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  • The autonomic effects of deep brain stimulation--a therapeutic opportunity.

    3 July 2018

    Deep brain stimulation (DBS) is an expanding field in neurosurgery and has already provided important insights into the fundamental mechanisms underlying brain function. One of the most exciting emerging applications of DBS is modulation of blood pressure, respiration and micturition through its effects on the autonomic nervous system. DBS stimulation at various sites in the central autonomic network produces rapid changes in the functioning of specific organs and physiological systems that are distinct from its therapeutic effects on central nervous motor and sensory systems. For example, DBS modulates several parameters of cardiovascular function, including heart rate, blood pressure, heart rate variability, baroreceptor sensitivity and blood pressure variability. The beneficial effects of DBS also extend to improvements in lung function. This article includes an overview of the anatomy of the central autonomic network, which consists of autonomic nervous system components in the cortex, diencephalon and brainstem that project to the spinal cord or cranial nerves. The effects of DBS on physiological functioning (particularly of the cardiovascular and respiratory systems) are discussed, and the potential for these findings to be translated into therapies for patients with autonomic diseases is examined.

  • A torque-based method demonstrates increased rigidity in Parkinson's disease during low-frequency stimulation.

    3 July 2018

    Low-frequency oscillations in the basal ganglia are prominent in patients with Parkinson's disease off medication. Correlative and more recent interventional studies potentially implicate these rhythms in the pathophysiology of Parkinson's disease. However, effect sizes have generally been small and limited to bradykinesia. In this study, we investigate whether these effects extend to rigidity and are maintained in the on-medication state. We studied 24 sides in 12 patients on levodopa during bilateral stimulation of the STN at 5, 10, 20, 50, 130 Hz and in the off-stimulation state. Passive rigidity at the wrist was assessed clinically and with a torque-based mechanical device. Low-frequency stimulation at ≤20 Hz increased rigidity by 24 % overall (p = 0.035), whereas high-frequency stimulation (130 Hz) reduced rigidity by 18 % (p = 0.033). The effects of low-frequency stimulation (5, 10 and 20 Hz) were well correlated with each other for both flexion and extension (r = 0.725 ± SEM 0.016 and 0.568 ± 0.009, respectively). Clinical assessments were unable to show an effect of low-frequency stimulation but did show a significant effect at 130 Hz (p = 0.002). This study provides evidence consistent with a mechanistic link between oscillatory activity at low frequency and Parkinsonian rigidity and, in addition, validates a new method for rigidity quantification at the wrist.

  • Long-term outcomes of deep brain stimulation for neuropathic pain.

    3 July 2018

    BACKGROUND: Deep brain stimulation (DBS) to treat neuropathic pain refractory to pharmacotherapy has reported variable outcomes and has gained United Kingdom but not USA regulatory approval. OBJECTIVE: To prospectively assess long-term efficacy of DBS for chronic neuropathic pain in a single-center case series. METHODS: Patient reported outcome measures were collated before and after surgery, using a visual analog score, short-form 36-question quality-of-life survey, McGill pain questionnaire, and EuroQol-5D questionnaires (EQ-5D and health state). RESULTS: One hundred ninety-seven patients were referred over 12 years, of whom 85 received DBS for various etiologies: 9 amputees, 7 brachial plexus injuries, 31 after stroke, 13 with spinal pathology, 15 with head and face pain, and 10 miscellaneous. Mean age at surgery was 52 years, and mean follow-up was 19.6 months. Contralateral DBS targeted the periventricular gray area (n = 33), the ventral posterior nuclei of the thalamus (n = 15), or both targets (n = 37). Almost 70% (69.4%) of patients retained implants 6 months after surgery. Thirty-nine of 59 (66%) of those implanted gained benefit and efficacy varied by etiology, improving outcomes in 89% after amputation and 70% after stroke. In this cohort, >30% improvements sustained in visual analog score, McGill pain questionnaire, short-form 36-question quality-of-life survey, and EuroQol-5D questionnaire were observed in 15 patients with >42 months of follow-up, with several outcome measures improving from those assessed at 1 year. CONCLUSION: DBS for pain has long-term efficacy for select etiologies. Clinical trials retaining patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.

