Subthalamic Nucleus Neuronal Activity Research Articles

Subthalamic nucleus input-output dynamics are correlated with Parkinson’s burden and treatment efficacy

The subthalamic nucleus (STN) is pivotal in basal ganglia function in health and disease. Micro-electrode recordings of >25,000 recording sites from 146 Parkinson’s patients undergoing deep brain stimulation (DBS) allowed differentiation between subthalamic input, represented by local field potential (LFP), and output, reflected in spike discharge rate (SPK). As with many natural systems, STN neuronal activity exhibits power-law dynamics characterized by the exponent α. We, therefore, dissected STN data into aperiodic and periodic components using the Fitting Oscillations & One Over F (FOOOF) tool. STN LFP showed significantly higher aperiodic exponents than SPK. Additionally, SPK beta oscillations demonstrated a downward frequency shift compared to LFP. Finally, the STN aperiodic and spiking parameters explained a significant fraction of the variance of the burden and treatment efficacy of Parkinson’s disease. The unique STN input-output dynamics may clarify its role in Parkinson’s physiology and can be utilized in closed-loop DBS therapy.

The anterior cingulate cortex controls the hyperactivity in subthalamic neurons in male mice with comorbid chronic pain and depression.

Neurons in the subthalamic nucleus (STN) become hyperactive following nerve injury and promote pain-related responses in mice. Considering that the anterior cingulate cortex (ACC) is involved in pain and emotion processing and projects to the STN, we hypothesize that ACC neurons may contribute to hyperactivity in STN neurons in chronic pain. In the present study, we showed that ACC neurons enhanced activity in response to noxious stimuli and to alterations in emotional states and became hyperactive in chronic pain state established by spared nerve injury of the sciatic nerve (SNI) in mice. In naïve mice, STN neurons were activated by noxious stimuli, but not by alterations in emotional states. Pain responses in STN neurons were attenuated in both naïve and SNI mice when ACC neurons were inhibited. Furthermore, optogenetic activation of the ACC-STN pathway induced bilateral hyperalgesia and depression-like behaviors in naive mice; conversely, inhibition of this pathway is sufficient to attenuate hyperalgesia and depression-like behaviors in SNI mice and naïve mice subjected to stimulation of STN neurons. Finally, mitigation of pain-like and depression-like behaviors in SNI mice by inhibition of the ACC-STN projection was eliminated by activation of STN neurons. Our results demonstrate that hyperactivity in the ACC-STN pathway may be an important pathophysiology in comorbid chronic pain and depression. Thus, the ACC-STN pathway may be an intervention target for the treatment of the comorbid chronic pain and depression.

Subthalamic nucleus neuronal activity entropy in the effective stimulation area in patients with Parkinson’s disease

One of the most successful and promising treatments for Parkinson’s disease today is deep brain stimulation (DBS). Accurate localization of the stimulation area is critical for the outcome of surgical DBS electrode implantation in the subthalamic nucleus (STN). To achieve this, microelectrode recording is used during surgery to precisely locate the STN borders [1], while test stimulations with a macroelectrode are widely employed to enhance DBS electrode placement accuracy. Thus, through testing multiple trajectories, the most clinically effective one can be selected. However, a comprehensive and reliable description of the specific single neuron activity associated with successful DBS electrode implantation is currently lacking. A study was conducted using microelectrode recordings (MER) of single neuron activity in the STN of 21 Parkinson’s disease patients (UPDRS III off/on=46.9/12.8) to identify the neuronal activity features associated with the most favorable clinical outcome of test stimulation. A comparative analysis of 29 activity parameters, such as firing rate, oscillatory activity intensity in different frequency ranges (Oscores), coefficient of variation, burst, pause index, among others [2], was conducted for 618 identified neurons. In addition, the approach of computing the entropy of the change in interspike intervals (ISI) of the pulse sequence [3] and the process of identifying patterns of neural activity using hierarchical clustering [4] were implemented. A comparative analysis of single neuron activity indicated notable (p 0.05) variations between disregarded and selected paths for the ultimate implantation of DBS electrode, solely relying on entropy parameters. Trajectories that delivered optimal test stimulation outcomes demonstrated reduced entropy of interspike intervals. Only the patterns of neuronal activity characterized by extended periods of steady firing and brief pauses, referred to as tonic and pause activity, respectively, were found to contribute to the difference in entropy between trajectories. In contrast, there were no statistically significant differences detected in entropy values associated with neurons demonstrating burst activity. Furthermore, we observed a positive and significant correlation between entropy values and the degree of improvement in disease presentation before and after administration of medication. A comparative analysis was conducted on the activity of single neurons along different trajectories with varied test stimulation responses. The results showed a weak effectiveness of linear parameters in determining the optimal electrode insertion path for improved clinical outcomes. However, the use of non-linear activity parameters, specifically entropy, in single neurons effectively differentiated trajectories with significant versus absent/insignificant test stimulation results. Furthermore, the significance of entropy in establishing the basal ganglia functions and describing information transfer processes in movement control is emphasized by interpreting this parameter as a measure of uncertainty or unpredictability of the information system in relation to the findings of other studies [5].

