Mechanisms of subthalamic and thalamic deep brain stimulation (DBS) studied in Parkinson's disease (PD) and essential tremor (ED)

Chronic high frequency electrical deep brain stimulation (DBS) has become a widely accepted treatment in drug refractory Parkinson's disease, essential tremor and dystonia. There is a growing demand for knowledge on the basic mechanisms of DBS, in particular for subthalamic nucleus (STN) stimulation. We showed the differential impact of STN DBS on cognitive and motor circuitries in three PET studies: STN stimulation facilitated premotor activation while motor parameters improved during routine, predictable and automatic movement. However, in situations requiring non-automated behaviour, DBS of the STN led to inflexibility in responses and impaired activation of the anterior cingulated, ventral striatum and a fronto-temporal network.

In essential tremor (ET) patients with electrodes in the thalamic nucleus ventralis intermedius (VIM), we have found remote effects of DBS in VIM projection areas, namely motor and parieto-insular vestibular cortex [Ceballos-Baumann et al. Neurology 2001]. Systematic modulations of DBS stimulation parameters yielded further insights into the mechanisms of DBS: increasing stimulation amplitude was associated with a linear raise in activity at the site of the subcortical electrode, but with a nonlinear response in the primary sensorimotor cortex. The reverse pattern was observed with increasing stimulation frequency. These results clearly refuted the theory of an ablation like effect of DBS. Instead, this study indicated that DBS allows a gradual tuning of activity within a neuronal circuit [Haslinger et al. Neuroimage 2003].

Recently we applied this parametric H215O PET design to characterize responses as linear and nonlinear functions of the experimentally modulated stimulus to clarify the unpredicted profound decrease of regional cerebral blood flow (rCBF) in the primary sensorimotor cortex associated with effective STN-stimulation found in our first STN study and in other laboratories. Gradual increases in STN stimulation frequency from 0– to the therapeutic range of >100Hz correlate with corresponding decreases in the activity of the motor cortex as measured with rCBF, consistent with upstream modulation of cortical subthalamic afferents. The finding suggests that the direct corticosubthalamic pathway plays a major role in STN in basal ganglia organization: It may represent a target on its right, possibly more likely to be devoid of cognitive and behavioural side effects as the nucleus itself.