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Background Dorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain. Objective We employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain. Methods Sixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to ‘MEG (magnetoencephalography) localized’ tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected. Results All participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS. Conclusion Our results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.

Cancer pain is common and challenging to manage - it is estimated that approximately 30% of cancer patients have pain that is not adequately controlled by analgesia. This paper discusses safe and effective neuroablative treatment options for refractory cancer pain. Current management of cancer pain predominantly focuses on the use of medications, resulting in a relative loss of knowledge of these surgical techniques and the erosion of the skills required to perform them. Here, we review surgical methods of modulating various points of the neural axis with the aim to expand the knowledge base of those managing cancer pain. Integration of neuroablative approaches may lead to higher rates of pain relief, and the opportunity to dose reduce analgesic agents with potential deleterious side effects. With an ever-increasing population of cancer patients, it is essential that neurosurgeons maintain or train in these techniques in tandem with the oncological multi-disciplinary team.

Visual Abstract, Highlights • DRGS at upper lumbar levels significantly reduces sympathetic nerve firing • Reduction in sympathetic activity appears to be independent to pain relief • DRGS significantly reduced BP at 6 months and 2 years • BP reduction was lateralized to DRGS on the left side • Three refractory hypertensives became normotensive after chronic stimulation., Summary This study hypothesized that dorsal root ganglion (DRG) stimulation would reduce sympathetic nerve activity and would alter hemodynamic variables. This study directly recorded muscle sympathetic nerve activity during ON and OFF stimulation of the DRG while measuring hemodynamic parameters. DRG stimulation significantly reduced the firing frequency of sympathetic nerves, as well as significantly reducing blood pressure, with greater reductions evident when stimulation was left-sided. Left-sided DRG stimulation lowers sympathetic nerve activity, leading to long-term phenotypic changes. This raises the potential of DRG stimulation being used to treat de novo autonomic disorders such as hypertension or heart failure.

Objective Deep brain stimulation (DBS) is a treatment option for refractory chronic cluster headache (CCH). Despite several recent prospective case series reporting a good outcome, the effectiveness and the optimal stimulation target of DBS for CCH remain unclear. We aimed to obtain precise estimates and predictors of long-term pain relief in an individual patient data meta-analysis. Furthermore, we aimed to construct a probabilistic stimulation map of effective DBS. Methods We invited investigators of published cohorts of patients undergoing DBS for CCH, identified by a systematic review of MEDLINE from inception to Febuary 15, 2019, to provide individual patient data on baseline covariates, pre- and postoperative headache scores at median (12-month) and long-term follow-up, in addition to individual imaging data to obtain individual electrode positions. We calculated a stimulation map using voxel-wise statistical analysis. We used multiple regression analysis to estimate predictors of pain relief. Results Among 40 patients from four different cohorts representing ~50% of all previously published cases, we found a significant 77% mean reduction in headache attack frequency over a mean follow-up of 44 months, with an overall response rate of 75%. Positive outcome was not associated with baseline covariates. We identified 2 hotspots of stimulation covering the midbrain ventral and retrorubral tegmentum. Interpretation This study supports the hypothesis that DBS provides long-term pain relief for the majority of CCH patients. Our stimulation map of the region of influence of therapeutic DBS identified an optimal anatomical target site that can help surgeons to guide their surgical planning in the future. ANN NEUROL 2020;88:956-969.

The practice of surgical intervention for the treatment of psychiatric disorders has a rich and fascinating history. Arguably dating back to more than 7 millennia ago, neurosurgery for psychiatric disease is shrouded in stigma, being widely portrayed in the media (almost invariably negatively). The first such procedure to be performed in modern history was conducted by the Swiss psychiatrist Gottlieb Burckhardt in 1882. The landscape of neurosurgery for psychiatric conditions has shifted constantly since, guided by new developments in neuroscience and surgical technology. In this article, we outline the salient events in the story of this field.

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson’s disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = −0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

Objectives: Dorsal root ganglion stimulation (DRGS) has become a popular neuromodulatory treatment for neuropathic pain. We used magnetoencephalography (MEG) to investigate potential biomarkers of pain and pain relief, based on the differences in power spectral density (PSD) during varying degrees of pain and how these oscillations change during DRGS-mediated pain relief. Materials and Methods: Thirteen chronic pain patients with implanted dorsal root ganglion stimulators were included in the MEG analysis. MEG Recordings were performed at rest while the stimulator was turned ON or OFF. Numerical rating scale (NRS) scores were also recorded before and after DRGS was turned OFF and ON. Power spectral and source localization analyses were then performed on preprocessed MEG recordings. Results: With DRGS-OFF, patients in severe pain had significantly increased cortical theta (4–7 Hz) power and decreased cortical alpha (7–13 Hz) power compared to patients reporting less pain. This shift in power toward lower frequencies was contrasted by a shift toward the higher frequency power spectrum (low beta 13–20 Hz activity) during DRGS-mediated pain relief. A significant correlation was found between the increase in low beta activity and the degree of reported pain relief. Conclusion: Our results demonstrate increased low-frequency power spectral activity in chronic pain patients in the absence of stimulation which shifts toward higher frequency power spectrum activity in response to therapeutic DRGS. These cortical changes in response to DRGS provide support for the use of neuroimaging in the search for potential biomarkers of pain.

Background: The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) in Parkinson’s disease (PD) and is believed to serve a role in sensorimotor integration. In addition to therapeutic neuromodulation, DBS facilitates the recording of local-field potentials (LFPs) in order to further understand the neurophysiological basis of disease. The capacity to wirelessly transmit these signals in real time has overcome the obstacle of externalization of electrodes during LFP recordings. Objective: Using the G102RS device (PINS Medical, China), we investigated the LFP changes in response to mechanical pain stimulation to further elucidate the representation of pain sensation in the basal ganglia. Methods: LFPs from 2 patients who had undergone bilateral STN-DBS were wirelessly recorded during no stimulation, low-frequency stimulation (60 and 90 Hz), and high-frequency stimulation (130 and 150 Hz) while introducing painful and nonpainful stimuli. Power spectral analysis was conducted to compare the changes in β frequency (13–30 Hz) during each stimulus. Results: During painful stimuli, STN power spectra (n = 4) revealed a significant increase in β activity compared to non-painful and no-stimulus epochs. Both low- and high-frequency stimulation produced a significant decrease in pain-related β activity. Conclusion: These 2 cases have demonstrated the potential for acute noxious stimuli to exacerbate pathologic β oscillatory activity in the STN. Our findings represent novel evidence of the neurophysiologic representation of pain in the STN of PD patients.