Differences in neuronal activity of subthalamic nuclei in asymmetric manifestation of Parkinson’s disease

Parkinson’s disease (PD) is a widely prevalent condition that has spurred extensive research into identifying its biological markers. Different models posit that various patterns of subthalamic nucleus (STN) activity may constitute such markers, but as yet, none have been established definitively. One major limitation of human studies in this area is the lack of a reliable control group. Therefore, patients with asymmetric motor symptoms in Parkinson’s disease are of great interest. I.I. Koloman and A.Sh. Chimagomedova [1] demonstrated that motor malfunctions’ asymmetry is indicative of asymmetry in the degenerative process within the substantia nigra. Additionally, while the disease normally manifests unilaterally, only a limited number of patients maintain notable distinctions in motor symptom severity as the condition advances. In our study, we analyzed the single-unit activity (SUA) and local field potentials (LFP) recordings obtained duringdeep brain stimulation (DBS) surgeries in 12 patients. Neurologists assessed the severity of bradykinesia, rigidity, and tremor using the UPDRS 3 scale to meet the inclusion criteria, and the difference between hemibodies for each symptom had to be at least 25%. The median disease duration at the time of surgery ranged from 6 to 22 years. The subthalamic nucleus that exhibits more pronounced disturbances on the contralateral side of the body is labeled as “affected”, while the opposite STN, acting as the conditional control, is labeled as “nonaffected”. For analysis, we used a hierarchical clustering method following Ward’s algorithm [2] to classify the recorded neurons into three groups based on their activity type: tonic, burst, and pause cells. We observed no significant differences in neuron activity between hemispheres, as well as the predicted hyperactivity of affected STN neurons outlined by the classical model [3] of basal ganglia functioning. However, the research demonstrates a significant increase in pause neurons and decrease in burst neurons within the affected nucleus. Furthermore, both of these types were found to be situated in the upper half of the STN, which is recognized as the motor region of the nucleus. Our hypothesis is that as the disease advances, some STN neurons (specifically burst neurons in our sample) modify their activity patterns towards a more rhythmic activity (pause neurons in our sample). This supports the notion that rhythmic STN neuron activity is linked to Parkinson’s disease [4]. LFPs were analyzed by estimating oscillation synchrony (o-scores) in multiple spectral bands following 1/f correction. Parkinson’s disease is typically associated with boosted oscillation power in the beta range (13–30 Hz). Our findings established that the power of oscillations in the low-frequency beta range (13–20 Hz) were indeed increased in the affected nucleus, but, in contrast to expectations, the power in the high-frequency part (20–30 Hz) of the band was significantly lower. This is in line with the modern theory of distinct physiological functions of oscillations in these subbands [5]. Additionally, we noticed a rise in frequency spectrum in the alpha range (8–12 Hz) and a decrease in the gamma range (30–60 Hz) in the impacted nucleus. Our findings indicate that a more rhythmic burst neuron activity mode and an increased number of pause neurons in the motor zone of the STN can serve as a marker for PD. Increased power oscillation in alpha and low-frequency beta bands, along with reduced synchronization in high-beta and gamma bands, may also be linked to this disorder. However, further investigation is necessary to determine their association with disease symptoms.

