Deep brain stimulation for psychiatric disorders: Are nucleus accumbens and medial forebrain bundle two branches of the same tree?

Purpose of this commentary is to discuss the relation of the nucleus accumbens (NA) with the medial forebrain bundle (MFB) and compare them as deep brain stimulation (DBS) targets in psychiatric disorders. Could a “bundle” be a more effective target than a “nucleus”? Or, more correctly, could an important “modulator” be a more effective target than a highly significant “pleasure center”? The answer hides in the fact that NA is a key component of the MFB. Thus NA dysfunction is synonym to MFB dysfunction. The NA is a “hot-spot” in the neurocircuitry of psychiatric disorders and further experimental investigation is needed for the MFB as a target for neuromodulation in depression, as well as to optimize benefit of psychiatric patients from neuromodulation treatment efforts. Are the NA and MFB two branches of the same tree? They definitely could be, particularly if the “tree” is the brain's “motivation super-system”.     

Non-invasive Brain Stimulation Therapy in Multiple Sclerosis: A Review of tDCS,rTMS and ECT Results

BackgroundMultiple sclerosis (MS) is a disabling neurological disorder presenting a variety of symptoms which are hard to control by actual drug regimens. Non-invasive brain stimulation (NIBS) techniques have been investigated in the past years for the improvement of several neurologic and psychiatric disorders.ObjectiveHere, we review the application of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (rTMS, iTBS) and electroconvulsive therapy (ECT) in MS patients.MethodsArticles were searched in common literature databases. Crosslinks were reviewed.ResultsECT was shown to be efficacious for the treatment of severe psychiatric disorders in 21 case reports. The results of tDCS and TMS for the treatment of depressive symptoms, fatigue, tactile sensory deficit, pain, motor performance, and spasticity were assessed in several studies and showed mixed results.ConclusionsOverall, data for the treatment of MS with NIBS is sparse regarding TMS and tDCS. Treatment of severe psychiatric disorders with ECT is only reported in single cases. More studies are needed to elucidate the potential role of NIBS in MS treatment.     

Acute stimulation in the external segment of the globus pallidus improves parkinsonian motor signs.

High frequency (>100Hz) electrical stimulation in both the external (GPe) and internal (GPi) segments of the globus pallidus was effective in improving parkinsonian motor signs. Improvement generally occurred at short latency (<5-10 seconds) in both GPe and GPi but was often (50% of the time) delayed in GPi. Dyskinetic movements were observed during stimulation within GPe and GPi but were more frequent in GPe (20% vs. 9%). These findings suggest that electrical stimulation in both GPe and GPi may ameliorate parkinsonian motor signs. The mechanisms responsible for these observations, however, may differ. The tendency for delayed responses with GPi stimulation suggests a more complex spatial-temporal profile of stimulation on the electrical activity of GPi neurons and/or its effect on network activity in pallido-thalamo-cortical circuitry. The rarity of delayed effects with GPe stimulation suggests a more direct role of synaptic inhibition or normalization of neuronal activity of GPi either directly by means of activation of striatopallidal fibers passing through GPe (direct pathway), by means of activation of GPe-->GPi or GPe-->subthalamic nucleus projections (indirect pathway) or indirectly by means of the tonic activation of adjacent fiber pathways. These data provide a rationale for the exploration of electrical stimulation in GPe in patients with medically intractable Parkinson's disease and provide a basis on which to develop further investigations into the use of chronic electrical stimulation for the treatment of Parkinson's disease and other movement disorders.     

Electrical stimulation of the dorsal columns of the spinal cord for Parkinson's disease

Spinal cord stimulation has been used for the treatment of chronic pain for decades. In 2009, our laboratory proposed, based on studies in rodents, that electrical stimulation of the dorsal columns of the spinal cord could become an effective treatment for motor symptoms associated with Parkinson's disease (PD). Since our initial report in rodents and a more recent study in primates, several clinical studies have now described beneficial effects of dorsal column stimulation in parkinsonian patients. In primates, we have shown that dorsal column stimulation activates multiple structures along the somatosensory pathway and desynchronizes the pathological cortico‐striatal oscillations responsible for the manifestation of PD symptoms. Based on recent evidence, we argue that neurological disorders such as PD can be broadly classified as diseases emerging from abnormal neuronal timing, leading to pathological brain states, and that the spinal cord could be used as a “channel” to transmit therapeutic electrical signals to disrupt these abnormalities. © 2017 International Parkinson and Movement Disorder Society     

