Alan D. Dorval, Warren M. Grill

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptom severity in persons with medically refractory parkinsonism. Despite clinical success and outcome similar to surgical lesion, the mechanisms of DBS remain unclear. We hypothesized that effective DBS regularizes neuronal activity in the basal ganglia, enabling downstream motor regions to function unimpeded by pathological information from the parkinsonian basal ganglia. We recorded changes in behavior and neuronal firing patterns in a rat model of parkinsonism. Multi-electrode arrays were implanted into healthy Long Evans rats: recording arrays in globus pallidus (GP) and substantia nigra pars reticulata (SNr), and stimulating arrays in STN. Hemi-parkinsonism was induced by unilateral injection of 6-OHDA in the medial forebrain bundle ipsi-lateral to the implanted arrays. Unit activity was recorded before and after exposure, and in the presences of 100Hz DBS. Neuronal activity was sorted based on cluster distance in the principle component space: 70 GP and 72 SNr neurons before 6-OHDA; and 30 GP and 21 SNr neurons after 6-OHDA, both with and without DBS. Firing pattern entropy was calculated from the distributions of interspike intervals as a measure of neuronal disorder.

Motor symptoms were assessed from video recordings of 30 minute trials of self-initiated forepaw use in a vertical reaching task. Most animals showed a marked 6-OHDA-induced forepaw use asymmetry (9/11). Exposure to 6-OHDA decreased firing rates in GP and increased firing rates in SNr, consistent with the classic direct/indirect pathway model of the parkinsonian basal ganglia. Changes in firing pattern entropy were mixed: 6-OHDA exposure tended to increase or decrease entropy in GP or SNr, respectively. Stimulation alleviated forepaw asymmetry (4/4), and increased neuronal firing rates in GP and SNr, consistent with previous studies. Furthermore, DBS reduced firing pattern entropy in both GP (p<.005, student T test) and SNr (p<.02), confirming that DBS reduces disordered activity in the basal ganglia. This work suggests that parkinsonism is not necessarily associated with increased basal ganglia disorder: healthy and parkinsonian neurons exhibited roughly equivalent capacity for information transmission. The quality, rather than the quantity, of output information from the parkinsonian basal ganglia may be detrimental to the function of downstream motor areas. Thus, DBS would alleviate symptoms by reducing the unwanted information, similar to the mechanisms of surgical lesion.

Supported by the National Institutes of Health, K25-NS053544 (ADD) and R01-NS040894 (WMG).