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Pain perception can be altered by activity in the periaqueductal gray (PAG). The PAG can decrease the incoming nociceptive signals at the level of the spinal dorsal horn, but it is not clear whether the PAG can also affect the sensory thalamus, ventral posterolateral and ventral posteromedial thalamic nuclei, to modulate pain. However, the PAG and the thalamus have direct connections with each other; so we postulated that the PAG may also modulate pain by inhibiting the sensory nuclei in the thalamus, and that these may also reciprocally influence the PAG. Here, by analyzing the local field potentials recorded from the sensory thalamus and the PAG in chronic pain patients with deep brain stimulation electrodes, we show that PAG stimulation inhibited the sensory thalamus with decreasing thalamic delta, theta, alpha and beta power, and sensory thalamus stimulation excited the PAG with increasing PAG delta and theta power. We demonstrate that the PAG and the sensory thalamus interact reciprocally at short latency, which may be related to pain modulation. © 2013 Springer-Verlag Berlin Heidelberg.

Deep brain stimulators were implanted in the left periaqueductal gray matter (PAG) and sensory thalamus for right sided neuropathic facial pain refractory to other treatments in a man aged 58 years. PAG stimulation 8 months later acutely reduced systolic blood pressure by 25 mm Hg during revision surgery. One year post procedure, ambulatory blood pressure monitoring demonstrated significant and sustained reduction in blood pressure with PAG stimulation. Mean systolic blood pressure decreased by 12.6 mm Hg and diastolic by 11.0 mm Hg, alongside reductions in variability of heart rate and pulse pressure. This neurosurgical treatment may prove beneficial for medically refractory hypertension.

The periaqueductal grey area (PAG) in the midbrain is an important area for both cardiovascular control and modulation of pain. However, the precise relationship between pain and blood pressure is unknown. We prospectively studied 16 patients undergoing deep brain stimulation of the rostral PAG for chronic pain. Pre-operatively, post-operatively, and at 1 year, pain scores were assessed using both visual analogue scores and the McGill Pain Questionnaire. Patients were tested post-operatively to determine whether electrical stimulation of the PAG would modulate blood pressure. We found that the degree of analgesia induced by deep brain stimulation of the rostral PAG in man is related to the magnitude of reduction in arterial blood pressure. We found that this relationship is linear and is related to reduced activity of the sympathetic nervous system. Thus stimulation of the PAG may partly control pain by reducing sympathetic activity as predicted by William James over a century ago.

BACKGROUND: Parkinson's disease (PD) is a debilitating illness associated with considerable impairment of quality of life and substantial costs to health care systems. Deep brain stimulation (DBS) is an established surgical treatment option for some patients with advanced PD. The EARLYSTIM trial has recently demonstrated its clinical benefit also in patients with early motor complications. We sought to evaluate the cost-effectiveness of DBS, compared to best medical therapy (BMT), among PD patients with early onset of motor complications, from a United Kingdom (UK) payer perspective.METHODS: We developed a Markov model to represent the progression of PD as rated using the Unified Parkinson's Disease Rating Scale (UPDRS) over time in patients with early PD. Evidence sources were a systematic review of clinical evidence; data from the EARLYSTIM study; and a UK Clinical Practice Research Datalink (CPRD) dataset including DBS patients. A mapping algorithm was developed to generate utility values based on UPDRS data for each intervention. The cost-effectiveness was expressed as the incremental cost per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were undertaken to explore the effect of parameter uncertainty.RESULTS: Over a 15-year time horizon, DBS was predicted to lead to additional mean cost per patient of £26,799 compared with BMT (£73,077/patient versus £46,278/patient) and an additional mean 1.35 QALYs (6.69 QALYs versus 5.35 QALYs), resulting in an incremental cost-effectiveness ratio of £19,887 per QALY gained with a 99% probability of DBS being cost-effective at a threshold of £30,000/QALY. One-way sensitivity analyses suggested that the results were not significantly impacted by plausible changes in the input parameter values.CONCLUSION: These results indicate that DBS is a cost-effective intervention in PD patients with early motor complications when compared with existing interventions, offering additional health benefits at acceptable incremental cost. This supports the extended use of DBS among patients with early onset of motor complications.

