Improved Outcomes and Therapy Longevity after Salvage Using a Novel Spinal Cord Stimulation System for Chronic Pain: Multicenter, Observational, European Case Series.

Spinal cord stimulation (SCS) is proven to effectively relieve chronic neuropathic pain. However, some implanted patients may face loss of efficacy (LoE) over time, and conversion to more recent devices may rescue SCS therapy. Recent SCS systems offer novel stimulation capabilities, such as temporal modulation and spatial neural targeting, and can be used to replace previous neurostimulators without changing existing leads. Our multicenter, observational, consecutive case series investigated real-world clinical outcomes in previously implanted SCS patients who were converted to a new implantable pulse generator. Data from 58 patients in seven European centers were analyzed (total follow-up 7.0 years, including 1.4 years after conversion). In the Rescue (LoE) subgroup (n = 51), the responder rate was 58.5% at the last follow-up, and overall pain scores (numerical rating scale) had decreased from 7.3 ± 1.7 with the previous SCS system to 3.5 ± 2.5 (p < 0.0001). Patients who converted for improved battery longevity (n = 7) had their pain scores sustained below 3/10 with their new neurostimulator. Waveform preferences were diverse and patient dependent (34.4% standard rate; 44.8% sub-perception modalities; 20.7% combination therapy). Our results suggest that patients who experience LoE over time may benefit from upgrading to a more versatile SCS system.

Anatomical characterisation of three different psychosurgical targets in the subthalamic area: from the basal ganglia to the limbic system.

Effective neural stimulation for the treatment of severe psychiatric disorders needs accurate characterisation of surgical targets. This is especially true for the medial subthalamic region (MSR) which contains three targets: the anteromedial STN for obsessive compulsive disorder (OCD), the medial forebrain bundle (MFB) for depression and OCD, and the "Sano triangle" for pathological aggressiveness. Blocks containing the subthalamic area were obtained from two human brains. After obtaining 11.7-Tesla MRI, blocks were cut in regular sections for immunohistochemistry. Fluorescent in situ hybridisation was performed on the macaque MSR. Electron microscopic observation for synaptic specialisation was performed on human and macaque subthalamic fresh samples. Images of human brain sections were reconstructed in a cryoblock which was registered on the MRI and histological slices were then registered. The STN contains glutamatergic and fewer GABAergic neurons and has no strict boundary with the adjacent MSR. The anteromedial STN has abundant dopaminergic and serotoninergic innervation with very sparse dopaminergic neurons. The MFB is composed of dense anterior dopaminergic and posterior serotoninergic fibres, and fewer cholinergic and glutamatergic fibres. Medially, the Sano triangle presumably contains orexinergic terminals from the hypothalamus, and neurons with strong nuclear oestrogen receptor-alpha staining with a decreased anteroposterior and mediolateral gradient of staining. These findings provide new insight regarding MSR cells and their fibre specialisation, forming a transition zone between the basal ganglia and the limbic systems. Our 3D reconstruction enabled us to visualize the main histological features of the three targets which should enable better targeting and understanding of neuromodulatory stimulation results in severe psychiatric conditions.

A single case report of STN-DBS for severe crack-cocaine dependence: double-blind ON vs. SHAM randomized controlled assessment.

Crack-cocaine dependence is a severe condition with a high mortality rate. This single case study report details the first deep brain stimulation (DBS) trial targeting the sub-thalamic nucleus (STN) for crack-cocaine dependence. The investigation aimed to assess the effects of STN-DBS on cocaine craving and cocaine use, as well as STN-DBS safety and tolerance in this indication. In this pilot study, we performed double blind cross-over trials, with "ON-DBS" vs. "SHAM-DBS" for 1-month periods. STN-DBS failed to reduce cocaine craving and use. An episode of DBS-induced hypomania occurred after several weeks of cocaine intake at stimulation parameters previously well tolerated. Future research on cocaine dependence should be conducted after a prolonged abstinence period and/or explore novel types of stimulation patterns.

Applicability and Validity of an e-Health Tool for the Appropriate Referral and Selection of Patients With Chronic Pain for Spinal Cord Stimulation: Results From a European Retrospective Study.

