Fiber-specific white matter reductions in Parkinson hallucinations and visual dysfunction

Abstract

Objective: To investigate the microstructural and macrostructural white matter changes that accompany visual hallucinations and low visual performance in Parkinson disease, a risk factor for Parkinson dementia.

Methods: We performed fixel-based analysis, a novel technique that provides metrics of specific fiber-bundle populations within a voxel (or fixel). Diffusion MRI data were acquired from patients with Parkinson disease (n = 105, of whom 34 were low visual performers and 19 were hallucinators) and age-matched controls (n = 35). We used whole-brain fixel-based analysis to compare microstructural differences in fiber density (FD), macrostructural differences in fiber bundle cross section (FC), and the combined FD and FC (FDC) metric across all white matter fixels. We then performed a tract-of-interest analysis comparing the most sensitive FDC metric across 11 tracts within the visual system.

Results: Patients with Parkinson disease hallucinations exhibited macrostructural changes (reduced FC) within the splenium of the corpus callosum and the left posterior thalamic radiation compared to patients without hallucinations. While there were no significant changes in FD, we found large reductions in the combined FDC metric in Parkinson hallucinators within the splenium (>50% reduction compared to nonhallucinators). Patients with Parkinson disease and low visual performance showed widespread microstructural and macrostructural changes within the genu and splenium of the corpus callosum, bilateral posterior thalamic radiations, and left inferior fronto-occipital fasciculus.

Conclusions: We demonstrate specific white matter tract degeneration affecting posterior thalamic tracts in patients with Parkinson disease with hallucinations and low visual performance, providing direct mechanistic support for attentional models of visual hallucinations.

Figure 1. Overview of the processing steps involved in FBA and VBA whole-brain analyses

(A) Processing steps for fixel-based analysis (FBA) and voxel-based analysis (VBA). Processing steps specific to FBA are shown on the left; those specific to VBA, on the right. (B) Illustration of the derived FBA and VBA metrics. DWI = diffusion-weighted imaging; FA = Fractional anisotropy; FC = fiber cross-section; FD = fiber density; FDC = fiber density and cross section combined; FOD = fiber orientation distribution; MD = mean diffusivity.

Figure 2. Fiber tract–specific reductions in PD/VH compared to PD/non-VH from whole-brain fixel-based analysis

(A) Patients with Parkinson disease (PD) with visual hallucinations (VH) vs patients with PD/non-VH. Patients with PD/VH showed changes in white matter macrostructure (as seen by reduction in fiber cross section [FC]) and the overall ability to relay information (as defined by reduction in the combined FC/fiber density [FDC] metric) compared to patients with PD/non-VH. Reduced FC and FDC are seen in the splenium of the corpus callosum and the left optic radiation in PD/VH. Percentage reduction in FC and FDC is shown (color bar reflects percentage reduction) (family-wise error [FWE]–corrected p < 0.05). (B) PD/VH vs PD/non-VH, direction of fibers. Loss of fiber tracts in PD/VH compared with PD/non-VH was seen particularly for left-right axons (color bar reflects direction of fiber loss: anterior-posterior, green; superior-inferior, blue; left-right, red) (FWE-corrected p < 0.05).

Figure 3. Fiber tract-specific reductions in PD low performers compared to PD high performers from whole-brain fixel-based analysis

Patients with Parkinson disease (PD) and low visual performance showed macrostructural (changes in fiber cross section [FC]) and microstructural changes (changes in fiber density [FD]). Microstructural changes are seen within the splenium of the corpus callosum, posterior thalamic radiations bilaterally, and left inferior fronto-occipital fasciculus. Macrostructural changes are seen within the corpus callosum. Changes in the combined FD/FC (FDC) metric are seen in the genu, splenium, bilateral thalamic radiations, and left inferior fronto-occipital fasciculus; this represents impaired overall ability to relay information in these tracts in PD low performers. Results are displayed as streamlines; these correspond to fixels that significantly differed between PD low performers and PD high performers (family-wise error–corrected p < 0.05). Streamlines are colored by percentage reduction in the PD low performers group compared to high performers for FD, FC, and FDC.

Figure 4. Significant tracts in patients with PD/VH and PD low performers; tract-of-interest analysis

(A) Reduction (mean, 95% confidence interval [CI]) in combined fiber density and cross-section (FDC) visualized as percentage reduction from the mean of patients with Parkinson disease (PD) without hallucinations (PD/non-VH). The posterior thalamic radiations bilaterally, inferior fronto-occipital fasciculi bilaterally, genu, and right superior longitudinal fasciculi survived false discovery rate (FDR) correction. (B) Reduction (mean, 95% CI) in FDC visualized as percentage reduction from the mean of patients with PD with high visual performance. Note that only the genu survived FDR correction. Tracts with significantly reduced FDC (p < 0.05) are shown in color; tracts where there are no significant changes in FDC are plotted in gray. (C) Anatomic representation of all analyzed tracts.