Neuronal Mechanisms Of Subthalamic Nucleus Deep Brain Stimulation

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One of the first hypotheses regarding the neuronal mechanism of action of DBS is that DBS inhibits activities within the stimulated target. A number of studies demonstrated that activity in structures receiving input from the DBS target was consistent with increased, not decreased, output from the stimulated structure. An example of GPi activity before, during, and after STN DBS in a nonhuman primate is shown in Figure 4. Note in this example, there is a significant reduction of neuronal activity immediately following discontinuation of the DBS. The current state of knowledge regarding the pathophysiological mechanisms of DBS has recently been reviewed (56-60).

A series of experiments studied the effects of STN DBS of different frequencies on neuronal responses in the GPi, GPe, MC, and putamen (61). The results demonstrated that the direct effects of DBS induced the same patterns of neuronal activities in these structures, regardless of the stimulation frequency (Fig. 5). The findings

Stimulalion for 30 sec

FIGURE 4 Microelectrode recording of the extracellular action potentials of a globus pallidus internal segment neuron in response to deep brain stimulation in the vicinity of the subthalamic nucleus. This is a 30-second baseline recording followed by 30 seconds of stimulation and then recording for an additional 30 seconds.

FIGURE 5 Representative poststimulus rasters and histograms of neuronal activity recorded from the cortex, putamen, globus pallidus external segment, and globus pallidus internal segment. The top portion of each figure is a raster of neuronal activity. Each dot represents the time of an extracellular action potential. Each row represents the segment of neuronal activity between successive stimulation pulses. Dividing the time into bins and summing across rows results in a histogram at the lower portion of each figure. For stimulation at 130 pulses per second (pps), the time of the rasters and histograms is 8 ms; for 100 pps, it is 10 ms; and for 50 pps, it is 20 ms. Abbreviations:GPe, globus pallidus external segment; GPi, globus pallidus internal segment.

FIGURE 5 Representative poststimulus rasters and histograms of neuronal activity recorded from the cortex, putamen, globus pallidus external segment, and globus pallidus internal segment. The top portion of each figure is a raster of neuronal activity. Each dot represents the time of an extracellular action potential. Each row represents the segment of neuronal activity between successive stimulation pulses. Dividing the time into bins and summing across rows results in a histogram at the lower portion of each figure. For stimulation at 130 pulses per second (pps), the time of the rasters and histograms is 8 ms; for 100 pps, it is 10 ms; and for 50 pps, it is 20 ms. Abbreviations:GPe, globus pallidus external segment; GPi, globus pallidus internal segment.

counter theories that high frequency DBS inhibits the target structure whereas low frequencies activate the target. Further, these findings demonstrate that the DBS effect propagates throughout the basal ganglia-thalamic-cortical system, consistent with that system being comprised of multiple oscillators that span the entire system.

Three types of responses have been found (61). The first are very early, with latencies less than 2 ms, in the MC and GPe. Figure 6 shows this early and narrow peak at approximately 1 to 2 ms, which is most consistent with, although not proof of, antidromic activation of the MC and GPe neurons whose axons project to the STN. The second response occurs at approximately 4 ms following the stimulus, and the third occurs at 6 to 8 ms (seen most clearly with the 100 and 50 pps DBS). STN DBS effects were examined in other structures, and similar patterns of response in the GPi, putamen, and VL thalamus were found except that these lacked the early response at latencies less than 2 ms, consistent with antidromic activation. We suspect that the intermediate peaks represent oligosynaptic orthodromic activity propagated within the basal ganglia-thalamic-cortical system, whereas the longer latency responses represent polysynaptic reentrant oscillatory activity through the basal ganglia-thalamic-cortical system. The third peak occurs between 6 to 8 ms following the DBS pulse. This also is the time that the subsequent DBS pulse would occur with DBS at 130 pps. It could be that the coincidence of the third peak in neuronal activity following a DBS pulse, and the next DBS pulse results in a re-enforcement of neuronal activity, causing an amplification or resonance effect. This would account for the increased magnitude of the neuronal responses associated with 130 pps DBS compared to 100 or 50 pps DBS, as shown in Figure 6.

The oscillator theory posits reentrant oscillations within the basal ganglia-thalamic-cortical system. Further, the theory holds that the main oscillator is the

Past-stimulus Histogram

Post-stimulus Htstogram

Past-stimulus Histogram

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