The significance of the loss of presynaptic inhibition for step initiation in parkinsonian individuals with freezing of gait.

Abstract

The article by Lira et al. (2020) recently published in The Journal of Physiology presents substantially interesting perspectives regarding the pathophysiology of freezing of gait (FOG) in Parkinson's disease (PD) subjects. The authors found significant associations between loss of presynaptic inhibition (PSI) and the FOG ratio and loss of PSI and anticipatory postural adjustment (APA) amplitude. The study is important considering the rarity of electrophysiological studies evaluating FOG pathophysiology and those focusing on presynaptic inhibition. However, we think that a few more points may be discussed for a better understanding of the report. The authors found that the PD subjects with FOG presented loss of PSI (i.e. the higher ratio of the conditioned H-reflex relative to the test H-reflex) during APAs before step initiation, whereas non-freezers and healthy control individuals presented PSI in both the tasks. They also found that the loss of PSI in freezers was associated with both small APA amplitudes and FOG severity. The significance of PSI in PD subjects has been studied in a limited number of works (Morita et al. 2000; Silva-Batista et al. 2017). PSI is found to be correlated with gait speed in non-freezers (Morita et al. 2000). The authors suggested that the disturbance of the central control of PSI may be a factor responsible for bradykinesia, gait disturbance and postural instability in that disease (Morita et al. 2000). In another study (Silva-Batista et al. 2017), improvement in the spinal inhibitory mechanisms including PSI was found to be positively associated with the postural instability and quality of life scores in PD subjects and improvement in this function was achieved after resistance training for 12 weeks (Silva-Batista et al. 2017). On the other hand, the electrophysiological studies on PD patients undergoing deep brain stimulation (DBS) surgery showed significant improvement in PSI soon after the therapy (Pierantozzi et al. 2008; Andrews et al. 2020). Combining these study results (Morita et al. 2000; Pierantozzi et al. 2008; Silva-Batista et al. 2017; Andrews et al. 2020; Lira et al. 2020), the significance of PSI in the motor output in PD is demonstrated. However, it is unclear whether this mechanism plays a role as a primary target, or represents, rather, a contributory mechanism to the disturbance in the cortical motor pathways, or represents an insufficient compensatory process to normalize the abnormal motor symptoms. The crucial point was that Lira et al. (2020) investigated the association between the PSI, FOG and APA in detail. Furthermore, they performed electrophysiological investigations during the functional task for freezers. Distinct from the other motor manifestations of PD, FOG is an episodic gait pattern and the responsible motor pathway improves soon after the resolution of FOG. In this study (Lira et al. 2020), the authors found that the non-freezer and healthy control groups presented higher PSI levels in the quiet stance than the freezer group. On the other hand, in the step initiation, the freezer group remarkably presented a higher ratio of the conditioned H-reflex relative to the test H-reflex (i.e. loss of PSI) than the non-freezer and healthy control groups, which reveals the role of the transient alteration of this spinal function in the occurrence of the FOG phenomenon. However, crucial questions are why the PSI deteriorates much more in FOG subjects and where the actual localizations and mechanisms underlying the loss of PSI are in these patients. Lewis & Barker (2009) proposed the cross-talk model to explain FOG pathophysiology in terms of supraspinal motor control. They emphasized that coordinated neural activities are dependent on a series of parallel neuronal networks passing through the basal ganglia. They hypothesized that in healthy subjects, these competing, yet complementary, networks permit tight regulation in the broad domains of motor, cognitive and limbic functions. However, in PD subjects with basal ganglia dysfunction, the motor pathways allow for an element of ‘cross-talk’ between competing inputs, which in turn could lead to a paroxysmal excessive inhibition of the thalamus and pedunculopontine nucleus triggering FOG. PSI constitutes also an important motor pathway at the spinal level for modulating muscle coordination by adjusting both supraspinal motor commands and sensory feedback. Similarly, in the hypothesis of Lewis & Barker (2009) regarding supraspinal control of FOG, during locomotion and particularly manoeuvres requiring task changing (gait initiation, turning in place, etc.), the complexity of the motor and sensory networks increases, possibly exceeding the spinal reserve executing PSI. Lira et al. (2020) emphasize that loss of PSI for step initiation in freezers may be due to FOG. However, in light of the above-mentioned discussions, we rather think that the episodic loss of PSI probably contributes causally to the occurrence and severity of FOG. The authors also found significant correlations between the loss of PSI in the step initiation and APA amplitude in freezers, and also correlations between the New Freezing of Gait Questionnaire scores and the APA amplitude (P < 0.05) (Lira et al. 2020). Impaired postural adjustment in preparation for stepping is a crucial hypothesis to explain the pathophysiology of FOG (Jacobs et al. 2009). It has been demonstrated that patients with FOG displayed multiple APAs during FOG and FOG was associated with a forward loss of balance, caused by an inability to couple a normal APA to the stepping motor pattern. The concurrent execution of these APAs and the motor components of initiation of gait make locomotion strictly a complex function, which might explain why FOG manifests generally during locomotion rather than the other motor processes. In this context, the electrophysiological confirmation of the association between APA and FOG as well as loss of APA and PSI in this study (Lira et al. 2020) was also critical and makes a crucial contribution. To clarify the precise causal association between the loss of PSI and FOG, future studies including serial investigations of PSI (using the H-reflex technique) after medical (at off- and on-periods) and non-medical interventions (physical therapy with visual cueing) are warranted. At this point, the investigation of the impact of DBS therapy in PSI in association with FOG may constitute an interesting research topic. The results of these studies may enlighten the role of PSI in the development of FOG episodes and these conclusions may also contribute to our understanding of the mechanisms underlying recovery of FOG as well as address the potential targets for treatment-based studies. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. B. Kocer and S. Comoglu: Neurology Clinic, Diskapi Yildirim Beyazit Training and Research Hospital, Şehit Ömer Halisdemir Street. No: 20 Altındag, Ankara, 06110, Turkey.