Reply from Jumes Leopoldino Oliveira Lira, Carlos Ugrinowitsch, Daniel Boari Coelho, Luis Augusto Teixeira, Andrea Cristina de Lima-Pardini, Fernando Henrique Magalhães, Egberto Reis Barbosa, Fay B. Horak, and Carla Silva-Batista

The Authors Reply,

We read with interest and enthusiasm the positive comments of Onder et al. on our innovative results about the loss of presynaptic inhibiton (PSI) for step initiation in people with Parkinson’s disease (PD) and freezing of gait (FOG [freezers]) and the recommendations for future studies.

Onder et al. found our study important considering the rarity of electrophysiological studies evaluating the relationship between FOG and PSI. Onder et al. raised two important questions from our findings: 1) Does PSI play a role as a primary target in the pathophysiology of FOG or does it represent a contributory mechanism to the cortical motor dysfunction? and 2) Does PSI represent an insufficient compensatory process for FOG?

Regarding the first question, we have found that loss of PSI, FOG severity, and decreased anticipatory postural adjustment (APA) are all related (Lira et al., 2020), which suggest that similar neural correlates explain all three. The mesencephalic locomotor region (MLR) may play an important role in the relationships among PSI, FOG, and APAs. MLR is a region of the midbrain that, when stimulated, increases postural tone for standing posture and induces stepping and running in the decerebrate cat (Shik & Orlovsky, 1976). MLR also has neurons related to APAs preceding step initiation (Sinnamon et al., 2000). Freezers have worse structural and functional deficits in pedunculopontine nucleus (PPN), one of the major nuclei of the MLR, than non-freezers and healthy controls (Fling et al., 2013). Over-activity of the output nuclei of the basal ganglia in freezers may lead to excessive paroxysmal inhibition of the already disordered PPN (Lewis & Barker, 2009). Inhibition of PPN likely has a negative influence on spinal inhibitory mechanisms related to postural preparation, such as PSI, before triggering FOG. PSI is crucial for postural preparation and walking (Faist et al., 1996; Nielsen, 2004) and FOG may be due to an inability to inhibit stance postural tone and initiate stepping (Nutt et al., 2011; Fling et al., 2013; Cohen et al., 2014). Taken together, we hypothesized that loss of PSI is due to lack of central inhibition (decreased MLR activation) when standing to allow for step initiation, which may contribute to occurrence of FOG events.

Regarding the second question, we agree that restoring PSI may compensate for supraspinal dysfunction during FOG episodes, as we have recently demonstrated that healthy elderly individuals have higher PSI levels associated with weaker APAs compared to healthy young individuals (Filho et al., 2021). The increase in PSI levels in elderly individuals has been considered an adaptive/compensatory phenomenon, due to age-related deterioration of supraspinal modulation (Morita et al., 1995; Filho et al., 2021). It is important to highlight that although we assessed PSI in the ON-medication state during no FOG episodes, we will test the hypothesis that the loss of PSI is greater during OFF-medication state than in ON state, as levodopa changes the excitability of the H-reflex in PD (McLeod & Walsh, 1972).

Onder et al. also suggest that to clarify the precise causal association between the loss of PSI and FOG, the use of physical therapy with visual cues are important. Although cues are applied to evoke a more goal-directed type of motor control, long-term consolidation and transfer of effects of visual cues are hampered in freezers (Ginis et al., 2018), suggesting that visual cues may not increase PSI in this population. Thus, we hypothesize that therapies need to cause persistent and permanent neurophysiological adaptations to restore PSI during APAs in freezers. As PSI is important for modulating muscle coordination by adjusting both supraspinal motor commands and sensory feedback at the spinal level (Nielsen, 2004), rehabilitation interventions focused on sensorimotor integration might restore PSI during APA in freezers.

We have recently demonstrated that 12 weeks of motor-cognitve balance training on unstable surfaces increases MLR activation and APA amplitude and decreases FOG severity in freezers (Silva-Batista et al., 2020). Previously, we found that 12 weeks of resistance training with instability were more effective than 12 weeks of resistance training alone in increasing PSI levels, at rest, in non-freezers (Silva-Batista et al., 2017). Taken together, we believe that interventions focused on challenging sensorimotor integration could restore PSI levels during APA in freezers, which in turn, would compensate for supraspinal dysfunction and overcome FOG episodes. From these considerations, we propose that large-scale trials investigating sensorimotor rehabilitation strategies specifically aimed at restoring PSI and reducing FOG in the long term are urgently needed to treat this disabling symptoms in PD.