Deep brain stimulation (DBS) of single-target nuclei has produced remarkable functional outcomes in a number of movement disorders such as Parkinson’s disease, essential tremor, and dystonia. While these benefits are well established, DBS efficacy and strategy for unusual, unclassified movement disorder syndromes is less clear. A strategy of dual pallidal and thalamic electrode placement is a rational approach in such cases where there is profound, medically refractory functional impairment. The authors report a series of such cases: midbrain cavernoma hemorrhage with olivary hypertrophy, spinocerebellar ataxia-like disorder of probable genetic origin, Holmes tremor secondary to brainstem stroke, and hemiballismus due to traumatic thalamic hemorrhage, all treated by dual pallidal and thalamic DBS. All patients demonstrated robust benefit from DBS, maintained in long-term follow-up. This series demonstrates the flexibility and efficacy, but also the limitations, of dual thalamo-pallidal stimulation for managing axial and limb symptoms of tremors, dystonia, chorea, and hemiballismus in patients with complex movement disorders.

Indirect targeting of the Ventralis Intermedius Nucleus (Vim) is widely used for functional neurosurgical procedures to treat essential tremor (ET). Here, we review if the laterality of the Vim depends on the diameter of the third ventricle and if a targeting approach that incorporates this correlation can facilitate targeting and yields accurate lead placement. We analyzed 15 consecutive ET patients. Vim targeting was adapted according to the width of the third ventricle and the lateral distance to the internal capsule (IC). Postoperative outcome was assessed 12 months post-OP based on the Bain-Findley score. Application of this targeting approach resulted in mean target coordinates of LAT 12.8 ± 1.5; AP −3.6 ± 1.0 and VERT 0 ± 0 mm and which projected onto the Vim. The laterality of IC and Vim are correlated to the width of the third ventricle. The mean postoperative tremor reduction was 63.0%. In summary, adjusting the lateral coordinate according to the width of the third ventricle leads to accurate targeting and effective tremor reduction.

Understanding the functional dynamics of neural oscillations in the sensory thalamus is essential for elucidating the perception and modulation of neuropathic pain. Local field potentials were recorded from the sensory thalamus of twelve neuropathic pain patients. Single and combinational neural states were defined by the activity state of a single or paired oscillations. Relationships between the duration or occurrence rate of neural state and pre-operative pain level or pain relief induced by deep brain stimulation were evaluated. Results showed that the occurrence rate of the single neural state of low-beta oscillation was significantly correlated with pain relief. The duration and occurrence rate of combinational neural states of the paired low-beta with delta, theta, alpha, high-beta or low-gamma oscillations were more significantly correlated with pain relief than the single neural states. Moreover, these significant combinational neural states formed a local oscillatory network with low-beta oscillation as a key node. The results also showed correlations between measures of combinational neural states and subjective pain level as well. The duration of combinational neural states of paired alpha with delta or theta oscillations and the occurrence rate of neural states of the paired delta with low-beta or low-gamma oscillations were significantly correlated with pre-operative pain level. In conclusion, this study revealed that the integration of oscillations and the functional dynamics of neural states were differentially involved in modulation and perception of neuropathic pain. The functional dynamics could be biomarkers for developing neural state-dependent deep brain stimulation for neuropathic pain.

Purpose Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance. Methods To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt. Results The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean − 8.3% versus − 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005). Conclusion PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.

OBJECTIVES: Minimally conscious state (MCS) is a disorder of consciousness in which minimal but definite behavioral evidence of self-awareness or environmental awareness is demonstrated. Deep brain stimulation (DBS) of various targets has been used to promote recovery in patients with disorders of consciousness with varying results. The aim of this systematic review was to assess the effects of DBS in MCS following traumatic brain injury (TBI). MATERIALS AND METHODS: A systematic literature review was carried out using a number of electronic bibliographic data bases to identify relevant studies. We included all studies describing applications of DBS on patients in MCS following TBI. RESULTS: Eight studies were identified, including a total of ten patients, aged 15-58 years. The time from injury to stimulation ranged from 3 to 252 months, with the duration of follow-up post-DBS ranging from 10 to 120 months. Seven patients improved their postsurgical outcome score measures (three patients with the coma recovery scale, one with the near coma scale, and three with the Glasgow outcome score). A descriptive favorable outcome was reported in one patient. Two patients were reported not to have shown any improvements following the intervention. CONCLUSIONS: Current evidence is based on a small population of heterogeneous patients. The time from injury to stimulation was significantly variable and problematic, as spontaneous recovery can occur within the first year of injury. Although seven patients showed promising results in validated outcome measures, evidence supporting the use of DBS in MCS patients following TBI is lacking. There is need for controlled and randomized studies.

Objective Respiratory abnormalities such as upper airway obstruction are common in Parkinson's disease (PD) and are an important cause of mortality and morbidity. We tested the effect of pedunculopontine region (PPNr) stimulation on respiratory maneuvers in human participants with PD, and separately recorded PPNr neural activity reflected in the local field potential (LFP) during these maneuvers. Methods Nine patients with deep brain stimulation electrodes in PPNr, and seven in globus pallidus interna (GPi) were studied during trials of maximal inspiration followed by forced expiration with stimulation OFF and ON. Local field potentials (LFPs) were recorded in the unstimulated condition. Results PEFR increased from 6.41 ± 0.63 L/sec in the OFF stimulation state to 7.5 L ± 0.65 L/sec in the ON stimulation state (z = −2.666, df = 8, P = 0.024). Percentage improvement in PEFR was strongly correlated with proximity of the stimulated electrode contact to the mesencephalic locomotor region in the rostral PPN (r = 0.814, n = 9, P = 0.008). Mean PPNr LFP power increased within the alpha band (7–11 Hz) during forced respiratory maneuvers (1.63 ± 0.16 μV2/Hz) compared to resting breathing (0.77 ± 0.16 μV2/Hz; z = −2.197, df = 6, P = 0.028). No changes in alpha activity or spirometric indices were seen with GPi recording or stimulation. Percentage improvement in PEFR was strongly positively correlated with increase in alpha power (r = 0.653, n = 14 (7 PPNr patients recorded bilaterally), P = 0.0096). Interpretation PPNr stimulation in PD improves indices of upper airway function. Increased alpha‐band activity is seen within the PPNr during forced respiratory maneuvers. Our findings suggest a link between the PPNr and respiratory performance in PD.

