Anti-Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct-Ligated Mice.

Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.

Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma?

Introduction: Heparin sulphate proteoglycans in the liver tumour microenvironment (TME) are key regulators of cell signalling, modulated by sulfatase-2 (SULF2). SULF2 overexpression occurs in hepatocellular carcinoma (HCC). Our aims were to define the nature and impact of SULF2 in the HCC TME. Methods: In liver biopsies from 60 patients with HCC, expression and localization of SULF2 were analysed associated with clinical parameters and outcome. Functional and mechanistic impacts were assessed with immunohistochemistry (IHC), in silico using The Cancer Genome Atlas (TGCA), in primary isolated cancer activated fibroblasts, in monocultures, in 3D spheroids, and in an independent cohort of 20 patients referred for sorafenib. IHC targets included αSMA, glypican-3, ß-catenin, RelA-P-ser536, CD4, CD8, CD66b, CD45, CD68, and CD163. SULF2 impact of peripheral blood mononuclear cells was assessed by migration assays, with characterization of immune cell phenotype using fluorescent activated cell sorting. Results: We report that while SULF2 was expressed in tumour cells in 15% (9/60) of cases, associated with advanced tumour stage and type 2 diabetes, SULF2 was more commonly expressed in cancer-associated fibroblasts (CAFs) (52%) and independently associated with shorter survival (7.2 vs. 29.2 months, p = 0.003). Stromal SULF2 modulated glypican-3/ß-catenin signalling in vitro, although in vivo associations suggested additional mechanisms underlying the CAF-SULF2 impact on prognosis. Stromal SULF2 was released by CAFS isolated from human HCC. It was induced by TGFß1, promoted HCC proliferation and sorafenib resistance, with CAF-SULF2 linked to TGFß1 and immune exhaustion in TGCA HCC patients. Autocrine activation of PDGFRß/STAT3 signalling was evident in stromal cells, with the release of the potent monocyte/macrophage chemoattractant CCL2 in vitro. In human PBMCs, SULF2 preferentially induced the migration of macrophage precursors (monocytes), inducing a phenotypic change consistent with immune exhaustion. In human HCC tissues, CAF-SULF2 was associated with increased macrophage recruitment, with tumouroid studies showing stromal-derived SULF2-induced paracrine activation of the IKKß/NF-κB pathway, tumour cell proliferation, invasion, and sorafenib resistance. Conclusion: SULF2 derived from CAFs modulates glypican-3/ß-catenin signalling but also the HCC immune TME, associated with tumour progression and therapy resistance via activation of the TAK1/IKKß/NF-κB pathway. It is an attractive target for combination therapies for patients with HCC.

c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.

Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-ß1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.

Implementation of pre-clinical methodologies to study fibrosis and test anti-fibrotic therapy.

Diseases where fibrosis plays a major role accounts for enormous morbidity and mortality and yet we have very little in our therapeutic arsenal despite decades of research and clinical trials. Our understanding of fibrosis biology is primarily built on data generated in conventional mono-culture or co-culture systems and in vivo model systems. While these approaches have undoubtedly enhanced our understanding of basic mechanisms, they have repeatedly failed to translate to clinical benefit. Recently, there had been a push to generate more physiologically relevant platforms to study fibrosis and identify new therapeutic targets. Here we review the state-of-the-art regarding the development and application of 3D complex cultures, bio-printing and precision cut slices to study pulmonary, hepatic and renal fibrosis.

Spinal Cord Stimulation for the Treatment of Chronic Pain Reduces Opioid Use and Results in Superior Clinical Outcomes When Used Without Opioids.

