Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity

Abstract

Parkinson's disease (PD) is associated with exaggerated oscillatory synchrony in the basal ganglia at frequencies over 8–35 Hz. Studies have demonstrated a suppression of local field potential (LFP) activity in the subthalamic nucleus (STN) upon treatment with the dopamine prodrug, levodopa, with the degree of suppression of power in the 8–35 Hz band correlating with the improvement in combined measures of bradykinesia and rigidity. However, these studies do not explicitly address the question of what is more important in predicting clinical change — synchronisation of neuronal activity or the specific frequency within the 8–35 Hz band over which the latter occurs. In addition, they have not demonstrated a relationship between treatment-induced changes in synchronisation and changes in bradykinesia or rigidity on their own. To this end, we collected and analysed LFP and clinical data in 30 patients with PD. We found significant correlations between levodopa-induced power suppression and rigidity and bradykinesia, when these clinical features were considered separately, but only when power suppression profiles were re-aligned to the frequency of peak synchronisation. Under these circumstances correlations with rigidity persisted despite partialising out the effect of bradykinesia and vice versa. These data suggest that levodopa-induced improvements in both rigidity and bradykinesia scale with the degree of suppression of oscillatory power in the STN LFP, and that this is true irrespective of the frequency at which synchronisation occurs across a broad band from 8–35 Hz.

Introduction

There seems little doubt that patients with advanced Parkinson's disease (PD) have prominent and synchronised neuronal oscillation at frequencies over 8–35 Hz in their cortico-basal ganglia loops (Engel et al., 2005, Schnitzler and Gross, 2005, Uhlhaas and Singer, 2006, Hammond et al., 2007). This activity is suppressed by treatments that improve parkinsonism and seems intimately related to voluntary movement, which is preceded by its suppression (Hammond et al., 2007). Indeed, the timing of the suppression correlates with the timing of subsequent movement (Kühn et al., 2004, Loukas and Brown, 2004, Williams et al., 2005, Doyle et al., 2005). These core observations led to the suggestion that such oscillatory activity may, when exaggerated, relate to bradykinesia (Brown, 2003). Whether this is true of activities across the whole 8–35 Hz band is unclear, with some reports suggesting that synchrony over the 13–20 Hz range may be of greater pathological significance (Priori et al., 2004, Marceglia et al., 2006). Any relationship between synchrony and rigidity is also unclear, although it is in line with the hypothesised role of physiological oscillatory activity in cortico-basal ganglia loops in promoting the postural state (Brown, 2007).

The relationship between oscillatory synchrony and clinical impairment can be investigated in patients with Parkinson's disease through recordings of neuronal activity made intra-operatively or recordings of local field potentials (LFPs) made just after functional neurosurgery, while leads from deep brain stimulation electrodes are still externalised. The usual target in such surgery is the subthalamic nucleus (STN). Two small studies have reported a positive correlation between % change in combined bradykinesia and rigidity scores and % change in the power in the STN LFP peak following treatment with levodopa (Kühn et al., 2006, Ray et al., 2008). A further intra-operative study has demonstrated a positive correlation between the incidence of oscillatory neurons in STN and the patient's benefit from dopaminergic medications, although not with baseline motor deficits off medication (Weinberger et al., 2006). However, these studies do not explicitly address the question of what is more important in predicting clinical change — synchronisation of neuronal activity or the specific frequency within the 8–35 Hz band over which the latter occurs. In addition, they have not demonstrated a relationship between treatment-induced changes in synchronisation and changes in bradykinesia or rigidity on their own. To this end, we collected and analysed LFP and clinical data in a large sample of patients, including those previously reported by Kühn et al., 2006, Ray et al., 2008, and a further 14 cases.