Bidirectional regulation of motor circuits using magnetogenetic gene therapy.

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

Deep brain stimulation for Tourette's syndrome.

Tourette's syndrome is a neuropsychiatric disorder characterized by formidable motor and vocal tics. Many individuals also present with comorbid neuropsychiatric conditions. Though patients often benefit from pharmacological and behavioral therapies, a subset of individuals develop severe, treatment-resistant symptoms that might necessitate more invasive interventions, such as Deep Brain Stimulation (DBS). DBS, particularly targeting regions like the globus pallidus internus (GPi) and the centromedian-parafascicular complex (CM-Pf) of the thalamus, has demonstrated effectiveness in reducing tic severity and improving quality of life. This review outlines the mechanism, clinical efficacy, and long-term outcome of DBS in TS. Results from clinical studies reveal significant reductions in tics. However, success with DBS is variable depending on a number of factors, including target selection and electrode placement. The use of DBS has ethical considerations, which include risks to the surgical procedure, the need for full and complete informed consent, and questions about the implications of such treatment on cognitive and emotional growth. Long-term follow-up will be required to ensure appropriate patient outcomes and complication management. Additional research and ethical debate will be needed with advancing DBS technology to ensure responsible and equitable treatment. This paper narratively summarizes the surgical options available for TS, with a focus on the current status of DBS in the management of the disease.

Low-beta versus high-beta band cortico-subcortical coherence in movement inhibition and expectation.

Beta band oscillations in the sensorimotor cortex and subcortical structures, such as the subthalamic nucleus (STN) and internal pallidum (GPi), are closely linked to motor control. Recent research suggests that low-beta (14.5-23.5 Hz) and high-beta (23.5-35 Hz) cortico-STN coherence arise through distinct networks, possibly reflecting indirect and hyperdirect pathways. In this study, we sought to probe whether low- and high-beta coherence also exhibit different functional roles in facilitating and inhibiting movement. Twenty patients with Parkinson's disease who had deep brain stimulation electrodes implanted in either STN or GPi performed a classical go/nogo task while undergoing simultaneous magnetoencephalography and local field potentials recordings. Subjects' expectations were manipulated by presenting go- and nogo-trials with varying probabilities. We identified a lateral source in the sensorimotor cortex for low-beta coherence, as well as a medial source near the supplementary motor area for high-beta coherence. Task-related coherence time courses for these two sources revealed that low-beta coherence was more strongly implicated than high-beta coherence in the performance of go-trials. Accordingly, average pre-stimulus low-beta but not high-beta coherence or spectral power correlated with overall reaction time across subjects. High-beta coherence during unexpected nogo-trials was higher compared to expected nogo-trials at a relatively long latency of 3 s after stimulus presentation. Neither low- nor high-beta coherence showed a significant correlation with patients' symptom severity at baseline assessment. While low-beta cortico-subcortical coherence appears to be related to motor output, the role of high-beta coherence requires further investigation.

Changes in D4 and GABAA subunit α3 receptors in the thalamic reticular nucleus caused by unilateral lesion of the globus pallidus.

The thalamic reticular nucleus controls information processing in thalamocortical neurons. GABAergic neurons present in this nucleus express the α3 subunit of post­synaptic GABAA receptors, which bind GABA from globus pallidus neurons. Pallidal neurons, in turn, have dopaminergic D4 receptors in their axon terminals. The thalamic reticular nucleus connects reciprocally with the thalamus, and it receives afferents from the brain cortex, as well as from other brain structures that have an important role in the modulation of the thalamic network. Based on the above, the purpose of this study was to assess the electrophysiological and molecular effects of unilateral lesion of the globus pallidus on the electric activity of the thalamic reticular nucleus. Two­month­old male rats were used. The right globus pallidus was lesioned with quinolinic acid. Seven days after the lesion, ipsilateral turning was registered, confirming the lesion. Afterward, electrophysiological evaluation of the right thalamic reticular nucleus' electrical activity was performed. Subsequently, mRNA expression for D4 receptors and subunit α3, as well as protein content were assessed in the right reticular nucleus. Pallidum lesion caused an increase in firing frequency and decreased firing bursts of reticular neurons. In addition, dopaminergic D4 mRNA, as well as protein increased. In contrast, GABAergic GABAA subunit α3 expression was suppressed, but protein content increased. These results show that the globus pallidus regulates firing in reticular neurons through D4 receptors and subunit α3 of GABAA receptor in the reticular nucleus of the thalamus.