OBJECTIVES: To support rational decision-making on spinal cord stimulation (SCS), a European expert panel developed an educational e-health tool using the RAND/University of California at Los Angeles Appropriateness Method. This retrospective study aimed to determine the applicability and validity of the tool using data from patients for whom SCS had been considered. MATERIALS AND METHODS: A total of 12 European implant centers retrieved data from 25 to 50 consecutive patients for whom SCS was considered in 2018-2019. For each patient, data were captured on the clinical and psychosocial variables included in the e-health tool, center decisions on SCS, and patient outcomes. Patient outcomes included global perception of effect by the patient and observer, and pain reduction (numeric pain rating scale) at six-month follow-up. RESULTS: In total, 483 patients were included, of whom 133 received a direct implant, 258 received an implant after a positive trial, 32 had a negative trial, and 60 did not receive SCS for reasons other than a negative trial. The most frequent indication was persistent spinal pain syndrome type 1 and type 2 (74%), followed by neuropathic pain syndromes (13%), complex regional pain syndrome (12%), and ischemic pain syndromes (0.8%). Data on the clinical and psychosocial variables were complete for 95% and 93% of patients, respectively, and missing data did not have a significant impact on the study outcomes. In patients who had received SCS, panel recommendations were significantly associated with patient outcomes (p < 0.001 for all measures). Substantial improvement ranged from 25% if the e-health tool outcome was "not recommended" to 83% if SCS was "strongly recommended". In patients who underwent a trial (N = 290), there was 3% of trial failure when SCS was "strongly recommended" vs 46% when SCS was "not recommended". CONCLUSIONS: Retrospective application of the e-health tool on patient data showed a strong relationship between the panel recommendations and both SCS trial results and treatment outcomes.

Early onset of sleep/wake disturbances in a progressive macaque model of Parkinson's disease.

Parkinsonian patients often experience sleep/wake disturbances, which may appear at an early stage of the disease; however, these disturbances have not been fully described. To better understand the evolution of these disturbances with respect to disease progression, we aimed to characterize these clinical signs in a progressive nonhuman primate model of Parkinson's disease. Three adult macaques (Macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of sleep/wake behavior via long-term neurophysiological recordings and underwent a modified multiple sleep latency test. Experiments were first performed in a healthy state and then during the progressive induction of a parkinsonian syndrome by intramuscular injections of low doses of MPTP. We observed an early onset of significant sleep/wake disturbances (i.e., before the appearance of motor symptoms). These disturbances resulted in (i) a disorganization of nighttime sleep with reduced deep sleep quality and (ii) an excessive daytime sleepiness characterized by sleep episodes occurring more rapidly in the morning and spreading through the middle of the day. The present study suggests that nighttime and daytime sleep/wake disturbances may appear early in the disease and should be considered in the development of biomarkers in further studies.

Patient selection for spinal cord stimulation: The importance of an integrated assessment of clinical and psychosocial factors.

BACKGROUND: A previously developed educational e-health tool considers both clinical and psychosocial factors when selecting patients with chronic pain for spinal cord stimulation (SCS). The validity of the composite recommendations was evaluated in a retrospective study, demonstrating a strong relationship with patient outcomes after SCS. METHODS: An additional retrospective analysis was performed to determine the added value of a psychosocial evaluation as part of the decision-making process on SCS. Data concerned 482 patients who were considered for SCS in 2018-2019. The analysis focused on the relationship between the different layers of the tool recommendations (clinical, psychosocial, composite) with trial results and patient outcomes at 6 months after SCS. Of the initial study population, 381 patients underwent SCS and had follow-up data on at least one of three pain-related outcome measures. RESULTS: Pain improvement was observed in 76% of the patients for whom SCS was strongly recommended based on merely the clinical aspects. This percentage varied by the level of psychosocial problems and ranged from 86% in patients without any compromising psychosocial factors to 60% in those with severe problems. Similarly, the severity of psychosocial problems affected trial results in patients for whom SCS was either recommended or strongly recommended. CONCLUSIONS: The strong relationship between psychosocial factors embedded in the SCS e-health tool and patient outcomes supports an integrated and multidisciplinary approach in the selection of patients for SCS. The educational e-health tool, combining both clinical and psychosocial aspects, is believed to be helpful for further education and implementation of this approach. SIGNIFICANCE STATEMENT: This study confirms the relevance of the psychosocial factors embedded in the educational SCS e-health tool (https://scstool.org/). The strong relationship between the severity of psychosocial factors with patient outcomes supports conducting a comprehensive psychological and behavioural assessment when determining the eligibility of patients for SCS.

