurons were found to express GABAA receptor subunits α1 , α3 , β2/3 , γ2 , and GABAB receptor subunits R1 and R2. However, no expression of GABAA receptor α2 subunit was detected. We also found a trend of increasing regional staining intensity for all positive GABAA receptor subunits from the dorsolateral pole to ventromedial extremities. The GAD+ interneurons showed relatively low expression of GABAA receptor subunits. These results provide the morphological basis of GABAergic transmission within the normal human subthalamic nucleus and evidence of GABA innervation through both GABAA and GABAB receptors on subthalamic principal neurons.

Human subthalamic oscillatory dynamics following somatosensory stimulation

ObjectiveElectrical median nerve somatosensory stimulation leads to a distinct modulation of cortical oscillations. Initial high frequency and gamma augmentation, as well as modulation of beta and alpha oscillations have been reported. We aimed at investigating the involvement of the subthalamic nucleus in somatosensory processing by means of local field potential recordings, since recordings during passive movements and peripheral somatosensory stimulation have suggested a prominent role. MethodsRecordings of subthalamic neuronal activity following median nerve stimulation in 11 Parkinson’s disease patients were performed. Time-frequency analysis from 1 to 500 Hz was averaged and analyzed. ResultsSeveral oscillatory components in response to somatosensory stimulation were revealed in the time-frequency analysis: (I) prolonged increase in alpha band power, followed by attenuation; (II) initial suppression of power followed by a subsequent rebound in the beta band; (III) early broad-frequency increase in gamma band power; (IV) and sustained increase of 160 Hz frequency oscillations throughout the trial. ConclusionsThese results further corroborate the involvement of the subthalamic nucleus in somatosensory processing. SignificanceThe present results not only support the notion of somatosensory processing in the subthalamic nucleus. Moreover, an improvement of somatosensory processing during subthalamic deep brain stimulation in Parkinson’s disease might be accounted for by enhancement of prevailing high frequency oscillations.

Movement-Related Activity of Human Subthalamic Neurons during a Reach-to-Grasp Task.

The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson’s disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans.

Algorithmic design of a noise-resistant and efficient closed-loop deep brain stimulation system: A computational approach.

Advances in the field of closed-loop neuromodulation call for analysis and modeling approaches capable of confronting challenges related to the complex neuronal response to stimulation and the presence of strong internal and measurement noise in neural recordings. Here we elaborate on the algorithmic aspects of a noise-resistant closed-loop subthalamic nucleus deep brain stimulation system for advanced Parkinson’s disease and treatment-refractory obsessive-compulsive disorder, ensuring remarkable performance in terms of both efficiency and selectivity of stimulation, as well as in terms of computational speed. First, we propose an efficient method drawn from dynamical systems theory, for the reliable assessment of significant nonlinear coupling between beta and high-frequency subthalamic neuronal activity, as a biomarker for feedback control. Further, we present a model-based strategy through which optimal parameters of stimulation for minimum energy desynchronizing control of neuronal activity are being identified. The strategy integrates stochastic modeling and derivative-free optimization of neural dynamics based on quadratic modeling. On the basis of numerical simulations, we demonstrate the potential of the presented modeling approach to identify, at a relatively low computational cost, stimulation settings potentially associated with a significantly higher degree of efficiency and selectivity compared with stimulation settings determined post-operatively. Our data reinforce the hypothesis that model-based control strategies are crucial for the design of novel stimulation protocols at the backstage of clinical applications.

Chronic L-DOPA administration increases the firing rate but does not reverse enhanced slow frequency oscillatory activity and synchronization in substantia nigra pars reticulata neurons from 6-hydroxydopamine-lesioned rats

The pathophysiology of Parkinson's disease (PD) and of L-DOPA-induced dyskinesia (LID) is associated with dysfunctional neuronal activity in several nuclei of the basal ganglia. Moreover, high levels of oscillatory activity and synchronization have also been described in both intra- and inter-basal ganglia nuclei and the cerebral cortex. However, the relevance of these alterations in the motor symptomatology related to Parkinsonism and LID is not fully understood. Recently, we have shown that subthalamic neuronal activity correlates with axial abnormal movements and that a subthalamic nucleus (STN) lesion partially reduces LID severity as well as the expression of some striatal molecular modifications. The aim of the present study was to assess, through single-unit extracellular recording techniques under urethane anaesthesia, neuronal activity of the substantia nigra pars reticulata (SNr) and its relationship with LID and STN hyperactivity together with oscillatory and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned and dyskinetic rats.Twenty-four hours after the last injection of L-DOPA the firing rate and the inhibitory response to an acute challenge of L-DOPA of SNr neurons from dyskinetic animals were increased with respect to those found in intact and 6-OHDA-lesioned rats. Moreover, there was a significant correlation between the mean firing rate of SNr neurons and the severity of the abnormal movements (limb and orolingual subtypes). There was also a significant correlation between the firing activity of SNr and STN neurons recorded from dyskinetic rats. In addition, low frequency band oscillatory activity and synchronization both within the SNr or STN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals and not or slightly affected by chronic treatment with L-DOPA.Altogether, these results indicate that neuronal SNr firing activity is relevant in dyskinesia and may be driven by STN hyperactivity. Conversely, low frequency oscillatory activity and synchronization seem to be more important in PD because they are not influenced by prolonged L-DOPA administration.

NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus.

The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease.

Dorsolateral subthalamic neuronal activity enhanced by median nerve stimulation characterizes Parkinson's disease during deep brain stimulation with general anesthesia.

Deep brain stimulation (DBS) surgery under general anesthesia is an alternative option for patients with Parkinson's disease (PD). However, few studies are available that report whether neuronal firing can be accurately recorded during this condition. In this study the authors attempted to characterize the neuronal activity of the subthalamic nucleus (STN) and elucidate the influence of general anesthetics on neurons during DBS surgery in patients with PD. The benefit of median nerve stimulation (MNS) for localization of the dorsolateral subterritory of the STN, which is involved in sensorimotor function, was explored. Eight patients with PD were anesthetized with desflurane and underwent contralateral MNS at the wrist during microelectrode recording of the STN. The authors analyzed the spiking patterns and power spectral density (PSD) of the background activity along each penetration track and determined the spatial correlation to the target location, estimated mated using standard neurophysiological procedures. The dorsolateral STN spiking pattern showed a more prominent bursting pattern without MNS and more oscillation with MNS. In terms of the neural oscillation of the background activity, beta-band oscillation dominated within the sensorimotor STN and showed significantly more PSD during MNS (p < 0.05). Neuronal firing within the STN could be accurately identified and differentiated when patients with PD received general anesthetics. Median nerve stimulation can enhance the neural activity in beta-band oscillations, which can be used as an index to ensure optimal electrode placement via successfully tracked dorsolateral STN topography.

Additional noradrenergic depletion aggravates forelimb akinesia and abnormal subthalamic nucleus activity in a rat model of Parkinson's disease

AimsThis study aims to identify the contribution of additional noradrenergic depletion to forelimb akinesia and abnormal subthalamic nucleus (STN) firing activity in Parkinson's disease (PD). Main methodsForelimb akinesia behaviors were tested in awake rats with noradrenergic N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions, unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra pars compacta (SNc) and with combined 6-OHDA and DSP-4 lesions. STN extracellular single-unit and local field potential (LFP) activities were examined in the animals that were anesthetized with urethane. Key findingsThe adjusting steps and the contralateral touches of rats in the forelimb akinesia behavior tests were markedly inhibited by a further noradrenergic lesion with DSP-4 in 6-OHDA+DSP-4-lesioned group when compared with those of 6-OHDA-lesioned animals (P<0.05 for all comparisons). Meanwhile, the neuronal firing pattern of STN also changed significantly towards more bursty in 6-OHDA+DSP-4-lesioned group (P<0.05). Compared with 6-OHDA-lesioned animals, an additional noradrenergic lesion increased the 0.3–2.5Hz oscillatory activity and the spike power of STN neurons (P<0.01 for both comparisons), and strengthened the synchronized oscillation between subthalamic neuronal firing and LFP activity in 6-OHDA+DSP-4-lesioned group (P<0.01). SignificanceThe results provide evidence to support the correlation between noradrenergic depletion and the further exaggerated dysfunction of STN electrical activity in PD and suggest that an aberrant noradrenergic system might play a specific role in the motor deficits of PD.

