Role of the globus pallidus in motor and non-motor symptoms of Parkinson's disease

The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore,bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease,particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity,and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.

Apelin-13 regulates electrical activity in the globus pallidus and induces postural changes in rats

The globus pallidus is the relay nucleus of the basal ganglia,and changes in its electrical activity can cause motor impairment.Apelin-13 is widely distributed in the central and peripheral nervous systems.It has been demonstrated that apelin-13 plays important roles in the regulation of blood pressure and other non-motor functions.However,its role in motor function has rarely been reported.In the present study,apelin-13(10μM/100μM)was injected into the globus pallidus of rats.The results showed that apelin-13 increased the spontaneous discharges in the majority of pallidal neurons.However,an apelin-13-induced inhibitory effect on the firing rate was also observed in a few pallidal neurons.In postural tests,after the systemic administration of haloperidol,unilateral pallidal injection of apelin-13 caused a contralateral deflection.Together,these findings suggest that apelin-13 regulates the electrical activity of pallidal neurons and thus participates in central motor control in rats.The study was approved by the Animal Ethics Committee of Qingdao University(approval No.20200615Wistar0451003020)on June 15,2020.

Research progress in the efficacy of deep brain stimulation with different targets in Parkinson's disease

Parkinson's disease(PD)is a chronic progressive neurodegenerative disease.Deep brain stimulation(DBS)is an effective treatment for patients with advanced PD.There are many DBS targets for PD,including subthalamic nucleus(STN),globus pallidus(GPi),meso-ventral thalamic nucleus(VIM),pontine peduncle nucleus(PPN),posterior subthalamic region(PSA)and zonation of undetermined zone(ZI).This paper summarizes the efficacy of each target in the treatment of PD with DBS,not only makes a systematic analysis and comparison of motor symptoms,but also makes a detailed description of the efficacy of non-motor symptoms,so as to provide a personalized treatment basis for PD patients to select appropriate target targets in DBS.

Changes of Monoanine Levels in Different Brain Regionsof Rat with Ventral GIobus Pailidus Injured by KainicAcid Injection

Ventral globus pallidus-injured rats by kainic acid(10 mg) were used to derter-mine the monoamine levels in four different brain regions.In this model,a great decrease of NE con-centration was observed in both hippocampus and frontal cortex compared with nonnal contro.This result hints that a damage of noradrenergic neurons in this model has occurred. DA concentrations in the four brain zones after kainic acid injection were all reduced, but only in the frontal cortex and striatum the pronounced reductions were discovered while DA turnover rates in frontal cortex, stria-tum and meddullapons were significantly reduced. These results revealed a DA metabolic disorder occurring in these regions.However,5-HT concentrations as well as DBH activity, expressed by ratio of NE/DA,showed no marked difference in this model. In our study it is found that the changes of monoamine levels in this model basically reflect those discovered in AD patients.

Orexin Directly Enhances the Excitability of Globus Pallidus Internus Neurons in Rat by Co-activating OX1 and OX2 Receptors

Orexin, released from the hypothalamus, has been implicated in various basic non-somatic functions including feeding, the sleep-wakefulness cycle, emotion,and cognition. However, the role of orexin in somatic motor control is still little known. Here, using whole-cell patch clamp recording and immunostaining, we investigated the effect and the underlying receptor mechanism of orexin-A on neurons in the globus pallidus internus（GPi）,a critical structure in the basal ganglia and an effective target for deep brain stimulation therapy. Our results showed that orexin-A induced direct postsynaptic excitation of GPi neurons in a concentration-dependent manner.The orexin-A-induced excitation was mediated via co-activation of both OX1 and OX2 receptors. Furthermore, the immunostaining results showed that OX1 and OX2 receptors were co-localized in the same GPi neurons. These results suggest that the central orexinergic system actively modulates the motor functions of the basal ganglia via direct innervation on GPi neurons and presumably participates in somatic-non-somatic integration.