  • Elevated gamma band power in humans receiving naloxone suggests dorsal periaqueductal and periventricular gray deep brain stimulation produced analgesia is opioid mediated.

    3 July 2018

    BACKGROUND: The midbrain periaqueductal and periventricular gray (PAVG) region is important for pain and autonomic modulation. We have previously described changes in blood pressure dependent upon dorsal or ventral electrode positioning with PAVG deep brain stimulation (DBS), yet controversy exists about whether DBS acts via endogenous opioid release. METHOD AND RESULTS: We combined local field potential (LFP) recording from PAVG DBS electrodes in humans with naloxone and saline infusions to determine whether dorsal and ventral PAVG DBS act through opioidergic or other mechanisms. Four awake human subjects were investigated. DBS were implanted contralateral to the painful body part. Electrode contact positions were mapped using MRI and brain atlas information. Naloxone then saline were randomly administered to the blinded subjects and pain rated using a numeric pain rating scale at 30s intervals for 3 min. Two subjects received dorsal DBS electrodes and two had ventral placements. Significantly elevated gamma frequency band (30-90 Hz) power concomitant with pain exacerbation was found with naloxone versus both saline and rest in dorsal not ventral PAVG LFPs (p<0.005). Significantly elevated delta frequency band (0-4 Hz) power (p=0.001) was seen in one ventral PAVG subject with both naloxone and saline infusions. CONCLUSIONS: Dorsal PAVG DBS may reduce pain by augmenting endogenous opioid release. Elevated gamma oscillations enhance awareness of worsening pain with opioid blockade. Ventral PAVG DBS may act by separate possibly autonomic mechanisms. Increased delta oscillations indicate a survival rhythm involved in the initiation of passive coping responses to homeostatic changes.

  • A role for the subthalamic nucleus in response inhibition during conflict.

    3 July 2018

    The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15-35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials--in which response times were elongated due to the Stroop effect--a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved.

  • Frequency specific activity in subthalamic nucleus correlates with hand bradykinesia in Parkinson's disease.

    3 July 2018

    Local field potential recordings made from the basal ganglia of patients undergoing deep brain stimulation have suggested that frequency specific activity is involved in determining the rate of force development and the peak force at the outset of a movement. However, the extent to which the basal ganglia might be involved in motor performance later on in a sustained contraction is less clear. We therefore recorded from the subthalamic nucleus region (STNr) in patients with Parkinson's disease (PD) as they made maximal voluntary grips. Relative to age-matched controls they had more rapid force decrement when contraction was meant to be sustained and prolonged release reaction time and slower rate of force offset when they were supposed to release the grip. These impairments were independent from medication status. Increased STNr power over 5-12 Hz (in the theta/alpha band) independently predicted better performance-reduced force decrement, shortened release reaction time and faster rate of force offset. In contrast, lower mean levels and progressive reduction of STNr power over 55-375 Hz (high gamma/high frequency) over the period when contraction was meant to be sustained were both strongly associated with greater force decrement over time. Higher power over 13-23 Hz (low beta) was associated with more rapid force decrement during the period when grip should have been sustained, and with a paradoxical shortening of the release reaction time. These observations suggest that STNr activities at 5-12 Hz and 55-375 Hz are necessary for optimal grip performance and that deficiencies of such activities lead to motor impairments. In contrast, increased levels of 13-25 Hz activity both promote force decrement and shorten the release reaction time, consistent with a role in antagonising (and terminating) voluntary movement. Frequency specific oscillatory activities in the STNr impact on motor performance from the beginning to the end of a voluntary grip.

  • Persistent suppression of subthalamic beta-band activity during rhythmic finger tapping in Parkinson's disease.

