Chronic high-frequency deep-brain stimulation in progressive myoclonic epilepsy in adulthood--report of five cases

Purpose: To assess the efficacy and tolerability of chronic high‐frequency deep brain stimulation (DBS) in adult patients with progressive myoclonic epilepsy (PME) syndromes. Methods: Five adult patients (four male, 28–39 years) with PME underwent chronic high‐frequency DBS according to a study protocol that had been approved by the local ethics committee. Electrodes were implanted in the substantia nigra pars reticulata (SNr)/subthalamic nucleus (STN) region in the first patient and additionally in the ventral intermediate nucleus (VIM) bilaterally in the following four cases. Follow‐up took place in intervals of 3 months and DBS effects were compared with baseline frequency of passive and activation‐induced myoclonic jerks and daily life performance 8 weeks prior to implantation. Key Findings: Follow‐up periods ranged from 12–42 months (median 24 months). The best clinical effects were seen with SNr/STN DBS in all patients. VIM stimulation failed to achieve acute therapeutic effects and revealed low side‐effect thresholds and even triggering of myoclonia. In all patients the reduction of myoclonic seizures was observed and ranged between 30% and 100% as quantified by a standardized video protocol. All patients reported clinically relevant improvements of various capabilities such as free standing and walking or improved fine motor skills. In one patient with an excellent initial response generalized tonic–clonic seizures increased after 3 months of stimulation following extensive trauma‐related surgery. The best effect was seen in the least impaired patient. Significance: DBS of the SNr/STN may be an effective treatment option for patients with PME. Less impaired patients may benefit more markedly.     

丘脑底核电刺激对癫痫大鼠模型基底节神经元放电的影响

目的应用不同频率的电刺激海人酸模型癫痫大鼠STN核,观察STN核以及SNr(黑质网状部)神经元细胞在刺激后放电频率的变化,研究电刺激STN对STN内神经元和SNr神经元放电的影响,探讨STN-DBS治疗癫痫的作用机制。方法10只癫痫大鼠为实验组,另10只正常大鼠作为对照组。参照大鼠立体定向图谱,将记录的玻璃微电极和刺激电极分别插入STN、SNr核团内,刺激频率分为三组,分别为30 Hz、130 Hz、260 Hz。通过单神经元放电细胞外记录方法分别于高频刺激前后记录脑内核团神经元放电情况,分析神经元在STN-HFS刺激前和刺激时放电改变情况。结果正常大鼠的STN及SNr神经元放电与癫痫模型大鼠相比,两者放电频率不存在显著性差异,对放电模式的分析发现两者也无明显差异(P>0.05)。癫痫大鼠的STN及SNr神经元在30 Hz的刺激过程中放电频率多数没有明显变化。随着放电频率的增加两种神经元在电刺激后多数神经元放电明显受到抑制。在130 Hz和260 Hz组,受抑制的神经元较30 Hz组明显增加,具有显著性差异(P<0.05)。结论本研究证实高频电刺激STN明显抑制了STN和SNr神经元的兴奋性,其效果与频率是相...     

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized.ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr).MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode.ResultsInhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003).InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.     

Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson's disease

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92-3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs.     

Basal ganglia neural responses during behaviorally effective deep brain stimulation of the subthalamic nucleus in rats performing a treadmill locomotion test

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). In spite of proven therapeutic success, the mechanism underlying the benefits of DBS has not been resolved. A multiple-channel single-unit recording technique was used in the present study to investigate basal ganglia (BG) neural responses during behaviorally effective DBS of the STN in a rat model of PD. Rats underwent unilateral dopamine (DA) depletion by injection of 6-hydroxyDA (6-OHDA) into one side of the medial forebrain bundle and subsequently developed a partial akinesia, which was assessed during the treadmill locomotion task. High frequency stimulation (HFS) of the STN restored normal treadmill locomotion behavior. Simultaneous recording of single unit activity in the striatum (STR), globus pallidus (GP), substantia nigra pars reticulata (SNr), and STN revealed a variety of neural responses during behaviorally effective HFS of the STN. Predominant inhibitory responses appeared in the STN stimulation site. Nearly equal numbers of excitatory and inhibitory responses were found in the GP and SNr, whereas more rebound excitatory responses were found in the STR. Mean firing rate did not change significantly in the STR, GP, and SNr, but significantly decreased in both sides of STN during DBS. A decrease in firing rate in the contralateral side of STN provides neural substrate for the clinical observation that unilateral DBS produces bilateral benefits in patients with PD. In addition to the firing rate changes, a decrease in burst firing was observed in the GP and STN. The present study indicates that DBS induces complex modulations of the BG circuit and further suggests that BG network reorganization, rather than a simple excitation or inhibition, may underlie the therapeutic effects of DBS in patients with PD.     