BACKGROUND: Chronic pain causes a significant burden to the US health care system, is difficult to treat, and remains a significant contributor to increased opioid use in the United States. Spinal cord stimulation (SCS) has been FDA approved for the treatment of chronic pain. OBJECTIVE: To evaluate the hypothesis that SCS reduces opioid use, and alone maintains clinical outcome measures of pain and psychosocial determinants of health. METHODS: In this prospective cohort study, we evaluated 86 patients undergoing SCS surgery for the treatment of chronic pain between September 2012 and August 2015. Preoperatively and postoperatively, patients completed the Numerical Rating Scale (NRS), McGill Pain Questionnaire (MPQ), Pain Catastrophizing Scale (PCS), Oswestry Disability Index (ODI), and Beck's Depression Inventory (BDI). VAS scores were retrospectively analyzed. RESULTS: Fifty-three patients used opioids before SCS implantation. The 33 nonusers had lower mean VAS, NRS, and ODI scores than both opioid groups at 1 yr and improved significantly at 1 yr on the VAS (P < .001), NRS (P < .001), MPQ (P = .002), PCS (P < .001), BDI (P = .04), and ODI (P = .002). After surgery, 41.5% remained opioids and 58.5% reduced/eliminated use. Discontinued (n = 29) or reduced (n = 2) use resulted in VAS, NRS, total MPQ, and ODI score reduction (P < .001, P = .002, P = .002, and P = .009 respectively). At 1 yr, survey scores in opioid users were unchanged. There was no difference between groups in revision or failure rates. CONCLUSION: Sixty-four percent of patients who were using opioids prior to SCS reduced (n = 2) or eliminated opioid use (n = 29) at 1 yr postoperatively. Patients who eliminated opioid use or never used opioids had superior clinical outcomes to those who continued use.

The use of focused ultrasound for the treatment of cutaneous allodynia associated with chronic migraine.

Chronic migraines (CM) are the third most common disease and are refractory to medical treatment in 15% of patients. Currently, temporary relief is achieved with steroid blocks or pulsed radiofrequency ablation, which have short-term benefits. Our project aims to develop a non-invasive treatment for medically refractory chronic migraine, which does not require a permanent implant. This project investigates the safety and effectiveness of pulsed focused ultrasound (FUS) in a validated rodent headache model of cutaneous allodynia associated with chronic migraine (CM) as compared to sumatriptan and ablative lesioning. We demonstrate a significant reduction in mechanical thresholds as measured through Von Frey filaments in CM in the forepaw and periorbital region (p < 0.001). Sumatriptan and pulsed FUS both significantly improve thresholds at day 3 after treatment in the periorbital region. Ablative lesioning has no effect. This study provides initial evidence that FUS may provide an important therapeutic option for patients suffering from CM.

Anatomical Correlates of Uncontrollable Laughter With Unilateral Subthalamic Deep Brain Stimulation in Parkinson's Disease.

INTRODUCTION: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for the management of motor complications in Parkinson's disease. Uncontrollable laughter has been reported as a rare side effect of STN stimulation. The precise mechanism responsible for this unique phenomenon remains unclear. We examined in detail the DBS electrode position and stimulation parameters in two patients with uncontrollable laughter during programming after STN-DBS surgery and illustrated the anatomical correlates of the acute mood changes with STN stimulation. CASE REPORT: Unilateral STN-DBS induced uncontrollable laughter with activation of the most ventral contacts in both patients. However, the location of the electrodes responsible for this adverse effect differed between the patients. In the first patient, the DBS lead was placed more inferiorly and medially within the STN. In the second patient, the DBS lead was implanted more anteriorly and inferiorly than initially planned at the level of the substantia nigra reticulata (SNr). CONCLUSION: Unilateral STN-DBS can induce acute uncontrollable laughter with activation of electrodes located more anterior, medial, and inferior in relationship with the standard stereotactic STN target. We suggest that simulation of ventral and medial STN, surrounding limbic structures or the SNr, is the most plausible anatomical substrate responsible for this acute mood and behavioral change. Our findings provide insight into the complex functional neuroanatomical relationship of the STN and adjacent structures important for mood and behavior. DBS programming with more dorsal and lateral contacts within the STN should be entertained to minimize the emotional side effects.