Atlas of the Striatum and Globus Pallidus in the Tree Shrew: Comparison with Rat and Mouse

The striatum and globus pallidus are principal nuclei of the basal ganglia. Nissl-and acetylcholinesterasestained sections of the tree shrew brain showed the neuroanatomical features of the caudate nucleus（Cd）,internal capsule（ic）, putamen（Pu）, accumbens, internal globus pallidus, and external globus pallidus. The ic separated the dorsal striatum into the Cd and Pu in the tree shrew, but not in rats and mice. In addition, computerbased 3 D images allowed a better understanding of the position and orientation of these structures. These data provided a large-scale atlas of the striatum and globus pallidus in the coronal, sagittal, and horizontal planes, the first detailed distribution of parvalbumin-immunoreactive cells in the tree shrew, and the differences in morphological characteristics and density of parvalbumin-immunoreactive neurons between tree shrew and rat. Our findings support the tree shrew as a potential model for human striatal disorders.

Neuronal firing in the globus pallidus internus and the ventrolateral thalamus related to parkinsonian motor symptoms

Background It has been proposed that parkinsonian motor signs result from hyperactivity in the output nucleus of the basal ganglia, which suppress the motor thalamus and cortical areas. This study aimed to explore the neuronal activity in the globus pallidus internus （GPi） and the ventrolateral thalamic nuclear group （ventral oral posterior/ventral intermediate, Vop/Vim） in patients with Parkinson＇s disease （PD）. Methods Twenty patients with PD who underwent neurosurgery were studied. Microelectrode recording was performed in the GPi （n=10） and the Vop/Vim （n=10） intraoperatively. Electromyography （EMG） contralateral to the surgery was simultaneously performed. Single unit analysis was carried out. The interspike intervals （ISI） and coefficient of variation （CV） of ISI were calculated. Histograms of ISI were constructed. A unified Parkinson＇s disease rating scale （UPDRS） was used to assess the clinical outcome of surgery. Results Three hundred and sixty-three neurons were obtained from 20 trajectories. Of 175 GPi neurons, there were 15.4% with tremor frequency, 69.2% with tonic firing, and 15.4% with irregular discharge. Of 188 thalamic neurons, there were 46.8% with tremor frequency, 22.9% with tonic firing, and 30.3% with irregular discharge. The numbers of three patterns of neuron in GPi and Vop/Vim were significantly different （P 〈0.001）. ISI analysis revealed that mean firing rate of the three patterns of GPi neurons was （80.9±63.9） Hz （n=78）, which was higher than similar neurons with 62.9 Hz in a normal primate. For the Vop/Vim group, ISI revealed that mean firing rate of the three patterns of neurons （n=95） was （23.2±17.1） Hz which was lower than similar neurons with 30 Hz in the motor thalamus of normal primates. UPDRS indicated that the clinical outcome of pallidotomy was （64.3±29.5）%, （83.4±19.1）% and （63.4±36.3）%, and clinical outcome of thalamotomy was （92.2±12.9）%, （68.0±25.2）% and （44.3±7.2）% for tremor, rigidity and bradykinesia, respectively. A significant difference of tremor and rigidity was found between GPi and VopNim （P 〈0.05）. Conclusions Different changes in neuronal firing rate and the pattern in GPi and Vop/Vim are likely responsible for parkinsonian motor signs. The results support the view that abnormal neuronal activity in GPi and Vop/Vim are involved in the pathophysiology of parkinsonism.

Off-line analysis of single-unit neuronal discharge in the globus pallidus region in Parkinson＇s disease

Background The accuracy of microelectrode-guided localization can make the operation safe and effective, but only experienced neurosurgeons are capable of performing this operation. A good index to identify neuronal discharges between globus pallidus interna and globus pallidus externa is needed. The aim of this research was to establish a good and practical electrophysiologic index to distinguish neuronal discharge in the interior globus pallidus from neuronal discharge in the exterior globus pallidus region of the brain in Parkinson＇s disease. The effect of neurons having an atypical discharge on successful surgical localization was also quantitatively evaluated Methods The study included 30 patients with primary Parkinson＇s disease who underwent pallidotomy between September 2000 and October 2002. During each pallidotomy, the neuronal discharges in the pallidum and its vicinity were recorded. The recorded spikes were used to calculate the frequency, burst index, pause index, and pause ratio of the single-unit discharge. The interior and exterior globus pallidus regions were compared in terms of frequency, burst index, pause index, and pause ratio. The sensitivity, specificity, false-negative ratio, false-positive ratio, and accuracy of those indices were then evaluated. Results The values of frequency, burst index, pause index, and pause ratio in the interior globus pallidus were （96±43） Hz, 2.31±1.81, 0.05±0.05, and 0.27±0.28, respectively, and in the exterior globus pallidus were （59±27） Hz, 0.88±0.63, 0.20±0.14, and 1.54±1.17, respectively. Use of the four indices to distinguish the two neuron types produced a sensitivity of 0.84, 0.78, 0.77, and 0.93 with a specificity of 0.64, 0.79, 0.88, and 0.87, respectively. The false-positive ratio was 0.36, 0.21, 0.12, and 0.13 and the false-negative ratio was 0.16, 0.22, 0.23, and 0.07 while the accuracy was 0.72, 0.79, 0.80, and 0.90, respectively. Conclusions Pause ratio is a relatively reliable index to distinguish neuronal discharges between the interior and exterior globus pallidus regions in Parkinson＇s disease. The effect of neurons with atypical discharge on the successful surgical localization would be reduced to 10% when the pause ratio is used as the index.