Stimulation of the pedunculopontine and cuneiform nuclei for freezing of gait and falls in Parkinson disease: Cross-over single-blinded study and long-term follow-up.

INTRODUCTION: Deep brain stimulation (DBS) of the mesencephalic locomotor region, composed of the pedunculopontine (PPN) and cuneiform (CuN) nuclei, has been proposed to treat dopa-resistant gait and balance disorders in Parkinson's disease (PD). Here, we report the long-term effects of PPN- or CuN-DBS on these axial disorders. METHODS: In 6 PD patients operated for mesencephalic locomotor region DBS and prospectively followed for more than 2 years, we assessed the effects of both PPN- and CuN-DBS (On-dopa) in a cross-over single-blind study by using clinical scales and recording gait parameters. Patients were also examined Off-DBS. RESULTS: More than 2 years after surgery, axial and Tinetti scores were significantly aggravated with both PPN- or CuN-DBS relative to before and one year after surgery. Gait recordings revealed an increased double-stance duration with both PPN- or CuN-DBS, higher swing phase duration with CuN-DBS and step width with PPN-DBS. With PPN- versus CuN-DBS, the step length, velocity and cadence were significantly higher; and the double-stance and turn durations significantly lower. Irrespective the target, we found no significant change in clinical scores Off-DBS compared to On-DBS. The duration of anticipatory postural adjustments as well as step length were lower with versus without PPN-DBS. We found no other significant changes in motor, cognitive or psychiatric scores, except an increased anxiety severity. CONCLUSION: In this long-term follow-up study with controlled assessments, PPN- or CuN-DBS did not improve dopa-resistant gait and balance disorders with a worsening of these axial motor signs with time, thus indicating no significant clinical effect.

Pedunculopontine and Cuneiform Nuclei Deep Brain Stimulation for Severe Gait and Balance Disorders in Parkinson's Disease: Interim Results from a Randomized Double-Blind Clinical Trial.

BACKGROUND: Dopa-resistant freezing of gait (FOG) and falls represent the dominant motor disabilities in advanced Parkinson's disease (PD). OBJECTIVE: We investigate the effects of deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), comprised of the pedunculopontine (PPN) and cuneiform (CuN) nuclei, for treating gait and balance disorders, in a randomized double-blind cross-over trial. METHODS: Six PD patients with dopa-resistant FOG and/or falls were operated for MLR-DBS. Patients received three DBS conditions, PPN, CuN, or Sham, in a randomized order for 2-months each, followed by an open-label phase. The primary outcome was the change in anteroposterior anticipatory-postural-adjustments (APAs) during gait initiation on a force platformResults:The anteroposterior APAs were not significantly different between the DBS conditions (median displacement [1st-3rd quartile] of 3.07 [3.12-4.62] cm with sham-DBS, 1.95 [2.29-3.85] cm with PPN-DBS and 2.78 [1.66-4.04] cm with CuN-DBS; p = 0.25). Step length and velocity were significantly higher with CuN-DBS vs. both sham-DBS and PPN-DBS. Conversely, step length and velocity were lower with PPN-DBS vs. sham-DBS, with greater double stance and gait initiation durations. One year after surgery, step length was significantly lower with PPN-DBS vs. inclusion. We did not find any significant change in clinical scales between DBS conditions or one year after surgery. CONCLUSION: Two months of PPN-DBS or CuN-DBS does not effectively improve clinically dopa-resistant gait and balance disorders in PD patients.

Real-World Outcomes Using a Spinal Cord Stimulation Device Capable of Combination Therapy for Chronic Pain: A European, Multicenter Experience.

