Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait

J Parkinsons Dis. 2022;12(4):1241-1250. doi: 10.3233/JPD-213062.


Background: Background: Parkinson's disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches.

Objective: We tested the hypothesis that structural integrity of brain regions (subthalamic nucleus and globus pallidus internus, GPi) which link basal ganglia to the mesencephalic locomotor region (MLR), a region involved in automatic gait, would be associated with FOG response to dopaminergic therapy.

Methods: In this observational study, thirty-six participants with PD and definite FOG were recruited to undergo diffusion kurtosis imaging (DKI) and multiple assessments of dopa responsiveness (UPDRS scores, gait times ON versus OFF medication).

Results: The right GPi in participants with dopa-unresponsive FOG showed reduced fractional anisotropy, mean kurtosis (MK), and increased radial diffusivity relative to those with dopa-responsive FOG. Furthermore, using probabilistic tractography, we observed reduced MK and increased mean diffusivity along the right GPi-MLR tract in dopa-unresponsive FOG. MK in the right GPi was associated with a subjective dopa-response for FOG (r = -0.360, df = 30, p = 0.043) but not overall motor dopa-response.

Conclusion: These results support structural integrity of the GPi as a correlate to dopa-response in FOG. Additionally, this study suggests DKI metrics may be a sensitive biomarker for clinical studies targeting dopaminergic circuitry and improvements in FOG behavior.

Keywords: Freezing; L-DOPA; Parkinson’s disease; connectivity; dopamine; gait; neuroimaging; tractography.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Dihydroxyphenylalanine
  • Dopamine
  • Gait
  • Gait Disorders, Neurologic* / diagnostic imaging
  • Gait Disorders, Neurologic* / drug therapy
  • Gait Disorders, Neurologic* / etiology
  • Globus Pallidus / diagnostic imaging
  • Humans
  • Parkinson Disease* / complications
  • Parkinson Disease* / diagnostic imaging
  • Parkinson Disease* / drug therapy


  • Dihydroxyphenylalanine
  • Dopamine