Objective We present long-term follow-up results and analysis of stimulation sites of a prospective cohort study of six patients with chronic cluster headaches undergoing deep brain stimulation of the ipsilateral posterior hypothalamic region. Methods The primary endpoint was the postoperative change in the composite headache severity score “headache load” after 12 months of chronic stimulation. Secondary endpoints were the changes in headache attack frequency, headache attack duration and headache intensity, quality of life measures at 12, 24, and 48 months following surgery. Stimulating contact positions were analysed and projected onto the steroetactic atlas of Schaltenbrand and Wahren. Results There was a significant reduction of headache load of over 93% on average at 12 months postoperatively that persisted over the follow-up period of 48 months ( p = 0.0041) and that was accompanied by a significant increase of reported quality of life measures ( p = 0.03). Anatomical analysis revealed that individual stimulating electrodes were located in the red nucleus, posterior hypothalamic region, mesencephalic pretectal area and centromedian nucleus of the thalamus. Conclusions Our findings confirming long-term effectiveness of deep brain stimulation for chronic cluster headaches suggest that the neuroanatomical substrate of deep brain stimulation-induced headache relief is probably not restricted to the posterior hypothalamic area but encompasses a more widespread area.

Motivation depends on dopamine, but might be modulated by acetylcholine which influences dopamine release in the striatum, and amplifies motivation in animal studies. A corresponding effect in humans would be important clinically, since anticholinergic drugs are frequently used in Parkinson’s disease, a condition that can also disrupt motivation. Reward and dopamine make us more ready to respond, as indexed by reaction times (RT), and move faster, sometimes termed vigour. These effects may be controlled by preparatory processes that can be tracked using EEG. We measured vigour in a placebo-controlled, double-blinded study of trihexyphenidyl (THP), a muscarinic antagonist, with an incentivised eye movement task and EEG. Participants responded faster and with greater vigour when incentives were high, but THP blunted these motivation effects, suggesting that muscarinic receptors facilitate invigoration by reward. Preparatory EEG build-up (contingent negative variation; CNV) was strengthened by high incentives and by muscarinic blockade. The amplitude of preparatory activity predicted both vigour and RT, although over distinct scalp regions. Frontal activity predicted vigour, whereas a larger, earlier, central component predicted RT. Indeed the incentivisation of RT was partly mediated by the CNV, though vigour was not. Moreover, the CNV mediated the drug’s effect on dampening incentives, suggesting that muscarinic receptors underlie the motivational influence on this preparatory activity. Taken together, these findings show that a muscarinic blocker used to treat Parkinson’s disease impairs motivated action in healthy people, and that medial frontal preparatory neural activity mediates this for RT.

The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of the midbrain and pons, playing an important role in modulating posture and locomotion. Deep brain stimulation of the PPN has been proposed as an emerging treatment for patients with Parkinson's disease (PD) or multiple system atrophy (MSA) who have gait-related atypical parkinsonian syndromes. In this study, we investigated PPN activities during gait to better understand its functional role in locomotion. Specifically, we investigated whether PPN activity is rhythmically modulated by gait cycles during locomotion. PPN local field potential (LFP) activities were recorded from PD or MSA patients with gait difficulties during stepping in place or free walking. Simultaneous measurements from force plates or accelerometers were used to determine the phase within each gait cycle at each time point. Our results showed that activities in the alpha and beta frequency bands in the PPN LFPs were rhythmically modulated by the gait phase within gait cycles, with a higher modulation index when the stepping rhythm was more regular. Meanwhile, the PPN–cortical coherence was most prominent in the alpha band. Both gait phase-related modulation in the alpha/beta power and the PPN–cortical coherence in the alpha frequency band were spatially specific to the PPN and did not extend to surrounding regions. These results suggest that alternating PPN modulation may support gait control. Whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control remains to be tested. SIGNIFICANCE STATEMENT The therapeutic efficacy of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) and the extent to which it can improve quality of life are still inconclusive. Understanding how PPN activity is modulated by stepping or walking may offer insight into how to improve the efficacy of PPN DBS in ameliorating gait difficulties. Our study shows that PPN alpha and beta activity was modulated by the gait phase, and that this was most pronounced when the stepping rhythm was regular. It remains to be tested whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control.

Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen–posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting., Raghu et al. report that the majority of variation in outcomes following pallidal DBS for cervical dystonia can be explained by electrode location and structural connectivity. Individual differences in the primary motor cortex–putamen–internal pallidal limb of the direct pathway offer the prospect of a personalized approach.

Objective This study aims to discriminate the dynamic synchronization states from the subthalamic local field potentials and investigate their correlations with the motor symptoms in Parkinson’s Disease (PD). Methods The resting-state local field potentials of 10 patients with PD were recorded from the subthalamic nucleus. The dynamic neural states of multiple oscillations were discriminated and analyzed. The Spearman correlation was used to investigate the correlations between occurrence rate or duration of dynamic neural states and the severity of motor symptoms. Results The proportion of long low-beta and theta synchronized state was significantly correlated with the general motor symptom and tremor, respectively. The duration of combined low/high-beta state was significantly correlated with rigidity, and the duration of combined alpha/high-beta state was significantly correlated with bradykinesia. Conclusions This study provides evidence that motor symptoms are associated with the neural states coded with multiple oscillations in PD. Significance This study may advance the understanding of the neurophysiological mechanisms of the motor symptoms and provide potential biomarkers for closed-loop deep brain stimulation in PD.