Given the differing mechanisms thought to underlie therapeutic sub- and supra-perception-based neurostimulative modalities, Spinal Cord Stimulation (SCS) systems designed for combined delivery of these approaches may help improve analgesic outcomes and quality of life, and reduce treatment failures. This multicenter, observational case-series evaluated 188 patients with chronic back and/or leg pain implanted with an SCS device capable of sequential or simultaneous delivery of sub-perception and supra-perception stimulation programming (i.e., combination therapy) at 16 in Europe. Following implantation, patients were provided with an array of advanced supra-perception programs (e.g., paresthesia-based SCS using multiple independent current sources), and a custom set of sub-perception programs optimized with specific waveforms and/or field shapes. A mean overall pain score of 7.9 ± 1.7 (Standard Deviation (SD)) was reported pre-trial (Baseline). Overall pain was reduced by 4.4 ± 2.8 points (NRS) at 3-months (n = 117) and at 12 months post-implant (n = 90), respectively (p < 0.0001). Substantial quality-of-life (EQ-5D-5L) improvement as assessed at last follow-up was also observed (n = 60). These results suggest that an implanted SCS device capable of combination therapy, while also enabled with patient-specific waveform optimization and stimulation field targeting capabilities, can enable highly effective pain relief and improve quality of life in patients suffering with chronic pain.

Emotions Modulate Subthalamic Nucleus Activity: New Evidence in Obsessive-Compulsive Disorder and Parkinson's Disease Patients.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation alleviates obsessive-compulsive disorder (OCD) symptoms, suggesting that this basal ganglia structure may play a key role in integrating limbic and motor information. We explored the modulation of STN neural activity by visual emotional information under different motor demands. METHODS: We compared STN local field potentials acquired in 7 patients with OCD and 15 patients with Parkinson's disease off and on levodopa while patients categorized pictures as unpleasant, pleasant, or neutral and pressed a button for 1 of these 3 categories depending on the instruction. RESULTS: During image presentation, theta power increased for unpleasant compared with neutral images in both patients with OCD and patients with Parkinson's disease. Only in patients with OCD was theta power also increased in pleasant compared with neutral trials. During the button press in patients with OCD, no modification of STN activity was seen on average, but theta power increased when the image triggering the motor response was unpleasant. Conversely, in patients with Parkinson's disease, a beta decrease was observed during the button press unrelated to the valence of the stimulus. Finally, in patients with OCD, a significant positive relationship was observed between the amplitude of the emotionally related theta response and symptom severity (measured using the Yale-Brown Obsessive Compulsive Scale). CONCLUSIONS: We highlighted modulations of STN theta band activity related to emotions that were specific to OCD and correlated with OCD symptom severity. STN theta-induced activity might therefore underlie dysfunction of the limbic STN and its related network leading to OCD pathophysiology.

Appropriate referral and selection of patients with chronic pain for spinal cord stimulation: European consensus recommendations and e-health tool.

BACKGROUND: Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic, neuropathic-like and ischaemic pain. However, the heterogeneity of patients in daily clinical practice makes it often challenging to determine which patients are eligible for this treatment, resulting in undesirable practice variations. This study aimed to establish patient-specific recommendations for referral and selection of SCS in chronic pain. METHODS: A multidisciplinary European panel used the RAND/UCLA Appropriateness Method (RUAM) to assess the appropriateness of (referral for) SCS for 386 clinical scenarios in four pain areas: chronic low back pain and/or leg pain, complex regional pain syndrome, neuropathic pain syndromes and ischaemic pain syndromes. In addition, the panel identified a set of psychosocial factors that are relevant to the decision for SCS treatment. RESULTS: Appropriateness of SCS was strongly determined by the neuropathic or neuropathic-like pain component, location and spread of pain, anatomic abnormalities and previous response to therapies targeting pain processing (e.g. nerve block). Psychosocial factors considered relevant for SCS selection were as follows: lack of engagement, dysfunctional coping, unrealistic expectations, inadequate daily activity level, problematic social support, secondary gain, psychological distress and unwillingness to reduce high-dose opioids. An educational e-health tool was developed that combines clinical and psychosocial factors into an advice on referral/selection for SCS. CONCLUSIONS: The RUAM was useful to establish a consensus on patient-specific criteria for referral/selection for SCS in chronic pain. The e-health tool may help physicians learn to apply an integrated approach of clinical and psychosocial factors. SIGNIFICANCE: Determining the eligibility of SCS in patients with chronic pain requires careful consideration of a variety of clinical and psychosocial factors. Using a systematic approach to combine evidence from clinical studies and expert opinion, a multidisciplinary European expert panel developed detailed recommendations to support appropriate referral and selection for SCS in chronic pain. These recommendations are available as an educational e-health tool (https://www.scstool.org/).