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. Ann Neurol 2012;72:144–147

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

Up to one-third of all patients with epilepsy have epilepsy refractory to medical therapy. Surgical options include temporal lobectomy, focal neocortical resection, stereotactic lesioning and neurostimulation. Neurostimulatory options comprise vagal nerve stimulation, trigeminal nerve stimulation and deep brain stimulation (DBS). DBS enables structures in the brain to be stimulated electrically by an implanted pacemaker after a minimally invasive neurosurgical procedure and has become the therapy of choice for Parkinson's disease refractory to or complicated by drug therapy. Here we review DBS for epilepsy, a powerful emerging treatment in the surgical armamentarium for drug refractory epilepsy, with a focus on extratemporal epilepsy. © 2011 Elsevier Ltd. All rights reserved.

There are abundant animal data attempting to identify the neural circuitry involved in cardiovascular control. Translating this research into humans has been made possible using functional neurosurgery during which deep brain stimulating electrodes are implanted into various brain nuclei for the treatment of chronic pain and movement disorders. This not only allows stimulation of the human brain, but also presents the opportunity to record neural activity from various brain regions. This symposium review highlights key experiments from the past decade that have endeavoured to identify the neurocircuitry responsible for integrating the cardiovascular response to exercise in humans. Two areas of particular interest are highlighted: the periaqueductal grey and the subthalamic nucleus. Our studies have shown that the periaqueductal grey (particularly the dorsal column) is a key part of the neurocircuitry involved in mediating autonomic changes adapted to ongoing behaviours. Emerging evidence also suggests that the subthalamic nucleus is not only involved in the control of movement, but also in the mediation of cardiovascular responses. Although these sites are unlikely to be the 'command' areas themselves, we have demonstrated that the two nuclei have the properties of being key integrating sites between the feedback signals from exercising muscle and the feedforward signals from higher cortical centres.

High-angle climbing is a physically and cognitively challenging activity. Whilst researchers have examined the physiological demands of climbing, the cognitive demands have been relatively neglected. In this experiment, we examined the performance of climbers when required to perform a dual climbing and word memory task, relative to single-task performance (word memory or climbing alone). Whilst there was no significant decrease in climbing distance during the dual-task condition, climbing efficiency was impaired, as was word recall. Participants' Energetic Arousal, Tense Arousal and Task-unrelated Thoughts (TUTs) all changed dependent on the condition, with arousal increasing after the climbing conditions, and TUTs decreasing after the memory-load conditions. These results could be expanded on in future research to examine the physical and cognitive demands of high-angle climbing in greater detail.

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

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.

The remarkable efficacy of deep brain stimulation (DBS) for a range of treatment-resistant disorders is still not matched by a comparable understanding of the underlying neural mechanisms. Some progress has been made using translational research with a range of neuroscientific techniques, and here we review the most promising emerging principles. On balance, DBS appears to work by restoring normal oscillatory activity between a network of key brain regions. Further research using this causal neuromodulatory tool may provide vital insights into fundamental brain function, as well as guide targets for future treatments. In particular, DBS could have an important role in restoring the balance of the brain’s default network and thus repairing the malignant brain states associated with affective disorders, which give rise to serious disabling problems such as anhedonia, the lack of pleasure. At the same time, it is important to proceed with caution and not repeat the errors from the era of psychosurgery.

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.

A rare case is described of acute disseminated intravascular coagulation (DIC) following isolated mild head injury with acute subdural haematoma, coagulopathy onset preceding craniotomy. Surgical treatment of the cause followed by swift diagnosis and treatment soon after surgery enabled a good outcome. Post-operative recollection of subdural and extadural blood was treated by further surgery. DIC following isolated mild head injury without axonal damage is rare, but fatal if missed. Thrombocytopaenia in head injured patients should be investigated expediently. Post-operative interim imaging (if not standard practice) should also be considered to exclude haemorrhagic recollection requiring further surgery.

