Download Subthalamic High-frequency Deep Brain Stimulation Evaluated in a

Subthalamic High Frequency Deep Brain Stimulation Elevates
rCBF at Electrode and Oxygen Consumption in Adjoining Cerebral
Cortex: Evidence of Spatially Differentiated Flow-Metabolism
Coupling.
C.R. BJARKAM*1, F. Andersen2, M. Larsen1, H. Watanabe2, L. Röhl3, P. Cumming2, J.C.
Sørensen4 and A. Gjedde2.
1: Dept. of Neurobiology, Inst. of Anatomy, University of Aarhus, Denmark.
2: PET-Center, University Hospital of Aarhus.
3: Dept. of Neuroradiology, University Hospital of Aarhus.
4: Dept. of Neurosurgery, University Hospital of Aarhus.
During the past decade, subthalamic high frequency deep brain stimulation (DBS) has
proven effective in the treatment of Parkinson's disease complicated with motor fluctuations
and L-dopa induced dyskinesias. The current claim holds that the electrical stimulation
inhibits neural activity in the subthalamic nucleus (STN). however, the exact mode of action
is still unknown. We developed a porcine model of subthalamic DBS in order to test the
hypothesis that inhibition of STN must elicit declines of both blood flow and oxygen
consumption in accordance with
a conventional understanding of the flow-metabolism
couple.
DBS-electrodes designed for human use (Itrel II system, Medtronic) were unilaterally
placed in the STN of three MPTP-intoxicated Goettingen minipigs, guided by stereotaxic
fiducials, stereotaxic procedures and electrophysiological measurements in accordance with
the Danish Council on Animal Research Ethics (DANCARE). Proper electrode positioning
was verified per-operatively by MRI.
Four-to-six weeks after the surgical procedure, the animals were anesthetized and placed
prone in a Siemens/CTI ECAT EXACT HR47 tomograph and scanned with three times 15Ooxygen and three times 15O-water before the stimulation ("baseline"). The electrode was then
activated with continuously unipolar stimulation (electrode negative, case positive, amplitude
3V, frequency 160 Hz, pulse-width 60 µs). Additional PET-scans with 15O-water and 15Ooxygen were then acquired 5 min, 30 min, 60 min, 120 min and 240 min after stimulation
onset ("poststimulation"). The PET-images were automatically registered to each pig's
individual MR-image before resampling and transformation into an average MRI brain based
on 22 Goettingen minipig brains. This procedure placed each PET-image in a common 3D
coordinate system and allowed DOT-analysis on the dynamic PET-images (Andersen et al.,
this meeting).
A comparison between the baseline and poststimulation 15O-water scans revealed a
profound increase in rCBF (p<0.001) at the electrode after stimulation onset, without no
increase in oxygen consumption in this area. Significant increases of oxygen consumption
occured in the ipsilateral sensorimotor cortex.
We conclude that subthalamic DBS of MPTP-intoxicated minipigs focally increases
rCBF and oxygen consumption, in direct contradiction of the conventional flow-metabolism
couple. The changes are consistent with a novel hypothesis of spatially differentiated flow and
oxygen metabolism coupling. We speculate that the increased rCBF at the site of stimulation
without concomitant increase in oxygen consumption is caused by a local inhibition of the
efferent neurons in the electrode area (preventing an increase of oxygen consumption) leading
to a compensatory increase of the oxygen consumption in the proximal parts of cortical
neurons projecting to the STN, while the increase in subthalamic blood flow is elicited by the
terminals of these neurons in the STN. Thus, the change of CMRO2 occurs at the proximal
end of neurons, while the change of blood flow occurs at the distal end.
Ref: Andersen F, Watanabe H, Bjarkam CR, The DaNex Study Group, Gjedde A,
Cumming P: Pig Brain Stereotaxic Standard Space: Mapping of Blood Flow Normative
Values and Effects of MPTP Intoxication. Submitted to NeuroImage.