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OBJECTIVE To obtain individual clinical and neuroimaging data of patients undergoing Deep Brain Stimulation for essential tremor from five different European centers to identify predictors of outcome and to identify an optimal stimulation site. METHODS We analysed retrospectively baseline covariates, pre- and postoperative clinical tremor scores (12-month) as well as individual imaging data from 119 patients to obtain individual electrode positions and stimulation volumes. Individual imaging and clinical data was used to calculate a probabilistic stimulation map in normalized space using voxel-wise statistical analysis. Finally, we used this map to train a classifier to predict tremor improvement. RESULTS Probabilistic mapping of stimulation effects yielded a statistically significant cluster that was associated with a tremor improvement greater than 50%. This cluster of optimal stimulation extended from the posterior subthalamic area to the ventralis intermedius nucleus and coincided with a normative structural-connectivity-based cerebello-thalamic tract (CTT). The combined features "distance between the stimulation volume and the significant cluster" and "CTT activation" were used as a predictor of tremor improvement. This correctly classified a greater than 50% tremor improvement with a sensitivity of 89% and a specificity of 57%. INTERPRETATION Our multicentre ET probabilistic stimulation map identified an area of optimal stimulation along the course of the CTT. The results of this study are mainly descriptive until confirmed in independent datasets, ideally through prospective testing. This target will be made openly available and may be used to guide surgical planning and for computer-assisted programming of deep brain stimulation in the future. This article is protected by copyright. All rights reserved.

Existing neurostimulation systems implanted for the treatment of neurodegenerative disorders generally deliver invariable therapy parameters, regardless of phase of the sleep/wake cycle. However, there is considerable evidence that brain activity in these conditions varies according to this cycle, with discrete patterns of dysfunction linked to loss of circadian rhythmicity, worse clinical outcomes and impaired patient quality of life. We present a targeted concept of circadian neuromodulation using a novel device platform. This system utilises stimulation of circuits important in sleep and wake regulation, delivering bioelectronic cues (Zeitgebers) aimed at entraining rhythms to more physiological patterns in a personalised and fully configurable manner. Preliminary evidence from its first use in a clinical trial setting, with brainstem arousal circuits as a surgical target, further supports its promising impact on sleep/wake pathology. Data included in this paper highlight its versatility and effectiveness on two different patient phenotypes. In addition to exploring acute and long-term electrophysiological and behavioural effects, we also discuss current caveats and future feature improvements of our proposed system, as well as its potential applicability in modifying disease progression in future therapies.

Neural oscillatory activities in basal ganglia have prominent roles in cognitive processes. However, the characteristics of oscillatory activities during cognitive tasks have not been extensively explored in human Globus Pallidus internus (GPi). This study aimed to compare oscillatory characteristics of GPi between dystonia and Parkinson's Disease (PD). A dystonia and a PD patient performed the Intra-Extra-Dimension shift (IED) task during both on and off-medication states. During the IED task, patients had to correctly choose between two visual stimuli containing shapes or lines based on a hidden rule via trial and error. Immediate auditory and visual feedback was provided upon the choice to inform participants if they chose correctly. Bilateral GPi Local Field Potentials (LFP) activity was recorded via externalized DBS leads. Transient high gamma activity (~ 100–150 Hz) was observed immediately after feedback in the dystonia patient. Moreover, these bursts were phase synchronous between left and right GPi with an antiphase clustering of phase differences. In contrast, no synchronous high gamma activity was detected in the PD patient with or without dopamine administration. The off-med PD patient also displayed enhanced low frequency clusters, which were ameliorated by medication. The current study provides a rare report of antiphase homotopic synchrony in human GPi, potentially related to incorporating and processing feedback information. The absence of these activities in off and on-med PD patient indicates the potential presence of impaired medication independent feedback processing circuits. Together, these findings suggest a potential role for GPi’s synchronized activity in shaping feedback processing mechanisms required in cognitive tasks.

Surgical neuromodulation through implantable devices allows for stimulation delivery to subcortical regions, crucial for symptom control in many debilitating neurological conditions. Novel closed-loop algorithms deliver therapy tailor-made to endogenous physiological activity, however rely on precise sensing of signals such as subcortical oscillations. The frequency of such intrinsic activity can vary depending on subcortical target nucleus, while factors such as regional anatomy may also contribute to variability in sensing signals. While artefact parameters have been explored in more ‘standard’ and commonly used targets (such as the basal ganglia, which are implanted in movement disorders), characterisation in novel candidate nuclei is still under investigation. One such important area is the brainstem, which contains nuclei crucial for arousal and autonomic regulation. The brainstem provides additional implantation targets for treatment indications in disorders of consciousness and sleep, yet poses distinct anatomical challenges compared to central subcortical targets. Here we investigate the region-specific artefacts encountered during activity and rest while streaming data from brainstem implants with a cranially-mounted device in two patients. Such artefacts result from this complex anatomical environment and its interactions with physiological parameters such as head movement and cardiac functions. The implications of the micromotion-induced artefacts, and potential mitigation, are then considered for future closed-loop stimulation methods.