King's Parkinson's Disease Pain Scale for Assessment of Pain Relief Following Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: Pain is a prevalent and debilitating nonmotor symptom of Parkinson's disease (PD) that is often inadequately managed. Deep brain stimulation (DBS) has been shown to relieve pain in PD but an effective method of identifying which types of PD pain respond to DBS has not been established. We examine the effects of DBS on different types of PD pain using the King's Parkinson's disease pain scale (KPDPS), the only validated scale of PD pain. METHODS: We prospectively followed 18 PD patients undergoing subthalamic nucleus (STN) or Globus pallidus interna (GPi) DBS. Subjects completed the KPDPS, low back disability index (LBDI), and McGill pain questionnaire (MPQ), preoperatively and at six months postoperatively. Subjects underwent the unified Parkinson's disease rating scale-III (UPDRS-III) with preoperative scores ON medication and postoperative scores ON medication/DBS stimulation. RESULTS: Of the 18 patients, a total of 12 subjects had STN DBS and 6 had GPi DBS. As a group, subjects showed improvement in total KPDPS score at six-month postoperative follow-up (p = 0.004). Fluctuation and nocturnal pain were most significantly improved (p = 0.006, 0.01, respectively). Significant improvements were found in fluctuation-related pain domain following GPi DBS. CONCLUSIONS: In this pilot study, we are the first group to employ KPDPS to monitor pain relief following DBS in PD patients. We demonstrate that fluctuation-related pain and nocturnal pain significantly improve with DBS. Use of the KPDPS in the future will allow better understanding of how STN and GPi DBS treat PD pain over time.

A minimally invasive catheter-based ultrasound technology for therapeutic interventions in brain: initial preclinical studies.

OBJECTIVE Minimally invasive procedures may allow surgeons to avoid conventional open surgical procedures for certain neurological disorders. This paper describes the iterative process for development of a catheter-based ultrasound thermal therapy applicator. METHODS Using an ultrasound applicator with an array of longitudinally stacked and angularly sectored tubular transducers within a catheter, the authors conducted experimental studies in porcine liver, in vivo and ex vivo, in order to characterize the device performance and lesion patterns. In addition, they applied the technique in a rodent model of Parkinson's disease to investigate the feasibility of its application in brain. RESULTS Thermal lesions with multiple shapes and sizes were readily achieved in porcine liver. The feasibility of catheter-based focused ultrasound in the treatment of brain conditions was demonstrated in a rodent model of Parkinson's disease. CONCLUSIONS The authors show proof of principle of a catheter-based ultrasound system that can create lesions with concurrent thermode-based measurements.

High-Intensity Ultrasound Treatment for Vincristine-Induced Neuropathic Pain.

BACKGROUND: Vincristine is a commonly used chemotherapeutic agent that results in debilitating untreatable peripheral neuropathy. OBJECTIVE: To determine the effects of pulsed high-intensity focused ultrasound (HIFU) on sensory thresholds in a validated vincristine-induced neuropathy (VIN) rodent model. METHODS: VIN was induced and mechanical allodynia was confirmed by nociceptive testing. von Frey fibers and Randall-Sellito test were used as measures of innocuous and noxious mechanical thresholds, respectively, and the hot plate test for thermal thresholds. Tests were performed before VIN, after 2 wk of vincristine, at 24, 48, 72, and 120 h after HIFU applied to the left L5 dorsal root ganglia at 3 Watts for 3 min. Comparisons were made between a VIN cohort who underwent HIFU, a VIN cohort who underwent sham HIFU, and naïve rodents who underwent HIFU. RESULTS: VIN HIFU rats had significantly increased mechanical thresholds at 24 h (P < .001), 48 h (P = .008), 72 h (P = .003), and 120 h (P = .03) after treatment, when compared to pre-HIFU thresholds. Furthermore, at 24 and 48 h following treatment, VIN HIFU rats had significantly higher innocuous and noxious mechanical thresholds and thermal thresholds than VIN sham HIFU rats (P < .001). Thresholds were not altered in naïve rodents who underwent HIFU. Histological data of L5 dorsal root ganglia of VIN HIFU rats suggest that transient cellular edema resolves by 48 h. CONCLUSION: Our data suggest that HIFU increases mechanical and thermal thresholds in VIN rodents. Whether HIFU can preclude the development of reduced thresholds in the VIN model warrants further study.

Occipital Nerve Stimulation Attenuates Neuronal Firing Response to Mechanical Stimuli in the Ventral Posteromedial Thalamus of a Rodent Model of Chronic Migraine.

