John-Stuart Brittain

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.

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.

Tremor suppression by rhythmic transcranial current stimulation.

Summary Tremor can dominate Parkinson’s disease and yet responds less well to dopaminergic medications than do other cardinal symptoms of this condition [1, 2]. Deep brain stimulation can provide striking tremor relief, but the introduction of stimulating electrodes deep in the substance of the brain carries significant risks, including those of hemorrhage [3]. Here, we pioneer an alternative approach in which we noninvasively apply transcranial alternating current stimulation (TACS) over the motor cortex [4, 5] to induce phase cancellation of the rest tremor rhythm. We first identify the timing of cortical oscillations responsible for rest tremor in the periphery by delivering tremor-frequency stimulation over motor cortex but do not couple this stimulation to the on-going tremor—instead, the rhythms simply “drift” in and out of phase alignment with one another. Slow alternating periods of phase cancellation and reinforcement result, informing on the phase alignments that induce the greatest change in tremor amplitude. Next, we deliver stimulation at these specified phase alignments to demonstrate controlled suppression of the on-going tremor. With this technique we can achieve almost 50% average reduction in resting tremor amplitude and in so doing form the basis of a closed-loop tremor-suppression therapy that could be extended to other oscillopathies.

Oscillations and the basal ganglia: Motor control and beyond

Oscillations form a ubiquitous feature of the central nervous system. Evidence is accruing from cortical and sub-cortical recordings that these rhythms may be functionally important, although the precise details of their roles remain unclear. The basal ganglia share this predilection for rhythmic activity which, as we see in Parkinsons disease, becomes further enhanced in the dopamine depleted state. While certain cortical rhythms appear to penetrate the basal ganglia, others are transformed or blocked. Here, we discuss the functional association of oscillations in the basal ganglia and their relationship with cortical activity. We further explore the neural underpinnings of such oscillatory activity, including the important balance to be struck between facilitating information transmission and limiting information coding capacity. Finally, we introduce the notion that synchronised oscillatory activity can be broadly categorised as immutability promoting rhythms that reinforce incumbent processes, and mutability promoting rhythms that favour novel processing.

Removing ECG noise from surface EMG signals using adaptive filtering.

Surface electromyograms (EMGs) are valuable in the pathophysiological study and clinical treatment for dystonia. These recordings are critically often contaminated by cardiac artefact. Our objective of this study was to evaluate the performance of an adaptive noise cancellation filter in removing electrocardiogram (ECG) interference from surface EMGs recorded from the trapezius muscles of patients with cervical dystonia. Performance of the proposed recursive-least-square adaptive filter was first quantified by coherence and signal-to-noise ratio measures in simulated noisy EMG signals. The influence of parameters such as the signal-to-noise ratio, forgetting factor, filter order and regularization factor were assessed. Fast convergence of the recursive-least-square algorithm enabled the filter to track complex dystonic EMGs and effectively remove ECG noise. This adaptive filter procedure proved a reliable and efficient tool to remove ECG artefact from surface EMGs with mixed and varied patterns of transient, short and long lasting dystonic contractions.

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.

A role for the subthalamic nucleus in response inhibition during conflict.

The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15–35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials—in which response times were elongated due to the Stroop effect—a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved.

The highs and lows of beta activity in cortico-basal ganglia loops

Oscillatory activity in the beta (13–30 Hz) frequency band is widespread in cortico‐basal ganglia circuits, and becomes prominent in Parkinsons disease (PD). Here we develop the hypothesis that the degree of synchronization in this frequency band is a critical factor in gating computation across a population of neurons, with increases in beta band synchrony entailing a loss of information‐coding space and hence computational capacity. Task and context drive this dynamic gating, so that for each state there will be an optimal level of network synchrony, and levels lower or higher than this will impair behavioural performance. Thus, both the pathological exaggeration of synchrony, as observed in PD, and the ability of interventions like deep brain stimulation (DBS) to excessively suppress synchrony can potentially lead to impairments in behavioural performance. Indeed, under physiological conditions, the manipulation of computational capacity by beta activity may itself present a mechanism of action selection and maintenance.

Rapid tremor frequency assessment with the iPhone accelerometer.

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.

Subthalamic Nucleus Local Field Potential Activity during the Eriksen Flanker Task Reveals a Novel Role for Theta Phase during Conflict Monitoring

The subthalamic nucleus (STN) is thought to play a central role in modulating responses during conflict. Computational models have suggested that the location of the STN in the basal ganglia, as well as its numerous connections to conflict-related cortical structures, allows it to be ideally situated to act as a global inhibitor during conflict. Additionally, recent behavioral experiments have shown that deep brain stimulation to the STN results in impulsivity during high-conflict situations. However, the precise mechanisms that mediate the “hold-your-horses” function of the STN remain unclear. We recorded from deep brain stimulation electrodes implanted bilaterally in the STN of 13 human subjects with Parkinsons disease while they performed a flanker task. The incongruent trials with the shortest reaction times showed no behavioral or electrophysiological differences from congruent trials, suggesting that the distracter stimuli were successfully ignored. In these trials, cue-locked STN theta band activity demonstrated phase alignment across trials and was followed by a periresponse increase in theta power. In contrast, incongruent trials with longer reaction times demonstrated a relative reduction in theta phase alignment followed by higher theta power. Theta phase alignment negatively correlated with subject reaction time, and theta power positively correlated with trial reaction time. Thus, when conflicting stimuli are not properly ignored, disruption of STN theta phase alignment may help operationalize the hold-your-horses role of the nucleus, whereas later increases in the amplitude of theta oscillations may help overcome this function.