CORRELATION BETWEEN SUBTHALAMIC ALPHA RHYTHMIC ACTIVITY AND MOTOR CONTROL IMPAIRMENT IN PARKINSONIAN PATIENTS

Increased oscillatory beta activity in basal ganglia is one of the main electrophysiological biomarkers of impaired motor control in Parkinson’s disease. However, the functional role of dynamical rhythmic processes during movements is still not investigated in detail. We used microelectrode recordings to investigate the subthalamic nucleus neuronal activity in 9 patients with Parkinson’s disease during deep brain stimulation surgery. We have shown that the amplitude of the subthalamic nucleus alpha (7–12 Hz) and low-beta (12–20 Hz) activity correlated with motor impairment indices in patients with Parkinson’s disease. Also, we have shown that, in contrast to beta rhythmic activity, the magnitude of alpha activity decreased significantly during motor tests execution. Moreover, the degree of rhythmic activity suppression in the alpha band correlated with the severity of bradykinesia. These results allow us to suppose that, along with beta activities, subthalamic nucleus neuronal alpha activity also participate in motor control of Parkinson’s disease patients.

A subthalamo-parabrachial glutamatergic pathway is involved in stress-induced self-grooming in mice.

Excessive self-grooming is an important behavioral phenotype of the stress response in rodents. Elucidating the neural circuit that regulates stress-induced self-grooming may suggest potential treatment to prevent maladaptation to stress that is implicated in emotional disorders. Stimulation of the subthalamic nucleus (STN) has been found to induce strong self-grooming. In this study we investigated the role of the STN and a related neural circuit in mouse stress-related self-grooming. Body-restraint and foot-shock stress-induced self-grooming models were established in mice. We showed that both body restraint and foot shock markedly increased the expression of c-Fos in neurons in the STN and lateral parabrachial nucleus (LPB). Consistent with this, the activity of STN neurons and LPB glutamatergic (Glu) neurons, as assessed with fiber photometry recording, was dramatically elevated during self-grooming in the stressed mice. Using whole-cell patch-clamp recordings in parasagittal brain slices, we identified a monosynaptic projection from STN neurons to LPB Glu neurons that regulates stress-induced self-grooming in mice. Enhanced self-grooming induced by optogenetic activation of the STN-LPB Glu pathway was attenuated by treatment with fluoxetine (18 mg·kg-1·d-1, p.o., for 2 weeks) or in the presence of a cage mate. Furthermore, optogenetic inhibition of the STN-LPB pathway attenuated stress-related but not natural self-grooming. Taken together, these results suggest that the STN-LPB pathway regulates the acute stress response and is a potential target for intervention in stress-related emotional disorders.

A nigro–subthalamo–parabrachial pathway modulates pain-like behaviors

The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain processing remains unknown. Here, we identify a pathway, consisting of GABAergic neurons in the SNr (SNrGABA) and glutamatergic neurons in the STN (STNGlu) and the lateral parabrachial nucleus (LPBGlu), that modulates acute and persistent pain states in both male and female mice. The activity of STN neurons was enhanced in acute and persistent pain states. This enhancement was accompanied by hypoactivity in SNrGABA neurons and strengthening of the STN–LPB glutamatergic projection. Reversing the dysfunction in the SNrGABA-STNGlu-LPBGlu pathway attenuated activity of LPBGlu neurons and mitigated pain-like behaviors. Therefore, the SNrGABA-STNGlu-LPBGlu pathway regulates pathological pain and is a potential target for pain management.

Bidirectional Optogenetic Modulation of the Subthalamic Nucleus in a Rodent Model of Parkinson's Disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a range of motor symptoms. Treatments are focused on dopamine replacement therapy or deep brain stimulation (DBS). The subthalamic nucleus (STN) is a common target for DBS treatment of PD. However, the function of the STN in normal conditions and pathology is poorly understood. Here, we show in rats that optogenetic modulation of STN neuronal activity exerts bidirectional control of motor function, where inhibition of the STN increases movement and STN activation decreases movement. We also examined the effect of bidirectional optogenetic manipulation STN neuronal activity under dopamine depleted condition using the bilateral rodent 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease. Optogenetic inhibition of the STN in the absence of dopamine had no impact on motor control yet STN excitation led to pronounced abnormal involuntary movement. Administration of levodopa rescued the abnormal involuntary movements induced by STN excitation. Although dopamine and STN dysfunction are well established in PD pathology, here we demonstrate simultaneous STN over activity and loss of dopamine lead to motor deficits. Moreover, we show the dysfunction of the STN is dependent on dopamine. This study provides evidence that the loss of dopamine and the over activity of the STN are key features of PD motor deficits. These results provide insight into the STN pathology in PD and therapeutic mechanism of targeting the STN for the treatment for PD.

