Parkinsonism State Uncouples Correlation Between Subthalamic Nucleus ß-Band Activity and Motor Performance (2013)

Deep brain stimulation (DBS) has provided relief for many patients with medically refractory movement disorders. While the mechanisms involved are not entirely understood, studies have shown that continuous high-frequency DBS in the subthalamic nucleus (STN) or globus pallidus interna reduces the severity of the motor impairments in Parkinson's disease in both humans and monkeys. A limitation of present DBS approaches is the lack of feedback to control the stimulation and optimize the therapeutic outcome. Several studies have demonstrated the potential for closed-loop stimulation to tailor stimulation to the pathological state [3,4]. One critical question is the internal signals to use for feedback control. The goal of this study was to evaluate for potentially useful feedback signals recorded in MPTP-induced hemi-parkinsonian non-human primates trained in an arm reaching task. An emphasis was placed on spectral analysis of the extracellular local field potentials (LFPs) recorded in the STN, and the relationship between spectral power and movement performance.Two Rhesus monkeys were trained in a reaching task that involved moving from a start pad to a touch screen. Using a delayed reaction time design, the animal had to place its hand on the start pad, then a target appeared on a touch screen (1 of 8 possible targets arranged circularly) representing the Instruction cue. The monkey was trained to wait to reach until the Go cue was provided with a randomized delay (500 to 1000 msec). After Go cue presentation, the animal was to reach to and touch the screen within the target boundaries. After training a hemi-parkinsonian state was induced by unilateral injection(s) of MPTP in the external carotid branch [2]. Animals were evaluated bi-weekly by an unbiased observer using a 25 point scoring system [1].A four-contact DBS electrode designed for the monkey was placed in the STN on the MPTP-injected side based on coordinates established by single unit microelectrode recordings and computer modeling based on integration of MRI and neuroanatomical data (AVIZO, Mercury Computer Systems, Inc.).Only LFP data from completed trials was analyzed. A completed trial required a reach that touched the screen within all the timing requirements, even outside the target. LFP recordings were down sampled to 1 KHz and detrended. The LFP data was selected in time windows of 500 ms before the Instruction cue (Instruction epoch), Go cue (Go epoch), and Movement onset (Move epoch), defined as the release of the starting pad. The spectral content was determined at 1 Hz resolution. Single electrode and the difference between adjacent electrodes were used in single and bipolar montages, respectively. Reaction time was measured between the Go cue and starting pad release. Reach time was measured between starting pad release and screen touch.One monkey had three intracarotid injections (0.5 mg/kg, 0.5 mg/kg, and 0.8 mg/kg) of MPTP and developed clinical scores ranging between 7–9. The second monkey received a single intracarotid injection of MPTP (0.65 mg/kg) and had clinical scores in the range of 8–9. Therefore, both animals developed a moderate parkinsonian state and both were evaluated over a period (pre- and post-MPTP) of ∼1.2 years. Although the animals performed the reach task proficiently prior to MPTP, both had considerable difficulty following MPTP. The number of attempted and successful reaches decreased in both animals. Reach time (pre-MPTP: 439 ± 32 ms and 314 ± 38 ms; post-MPTP: 663 ± 121 ms and 570 ± 69 ms) and reaction time (pre-MPTP: 385 ± 58 ms and 359 ± 31 ms; post-MPTP: 490 ± 155 ms and 457 ± 91 ms) increased significantly (p < 0.05) in both animals following MPTP.We examined the spectral power in the STN field potentials during single trials. Trials were sorted into successful and unsuccessful reaches based on whether the animal touched the screen within the target or outside the target, respectively. For each trial, the highest power within the β-band range (12–20 Hz) was determined. Figure 1 shows the results from one monkey using a bipolar montage between electrodes 0 and 1 (with 0 being the most caudal electrode). Pre-MPTP trials (unshaded area) have relatively low amplitude peak β-band power. After MPTP (shaded area), the maximum power within the β-band is markedly increased.There are several features of these plots to note. First, the data from movement trials are plotted sequentially. Therefore, the x-axis is not linear in time. Second, the number of successful reaches is greater than unsuccessful reaches, therefore the trial numbers (x-axis) differ markedly. The increase in β-band peak power occurs in all epochs (Instruction, Go and Move). In addition, we would emphasize the variability from trial to trial. While increases in β-band power occur, there are also many trials in which the β-band power is at levels comparable to pre-MPTP trials. The increase in β-power is also evident in both successful and error trials. The peak β-power continues to increase until the end of the recordings. The second monkey also exhibits a dramatic increase in peak β-band power on individual trials following MPTP. However, the increase in power diminished toward the end of the recording period (data not shown). Increases in β-band peak power were common for other electrode pairs.Using this trial-based analysis, we assessed the relation between motor performance and β-band power. Specifically, we tested whether reaction or reach time is significantly correlated with the peak power in the β-band. The correlation analysis was done for each of the three epochs (Instruction, Go and Move), pre and post-MPTP. Pre-MPTP, significant correlations were most often observed with reach time. As shown in Figure 2 there is a significant correlation between reach time and peak β-band power based on the 500 msec period prior to the Go cue.A positive relationship between reach time and peak power in the β-band was common prior to MPTP for both monkeys, with the strongest relationship for successful trials. In the summary plots in Figure 3, a probability of “1” for the reach time correlations for pre-MPTP success trials means that for each of the four bipolar montages, a significant correlation between reach time and β-band power was found. Significant correlations were common for each alignment period, particularly for successful trials. The correlations between β-band power and unsuccessful reaches was less.Following MPTP the probability of a significant correlation between reach time and β-band peak power declines. This is evident for the Go cue time window as shown in Figure 2. This loss of correlation is true for all three alignment time points in both animals (Figure 3).Examining the β-band activity independently of the other frequencies provides a convincing demonstration that MPTP triggers the β-power increase at all epochs during a reach. Furthermore, the bipolar montage shows the increase in β-band power to be localized to the STN. The single trial analysis is encouraging, offering a single trial marker of the parkinsonian state.The significant correlation of β-band power with behavioral parameters observed in healthy subjects is degraded in the parkinsonian state, suggesting that functional signals are masked by pathological activity. This is consistent with the view that excessive β-power reduces motor performance.Further studies are needed to characterize the differences between pathological and physiological β-band activity, both during rest and well defined motor tasks such as reach, possibly resulting in spectral templates of optimal or improved STN activity. Stimulating and recording simultaneously on the same contact could characterize the spectral content of current STN activity using repeated recordings over relative short time windows. Minimizing the differences between the current spectral content and the spectral template could be a strategy to continuously optimize stimulation parameters.