The history of stereotactic neurosurgery in the United Kingdom of Great Britain and Northern Ireland is reviewed. Horsley and Clarke's primate stereotaxy at the turn of the 20th century and events surrounding it are described, including Mussen's development of a human version of the apparatus. Stereotactic surgery after the Second World War is reviewed, with an emphasis on the pioneering work of Gillingham, Hitchcock, Knight, and Watkins and the contributions from Bennett, Gleave, Hughes, Johnson, McKissock, McCaul, and Dutton after the influences of Dott, Cairns, and Jefferson. Forster's introduction of gamma knife radiosurgery is summarized, as is the application of computed tomography by Hounsfield and Ambrose. Contemporary contributions to the present day from Bartlett, Richardson, Miles, Thomas, Gill, Aziz, Hariz, and others are summarized. The current status of British stereotactic neurosurgery is discussed.

The security of medical devices is critical to good patient care, especially when the devices are implanted. In light of recent developments in information security, there is reason to be concerned that medical implants are vulnerable to attack. The ability of attackers to exert malicious control over brain implants ("brainjacking") has unique challenges that we address in this review, with particular focus on deep brain stimulation implants. To illustrate the potential severity of this risk, we identify several mechanisms through which attackers could manipulate patients if unauthorized access to an implant can be achieved. These include blind attacks in which the attacker requires no patient-specific knowledge and targeted attacks that require patient-specific information. Blind attacks include cessation of stimulation, draining implant batteries, inducing tissue damage, and information theft. Targeted attacks include impairment of motor function, alteration of impulse control, modification of emotions or affect, induction of pain, and modulation of the reward system. We also discuss the limitations inherent in designing implants and the trade-offs that must be made to balance device security with battery life and practicality. We conclude that researchers, clinicians, manufacturers, and regulatory bodies should cooperate to minimize the risk posed by brainjacking.

A functioning thalamus is essential for treatment of patients with disorders of consciousness (DOC) using deep brain stimulation (DBS). This work aims to identify the potential biomarkers related to consciousness from the thalamic deep brain local field potentials (LFPs) in DOC patients. The frequency features of central thalamic LFPs were characterized with spectral analysis. The features were further compared to those of LFPs from the ventroposterior lateral nucleus of the thalamus (VPL) in patients with pain. There are several distinct characteristics of thalamic LFPs found in patients with DOC. The most important feature is the oscillation around 10Hz which could be relevant to the existence of residual consciousness, whereas high power below 8Hz seemed to be associated with loss of consciousness. The invasive deep brain recording tool opens a unique way to explore the brain function in consciousness, awareness and alertness and clarify the potential mechanisms of thalamic stimulation in DOC.

Deep brain stimulation 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 for Parkinson's disease, refractory to, or complicated by, drug therapy. Its efficacy has been demonstrated robustly by randomized, controlled clinical trials, with multiple novel brain targets having been discovered in the last 20 years. Multifarious clinical indications for deep brain stimulation now exist, including dystonia and tremor in movement disorders; depression, obsessive-compulsive disorder and Tourette's syndrome in psychiatry; epilepsy, cluster headache and chronic pain, including pain from stroke, amputation, trigeminal neuralgia and multiple sclerosis. Current research argues for novel indications, including hypertension and orthostatic hypotension. The development, principles, indications and effectiveness of the technique are reviewed here. While deep brain stimulation is a standard and widely accepted treatment for Parkinson's disease after 20 years of experience, in chronic pain it remains restricted to a handful of experienced, specialist centers willing to publish outcomes despite its use for over 50 years. Reasons are reviewed and novel approaches to appraising clinical evidence in functional neurosurgery are suggested.

Deep brain stimulation has shown remarkable potential in alleviating otherwise treatment-resistant chronic pain, but little is currently known about the underlying neural mechanisms. Here for the first time, we used noninvasive neuroimaging by magnetoencephalography to map changes in neural activity induced by deep brain stimulation in a patient with severe phantom limb pain. When the stimulator was turned off, the patient reported significant increases in subjective pain. Corresponding significant changes in neural activity were found in a network including the mid-anterior orbitofrontal and subgenual cingulate cortices; these areas are known to be involved in pain relief. Hence, they could potentially serve as future surgical targets to relieve chronic pain. © 2007 Lippincott Williams & Wilkins, Inc.