Neurons in the Monkey's Subthalamic Nucleus Differentially Encode Motivation and Effort.

The understanding of the electrophysiological properties of the subthalamic nucleus (STN) neurons is crucial since it represents the main target of deep brain stimulation for the treatment of Parkinson's disease and obsessive-compulsive disorders. The study of its nonmotor properties could shed light on the cognitive and motivational alterations possibly encountered after stimulation. In this study, we recorded the activity of STN neurons in two male behaving monkeys (Macaca mulatta) while they performed a visuomotor motivational task in which visual cues indicated which amount of force was required to obtain which amount of reward. Our results evidenced force- and reward-modulated neurons. After the occurrence of the visual stimuli, the force-modulated neurons mainly fired when a high effort was required. Differently, the activity of the population of reward-modulated neurons encoded the motivational value of the stimuli. This population consisted of neurons increasing or decreasing their activity according to the motivational ranking of the task conditions. Both populations could play complementary roles, one in the implementation of the difficulty of the action and the other in enhancing or slowing its execution based on the subjective value of each condition.SIGNIFICANCE STATEMENT An increasing number of studies confers a role to the subthalamic nucleus (STN) in motivational and reward-related processes. However, the electrophysiological bases of such properties at the neuronal level remain unclear. The present study investigated the modulation of STN neuronal activity in monkeys performing a motivational task in which the force to produce and the reward obtained were manipulated. We found two main populations of neurons, one modulated by the effort required and the other integrating the motivational subjective value of the stimuli. This last population could help at improving decision-making to act or not, depending on the subjective value set by the motivational context. This highlights the pivotal role of STN in the valuation of cost/benefit for decision-making processes.

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.

Serotonergic control of the glutamatergic neurons of the subthalamic nucleus.

The subthalamic nucleus (STN) houses a dense cluster of glutamatergic neurons that play a central role in the functional dynamics of the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. Numerous anatomical, electrophysiological, neurochemical and behavioral studies have reported that serotonergic neurons from the midbrain raphe nuclei modulate the activity of STN neurons. Here, we describe this serotonergic innervation and the nature of the regulation exerted by serotonin (5-hydroxytryptamine, 5-HT) on STN neuron activity. This regulation can occur either directly within the STN or at distal sites, including other structures of the basal ganglia or cortex. The effect of 5-HT on STN neuronal activity involves several 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT2C and 5-HT4 receptors, which have garnered the highest attention on this topic. The multiple regulatory effects exerted by 5-HT are thought to be modified under pathological conditions, altering the activity of the STN, or due to the benefits and side effects of treatments used for Parkinson's disease, notably the dopamine precursor l-DOPA and high-frequency STN stimulation. Originally understood as a motor center, the STN is also associated with decision making and participates in mood regulation and cognitive performance, two domains of personality that are also regulated by 5-HT. The literature concerning the link between 5-HT and STN is already important, and the functional overlap is evident, but this link is still not entirely understood. The understanding of this link between 5-HT and STN should be increased due to the possible importance of this regulation in the control of fronto-STN loops and inherent motor and non-motor behaviors.

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.

Internal States Influence the Representation and Modulation of Food Intake by Subthalamic Neurons.

