Correlation between cortical beta power and gait speed is suppressed in a parkinsonian model, but restored by therapeutic deep brain stimulation

Highlights

• In a ratmodel of PD, we quantified motor-cortical beta power versus gait speed during effective & ineffective DBS of STN.

• Therapeutic and non-therapeutic STN DBS suppresses cortical beta power both at rest and during unrestrained movement.

• Therapeutic, but not non-therapeutic, STN DBS restores the asymptomatic relationship between beta power and gait speed.

Abstract

The motor cortex and subthalamic nucleus (STN) of patients with Parkinson's disease (PD) exhibit abnormally high levels of electrophysiological oscillations in the ~12–35 Hz beta-frequency range. Recent studies have shown that beta is partly carried forward to regulate future motor states in the healthy condition, suggesting that steady state beta power is lower when a sequence of movements occurs in a short period of time, such as during fast gait. However, whether this relationship between beta power and motor states persists upon parkinsonian onset or in response to effective therapy is unclear. Using a 6-hydroxy dopamine (6-OHDA) rat model of PD and a custom-built behavioral and neurophysiological recording system, we aimed to elucidate a better understanding of the mechanisms underlying cortical beta power and PD symptoms. In addition to elevated levels of beta oscillations, we show that parkinsonian onset was accompanied by a decoupling of movement intensity — quantified as gait speed — from cortical beta power. Although subthalamic deep brain stimulation (DBS) reduced general levels of beta oscillations in the cortex of all PD animals, the brain's capacity to regulate steady state levels of beta power as a function of movement intensity was only restored in animals with therapeutic DBS. We propose that, in addition to lowering general levels of cortical beta power, restoring the brain's ability to maintain this inverse relationship is critical for effective symptom suppression.

Introduction

Parkinsonian symptoms are associated with neural activity in the 15–30 Hz beta band, most notably in the basal ganglia (Brown et al., 2001; Chen et al., 2010; Pogosyan et al., 2010). Data from non-human-primate and rodent models show that parkinsonian severity increases with beta power not only in basal ganglia (Avila et al., 2010; Deffains et al., 2016; Mallet et al., 2008a), but also in motor cortex (Lehmkuhle et al., 2009; Mallet et al., 2008b; Sharott et al., 2005). Recent human studies support that, for at least some behaviors, PD is associated with elevated levels of cortical beta activity, including cortical-subcortical beta coherence (Hirschmann et al., 2011; Litvak et al., 2011), cortical beta phase-amplitude coupling (de Hemptinne et al., 2013; Malekmohammadi et al., 2018), and cortical beta power (Crowell et al., 2012; George et al., 2013). In healthy individuals, beta activity is best known for its associations with motor suppression: cortical beta power increases upon motor task completion (Heinrichs-Graham et al., 2017; Jurkiewicz et al., 2006) and anticipated movement cancellation (Picazio et al., 2014; Zhang et al., 2008). In addition, beta-band drive to motor cortex slows reaction times (McAllister et al., 2013) and response speeds (Pogosyan et al., 2009). Considerations of beta activity's conspicuousness in PD and elevation amid regular motor suppression has led to the widespread hypothesis that persistently high beta activity underlies some motor symptoms of PD, such as hypokinesia and rigidity.

In non-parkinsonian individuals, beta power variations are associated with voluntary motor activity (Fry et al., 2016; Jurkiewicz et al., 2006). Motor cortical beta power decreases before movement onset (Leocani et al., 1997; Pfurtscheller and Berghold, 1989), and rebounds after movement offset (Cassim et al., 2001; Pfurtscheller et al., 1996). These post-movement associated beta rebounds — also known as event related synchronizations — are thought to suppress movement by inhibiting the motor network during action termination (Heinrichs-Graham et al., 2017; Salmelin et al., 1995). Similarly, the aforementioned pre-movement associated beta suppressions — also known as event related desynchronizations — are thought to enable movement by disinhibiting the motor network during action preparation (Pape and Siegel, 2016; Zhang et al., 2008). Although this relationship is well characterized, its time-varying nature (between present beta power changes and past-versus-future body kinematics) remains difficult to set within a framework of neurally driven movement.

In a leading model, beta activity correlates with changes in motor states: high beta power denotes maintenance of the present state, while low beta power denotes an abrupt shift in motor behavior (Engel and Fries, 2010; Gilbertson et al., 2005). In this model, aberrant parkinsonian beta power commands adherence to the behavioral status quo: if at rest, stay at rest. And, therapies that suppress beta power re-enable behavioral modulation, alleviating hypokinetic symptoms. This model suggests that cortical beta power should have a similar value during all sustained (c.f., changing) motor activity levels, e.g., standing, walking, and running. However, recent work suggests that after accounting for onset and offset effects, beta activity varies inversely with metrics of movement intensity. Tasks more intense than slow walking correspond to less beta power, including fast walking (Lisi and Morimoto, 2015) and bike riding (Storzer et al., 2016). Tasks less intense than slow walking correspond to more beta power, including walking at fixed speed on a treadmill (Bulea et al., 2015) or with a gait stabilization system that support body weight (Bruijn et al., 2015). Whether this relationship persists in PD is unknown. Phrased explicitly: does the elevated beta activity observed in PD still modulate with movement intensity?

In this study we sought to understand the relationship between cortical beta power and changes in movement speed using a rodent model of PD in response to a variety of putatively therapeutic DBS patterns. From previous work, we expected overall beta activity to increase with PD onset, and to decrease with therapeutic DBS. Extending existing ideas, we hypothesized that the cortico-subthalamic network would maintain a consistent inverse relationship between beta power and movement speed in the healthy condition, but would lose the ability to maintain that relationship upon entering the parkinsonian state. We tested these hypotheses in a unilateral 6-OHDA rat model of PD and quantified the impact of effective and ineffective STN-DBS on the relationship between cortical beta power and movement speed. Our results support the idea that a stable, inverse relationship between beta power and movement speed is disrupted by PD. Mean levels of cortical beta power were lowered by both effective and ineffective DBS. But only effective stimulation restored the ability to modulate steady state cortical beta power as a function of motor activity. Thus, therapeutic DBS may allow the brain to carry meaningful levels of cortical beta activity forward from previous motor states, thereby restoring dynamic control of motor behavior.