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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. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? What is the role of dorsal anterior cingulate cortex (ACC) in respiration control in humans? What is the main finding and its importance? Direct evidence is provided for a role of the ACC in respiratory control in humans. The neurophysiological responses in dorsal ACC to different breathing tasks varied and were different between left and right ACC., Abstract: The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggests an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath-holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath-holding task induced significant unilateral left-sided ACC changes in LFP power, including an increased activity in lower frequency bands (3-5 Hz) and decreased activity in higher frequency bands (12-26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO 2 ) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left-sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans., (© 2020 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

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.

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  μ V 2 /Hz) compared to resting breathing (0.77 ± 0.16  μ V 2 /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., Competing Interests: Prof Green is on an Executive Advisory Board (Movement Disorders) for Abbott and holds a consultancy agreement with Abbott. He also has a Consultancy agreement with Renishaw plc. He has given Expert testimony (unrelated) and receives Royalties from Oxford University Press (unrelated). He holds an MRC grant (unrelated to this project).

Introduction: The role of the anterior cingulate cortex (ACC) is still controversial. The ACC has been implicated in such diverse functions as cognition, arousal and emotion in addition to motor and autonomic control. Therefore the ACC is the ideal candidate to orchestrate cardiovascular performance in anticipation of perceived skeletal activity. The aim of this experiment was to investigate whether the ACC forms part of the neural network of central command whereby cardiovascular performance is governed by a top-down mechanism., Methods & Results: Direct local field potential (LFP) recordings were made using intraparenchymal electrodes in six human ACC's to measure changes in neuronal activity during performance of a motor task in which anticipation of exercise was uncoupled from skeletal activity itself. Parallel cardiovascular arousal was indexed by electrocardiographic changes in heart rate. During anticipation of exercise, ACC LFP power within the 25-60 Hz frequency band increased significantly by 21% compared to rest (from 62.7 μV 2 /Hz (±SE 4.94) to 76.0μV 2 /Hz (±SE 7.24); p = 0.004). This 25-60 Hz activity increase correlated with a simultaneous heart rate increase during anticipation (Pearson's r = 0.417, p = 0.016)., Conclusions/significance: We provide the first invasive electrophysiological evidence to support the role of the ACC in both motor preparation and the top-down control of cardiovascular function in exercise. This further implicates the ACC in the body's response to the outside world and its possible involvement in such extreme responses as emotional syncope and hyperventilation. In addition we describe the frequency at which the neuronal ACC populations perform these tasks in the human., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Both the cerebral cortex and subcortical structures play important roles in consciousness. Some evidence points to general anaesthesia-induced unconsciousness being associated with distinct patterns of superficial cortical electrophysiological oscillations, but how general anaesthetics influence deep brain neural oscillations and interactions between oscillations in humans is poorly understood., Methods: Local field potentials were recorded in discrete deep brain regions, including anterior cingulate cortex, sensory thalamus, and periaqueductal grey, in humans with implanted deep brain electrodes during induction of unconsciousness with propofol. Power-frequency spectra, phase-amplitude coupling, coherence, and directed functional connectivity analysis were used to characterise local field potentials in the awake and unconscious states., Results: An increase in alpha (7-13 Hz) power and decrease in gamma (30-90 Hz) power were observed in both deep cortical (ACC, anterior cingulate cortex) and subcortical (sensory thalamus, periaqueductal grey) areas during propofol-induced unconsciousness. Robust alpha-low gamma (30-60 Hz) phase-amplitude coupling induced by general anaesthesia was observed in the anterior cingulate cortex but not in other regions studied. Moreover, alpha oscillations during unconsciousness were highly coherent within the anterior cingulate cortex, and this rhythm exhibited a bidirectional information flow between left and right anterior cingulate cortex but stronger left-to-right flow., Conclusion: Propofol increases alpha oscillations and attenuates gamma oscillations in both cortical and subcortical areas. The alpha-gamma phase-amplitude coupling and the functional connectivity of alpha oscillations in the anterior cingulate cortex could be specific markers for loss of consciousness., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.