Patient Selection for Deep Brain Stimulation for Pantothenate Kinase-Associated Neurodegeneration.

Clinical Vignette: A 23-year-old woman with pantothenate kinase-associated neurodegeneration (PKAN) presented with medication-refractory generalized dystonia and an associated gait impairment. Clinical Dilemma: Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) can be an effective treatment for dystonia. However, outcomes for PKAN DBS have been variable and there are no standardized criteria for patient selection. Clinical Solution: Bilateral GPi DBS implantation resulted in improvement in dystonia and gait. The benefit has persisted over one year after implantation. Gap in Knowledge: PKAN is a rare neurodegenerative disorder and evidence supporting the use of PKAN DBS has been largely limited to case reports and case series. Consequently, there is a paucity of long-term data, especially on gait-related outcomes. Expert Commentary: The clinical characteristics of dystonia that respond to DBS tend to respond in PKAN. Clinicians counselling patients about the effects of DBS for PKAN should thoughtfully discuss gait and postural instability as important aspects to consider, especially as the disease will progress post-DBS.

Quantitative Susceptibility Mapping Values Quantification in Deep Gray Matter Structures for Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVES: This systematic review and meta-analysis aimed to investigate the role of magnetic susceptibility (χ) in deep gray matter (DGM) structures, including the putamen (PUT), globus pallidus (GP), caudate nucleus (CN), and thalamus, in the most common types of multiple sclerosis (MS) and relapsing-remitting MS (RRMS), using quantitative susceptibility mapping (QSM). METHODS: The literature was systematically reviewed up to November 2023, adhering to PRISMA guidelines. This study was conducted using a random-effects model to calculate the standardized mean difference (SMD) in QSM values between patients with RRMS and healthy controls (HCs). Publication bias and risk of bias were also assessed. RESULTS: Nine studies involving 1074 RRMS patients with RRMS and 640 HCs were included in the meta-analysis. The results showed significantly higher QSM (χ) values in the PUT (SMD = 0.40, 95% confidence interval [CI] = 0.22-0.59, p = .000), GP (SMD = 0.60, 95% CI = 0.50-0.70, p = .00), and CN (SMD = 0.40, 95% CI = 0.15-0.66, p = .005) of RRMS patients compared to HCs. However, there were no significant differences in the QSM values in the thalamus between patients with RRMS and HCs (SMD = -0.33, 95% CI -0.67-0.01, p = .026). Age- and sex-based subgroup analysis demonstrated that younger patients (< 40 years) in the PUT, GP, and CN groups and larger male populations (> 25%) in the PUT and GP groups had more significant χ. Interestingly, thalamic QSM values were found to decrease in RRMS patients over 40 years of age and in higher male populations. Sex-based subgroup analysis indicated higher iron levels in the PUT and GP of RRMS patients regardless of sex. QSM values were higher in certain brain regions (PUT, GP, and CN) during the early stages (disease duration < 9.6 years) of RRMS, but lower in the thalamus during the later stages (disease duration > 9.6 years) than HCs. DISCUSSION/CONCLUSION: QSM may serve as a biomarker for understanding χ value alterations such as iron dysregulation and its contribution to neurodegeneration in RRMS, especially in the basal ganglia nuclei including PUT, GP, and CN.

BMI and deep brain stimulation: A comprehensive review and future directions with AI integration.

Deep brain stimulation (DBS) has revolutionized the treatment of movement disorders, including Parkinson's disease (PD), essential tremors, dystonia, and treatment-refractory obsessive-compulsive disorder (OCD). This systematic review and meta-analysis aimed to assess the impact of DBS on Body Mass Index (BMI). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, data from 49 studies were reviewed, with 46 studies specifically focusing on BMI and DBS. These studies involved 1,478 participants, predominantly PD patients, with an average age of 58.82 years. The primary DBS implantation site was the subthalamic nucleus (STN). Over six months, the mean BMI increased from 25.69 to 27.41, despite a reduction in daily energy intake from 1992 to 1873 kJ. While the findings suggest a correlation between DBS and weight gain, the study has limitations. The sample largely comprised PD patients (91%), preventing analysis of other subtypes. Additionally, most studies focused on the STN, limiting comparisons with other targets like the globus pallidus internus (GPi). Inconsistencies in assessing daily energy intake and food consumption further complicate the results. Integrating artificial intelligence (AI) in future research could address these gaps. For example, machine learning algorithms, such as those used by Oliveira et al., can predict post-DBS weight changes based on pre-surgical BMI and demographic factors. Similarly, AI-driven models like CLOVER-DBS can optimize DBS settings for improved motor control in PD patients. In conclusion, DBS affects BMI, and AI has the potential to enhance the precision of future studies.