Deep brain stimulation of the subthalamic nucleus (STN) is an effective therapy for motor deficits in Parkinson's disease (PD), but commonly causes weight gain in late-phase PD patients probably by increasing feeding motivation. It is unclear how STN neurons represent and modulate feeding behavior in different internal states. In the present study, we found that feeding caused a robust activation of STN neurons in mice (GCaMP6 signal increased by 48.4% ± 7.2%, n = 9, P = 0.0003), and the extent varied with the size, valence, and palatability of food, but not with the repetition of feeding. Interestingly, energy deprivation increased the spontaneous firing rate (8.5 ± 1.5 Hz, n = 17, versus 4.7 ± 0.7 Hz, n = 18, P = 0.03) and the depolarization-induced spikes in STN neurons, as well as enhanced the STN responses to feeding. Optogenetic experiments revealed that stimulation and inhibition of STN neurons respectively reduced (by 11% ± 6%, n = 6, P = 0.02) and enhanced (by 36% ± 15%, n = 7, P = 0.03) food intake only in the dark phase. In conclusion, our results support the hypothesis that STN neurons are activated by feeding behavior, depending on energy homeostatic status and the palatability of food, and modulation of these neurons is sufficient to regulate food intake.

Dysregulation of external globus pallidus-subthalamic nucleus network dynamics in parkinsonian mice during cortical slow-wave activity and activation.

Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Using cell class-specific optogenetic identification and inhibition during cortical slow-wave activity and activation, we report that, in dopamine-depleted mice, (1) D2 dopamine receptor expressing striatal projection neurons (D2-SPNs) discharge at higher rates, especially during cortical activation, (2) prototypic parvalbumin-expressing GPe neurons are excessively patterned by D2-SPNs even though their autonomous activity is upregulated, (3) despite being disinhibited, STN neurons are not hyperactive, and (4) STN activity opposes striatopallidal patterning. These data argue that in parkinsonian mice abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment. Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally positioned network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Following the loss of dopamine, the activities of GPe and STN neurons become more temporally offset and strongly correlated with cortical oscillations below 40Hz. Previous studies utilized cortical slow-wave activity and/or cortical activation (ACT) under anaesthesia to probe the mechanisms underlying the normal and pathological patterning of basal ganglia activity. Here, we combined this approach with in vivo optogenetic inhibition to identify and interrupt the activity of D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs), parvalbumin-expressing prototypic GPe (PV GPe) neurons, and STN neurons. We found that, in dopamine-depleted mice, (1) the firing rate of D2-SPNs was elevated, especially during cortical ACT, (2) abnormal phasic suppression of PV GPe neuron activity was ameliorated by optogenetic inhibition of coincident D2-SPN activity, (3) autonomous PV GPe neuron firing ex vivo was upregulated, presumably through homeostatic mechanisms, (4) STN neurons were not hyperactive, despite being disinhibited, (5) optogenetic inhibition of the STN exacerbated abnormal GPe activity, and (6) exaggerated beta band activity was not present in the cortex or GPe-STN network. Together with recent studies, these data suggest that in dopamine-depleted mice abnormally correlated and temporally offset PV GPe and STN neuron activity is generated in part by elevated striatopallidal transmission, while compensatory plasticity prevents STN hyperactivity and limits cortical entrainment.

Frequency-Specific Optogenetic Deep Brain Stimulation of Subthalamic Nucleus Improves Parkinsonian Motor Behaviors.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy for the motor symptoms of Parkinson's disease (PD). However, the neural elements mediating symptom relief are unclear. A previous study concluded that direct optogenetic activation of STN neurons was neither necessary nor sufficient for relief of parkinsonian symptoms. However, the kinetics of the channelrhodopsin-2 (ChR2) used for cell-specific activation are too slow to follow the high rates required for effective DBS, and thus the contribution of activation of STN neurons to the therapeutic effects of DBS remains unclear. We quantified the behavioral and neuronal effects of optogenetic STN DBS in female rats following unilateral 6-hydroxydopamine (6-OHDA) lesion using an ultrafast opsin (Chronos). Optogenetic STN DBS at 130 pulses per second (pps) reduced pathologic circling and ameliorated deficits in forelimb stepping similarly to electrical DBS, while optogenetic STN DBS with ChR2 did not produce behavioral effects. As with electrical DBS, optogenetic STN DBS exhibited a strong dependence on stimulation rate; high rates produced symptom relief while low rates were ineffective. High-rate optogenetic DBS generated both increases and decreases in firing rates of single neurons in STN, globus pallidus externa (GPe), and substantia nigra pars reticular (SNr), and disrupted β band oscillatory activity in STN and SNr. High-rate optogenetic STN DBS can indeed ameliorate parkinsonian motor symptoms through reduction of abnormal oscillatory activity in the STN-associated neural circuit, and these results highlight that the kinetic properties of opsins have a strong influence on the effects of optogenetic stimulation.SIGNIFICANCE STATEMENT Whether STN local cells contribute to the therapeutic effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) remains unclear. We re-examined the role of STN local cells in mediating the symptom-relieving effects of STN DBS using cell type-specific optogenetic stimulation with a much faster opsin, Chronos. Direct optogenetic stimulation of STN neurons was effective in treating the symptoms of parkinsonism in the 6-hydroxydopamine (6-OHDA) lesion rat. These results highlight that the kinetic properties of opsins can have a strong influence on the effects of optogenetic activation/inhibition and must be considered when employing optogenetic to study high-rate neural stimulation.