Deep brain stimulation of the pedunculopontine nucleus and surrounding region (PPNR) is a novel treatment strategy for gait freezing in Parkinson's disease (PD). However, clinical results have been variable, in part because of the paucity of functional information that might help guide selection of the optimal surgical target. In this study, we use simultaneous magnetoencephalography and local field recordings from the PPNR in seven PD patients, to characterize functional connectivity with distant brain areas at rest. The PPNR was preferentially coupled to brainstem and cingulate regions in the alpha frequency (8-12 Hz) band and to the medial motor strip and neighboring areas in the beta (18-33 Hz) band. The distribution of coupling also depended on the vertical distance of the electrode from the pontomesencephalic line: most effects being greatest in the middle PPNR, which may correspond to the caudal pars dissipata of the pedunculopontine nucleus. These observations confirm the crucial position of the PPNR as a functional node between cortical areas such as the cingulate/ medial motor strip and other brainstem nuclei, particularly in the dorsal pons. In particular they suggest a special role for the middle PPNR as this has the greatest functional connectivity with other brain regions., Competing Interests: Conflict of Interest: None declared.

Objective . Reduced verbal fluency is a strikingly uniform finding following deep brain stimulation (DBS) for Parkinson's disease (PD). The precise cognitive mechanism underlying this reduction remains unclear, but theories have suggested reduced motivation, linguistic skill, and/or executive function. It is of note, however, that previous reports have failed to consider the potential role of any changes in speed of processing. Thus, the aim of this study was to examine verbal fluency changes with a particular focus on the role of cognitive speed. Method . In this study, 28 patients with PD completed measures of verbal fluency, motivation, language, executive functioning, and speed of processing, before and after DBS. Results . As expected, there was a marked decline in verbal fluency but also in a timed test of executive functions and two measures of speed of processing. Verbal fluency decline was associated with markers of linguistic and executive functioning, but not after speed of processing was statistically controlled for. In contrast, greater decline in verbal fluency was associated with higher levels of apathy at baseline, which was not associated with changes in cognitive speed. Discussion . Reduced generativity and processing speed may account for the marked reduction in verbal fluency commonly observed following DBS.

Background: Traumatic brain injury (TBI) is a worldwide health concern associated with significant morbidity and mortality. In the United States, severe TBI is managed according to recommendations set forth in 2007 by the Brain Trauma Foundation (BTF), which were based on relatively low quality clinical trials. These guidelines prescribed the use of hypothermia for the management of TBI. Several randomized controlled trials (RCTs) of hypothermia for TBI have since been conducted. Despite this new literature, there is ongoing controversy surrounding the use of hypothermia for the management of severe TBI., Methods: We searched the PubMed database for all RCTs of hypothermia for TBI since 2007 with the intent to review the methodology outcomes of these trials. Furthermore, we aimed to develop evidence-based, expert opinions based on these recent studies., Results: We identified 8 RCTs of therapeutic hypothermia published since 2007 that focused on changes in neurologic outcomes or mortality in patients with severe TBI. The majority of these trials did not identify improvement with the use of hypothermia, though there were subgroups of patients that may have benefited from hypothermia. Differences in methodology prevented direct comparison between studies., Conclusions: A growing body of literature disfavors the use of hypothermia for the management of severe TBI. In general, empiric hypothermia for severe TBI should be avoided. However, based on the results of recent trials, there may be some patients, such as those in Asian centers or with focal neurologic injury, who may benefit from hypothermia., Competing Interests: There are no conflicts of interest.

Objectives: Documentation of urgent referrals to neurosurgical units and communication with referring hospitals is critical for effective handover and appropriate continuity of care within a tertiary service. Referrals to our neurosurgical unit were audited and we found that the majority of referrals were not documented and this led to more calls to the on-call neurosurgery registrar regarding old referrals. We implemented a new referral system in an attempt to improve documentation of referrals, communication with our referring hospitals and to professionalise the service we offer them., Methods: During a 14-day period, number of bleeps, missed bleeps, calls discussing new referrals and previously processed referrals were recorded. Whether new referrals were appropriately documented and referrers received a written response was also recorded. A commercially provided secure cloud-based data archiving telecommunications and database platform for referrals was subsequently introduced within the Trust and the questionnaire repeated during another 14-day period 1 year after implementation., Results: Missed bleeps per day reduced from 16% (SD ± 6.4%) to 9% (SD ± 4.8%; df = 13, paired t-tests p = 0.007) and mean calls per day clarifying previous referrals reduced from 10 (SD ± 4) to 5 (SD ± 3.5; df = 13, p = 0.003). Documentation of new referrals increased from 43% (74/174) to 85% (181/210), and responses to referrals increased from 74% to 98%., Conclusion: The use of a secure cloud-based data archiving telecommunications and database platform significantly increased the documentation of new referrals. This led to fewer missed bleeps and fewer calls about old referrals for the on call registrar. This system of documenting referrals results in improved continuity of care for neurosurgical patients, a significant reduction in risk for Trusts and a more efficient use of Registrar time.