The field of neurostimulation for the treatment of chronic pain is a rapidly developing area of medicine. Although neurostimulation therapies have advanced significantly as a result of technologic improvements, surgical planning, device placement, and postoperative care are of equal importance to optimize outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for these often-overlooked areas of neurostimulation practice.Authors were chosen based on their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from the last NACC publication in 2017 to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on evidence strength and consensus when evidence was scant.This NACC project provides guidance on preoperative assessment, intraoperative techniques, and postoperative management in the form of consensus points with supportive evidence. These results are based on grade of evidence, strength of consensus, and expert opinion.The NACC has given guidance for a surgical plan that encompasses the patient journey from the planning stage through the surgical experience and postoperative care. The overall recommendations are designed to improve efficacy and the safety of patients undergoing these neuromodulation procedures and are intended to apply throughout the international community.

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.

BackgroundIn Essential tremor (ET), involuntary shaking of the upper limbs during isometric muscle contraction closely reflects the patterns of neural activity measured in the thalamus - a key element of the tremorgenic circuit. Phase-specific deep brain stimulation (DBS) builds upon this observation while using accelerometery of the trembling limb to trigger repetitive electrical perturbations to the thalamus and surrounding areas at a specific time within the tremor cycle. This closed-loop strategy has been shown to induce clinically significant postural tremor relief while delivering less than half the energy of conventional DBS.ObjectiveThe main aim of the study was to evaluate treatment efficacy across different contexts and movement states.MethodsWe used accelerometery and a digitizing tablet to record the peripheral tremor dynamics of 4 DBS implanted ET patients while alternating stimulation strategies (no stimulation, continuous open-loop and phase-specific) and movement states (intermittent posture holding and spiral drawing).ResultsIn addition to observing a suppressive effect of phase-specific DBS on both postural and kinetic tremor, our results reinforce the key role of phase-specificity to achieve tremor control in postural motor states and highlight the difficulty of quantifying phase-dependent effects during continuous movement. Moreover, this study supports the hypothesis that ET patients with more stable tremor characteristics benefit the most from phase-specific DBS.ConclusionsBy creating a better understanding of the dynamic relationship between central and peripheral tremor activity, this study provides important insights for the development of effective patient and context-specific therapeutic approaches for ET.

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.

The dorsal anterior cingulate cortex (dACC) is a key node in the human salience network. It has been ascribed motor, pain-processing and affective functions. However, the dynamics of information flow in this complex region and how it responds to inputs remain unclear and are difficult to study using non-invasive electrophysiology. The area is targeted by neurosurgery to treat neuropathic pain. During deep brain stimulation surgery, we recorded local field potentials from this region in humans during a decision-making task requiring motor output. We investigated the spatial and temporal distribution of information flow within the dACC. We demonstrate the existence of a distributed network within the anterior cingulate cortex where discrete nodes demonstrate directed communication following inputs. We show that this network anticipates and responds to the valence of feedback to actions. We further show that these network dynamics adapt following learning. Our results provide evidence for the integration of learning and the response to feedback in a key cognitive region.

Neural oscillatory activities in basal ganglia have prominent roles in cognitive processes on local and global scales. However, the characteristics of high frequency oscillatory activities during cognitive tasks have not been extensively explored in human Globus Pallidus internus (GPi). This study aimed to investigate amplitude and interhemispheric coupling of bilateral GPi high gamma bursts in dystonia and Parkinson’s Disease (PD) patients, in on and off medication states, after feedback during the Intra-Extra-Dimension shift (IED) task. Bilateral GPi Local Field Potentials (LFP) activity was recorded via externalized DBS electrodes during the IED task. Inter hemisphere phase synchrony was assessed using Inter-Site Phase Clustering (ISPC). Transient high gamma activity (∼100-150Hz) was observed immediately after feedback in the dystonia patient. Moreover, these bursts were phase synchronous between left and right GPis with an antiphase clustering of phase differences. In contrast, no synchronous high gamma activity was detected in the PD patient with or without dopamine administration. The off-med PD patient displayed enhanced low frequency clusters ameliorated by medication in the on-med state. Furthermore, an increased low frequency activity was observed after feedback of incorrect trials in both disease states. The current study provides a rare report of antiphase homotopic synchrony in human GPi, potentially related to incorporating and processing feedback information. The absence of these activities in off and on-med PD indicates the potential presence of impaired medication independent circuits related to feedback processing. Together, these findings are helpful in pointing to the potential role of GPi’s synchronized high frequency activity in cognitive tasks and feedback information processing.

