Human Globus Pallidus Internus Research Articles

Neural oscillatory characteristics of feedback-associated activity in globus pallidus interna

Neural oscillatory activities in basal ganglia have prominent roles in cognitive processes. However, the characteristics of oscillatory activities during cognitive tasks have not been extensively explored in human Globus Pallidus internus (GPi). This study aimed to compare oscillatory characteristics of GPi between dystonia and Parkinson's Disease (PD). A dystonia and a PD patient performed the Intra-Extra-Dimension shift (IED) task during both on and off-medication states. During the IED task, patients had to correctly choose between two visual stimuli containing shapes or lines based on a hidden rule via trial and error. Immediate auditory and visual feedback was provided upon the choice to inform participants if they chose correctly. Bilateral GPi Local Field Potentials (LFP) activity was recorded via externalized DBS leads. Transient high gamma activity (~ 100–150 Hz) was observed immediately after feedback in the dystonia patient. Moreover, these bursts were phase synchronous between left and right GPi with an antiphase clustering of phase differences. In contrast, no synchronous high gamma activity was detected in the PD patient with or without dopamine administration. The off-med PD patient also displayed enhanced low frequency clusters, which were ameliorated by medication. The current study provides a rare report of antiphase homotopic synchrony in human GPi, potentially related to incorporating and processing feedback information. The absence of these activities in off and on-med PD patient indicates the potential presence of impaired medication independent feedback processing circuits. Together, these findings suggest a potential role for GPi’s synchronized activity in shaping feedback processing mechanisms required in cognitive tasks.

P 16 Effects of pallidal deep brain stimulation on striatal medium spiny neurons in the animal model of the dystonic dtsz mutant hamster

Introduction: Electric stimulation of the deep brain nuclei, such as globus pallidus internus (GPi), indicated the most relevant therapeutic option for patients with severe dystonias. However, the mechanisms of the deep brain stimulation (DBS) of the GPi are far from understood. Dystonia, a hyperkinetic movement disorder, is thought to result from an imbalance in the direct and indirect pathway arises from disturbance in the striatum. In the dt sz mutant hamster, a model of inherited generalized, paroxysmal dystonia, it has been already shown that the number of parvalbumin-positive gabaergic interneurons declined, which leads to uncontrolled projections via the medium spiny neurons (MSN) (see also Paap, et al. (2020), DOI: 10.1016/j.nbd.2020.105163). We hypothesized that DBS via backfiring, or indirectly via thalamic and cortical coupling, modifies striatal network function. Materials & Methods: The dt sz mutant hamsters were bilaterally implanted with stimulation electrodes targeting the entopeduncular nucleus (EPN; equivalent of the human GPi). DBS (130 Hz, rectangular pulse of 50 µA and 60 µs) and sham-DBS was performed in vivo in unanaesthetized animals for three hours. Acute brain slices of stim- and sham-groups were immediately prepared after the DBS has been terminated. Additionally, acute brain slices were obtained from untreated dt sz mutant hamsters (native group) to assess the effects of electrode implantation. With whole-cell patch clamp recordings, we investigated the spontaneous cortico-striatal synaptic activity and the characteristics of the D1- (direct pathway) and D2- (indirect pathway) MSN, which are capable of being differentiated by adding the D2-agonist sumanirole. Additionally, molecular analysis was performed for studying the DBS effect on ion channel gene expression. Results: In view of spontaneous release activity from cortical projections, our study indicated a strong dampening effect on the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSC) of the stim-group in contrast to sham-group. The specific cellular parameters of D1- and D2-MSN, which include resting membrane potential, input resistance, membrane capacity, rheobase, and firing properties of action potentials, did not differ between native-, sham-, and stim- group. Conclusions: To conclude, while short-term EPN-DBS obviously dampens spontaneous presynaptic glutamate release at cortico-striatal synapses, there is no alteration on MSN properties. Future studies will consider the effects of long-term stimulation on synaptic plasticity by a novel implantable stimulation system which enables DBS over weeks (see also Plocksties et al. (2021). DOI: 10.1088/1741-2552/ac23e1). This study is supported by the German Research Foundation (DFG) within the Collaborative Research Centre (SFB 1270/1 ELAINE 299150580)

Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapeutic principle in Parkinson's disease, but the underlying mechanisms, particularly mediating non-motor actions, remain largely enigmatic. Objective/hypothesisThe delayed onset of neuropsychiatric actions in conjunction with first experimental evidence that STN-DBS causes disease-modifying effects prompted our investigation on how cellular plasticity in midbrain dopaminergic systems is affected by STN-DBS. MethodsWe applied unilateral or bilateral STN-DBS in two independent cohorts of 6-hydroxydopamine hemiparkinsonian rats four to eight weeks after dopaminergic lesioning to allow for the development of a stable dopaminergic dysfunction prior to DBS electrode implantation. ResultsAfter 5 weeks of STN-DBS, stimulated animals had significantly more TH+ dopaminergic neurons and fibres in both the nigrostriatal and the mesolimbic systems compared to sham controls with large effect sizes of gHedges = 1.9–3.4. DBS of the entopeduncular nucleus as the homologue of the human Globus pallidus internus did not alter the dopaminergic systems. STN-DBS effects on mesolimbic dopaminergic neurons were largely confirmed in an independent animal cohort with unilateral STN stimulation for 6 weeks or for 3 weeks followed by a 3 weeks washout period. The latter subgroup even demonstrated persistent mesolimbic dopaminergic plasticity after washout. Pilot behavioural testing showed that augmentative dopaminergic effects on the mesolimbic system by STN-DBS might translate into improvement of sensorimotor neglect. ConclusionsOur data support sustained neurorestorative effects of STN-DBS not only in the nigrostriatal but also in the mesolimbic system as a potential factor mediating long-latency neuropsychiatric effects of STN-DBS in Parkinson's disease.

Neurophysiological Correlates of Gait in the Human Basal Ganglia and the PPN Region in Parkinson's Disease.

This study aimed to characterize the neurophysiological correlates of gait in the human pedunculopontine nucleus (PPN) region and the globus pallidus internus (GPi) in Parkinson’s disease (PD) cohort. Though much is known about the PPN region through animal studies, there are limited physiological recordings from ambulatory humans. The PPN has recently garnered interest as a potential deep brain stimulation (DBS) target for improving gait and freezing of gait (FoG) in PD. We used bidirectional neurostimulators to record from the human PPN region and GPi in a small cohort of severely affected PD subjects with FoG despite optimized dopaminergic medications. Five subjects, with confirmed on-dopaminergic medication FoG, were implanted with bilateral GPi and bilateral PPN region DBS electrodes. Electrophysiological recordings were obtained during various gait tasks for 5 months postoperatively in both the off- and on-medication conditions (obtained during the no stimulation condition). The results revealed suppression of low beta power in the GPi and a 1–8 Hz modulation in the PPN region which correlated with human gait. The PPN feature correlated with walking speed. GPi beta desynchronization and PPN low-frequency synchronization were observed as subjects progressed from rest to ambulatory tasks. Our findings add to our understanding of the neurophysiology underpinning gait and will likely contribute to the development of novel therapies for abnormal gait in PD.Clinical Trial Registration: Clinicaltrials.gov identifier; NCT02318927.

Neuronal firing activity in the basal ganglia after striatal transplantation of dopamine neurons in hemiparkinsonian rats

The loss of nigral dopaminergic neurons and the resulting dopamine (DA) depletion in the striatum (STR) lead to altered neuronal activity and enhanced beta activity in various regions of the basal ganglia (BG) motor loop in patients with Parkinson’s disease and in rodents in the 6-hydroxydopamine (6-OHDA)-lesioned rat model. Intrastriatal DA graft implantation has been shown to re-innervate the host brain and restore DA input.Here, DA cell grafts were implanted into the STR of 6-OHDA-lesioned rats and the effect on neuronal activity under urethane anesthesia (1.4g/kg, injected intraperitoneally) was tested in the entopeduncular nucleus (EPN, the equivalent to the human globus pallidus internus), the output nucleus of the BG, and the globus pallidus (GP, the equivalent to the human globus pallidus externus), a key region in the indirect pathway.In animals, which were transplanted with cells derived from the ventral mesencephalon of embryonic day 12 rat embryos into the STR, the rotational behavior induced by DA agonists in 6-OHDA-lesioned rats was significantly improved. This was accompanied by alleviated EPN firing rate and reinstated patterns of neuronal activity in the GP and EPN. Analysis of oscillatory activity revealed enhanced beta activity in both regions, which was reduced after grafting.In summary these data indicate restoration of BG motor loop toward normal activity by DA graft integration.