BACKGROUND: Chronic migraine (CM) is a highly debilitating disease, and many patients remain refractory to medicinal therapy. Given the convergent nature of neuronal networks in the ventral posteromedial nucleus (VPM) and the evidence of sensitization of pain circuitry in this disease, we hypothesize CM rats will have increased VPM neuronal firing, which can be attenuated using occipital nerve stimulation (ONS). OBJECTIVE: To determine whether VPM firing frequency differs between CM and sham rats, and whether ONS significantly alters firing rates during the application of mechanical stimuli. METHODS: Fourteen male Sprague-Dawley rats were infused with inflammatory media once daily through an epidural cannula for 2 wk to induce a CM state. Sham animals (n = 6) underwent cannula surgery but received no inflammatory media. ONS electrodes were implanted bilaterally and single-unit recordings were performed in the VPM of anesthetized rats during mechanical stimulation of the face and forepaw in the presence and absence of ONS. RESULTS: CM rats had significantly higher neuronal firing rates (P < .001) and bursting activity (P < .01) in response to mechanical stimuli when compared to shams. ONS significantly reduced neuronal firing in the VPM of CM rats during the application of 0.8 g (P = .04), 4.0 g (P = .04), and 15.0 g (P = .02) Von Frey filaments. ONS reduced bursting activity in CM rats during the 4.0 and 15 g filaments (P < .05). No significant changes in bursting activity or firing frequency were noted in sham animals during ONS. CONCLUSION: We demonstrate that neuronal spike frequencies and bursting activity in the VPM are increased in an animal model of CM compared to shams. Our results suggest that the mechanism of ONS may involve attenuation of neurons in the VPM of CM rats during the application of mechanical stimuli.

Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats.

Chronic pain is the most common non-motor symptom of Parkinson's disease (PD) and is often overlooked. Unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle lesioned rats used as models for PD exhibit decreased sensory thresholds in the left hindpaw. Subthalamic deep brain stimulation (STN DBS) increases mechanical thresholds and offers improvements with chronic pain in PD patients. However, individual responses to STN high frequency stimulation (HFS) in parkinsonian rats vary with 58% showing over 100% improvement, 25% showing 30-55% improvement, and 17% showing no improvement. Here we augment STN DBS by supplementing with a serotonin-norepinephrine reuptake inhibitor commonly prescribed for pain, duloxetine. Duloxetine was administered intraperitoneally (30mg/kg) in 15 parkinsonian rats unilaterally implanted with STN stimulating electrodes in the lesioned right hemisphere. Sensory thresholds were tested using von Frey, Randall-Selitto and hot-plate tests with or without duloxetine, and stimulation to the STN at HFS (150Hz), low frequency (LFS, 50Hz), or off stimulation. With HFS or LFS alone (left paw; p=0.016; p=0.024, respectively), animals exhibited a higher mechanical thresholds stable in the three days of testing, but not with duloxetine alone (left paw; p=0.183). Interestingly, the combination of duloxetine and HFS produced significantly higher mechanical thresholds than duloxetine alone (left paw, p=0.002), HFS alone (left paw, p=0.028), or baseline levels (left paw; p<0.001). These findings show that duloxetine paired with STN HFS increases mechanical thresholds in 6-OHDA-lesioned animals more than either treatment alone. It is possible that duloxetine augments STN DBS with a central and peripheral additive effect, though a synergistic mechanism has not been excluded.

Effect of low-frequency deep brain stimulation on sensory thresholds in Parkinson's disease.

OBJECTIVE Chronic pain is a major distressing symptom of Parkinson's disease (PD) that is often undertreated. Subthalamic nucleus (STN) deep brain stimulation (DBS) delivers high-frequency stimulation (HFS) to patients with PD and has been effective in pain relief in a subset of these patients. However, up to 74% of patients develop new pain concerns while receiving STN DBS. Here the authors explore whether altering the frequency of STN DBS changes pain perception as measured through quantitative sensory testing (QST). METHODS Using QST, the authors measured thermal and mechanical detection and pain thresholds in 19 patients undergoing DBS via HFS, low-frequency stimulation (LFS), and off conditions in a randomized order. Testing was performed in the region of the body with the most pain and in the lower back in patients without chronic pain. RESULTS In the patients with chronic pain, LFS significantly reduced heat detection thresholds as compared with thresholds following HFS (p = 0.029) and in the off state (p = 0.010). Moreover, LFS resulted in increased detection thresholds for mechanical pressure (p = 0.020) and vibration (p = 0.040) compared with these thresholds following HFS. Neither LFS nor HFS led to changes in other mechanical thresholds. In patients without chronic pain, LFS significantly increased mechanical pain thresholds in response to the 40-g pinprick compared with thresholds following HFS (p = 0.032). CONCLUSIONS Recent literature has suggested that STN LFS can be useful in treating nonmotor symptoms of PD. Here the authors demonstrated that LFS modulates thermal and mechanical detection to a greater extent than HFS. Low-frequency stimulation is an innovative means of modulating chronic pain in PD patients receiving STN DBS. The authors suggest that STN LFS may be a future option to consider when treating Parkinson's patients in whom pain remains the predominant complaint.