Beyond Pallidal or Subthalamic Deep Brain Stimulation to Treat Dystonia.

Deep brain stimulation of the subthalamic nucleus and globus pallidus internus is approved by the Food and Drug Administration for treating dystonia. Both targets have shown effectiveness in improving symptoms, but post-operative outcomes can vary significantly among patients. This variability has led researchers to explore alternative neuromodulation targets that might offer more consistent results. Emerging research has highlighted several promising new targets for DBS in dystonia. This review examines pre-clinical and clinical data on novel DBS targets for dystonia and explores non-invasive neuromodulation studies that shed light on the disease's underlying pathological circuitry.

Directional Stimulus-Evoked Pallidal Electrophysiology in Primary Dystonia.

Background: Deep brain stimulation for dystonia improves motor symptoms but variable and delayed responses challenge patient selection, targeting, and device programming. Case Report: Here we studied intracranial electrophysiology in a patient with primary dystonia and observed evoked resonant neural activity (ERNA) in the globus pallidus interna. These local stimulus-evoked potentials displayed refractory periods and paired-pulse facilitation at clinically relevant interstimulus intervals. Sensing from directional DBS contacts localized ERNA to an effective stimulation site in the ventral posterolateral portion of the pallidum. Discussion: To the best of our knowledge, this is the first observation of ERNA in the globus pallidus interna in a patient with primary dystonia. Stimulus-evoked activity could eventually guide both directional and adaptive stimulation for dystonia and other complex neuropsychiatric disorders.

Striato-pallidal oscillatory connectivity correlates with symptom severity in dystonia patients.

Dystonia is a hyperkinetic movement disorder that has been associated with an imbalance towards the direct pathway between striatum and internal pallidum, but the neuronal underpinnings of this abnormal basal ganglia pathway activity remain unknown. Here, we report invasive recordings from ten dystonia patients via deep brain stimulation electrodes that allow for parallel recordings of several basal ganglia nuclei, namely the striatum, external and internal pallidum, that all displayed activity in the low frequency band (3-12 Hz). In addition to a correlation with low-frequency activity in the internal pallidum (R = 0.88, P = 0.001), we demonstrate that dystonic symptoms correlate specifically with low-frequency coupling between striatum and internal pallidum (R = 0.75, P = 0.009). This points towards a pathophysiological role of the direct striato-pallidal pathway in dystonia that is conveyed via coupling in the enhanced low-frequency band. Our study provides a mechanistic insight into the pathophysiology of dystonia by revealing a link between symptom severity and frequency-specific coupling of distinct basal ganglia pathways.

Effect of deep brain stimulation on postoperative body mass index: A systematic review and meta-analysis.

BACKGROUND: Deep Brain Stimulation (DBS) is FDA-approved for several movement disorders; such as Parkinson's disease, dystonia, and neuropsychiatric disorders. There are various reports of Body mass index (BMI) changes following different DBS targets in various disorders. AIM: A comprehensive systematic review and meta-analysis were conducted to investigate the impact of DBS on patients' Body Mass Index (BMI) and provide an in-depth overview of its underlying mechanisms. MATERIALS AND METHODS: We conducted research according to PRISMA guidelines. Our study assessed comprehensively electronic databases, including Pubmed, Scopus, Embase, web of science, and the Cochrane Library, up to May 2024. The random-effect model analysis was performed by the Comprehensive Meta-analysis software (CMA) version 3.0. As well, Cochran's Q test was used to determine the statistical heterogeneity of included studies. RESULT: This systematic review ultimately included 49 studies, 46 of which entered the meta-analysis. The total number of patients was 1478, consisting of Parkinson's disease (PD), dystonia, and the obsessive compulsive disorder (OCD) patients. The most common DBS target was subthalamic nucleus, followed by globus pallidus internus (GPi). Our meta-analysis depicted the BMI of participants significantly mount after DBS electrode implantation (SMD = -0.542, 95%CI: -0.678 to -0.406, and P-value < 0.001). However, moderate to high heterogeneity was detected among the studies (I2 = 67.566%). Additionally, the Daily energy intake (DEI) of patients significantly decreased after DBS (SMD: 0.457, 95%CI; 0.205 to 0.709, and P-value < 0.001). CONCLUSION: STN and GPi DBS can lead to weight gain through distinct central pathways in various movement and neuropsychiatric disorders, posing a potential risk for obesity, insulin resistance, and metabolic syndrome.