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.

Beta power suppression in the basal ganglia is stronger during movements that require high force levels and high movement effort but it has been difficult to dissociate the two. We recorded scalp EEG and basal ganglia local field potentials in Parkinson's disease patients (11 STN, 7 GPi) ON and OFF dopaminergic medication while they performed a visually-guided force matching task using a pen on a force-sensitive graphics tablet. Force adjustments were accompanied by beta power suppression irrespective of whether the force was increased or reduced. Before the adjustment was completed, beta activity returned. High beta power was specifically associated with slowing of the force adjustment. ON medication, the peak force rate was faster and cortico-basal ganglia beta phase coupling was more readily modulated. In particular, phase decoupling was stronger during faster adjustments. The results suggest that beta power in the basal ganglia does not covary with force per se, but rather with a related factor, the absolute force rate, or a more general concept of movement effort. The results also highlight that beta activity reappears during stabilization of isometric contractions, and that dopamine-related suppression of cortico-basal ganglia beta coupling is linked to faster force adjustments.

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.

There is growing interest in using adaptive neuro-modulation to provide a more personalized therapy experience that might improve patient outcomes. Current implant technology, however, can be limited in its adaptive algorithm capability. To enable exploration of adaptive algorithms with chronic implants, we designed and validated the, ‘Picostim DyNeuMo Mk-1’, (DyNeuMo Mk-1 for short), a fully-implantable, adaptive research stimulator that titrates stimulation based on circadian rhythms (e.g. sleep, wake) and the patient’s movement state (e.g. posture, activity, shock, free-fall). The design leverages off-the-shelf consumer technology that provides inertial sensing with low-power, high reliability, and relatively modest cost. The DyNeuMo Mk-1 system was designed, manufactured and verified using ISO 13485 design controls, including ISO 14971 risk management techniques to ensure patient safety, while enabling novel algorithms. The system was validated for an intended use case in movement disorders under an emergency-device authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA). The algorithm configurability and expanded stimulation parameter space allows for a number of applications to be explored in both central and peripheral applications. Intended applications include adaptive stimulation for movement disorders, synchronizing stimulation with circadian patterns, and reacting to transient inertial events such as posture changes, general activity, and walking. With appropriate design controls in place, first-in-human research trials are now being prepared to explore the utility of automated motion-adaptive algorithms.

There is growing interest in using adaptive neuro-modulation to provide a more personalized therapy experience that might improve patient outcomes. Current implant technology, however, can be limited in its adaptive algorithm capability. To enable exploration of adaptive algorithms with chronic implants, we designed and validated the ‘Picostim DyNeuMo Mk-1’ (DyNeuMo Mk-1 for short), a fully-implantable, adaptive research stimulator that titrates stimulation based on circadian rhythms (e.g. sleep, wake) and the patient’s movement state (e.g. posture, activity, shock, free-fall). The design leverages off-the-shelf consumer technology that provides inertial sensing with low-power, high reliability, and relatively modest cost. The DyNeuMo Mk-1 system was designed, manufactured and verified using ISO 13485 design controls, including ISO 14971 risk management techniques to ensure patient safety, while enabling novel algorithms. The system was validated for an intended use case in movement disorders under an emergency-device authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA). The algorithm configurability and expanded stimulation parameter space allows for a number of applications to be explored in both central and peripheral applications. Intended applications include adaptive stimulation for movement disorders, synchronizing stimulation with circadian patterns, and reacting to transient inertial events such as posture changes, general activity, and walking. With appropriate design controls in place, first-in-human research trials are now being prepared to explore the utility of automated motion-adaptive algorithms.

Beta oscillations are readily observed in motor cortex and the basal ganglia, but to which extent they are functionally relevant is unclear. To understand how activity transfer between different nodes of the cortico-basal ganglia network is affected by cortical beta oscillations in different behavioural conditions, we recorded local field potentials and electroencephalography (EEG) activity in a low-force motor control task and during rest in Parkinson's patients undergoing deep brain stimulation (DBS) surgery. The patients received DBS of either the subthalamic nucleus (STN) or the internal globus pallidus (GPi), which allowed us to investigate if STN and GPi broad-band high-frequency activity (HFA; >150 Hz) is co-modulated with the phase of motor cortical beta activity. We found significant modulation patterns in the STN and the GPi, which were inverted while patients performed the task, showing that GPi activity fluctuations likely are crafted by other inputs than the direct excitatory STN afferents. We also found that consistent STN modulation disappeared during rest, showing disengagement in this condition, while GPi modulation was maintained, again evidencing that beta-band activity fluctuations in the GPi can be relatively independent of those in the STN. The difference between HFA modulation patterns in the task and rest recordings suggests a potential functional role of beta phase-locked HFA modulation in controlling sustained contractions. Examination of HFA co-modulation patterns at different sites of the cortico-basal ganglia-thalamo-cortical network under different behavioural conditions may provide a tool with which to define the impact of beta synchronization on network communication.