The human globus pallidus internus is sensitive to rewards – Evidence from intracerebral recordings

BackgroundThe globus pallidus internus (GPi) is the final output relay of the basal ganglia for the control of movements but has also been shown to belong to a second pathway projecting to the lateral habenula. This latter pathway is related to reward processing. MethodThis prompted us to record, in eight patients receiving deep brain stimulation of the GPi for the alleviation of various movement disorders, local field potentials (LFP) while these patients performed a lottery task. The task entailed choosing between a higher and a lower number, which changed their color after the patient's choice with red (green) signaling a loss (win, in Euro cents) corresponding to the chosen number. ResultsSurface recordings showed a feedback related negativity from a frontal midline site, while time domain averages in the GPi showed differential modulation depending on the valence of the stimulus with polarity inversion indicating that this reward-modulated activity was indeed generated locally. Furthermore, wavelet decomposition of the LFP showed a reward-related response in the high beta/low gamma range. ConclusionWe conclude that human GPi is involved in reward processing, possibly in relation to the lateral habenula.

Coherence of neuronal firing of the entopeduncular nucleus with motor cortex oscillatory activity in the 6-OHDA rat model of Parkinson's disease with levodopa-induced dyskinesias.

The pathophysiological mechanisms leading to dyskinesias in Parkinson's disease (PD) after long-term treatment with levodopa remain unclear. This study investigates the neuronal firing characteristics of the entopeduncular nucleus (EPN), the rat equivalent of the human globus pallidus internus and output nucleus of the basal ganglia, and its coherence with the motor cortex (MCx) field potentials in the unilateral 6-OHDA rat model of PD with and without levodopa-induced dyskinesias (LID). 6-hydroxydopamine-lesioned hemiparkinsonian (HP) rats, 6-OHDA-lesioned HP rats with LID (HP-LID) rats, and naïve controls were used for recording of single-unit activity under urethane (1.4 g/kg, i.p) anesthesia in the EPN "on" and "off" levodopa. Over the MCx, the electrocorticogram output was recorded. Analysis of single-unit activity in the EPN showed enhanced firing rates, burst activity, and irregularity compared to naïve controls, which did not differ between drug-naïve HP and HP-LID rats. Analysis of EPN spike coherence and phase-locked ratio with MCx field potentials showed a shift of low (12-19 Hz) and high (19-30 Hz) beta oscillatory activity between HP and HP-LID groups. EPN theta phase-locked ratio was only enhanced in HP-LID compared to HP rats. Overall, levodopa injection had no stronger effect in HP-LID rats than in HP rats. Altered coherence and changes in the phase lock ratio of spike and local field potentials in the beta range may play a role for the development of LID.

Effect of Deep Brain Stimulation on Levodopa-Induced Dyskinesias and Striatal Oscillatory Local Field Potentials in a Rat Model of Parkinson's Disease

BackgroundIn Parkinson's disease (PD) dyskinesias appear after long-term dopaminergic treatment. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internus (GPi) is a well-established treatment option for both PD symptoms and complications of medication. ObjectiveTo elucidate physiological mechanisms of the effect of DBS on levodopa-induced dyskinesias (LID) we investigated both DBS in the GPi and the centromedian-parafascicular complex (CM-Pf), which are part of an internal basal ganglia loop connecting with the dorsolateral striatum. In particular, we focused on changes of oscillatory activity in the dorsolateral striatum, which also presents the entrance region of the basal ganglia (BG). Methods6-Hydroxydopamine (6-OHDA) hemiparkinsonian (HP) rats and 6-OHDA lesioned HP rats with LID (HP-LID) were used to compare the effect of DBS in the entopeduncular nucleus (EPN, the equivalent to the human GPi) and the thalamic parafascicular nucleus (Pf, the equivalent of the human CM-Pf) on dyskinesias and neuronal oscillatory activity of selected frequency bands in the dorsolateral striatum on and off levodopa. ResultsIn HP-LID rats the relative beta and gamma power was lower, while relative theta power was higher as compared to HP rats. Chronic DBS of either the EPN or the Pf improved dyskinesia scores in HP-LID rats, and no differences in oscillatory activity were observed between groups. ConclusionsStimulation of the Pf has a specific impact on dyskinesias, which is similar to that found after EPN stimulation, and which is accompanied by changes of oscillatory activity.