Clinical outcome and intraoperative neurophysiology for focal limb dystonic tremor without generalized dystonia treated with deep brain stimulation.

OBJECTIVES: Dystonic tremor (DT) is defined as a postural/kinetic tremor occurring in the body region affected by dystonia. DT is typically characterized by focal tremors with irregular amplitudes and variable frequencies typically below 7Hz. Pharmacological treatment is generally unsuccessful and guidelines for deep brain stimulation (DBS) targeting and indications are scarce. In this article, we present the outcome and neurophysiologic data of two patients with refractory, focal limb DT treated with Globus Pallidus interna (Gpi) DBS and critically review the current literature regarding surgical treatment of DT discussing stereotactic targets and treatment considerations. PATIENTS AND METHODS: A search of literature concerning treatment of DT was conducted. Additionally, Gpi DBS was performed in two patients with DT and microelectrode recordings for multi unit analysis (MUAs) and local field potentials (LFPs) were obtained. RESULTS: The mean percentage improvement in tremor severity was 80.5% at 3 years follow up. MUAs and LFPs did not show significant differences in DT patients compared with other forms of dystonia or PD except for higher interspikes bursting indices. LFP recordings in DT demonstrated high power at low frequencies with action (<3.5Hz). CONCLUSIONS: Gpi DBS is an effective treatment in patients with focal limb DT without associated generalized dystonia. Intraoperative neurophysiologic findings suggest that DT is part of phenotypic motor manifestations in dystonia.

Clinical Outcome and Characterization of Local Field Potentials in Holmes Tremor Treated with Pallidal Deep Brain Stimulation.

BACKGROUND: Holmes tremor (HT) is an irregular, low-frequency rest tremor associated with prominent action and postural tremors. Currently, the most effective stereotactic target and neurophysiologic characterization of HT, specifically local field potentials (LFPs) are uncertain. We present the outcome, intraoperative neurophysiologic analysis with characterization of LFPs in a patient managed with left globus pallidus interna deep brain stimulation (Gpi DBS). CASE REPORT: A 24-year-old male underwent left Gpi DBS for medically refractory HT. LFPs demonstrated highest powers in the delta range in Gpi. At the 6-month follow-up, a 90% reduction in tremor was observed. DISCUSSION: Pallidal DBS should be considered as an alternative target for management of refractory HT. LFP demonstrated neuronal activity associated with higher power in the delta region, similarly seen in patients with generalized dystonia.

Subthalamic deep brain stimulation alters neuronal firing in canonical pain nuclei in a 6-hydroxydopamine lesioned rat model of Parkinson's disease.