Chemogenetic Restoration of Autonomous Subthalamic Nucleus Activity Ameliorates Parkinsonian Motor Dysfunction

Excessive, synaptically-driven synchronization of subthalamic nucleus (STN) neurons is widely thought to contribute to akinesia, bradykinesia, and rigidity in Parkinson’s disease (PD). Electrophysiological, optogenetic, chemogenetic, genetic, 2-photon imaging, and pharmacological approaches revealed that the autonomous activity of STN neurons, which opposes synaptic synchronization, was downregulated in both toxin and genetic mouse models of PD. Loss of autonomous spiking was due to increased transmission of D2-striatal projection neurons, leading in the STN to elevated activation of NMDA receptors and generation of reactive oxygen species that promoted KATP channel opening. Chemogenetic restoration of autonomous firing in STN neurons reduced synaptic patterning and ameliorated Parkinsonian motor dysfunction, arguing that elevating intrinsic STN activity is an effective therapeutic intervention in PD.

Single unit activity of subthalamic nucleus of patients with Parkinson’s disease under local and generalized anaesthesia: Multifactor analysis

The analysis of neuronal activity in human brain is a complicated task as it meets several limitations, including small sample sizes, dependent variables in the dataset and the short duration of recordings that entangles the analysis procedure. Here, we present the comparative research of neuronal activity in subthalamic nucleus (STN) of 8 Parkinsonian patients undergoing DBS surgery in awake state and under propofol anaesthesia using different statistical approaches. We studied 25 parameters of single unit activity and performed a direct comparison of the parameters between the groups to characterise the changes in STN activity under anaesthesia. We found a significant decrease in firing rate and a prominent increase in bursting of neurons in the anaesthetised state. Also, these data were used to determine the most important parameters for classification. We revealed the differences between parametric and nonparametric approaches regarding the identification of the most important spike train features. The random forest trees algorithm showed a greater accuracy of classification (91.7 ± 1.8%) compared to generalised linear models (82.4 ± 3.8%). The lists of the features important for classification according to F-scores and random forest trees also differed markedly. Our results indicate that feature interactions play a key role in neuronal activity analysis and must be taken into account.

Subthalamic nucleus high frequency stimulation prevents and reverses escalated cocaine use.

One of the key features of addiction is the escalated drug intake. The neural mechanisms involved in the transition to addiction remain to be elucidated. Since abnormal neuronal activity within the subthalamic nucleus (STN) stands as potential general neuromarker common to impulse control spectrum deficits, as observed in obsessive-compulsive disorders, the present study recorded and manipulated STN neuronal activity during the initial transition to addiction (i.e., escalation) and post-abstinence relapse (i.e., re-escalation) in rats with extended drug access. We found that low-frequency (theta and beta bands) neuronal oscillations in the STN increase with escalation of cocaine intake and that either lesion or high-frequency stimulation prevents the escalation of cocaine intake. STN-HFS also reduces re-escalation after prolonged, but not short, protracted abstinence, suggesting that STN-HFS is an effective prevention for relapse when baseline rates of self-administration have been re-established. Thus, STN dysfunctions may represent an underlying mechanism for cocaine addiction and therefore a promising target for the treatment of addiction.

Lead-Induced Atypical Parkinsonism in Rats: Behavioral, Electrophysiological, and Neurochemical Evidence for a Role of Noradrenaline Depletion.