Background High-frequency thalamic stimulation is an effective therapy for essential tremor, which mainly affects voluntary movements and/or sustained postures. However, continuous stimulation may deliver unnecessary current to the brain due to the intermittent nature of the tremor. Objective We proposed to close the loop of thalamic stimulation by detecting tremor-provoking movement states using local field potentials recorded from the same electrodes implanted for stimulation, so that the stimulation is only delivered when necessary. Methods Eight patients with essential tremor participated in this study. Patient-specific support vector machine classifiers were first trained using data recorded while the patient performed tremor-provoking movements. Then, the trained models were applied in real-time to detect these movements and triggered the delivery of stimulation. Results Using the proposed method, stimulation was switched on for 80.37 ± 7.06% of the time when tremor-evoking movements were present. In comparison, the stimulation was switched on for 12.71 ± 7.06% of the time when the patients were at rest and tremor-free. Compared with continuous stimulation, a similar amount of tremor suppression was achieved while only delivering 36.62 ± 13.49% of the energy used in continuous stimulation. Conclusions The results suggest that responsive thalamic stimulation for essential tremor based on tremor-provoking movement detection can be achieved without any requirement for external sensors or additional electrocorticography strips. Further research is required to investigate whether the decoding model is stable across time and generalizable to the variety of activities patients may engage with in everyday life. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

New Findings What is the central question of this study? This study investigated the role of dorsal ACC in respiration control using local field potential recordings in human ACC. What is the main finding and its importance? The results suggest that the neurophysiological responses in dorsal ACC to different breathing tasks varied and were different between left and right ACC. In addition, the differential lateralisation of the left and right ACC was demonstrated by tractography analysis. Abstract The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggest an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath holding task induced significant unilateral left‐sided ACC changes in LFP power, including an increased activity in lower frequency bands (3‐5 Hz) and decreased activity in higher frequency bands (12‐26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO2) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left‐sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans.

This article charts the history of deep brain stimulation (DBS) as applied to alleviate a number of neurological disorders, while in parallel mapping the electrophysiological circuits involved in generating and integrating neural signals driving the cardiorespiratory system during exercise. With the advent of improved neuroimaging techniques, neurosurgeons can place small electrodes into deep brain structures with a high degree accuracy to treat a number of neurological disorders, such as movement impairment associated with Parkinson's disease and neuropathic pain. As well as stimulating discrete nuclei and monitoring autonomic outflow, local field potentials can also assess how the neurocircuitry responds to exercise. This technique has provided an opportunity to validate in humans putative circuits previously identified in animal models. The central autonomic network consists of multiple sites from the spinal cord to the cortex involved in autonomic control. Important areas exist at multiple evolutionary levels, which include the anterior cingulate cortex (telencephalon), hypothalamus (diencephalon), periaqueductal grey (midbrain), parabrachial nucleus and nucleus of the tractus solitaries (brainstem), and the intermediolateral column of the spinal cord. These areas receive afferent input from all over the body and provide a site for integration, resulting in a coordinated efferent autonomic (sympathetic and parasympathetic) response. In particular, emerging evidence from DBS studies have identified the basal ganglia as a major sub-cortical cognitive integrator of both higher center and peripheral afferent feedback. These circuits in the basal ganglia appear to be central in coupling movement to the cardiorespiratory motor program. © 2020 American Physiological Society. Compr Physiol 10:1085-1104, 2020.

Pain and other symptoms of autonomic dysregulation such as hypertension, dyspnoea and bladder instability can lead to intractable suffering. Incorporation of neuromodulation into symptom management, including palliative care treatment protocols, is becoming a viable option scientifically, ethically, and economically in order to relieve suffering. It provides further opportunity for symptom control that cannot otherwise be provided by pharmacology and other conventional methods.

Purpose To elucidate the efficacy of dorsal root ganglion stimulation in the treatment of chronic neuropathic pain confined to the knee. Methods Retrospective analysis of prospectively collected data of 14 consecutive patients undergoing dorsal root ganglion stimulation for chronic knee pain, in a single centre. The primary outcome measure was pain reduction assessed by numeric pain rating scale score pre-operatively and post-operatively. Secondary outcomes included quantification of percentage of pain area covered by stimulation, and reduction in usage of opioid medications. Responders were defined as patients that experienced a greater than or equal to 50% improvement in their pre-operative pain score. Results 14 patients were implanted with dorsal root ganglion stimulator (DRG) electrodes. 8 had a single L3 lead implanted, 1 patient had a single L4 lead implanted, and 3 patients had 2 leads implanted (L3 and L4). 2 patients had their leads explanted: 1 for non-efficacy, and 1 for repeated electrode displacement. The most common indication for surgery was type 2 complex regional pain syndrome (CRPS), secondary to either trauma or post-operative chronic pain (either knee replacement or arthroscopy). Median pre-op numeric rating scale score was 8.5, median post-op numeric rating scale score was 2 (p=0.002, Wilcoxon signed rank test). The median improvement in pain score was 80%. All 12 patients undergoing chronic stimulation were responders. Median coverage of pain area was 85%. All but 1 patient that was on opioid medication prior to surgery had reduced the dosage of regular opioid. Conclusion In selected patients, dorsal root ganglion stimulation is an extremely efficacious means of treating otherwise refractory chronic knee pain.