For almost one hundred years, the exact role of human brain structures controlling the cardiorespiratory response to exercise (‘central command’) has been sought. Animal experiments and functional imaging studies have provided clues, but the underlying electrophysiological activity of proposed relevant neural sites in humans has never been measured. In this study, local field potentials were directly recorded in a number of ‘deep’ brain nuclei during an exercise task designed to dissociate the exercise from peripheral feedback mechanisms. Several patient groups had electrodes implanted sterotaxically for the treatment of movement disorder or chronic pain. Fast Fourier transform analysis was applied to the neurograms to identify the power of fundamental spectral frequencies. Anticipation of exercise resulted in increases in heart rate, blood pressure and ventilation. The greatest neural changes were found in the periaqueductal grey area (PAG) where anticipation of exercise was accompanied by an increase of 43% in the power of the 12–25 Hz frequency band (P = 0.007). Exercise increased the activity by 87% compared to rest (P = 0.006). Changes were also seen in the 60–90 Hz band when anticipation or exercise increased power by 32% (P = 0.006) and 109% (P < 0.001), respectively. In the subthalamic nucleus there was a reduction in the power of the beta frequency during both anticipation (7.6 ± 0.68% P = 0.001) and exercise (17.3 ± 0.96% P < 0.001), whereas an increase was seen with exercise only at higher frequencies (93 ± 1.8% P = 0.007). No significant changes were seen in the globus pallidus during anticipation of exercise. We provide direct electrophysiological evidence highlighting the PAG as an important subcortical area in the neural circuitry of the cardiorespiratory response to exercise, since stimulation of this structure is known to alter blood pressure in awake humans.

Background Multiple oscillations emerging from the same neuronal substrate serve to construct a local oscillatory network. The network usually exhibits complex behaviors of rhythmic, balancing and coupling between the oscillations, and the quantification of these behaviors would provide valuable insight into organization of the local network related to brain states. New method An integrated approach to quantify rhythmic, balancing and coupling neural behaviors based upon power spectral analysis, power ratio analysis and cross-frequency power coupling analysis was presented. Deep brain local field potentials (LFPs) were recorded from the thalamus of patients with neuropathic pain and dystonic tremor. t-Test was applied to assess the difference between the two patient groups. Results The rhythmic behavior measured by power spectral analysis showed significant power spectrum difference in the high beta band between the two patient groups. The balancing behavior measured by power ratio analysis showed significant power ratio differences at high beta band to 8–20 Hz, and 30–40 Hz to high beta band between the patient groups. The coupling behavior measured by cross-frequency power coupling analysis showed power coupling differences at (theta band, high beta band) and (45–55 Hz, 70–80 Hz) between the patient groups. Comparison with existing method The study provides a strategy for studying the brain states in a multi-dimensional behavior space and a framework to screen quantitative characteristics for biomarkers related to diseases or nuclei. Conclusions The work provides a comprehensive approach for understanding the complex behaviors of deep brain LFPs and identifying quantitative biomarkers for brain states related to diseases or nuclei.

The frontal cortex and basal ganglia form a set of parallel but mostly segregated circuits called cortico-basal ganglia loops. The oculomotor loop controls eye movements and can direct relatively simple movements, such as reflexive prosaccades, without external help but needs input from “higher” loops for more complex behaviors. The antisaccade task requires the dorsolateral prefrontal cortex, which is part of the prefrontal loop. Information flows from prefrontal to oculomotor circuits in the striatum, and directional errors in this task can be considered a measure of failure of prefrontal control over the oculomotor loop. The antisaccadic error rate (AER) is increased in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has no effect on the AER, but a previous case suggested that DBS of the globus pallidus interna (GPi) might. Our aim was to compare the effects of STN DBS and GPi DBS on the AER. We tested eye movements in 14 human DBS patients and 10 controls. GPi DBS substantially reduced the AER, restoring lost higher control over oculomotor function. Interloop information flow involves striatal neurons that receive cortical input and project to pallidum. They are normally silent when quiescent, but in PD they fire randomly, creating noise that may account for the degradation in interloop control. The reduced AER with GPi DBS could be explained by retrograde stimulation of striatopallidal axons with consequent activation of inhibitory collaterals and reduction in background striatal firing rates. This study may help explain aspects of PD pathophysiology and the mechanism of action of GPi DBS.SIGNIFICANCE STATEMENTParkinson's disease causes symptoms including stiffness, slowness of movement, and tremor. Electrical stimulation of specific areas deep in the brain can effectively treat these symptoms, but exactly how is not fully understood. Part of the cause of such symptoms may be impairments in the way information flows from one circuit within the brain to another, as a result of overactivity of certain nerve cells. By demonstrating that stimulation of an area called the globus pallidus interna partially reverses deficits in voluntary control of eye movements, this study shows that stimulation can improve information flow between circuits, probably by calming down the overactive cells.

