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■ -V 'V'v'

0 04112 0.021 0.036 II.1MB 0.06 11J172 Time since :'ioi' pulse In seconds

0 0J112 0.021 0.036 0-010 O.Oli 0,072 Time since stimulation pulse Insecomh

0 04112 0.021 0.036 II.1MB 0.06 11J172 Time since :'ioi' pulse In seconds

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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Irregular Stimulaiton

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