Background: Lead neurotoxicity is a major health problem known as a risk factor for neurodegenerative diseases, including the manifestation of parkinsonism-like disorder. While lead is known to preferentially accumulate in basal ganglia, the mechanisms underlying behavioral disorders remain unknown. Here, we investigated the neurophysiological and biochemical correlates of motor deficits induced by sub-chronic injections of lead.Methods: Sprague Dawely rats were exposed to sub-chronic injections of lead (10 mg/kg, i.p.) or to a single i.p. injection of 50 mg/kg N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a drug known to induce selective depletion of noradrenaline. Rats were submitted to a battery of behavioral tests, including the open field for locomotor activity and rotarod for motor coordination. Electrophysiological recordings were carried out in three major basal ganglia nuclei, the subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNr). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, noradrenaline, and serotonin) and their metabolites has been determined using HPLC.Results: Lead intoxication significantly impaired exploratory and locomotor activity as well as motor coordination. It resulted in a significant reduction in the level of noradrenaline in the cortex and dopamine and its metabolites, DOPAC, and HVA, in the striatum. The tissue level of serotonin and its metabolite 5-HIAA was not affected in the two structures. Similarly, DSP-4, which induced a selective depletion of noradrenaline, significantly decreased exploratory, and locomotor activity as well as motor coordination. L-DOPA treatment did not improve motor deficits induced by lead and DSP-4 in the two animal groups. Electrophysiological recordings showed that both lead and DSP-4 did not change the firing rate but resulted in a switch from the regular normal firing to irregular and bursty discharge patterns of STN neurons. Neither lead nor DSP-4 treatments changed the firing rate and the pattern of GP and SNr neurons.Conclusions: Our findings provide evidence that lead represents a risk factor for inducing parkinsonism-like deficits. As the motor deficits induced by lead were not improved by L-DOPA, we suggest that the deficits may be due to the depletion of noradrenaline and the parallel disorganization of STN neuronal activity.

Neuronal firing rate and oscillatory activity in subthalamic nucleus associated with Parkinson's disease progression

Objective To explore whether neuronal firing rate and proportion of oscillatory neuronal activity in subthalamic nucleus (STN) is associated with Parkinson's disease (PD) progression. Methods Twenty-two patients with PD treated with STN deep brain stimulation (DBS) at Beijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University from March 2015 to March 2016 were analyzed retrospectively. Microelectrode recording was performed in the STN. Single unit analysis including interspike interval (ISI) was used to study neuronal firing rate and patterns. Power spectral analysis was used to evaluate neuronal oscillation.Clinical outcome was assessed using Unified Parkinson's Disease Rating Scales (UPDRS III) pre-and post-surgery. The groups of the early stage and the advanced-stage were defined based on the UPDRS III scores, disease duration and the side of initial symptoms. Results Of total 163 neurons identified from 32 STN, there were 66 neurons with mean firing rate of 46.2±13.6 Hz obtained from the patients in the early-stage group whereas 97 neurons with mean firing rate of 59.9±17.1 Hz were obtained from patients in the advanced-stage group. Power spectral analysis showed that there were 27 (40.9%) oscillatory neurons identified from the STN neurons in the early-stage patient group (n=66) whereas 55 (56.7%) oscillatory neurons were identified from the STN neurons in the advanced-stage patient group (n=95). Further analysis found that 29.7% (8/27) β oscillatory neurons were observed in the early stage group whereas 52.7% (29/55) β oscillatory neurons were observed in the advanced stage group. When comparing the mean firing rate and proportion of oscillatory neurons in the STN of early-stage group with that of neurons in the STN of advanced-stage group, it was found that there was a 29. 6% increase STN mean firing rate of neurons (46.2±13.6 Hz vs. 59.9±17.1 Hz, P<0.05) and a 36.8% increase proportion of oscillatory neurons (40.9% vs. 56.7%) between the two groups. In particular, a 77.8% increase proportion of β oscillatory neurons was obtained between the early-stage and advanced-stage groups (29.7% vs.52.8%, P<0.01). Conclusion The results strongly suggest that both subthalamic nucleus neuronal firing rate and proportion of β oscillatory neurons increase with PD progression. Key words: Parkinson disease; Subthalamic nucleus; Microelectrodes; Neurons; Neuronal firing rate; Oscillatory activity