Structural MRI Correlates of Anosognosia in Huntington's Disease.

Background: Anosognosia, or unawareness of symptoms, is common in Huntington's disease (HD), but the neuroanatomical basis of this is unknown. Objective: To identify neuroanatomical correlates of HD anosognosia using structural MRI data. Methods: We leveraged a pre-processed dataset of 570 HD participants across the well-characterized PREDICT-HD and TRACK-HD cohort studies. Anosognosia index was operationalized as the score discrepancies between HD participants and their caregivers on the Frontal Systems Behavior Scale (FrSBe). Results: Univariate correlation analyses identified volumes of globus pallidus, putamen, caudate, basal forebrain, substantia nigra, angular gyrus, and cingulate cortex as significant correlates of anosognosia after correction for multiple comparisons. A multivariable model constructed with stepwise regression that included volumetric data showed globus pallidus volume alone explained more variance in anosognosia severity than motor impairment or CAP score alone. Conclusions: Anosognosia appears to be related to degeneration affecting both cortical and subcortical areas. Globus pallidus neurodegeneration in particular appears to be a key process of importance.

Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensembles.

Defining spatial synchronisation of pathological beta oscillations is important, given that many theories linking them to parkinsonian symptoms propose a reduction in the dimensionality of the coding space within and/or across cortico-basal ganglia structures. Such spatial synchronisation could arise from a single process, with widespread entrainment of neurons to the same oscillation. Alternatively, the partially segregated structure of cortico-basal ganglia loops could provide a substrate for multiple ensembles that are independently synchronized at beta frequencies. Addressing this question requires an analytical approach that identifies groups of signals with a statistical tendency for beta synchronisation, which is unachievable using standard pairwise measures. Here, we utilized such an approach on multichannel recordings of background unit activity (BUA) in the external globus pallidus (GP) and subthalamic nucleus (STN) in parkinsonian rats. We employed an adapted version of a principle and independent component analysis-based method commonly used to define assemblies of single neurons (i.e., neurons that are synchronized over short timescales). This analysis enabled us to define whether changes in the power of beta oscillations in local ensembles of neurons (i.e., the BUA recorded from single contacts) consistently covaried over time, forming a "beta ensemble". Multiple beta ensembles were often present in single recordings and could span brain structures. Membership of a beta ensemble predicted significantly higher levels of short latency (<5 ms) synchrony in the raw BUA signal and phase synchronisation with cortical beta oscillations, suggesting that they comprised clusters of neurons that are functionally connected at multiple levels, despite sometimes being non-contiguous in space. Overall, these findings suggest that beta oscillations do not comprise of a single synchronisation process, but rather multiple independent activities that can bind both spatially contiguous and non-contiguous pools of neurons within and across structures. As previously proposed, such ensembles provide a substrate for beta oscillations to constrain the coding space of cortico-basal ganglia circuits.

Pallidal and Thalamic Deep Brain Stimulation in the Treatment of Unilateral Dystonia: A Prospective Assessment.

BACKGROUND: The complexities of unilateral dystonia have led to exploring simultaneous (dual) globus pallidus internus (GPi) and motor ventral thalamus (Vim/Vop) deep brain stimulation (DBS), yet detailed assessments are lacking. OBJECTIVES: To assess the efficacy of GPi, Vim/Vop, and dual DBS in unilateral dystonia. METHODS: Three patients with unilateral dystonia (two idiopathic, one acquired), implanted with two DBS electrodes targeting ipsilateral Vim/Vop and GPi, were included. Three stimulation modalities were assessed. First, one electrode was activated, then the other, and finally, both electrodes were activated simultaneously. RESULTS: DBS yielded substantial symptomatic reductions in all three evaluated stimulation modalities. Patients exhibited varying responses regarding quality-of-life and depressive symptoms. Treatment satisfaction didn't align with clinical improvements, potentially affected by unrealistic expectations. CONCLUSIONS: This study contributes critical insights into GPi, Vim/Vop and simultaneous stimulation for unilateral dystonia. The safety of the procedure underscores the promise of this approach.

Neural pathways associated with reduced rigidity during pallidal deep brain stimulation for Parkinson's disease.