Background: Magnetic resonance imaging (MRI)-verified deep brain stimulation relies on the correct interpretation of stereotactic imaging documenting lead location in relation to visible anatomic target. However, it has been suggested that local signal distortion from the lead itself renders its depiction on MRI unreliable., Objective: To compare lead location on stereotactic MRI with subsequent location of its brain track after removal., Methods: Patients underwent deep brain stimulation with the use of MRI-guided and MRI-verified Leksell frame approach. Infection or suboptimal efficacy required lead removal and subsequent reimplantation by using the same technique. Postimplantation stereotactic MR images were analyzed. Lateral (x) and anteroposterior (y) distances from midcommissural point to center of the lead hypointensity were recorded at the anterior commissure-posterior commissure plane (pallidal electrode) or z = -4 (subthalamic electrode). Stereotactic MRI before the second procedure, x and y distances from the center of the visible lead track hypointensity to midcommissural point were independently recorded. Vectorial distance from center of the lead hypointensity to the center of its track was calculated., Results: Sixteen electrode tracks were studied in 10 patients. Mean differences between lead artifact location and lead track location were: x coordinate 0.4 mm ± 0.2; y coordinate 0.6 mm ± 0.3. Mean vectorial distance was 0.7 mm ± 0.2., Conclusion: Stereotactic distance between lead location and subsequent brain track location on MRI was small. The mean discrepancy was approximately half the deep brain stimulation lead width. This suggests that lead hypointensity seen on postimplantation MRI is indeed an accurate representation of its real location within deep brain structures.

Introduction: Deep brain stimulation (DBS) can provide dramatic essential tremor (ET) relief, however no Class I evidence exists., Materials and Methods: Analysis methods: I) traditional cohort analysis; II) N-of-1 single patient randomised control trial and III) signal-to-noise (S/N) analysis. 20 DBS electrodes in ET patients were switched on and off for 3-min periods. Six pairs of on and off periods in each case, with the pair order determined randomly. Tremor severity was quantified with tremor evaluator and patient was blinded to stimulation. Patients also stated whether they perceived the stimulation to be on after each trial., Results: I) Mean end-of-trial tremor severity 0.84 out of 10 on, 6.62 Off, t = - 13.218, p < 0.0005. II) N-of-1: 60% of cases had 12 correct perceptions (p = 0.001), 20% had 11 correct perceptions (p = 0.013). III) S/N: > 80% tremor reduction occurred in 99/114 'On' trials (87%), and 3/114 'Off' trials (3%). S/N ratio for 80% improvement with DBS versus spontaneous improvement was 487,757-to-1., Conclusions: DBS treatment effect on ET is too large for bias to be a plausible explanation. Formal N-of-1 trial design, and S/N ratio method for presenting results, allows this to be demonstrated convincingly where conventional randomised controlled trials are not possible., Classification of Evidence: This study is the first to provide Class I evidence for the efficacy of DBS for ET.

Object: Bibliometrics are the methods used to quantitatively analyze scientific literature. In this study, bibliometrics were used to quantify the scientific output of neurosurgical departments throughout Great Britain and Ireland., Methods: A list of neurosurgical departments was obtained from the Society of British Neurological Surgeons website. Individual departments were contacted for an up-to-date list of consultant (attending) neurosurgeons practicing in these departments. Scopus was used to determine the h-index and m-quotient for each neurosurgeon. Indices were measured by surgeon and by departmental mean and total. Additional information was collected about the surgeon's sex, title, listed superspecialties, higher research degrees, and year of medical qualification., Results: Data were analyzed for 315 neurosurgeons (25 female). The median h-index and m-quotient were 6.00 and 0.41, respectively. These were significantly higher for professors (h-index 21.50; m-quotient 0.71) and for those with an additional MD or PhD (11.0; 0.57). There was no significant difference in h-index, m-quotient, or higher research degrees between the sexes. However, none of the 16 British neurosurgery professors were female. Neurosurgeons who specialized in functional/epilepsy surgery ranked highest in terms of publication productivity. The 5 top-scoring departments were those in Addenbrooke's Hospital, Cambridge; St. George's Hospital, London; Great Ormond Street Hospital, London; National Hospital for Neurology and Neurosurgery, Queen Square, London; and John Radcliffe Hospital, Oxford., Conclusions: The h-index is a useful bibliometric marker, particularly when comparing between studies and individuals. The m-quotient reduces bias toward established researchers. British academic neurosurgeons face considerable challenges, and women remain underrepresented in both clinical and academic neurosurgery in Britain and Ireland.