Complex analysis of neuronal spike trains of deep brain nuclei in patients with Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been used to alleviate symptoms of Parkinson's disease. During image-guided stereotactic surgery, signals from microelectrode recordings are used to distinguish the STN from adjacent areas, particularly from the substantia nigra pars reticulata (SNr). Neuronal firing patterns based on interspike intervals (ISI) are commonly used. In the present study, arrival time-based measures, including Lempel-Ziv complexity and deviation-from-Poisson index were employed. Our results revealed significant differences in the arrival time-based measures among non-motor STN, motor STN and SNr and better discrimination than the ISI-based measures. The larger deviations from the Poisson process in the SNr implied less complex dynamics of neuronal discharges. If spike classification was not used, the arrival time-based measures still produced statistical differences among STN subdivisions and SNr, but the ISI-based measures only showed significant differences between motor and non-motor STN. Arrival time-based measures are less affected by spike misclassifications, and may be used as an adjunct for the identification of the STN during microelectrode targeting.     

Deep brain stimulation of the substantia nigra pars reticulata exerts long lasting suppression of amygdala-kindled seizures

Deep brain stimulation (DBS) has been used to treat a variety of neurological disorders including epilepsy. However, we have limited knowledge about effective target areas, optimal stimulation parameters, and long-term effect of DBS on epileptic seizures. Here we examined the effects of DBS of the substantia nigra pars reticulata (SNr) on amygdala-kindled seizures. Microwire electrodes were implanted into the SNr and amygdala of adult male rats. When stage 5-kindled seizures were achieved by daily amygdala kindling, high frequency stimulation was delivered to the SNr bilaterally 1 s after cessation of kindling. Our DBS protocol completely blocked kindled seizures in 10 out of 23 (43.5%) rats studied. Furthermore, when the same amygdala kindling procedure was performed 24 h later without DBS, the kindling failed to elicit any seizure signs in 6 of these 10 rats. Some of the post-DBS period of seizure suppression lasted for up to 4 days. In other 3 rats, only mild stage 1 to 2 seizures appeared following amygdala kindling. Only 1 of the 10 rats for which DBS had blocked kindled seizures exhibited full-scale 5 stage-kindled seizures 24 h after DBS. These results suggest that highly plastic neural networks are involved in amygdala-kindled seizures and that DBS, if well timed with the onset of amygdala kindling, may exert long lasting effects on the networks that may prevent the recurrence of kindled seizures.     

Long‐Term Follow‐Up Study of Chronic Deep Brain Stimulation of the Subthalamic Nucleus for Cervical Dystonia

Objectives. Medically refractory cervical dystonia has recently been treated using deep brain stimulation (DBS), targeting the subthalamic nucleus (STN). There has been limited literature regarding short‐term outcomes and no literature regarding long‐term outcomes for refractory cervical dystonia following DBS of the STN. Materials and Methods. Two patients with medically refractory cervical dystonia underwent STN DBS. Patients were rated using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) preoperatively and immediately postoperatively as well as just prior to turning on the stimulators and subsequently at 24–48 hours, six months, one, two, and three years after stimulation. Microrecordings were used to identify the STN and substantia nigra reticulata (SNr). Results. Significant immediate and sustained long‐term improvements were seen in motor, disability, pain, and total TWSTRS scores. In one patient, only unilateral stimulation was required. The STN and SNr were easily identified as having activity similar to off‐state Parkinson's patients. Conclusions. DBS therapy for cervical dystonia utilizing the STN as the surgical target may be novel and may be an alternative target to the globus pallidus internus as supported by this first long‐term outcome report. Further studies need to be performed to confirm these conclusions.     