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.

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

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.

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.

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.

Objective: To determine the validity of the key mathematical assumptions used in electrical impedance tomography for human head tissues. Approach:Conductivity and permittivity data collected from available literature for each tissue within the human head have been evaluated and critiqued. The most relevant dielectric tissue data for each tissue was then used to assess the validity of the mathematical assumptions of electrical impedance tomography in terms of their suitability for human head imaging in order to estimate related errors. Main Results:For induced currents with frequencies greater than 200 Hz the internal current source density is negligible. The assumption that magnetic effects are negligible is valid to an error of 1.7% for human head tissues for frequencies below 1 MHz. The capacitive effects are negligible for CSF, dura mater, blood, bone (cortical), and deep tissue skin for frequencies less than 3.2 MHz, 320 kHz, 25 kHz, 3.2 kHz, and 130 Hz respectively. However, the capacitive effects are not negligible for brain tissues, as the minimum error for brain tissues across the frequency range of 10 Hz to 100 GHz is 6.2% at 800 Hz, and the maximum error is 410% at 20 GHz. Significance:It is often assumed that the mathematical reduction of the base equations is valid for human head tissues over a broad frequency range; this study shows that these assumptions are not true for all tissues at all frequencies. False assumptions will result in greater errors and local distortions within tomographic images of the human head using electrical impedance tomography. This study provides the relationships between injected current frequency and the validity of the mathematical assumptions for each individual tissue, providing greater awareness of the magnitude of possible distortions.

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.

Introduction and objectives Deep brain stimulation (DBS) of motor thalamic nuclei is a therapy used to alleviate essential tremor or freezing of gait. Electrodes are surgically inserted to provide high frequency electrical stimulation to a specific nucleus which is thought to create a reversible virtual lesion. We aimed to determine what effect this might have on experimentally induced or pre-existing breathlessness. On the basis of anecdotal comments by one patient we hypothesized that motor thalamic DBS would increase breathlessness sensitivity. Methods Eleven patients with bilateral electrodes in the Ventral Intermediate Nucleus (VIM) for relief of essential tremor were studied (mean age ±sd =65±10.7, Male=9). Air Hunger (AH) a particularly unpleasant facet of breathlessness was induced experimentally by raising inspired CO2 while ventilation was restricted to baseline levels. Two steady state 5 min AH tests were performed in random order; once with DBS turned ON and once with it turned OFF. Test level of hypercapnia was the same for ON and OFF states (mean ±sd end-tidal PCO242±3 mmHg). Patients rated AH on a 100 mm visual analogue scale (VAS) every 15 s. AH ratings in the last minute of each test were averaged and mean levels compared for ON and OFF states. Results Ten of eleven patients rated less AH with DBS ON (median reduction −12 mmVAS; range −9 to −52 mmVAS). Overall mean ±sd steady state AH was significantly different (p=0.018; paired t-test) with 49±28 mmVAS for the ON state and 65±26 mmVAS for the OFF state. This difference exceeded minimal clinically important difference of 10 mmVAS. Conclusions Contrary to expectations, DBS of motor thalamic nuclei (VIM) substantially reduced experimentally induced hypercapnic AH. We suggest that ‘virtual lesion’ created by the DBS blocks the ascending dyspnoea signal. The extent of the relief suggests that DBS may prove to be a viable therapy for intractable dyspnoea in the worst affected patients whose breathlessness is refractory to current treatment options.

Background: Lower urinary tract symptoms occur in 27% to 86% of patients with Parkinson's disease (PD), however, the mechanisms responsible for bladder dysfunction are not fully understood. This study utilized magnetic resonance imaging (MRI) to test the hypothesis that key brainstem bladder control areas (including the pontine micturition center and the pontine continence center (PCC) and their links with the basal ganglia are important in the development of urinary storage symptoms in PD. Methods: Seventeen patients with PD completed a “bladder symptom questionnaire” and underwent diffusion‐weighted MRI (1.5 T). Storage symptom severity and MRI measures of white matter microstructural integrity were correlated using tract‐based spatial statistics. Results: Mean diffusivity in the ventral brainstem correlated significantly with the bladder symptom severity in areas close to the predicted anatomical co‐ordinates of the PCC. Tracts seeded from these regions passed via areas involved in pelvic floor musculature control and urinary voiding including the cerebellum, pallidum, and precentral gyrus. Conclusion: We used diffusion‐weighted MRI to investigate the role of the brainstem and its structural connections in the development of urinary storage symptoms in PD. Our data suggest that the brainstem degenerative change in the vicinity of the PCC may be implicated in the pathogenesis of storage symptoms in these patients.