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

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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.

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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

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FIGURE 6 Representative examples of normalized poststimulation histograms for individual neurons in various structures. Each graph represents the changes in probability of neuronal activity in time bins during the inter deep brain stimulation (DBS) stimulus interval. The graphs are represented as z-score changes from the no-DBS condition (31). Each graph represents data obtained during DBS at 130 Hz, 100 Hz, and 50 Hz. Visual inspection classified the poststimulation histograms into those where there is no difference in the responses with different DBS frequencies and those with differences. The numbers in each class are expressed as a ratio to the total number of neurons recorded in the structure presented in the top right-hand corner of the poststimulus histograms. In the cortex, most neurons (14/20) had the same pattern of response to different DBS frequencies; however, the 130 Hz produced the greatest early response. In 6/20, the patterns and magnitudes were not different. Similar results are shown for globus pallidus internal and external segments and the putamen. The z score was computed based on the mean and the standard deviation of the pres-timulation baseline. Thus, if a neuron's discharge rate went from a prestimulation average of 30 to 130 Hz with 130 Hz DBS, then the z score would be very large. Abbreviations: Ctx, cortex; GPe, globus pallidus external segment; GPi, globus pallidus internal segment; Pt, putamen.

disynaptic positive feedback loop comprised of the MC and VL thalamus. Assuming an approximate 3.8-ms combined conduction velocity and synaptic delay for each limb of the disynaptic feedback loop (31), the reentrant frequency would be approximately 130 Hz. The other loops through the basal ganglia-thalamic-cortical system interact with the main loop MC ^ VL to modulate activity within the MC and VL. An extension of the oscillator theory to DBS mechanisms of action is the resonance theory. The optimal DBS frequency of approximately 130 pps amplifies by resonance the inherent oscillator frequencies within the basal ganglia-thalamic-cortical system. Studies in nonhuman primates provide direct evidence of multiple and high frequencies within the basal ganglia-thalamic-cortical system (62) and evidence of resonance amplification by DBS (63).

There are some preliminary data for a behavioral resonance effect with STN DBS, as shown in Figure 7. A nonhuman primate was trained to perform an arm

FIGURE 7 Perievent rasters and histograms for a putamen neuron recorded in a nonhuman primate. There is no meaningful modulation of neuronal activity with behavior (appearance of the "go" signal at time zero is indicated by the up-arrow). However, with 130 pps and to a lesser extent with 100 pps deep brain stimulation (DBS), there is a consistent modulation, suggesting that the DBS has enlisted the neuron into being meaningfully related to the behavior. Abbreviation: DBS, deep brain stimulation.

FIGURE 7 Perievent rasters and histograms for a putamen neuron recorded in a nonhuman primate. There is no meaningful modulation of neuronal activity with behavior (appearance of the "go" signal at time zero is indicated by the up-arrow). However, with 130 pps and to a lesser extent with 100 pps deep brain stimulation (DBS), there is a consistent modulation, suggesting that the DBS has enlisted the neuron into being meaningfully related to the behavior. Abbreviation: DBS, deep brain stimulation.

movement task in response to a go signal (61). Neuronal recordings were performed with no DBS of the STN, and then DBS at 130, 100, and 50 pps. There was no modulation of the putamen neuronal activity correlated with performance of the task under the no DBS condition. It appeared that this neuron was not involved with generating the behavior. However, with 130-pps STN DBS, the neuron modulated its activities consistent with the behavior. It is as though the neuron was recruited in the neuronal mechanisms associated with generating the behavior. Interestingly, DBS at 100 and 50 pps was less effective in recruiting the neuronal activity into the task.

The oscillatory theory holds that the multiple frequency oscillations within the basal ganglia-thalamic-cortical system are organized in a precise manner to orchestrate the precise timing of agonist and antagonist muscle activities to carry out normal behavior. The main oscillator fundamental to this process is the approximately 130-Hz MC ^ VL feedback loop. However, side loops at lower frequencies, such as MC ^ putamen ^ GPe ^ STN ^ GPi ^ VL ^ MC and MC ^ STN ^ GPi ^ VL, modulate the discharge activity of the MC in a manner necessary to appropriately drive agonist and antagonist muscles. Perhaps, these different oscillators interact as an inverse Fourier transformation. Such interactions can be based on resonance, synchronization, beat interactions, and others that go well beyond the one-dimensional push-pull systems, which exemplify the current theories (7).

It also is possible for DBS at different frequencies to interact or resonate with other side loops and disrupt normal oscillator interactions within the basal ganglia-thalamic-cortical system. This may explain why STN DBS at low frequencies, such as 10 pps, worsens PD symptoms (64). Also, cycling STN DBS at the same overall frequency as regular DBS results in slower movement times in PD subjects (65).

It has also been demonstrated that modulated and irregular STN DBS worsens PD motor performance. A patient with PD was implanted with bilateral STN DBS. The leads were externalized and stimulated before implantation of the implantable pulse generators. Stimulation was performed across the most proximal and distal contacts with bipolar current, ranging from 1 to 5 mA. Current was increased until any effect was noted. Each phase of the stimulation pulse was 0.2-ms long. The patterns of stimulation were regular, irregular, and modulated (Fig. 8). The different patterns were stimulated in a randomized sequence. An investigator blinded to the stimulation parameters assessed the patient. Measures were taken from the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). These measures con-

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FIGURE 8 Illustration showing irregular and modulating stimulation at the same overall frequency.

FIGURE 9 Changes in the Unified Parkinson's Disease Rating Scale for finger-tapping in the left-hand contralateral to the deep brain stimulation (DBS) lead and to the ipsilateral hand (right) in a single subject with Parkinson's disease and subthalamic nucleus DBS. The evaluator was blinded to the pattern of stimulation. The 130 pps DBS modulated at 2 Hz worsened motor performance (negative change in score), but regular DBS at 130 pps improved motor performance. Irregular DBS at 130 pps average did not have a marked effect.

FIGURE 9 Changes in the Unified Parkinson's Disease Rating Scale for finger-tapping in the left-hand contralateral to the deep brain stimulation (DBS) lead and to the ipsilateral hand (right) in a single subject with Parkinson's disease and subthalamic nucleus DBS. The evaluator was blinded to the pattern of stimulation. The 130 pps DBS modulated at 2 Hz worsened motor performance (negative change in score), but regular DBS at 130 pps improved motor performance. Irregular DBS at 130 pps average did not have a marked effect.

sisted of (i) muscle tone, (ii) finger-tapping speed, (iii) hand opening-closing speed, (iv) arm pronation-supination speed, (v) rest tremor, and (vi) postural tremor. Other measures in the UPDRS motor section could not be performed, because the patient was restricted to the operating table.

Computer programs controlled the stimulation patterns in which regular, irregular, and modulated 130-pps DBS was delivered (Fig. 8). The results of the stimulation are shown in Figure 9. For left-sided finger-tapping (contralateral to DBS), the greatest improvement was with regular stimulation and with stimulation modulated at 10 Hz, with the same overall stimulation frequency of 130 pps. All other stimulation patterns actually worsened finger-tapping. On the right side (ipsilateral to DBS), the only improvement was noted with regular stimulation. Thus, stimulation modulated at 5 and 2 Hz actually worsened finger-tapping, although the overall frequency was at the same high rate of 130 pps. Similar results were obtained for rapid left-hand opening and closing. The greatest improvement on the right-side DBS was with regular stimulation. Stimulation modulated at 10 Hz and 5 Hz produced some improvement, but stimulation modulated at 2 Hz produced no improvement in hand opening and closing. Stimulation at all patterns showed worsened performance on the right side that did not vary with stimulation pattern.

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