Deep brain stimulation in epilepsy.

Since the pioneering studies of Cooper et al. to influence epilepsy by cerebellar stimulation, numerous attempts have been made to reduce seizure frequency by stimulation of deep brain structures. Evidence from experimental animal studies suggests the existence of a nigral control of the epilepsy system. It is hypothesized that the dorsal midbrain anticonvulsant zone in the superior colliculi is under inhibitory control of efferents from the substantia nigra pars reticulata. Inhibition of the subthalamic nucleus (STN) could release the inhibitory effect of the substantia nigra pars reticulata on the dorsal midbrain anticonvulsant zone and thus activate the latter, raising the seizure threshold. Modulation of the seizure threshold by stimulation of deep brain structures-in particular, of the STN-is a promising future treatment option for patients with pharmacologically intractable epilepsy. Experimental studies supporting the existence of the nigral control of epilepsy system and preliminary results of STN stimulation in animals and humans are reviewed, and alternative mechanisms of seizure suppression by STN stimulation are discussed.     

Influence of the frequency parameter on extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas gamma-aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency-dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep-brain-stimulation mechanisms.     

High‐frequency stimulation of the subthalamic nucleus restores neural and behavioral functions during reaction time task in a rat model of Parkinson's disease

Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson's disease (PD) and other neuropsychiatric disorders. Our previous work has shown that DBS in the subthalamic nucleus (STN) can improve major motor deficits, and induce a variety of neural responses in rats with unilateral dopamine (DA) lesions. In the present study, we examined the effect of STN DBS on reaction time (RT) performance and parallel changes in neural activity in the cortico‐basal ganglia regions of partially bilateral DA‐ lesioned rats. We recorded neural activity with a multiple‐channel single‐unit electrode system in the primary motor cortex (MI), the STN, and the substantia nigra pars reticulata (SNr) during RT test. RT performance was severely impaired following bilateral injection of 6‐OHDA into the dorsolateral part of the striatum. In parallel with such behavioral impairments, the number of responsive neurons to different behavioral events was remarkably decreased after DA lesion. Bilateral STN DBS improved RT performance in 6‐OHDA lesioned rats, and restored operational behavior‐related neural responses in cortico‐basal ganglia regions. These behavioral and electrophysiological effects of DBS lasted nearly an hour after DBS termination. These results demonstrate that a partial DA lesion‐induced impairment of RT performance is associated with changes in neural activity in the cortico‐basal ganglia circuit. Furthermore, STN DBS can reverse changes in behavior and neural activity caused by partial DA depletion. The observed long‐lasting beneficial effect of STN DBS suggests the involvement of the mechanism of neural plasticity in modulating cortico‐basal ganglia circuits. © 2009 Wiley‐Liss, Inc.     

Prolonged blockade of NMDA or mGluR5 glutamate receptors reduces nigrostriatal degeneration while inducing selective metabolic changes in the basal ganglia circuitry in a rodent model of Parkinson's disease

We compared the neuroprotective and metabolic effects of chronic treatment with ionotropic or metabotropic glutamate receptor antagonists, in rats bearing a unilateral nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). The ionotropic, N-methyl-D-aspartate receptor antagonist MK-801 increased cell survival in the substantia nigra pars compacta (SNc) and corrected the metabolic hyperactivity (increased cytochrome oxidase activity) of the ipsilateral substantia nigra pars reticulata (SNr) associated with the lesion, but showed no effects on the 6-OHDA-induced hyperactivity of the subthalamic nucleus (STN). Significant-although less pronounced-protection of SNc neurons was also observed following treatment with the metabotropic glutamate receptor (mGluR5) antagonist 2-methyl-6-(phenylehtynyl)-pyridine (MPEP). As opposed to MK-801, MPEP abolished the STN metabolic hyperactivity associated with the nigrostriatal lesion, without affecting SNr activity. Specific modulation of STN hyperactivity obtained with mGluR5 blockade may, therefore, open interesting perspectives for the use of this class of compounds in the treatment of Parkinson's disease.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Bilateral deep brain stimulation of subthalamic nucleus STN in the surgical treatment of Parkinson's disease