Summary Background Gamma knife radiosurgery is regarded as the gold-standard stereotactic radiosurgery modality for the treatment of intracranial tumours, and its use has been expanded for the treatment of intraocular malignancies. The aim of this study was to systematically evaluate the efficacy, outcomes, and complications of gamma knife radiosurgery for uveal melanomas and metastases. Methods We did a systematic review and meta-analysis to aggregate the clinical outcomes of patients with uveal melanomas or intraocular metastases treated primarily with gamma knife radiosurgery. We searched MEDLINE and Embase for studies published between Sept 1, 1960, and Feb 1, 2020, reporting the use of gamma knife radiosurgery as primary treatment for uveal melanoma or uveal metastases. The search was restricted to clinical studies and relevant grey literature published in English. Studies reporting treatment of benign tumours, extraocular tumours, or other forms of stereotactic radiosurgery were excluded to reduce heterogeneity. No restrictions were placed on participant criteria. Local tumour control and tumour regression were extracted as the primary outcomes and analysed via a random-effects meta-analysis of proportions using the DerSimonian and Laird method with a Freeman-Tukey double arcsine transformation. This study is registered with PROSPERO, CRD42019148165. Findings Our search returned 454 studies, of which 109 were assessed for full-text eligibility. 52 studies, reporting on 1010 patients with uveal melanoma and 34 intraocular metastases, were eligible for systematic review. 28 studies were included in the meta-analysis. 840 of 898 patients (0·96, 95% CI 0·94–0·97; I2=16%) from 19 studies had local control, and 378 of 478 patients (0·81, 0·70–0·90; I2=83%) from 16 studies experienced tumour regression. Interpretation Gamma knife radiosurgery is an efficacious primary method of treating uveal melanomas and intraocular metastases, with reliable tumour control rates. Randomised controlled trials should further evaluate the safety and efficacy of gamma knife radiosurgery in this setting. Funding The Rhodes Trust and the Howard Brain Sciences Foundation.

Over 7% of the Western population suffer from intractable pain and despite pharmacotherapy, many patients’ pain is refractory [...]

Objectives Neuromodulation is a treatment option for people suffering from painful diabetic neuropathy (PDN) unresponsive to conventional pharmacotherapy. We systematically examined the pain outcomes of patients with PDN receiving any type of invasive neuromodulation for treatment of neuropathic pain. Materials and methods MEDLINE and Embase were searched through 10 January 2020, without language restriction. All study types were included. Two reviewers independently screened publications and extracted data. Quantitative meta-analysis was performed with pain scores converted to a standard 100-point scale. Randomized controlled trial (RCT) scores were pooled using the inverse variance method and expressed as mean differences. Results RCTs of tonic spinal cord stimulation (t-SCS) showed greater pain improvement than best medical therapy at six months (intention-to-treat: 38/100, 95% CI: 29-47). By per-protocol analysis, case series of t-SCS and dorsal root ganglion stimulation (DRGS) showed improvement by 56 (95% CI: 39-73) and 55 (22-87), respectively, at 12 months. For t-SCS, the rate of failing a therapeutic stimulation trial was 16%, the risk of infection was 4%, and the rate of lead problems requiring surgery to resolve was 4% per year of follow-up. High-frequency SCS and burst SCS both showed efficacy, with few patients studied. Conclusion Efficacious, lasting and safe surgical pain management options are available to diabetic patients suffering from PDN. Tonic-SCS is the established standard of treatment; however, other SCS paradigms and DRGS are emerging as promising treatments offering comparable pain benefits, but with few cases published to date. Randomized controlled trials are ongoing to assess their relative merits.

Acute pain and resting arterial blood pressure (BP) are positively correlated in patients with chronic pain. However, it remains unclear whether treatment for chronic pain reduces BP. Therefore, in a retrospective study design, we tested the hypothesis that implantation of an epidural spinal cord stimulator (SCS) device to treat chronic pain would significantly reduce clinic pain ratings and BP and that these reductions would be significantly correlated. Pain ratings and BP in medical records were collected before and after surgical implantation of a SCS device at the University of Iowa Hospitals and Clinics between 2008 and 2018 (n = 213). Reductions in pain rating [6.3 ± 2.0 vs. 5.0 ± 1.9 (scale: 0–10), P

A cognitive task, the n-back task, was used to interrogate the cognitive dimension of pain in patients with implanted dorsal root ganglion stimulators (DRGS). Magnetoencephalography (MEG) signals from thirteen patients with implanted DRGS were recorded at rest and while performing the n-back task at three increasing working memory loads with DRGS-OFF and the task repeated with DRGS-ON. MEG recordings were pre-processed, then power spectral analysis and source localization were conducted. DRGS resulted in a significant reduction in reported pain scores (mean 23%, p = 0.001) and gamma oscillatory activity (p = 0.036) during task performance. DRGS-induced pain relief also resulted in a significantly reduced reaction time during high working memory load (p = 0.011). A significant increase in average gamma power was observed during task performance compared to the resting state. However, patients who reported exacerbations of pain demonstrated a significantly elevated gamma power (F(3,80) = 65.011612, p &lt, 0.001, adjusted p-value = 0.01), compared to those who reported pain relief during the task. Our findings demonstrate that gamma oscillatory activity is differentially modulated by cognitive load in the presence of pain, and this activity is predominantly localized to the prefrontal and anterior cingulate cortices in a chronic pain cohort.

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20–30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.SIGNIFICANCE STATEMENTGait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20–30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies.

Objective Dorsal root ganglion stimulation (DRGS) received its first regulatory approval (CE marking in Europe) in late 2011, and so its use is now almost six years old. Several thousand patients have already been treated, and a landmark trial in lower limb complex regional pain syndrome (CRPS) and causalgia has recently been published. Methods In this review we have summarized the literature to date on the use of DRGS in the treatment of neuropathic pain. Results The results so far are encouraging, with reports of successful use in treating a wide range of indications including postsurgical pain, CRPS, and phantom pain. Treatment of failed back surgery syndrome (FBSS) appears less successful. The therapy is still young, and long term results are not yet available. There is now good randomized clinical trial (RCT) evidence that DRGS provides superior pain relief to spinal cord stimulation for CRPS and causalgia of the lower limb, and produces stimulation that is more posturally stable, with more precise paraesthesia coverage. However evidence of this quality for other indications and pain locations is lacking. Conclusion There is now Class A RCT evidence that DRGS provides superior pain relief to SCS for CRPS and causalgia of the lower limb. In the coming years we hope that randomized controlled trials will be performed on an indication-by-indication basis, which, together with the publication of longer term follow-up data, will provide a more complete understanding of the role of DRGS in the treatment of neuropathic pain syndromes.