Enhancements in motor performance have been demonstrated in response to intense stimuli both in healthy subjects and in the form of ‘paradoxical kinesis’ in patients with Parkinson's disease. Here we identify a mid-latency evoked potential in local field potential recordings from the region of the subthalamic nucleus, which scales in amplitude with both the intensity of the stimulus delivered and corresponding enhancements in biomechanical measures of maximal handgrips, independent of the dopaminergic state of our subjects with Parkinson's disease. Recordings of a similar evoked potential in the related pedunculopontine nucleus – a key component of the reticular activating system – provide support for this neural signature in the subthalmic nucleus being a novel correlate of ascending arousal, propagated from the reticular activating system to exert an ‘energizing’ influence on motor circuitry. Future manipulation of this system linking arousal and motor performance may provide a novel approach for the non-dopaminergic enhancement of motor performance in patients with hypokinetic disorders such as Parkinson's disease., Highlights • We identify an evoked potential in the subthalamic nucleus of Parkinsonian patients. • This scales with enhancements in motor performance by loud sounds. • The same is seen in the pedunculopontine nucleus of the reticular activating system. • The potential may be a neural marker of movement energization by phasic arousal.

Background Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a new treatment for alleviating intractable neuropathic pain. However, it fails to help some patients. The large size of the ACC and the intersubject variability make it difficult to determine the optimal site to position DBS electrodes. The aim of this work was therefore to compare the ACC connectivity of patients with successful versus unsuccessful DBS outcomes to help guide future electrode placement. Methods Diffusion magnetic resonance imaging (dMRI) and probabilistic tractography were performed preoperatively in 8 chronic pain patients (age 53.4 ± 6.1 years, 2 females) with ACC DBS, of whom 6 had successful (SO) and 2 unsuccessful outcomes (UOs) during a period of trialing. Results The number of patients was too small to demonstrate any statistically significant differences. Nevertheless, we observed differences between patients with successful and unsuccessful outcomes in the fiber tract projections emanating from the volume of activated tissue around the electrodes. A strong connectivity to the precuneus area seems to predict unsuccessful outcomes in our patients (UO: 160n/SO: 27n), with ( n ), the number of streamlines per nonzero voxel. On the other hand, connectivity to the thalamus and brainstem through the medial forebrain bundle (MFB) was only observed in SO patients. Conclusions These findings could help improve presurgical planning by optimizing electrode placement, to selectively target the tracts that help to relieve patients' pain and to avoid those leading to unwanted effects.

Objectives: Rest tremor is a cardinal symptom of Parkinson's disease (PD), and is readily suppressed by deep brain stimulation (DBS) of the subthalamic nucleus (STN). The therapeutic effect of the latter on bradykinesia and rigidity has been associated with the suppression of exaggerated beta (13-30 Hz) band synchronization in the vicinity of the stimulating electrode, but there is no correlation between beta suppression and tremor amplitude. In the present study, we investigate whether tremor suppression is related to suppression of activities at other frequencies.Materials and Methods: We recorded hand tremor and contralateral local field potential (LFP) activity from DBS electrodes during stimulation of the STN in 15 hemispheres in 11 patients with PD. DBS was applied with increasing voltages starting at 0.5 V until tremor suppression was achieved or until 4.5 V was reached.Results: Tremor was reduced to 48.9% +/- 10.9% of that without DBS once stimulation reached 2.5-3 V (t14 = -4.667, p Conclusions: Our findings support a relationship between low gamma oscillations and PD tremor, and reinforce the principle that the subthalamic LFP is a rich signal that may contain information about the severity of multiple different Parkinsonian features.