Modulation of firing activity by endogenous GABA_A receptors in the globus pallidus of MPTP-treated parkinsonian mice

The globus pallidus in rodents,equivalent to the external segment of the globus pallidus in primates,plays an important role in movement regulation.Previous studies have shown abundant γ-aminobutyric acid（GABA）ergic innervation and GABAA receptors in the globus pallidus.In this study,we investigated the effects of endogenous GABAA receptors on the spontaneous firing activity of pallidal neurons in both normal and MPTP-treated mice using multi-barrel electrodes extracellular recordings in vivo.We found that in normal mice,pressure ejection of 0.1 mmol/L gabazine,a specific GABA A receptor antagonist,increased the spontaneous firing rate of globus pallidus neurons by 27.6 ± 5.6%.Furthermore,in MPTP mice（14 days after MPTP treatment）,0.1 mmol/L gabazine increased the firing rates by 51.0 ± 7.9%,significantly greater than in normal mice.These results suggest that endogenous GABAA receptors modulate the activity of globus pallidus neurons.The present findings may provide a rationale for investigations into the potential role of GABAA receptors in Parkinson’s disease.

Effects of pallidal neurotensin on haloperidol-induced parkinsonian catalepsy: behavioral and electrophysiological studies

Objective The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms. Methods Behavioral experiments and electrophysiological recordings were performed in the present study. Results Bilateral infusions of neurotensin into the globus pallidus reversed haloperidolinduced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin. Conclusion Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.

Target Selection Recommendations Based on Impact of Deep Brain Stimulation Surgeries on Nonmotor Symptoms of Parkinson＇s Disease

Objective： This review examines the evidence that deep brain stimulation （DBS） has extensive impact on nonmotor symptoms （NMSs） of patients with Parkinson＇s disease （PD）. Data Sources： We retrieved information from the PubMed database up to September, 2015, using various search terms and their combinations including PD, NMSs, DBS, globus pallidus internus （GPi）, subthalamic nucleus （STN）, and ventral intermediate thalamic nucleus. Study Selection： We included data from peer-reviewed journals on impacts of DBS on neuropsychological profiles, sensory function, autonomic symptoms, weight changes, and sleep disturbances. For psychological symptoms and cognitive impairment, we tried to use more reliable proofs： Random, control, multicenter, large sample sizes, and long period follow-up clinical studies. We categorized the NMSs into four groups： those that would improve definitively following DBS; those that are not significantly affected by DBS; those that remain controversial on their surgical benefit; and those that can be worsened by DBS. Results： In general, it seems to be an overall beneficial effect of DBS on NMSs, such as sensory, sleep, gastrointestinal, sweating, cardiovascular, odor, urological symptoms, and sexual dysfunction, GPi-DBS may produce similar results; Both STN and Gpi-DBS are safe with regard to cognition and psychology over long-term follow-up, though verbal fluency decline is related to DBS： The impact of DBS on behavioral addictions and dysphagia is still uncertain. Conclusions： As the motor effects of STN-DBS and GPi-DBS are similar, NMSs may determine the target choice in surgery of future patients.

