Loss of presynaptic inhibition for step initiation in parkinsonian individuals with freezing of gait

Abstract

Key points: Individuals with freezing of gait (FoG) due to Parkinson's disease (PD) have small and long anticipatory postural adjustments (APAs) associated with delayed step initiation. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs due to supraspinal dysfunction. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, it may be deficient in freezers during APAs. We show that freezers presented PSI in quiet stance (control task), but they presented loss of PSI (i.e. higher ratio of the conditioned H-reflex relative to the test H-reflex) during APAs before step initiation (functional task), whereas non-freezers and healthy control individuals presented PSI in both the tasks. The loss of PSI in freezers was associated with both small APA amplitudes and FoG severity. We hypothesize that loss of PSI during APAs for step initiation in freezers may be due to FoG.

Abstract: Freezing of gait (FoG) in Parkinson's disease involves deficient anticipatory postural adjustments (APAs), resulting in a cessation of step initiation due to supraspinal dysfunction. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, here we hypothesized a loss of PSI in freezers during APA for step initiation, which would be associated with FoG severity. Seventy individuals [27 freezers, 22 non-freezers, and 21 age-matched healthy controls (HC)] performed a 'GO'-commanded step initiation task on a force platform under three conditions: (1) without electrical stimulation, (2) test Hoffman reflex (H-reflex) and (3) conditioned H-reflex. They also performed a control task (quiet stance). In the step initiation task, the H-reflexes were evoked on the soleus muscle when the amplitude of the APA exceeded 10-20% of the mean baseline mediolateral force. PSI was quantified by the ratio of the conditioned H-reflex relative to the test H-reflex in both the tasks. Objective assessment of FoG severity (FoG-ratio) was performed. Freezers presented lower PSI levels during quiet stance than non-freezers and HC (P < 0.05). During step initiation, freezers presented loss of PSI and lower APA amplitudes than non-freezers and HC (P < 0.05). Significant correlations were only found for freezers between loss of PSI and FoG-ratio (r = 0.59, P = 0.0005) and loss of PSI and APA amplitude (r = -0.35, P < 0.036). Our findings suggest that loss of PSI for step initiation in freezers may be due to FoG.

Keywords: H-reflex; inhibition; sensorimotor integration; spinal inhibitory mechanism; step initiation; ‘freezers’.

Figure 1.

Experimental setup and respective signals. (A) Task examples: (A1) quiet stance; (A2) performing step initiation task with lateral weight shift associated with the anticipatory postural adjustment (APA) after a verbal imperative “GO” signal and stepping. H-reflexes (test and conditioned) were triggered during quiet stance (A1) and during APAs for step initiation (A2). (B) Example of an H-reflex triggered at the onset of APA (duration shaded). Solid line shows mediolateral force (Fml) amplitude during the APA and dashed line shows forward displacement of the reflective marker attached to the ankle during the step. (C) Representative traces of test and conditioned H-reflexes (average over 15 responses) for a freezer, non-freezer, and age-matched healthy individual during quiet stance and in APA for step initiation.

Figure 2.

Means ± SD for the ratio of the conditioned H-reflex relative to the test H-reflex (i.e., presynaptic inhibition [PSI]) during quiet stance and step initiation. As can be seen, every freezer showed loss of PSI (i.e., higher ratio of the conditioned H-reflex relative to the test H-reflex) during APA in the step initiation (above the dashed line), but presented PSI levels during quiet stance, whereas every non-freezers and age-matched healthy individuals (HC) showed PSI in both the tasks. *Different from quiet stance values (P<0.05). ^#Different from quiet stance values of the non-freezer and HC groups (P<0.05). ^&Different from quiet stance values of the HC group (P<0.05). ^€Different from step initiation values of the non-freezer and HC groups (P<0.05). ^¥Different from step initiation values of the HC group (P<0.05).

Figure 3.

Means ± SD for the amplitude (A) and duration (B) of the anticipatory postural adjustments (APA) in the step initiation for the freezer, non-freezer, and age-matched healthy controls (HC) groups. *HC presented higher APA amplitudes and shorter APA durations than the individuals with PD (P<0.05). ^#Non-freezer presented higher APA amplitudes than the freezers (P<0.05).

Figure 4.

Correlation of loss of presynaptic inhibition (i.e., higher ratio of the conditioned H-reflex relative to the test H-reflex) with anticipatory postural adjustment (APA) amplitude (A) and with freezing severity (FoG-ratio) (B), and correlation of the subjective severity of freezing (New Freezing of Gait Questionnaire [NFoGQ] scores) with APA amplitude (C). Spearman’s r-values and P-values are shown.