Dopamine deficiency in the nigrostriatal system leads to a series of changes in the basal ganglia, resulting in an increased neuronal activity of the subthalamic nucleus (STN). Reduction of the STN glutaminergic excitatory effect on the main output structures of the basal ganglia (globus pallidum pars interna GPi and substantia nigra pars reticulata SNr) is accompanied by a marked alleviation of parkinsonian motor sings in the MPTP monkey model of parkinsonism. Also a high-frequency stimulation of STN in the MPTP monkey model of parkinsonism produced the same clinical effect as did lesioning. Due to these observations bilateral deep subthalamic stimulation was introduced in the treatment of PD patients with severe akinetic-rigid form of this disease. Four patients with akinetic-rigid PD form of PD were included in the study. The electrodes for deep brain stimulation were implanted in two separate surgical interventions in every case. The second implantation was performed not earlier than at least 3 months after the first procedure. Evaluations using the UPDRS were conducted before surgery in "on" and "off" conditions and at 3, 6 and 12 months after the bilateral implantation. Bilateral DBS STN seems to be the best stereotactic target in controlling motor symptoms in the "off" condition in the treatment of PD patients with severe symptoms. The technique enables a dramatic reduction in the daily dose of L-dopa.     

Electrical Stimulation of the Substantia Nigra Pars Reticulata (SNr) Suppresses Chemically Induced Neocortical Seizures in Rats

Deep brain stimulation is an alternate treatment strategy for intractable epilepsy. The effects of low- and high-frequency electrical stimulation to the substantia nigra pars reticulata (SNr) of different sides on chemically induced neocortical seizure were investigated in the present study. After neocortical seizure was induced by ferric chloride injection into the left sensorimotor cortex, SNr was stimulated ipsilaterally, contralaterally, or bilaterally at frequencies of 130 or 20 Hz in rats. Unilateral and bilateral stimulation at 130 Hz reduced significantly the number of seizures but not their duration. Ipsilateral, contralateral as well as bilateral stimulations at 130 Hz were all equally effective, producing reductions in seizures of 63.62, 77.84, and 68.74 % compared with the control group, respectively. Electrical stimulation at 20 Hz did not reduce the number or duration of seizures regardless of the side stimulated. Both unilateral and bilateral stimulations of SNr at 130 Hz can suppress ictogenesis in the cortex, but electrical stimulation at 130 or 20 Hz does not reduce the severity of individual seizures. The frequency of stimulation is paramount in suppressing neocortical seizures in which DBS at least targets SNr.     

Kainic acid-induced substantia nigra seizure in rats: behavior, EEG and metabolism

RATIONALE: In order to clarify the role of substantia nigra pars reticulata (SNr) upon the development of epileptic seizure, kainic acid (KA) was injected into a unilateral SNr. MATERIALS AND METHODS: Wistar rats weighing 250-350 g were used. A stainless-steel cannula and depth electrode were inserted stereotaxically into the left substantia nigra pars reticulata (SNr). At 7 days after surgery, 1.0 microg of KA was injected into the left SNr. Experiment 1: In eight rats, behavior and electroencephalograms (EEG) were continuously recorded for about 30 h, and intermittently monitored following 1 month. Experiment 2: Two hours after KA injection into SNr, rats demonstrated status epilepticus. Then, 100 microCi/kg of [(14)C]2-deoxyglucose (2-DG) was intravenously injected in seven rats, and the rats were processed for autoradiographic study. RESULTS: Changes in behavior and EEG: On EEG, a secondary generalized seizure status was observed at about 70 min after KA injection. In video, limbic seizure manifestations such as salivation were observed as a initial symptom and followed by rolling and generalized tonic seizures. [(14)C]deoxyglucose autoradiographic study demonstrated increased local cerebral glucose metabolism in the medial and lateral septal nucleus, substantia nigra, hippocampus, parietal cortex, piriform cortex, medial and lateral geniculate nucleus, anterodorsal, lateral and ventral nucleus of the thalamus, amygdala and midbrain reticular formation. SUMMARY: The result suggested that the substantia nigra played an important role in the secondary generalization in the substantia nigra seizure model due to the decreased function of the GABAergic projection system induced by an excessive epileptic excitation of SNr.     