ObjectivesTo investigate the role of beta oscillations in urinary voiding and their association with lower urinary tract symptoms in Parkinson disease (PD).MethodsWe used surgically implanted deep brain stimulation electrodes to record local field potential signals from the subthalamic nucleus (STN) and globus pallidus interna (GPi) of patients with PD during urinary voiding. Five patients with STN electrodes and 5 patients with GPi electrodes were tested. We also explored correlations between beta oscillatory power and urinary symptoms assessed by the International Consultation on Incontinence Lower Urinary Tract Symptoms questionnaire.ResultsBeta suppression occurred during urinary voiding in the GPi (p < 0.05) but not the STN. Furthermore, the beta signal in the GPi during voiding correlated significantly with severity of incontinence and urinary frequency (p < 0.05).ConclusionsIn this study, we have demonstrated that local field potentials can provide information about the neural control of the bladder. Our findings suggest that the GPi is implicated in the process of urinary voiding and that its mechanism of action is linked to signals in the beta frequency band. Moreover, our correlational analyses show that beta oscillations may be implicated more generally in the pathophysiology of lower urinary tract symptoms in PD.

Purpose: Epilepsy is a common neurological condition characterised by recurrent unprovoked seizures and often treatable with appropriate medication. However, almost 30% of cases are pharmacoresistant and while a proportion of these may be amenable to resective surgery, a gene therapy approach could be an attractive alternative option. Neuropeptide Y (NPY) has anticonvulsant and anti-epileptogenic properties in animal models of temporal lobe epilepsy when delivered by an adeno-associated viral (AAV) vector. Here we sought to demonstrate successful secretion of NPY from AAV-transduced human neuronal cells, which would be essential in planning any clinical trial. Methods: A human neuroblastoma cell line (SH-SY5Y) was used to assess in vitro whether an AAV vector manufactured to clinical-grade protocols would be effective at transducing these cells to express NPY. Optimal transduction efficiency was first achieved with retinoic acid and tetradecanoylphorpol-13-acetate (TPA) treatment, prior to expose to AAV1-green fluorescent protein (GFP) reporter vector, AAV1-NPY therapeutic vector or sham treated with no vector. Levels of NPY in cell supernatants were determined using two antibody-based methods Results: We found that the levels of NPY released into the cell culture media supernatant, and protein extracts of the cell pellet, were significantly higher following exposure to AAV1-NPY than when compared to either a control GFP reporter vector (AAV1-GFP) or sham treated controls. Conclusion: This first demonstration that an AAV-NPY construct can successfully transduce human neuronal cells supports the pre-clinical development of a clinical trial using AAV-based NPY for pharmacoresistant epilepsy.

Objectives Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been successfully used to treat both Parkinson’s disease (PD) and dystonia. Local field potentials (LFPs) recorded from the STN of PD patients demonstrate prominent beta frequency band activity. It is unclear whether such activity occurs in the STN in dystonia, and, if not, whether dystonia has another distinctive neural population activity in the STN. Methods Twelve patients with PD, and eight patients with dystonia underwent DBS electrode implantation targeting the STN. Seven dystonia patients were off medication and one was on aripiprazole and clonazepam. LFPs were recorded from the DBS electrodes in PD in the on/off medication states and in dystonia. Power spectra and temporal dynamics measured by the with Lempel-Ziv complexity of the LFPs were compared among these states. Results Normalised power spectra and Lempel-Ziv complexity of subthalamic LFPs differed between dystonia off and PD on/off, and between PD off and on over the low frequency, beta and high gamma bands. Patients with dystonia and off medication had lower beta power but higher low frequency and high gamma power than PD. Spectral power in the low beta frequency (11-20 Hz) range was attenuated in medicated PD. Conclusion The results suggest that dystonia and PD are characterized by different patterns of oscillatory activities even within the same nucleus, and exaggerated beta activity may relate to hypo-dopaminergic status.

BackgroundSubcortical structures including the basal ganglia have been proposed to be crucial for arousal, consciousness, and behavioural responsiveness. However, how basal ganglia contributes to the loss and recovery of consciousness during anaesthesia has not been well characterized.MethodsIn this study, using local field potentials (LFPs) from subthalamic nucleus (STN) and scalp electroencephalogram in 12 Parkinson’s disease patients, we investigate STN neural signatures during propofol general anaesthesia and during intubation as an arousal intervention in anaesthesia.ResultsPropofol-induced anaesthesia resulted in changes in multiple frequency bands in STN LFPs, including increased low-frequency activities (slow-wave oscillation, delta, theta, and alpha bands) and decreased higher-frequency activities. This was also accompanied by increased STN-frontal cortical coherence in alpha frequency band. Beta and high-gamma activities in the STN temporally increased during intubation compared to the status of loss of consciousness. We also show that the dynamic changes in the high frequency activities (80-180 Hz) in STN LFPs induced by propofol and intubation correlated with power-law exponent in the power spectra between 2 and 80 Hz.ConclusionsOur findings suggest that anaesthesia and intubation induced changes in the STN LFPs in multiple frequency bands. They are also consistent with the hypothesis that the power-law exponent in the power spectra between 2 and 80 Hz reflect the excitation/inhibition balance in the STN, which is modulated by anaesthesia and intubation, and further modulate the high frequency activity.

Deep brain stimulation (DBS) is a minimally invasive targeted neurosurgical intervention that enables structures deep in the brain to be stimulated electrically by an implanted pacemaker. It has become the treatment of choice in Parkinson’s disease patients with either disabling medication side effects, on-off fluctuations, or tremor. Its efficacy in Parkinson’s disease has been demonstrated robustly by randomized controlled clinical trials, with numerous brain areas having been targeted in the last two decades for indications including dystonia and tremor in movement disorders; depression, obsessive-compulsive disorder, and Tourette’s syndrome in psychiatry; epilepsy, cluster headache, and chronic pain. The principles of framed stereotactic surgery enabling DBS electrode placement are reviewed here, before describing the putative mechanisms underlying DBS and its action upon individual neurons. Recent and future developments in DBS technology such as segmented, directional leads, and smart, adaptive stimulation are then discussed alongside related technological advances such as diffusion tensor imaging, robotic surgery, and molecular and cellular therapies. The role of stereotactic lesions in the era of DBS and the different modalities of lesioning are then summarized.

Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) was offered to chronic pain patients who had exhausted medical and surgical options. However, several patients developed recurrent seizures. This work was conducted to assess the effect of ACC stimulation on the brain activity and to guide safe DBS programming. A sensing-enabled neurostimulator (Activa PC + S) allowing wireless recording through the stimulating electrodes was chronically implanted in three patients. Stimulation patterns with different amplitude levels and variable ramping rates were tested to investigate whether these patterns could provide pain relief without triggering after-discharges (ADs) within local field potentials (LFPs) recorded in the ACC. In the absence of ramping, AD activity was detected following stimulation at amplitude levels below those used in chronic therapy. Adjustment of stimulus cycling patterns, by slowly ramping on/off (8-s ramp duration), was able to prevent ADs at higher amplitude levels while maintaining effective pain relief. The absence of AD activity confirmed from the implant was correlated with the absence of clinical seizures. We propose that AD activity in the ACC could be a biomarker for the likelihood of seizures in these patients, and the application of sensing-enabled techniques has the potential to advance safer brain stimulation therapies, especially in novel targets.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) is dedicated to improving the safety and efficacy of neuromodulation and thus improving the lives of patients undergoing neuromodulation therapies. With continued innovations in neuromodulation comes the need for evolving reviews of best practices. Dorsal root ganglion (DRG) stimulation has significantly improved the treatment of complex regional pain syndrome (CRPS), among other conditions. Through funding and organizational leadership by the International Neuromodulation Society (INS), the NACC reconvened to develop the best practices consensus document for the selection, implantation and use of DRG stimulation for the treatment of chronic pain syndromes. METHODS: The NACC performed a comprehensive literature search of articles about DRG published from 1995 through June, 2017. A total of 2538 article abstracts were then reviewed, and selected articles graded for strength of evidence based on scoring criteria established by the US Preventive Services Task Force. Graded evidence was considered along with clinical experience to create the best practices consensus and recommendations. RESULTS: The NACC achieved consensus based on peer-reviewed literature and experience to create consensus points to improve patient selection, guide surgical methods, improve post-operative care, and make recommendations for management of patients treated with DRG stimulation. CONCLUSION: The NACC recommendations are intended to improve patient care in the use of this evolving therapy for chronic pain. Clinicians who choose to follow these recommendations may improve outcomes.

Background Deep brain stimulation (DBS) is a well-established treatment to reduce tremor, notably in Parkinson disease. DBS may also be effective in post-traumatic tremor, one of the most common movement disorders caused by head injury. However, the cohorts of patients often have multiple lesions that may impact the outcome depending on which fiber tracts are affected. Case Description A 20-year-old man presented after road traffic accident with severe closed head injury and polytrauma. Computed tomography scan showed left frontal and basal ganglia hemorrhagic contusions and intraventricular hemorrhage. A disabling tremor evolved in step with motor recovery. Despite high-intensity signals in the intended thalamic target, a visual analysis of the preoperative diffusion tensor imaging revealed preservation of connectivity of the intended target, ventralis oralis posterior thalamic nucleus (VOP). This was confirmed by the postoperative tractography study presented here. DBS of the VOP/zona incerta was performed. Six months postimplant, marked improvement of action (postural, kinetic, and intention) tremor was achieved. Conclusions We demonstrated a strong connectivity between the VOP and the superior frontal gyrus containing the premotor cortex and other central brain areas responsible for movement control. In spite of an existing lesion in the target, the preservation of these tracts may be relevant to the improvement of the patient's symptoms by DBS.

This scientific commentary refers to ‘Directional deep brain stimulation: an intraoperative double-blind pilot study', by Pollo et al ., (doi:10.1093/brain/awu102). Over the last two decades, deep brain stimulation has become widely accepted as a treatment for Parkinson’s disease, dystonia and tremor, and its use is increasing in disorders such as obsessive-compulsive disorder, depression and pain. The primary objective is always to achieve symptom suppression with few or no side effects; in other words, to attain as wide a therapeutic window as possible. In the past, efforts to achieve this were focused largely on ensuring accurate electrode placement, be it with the help of imaging and/or with microelectrode recordings. Excellent results can be obtained in this way, but unwanted side effects still occur in ∼13% of patients (Deuschl et al. , 2006). Today, a number of new technologies are under development to address this problem. In this issue of Brain , Pollo et al. present data from a randomized clinical trial in which one of these approaches—directional stimulation—produces a wider therapeutic window than traditional methods (Pollo et al. , 2014). To put this result into context, it is worth reviewing, albeit briefly, some of the other strategies that are under development with the aim of maximizing therapeutic benefit while minimizing side effects. ### Demand pacemakers Currently, most pacemakers deliver stimulation continuously at a fixed rate, in what is a rather simple but nevertheless effective therapy. However, constant stimulation can incur unwanted side effects by spreading to other fibre tracts or by disrupting normal brain signals embedded in pathological activity. Alteration of such ‘normal’ signals may affect emotion or cognition, for example. By targeting stimulation specifically …

Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a recent technique that has shown some promising short-term results in patients with chronic refractory neuropathic pain. Three years after the first case series, we assessed its efficacy on a larger cohort, with longer follow-up.Twenty-four patients (19 males; average age, 49.1 years) with neuropathic pain underwent bilateral ACC DBS. Patient-reported outcome measures were collected before and after surgery, using the Numerical Rating Scale (NRS), Short-Form 36 quality of life (SF-36), McGill Pain Questionnaire (MPQ), and EuroQol 5-domain quality of life (EQ-5D) questionnaire.Twenty-two patients after a trial week were fully internalized and 12 had a mean follow-up of 38.9 months. Six months after surgery the mean NRS score decreased from 8.0 to 4.27 (P = 0.004). There was a significant improvement in the MPQ (mean, -36%; P = 0.021) and EQ-5D score significantly decreased (mean, -21%; P = 0.036). The physical functioning domain of SF-36 was significantly improved (mean, +54.2%; P = 0.01). Furthermore, in 83% of these patients, at 6 months, NRS score was improved by 60% (P < 0.001) and MPQ decreased by 47% (P < 0.01). After 1 year, NRS score decreased by 43% (P < 0.01), EQ-5D was significantly reduced (mean, -30.8; P = 0.05) and significant improvements were also observed for different domains of the SF-36. At longer follow-ups, efficacy was sustained up to 42 months in some patients, with an NRS score as low as 3.Follow-up results confirm that ACC DBS alleviates chronic neuropathic pain refractory to pharmacotherapy and improves quality of life in many patients.