Neuronal firing activity and gene expression changes in the subthalamic nucleus after transplantation of dopamine neurons in hemiparkinsonian rats

Dopamine (DA) depletion in the nigrostriatal system leads to basal ganglia dysfunction both in Parkinson's disease (PD) and in 6-hydroxy dopamine (6-OHDA)-lesioned rats with neuronal hyperactivity in the subthalamic nucleus (STN), i.e. increased firing rate and burst activity, together with enhanced beta oscillatory activity. Moreover, intrastriatal transplantation of DA neurons has been shown to functionally re-innervate the host striatum and restore DA input.However, the effects of those transplanted cells on the STN are not well characterized. Therefore, we transplanted cells, derived from the ventral mesencephalon of E12 rat embryos, intrastriatally in the unilateral 6-OHDA-lesioned rat model of PD. We combined behavioral and histological findings with electrophysiological extracellular recordings in the STN, as well as qRT-PCR analyses of dopaminergic, GABAergic, and glutamatergic transporter and receptor genes in the striatum and the STN. Transplanted animals displayed improved rotational behavior after amphetamine injection by 50% in rats with small grafts (586±109 SEM dopamine cells), or even overcompensation by 116% in rats with large grafts (3486±548 SEM dopamine cells). Electrophysiological measurements revealed, that in rats with large grafts burst activity was not affected, while STN neuronal firing rate, as well as beta oscillatory activity was alleviated, whereas small grafts had less impact. Interestingly, both behavioral and electrophysiological measures were dependent on the number of surviving tyrosine hydroxylase positive cells. Although grafted rats displayed restored expression of the GABA synthesizing enzymes Gad65 and Gad67 in the striatum compared to naive rats, the grafts induced a decreased mRNA expression of dopamine receptor Drd2, glutamate receptors AMPA3, NMDA2A, and NMDA2B, and glutamate transporter Eaat3. Interestingly, the NMDA receptor subunit 2B and glutamate transporter Eaat3 were also less expressed in the STN of grafted animals compared to naive rats.In summary, DA grafts restore functional deficits and cause partial improvement of subthalamic neuronal activity. Incomplete recovery, however, may be due to decreased receptor gene expression induced by DA grafts in the striatum and in the STN.

Pathological gambling in Parkinson's disease: Subthalamic oscillations during economics decisions

Pathological gambling develops in up to 8% of patients with Parkinson's disease. Although the pathophysiology of gambling remains unclear, several findings argue for a dysfunction in the basal ganglia circuits. To clarify the role of the subthalamic nucleus in pathological gambling, we studied its activity during economics decisions. We analyzed local field potentials recorded from deep brain stimulation electrodes in the subthalamic nucleus while parkinsonian patients with (n = 8) and without (n = 9) pathological gambling engaged in an economics decision-making task comprising conflictual trials (involving possible risk-taking) and non conflictual trials. In all parkinsonian patients, subthalamic low frequencies (2-12 Hz) increased during economics decisions. Whereas, in patients without gambling, low-frequency oscillations exhibited a similar pattern during conflictual and non conflictual stimuli, in those with gambling, low-frequency activity increased significantly more during conflictual than during non conflictual stimuli. The specific low-frequency oscillatory pattern recorded in patients with Parkinson's disease who gamble could reflect a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. When parkinsonian patients process stimuli related to an economics task, low-frequency subthalamic activity increases. This task-related change suggests that the cognitive-affective system that drives economics decisional processes includes the subthalamic nucleus. The specific subthalamic neuronal activity during conflictual decisions in patients with pathological gambling supports the idea that the subthalamic nucleus is involved in behavioral strategies and in the pathophysiology of gambling.

Emerging dysfunctions consequent to combined monoaminergic depletions in parkinsonism

The loss of dopamine (DA) neurons has been the pathophysiological focus of the devastating conditions of Parkinson's disease, but depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD. The present study aimed to investigate, in rats, the respective role of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) depletions on motor and non-motor behaviors and on subthalamic (STN) neuronal activity. We show that NA or DA depletion significantly decreased locomotor activity and enhanced the proportion of bursty and irregular STN neurons. Anxiety-like states required DA depletion plus the depletion of 5-HT or NA. Anhedonia and “depressive-like” behavior emerged only from the combined depletion of all three monoamines, an effect paralleled by an increase in the firing rate and the proportion of bursty and irregular STN neurons. Here, we provide evidence for the exacerbation of behavioral deficits when NA and/or 5-HT depletions are combined with DA depletion, bringing new insight into the combined roles of the three monoamines in PD.