Parkinsons disease (PD) is a neurodegenerative disorder caused in part by the loss of dopaminergic neurones in the substantia nigra (pars compacta). This results in disruption of the normal oscillatory and synchronous neuronal activity between the cortex, globus pallidus interna (GPi) and subthalamic nuleus (STN), The three cardinal clinical manifestations of PD are bradykinesia, tremor and rigidity. Gait and postural instability is often also seen. This chapter explores the place of surgery in the management of PD. It was once the mainstay of treatment, in the form of ablative surgeries such as pedunculotomy, and was then made largely redundant by the advent of dopaminergic drugs. However, it was found that dopaminergic drugs caused side effects including dyskinesias, which could be severely incapacitating. Once again, surgery (commonly taking the form of deep brain stimulation) became an important modality in the management of PD, not only to treat the cardinal symptoms of the disease itself, but also to treat the dyskinetic side effects of medical therapy.

It is unclear whether Hebbian-like learning occurs at the level of long-range white matter connections in humans, i.e., where measurable changes in structural connectivity (SC) are correlated with changes in functional connectivity. However, the behavioral changes observed after deep brain stimulation (DBS) suggest the existence of such Hebbian-like mechanisms occurring at the structural level with functional consequences. In this rare case study, we obtained the full network of white matter connections of one patient with Parkinson’s disease (PD) before and after long-term DBS and combined it with a computational model of ongoing activity to investigate the effects of DBS-induced long-term structural changes. The results show that the long-term effects of DBS on resting-state functional connectivity is best obtained in the computational model by changing the structural weights from the subthalamic nucleus (STN) to the putamen and the thalamus in a Hebbian-like manner. Moreover, long-term DBS also significantly changed the SC towards normality in terms of model-based measures of segregation and integration of information processing, two key concepts of brain organization. This novel approach using computational models to model the effects of Hebbian-like changes in SC allowed us to causally identify the possible underlying neural mechanisms of long-term DBS using rare case study data. In time, this could help predict the efficacy of individual DBS targeting and identify novel DBS targets. MLK is supported by the TrygFonden Charitable Foundation and ERC Consolidator Grant: CAREGIVING (n. 615539). TZ is supported by the Medical Research Council, Norman Collisson Foundation, Charles Wolfson Charitable Trust, and NIHR Biomedical Research Centre. GD is supported by the ERC Advanced Grant: DYSTRUCTURE (n. 295129), by the Spanish Research Project SAF2010-16085, by the CONSOLIDER-INGENIO 2010 Programme CSD2007–00012, by the FP7-ICT BrainScales and by the Brain Network Recovery Group through the James S. McDonnell Foundation.

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.

Deep brain stimulation (DBS) for pain was one of the earliest indications for the therapy. This study reports the outcome of DBS of the sensory thalamus and the periventricular and peri-aqueductal grey area (PVG/PAG) complex for different intractable neuropathic pain syndromes. Forty-seven patients (30 males and 17 females) were selected for surgery; they were suffering from any of the following types of pain: post-stroke neuropathic pain, phantom limb pain, post-herpetic neuralgia, anaesthesia dolorosa, brachial plexus injury and neuropathic pain secondary to neural damage from a variety of causes. Of the 47 patients selected for trial stimulation, 38 patients proceeded to permanent implantation. Patients suffering from post-stroke pain were the most likely to fail trial stimulation (33%), in contrast to individuals with phantom limb/post-brachial plexus injury pain and anaesthesia dolorosa, all of whom underwent permanent implantation. PVG stimulation alone was optimal in 17 patients (53%), whilst a combination of PVG and thalamic stimulation produced the greatest degree of analgesia in 11 patients (34%). Thalamic stimulation alone was optimal in 4 patients (13%). DBS of the PVG alone was associated with the highest degree of pain alleviation, with a mean improvement of 59% (p or =50% improvement in 66% of patients. Post-stroke pain responds in 70% of patients. We conclude that the outcomes of surgery appear to vary according to aetiology, but it would appear that the effects are best for phantom limb syndromes, head pain and anaesthesia dolorosa.