Clinical perspectives of adaptive deep brain stimulation

BackgroundThe application of stimulators implanted directly over deep brain structures (i.e., deep brain stimulation, DBS) was developed in the late 1980s and has since become a mainstream option to treat several neurological conditions. Conventional DBS involves the continuous stimulation of the target structure, which is an approach that cannot adapt to patients’ changing symptoms or functional status in real-time. At the beginning of 2000, a more sophisticated form of stimulation was conceived to overcome these limitations. Adaptive deep brain stimulation (aDBS) employs on-demand, contingency-based stimulation to stimulate only when needed. So far, aDBS has been tested in several pathological conditions in animal and human models.ObjectiveTo review the current findings obtained from application of aDBS to animal and human models that highlights effects on motor, cognitive and psychiatric behaviors.Findingswhile aDBS has shown promising results in the treatment of Parkinson's disease and essential tremor, the possibility of its use in less common DBS indications, such as cognitive and psychiatric disorders (Alzheimer's disease, obsessive-compulsive disorder, post-traumatic stress disorder) is still challenging.ConclusionsWhile aDBS seems to be effective to treat movement disorders (Parkinson's disease and essential tremor), its role in cognitive and psychiatric disorders is to be determined, although neurophysiological assumptions are promising.     

The Role of the Cerebellum in Degenerative Ataxias and Essential Tremor: Insights From Noninvasive Modulation of Cerebellar Activity

Over the last three decades, measuring and modulating cerebellar activity and its connectivity with other brain regions has become an emerging research topic in clinical neuroscience. The most important connection is the cerebellothalamocortical pathway, which can be functionally interrogated using a paired-pulse transcranial magnetic stimulation paradigm. Cerebellar brain inhibition reflects the magnitude of suppression of motor cortex excitability after stimulating the contralateral cerebellar hemisphere and therefore represents a neurophysiological marker of the integrity of the efferent cerebellar tract. Observations that cerebellar noninvasive stimulation techniques enhanced performance of certain motor and cognitive tasks in healthy individuals have inspired attempts to modulate cerebellar activity and connectivity in patients with cerebellar diseases in order to achieve clinical benefit. We here comprehensively explore the therapeutic potential of these techniques in two movement disorders characterized by prominent cerebellar involvement, namely the degenerative ataxias and essential tremor. The article aims to illustrate the (patho)physiological insights obtained from these studies and how these translate into clinical practice, where possible by addressing the association with cerebellar brain inhibition. Finally, possible explanations for some discordant interstudy findings, shortcomings in our current understanding, and recommendations for future research will be provided. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

功能性电刺激结合重复经颅磁刺激用于缺血性脑卒中偏瘫患者步行障碍恢复的临床观察

目的 观察功能性电刺激结合重复经颅磁刺激用于缺血性脑卒中偏瘫患者步行障碍恢复的临床疗效。方法 将53例缺血性脑卒中偏瘫患者随机分为对照组、治疗组、假治疗组3组,在均接受常规康复训练的基础上对照组接受功能性电刺激治疗,治疗组接受功能性电刺激及重复经颅磁刺激治疗,假治疗组接受功能性电刺激及假重复经颅磁刺激治疗; 治疗前及治疗8周后采用步态运动学参数、时间参数、距离参数及Amer-Lindholm分级对3组患者的下肢综合运动功能进行评定。结果 治疗前3组患者步态运动学参数、时间参数、距离参数及Amer-Lindholm分级评分均无显著差异(P>0.05),治疗8周后3组患者上述指标明显改善且治疗组改善幅度明显优于其余2组(P<0.05)。结论 功能性电刺激联合重复经颅磁刺激治疗有利于改善缺血性脑卒中偏瘫患者的步行运动功能。     

Two types of diencephalically driven RSA (theta) as a means of studying memory formation in mice

In mice, electrical stimulation of the medial forebrain bundle (MFB) drove hippocampal RSA with a frequency range of 7–9 Hz, whereas stimulation of the dorsomedial hypothalamus (DMH) drove RSA at 9–12 Hz. The post-trial effects of both stimulations on operant conditioning were tested. Improved retention was observed, but MFB stimulation had a short gradient of effectiveness (5 min), whereas DMH stimulation had a long gradient (up to 1 h post-training).     