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) can markedly reduce muscle rigidity in people with Parkinson's disease (PD); however, the mechanisms mediating this effect are poorly understood. Computational modeling of DBS provides a method to estimate the relative contributions of neural pathway activations to changes in outcomes. In this study, we generated subject-specific biophysical models of GPi DBS (derived from individual 7-T MRI), including pallidal efferent, putamenal efferent, and internal capsule pathways, to investigate how activation of neural pathways contributed to changes in forearm rigidity in PD. Ten individuals (17 arms) were tested off medication under four conditions: off stimulation, on clinically optimized stimulation, and on stimulation specifically targeting the dorsal GPi or ventral GPi. Quantitative measures of forearm rigidity, with and without a contralateral activation maneuver, were obtained with a robotic manipulandum. Clinically optimized GPi DBS settings significantly reduced forearm rigidity (P < 0.001), which aligned with GPi efferent fiber activation. The model demonstrated that GPi efferent axons could be activated at any location along the GPi dorsal-ventral axis. These results provide evidence that rigidity reduction produced by GPi DBS is mediated by preferential activation of GPi efferents to the thalamus, likely leading to a reduction in excitability of the muscle stretch reflex via overdriving pallidofugal output.NEW & NOTEWORTHY Subject-specific computational models of pallidal deep brain stimulation, in conjunction with quantitative measures of forearm rigidity, were used to examine the neural pathways mediating stimulation-induced changes in rigidity in people with Parkinson's disease. The model uniquely included internal, efferent and adjacent pathways of the basal ganglia. The results demonstrate that reductions in rigidity evoked by deep brain stimulation were principally mediated by the activation of globus pallidus internus efferent pathways.

Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson's Disease.

In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

An escape-enhancing circuit involving subthalamic CRH neurons mediates stress-induced anhedonia in mice.

Chronic predator stress (CPS) is an important and ecologically relevant tool for inducing anhedonia in animals, but the neural circuits underlying the associated neurobiological changes remain to be identified. Using cell-type-specific manipulations, we found that corticotropin-releasing hormone (CRH) neurons in the medial subthalamic nucleus (mSTN) enhance struggle behaviors in inescapable situations and lead to anhedonia, predominately through projections to the external globus pallidus (GPe). Recordings of in vivo neuronal activity revealed that CPS distorted mSTN-CRH neuronal responsivity to negative and positive stimuli, which may underlie CPS-induced behavioral despair and anhedonia. Furthermore, we discovered presynaptic inputs from the bed nucleus of the stria terminalis (BNST) to mSTN-CRH neurons projecting to the GPe that were enhanced following CPS, and these inputs may mediate such behaviors. This study identifies a neurocircuitry that co-regulates escape response and anhedonia in response to predator stress. This new understanding of the neural basis of defensive behavior in response to predator stress will likely benefit our understanding of neuropsychiatric diseases.

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.

Rescue Lead Implantation After Deep Brain Stimulation for Parkinson's Disease: A Single-Center Experience and Case Series.

BACKGROUND AND OBJECTIVES: Despite the well-established efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's Disease (PD), there remains a subset of patients with only a moderate improvement in symptoms even with appropriate lead placement and optimal programming. In patients with persistent tremor or dyskinesias, one consideration is the addition of a second "rescue lead" to provide dual stimulation to primary and secondary targets to address the refractory component. This study aimed to assess all "rescue lead" cases from our institution and characterize the patients and their outcomes. METHODS: Records of all patients with PD treated at our institution between 2005 and 2023 were retrospectively reviewed. Clinical data of all patients treated with a second rescue lead to supplement a positive but inadequate initial DBS response were collected and reviewed. RESULTS: Of 670 patients with PD treated at our institution during the study period, 7 were managed with a rescue lead. All 7 were initially treated with STN DBS with a partial improvement in underlying symptoms, had confirmed appropriate lead placement, and underwent thorough programming. Four patients underwent rescue with a globus pallidus interna lead for persistent dyskinesias, all with subsequent improvement in their dyskinesias. Three patients had persistent tremors that were treated with a rescue ventrointermediate thalamus stimulation with subsequent improvement in tremor scores. There were no operative complications, and all patients tolerated dual stimulation. CONCLUSION: For a small subset of patients with PD with persistent dyskinesias or tremors after STN DBS despite optimized lead parameters and adequate lead placement, rescue lead placement offers an effective treatment option.