Jonathan A. Hyam

Comparison of P-POSSUM risk-adjusted mortality rates after surgery between patients in the USA and the UK

The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) criteria have been used to assess surgical risk in patients in the UK. The aim was to determine how applicable these criteria are to patients undergoing surgery in the USA.

Pedunculopontine nucleus stimulation improves gait freezing in Parkinson disease.

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.

A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation.

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.

Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism

The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinsons 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.

Thalamotomy versus thalamic stimulation for multiple sclerosis tremor.

Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P > 0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P < 0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

Bilateral globus pallidus stimulation for severe Tourette's syndrome: a double-blind, randomised crossover trial

BACKGROUNDnDeep brain stimulation (DBS) has been proposed as a treatment option for severe Tourettes syndrome on the basis of findings from open-label series and small double-blind trials. We aimed to further assess the safety and efficacy of bilateral globus pallidus internus (GPi) DBS in patients with severe Tourettes syndrome.nnnMETHODSnIn a randomised, double-blind, crossover trial, we recruited eligible patients (severe medically refractory Tourettes syndrome, age ≥20 years) from two clinics for tertiary movement disorders in the UK. Enrolled patients received surgery for GPi DBS and then were randomly assigned in a 1:1 ratio (computer-generated pairwise randomisation according to order of enrolment) to receive either stimulation on-first or stimulation off-first for 3 months, followed by a switch to the opposite condition for a further 3 month period. Patients and rating clinicians were masked to treatment allocation; an unmasked clinician was responsible for programming the stimulation. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) total score between the two blinded conditions, assessed with repeated measures ANOVA, in all patients who completed assessments during both blinded periods. After the end of the blinded crossover phase, all patients were offered continued DBS and continued to have open-label stimulation adjustments and objective assessments of tic severity until database lock 1 month after the final patients final trial-related visit. This trial is registered with ClinicalTrials.gov, number NCT01647269.nnnFINDINGSnBetween Nov 5, 2009, and Oct 16, 2013, we enrolled 15 patients (11 men, four women; mean age 34·7 years [SD 10·0]). 14 patients were randomly assigned and 13 completed assessments in both blinded periods (seven in the on-first group, six in the off-first group). Mean YGTSS total score in these 13 patients was 87·9 (SD 9·2) at baseline, 80·7 (SD 12·0) for the off-stimulation period, and 68·3 (SD 18·6) for the on-stimulation period. Pairwise comparisons in YGTSS total scores after Bonferroni correction were significantly lower at the end of the on-stimulation period compared with the off-stimulation period, with a mean improvement of 12·4 points (95% CI 0·1-24·7, p=0·048), equivalent to a difference of 15·3% (95% CI 5·3-25·3). All 15 patients received stimulation in the open-label phase. Overall, three serious adverse events occurred (two infections in DBS hardware at 2 and 7 weeks postoperatively, and one episode of deep-brain-stimulation-induced hypomania during the blinded on-stimulation period); all three resolved with treatment.nnnINTERPRETATIONnGPi stimulation led to a significant improvement in tic severity, with an overall acceptable safety profile. Future research should concentrate on identifying the most effective target for DBS to control both tics and associated comorbidities, and further clarify factors that predict individual patient response.nnnFUNDINGnUK National Health Service.

Ventral periaqueductal grey stimulation alters heart rate variability in humans with chronic pain

BACKGROUNDnThe 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.nnnMETHODS AND RESULTSn16 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.nnnCONCLUSIONSnVentral PAG DBS may increase parasympathetic activity to reduce pain via anatomical connections distinct from dorsal PAG DBS, which may act by sympathetic mechanisms.

A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation

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.

Contrasting connectivity of the ventralis intermedius and ventralis oralis posterior nuclei of the motor thalamus demonstrated by probabilistic tractography.

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/mm2, 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.

Identifying cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery.

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.