A systematic review of the clinical efficacy of transcranial direct current stimulation (tDCS) in psychiatric disorders

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique, which can be used to selectively disrupt patterns of neural activity that are associated with symptoms of mental illness. tDCS has been implemented in numerous therapeutic trials across a range of patient populations, with a rapidly increasing number of studies being published each year. This systematic review aimed to evaluate the efficacy of tDCS in the treatment of psychiatric disorders. Four electronic databases were searched from inception until December 2015 by two independent reviewers, and 66 eligible studies were identified. Depression was the most extensively researched condition, followed by schizophrenia and substance use disorders. Data on obsessive compulsive disorder, generalised anxiety disorder, and anorexia nervosa were also obtained. The quality of included studies was appraised using a standardised assessment framework, which yielded a median score corresponding to “weak” on the three-point scale. This improved to “moderate” when case reports/series were excluded from the analysis. Overall, data suggested that tDCS interventions comprising multiple sessions can ameliorate symptoms of several major psychiatric disorders, both acutely and in the long-term. Nevertheless, the tDCS field is still in its infancy, and several methodological and ethical issues must be addressed before clinical efficacy can truly be determined. Studies probing the mechanisms of action of tDCS and those facilitating the definition of optimised stimulation protocols are warranted. Furthermore, evidence from large-scale, multi-centre randomised controlled trials is required if the transition of this therapy from the laboratory to the clinic is to be considered.     

Neurostimulation therapies in depression: a review of new modalities

OBJECTIVE: In response to an increased understanding of the neurobiology of severe psychiatric disorders, new therapeutic modalities are entering clinical practice that involve the direct stimulation of the brain. METHOD: We provide a review of published literature regarding the clinical use of vagus nerve stimulation (VNS) therapy, transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) in psychiatric disorders, with an emphasis on treatment-resistant depression (TRD). RESULTS: Vagus nerve stimulation is approved for use in both the EU and US for TRD. TMS has been approved for TRD in Canada, Australia, New Zealand, the European Union and Israel, but not yet in the United States. DBS remains in the early stages of investigation. CONCLUSION: While additional studies are clearly warranted, treatments that directly stimulate the brain appear to hold great therapeutic promise for severe psychiatric disorders.     

Chasing Tics in the Human Brain: Development of Open,Scheduled and Closed Loop Responsive Approaches to Deep Brain Stimulation for Tourette Syndrome

Tourette syndrome is a childhood-onset disorder characterized by a combination of motor and vocal tics, often associated with psychiatric comorbidities including attention deficit and hyperactivity disorder and obsessive-compulsive disorder. Despite an onset early in life, half of patients may present symptoms in adulthood, with variable degrees of severity. In select cases, the syndrome may lead to significant physical and social impairment, and a worrisome risk for self injury. Evolving research has provided evidence supporting the idea that the pathophysiology of Tourette syndrome is directly related to a disrupted circuit involving the cortex and subcortical structures, including the basal ganglia, nucleus accumbens, and the amygdala. There has also been a notion that a dysfunctional group of neurons in the putamen contributes to an abnormal facilitation of competing motor responses in basal ganglia structures ultimately underpinning the generation of tics. Surgical therapies for Tourette syndrome have been reserved for a small group of patients not responding to behavioral and pharmacological therapies, and these therapies have been directed at modulating the underlying pathophysiology. Lesion therapy as well as deep brain stimulation has been observed to suppress tics in at least some of these cases. In this article, we will review the clinical aspects of Tourette syndrome, as well as the evolution of surgical approaches and we will discuss the evidence and clinical responses to deep brain stimulation in various brain targets. We will also discuss ongoing research and future directions as well as approaches for open, scheduled and closed loop feedback-driven electrical stimulation for the treatment of Tourette syndrome.     