Anatomo-Functional Mapping of the Primate Mesencephalic Locomotor Region Using Stereotactic Lesions.

BACKGROUND: Dysfunction of the mesencephalic locomotor region has been implicated in gait disorders. However, the role of its 2 components, the pedunculopontine and the cuneiform nuclei, in locomotion is poorly understood in primates. OBJECTIVES: To analyze the effect of cuneiform lesions on gait and balance in 2 monkeys and to compare them with those obtained after cholinergic pedunculopontine lesions in 4 monkeys and after lesions in both the cuneiform and pedunculopontine nuclei in 1 monkey. METHODS: After each stereotactic lesion, we performed a neurological examination and gait and balance assessments with kinematic measures during a locomotor task. The 3-dimensional location of each lesion was analyzed on a common brainstem space. RESULTS: After each cuneiform lesion, we observed a contralateral cervical dystonia including an increased tone in the proximal forelimb and an increase in knee angle, back curvature and walking speed. Conversely, cholinergic pedunculopontine lesions increased tail rigidity and back curvature and an imbalance of the muscle tone between the ipsi- and contralateral hindlimb with decreased knee angles. The walking speed was decreased. Moreover, pedunculopontine lesions often resulted in a longer time to waking postsurgery. CONCLUSIONS: The location of the lesions and their behavioral effects revealed a somatotopic organization of muscle tone control, with the neck and forelimb represented within the cuneiform nucleus and hindlimb and tail represented within the pedunculopontine nucleus. Cuneiform lesions increased speed, whereas pedunculopontine lesions decreased it. These findings confirm the complex and specific role of the cuneiform and pedunculopontine nuclei in locomotion and suggest the role of the pedunculopontine in sleep control. © 2020 International Parkinson and Movement Disorder Society.

Clinical and anatomical predictors for freezing of gait and falls after subthalamic deep brain stimulation in Parkinson's disease patients.

INTRODUCTION: Freezing of gait (FOG) and falls are the most disabling motor symptoms in Parkinson's disease (PD) patients. The effects of subthalamic deep-brain-stimulation (STN-DBS) on FOG and falls are still a matter of controversy, and factors contributing to their outcome have yet to be defined. METHODS: We examined the relationship between FOG and falls after STN-DBS and preoperative clinical features, MRI voxel-based-morphometry (VBM) analysis and statistical mapping of electrode locations. RESULTS: 331 patients (age at surgery = 57.7 ±â€¯8.4 years; disease duration = 12.5 ±â€¯5 years) were included in the final analysis, with VBM analysis in 151 patients. After surgery, FOG was aggravated in 93 patients and falls in 75 patients. After surgery, FOG severity was related to its level before surgery without dopaminergic treatment, the dopaminergic treatment dosage and severity of motor fluctuations after surgery; and falls severity to lower postoperative cognitive performance. VBM analyses revealed that, relative to other patient groups, patients with FOG worsening had putamen grey matter density decrease, and fallers patients a left postcentral gyrus atrophy. The best effects of STN-DBS on FOG and falls were associated with the location of contacts within the STN, but no specific location related to aggravation. CONCLUSIONS: FOG and falls are reduced after STN-DBS in about 1/3 of patients, with the best effects obtained for electrodes located within the STN. Clinicians should be aware that, after STN-DBS, FOG severity is related to preoperative FOG severity whatever its dopa-sensitivity; and falls to lower postoperative cognitive performance; and atrophy of cortico-subcortical brain areas.