Background: Bilateral anterior cingulotomy is a palliative procedure occasionally used for cancer pain, and human studies suggest anterior cingulate cortex is active in dyspnoeic states., Objectives: A case of debilitating thoracic wall pain due to malignant mesothelioma relieved by bilateral anterior cingulotomy is described and changes in dyspnoea investigated., Results: Improvements in pain, dyspnoea and the extent to which either symptom bothered the patient was seen for 2 months after surgery before disease progression led to death 5 months after surgery. Quality of life improvements were also seen for 2 months after surgery and pain relief was sustained from surgery to death. Arterial blood gas and lung function tests were unchanged by surgery, suggesting a reduction in pain and dyspnoea awareness by cingulotomy., Conclusions: Bilateral anterior cingulotomy effectively relieved both pain and dyspnoea. The role of the anterior cingulate cortex in pain and autonomic control of respiration is discussed alongside the evidence for this palliative procedure for cancer pain.

Infant vocalizations are among the most biologically salient sounds in the environment and can draw the listener to the infant rapidly in both times of distress and joy. A region of the midbrain, the periaqueductal gray (PAG), has long been implicated in the control of urgent, survival-related behaviours. To test for PAG involvement in the processing of infant vocalizations, we recorded local field potentials from macroelectrodes implanted in this region in four adults who had undergone deep brain stimulation. We found a significant difference occurring as early as 49 ms after hearing a sound in activity recorded from the PAG in response to infant vocalizations compared with constructed control sounds and adult and animal affective vocalizations. This difference was not present in recordings from thalamic electrodes implanted in three of the patients. Time frequency analyses revealed distinct patterns of activity in the PAG for infant vocalisations, constructed control sounds and adult and animal vocalisations. These results suggest that human infant vocalizations can be discriminated from other emotional or acoustically similar sounds early in the auditory pathway. We propose that this specific, rapid activity in response to infant vocalizations may reflect the initiation of a state of heightened alertness necessary to instigate protective caregiving., (© The Author (2013). Published by Oxford University Press.)

Neurosurgery can alter cardiorespiratory performance via central networks and includes deep brain stimulation (DBS), a routinely employed therapy for movement disorders and chronic pain syndromes. We review the established cardiovascular effects of DBS and the presumed mechanism by which they are produced via the central autonomic network. We then review the respiratory effects of DBS, including modulation of respiratory rate and lung function indices, and the mechanisms via which these may occur. We conclude by highlighting the potential future therapeutic applications of DBS for intractable airway diseases., (© 2014 Elsevier B.V. All rights reserved.)

Most of the time the bladder is locked in storage mode, switching to voiding only when it is judged safe and/or socially appropriate to urinate. Here we show, in humans and rodents, that deep brain stimulation in the periaqueductal gray matter can rapidly and reversibly manipulate switching within the micturition control circuitry, to defer voiding and maintain urinary continence, even when the bladder is full. Manipulation of neural continence pathways by deep brain stimulation may offer new avenues for the treatment of urinary incontinence of central origin., (Copyright © 2012 American Neurological Association.)

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.