INTRODUCTION: Chronic pain is one of the most common non-motor symptoms of Parkinson's disease (PD) affecting up to 85% of patients. Previous studies have established that reduced mechanical and thermal thresholds occur in both idiopathic PD patients and animal models of PD, suggesting that changes may occur in sensory processing circuits. Improvements in sensory thresholds are achieved using subthalamic nucleus (STN) deep brain stimulation (DBS), however the mechanism by which this occurs remains unresolved. MATERIALS AND METHODS: We examined unilateral medial forebrain bundle 6-hydroxydopamine (6OHDA) rat model of PD to determine whether STN DBS alters neuronal firing rates in brain areas involved in ascending and descending pain processing. Specifically, single unit in vivo recordings were conducted in the anterior cingulate cortex (ACC), the periaqueductal grey (PAG), and the ventral posteriolateral nucleus of the thalamus (VPL), before, during and after stimulation was applied to the STN at 50 or 150Hz. RESULTS: Sham and 6OHDA lesioned animals have similar neuronal firing activity in the VPL, ACC and PAG before stimulation was applied (p>0.05). In 6OHDA lesioned rats, both low frequency stimulation (LFS) (p<0.01) and high frequency stimulation (HFS) (p<0.05) attenuated firing frequency in the ACC. In shams, only LFS decreased firing frequency. A subset of neurons in the PAG was significantly attenuated in both sham and 6OHDA lesioned animals during HFS and LFS (p<0.05), while another subset of PAG neuronal activity significantly increased in 6OHDA lesioned rats during HFS (p<0.05). Finally, low or high frequency STN DBS did not alter neuronal firing frequencies in the VPL. CONCLUSIONS: Our results suggest that STN DBS alters neuronal firing in descending pain circuits. We hypothesize that STN DBS attenuates excitatory projections from the ACC to the PAG in 6OHDA lesioned rats. Following this, neurons in the PAG respond by either increasing (during HFS only) or decreasing (during both LFS and HFS), which may modulate descending facilitation or inhibition at the level of the spinal cord. Future work should address specific neuronal changes in the ACC and PAG that occur in a freely moving parkinsonian animal during a pain stimulus treated with STN DBS.

The Effects of Mechanical and Thermal Stimuli on Local Field Potentials and Single Unit Activity in Parkinson's Disease Patients.

BACKGROUND: Chronic pain is a major, debilitating symptom of Parkinson's disease (PD). Although, deep brain stimulation (DBS) has been shown to improve pain outcomes, the mechanisms underlying this phenomenon are unclear. Microelectrode recording allows us to measure both local field potentials (LFPs) and single neuronal unit activity (SUA). OBJECTIVE: In this study, we examined how single unit and LFP oscillatory activity in the basal ganglia are impacted by mechanical and thermal sensory stimuli and explored their role in pain modulation. METHODS: We assessed changes in LFPs and SUAs in the subthalamic nucleus (STN), globus pallidus interna (Gpi), and globus pallidus externa (Gpe) following exposure with mechanical or thermal stimuli. Sensory thresholds were determined pre-operatively using quantitative sensory testing. Based on these data, patients were exposed to innocuous and noxious mechanical, pressure, and thermal stimuli at individualized thresholds. RESULTS: In the STN, LFP alpha oscillatory activity and SUA increased in response to innocuous mechanical stimuli; SUA further increased in response to noxious mechanical, noxious pressure, and noxious thermal stimuli (p < 0.05). In the Gpe, LFP low betaactivity and SUA increased with noxious thermal stimuli; SUA also increased in response to innocuous thermal stimuli (p < 0.05). In the Gpi, innocuous thermal stimuli increased LFP gammaactivity; noxious pressure stimuli decreased low betaactivity; SUA increased in response to noxious thermal stimuli (p < 0.05). DISCUSSION: Our study is the first to demonstrate that mechanical and thermal stimuli alter basal ganglia LFPs and SUAs in PD. While STN SUA increases nearly uniformly to all sensory stimuli, SUA in the pallidal nuclei respond solely to thermal stimuli. Similarly, thermal stimuli yield increases in pallidal LFP activity, but not STN activity. We speculate that DBS may provide analgesia through suppression of stimuli-specific changes in basal ganglia activity, supporting a role for these nuclei in sensory and pain processing circuits.

Treatment of impulse control disorders in Parkinson's disease: Practical considerations and future directions.

Impulse control disorders (ICDs) including compulsive gambling, buying, sexual behaviors, and eating occur relatively frequently in Parkinson disease (PD) with at least one ICD identified in 14% of PD patients in a large, multicenter, observational study. ICDs behaviors range widely in severity but can lead to catastrophic consequences, including financial ruin, divorce, loss of employment, and increased health risks. The main risk factor for ICDs in PD is the use of Dopamine agonists (DAs) and discontinuation of the offending agent is considered first line treatment. However, many patients do not tolerate this intervention as consequence of increased motor and psychiatric disability or appearance of DA withdrawal syndrome. In this article, we review current management strategies and emerging new interventions for treatment of ICDs in PD. Pharmacological treatment should be individualized based on patient's unique neuropsychiatric profile, social support, medical comorbidities, tolerability and motor symptoms.