Calretinin as a marker of specific neuronal subsets in primate substantia nigra and subthalamic nucleus

Neurons immunoreactive for the calcium-binding protein calretinin (CR) were visualized in the substantia nigra (SN) pars compacta (SNc), reticulata (SNr) and lateralis (SNI), the ventral tegmental area (VTA) and the subthalamic nucleus (STN) of squirrel monkeys. The density of CR perikarya was high in VTA, moderate in SNc, low in SNr/SNI, and very low in STN. The SNc/VTA complex also displayed a CR-rich neuropil. Some CR perikarya and fibers occurred in specific sectors of STN. These data suggest that CR may play a role in specific neuronal subpopulations in all components of primate basal ganglia.     

Subthalamic nucleus lesions alter basal and dopamine agonist stimulated electrophysiological output from the rat basal ganglia

The subthalamic nucleus (STN) is an important link in the "indirect" striatal efferent pathway. To assess its role on basal ganglia output via the substantia nigra pars reticulata (SNr), we monitored the single unit activities of SNr neurons in chloral hydrate-anesthetized rats 5-8 days after bilateral kainic acid lesions (0.75 microg/0.3 microl/side) of the STN. Consistent with loss of an excitatory input, the average basal firing rate of SNr neurons was significantly reduced in STN-lesioned animals. Moreover, the lesions modified the responses of SNr neurons to individual and concurrent stimulation of striatal D1 and D2 receptors. Bilateral striatal infusions of the D1/D2 agonist apomorphine (10 microg/microl/side) into the ventral-lateral striatum (VLS) were previously shown to cause significant increases in SNr cell firing (to 133% of baseline) in normal rats. However, in STN-lesioned rats, identical infusions caused no overall change in SNr activity (mean, 103% of basal rates). Conversely, selective stimulation of striatal D2 receptors by bilateral co-infusion of the D2 agonist quinpirole and the D1 antagonist SCH 23390 that previously caused little change in SNr firing in normal rats significantly inhibited their firing in STN-lesioned rats. Finally, the modest excitatory responses of SNr neurons to selective stimulation of striatal D1 receptors by co-infusions of SKF 82958 with the D2 antagonist YM09151-2 were not altered by lesions of the STN. These results implicate the STN as a mediator of excitatory response of SNr neurons to D2, and mixed D1/D2, dopamine receptor agonists in normal rats, and challenge conventional views on the role of the STN and the "indirect" pathway in regulating dopamine-stimulated output from the SNr.     

Elevated potassium provides an ionic mechanism for deep brain stimulation in the hemiparkinsonian rat

The mechanism of high‐frequency stimulation used in deep brain stimulation (DBS) for Parkinson's disease (PD) has not been completely elucidated. Previously, high‐frequency stimulation of the rat entopeduncular nucleus, a basal ganglia output nucleus, elicited an increase in [K⁺]_e to 18 mm , in vitro. In this study, we assessed whether elevated K⁺ can elicit DBS‐like therapeutic effects in hemiparkinsonian rats by employing the limb‐use asymmetry test and the self‐adjusting stepping test. We then identified how these effects were meditated with in‐vivo and in‐vitro electrophysiology. Forelimb akinesia improved in hemiparkinsonian rats undergoing both tests after 20 mm KCl injection into the substantia nigra pars reticulata (SNr) or the subthalamic nucleus. In the SNr, neuronal spiking activity decreased from 38.2 ± 1.2 to 14.6 ± 1.6 Hz and attenuated SNr beta‐frequency (12–30 Hz) oscillations after K⁺ treatment. These oscillations are commonly associated with akinesia/bradykinesia in patients with PD and animal models of PD. Pressure ejection of 20 mm KCl onto SNr neurons in vitro caused a depolarisation block and sustained quiescence of SNr activity. In conclusion, our data showed that elevated K⁺ injection into the hemiparkinsonian rat SNr improved forelimb akinesia, which coincided with a decrease in SNr neuronal spiking activity and desynchronised activity in SNr beta frequency, and subsequently an overall increase in ventral medial thalamic neuronal activity. Moreover, these findings also suggest that elevated K⁺ may provide an ionic mechanism that can contribute to the therapeutic effects of DBS for the motor treatment of advanced PD.