Ned Jenkinson

Translational principles of deep brain stimulation

Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful, but it can also provide new insights into fundamental brain functions through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization that underlie human brain function. The precise mechanisms of action for DBS remain uncertain, but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.

New insights into the relationship between dopamine, beta oscillations and motor function

Synchronised neuronal oscillations at beta frequencies are prevalent in the human motor system, but their function is unclear. In this Opinion article, we propose that the levels of beta oscillations provide a measure of the likelihood that a new voluntary action will need to be actuated. Oscillatory beta activity is in turn modulated by net dopamine levels at sites of cortical input to the basal ganglia. We hypothesise that net dopamine levels are modulated in response to salient internal and external cues. Crucially, the resulting modulation of beta activity is predictive, enabling the appropriate prospective resourcing and preparation of potential actions. Loss of dopamine, as in Parkinsons disease, annuls this function, unless net dopaminergic activity can be elevated through medication.

Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation.

Parkinsons disease is treated pharmacologically with dopamine replacement medication and, more recently, by stimulating basal-ganglia nuclei such as the subthalamic nucleus (STN). Depth recordings after this procedure have revealed excessive activity at frequencies between 8 and 35 Hz (Brown et al., 2001; Kuhn et al., 2004; Priori et al., 2004) that are reduced by dopamine therapy in tandem with improvements in bradykinesia/rigidity, but not tremor (Kuhn et al., 2006). It has also been shown that improvements in motor symptoms after dopamine correlate with single unit activity in the beta range (Weinberger et al., 2006). We recorded local field potentials (LFPs) from the subthalamic nucleus of patients with Parkinsons disease (PD) after surgery to implant deep brain stimulating electrodes while they were on and off dopaminergic medication. As well as replicating Kuhn et al., using the same patients we were able to extend Weinberger et al. to show that LFP beta oscillatory activity correlated with the degree of improvement in bradykinesia/rigidity, but not tremor, after dopamine medication. We also found that the power of beta oscillatory activity uniquely predicted improvements in bradykinesia/rigidity, but again not tremor, after stimulation of the STN in a regression analysis. However improvements after STN stimulation related inversely to beta power, possibly reflecting the accuracy of the electrode placement and/or the limits of STN stimulation in patients with the greatest levels of beta oscillatory activity.

Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey

We have studied the effects of stimulating the pedunculopontine nuclei through a fully implanted macroelectrode with a s.c. implantable pulse generator whose parameters can be programmed telemetrically, in a macaque before and after inducing Parkinsonian akinesia with MPTP. Our results show that in the normal monkey high frequency stimulation of the pedunculopontine nuclei reduces motor activity while low frequency stimulation increases it significantly over baseline. After making the monkey Parkinsonian with MPTP, unilateral low frequency stimulation of the pedunculopontine nuclei led to significant increases in activity. These results suggest that pedunculopontine nuclei stimulation could be clinically effective in treating advanced Parkinsons disease and other akinetic disorders.

Driving oscillatory activity in the human cortex enhances motor performance

Summary Voluntary movement is accompanied by changes in the degree to which neurons in the brain synchronize their activity within discrete frequency ranges. Two patterns of movement-related oscillatory activity stand out in human cortical motor areas. Activity in the beta frequency (15–30 Hz) band is prominent during tonic contractions but is attenuated prior to and during voluntary movement [1]. Without such attenuation, movement may be slowed, leading to the suggestion that beta activity promotes postural and tonic contraction, possibly at a cost to the generation of new movements [2, 3]. In contrast, activity in the gamma (60–90 Hz) band increases during movement [4]. The direction of change suggests that gamma activity might facilitate motor processing. In correspondence with this, increased frontal gamma activity is related with reduced reaction times [5]. Yet the possibility remains that these functional correlations reflect an epiphenomenal rather than causal relationship. Here we provide strong evidence that oscillatory activities at the cortical level are mechanistically involved in determining motor behavior and can even improve performance. By driving cortical oscillations using noninvasive electrical stimulation, we show opposing effects at beta and gamma frequencies and interactions with motor task that reveal the potential quantitative importance of oscillations in motor behavior.

Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner.

Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and “gold standard” histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.

Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus.

The pedunculopontine nucleus is composed of cholinergic and non‐cholinergic neurones and is located in the caudal pontomesencephalic tegmentum. Evidence suggests that the nucleus plays a role in the production and control of movement. The nucleus has dense interconnections with the basal ganglia, as well as with other areas of the brain associated with motor control. Electrical stimulation of the pedunculopontine nucleus in the decerebrate cat or rat produces organized locomotor movements. Physiological studies show that the pedunculopontine nucleus modulates its activity in response to locomotion, as well as voluntary arm and eye movements. Degeneration of the pedunculopontine nucleus is seen in post‐mortem brains in humans with Parkinsons disease and Parkinsonian syndromes. In animal models of Parkinsons disease, metabolic changes are seen in the pedunculopontine nucleus, and chemical inhibition or mechanical disruption of the nucleus can produce an akinetic state in animals and man. In this paper we review the literature in support of the suggestion that some of the symptoms of Parkinsons disease are caused by dysfunction of the pedunculopontine nucleus. In accordance with this view, direct stimulation of the nucleus can ameliorate some symptoms of the disease, as demonstrated in both experimental animals and man.

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.

Adaptation to rotated visual feedback: a re-examination of motor interference.

We have tested human visuo-motor adaptation in rotated-feedback tasks in which subjects first learn to move a cursor to visual targets with a rotational perturbation between joystick and cursor, and are then challenged with the opposing rotation. We then retest the subjects in the original adaptation task, to measure retention of a short-term memory of its earlier learning. Others have used similar tasks and report retrograde interference between one task and the short-term motor memory of the preceding task, such that later performance is impaired. However, we show that in the short-term conditions tested here, these effects can be considered as anterograde interference effects between the two tasks and we find no evidence of retrograde interference.

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.