High frequency stimulation can block axonal conduction

High frequency stimulation (HFS) is used to control abnormal neuronal activity associated with movement, seizure, and psychiatric disorders. Yet, the mechanisms of its therapeutic action are not known. Although experimental results have shown that HFS suppresses somatic activity, other data has suggested that HFS could generate excitation of axons. Moreover it is unclear what effect the stimulation has on tissue surrounding the stimulation electrode. Electrophysiological and computational modeling literature suggests that HFS can drive axons at the stimulus frequency. Therefore, we tested the hypothesis that unlike cell bodies, axons are driven by pulse train HFS. This hypothesis was tested in fibers of the hippocampus both in-vivo and in-vitro. Our results indicate that although electrical stimulation could activate and drive axons at low frequencies (0.5–25 Hz), as the stimulus frequency increased, electrical stimulation failed to continuously excite axonal activity. Fiber tracts were unable to follow extracellular pulse trains above 50 Hz in-vitro and above 125 Hz in-vivo. The number of cycles required for failure was frequency dependent but independent of stimulus amplitude. A novel in-vitro preparation was developed, in which, the alveus was isolated from the remainder of the hippocampus slice. The isolated fiber tract was unable to follow pulse trains above 75 Hz. Reversible conduction block occurred at much higher stimulus amplitudes, with pulse train HFS (> 150 Hz) preventing propagation through the site of stimulation. This study shows that pulse train HFS affects axonal activity by: (1) disrupting HFS evoked excitation leading to partial conduction block of activity through the site of HFS; and (2) generating complete conduction block of secondary evoked activity, as HFS amplitude is increased. These results are relevant for the interpretation of the effects of HFS for the control of abnormal neural activity such as epilepsy and Parkinson's disease.     

2nd European Conference on Schizophrenia Research: From Research to Practice

For decades, the most severe, protracted and therapy-resistant forms of major depression have compelled clinicians and researchers to look for last resort treatment. Early psychosurgical procedures were hazardous and often associated with severe and persistent side effects including avolition, apathy and change of personality. With the introduction of psychopharmacological treatments in the 1950s, the frequency of ablative procedures declined rapidly. The past decade, however, has witnessed the resurgence of surgical strategies as a result of refined techniques and advances such as high frequency stimulation of deep brain nuclei. Recent data suggest that the overall effect of high frequency stimulation lies in the functional inhibition of neural activity in the region stimulated. Contrary to other psychosurgical procedures, high frequency stimulation reversibly modulates targeted brain areas and allows a postsurgical adaption of the stimulation parameters according to clinical outcome. With increased understanding of the brain regions and functional circuits involved in the pathogenesis of psychiatric disorders, major depression has emerged as a target for new psychosurgical approaches to selectively and precisely modulate neural areas involved in the disease process. Recent studies of minimally intervening procedures report good clinical outcome in the treatment of therapy-resistant forms of major depression. High frequency stimulation was successfully applied in several small samples of patients with treatment-resistant depression when the stimulation focused on different areas, e.g., nucleus accumbens, the lateral habenula or cortical areas. Nevertheless, the reticence toward psychosurgery, even for those patients suffering from the most debilitating forms of depression, still prevails, even though recent studies have shown significant improvement in terms of quality of life with the limitation that the number of treated cases has been small. In any event, valid and unambiguous criteria for patient eligibility have yet to be refined and standardized. In this review, we suggest possible standard criteria for the application of deep brain stimulation on patients suffering from otherwise treatment-resistant depression.     

Functional electrical stimulation in neurological disorders

Functional electrical stimulation (FES) refers to electrical stimulation of muscles in order to improve the impaired motor function. This is achieved by activating skeletal muscles with constant frequency trains of stimulations. This method has been found useful in various neurological disorders like hemiplegia, foot drop and paraplegia including spinal cord injuries. The first half of this review focuses on the broad clinical applications of functional electrical stimulation, its mechanism of action and the complications of this mode of therapy. Advanced Parkinson's disease (PD) is characterized by marked slowing of gait and frequent freezing episodes. Medical and surgical treatments are often ineffective in managing freezing episodes. The second half of this review discusses briefly the gait abnormalities in PD and the available treatment options. The possible role of FES in improving gait in parkinsonism and the importance of future research in this direction are highlighted.     

