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

    28 January 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.

    23 March 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.

    19 February 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.

    2 February 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.

    25 December 2017

    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.

  • The effect of exercise on the development of respiratory depression during sustained isocapnic hypoxia in humans.

    6 March 2018

    The purpose of this study was to examine whether sustained hypoxia during exercise attenuates the degree of decline in hypoxic ventilatory sensitivity which occurs during sustained hypoxia at rest. The acute ventilatory response to hypoxia (AHVR) was used as a measure of the hypoxic ventilatory chemoreflex sensitivity. Seven subjects undertook three protocols. Protocol A was designed to assess the reduction in AHVR as a result of 20 min of isocapnic hypoxia (end-tidal PO2 50 mm Hg) at rest. The first AHVR (control) was measured on exposure to the hypoxia, and the second AHVR (test) measured 6 min after the end of the hypoxic period. Protocols B and C were designed to assess the reduction in AHVR as a result of 20 min of isocapnic hypoxic exercise (70 W). In protocol B, the AHVR (test) was measured at rest, 6 min after the end of 20 min of isocapnic hypoxic (end-tidal PO2 55 mm Hg) exercise. In protocol C, the AHVR (control) as measured at rest, 6 min after the end of 20 min of euoxic (end-tidal PO2 100 mm Hg) isocapnic exercise. There was a 30 +/- 5% decline (mean +/- SEM) in the magnitude of the AHVR after the period of sustained hypoxia at rest. There was an 11 +/- 7% decline in the magnitude of the resting AHVR after the period of sustained hypoxic exercise. The percentage change in AHVR following hypoxic exercise was significantly less than following hypoxia at rest (p < 0.05; paired t test). We conclude that the decline in hypoxic chemoreflex sensitivity which occurs during sustained hypoxia at rest is genuinely attenuated as a result of exercise.

  • Effect of pain and audiovisual stimulation on the depression of acute hypoxic ventilatory response by low-dose halothane in humans.

    8 December 2017

    BACKGROUND: The effects of different low-dose volatile agents in blunting the acute hypoxic ventilatory response (AHVR) are variable. Arousal (due to audiovisual stimulation) may prevent isoflurane-induced blunting of AHVR. The purpose of this study was to assess whether this was also the case for halothane. The authors also assessed the effects of pain on the interaction of halothane and AHVR. METHODS: Step decreases in end-tidal partial pressure of oxygen using dynamic end-tidal forcing were performed from normoxia to hypoxia (50 mmHg) in 10 healthy volunteers, with end-tidal partial pressure of carbon dioxide held 1-2 mmHg above normal, in six protocols: (1) control conditions (darkened, quiet room, eyes closed) without halothane and (2) with 0.1 minimum alveolar concentration (MAC) halothane; (3) audiovisual stimulation (bright room, loud television) without halothane and (4) with 0.1 MAC halothane; (5) pain (electrical stimulation of skin over the tibia to produce a visual analog pain score of 5-6 out of 10) without halothane and (6) with 0.1 MAC halothane. The Bispectral Index of the electroencephalogram was also monitored. RESULTS: Halothane did not affect normoxic minute ventilation in any arousal state but significantly reduced the magnitude of AHVR by 50% regardless of the background arousal state (P < 0.001). Bispectral Index values were reduced by halothane only in the absence of arousal (P < 0.003). Both pain and audiovisual stimulation modestly increased normoxic minute ventilation (P < 0.002) and AHVR (P < 0.003). CONCLUSIONS: Audiovisual stimulation does not prevent the blunting of AHVR by low-dose halothane. This result with halothane differs from previous results with isoflurane. Therefore, different anesthetics interact in different ways with arousal states. This finding raises the possibility that different anesthetics might differentially affect the hypoxic chemoreflex loop or that they might act in the brain at sites separate from the chemoreflex loop, differently to influence the wakefulness drive to ventilation.

  • The ventilatory effects of sustained isocapnic hypoxia during exercise in humans.

    26 December 2017

    To investigate how the ventilatory response to isocapnic hypoxia is modified by steady-state exercise, five subjects were studied at rest and performing 70 W bicycle exercise. At rest, isocapnic hypoxia (end-tidal PO2 50 Torr) for 25 min resulted in a biphasic response: an initial increase in ventilation was followed by a subsequent decline (HVD). During exercise, an end-tidal PO2 of 55-60 Torr was used. The magnitude of the initial ventilatory response to isocapnic hypoxia was increased from a mean +/ SE of 1.43 +/- 0.323 L/min per % arterial desaturation at rest to 2.41 +/- 0.424 L/min per % during exercise (P less than 0.05), but the magnitude of the HVD was reduced from 0.851 +/- 0.149 L/min per % at rest to 0.497 +/- 0.082 L/min per % during exercise (P less than 0.05). The ratio of HVD to the acute hypoxia response was reduced from 0.696 +/- 0.124 at rest to 0.202 +/- 0.029 during exercise (P less than 0.01). We conclude that while exercise augments the ventilatory sensitivity to hypoxia, it also has a direct effect on the mechanisms by which sustained hypoxia depresses peripheral chemosensitivity.

  • 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

  • Dorrington Group

    10 July 2016

    Human physiology: the pulmonary circulation, age, iron, and exercise