High-Frequency Oscillations in the Pallidum: A Pathophysiological Biomarker in Parkinson's Disease?

Abstract

Background: Abnormal oscillatory neural activity in the beta-frequency band (13-35 Hz) is thought to play a role in Parkinson's disease (PD); however, increasing evidence points to alterations in high-frequency ranges (>100 Hz) also having pathophysiological relevance.

Objectives: Studies have found that power in subthalamic nucleus (STN) high-frequency oscillations is increased with dopaminergic medication and during voluntary movements, implicating these brain rhythms in normal basal ganglia function. The objective of this study was to investigate whether similar signaling occurs in the internal globus pallidus (GPi), a nucleus increasingly used as a target for deep brain stimulation (DBS) for PD.

Methods: Spontaneous and movement-related GPi field potentials were recorded from DBS leads in 5 externalized PD patients on and off dopaminergic medication, as well as from 3 rhesus monkeys before and after the induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine.

Results: In the parkinsonian condition, we identified a prominent oscillatory peak centered at 200-300 Hz that increased during movement. In patients the magnitude of high-frequency oscillation modulation was negatively correlated with bradykinesia. In monkeys, high-frequency oscillations were mostly absent in the naive condition but emerged after the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. In patients, spontaneous high-frequency oscillations were significantly attenuated on-medication.

Conclusions: Our findings provide evidence in support of the hypothesis that exaggerated, movement-modulated high-frequency oscillations in the GPi are pathophysiological features of PD. These findings suggest that the functional role(s) of high-frequency oscillations may differ between the STN and GPi and motivate additional investigations into their relationship to motor control in normal and diseased states.

Keywords: Parkinson's disease; deep brain stimulation; high-frequency oscillations; internal globus pallidus; local field potentials.

Figure 1.. Resting state and movement-related high-frequency oscillations recorded from DBS leads in the GPi of PD patients.

(A) Oscillatory activity observed in the GPi of five externalized DBS patients, derived from rest recordings. Median power spectral density shown (see Methods). (B) GPi oscillatory activity during a touchscreen reaching task. Trial-averaged spectrograms aligned to reach onset (t = 0) in higher (100–350 Hz, upper panels) and lower (8–35 Hz, lower panels) frequency ranges for each patient are shown. Median times of go cue and initial target touch on the touchscreen relative to reach onset are indicated by gray, green and black arrows, respectively. Numbers of reach trials included in analysis (out of 50) are shown in panel D. (C) Left panel: schematic of an Abbott directional “1–3-3–1” lead (left panel), illustrating in red that bipolar paired recordings from vertically adjacent segments were used in this study. Right panels: DBS lead implant locations for each patient, estimated from preoperative MRI and postoperative CT scans. Axial reconstructions are shown, with recording segment direction indicated in red. Recordings were made in left GPi in Pt 1, Pt 2 and Pt 4 and in right GPi in Pt 3 and Pt 5; right GPi images were mirrored for visualization. *Posterolateral segments were chosen for analysis in all patients except Pt 4 (see Methods). (D) HFO (100–300 Hz) band power calculated in a pre-movement period 1 sec duration prior to go-cue compared to band power calculated in a 1 sec duration period beginning with reach onset. In every patient there was a significant increase in HFO band power during reach (Wilcoxon Rank-sum (WRS) test, * p<0.05). (E) Relationship between HFO band power modulation depth during reach and reach duration. Across patients there was a strong negative linear relationship between HFO band power modulation and reach duration which did not reach statistical significance (Pearson, Rho = −0.868, p = 0.0565). (F) Relationship between movement related changes in HFO power and clinical ratings of bradykinesia. Across patients there was a strong negative linear relationship between HFO band power modulation and off-medication UPDRS-III bradykinesia subscores (Pearson, Rho = −0.988, p = 0.0016).

Figure 2.. Relationship between beta (13–35 Hz) and HFO band power modulation during reach.

Left panel: Band power over time, relative to reach onset, from Pt 2, illustrating concomitant modulations in beta and HFO band power. Right panel: Across patients, there was a strong linear relationship between the magnitude of beta power decrease and HFO power increase (Pearson, Rho = 0.956, p = 0.011).

Figure 3.. Exaggerated HFO activity is a feature of the parkinsonian condition.

(A) High-frequency oscillations observed in the GPi of five externalized DBS patients were reduced after dopaminergic medication (L-dopa) was administered. Data shown are median power spectral densities from rest recordings in medication off (black) and L-dopa conditions (blue); shaded regions indicate 25–75^th percentiles. Plots for each patient are shown separately for higher frequencies (65–500 Hz, upper) and lower frequencies (5–55 Hz, lower). (B) Power spectral densities based on resting state data collected in three monkeys before (naïve, black) and after systemic intramuscular administration of the neurotoxin MPTP (parkinsonian, red), illustrating an emergence of high-frequency oscillations in the parkinsonian condition.

Figure 4.. Reach-related modulation of HFO activity relative to the parkinsonian condition.

(A) GPi oscillatory activity in PD patients collected during the touchscreen reaching task in both medication on (L-dopa) and medication off conditions. Trial-averaged spectrograms aligned to reach onset (time = 0) for each patient are shown. (B) HFO band power modulation during the reach task in medication on and off conditions, calculated as absolute power change and percent change relative to baseline, * p<0.05, WRS-test. (C) Trial averaged spectrograms from monkey 3, in naive, mild (after 3 systemic intramuscular MPTP injections) and moderate (after subsequent intracarotid MPTP injection) parkinsonian conditions. n reflects number of reaches in each PD condition used to generate spectrograms and panel (D) boxplots. (D) Progressive increase in reach-related HFO modulation was observed with increasing parkinsonian severity, *** p<0.001. To aid visualization boxplot outliers are not shown (Left: 6, 11 and 1 outliers for naïve, mild and moderate states, respectively; Right: 6, 8 and 0 outliers for naïve, mild and moderate states, respectively).