Phenytoin is often used to prevent postcraniotomy seizures, but is not always effective. We investigate changes in plasma phenytoin level ([phenytoin]) following craniotomy. The [phenytoin] in 28 patients who were receiving phenytoin (oral/ intravenous) and undergoing a craniotomy were prospectively measured 24 h preoperatively, immediately pre- and postcraniotomy, 24 and 48 h postoperatively. Factors examined included patients' age, sex, pathology, preoperative [phenytoin], operative duration and blood loss. Fifteen patients had [phenytoin] concentrations outside the therapeutic range. Twenty-five patients experienced a decrease in [phenytoin] immediately postcraniotomy: pre-, post- and 24 h postcraniotomy mean [phenytoin] were 13.4, 10.0 and 12.9 mg/l, respectively. Preoperative [phenytoin], operative duration and blood loss had significant correlation with the decrease in [phenytoin] (p < 0.05). In conclusion, < 50% of the patients had therapeutic preoperative [phenytoin]. In most patients, [phenytoin] decreases by 26% after craniotomy and returns to preoperative level within 24 h. These may contribute to early postoperative seizure development.

The periaqueductal grey matter is known to play a role in cardiovascular control in animals. Cardiovascular responses to electrical stimulation of the periventricular/periaqueductal grey matter were measured in 15 awake human study participants following implantation of deep brain stimulating electrodes for treatment of chronic pain. We found that stimulation of the ventral periventricular/periaqueductal grey matter caused a mean reduction in systolic blood pressure of 14.2+/-3.6 mmHg in seven patients and stimulation of the dorsal periventricular/periaqueductal grey matter caused a mean increase of 16.7+/-5.9 mmHg in six patients. A comparison between ventral and dorsal electrodes demonstrated significant differences (P

CASE REPORT: The authors report the case of an immature teratoma of the left parieto-occipital region in a 13-year-old girl. The patient had a computed tomographic (CT) scan of the brain aged 10 months old, following a minor head injury. This demonstrated an abnormality in the same region, which had been reported as 'a cortical malformation'.DIAGNOSIS: We propose that the lesion on the original imaging is a mature teratoma or other silent dystopic germ cell element that subsequently transformed into the immature teratoma.DISCUSSION: The potential triggers for such a transformation and the management of patients with similar incidental radiological findings are discussed.

The authors report the first case of successful implantation of a dorsal root ganglion stimulator at L1 and L2 for sustained improvement in chronic pelvic girdle pain.

Deep brain stimulation (DBS) is a remarkably effective clinical tool, used primarily for movement/ndisorders. DBS relies on precise targeting of specific brain regions to rebalance the oscillatory behaviour/nof whole-brain neural networks. Traditionally, DBS targeting has been based upon animal/nmodels (such asMPTPfor Parkinson’s disease) but has also been the result of serendipity during/nhuman lesional neurosurgery. There are, however, no good animal models of psychiatric disorders/nsuch as depression and schizophrenia, and progress in this area has been slow. In this paper, we use/nadvanced tractography combined with whole-brain anatomical parcellation to provide a rational/nfoundation for identifying the connectivity ‘fingerprint’ of existing, successful DBS targets. This/nknowledge can then be used pre-surgically and even potentially for the discovery of novel targets. First,/nusing data from our recent case series of cingulate DBS for patients with treatment-resistant chronic/npain, we demonstrate how to identify the structural ‘fingerprints’ of existing successful and unsuccessful/nDBS targets in terms of their connectivity to other brain regions, as defined by the whole-brain/nanatomical parcellation. Second, we use a number of different strategies to identify the successful fingerprints/nof structural connectivity across four patients with successful outcomes compared with/ntwo patients with unsuccessful outcomes. This fingerprinting method can potentially be used presurgically/nto account for a patient’s individual connectivity and identify the best DBS target. Ultimately,/nour novel fingerprinting method could be combined with advanced whole-brain computational/nmodelling of the spontaneous dynamics arising from the structural changes in disease, to/nprovide new insights and potentially new targets for hitherto impenetrable neuropsychiatric/ndisorders. We thank Ms Eloise Starkfor her valuable comments. MLK was supported by the ERC ConsolidatorGrant:/nCAREGIVING (n. 615539) and the TrygFonden Charitable Foundation. GD was supported by the ERC Advanced/nGrant: DYSTRUCTURE (n. 295129), by the Spanish Research Project SAF2010-16085 and the FP7-ICT BrainScales.

