Thalamic morphology predicts the onset of freezing of gait in Parkinson’s disease

Abstract

The onset of freezing of gait (FOG) in Parkinson’s disease (PD) is a critical milestone, marked by a higher risk of falls and reduced quality of life. FOG is associated with alterations in subcortical neural circuits, yet no study has assessed whether subcortical morphology can predict the onset of clinical FOG. In this prospective multimodal neuroimaging cohort study, we performed vertex-based analysis of grey matter morphology in fifty-seven individuals with PD at study entry and two years later. We also explored the behavioral correlates and resting-state functional connectivity related to these local volume differences. At study entry, we found that freezers (N = 12) and persons who developed FOG during the course of the study (converters) (N = 9) showed local inflations in bilateral thalamus in contrast to persons who did not (non-converters) (N = 36). Longitudinally, converters (N = 7) also showed local inflation in the left thalamus, as compared to non-converters (N = 36). A model including sex, daily levodopa equivalent dose, and local thalamic inflation predicted conversion with good accuracy (AUC: 0.87, sensitivity: 88.9%, specificity: 77.8%). Exploratory analyses showed that local thalamic inflations were associated with larger medial thalamic sub-nuclei volumes and better cognitive performance. Resting-state analyses further revealed that converters had stronger thalamo-cortical coupling with limbic and cognitive regions pre-conversion, with a marked reduction in coupling over the two years. Finally, validation using the PPMI cohort suggested FOG-specific non-linear evolution of thalamic local volume. These findings provide markers of, and deeper insights into conversion to FOG, which may foster earlier intervention and better mobility for persons with PD.

More Than Just Static: Dynamic Functional Connectivity Changes of the Thalamic Nuclei to Cortex in Parkinson's Disease With Freezing of Gait

“…The thalamus, as a key node in the basal ganglia-thalamocortical and cerebellothalamocortical circuits, plays a crucial role in the modulation of gait. Thalamic morphology predicts the onset of FOG in PD (5). Although isolated thalamus lesions seldom induce FOG, disruption of thalamic neural activity and functional connections contribute to the development of FOG.…”

Reduced Norepinephrine Transporter Binding in Parkinson’s disease with dopa Responsive Freezing Gait

“…This work adds to a growing body of knowledge demonstrating structural and functional changes in the thalamus – and in the connections of the thalamus to other brain regions – in PD patients with FOG. In a prospective MRI neuroimaging study, D’Cruz et al 58 showed local inflations in bilateral thalami in patients who presented with or would later develop FOG. These inflations involved medial thalamic sub-nuclei volumes which are highly innervated by NA pathways.…”

“…This work adds to a growing body of knowledge demonstrating structural and functional changes in the thalamus -and in the connections of the thalamus to other brain regions -in PD patients with FOG. In a prospective MRI neuroimaging study, D'Cruz et al 58 Other studies have shown several anatomical changes in connections between the thalamus and other brain regions in FOG, including some known to be crucial for balance and gait. These include diminished structural connectivity between the thalamus and mesencephalic locomotor region and reduced thalamic fiber tracts in the right hemisphere in FOG 59 and more pronounced white matter abnormalities in multiple tracts connecting to the thalamus in FOG 60 .…”

Discussion of Research Priorities for Gait Disorders in Parkinson's Disease

“…Connections of the medial thalamic nuclei with cortical associative and limbic areas are enhanced with the appearance of FOG in patients with PD 47 . The increased coupling to those nonmotor cortical areas has been interpreted as compensation to deficient sensorimotor integration or reinforcement of malfunctioning circuits 48 . The cerebellum, a major player in postural control, may also be involved in FOG mechanisms and FOG triggering.…”