    3 July 2018

    OBJECTIVE: The function of synchronous oscillatory activity at beta band (15-30Hz) frequencies within the basal ganglia is unclear. Here we sought support for the hypothesis that beta activity has a global function within the basal ganglia and is not directly involved in the coding of specific biomechanical parameters of movement. METHODS: We recorded local field potential activity from the subthalamic nuclei of 11 patients with Parkinson's disease during a synchronized tapping task at three different externally cued rates. RESULTS: Beta activity was suppressed during tapping, reaching a minimum that differed little across the different tapping rates despite an increase in velocity of finger movements. Thus beta power suppression was independent of specific motor parameters. Moreover, although beta oscillations remained suppressed during all tapping rates, periods of resynchronization between taps were markedly attenuated during high rate tapping. As such, a beta rebound above baseline between taps at the lower rates was absent at the high rate. CONCLUSION: Our results demonstrate that beta desynchronization in the region of the subthalamic nucleus is independent of motor parameters and that the beta resynchronization is differentially modulated by rate of finger tapping, SIGNIFICANCE: These findings implicate consistent beta suppression in the facilitation of continuous movement sequences.

  • Stimulation of the subthalamic nucleus improves velocity of ballistic movements in Parkinson's disease.

    3 July 2018

    High-frequency stimulation of the subthalamic nucleus can markedly improve motor function in patients with Parkinson's disease. However, the underlying mechanisms mediating these improvements are not well understood. In particular, whether motor function is differentially improved in distal or proximal movements is not fully determined. Also, whether reaction time is improved along with other motor parameters is still a matter of debate. Here, we test patients OFF and ON subthalamic nucleus stimulation by capturing simple ballistic movements across four joints using kinematic motion analysis. We show that velocity, but not reaction time, is significantly improved with stimulation. There was no strong differential effect between joints. These results add evidence that deep brain stimulation of the subthalamic nucleus can enhance performance of ballistic movements in Parkinson's disease, and demonstrate that the subthalamic nucleus may be important in driving parameters of motor control after the response has been initiated.

  • Deep brain stimulation for pain.

    3 July 2018

    Deep brain stimulation (DBS) is a neurosurgical intervention whose efficacy, safety, and utility have been shown in the treatment of movement disorders. For the treatment of chronic pain refractory to medical therapies, many prospective case series have been reported, but few have published findings from patients treated during the past decade using current standards of neuroimaging and stimulator technology. We summarize the history, science, selection, assessment, surgery, and personal clinical experience of DBS of the ventral posterior thalamus, periventricular/periaqueductal gray matter, and, latterly, the rostral anterior cingulate cortex (Cg24) in 100 patients treated now at two centers (John Radcliffe Hospital, Oxford, UK, and Hospital de São João, Porto, Portugal) over 12 years. Several experienced centers continue DBS for chronic pain with success in selected patients, in particular those with pain after amputation, brachial plexus injury, stroke, and cephalalgias including anesthesia dolorosa. Other successes include pain after multiple sclerosis and spine injury. Somatotopic coverage during awake surgery is important in our technique, with cingulate DBS considered for whole-body pain or after unsuccessful DBS of other targets. Findings discussed from neuroimaging modalities, invasive neurophysiological insights from local field potential recording, and autonomic assessments may translate into improved patient selection and enhanced efficacy, encouraging larger clinical trials.

  • Wood Group

    10 July 2016

    Nucleic Acid Gene Therapy in Brain and Muscle

  • Zaccolo Group

    10 July 2016

    Cyclic Nucleotides signalling

  • Ashley Group

    10 July 2016

    The role of calcium as an intracellular second messenger in cells

  • Becker Group

    10 July 2016

    Understanding Cerebellar Development and Disease

  • Buckler Group

    10 July 2016

    Cellular mechanisms of oxygen and acid sensing in arterial chemoreceptors

  • Butt Group

    10 July 2016

    Optical probing of neural networks in the developing neocortex

  • Carr Group

    10 July 2016

    Optimising cardiac stem cell therapy by finding the best conditions for the cells in the lab and in the heart

  • Christian Group

    10 July 2016

    Glucocorticoids, Annexin 1 and the Neuroendocrine–Immune Interface

  • Clarke Group

    10 July 2016

    Diet, exercise and disease

  • Cragg Group

    10 July 2016

    Monoamine transmission: from motivation to movement