Modulation of motor cortex by subthalamic stimulation in Parkinson's disease

Following the classical model of basal ganglia organisation, STN deep brain stimulation (DBS) in Parkinson's disease (PD) induces a lesion like block of excessive activity of the STN and of its excitatory projections. This model neglects the influence of direct excitatory cortico-subthalamic projections from motor cortex. Previous studies revealed a decrease of resting rCBF in the primary sensorimotor cortex due to effective STN DBS. We therefore hypothesized that gradual increases in STN stimulation frequency correlate with the rCBF in the motor cortex.

We studied 6 patients with bilateral DBS within the STN for treatment of strictly akinetic PD. Each patient underwent 12 3D H215O PET scans. Scans were performed at rest with bilateral STN stimulators 'off'(=0Hz) (1 scan) or 'on' (11 scans). For the 'on'-condition the stimulation frequency of both stimulators was stepwise varied from scan to scan (5Hz to 190Hz). We applied a statistical approach using a hierarchical set of two orthogonalized basic functions for each patient: a first order and second order expansion of the successive levels of stimulation frequency. For characterization of rCBF responses to increasing stimulation frequency, individual rCBF as well mean fitted rCBF across all patients were plotted for the peak activated voxels.

We found strong negative correlations with stimulation frequency within bilateral primary motor cortex as well as in caudal parts of mesial premotor cortex. Here, rCBF responses showed strongly correlated decreases of rCBF with increasing stimulation frequency. In contrast, when looking for positive correlations of rCBF to increasing frequency we detected strong activation clusters around the stimulated nucleus, the STN bilaterally. Here, rCBF responses depicted an increase of rCBF with increasing stimulation frequency.

Our findings suggest that STN stimulation directly modulates the cortico-subthalamic pathway. This is underlined by the strong correlation between gradual increases of stimulation frequency and rCBF within primary motor cortex and mesial premotor cortex. This indicates an active upstream modulation of direct cortico-subthalamic connections as an important mechanism of STN DBS. Here high frequency stimulation could interrupt the drive from frontal cortical areas as a possible source for excessive activity of the STN in PD.