Human Subthalamic Neuron Spiking Exhibits Subtle Responses to Sedatives

During deep brain stimulation implant surgery, microelectrode recordings are used to map the location of targeted neurons. The effects produced by propofol or remifentanil on discharge activity of subthalamic neurons were studied intraoperatively to determine whether they alter neuronal activity. Microelectrode recordings from 11 neurons, each from individual patients, were discriminated and analyzed before and after administration of either propofol or remifentanil. Subthalamic neurons in rat brain slices were recorded in patch-clamp to investigate cellular level effects. Neurons discharged at 42 ± 9 spikes/s (mean ± SD) and showed a common pattern of inhibition that lasted 4.3 ms. Unique discharge profiles were evident for each neuron, seen using joint-interval analysis. Propofol (intravenous bolus 0.3 mg/kg) produced sedation, with minor effects on discharge activity (less than 2.0% change in frequency). A prolongation of recurrent inhibition was evident from joint-interval analysis, and propofol's effect peaked within 2 min, with recovery evident at 10 min. Subthalamic neurons recorded in rat brain slices exhibited inhibitory synaptic currents that were prolonged by propofol (155%) but appeared to lack tonic inhibitory currents. Propofol did not alter membrane potential, membrane resistance, current-evoked discharge, or holding current during voltage clamp. Remifentanil (0.05 mg/kg) had little effect on overall subthalamic neuron discharge activity and did not prolong recurrent inhibition. These results help to characterize the circuit properties and feedback inhibition of subthalamic neurons and demonstrate that both propofol and remifentanil produce only minor alterations of subthalamic neuron discharge activity that should not interfere with deep brain stimulation implant surgery.

Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy

Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive–compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1–8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative–limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative–limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology.

Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

Rationale:It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density.Objective:The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats.Results:We have previously shown that Δ9-tetrahydrocannabinol (Δ9-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ9-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats.Conclusions:Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

Regulation of subthalamic neuron activity by endocannabinoids

High levels of anandamide are located in the basal ganglia. The subthalamic nucleus (STN) is considered to be an important modulator of basal ganglia output. The present study aims at characterizing the modulation of the electrical activity of STN neurons by exogenous anandamide or endocannabinoids. Single-unit extracellular recordings in anesthetized rats and patch-clamp techniques in rat brain slices containing the STN were performed. Immunohistochemical assays were used. In vivo, anandamide administration produced two opposite effects (inhibition or stimulation) on STN neuron firing rates, depending of the precise location of the neuron within the nucleus. These effects were enhanced by prior inhibition of fatty acid amide hydrolase with URB597, but not by the inhibitor of carrier-mediated anandamide transport AM404. Rimonabant, a specific CB(1) receptor antagonist, also produced inhibition or stimulation of STN neuron activity when administered alone or after anandamide. These effects seem to be mediated by indirect mechanisms since: (1) STN neuron activity is not modified by the cannabinoid agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in vitro; (2) no depolarization-induced suppression of inhibition phenomena were observed; and (3) CB(1) receptor immunolabeling was not detected in the STN, but was abundant in areas which project efferents to this nucleus. Moreover, chemical lesion of the globus pallidus abolished the stimulatory effect of anandamide and microinfusion of anandamide into the prefrontal cortex led to inhibition of STN neuron activity. The present results show that endocannabinoids exert a tonic control on STN activity via receptors located outside the nucleus. These findings may contribute to enhance our understanding of the role of the endocannabinoid system in motor control.

Abstracts of The Movement Disorder Society's Thirteenth International Congress of Parkinson's Disease and Movement Disorders

Objective: Study the subthalamic (STN) neuronal activity in patients with Obsessive Compulsive Disorders (OCD). Background: Dysfunction in the basal ganglia circuitry has been implicated in obsessive and compulsive disorder (OCD). In a recent clinical research program, high frequency electrical stimulation of the STN has proved to be efficient in alleviating obsessions and compul sions in OCD patients and permitted to study neuronal activity in this disorder (Mallet et al, 2008). Methods: Unit neuronal activity of STN neurons were recorded in awake OCD patients at rest and compared to data obtained in patients with Parkinson’s disease (PD). The mean firing rate and interspike intervals were calculated for each cell. The firing pattern was classified as regular, irregular or bursting (Kaneoke and Vitek, 1996). Neuronal activity was also sampled for each period and epochs of elevated discharge rate were classified as burst using a Poisson surprise analysis. Spike trains with S>=3 were considered to be bursts. Percentages of action potentials and duration with S>=3 and mean S value were calculated for each cell. The precise localization of neuronal activity recordings was performed using a 3-D deformable basal ganglia atlas with a particular reference to STN subterritories. Results: 156 STN neurons were isolated in 11 OCD patients and 113 neurons in 10 PD patients. In comparison to PD, the mean discharge frequency of STN neurons was lower in OCD patient (24.1+/-14.1 Hz vs 32.1+/-17.7 Hz, P =3 (17.7 6 4.7 vs 14.9 6 5.6 %, P<10-4). Conclusions: In OCD patients, the subthalamic neuronal activity seems abnormal with an increase in the bursting type activity. This is in line with the hypothesis of the role of basal ganglia, and the subthalamic nucleus, in the physiopathology of this disorder.