The physician is often seeking more efficient ways of performing patient assessments. Currently, measuring tremor frequency requires expensive and bulky equipment. We propose the use of the in-built accelerometer of the iPhone via the iSeismo application for rapid measurement of tremor frequency. We use this device in a series of 7 different tremor cases, and show that the frequency measurements on the iSeismo graph closely match the more sophisticated EMG analysis during tremor. This is a preliminary confirmation of the usefulness of this device in the clinical setting for quick assessment of the dominant frequency component in a variety of tremors.

Long-term outcome of deep brain stimulation in generalised dystonia BACKGROUND: There is solid evidence of the long term efficacy of deep brain stimulation of the globus pallidus pars interna in the treatment of generalised dystonia. However there are conflicting reports concerning whether certain subgroups gain more benefit from treatment than others. We analysed the results of a series of 60 cases to evaluate the effects of previously proposed prognostic factors including dystonia aetiology, dystonia phenotype, age at onset of dystonia, and duration of dystonia prior to treatment.METHODS: 60 patients with medically intractable primary or secondary generalised dystonia were treated with deep brain stimulation of the globus pallidus pars interna during the period 1999-2010 at the Department of Neurosurgery in Oxford, UK. Patients were assessed using the Burke-Fahn-Marsden (BFM) Dystonia Rating Scale prior to surgery, 6 months after implantation and thereafter at 1 year, 2 years and 5 years follow-up.RESULTS: The group showed mean improvements in the BFM severity and disability scores of 43% and 27%, respectively, by 6 months, and this was sustained. The results in 11 patients with DYT gene mutations were significantly better than in non-genetic primary cases. The results in 12 patients with secondary dystonia were not as good as those seen in non-genetic primary cases but there remained a significant beneficial effect. Age of onset of dystonia, duration of disease prior to surgery, and myoclonic versus torsional disease phenotype had no significant effect on outcome.CONCLUSIONS: The aetiology of dystonia was the sole factor predicting a better or poorer outcome from globus pallidus pars interna stimulation in this series of patients with generalised dystonia. However even the secondary cases that responded the least well had a substantial reduction in BFM scores compared with preoperative clinical assessments, and these patients should still be considered for deep brain stimulation.

Professor Giles Brindley MD, FRCP, FRS (Fig. 1) is one of Britain's great physiologists. Coming from humble beginnings, Brindley became a world-renowned figure in the research and innovation of vis...

Background and purpose Deep brain stimulation (DBS) for Parkinson disease (PD) has traditionally been reserved for the late stages of the disease. There is evidence that DBS is also effective if applied earlier in the disease course. Changes in the frequency of DBS procedures in the UK over a 15-year period were investigated. Methods A retrospective review was performed of patient age and disease duration for DBS surgery for PD in UK neurosurgical units from 1997 to 2012 using departmental databases. Results The number of DBS procedures in the UK increased from three in 1997 to over 80 per year during this period. The mean age at the time of surgery (60 years) and the mean duration of PD at the time of DBS (11 years) remained unchanged over 15 years. Conclusions The age and disease duration at which DBS is performed for PD in the UK has been static over a 15-year period and DBS appears to remain a therapy for PD applied late in its course. This may change in the light of clinical evidence suggesting a benefit for earlier DBS.

Nonlinear interaction between neural oscillations may be a biomarker for closed-loop deep brain stimulation (DBS) in Parkinson's disease. Bispectral analysis is an effective tool to detect quadratic phase coupling. In this paper we applied bispectral analysis to local field potentials (LFPs) recorded from Parkinsonism patients' subthalamic nucleus (STN) during tremor and resting states. The significance of the coupling was statistically tested using bispectrum estimation with surrogate data approaches. Strong phase couplings were found in both states, whereas the coupling frequencies varied. There are bispectral peaks around 3–6Hz in both states and the peak amplitudes in tremor state are twice larger than those in resting state, while the bispectra in resting state shows peaks in narrow frequency bands of 7–9Hz, 10–12Hz and 15–17Hz. The measure of these nonlinear interactions between neural oscillations of local field potentials can be used to distinguish pathological states in Parkinson's disease and could contribute to the development of intelligent deep brain stimulation strategies.