Background: Deep brain stimulation (DBS) of subcortical brain areas such as the periaqueductal grey and subthalamic nucleus has been shown to alter cardiovascular autonomic performance. The supramedullary circuitry controlling respiratory airways is not well defined and has not been tested in humans., Objective: To use direct electric stimulation via DBS macroelectrodes to test whether airway resistance could be manipulated by these areas in awake humans., Methods: Thirty-seven patients with in-dwelling deep brain electrodes for movement disorders or chronic pain underwent spirometry according to the European Respiratory Society guidelines. Testing was performed randomly 3 times on stimulation and 3 times off stimulation; patients were blinded to the test. Thoracic diameter changes were measured by a circumferential pressure-sensitive thoracic band. Ten periaqueductal grey and 10 subthalamic nucleus patients were tested. To control for confounding pain and movement disorder relief, the sensory thalamus in 7 patients and globus pallidus interna in 10 patients, respectively, were also tested., Results: Peak expiratory flow rate (PEFR) increased significantly with periaqueductal grey and subthalamic nucleus stimulation by up to 14% (P = .02 and .005, respectively, paired-samples Student t tests). Stimulation of control nuclei produced no significant PEFR change. Similarly, changes in thoracic diameter reflecting skeletal activity rather than airway caliber did not correlate with the improvement in PEFR. Forced expiratory volume in 1 second was unchanged by stimulation., Conclusion: DBS can improve PEFR in chronic pain and movement disorder patients. This finding provides insights into the neural modulation of respiratory performance and may explain some of the subjective benefits of DBS.

The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinson's disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress 'task irrelevant' distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects.

Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON) and compared with pain experienced with no stimulation (DBS OFF). We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray) and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain.

Background: Targeting of the motor thalamus for the treatment of tremor has traditionally been achieved by a combination of anatomical atlases and neuroimaging, intraoperative clinical assessment, and physiological recordings., Objective: To evaluate whether thalamic nuclei targeted in tremor surgery could be identified by virtue of their differing connections with noninvasive neuroimaging, thereby providing an extra factor to aid successful targeting., Methods: Diffusion tensor tractography was performed in 17 healthy control subjects using diffusion data acquired at 1.5-T magnetic resonance imaging (60 directions, b value = 1000 s/mm, 2 × 2 × 2-mm³ voxels). The ventralis intermedius (Vim) and ventralis oralis posterior (Vop) nuclei were identified by a stereotactic neurosurgeon, and these sites were used as seeds for probabilistic tractography. The expected cortical connections of these nuclei, namely the primary motor cortex (M1) and contralateral cerebellum for the Vim and M1, the supplementary motor area, and dorsolateral prefrontal cortex for the Vop, were determined a priori from the literature., Results: Tractogram signal intensity was highest in the dorsolateral prefrontal cortex and supplementary motor area after Vop seeding (P < .001, Wilcoxon signed-rank tests). High intensity was seen in M1 after seeding of both nuclei but was greater with Vim seeding (P < .001). Contralateral cerebellar signal was highest with Vim seeding (P < .001)., Conclusion: Probabilistic tractography can depict differences in connectivity between intimate nuclei within the motor thalamus. These connections are consistent with published anatomical studies; therefore, tractography may provide an important adjunct in future targeting in tremor surgery.

Background: Pedunculopontine nucleus (PPN) stimulation is a novel therapy for Parkinson disease. However, controversies remain regarding the clinical application of this new therapy, including patient selection, electrode positioning, and how best to assess outcomes., Objective: To clarify the clinical application of PPN stimulation in Parkinson disease., Methods: Five consecutive patients with Parkinson disease complicated by severe gait freezing, postural instability, and frequent falls (all persisting even while the patient was on medication) received bilateral stimulation of the mid-lower PPN without costimulation of other brain targets. Outcomes were assessed prospectively over 2 years with gait-specific questionnaires and the Unified Parkinson Disease Rating Scale (part III)., Results: The primary outcome, the Gait and Falls Questionnaire score, improved significantly with stimulation. Benefits were maintained over 2 years. Unified Parkinson Disease Rating Scale (part III) items assessing gait and posture were relatively insensitive to these treatment effects. Beneficial effects often appeared to outlast stimulation for hours or longer. Thus, single-session on- vs off-stimulation assessments may be susceptible to "delayed washout effects." Stimulation of the PPN did not change akinesia scores or dopaminergic medication requirements., Conclusion: Bilateral stimulation of the mid-lower PPN (more caudal than previous reports) without costimulation of other brain targets may be beneficial for the subgroup of patients with Parkinson disease who experience severe gait freezing and postural instability with frequent falls, which persist even while on medication. Choosing appropriate outcome measures and accounting for the possibility of prolonged stimulation washout effects appear to be important for detecting the clinical benefits.

Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli--a phenomenon known as 'StartReact'. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation.

Emotion and reward have been proposed to be closely linked to conscious experience, but empirical data are lacking. The anterior cingulate cortex (ACC) plays a central role in the hedonic dimension of conscious experience; thus potentially a key region in interactions between emotion and consciousness. Here we tested the impact of emotion on conscious experience, and directly investigated the role of the ACC. We used a masked paradigm that measures conscious reportability in terms of subjective confidence and objective accuracy in identifying the briefly presented stimulus in a forced-choice test. By manipulating the emotional valence (positive, neutral, negative) and the presentation time (16 ms, 32 ms, 80 ms) we measured the impact of these variables on conscious and subliminal (i.e. below threshold) processing. First, we tested normal participants using face and word stimuli. Results showed that participants were more confident and accurate when consciously seeing happy versus sad/neutral faces and words. When stimuli were presented subliminally, we found no effect of emotion. To investigate the neural basis of this impact of emotion, we recorded local field potentials (LFPs) directly in the ACC in a chronic pain patient. Behavioural findings were replicated: the patient was more confident and accurate when (consciously) seeing happy versus sad faces, while no effect was seen in subliminal trials. Mirroring behavioural findings, we found significant differences in the LFPs after around 500 ms (lasting 30 ms) in conscious trials between happy and sad faces, while no effect was found in subliminal trials. We thus demonstrate a striking impact of emotion on conscious experience, with positive emotional stimuli enhancing conscious reportability. In line with previous studies, the data indicate a key role of the ACC, but goes beyond earlier work by providing the first direct evidence of interaction between emotion and conscious experience in the human ACC.

Groups III and IV afferents carry sensory information regarding the muscle exercise pressor reflex, although the central integrating circuits of the reflex in humans are still poorly defined. Emerging evidence reports that the periaqueductal gray (PAG) could be a major site for integrating the "central command" component that initiates the cardiovascular response to exercise, since this area is activated during exercise and direct stimulation of the dorsal PAG causes an increase in arterial blood pressure (ABP) in humans. Here we recorded local field potentials (LFPs) from various "deep" brain nuclei during exercise tasks designed to elicit the muscle pressor reflex. The patients studied had undergone neurosurgery for the treatment of movement or pain disorders, thus had electrodes implanted stereotactically either in the PAG, subthalamic nucleus, globus pallidus interna, thalamus, hypothalamus, or anterior cingulate cortex. Fast Fourier transform analysis was applied to the neurograms to identify the power of fundamental spectral frequencies. Our PAG patients showed significant increases in LFP power at frequencies from 4 to 8 Hz (P < 0.01), 8 to 12 Hz (P < 0.001), and 12 to 25 Hz (P < 0.001). These periods were associated with maintained elevated ABP during muscle occlusion following exercise. Further increases in exercise intensity resulted in corresponding increases in PAG activity and ABP. No significant changes were seen in the activity of other nuclei during occlusion. These electrophysiological data provide direct evidence for a role of the PAG in the integrating neurocircuitry of the exercise pressor reflex in humans.

Objectives: Pallidal stimulation and pallidotomy are known to improve the symptoms of Parkinson's disease (PD). However, it is not known which modality produces greater benefit in patients who have already undergone unilateral pallidotomy. It is also suggested that the original pallidal surgery provides a greater benefit than subsequent pallidal surgery. The aim of this study was to analyze which modality produced greater PD symptom improvement in patients with a prior pallidotomy and whether the chronological order of the pallidal surgery influenced the size of the improvement., Methods: Five patients who had undergone a prior unilateral pallidotomy for PD were studied. Because of ongoing Parkinsonian symptoms, all patients subsequently underwent contralateral pallidal surgery, either a further pallidotomy or pallidal stimulation. All surgeries were performed by a single functional neurosurgeon and the patients prospectively assessed and scored at routine follow-ups. Paired-sample t-tests were used to detect differences in outcomes after first and second surgeries., Results: Two patients underwent pallidal stimulation and three underwent a second pallidotomy. Mean follow-up was 13.5 months and 12.3 months, respectively. Greater percentage improvements in the majority of scores were found after pallidal stimulation compared with a second pallidotomy, namely Unified Parkinson's Disease Rating Scale (UPDRS) II off (25.22% vs. -3.27%), UPDRS III off (36.15% vs. 5.21%), rigidity (58.34% vs. 11.54%), tremor (5.56% vs. -30.48%), bradykinesia (48.55% vs. -2.23%), gait composite (16.52% vs. -51.79%), dyskinesia duration (83.33% vs. 66.67%), dyskinesia disability (100% vs. 66.67%), speech (10% vs. -50%), and the proportion of the day spent in the "off" state (50% vs. 25%). Comparing outcomes after the first surgery to those after the second surgery, statistical differences were found in dyskinesia duration improvement and ipsilateral dyskinesia improvement after the second surgery (p < 0.004 and p = 0.021, respectively)., Conclusions: Pallidal stimulation produced greater symptom improvement than a second pallidotomy and subsequent surgery did not produce inferior results to the original pallidal surgery., (© 2010 International Neuromodulation Society.)