The autonomic nervous system (ANS) is involved in the regulation of physiologic and homeostatic parameters relating particularly to the visceral organs and the co-ordination of physiological responses to threat. Blood pressure and heart rate, respiration, pupillomotor reactivity, sexual function, gastrointestinal secretions and motility, and urine storage and micturition are all under a degree of ANS control. Furthermore, there is close integration between the ANS and other neural functions such as emotion and cognition, and thus brain regions that are known to be important for autonomic control are also implicated in emotional functions. In this review we explore the role of the central ANS in the control of the bladder, and the implications of this for bladder dysfunction in diseases of the ANS.

Objective To quantify the relationship between the electrical power requirement to achieve pain relief and the position of the active electrode of dorsal root ganglion stimulators within the spinal nerve root exit foramen. Materials and Methods Retrospective analysis of prospectively collected data of 92 consecutive patients undergoing dorsal root ganglion stimulation (DRGS) for chronic pain in a single center. Cervical and sacral cases, and failed trials/explanted DRGS were excluded, so we report on 57 patients with 78 implanted leads. Anteroposterior and lateral fluoroscopic images of the lead in the exit foramen were examined, and the active electrode positions were put into categories depending on their location relative to fixed anatomical landmarks. The clinical outcome and the power requirements for each of these groups of electrodes were then analyzed. Overall pain outcome was assessed by numeric pain rating scale score pre‐operatively and post‐operatively. Results There was no significant relationship between power requirements and mediolateral electrode position, although the lowest average was observed with electrode positions directly below the center of the pedicle. On lateral x‐ray, the lowest power requirements were observed in the electrodes positioned superodorsally or dorsally within the foramen. Importantly, power requirements in this location were consistently low, while the power requirements in other locations were not only higher but also much more variable. Electrodes in the superodorsal position required a median output power almost four times lower than electrodes in other positions (p = 0.002). Clinical outcome was not significantly related to power requirement or foraminal position. Conclusion Aiming for a superodorsal electrode position on lateral intraoperative fluoroscopy is desirable, since siting leads in this location reduces the required stimulator output power very substantially and thus will extend battery life. Position within the foramen does not determine clinical outcome, and so the implanter can safely aim for the low power site without detriment to the analgesic efficacy of the system.

Infarction of the insula is a common scenario with large tissue-volume strokes in the middle cerebral artery territory. Considered to be part of the central autonomic network, infarction of this region is associated with autonomic disturbances, in particular cardiovascular dysregulation. Risk of aspiration following stroke is also associated with involvement of the insula, consistent with its purported participation in complex functions of the mouth and pharynx. Strokes restricted to the insula are rare and present with a broad range of symptoms that offer a window of insight into the diverse functionality of the insular cortex. Chemosensory, autonomic, vestibular, auditory, somatosensory, language and oropharyngeal functional deficits are all recognised, among others. Long-term sequelae are unknown but profound symptoms, such as hemiparesis, are usually transient. Understanding the patterns of dysfunction highlighted provides the basis for future strategies to optimise stroke management on the discovery of insula involvement.

Background Trigeminal Neuropathic Pain (TNP) is a chronic facial pain syndrome caused by a lesion or disease affecting one or more branches of the trigeminal nerve. It may, for example, result from accidental injury to a branch of the trigeminal nerve by trauma or during surgery; it may also be idiopathic. TNP is typically constant, in contrast to most cases of the commoner trigeminal neuralgia. In some cases, pain may be refractory to pharmacological treatment. Peripheral nerve field stimulation is recognized as an effective minimally invasive surgical treatment option for this debilitating condition. To date, stimulation has used conventional tonic waveforms, which generate paraesthesia in the stimulated area. This is the first report of the use of paraesthesia‐free burst pattern stimulation for TNP. Methods Seven patients were treated at the John Radcliffe Hospital for TNP from 2016 to 2018. Mean duration of preoperative symptoms was five years. All patients had exhausted pharmacological measures to limited effect. The initial three patients had tonic stimulation with the subsequent four having burst stimulation. Outcome was assessed using the numeric pain rating scale preoperatively and postoperatively at three and six months and one year. Side‐effects and complications were also assessed as well as reduction in analgesic medication use. Results All patients achieved pain reduction of at least 50% at 6 months (range 50–100%, mean 81%, p = 0.0082). Those in the burst stimulation group were paraesthesia free. One patient developed a postoperative infection for which the system had to be removed and is awaiting reimplantation. There were no other complications in either group. Conclusion Burst stimulation conferred similar pain control to tonic stimulation in our small cohort, and there were similar reductions in pain medication use. An additional benefit of burst stimulation is freedom from paraesthesia. Larger scale studies are needed to further evaluate burst stimulation and compare its efficacy with that of tonic stimulation.

BACKGROUND: Occipital nerve stimulation (ONS) is widely used for headache syndromes including chronic migraine (CM) and chronic cluster headache (CCH). The paraesthesia associated with tonic stimulation can be bothersome and can limit therapy. It is now clear in spinal cord stimulation that paraesthesia-free waveforms can produce effective analgesia, but this has not been reported in ONS for CM or CCH. MATERIALS AND METHODS: seventeen patients (12 CM and 5 CCH) were treated with bilateral burst pattern ONS, including 4 who had previously had tonic ONS. Results were assessed in terms of the frequency of headaches (number of headache days per month for CM, and number of attacks per day for CCH) and their intensity on the numeric pain rating scale. RESULTS: Burst ONS produced a statistically significant mean reduction of 10.2 headache days per month in CM. In CCH, there were significant mean reductions in headache frequency (92%) and intensity (42%). CONCLUSION: Paraesthesia is not necessary for good quality analgesia in ONS. Larger studies will be required to determine whether the efficacies of the two stimulation modes differ. Burst ONS is imperceptible and therefore potentially amenable to robustly blinded clinical trials.