Tackling psychosocial maladjustment in Parkinson's disease patients following subthalamic deep-brain stimulation: A randomised clinical trial.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for the motor and non-motor signs of Parkinson's disease (PD), however, psychological disorders and social maladjustment have been reported in about one third of patients after STN-DBS. We propose here a perioperative psychoeducation programme to limit such social and familial disruption. METHODS: Nineteen PD patients and carers were included in a randomised single blind study. Social adjustment scale (SAS) scores from patients and carers that received the psychoeducation programme (n = 9) were compared, both 1 and 2 years after surgery, with patients and carers with usual care (n = 10). Depression, anxiety, cognitive status, apathy, coping, parkinsonian disability, quality-of-life, carers' anxiety and burden were also analysed. RESULTS: Seventeen patients completed the study, 2 were excluded from the final analysis because of adverse events. At 1 year, 2/7 patients with psychoeducation and 8/10 with usual care had an aggravation in at least one domain of the SAS (p = .058). At 2 years, only 1 patient with psychoeducation suffered persistent aggravated social adjustment as compared to 8 patients with usual care (p = .015). At 1 year, anxiety, depression and instrumental coping ratings improved more in the psychoeducation than in the usual care group (p = .038, p = .050 and p = .050, respectively). No significant differences were found between groups for quality of life, cognitive status, apathy or motor disability. CONCLUSIONS: Our results suggest that a perioperative psychoeducation programme prevents social maladjustment in PD patients following STN-DBS and improves anxiety and depression compared to usual care. These preliminary data need to be confirmed in larger studies.

Anatomical evidence for functional diversity in the mesencephalic locomotor region of primates.

The mesencephalic locomotor region (MLR) is a highly preserved brainstem structure in vertebrates. The MLR performs a crucial role in locomotion but also controls various other functions such as sleep, attention, and even emotion. The MLR comprises the pedunculopontine (PPN) and cuneiform nuclei (CuN) but their specific roles are still unknown in primates. Here, we sought to characterise the inputs and outputs of the PPN and CuN to and from the basal ganglia, thalamus, amygdala and cortex, with a specific interest in identifying functional anatomical territories. For this purpose, we used tract-tracing techniques in monkeys and diffusion weighted imaging-based tractography in humans to understand structural connectivity. We found that MLR connections are broadly similar between monkeys and humans. The PPN projects to the sensorimotor, associative and limbic territories of the basal ganglia nuclei, the centre median-parafascicular thalamic nuclei and the central nucleus of the amygdala. The PPN receives motor cortical inputs and less abundant connections from the associative and limbic cortices. In monkeys, we found a stronger connection between the anterior PPN and motor cortex suggesting a topographical organisation of this specific projection. The CuN projected to similar cerebral structures to the PPN in both species. However, these projections were much stronger towards the limbic territories of the basal ganglia and thalamus, to the basal forebrain (extended amygdala) and the central nucleus of the amygdala, suggesting that the CuN is not primarily a motor structure. Our findings highlight the fact that the PPN integrates sensorimotor, cognitive and emotional information whereas the CuN participates in a more restricted network integrating predominantly emotional information.

Voluntary control of intracortical oscillations for reconfiguration of network activity.

Voluntary control of oscillatory activity represents a key target in the self-regulation of brain function. Using a real-time closed-loop paradigm and simultaneous macro- and micro-electrode recordings, we studied the effects of self-induced intracortical oscillatory activity (4-8 Hz) in seven neurosurgical patients. Subjects learned to robustly and specifically induce oscillations in the target frequency, confirmed by increased oscillatory event density. We have found that the session-to-session variability in performance was explained by the functional long-range decoupling of the target area suggesting a training-induced network reorganization. Downstream effects on more local activities included progressive cross-frequency-coupling with gamma oscillations (30-120 Hz), and the dynamic modulation of neuronal firing rates and spike timing, indicating an improved temporal coordination of local circuits. These findings suggest that effects of voluntary control of intracortical oscillations can be exploited to specifically target plasticity processes to reconfigure network activity, with a particular relevance for memory function or skill acquisition.