Infection in the context of implant surgery is a dreaded complication, usually necessitating the removal of all affected hardware. Severe dystonia is a debilitating condition that can present as an emergency and can occasionally be life threatening. The authors present 2 cases of severe dystonia in which deep brain stimulation was maintained despite the presence of infection, using ongoing stimulation by externalization of electrode wires and an extracorporeal pulse generator. This allowed the infection to clear and wounds to heal while maintaining stimulation. This strategy is similar to that used in the management of infected cardiac pacemakers. The authors suggest that this prolonged extracorporeal stimulation should be considered by neurosurgeons in the face of this difficult clinical situation.

Introduction:   Deep brain stimulation applied to the periaqueductal grey matter (PAG) of the midbrain in humans has been shown to increase or decrease arterial blood pressure during rest and to resist the postural fall on standing. The mechanism by which this effect is elicited is unknown. We hypothesize that PAG stimulation modulates performance of the autonomic nervous system., Methods:   Five consecutive male patients of a mean age of 49.1 years underwent PAG stimulation for intractable pain syndromes. Intra-operatively, blood pressure and heart rate were recorded continuously while patients were awake (four patients) or under general anesthesia (one patient). Recordings were made for 100 sec before stimulation, 100 sec during stimulation at one or two electrode locations within the PAG, and for 100 sec after stimulation., Results:   Stimulation altered not only systolic and diastolic blood pressure but also heart rate. During stimulation, systolic blood pressure increased in three electrode positions by 7.2-10.2 mmHg, decreased in two electrode positions by 3.1-11.5 mmHg, and was unchanged in two electrode positions. Heart rate variability also changed during stimulation. Percentage systolic blood pressure change was positively correlated with change in high-frequency power (Pearson's r= 0.685, p= 0.09, N= 7), low-frequency : high-frequency power ratio (r= 0.667, p= 0.10, N= 7), and low-frequency power (r= 0.818, p= 0.02, N= 7), the latter of which was statistically significant. The percentages of the variance explained (r(2)) were 46.9, 44.5, and 66.9, respectively., Conclusions:   PAG stimulation modulates autonomic nervous system activity and thereby elicits changes in cardiovascular performance. Understanding of the mechanisms by which this therapy causes cardiovascular modulation will inform future innovation in this field with the aim of improving the efficacy and safety of patient treatment options., (© 2010 International Neuromodulation Society.)

Background: The midbrain periaqueductal grey (PAG) area is important for both pain modulation and cardiovascular control via the autonomic nervous system (ANS). While changes in blood pressure dependent upon dorsal or ventral electrode positioning have been described with PAG deep brain stimulation (DBS), little is known mechanistically about the relationships between pain and cardiovascular regulation in humans. Heart rate variability (HRV) is an established measure of cardiovascular regulation, and an index of autonomic function., Methods and Results: 16 patients undergoing DBS of the rostral PAG for chronic neuropathic pain were investigated post-operatively to determine whether PAG stimulation would alter HRV, and the subjects' perception of pain. Mean heart rate together with HRV, time and frequency domain measures, low frequency (LF) and high frequency (HF) power components of heart rate and the ratio of LF to HF were calculated before and during DBS. Ventral but not dorsal PAG DBS significantly decreased the ratio of LF to HF power (p<0.05, n=8) with HF power significantly increased. Changes in LF/HF ratio correlated significantly with subjective reporting of analgesic efficacy using a visual analogue score (VAS; gamma(2)=0.36, p=0.01, n=16). Diffusion tensor imaging and probabilistic tractography of 17 normal controls' seeding voxels from the mean ventral and dorsal PAG stimulation sites of the 16 patient cohort revealed significant differences between rostral tract projections and separate, adjacent projections to ipsilateral dorsolateral medulla., Conclusions: Ventral PAG DBS may increase parasympathetic activity to reduce pain via anatomical connections distinct from dorsal PAG DBS, which may act by sympathetic mechanisms., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