Competence of nerve tissue as distal insert promoting nerve regeneration in a silicone chamber

In some medial forebrain bundle (MFB) sites, self-stimulation is often modulated by hunger or satiety. With electrodes in the nucleus accumbens (NAC) such modulation rarely occurs. The influence of food deprivation on MFB self-stimulation is the main basis for the hypothesis that electrical stimulation of the MFB can mimic the rewarding effect of food for hungry animals. To investigate this hypothesis, unit activity was recorded from the lateral hypothalamic area (LHA) of freely moving rats during rewarding stimulation at loci in both MFB and NAC, and during food ingestion. Of 63 neurons tested during MFB stimulation, 41 were inhibited, 19 were activated, and 3 were not influenced. NAC stimulation suppressed 8 of the 31 neurons tested, excited 16, and elicited no response in the remaining 7. During ingestion, 29 of the 63 neurons tested were inhibited and one was facilitated. Of 29 neurons suppressed by food, 20 were also inhibited by rewarding MFB stimulation, but 10 of 13 neurons inhibited by food were excited by rewarding NAC stimulation. Thus, most LHA neurons inhibited during feeding were also inhibited by rewarding MFB stimulation. Rewarding NAC stimulation, however, does not inhibit most LHA neurons that are inhibited by food. This result suggests that LHA neurons which are inhibited by food might be involved in mediation of the rewarding effect of electrical stimulation at some sites in the MFB. Nevertheless, self-stimulation may occur by activating reward processes other than those related to food, because rewarding NAC stimulation does not inhibit LHA neurons which are suppressed by food.     

Non pharmacological treatment for neuropathic pain: Invasive and non-invasive cortical stimulation

The use of medications in chronic neuropathic pain may be limited with regard to efficacy and tolerance. Therefore, non-pharmacological approaches, using electrical stimulation of the cortex has been proposed as an alternative. First, in the early nineties, surgically-implanted epidural motor cortex stimulation (EMCS) was proven to be effective to relieve refractory neuropathic pain. Later, non-invasive stimulation techniques were found to produce similar analgesic effects, at least by means of repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1). Following “high-frequency” rTMS (e.g., stimulation frequency ranging from 5 to 20 Hz) delivered to the precentral gyrus (e.g., M1 region), it is possible to obtain an analgesic effect via the modulation of several remote brain regions involved in nociceptive information processing or control. This pain reduction can last for weeks beyond the time of the stimulation, especially if repeated sessions are performed, probably related to processes of long-term synaptic plasticity. Transcranial direct current stimulation (tDCS), another form of transcranial stimulation, using low-intensity electrical currents, generally delivered by a pair of large electrodes, has also shown some efficacy to improve patients with chronic pain syndromes. The mechanism of action of tDCS differs from that of EMCS and rTMS, but the cortical target is the same, which is M1. Although the level of evidence of therapeutic efficacy in the context of neuropathic pain is lower for tDCS than for rTMS, interesting perspectives are opened by using at-home tDCS protocols for long-term management. Now, there is a scientific basis for recommending both EMCS and rTMS of M1 to treat refractory chronic neuropathic pain, but their application in clinical practice remains limited due to practical and regulatory issues.     

Non-invasive Cerebellar Stimulation—a Consensus Paper

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.     

Dopamine efflux in the rat striatum evoked by electrical stimulation of the subthalamic nucleus: potential mechanism of action in Parkinson's disease

