Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease
Grafton ST, Turner RS, Desmurget M, Bakay R, Delong M, Vitek J, et al.;
Commented by , 23 Jun 2006
Background
Deep brain stimulation (DBS) of subthalamic nucleus (STN) is an effective way of improving parkinsonian disability and motor complications in patients with Parkinson disease (PD). The effects of DBS on functional activation of motor cortex and related cortical areas have not been well understood.
Objectives
The objective of this study was to assess whether therapeutic unilateral DBS of the STN in patients with PD leads to normalization in the pattern of brain activation during movement execution and control of movement extent.
Methods
Six patients with PD were imaged off medication by PET during performance of a visually guided tracking test with the DBS voltage programmed for effective (therapeutic) or ineffective (subtherapeutic) stimulation. Data from ineffective stimulation period were compared with a group of 13 age-matched control subjects to identify sites with abnormal pattern of activation.
Conjunction analysis was used to identify those areas in patients with PD where activity normalized when they were treated with effective stimulation.
Results
During movement execution effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum towards a normal pattern. At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reduction of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited associated with reductions of activity in primary motor cortex, SMA and basal ganglia.
The authors concluded that effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as wide-spread, nonspecific reductions of compensatory or competing cortical activity.
Professor Emre's comments
Following the identification of direct and indirect pathways in the motor circuitry of basal ganglia (BG) and the role of dopamin in this circuit, a simple model of PD was proposed, which suggested an increased inhibitory BG output with a resulting suppression of the normal thalamo-cortical activation.
Subsequently, an alternative hypothesis was put forward that it is not simply an increased output of BG which causes motor dysfunction, it is rather a "disturbed" pattern of output which induces pathological patterns of activation in cortical motor areas.
STN plays a crucial role in this circuit as it drives the both output nuclei of BG, substantia nigra pars reticulata and internal segment of globus pallidus and as there is an increased activity of STN in patients with PD. The benefical effects of STN stimulation has been well documented (ref. 1), the mechanisms by which these effects are brought about, however, have been unclear. One obvious assumption to make was that STN DBS reduces the overactivity of STN in PD (ref. 2).
This study provides further insight about what really happens in motor cortex and related areas when there is an effective STN stimulation. It seems that during resting state pathologically overactive areas are normalized, during movement hypoactive areas are brought back to normal levels and overactive areas (which are thought to be recruited in an effort to compensate for underactivity in other areas) are suppressed.
Thus the results of this study are compatible with the notion that in PD pallidothalamic input is not only excessively inhibitory, but also disruptive, resulting in a general underactivation of appropriate cortical motor areas as well as inappropriate modulation of brain activity to meet the ongoing demands of the motor task.
The DBS of STN seems to normalize this disruptive pattern of activity. This makes indeed sense and also explains the results of previous imaging and deep brain recording studies which revealed findings incompatible with the simple increased BG output model of PD (ref. 3, ref. 4).
References
1. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. New England Journal of Medicine 2003; 349 (20); 1925-1934 (Free full text article)
2. Limousin P, Greene J, Pollak P, Rothwell J, Benabid AL, Frackowiak R.Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease. Annals of Neurology 1997; 42 (3); 283-291
3. Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. Journal of Neuroscience 2003, 23 (5); 1916-1923 (Free full text article)
4. Hershey T, Revilla FJ, Wernle AR, McGee-Minnich L, Antenor JV, Videen TO, et al. Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD. Neurology 2003; 61 (6); 816-821