In this paper, we present an analysis of magnetoencephalography (MEG) signals from a patient with whole-body chronic pain in order to investigate changes in neural activity induced by DBS. The patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). Using MEG to reconstruct the neural activity of interest is challenging because of interference to the signal from the DBS device. We demonstrate that a null-beamformer can be used to localise neural activity despite artefacts caused by the presence of DBS electrodes and stimulus pulses. We subsequently verified the accuracy of our source localisation by correlating the predicted DBS electrode positions with their actual positions, previously identified using anatomical imaging. We also demonstrated increased activity in pain-related regions including the pre-supplementary motor area, brainstem periaqueductal gray and medial prefrontal areas when the patient was in pain compared to when the patient experienced pain relief.

Clinical Report: We report the case of a 56 year-old woman who presented with worsening speech and poor seizure control eleven years after undergoing wrapping of a middle cerebral artery aneurysm. Radiological and histological findings were consistent with a muslin granuloma with a large cystic component. The cyst was drained endoscopically and an Omaya reservoir placed. The patient's speech improved and so did their seizure control., Discussion: This is the first case in which this rare complication of aneurysm surgery has caused speech deterioration. This is also the first case in which neuroendoscopy has been successfully employed to obtain tissue for diagnosis and to treat such a lesion.

We present the case of an unexpected response by the cerebral vasculature to bypass surgery. A 66-year-old man sustained a subarachnoid haemorrhage and cerebral angiography showed a large fusiform anterior communicating artery (ACoA) aneurysm and an anomalous anterior circulation. The right A1 segment was hypoplastic and blood supply to the entire right A2 was from the left anterior circulation via the ACoA. The aneurysm was therefore not amenable to endovascular coiling or surgical clipping alone. An extracranial-intracranial bypass was performed to revascularize the territory of the right A2 independently of the ACoA to allow the latter vessel to be clipped. Although the bypass graft was patent on post-operative cerebral angiography, it was in fact only perfusing a limited, peripheral anterior cerebral artery territory. The bulk of the right anterior circulation was derived retrogradely by latent collaterals from the internal carotid and ophthalmic arteries via small dural vessels which were not apparent prior to surgery.

We present the first case of spontaneous otogenic pneumocephalus presenting with a rapid deterioration in conscious level. This occurred in a 69-year-old woman who was subsequently treated with a subtemporal, extradural exploration and packing of the multiple defects in the mastoid air cells. The patient made a full neurological recovery within 10 weeks. Spontaneous otogenic pneumocephalus is a rare condition and was previously understood to present with subtle symptoms of headache, aphasia and cognitive deficits. This case, however, establishes how it can cause a rapid decline towards coma.

Tremor in multiple sclerosis is considered to be a persistent and progressive sign. We describe five patients with multiple sclerosis in whom upper limb tremor severity gradually decreased over a period of several years after deep brain stimulation. In every case this attenuation of tremor was accompanied by increasing pyramidal weakness in the relevant upper limb. In two patients this attenuation of tremor remained after stimulation was permanently switched off. In one other patient, where upper limb strength remained normal, tremor severity gradually worsened in spite of continuing stimulation. There was a highly significant difference (p = 0.0007) between the changes in intention tremor severities when the arms with increasing pyramidal weakness (n = 9) were compared to those in which normal strength was retained throughout follow-up period (n = 3); intention tremor decreased in the former and increased in the latter by means of -3.66 and +4.0 points of a 0-10 tremor scale respectively. There was also a significant correlation (0.699; p = 0.0359) between decreasing upper limb strength and decreasing intention tremor severity for the upper limbs of patients that had undergone contralateral DBS.