Deep brain stimulation of the entopeduncular nucleus in rats prevents apomorphine-induced deficient sensorimotor gating

Pharmacologically induced stereotypies and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as endophenotypes for certain symptoms common to neuropsychiatric disorders, such as schizophrenia and Tourette's syndrome (TS) among others. We here investigated whether high frequency deep brain stimulation (DBS) of the rat's entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve PPI-deficits and stereotypies induced by the dopamine receptor agonist apomorphine.Electrodes were stereotactically implanted bilaterally in the EPN of 13 Sprague-Dawley rats. After one week of recovery the rats were stimulated with an amplitude 20% below their individual threshold for side effects (130Hz, 80μs pulse width) or sham-stimulated for epochs of five days. At the end of each epoch the effect of ongoing stimulation or sham-stimulation on apomorphine-induced stereotypies (vehicle and 0.5mg/kg) and deficient PPI (vehicle and 1.0mg/kg) were tested.In nine rats, in which the full protocol could be applied and in which the electrode position was histologically confirmed in the target, EPN DBS did not affect baseline PPI but counteracted the apomorphine-induced PPI-deficit, while apomorphine-induced stereotypies were not affected by DBS.This work indicates an important role of the EPN in the modulation of apomorphine-induced deficient prepulse inhibition. This model may be useful to further investigate the pathophysiological of deficient sensorimotor gating and mechanisms of action of DBS in certain neuropsychiatric disorders.

Lesions of the rat entopeduncular nucleus further deteriorate N-methyl- d-aspartate receptor antagonist-induced deficient prepulse inhibition

Lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), have been shown to improve deficient prepulse inhibition (PPI) induced by the dopamine agonist apomorphine. We here tested the effect of EPN lesions on the PPI-disruptive effect of the non-competitive NMDA receptor antagonist dizocilpine in rats. Neurotoxic bilateral lesions of the EPN were induced by ibotenic acid (4 μg in 0.4 μl). Rats were tested for PPI and locomotor activity after systemic injection of dizocilpine (vehicle and 0.15 mg/kg). Bilateral EPN lesions further deteriorated the PPI deficit induced by dizocilpine, while locomotion was not affected. This work indicates that the EPN is an important brain region within the neuronal circuit responsible for NMDA receptor antagonist-induced PPI deficits.

Lesions of the entopeduncular nucleus in rats prevent apomorphine-induced deficient sensorimotor gating

Dopamine-induced hyperactivity and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as animal models for neuropsychiatric disorders such as schizophrenia and Tourette's syndrome. We here investigated whether excitotoxic lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve apomorphine-induced PPI-deficits and hyperactivity. Additionally, we investigated the effect of EPN lesions on cognition, motivation and motor skills. In male Sprague Dawley rats bilateral EPN lesions were induced by stereotactic injection of ibotenate (4 μg in 0.4 μl phosphate buffered saline, PBS) or sham-lesions by injection of vehicle PBS. After one week, rats were tested for learning and memory (continuous and delayed alternation, T-maze), for motivation (progressive ratio test with breakpoint of 3 min inactivity, Skinner box), and for motor skills (rotating rod). Thereafter, rats were tested for PPI of ASR (startle response system) after subcutaneous injection of apomorphine (1.0 mg/kg and vehicle) and for locomotor activity (0.5 mg/kg and vehicle). Ibotenate-induced EPN lesions did not affect learning and memory, motivation or motor skills. Basal locomotor activity and PPI was also not affected, but EPN lesions ameliorated apomorphine-induced hyperlocomotion and deficient PPI. This work indicates an important role of the EPN for the modulation of dopamine agonist-induced deficient sensorimotor gating and hyperlocomotion, without affecting normal behavioral function.

Deep brain stimulation changes basal ganglia output nuclei firing pattern in the dystonic hamster

Dystonia is a heterogeneous syndrome of movement disorders characterized by involuntary muscle contractions leading to abnormal movements and postures. While medical treatment is often ineffective, deep brain stimulation (DBS) of the internal pallidum improves dystonia. Here, we studied the impact of DBS in the entopeduncular nucleus (EP), the rodent equivalent of the human globus pallidus internus, on basal ganglia output in the dt sz -hamster, a well-characterized model of dystonia by extracellular recordings. Previous work has shown that EP-DBS improves dystonic symptoms in dt sz -hamsters. We report that EP-DBS changes firing pattern in the EP, most neurons switching to a less regular firing pattern during DBS. In contrast, EP-DBS did not change the average firing rate of EP neurons. EP neurons display multiphasic responses to each stimulation impulse, likely underlying the disruption of their firing rhythm. Finally, neurons in the substantia nigra pars reticulata display similar responses to EP-DBS, supporting the idea that EP-DBS affects basal ganglia output activity through the activation of common afferent fibers.