The precise mechanism whereby continuous high-frequency electrical stimulation of the subthalamic nucleus ameliorates motor symptoms of Parkinson's disease is unknown. We examined the effects of high-frequency stimulation of regions dorsal to and within the subthalamic nucleus on dopamine efflux in the striatum of urethane-anaesthetized rats using constant potential amperometry. Complementary extracellular electrophysiological studies determined the activity of subthalamic nucleus neurons in response to similar electrical stimulation of the subthalamic nucleus. High-frequency stimulation of the subthalamic nucleus increased action potential firing in the subthalamic nucleus only during the initial stimulation period and was followed by a cessation of firing over the remainder of stimulation. Electrical stimulation of the subthalamic nucleus with 15 pulses elicited stimulus-time-locked increases in striatal dopamine efflux with maximal peak effects occurring at 50 Hz frequency and 300 microA intensity. Extended subthalamic nucleus stimulation (1000 pulses at 50 Hz; 300 microA) elicited a similar peak increase in striatal dopamine efflux that was followed by a relatively lower steady-state elevation in extracellular dopamine over the course of stimulation. In contrast, extended stimulation immediately adjacent and dorsal to the subthalamic nucleus resulted in an 11-fold greater increase in dopamine efflux that remained elevated over the course of the stimulation. Immunohistochemical staining for tyrosine hydroxylase revealed catecholaminergic fibers running immediately dorsal to and through the subthalamic nucleus. Taken together, these results suggest that enhanced dopamine release within the basal ganglia may be an important mechanism whereby high-frequency stimulation of the subthalamic nucleus improves motor symptoms of Parkinson's disease.     

Cortical inhibition in motor and non-motor regions: a combined TMS-EEG study

A number of studies using paired pulse transcranial magnetic stimulation (TMS) have demonstrated that cortical inhibition (CI) of the motor cortex can be recorded and also gauged through surface electromyography. However, recording CI from other brain regions that are more directly related with the pathophysiology of some neurologic and psychiatric disorders (e.g., dorsolateral prefrontal cortex (DLPFC) in schizophrenia) was previously fraught with technical difficulties. This study was therefore designed to examine, through a combination of TMS with EEG, whether CI could be measured directly from the motor cortex, DLPFC, and another non-motor region. To index CI, long interval cortical inhibition (LICI; a TMS paradigm) was used in the motor cortex and DLPFC in 14 healthy subjects, and in the parietal lobe in 5 of those subjects. In the motor cortex, LICI resulted in a significant suppression in mean cortical evoked activity on EEG (37.31 +/- 47.51%). In the DLPFC, LICI resulted in a significant suppression (32.45 +/- 47.86%) in mean cortical evoked activity and did not correlate with LICI in the motor cortex although they did not significantly differ. In the parietal lobe, LICI resulted in significant suppression (47.76 +/- 44.70%) in mean cortical evoked activity. In conclusion, CI in the dorsolateral prefrontal cortex, motor cortex and parietal cortex were similar at 120% of motor threshold. These data suggest that CI can be recorded by combining TMS with EEG and may facilitate future research attempting to ascertain the role of CI in the pathophysiology of several neurologic and psychiatric disorders.     

High-frequency stimulation of the globus pallidus interna nucleus modulates GFRα1 gene expression in the basal ganglia

Deep brain stimulation (DBS) is an established therapy for movement disorders such as Parkinson’s disease (PD). Although the efficacy of DBS is clear, its precise molecular mechanism remains unknown. The glial cell line derived factor (GDNF) family of ligands has been shown to confer neuroprotective effects on dopaminergic neurons, and putaminal infusion of GDNF have been investigated in PD patients with promising results. Despite the potential therapeutic role of GDNF in alleviating motor symptoms, there is no data on the effects of electrical stimulation on GDNF-family receptor (GFR) expression in the basal ganglia structures. Here, we report the effects of electrical stimulation on GFRα1 isoforms, particularly GFRα1a and GFRα1b. Wistar rats underwent 2 hours of high frequency stimulation (HFS) at the globus pallidus interna nucleus. A control group was subjected to a similar procedure but without stimulation. The HFS group, sacrificed 24 hours after treatment, had a threefold decrease in mRNA expression level of GFRα1b (p = 0.037), but the expression level reverted to normal 72 hours after stimulation. Our preliminary data reveal the acute effects of HFS on splice isoforms of GFRα1, and suggest that HFS may modulate the splice isoforms of GFRα1a and GFRα1b to varying degrees. Going forward, elucidating the interactions between HFS and GFR may shed new insights into the complexity of GDNF signaling in the nervous system and lead to better design of clinical trials using these signaling pathways to halt disease progression in PD and other neurodegenerative diseases.