Properties of oscillatory neuronal activity in the basal ganglia and thalamus in patients with Parkinson’s disease

Background:The cardinal features of Parkinson’s disease(PD)are bradykinesia,rigidity and rest tremor.Abnormal activity in the basal ganglia is predicted to underlie the mechanism of motor symptoms.This study aims to characterize properties of oscillatory activity in the basal ganglia and motor thalamus in patients with PD.Methods:Twenty-nine patients with PD who underwent bilateral or unilateral electrode implantation for subthalamic nucleus(STN)DBS(n=11),unilateral pallidotomy(n=9)and unilateral thalamotomy(n=9)were studied.Microelectrode recordings in the STN,globus pallidus internus(GPi)and ventral oral posterior/ventral intermediate of thalamus(Vop/Vim)were performed.Electromyography of the contralateral limbs was recorded.Single unit characteristics including interspike intervals were analyzed.Spectral and coherence analyses were assessed.Mean spontaneous firing rate(MSFR)of neurons was calculated.Analysis of variance and χ^(2) test were performed.Results:Of 76 STN neurons,39.5% were 4–6 Hz band oscillatory neurons and 28.9% were β frequency band(βFB)oscillatory neurons.The MSFR was 44.2±7.6 Hz.Of 62 GPi neurons,37.1% were 4–6 Hz band oscillatory neurons and 27.4% were βFB neurons.The MSFR was 80.9±9.6 Hz.Of 44 Vop neurons,65.9% were 4–6 Hz band oscillatory neurons and 9%were βFB neurons.The MSFR was 24.4±4.2 Hz.Of 30 Vim oscillatory neurons,70% were 4–6 Hz band oscillatory neurons and 13.3% were β FB neurons.The MSFR was 30.3±3.6 Hz.Further analysis indicated that proportion of βFB oscillatory neurons in STN and GPi was higher than that of similar neurons in the Vop and Vim(P<0.05).Conversely,the proportion of 4–6 Hz band oscillatory neurons and tremor related neurons in the Vim and Vop was higher than that of STN and GPi(P<0.05).The highest MSFR was for GPi oscillatory neurons whereas the lowest MSFR was for Vop oscillatory neurons(P<0.005).Conclusion:The alterations in neuronal activity in basal ganglia play a critical role in generation of parkinsonism.β oscillatory activity is more prominent in basal ganglia than in thalamus suggesting that the activity likely results from dopaminergic depletion.While both basal ganglia and thalamus have tremor activity,the thalamus appears to play a more important role in tremor production,and basal ganglia β oscillatory activity might be the trigger.

Update on deep brain stimulation in Parkinson’s disease

Deep brain stimulation(DBS)is considered a safe and well tolerated surgical procedure to alleviate Parkinson’s disease(PD)and other movement disorders symptoms along with some psychiatric conditions.Over the last few decades DBS has been shown to provide remarkable therapeutic effect on carefully selected patients.Although its precise mechanism of action is still unknown,DBS improves motor functions and therefore quality of life.To date,two main targets have emerged in PD patients:the globus pallidus pars interna and the subthalamic nucleus.Two other targets,the ventralis intermedius and zona incerta have also been selectively used,especially in tremor-dominant PD patients.The main indications for PD DBS have traditionally been motor fluctuations,debilitating medication induced dyskinesias,unpredictable“off time”state,and medication refractory tremor.Medication refractory tremor and intolerable dyskinesia are potential palliative indications.Besides aforementioned targets,the brainstem pedunculopontine nucleus(PPN)is under investigation for the treatment of ON-state freezing of gait and postural instability.In this article,we will review the most recent literature on DBS therapy for PD,including cutting-edge advances and data supporting the role of DBS in advanced neural-network modulation.

Deep brain stimulation for dystonia

Deep brain stimulation(DBS)is an effective surgical treatment for medication-refractory movement disorders,and has been approved by the United States Food and Drug Administration for treatment of dystonia.The success of DBS in the treatment of dystonia depends on our understanding of the anatomy and physiology of this disorder and close collaboration between neurosurgeons,neurologists,clinical neurophysiologists,neuroradiologists and neuropsychologists.Currently,pallidal DBS is an established treatment option for medically refractive dystonia.This review is intended to provide a comprehensive review of the use of DBS for dystonia,focusing mainly on the surgical aspects,clinical outcome,MRI findings and side effects of DBS.

Deep brain stimulation in Parkinson’s disease

For the last 50 years,levodopa has been the cornerstone of Parkinson’s disease management.However,a majority of patients develop motor complications a few years after therapy onset.Deep brain stimulation has been approved by the FDA as an adjunctive treatment in Parkinson disease,especially aimed at controlling these complications.However,the exact mechanism of action of deep brain stimulation,the best nucleus to target as well as the best timing for surgery are still debatable.We here provide an in-depth and critical review of the current literature on this topic.