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. 2024 Aug 27;103(4):e209695.
doi: 10.1212/WNL.0000000000209695. Epub 2024 Aug 7.

White Matter Microstructural Changes Using Ultra-Strong Diffusion Gradient MRI in Adult-Onset Idiopathic Focal Cervical Dystonia

Claire L MacIver  1 , Derek Jones  1 , Katy Green  1 , Konrad Szewczyk-Krolikowski  1 , Andre Doring  1 , Chantal M W Tax  1 , Kathryn J Peall  1
Affiliations

White Matter Microstructural Changes Using Ultra-Strong Diffusion Gradient MRI in Adult-Onset Idiopathic Focal Cervical Dystonia

Claire L MacIver et al. Neurology. .

Abstract

Background and objectives: Adult-onset idiopathic focal cervical dystonia (AOIFCD) involves abnormal posturing of the cervical musculature and, in some individuals, an associated head tremor. Existing neuroimaging studies have implicated key motor networks. However, measures used to date lack specificity toward underlying pathophysiologic differences. We aim to assess white matter motor pathways for localized, microstructural differences, which may aid in understanding underlying mechanisms.

Methods: Individuals diagnosed with AOIFCD and an age- and sex-matched control group were prospectively recruited through the Welsh Movement Disorders Research Network. All participants underwent in-depth clinical phenotyping and MRI (structural and diffusion sequences) using ultra-strong diffusion gradients. Tractography (whole-tract median values) and tractometry (along tract profiling) were performed for key white matter motor pathways assessing diffusion kurtosis imaging (DKI), neurite orientation dispersion and density imaging (NODDI), and standard model parameters. Groups were compared using linear model analysis with Bonferroni multiple comparison correction.

Results: Fifty participants with AOIFCD and 30 healthy control participants were recruited, with 46 with AOIFCD and 30 healthy controls included for analysis (33 without head tremor, 13 with head tremor). Significant differences were observed in the anterior thalamic radiations (lower mid-tract fractional anisotropy [estimate = -0.046, p = 3.07 × 10-3], radial kurtosis [estimate = -0.165, p = 1.42 × 10-4], f-intra-axonal signal fraction [estimate = -0.044, p = 2.78 × 10-3], p2 orientation coherence [estimate = -0.043, p = 1.64 × 10-3], higher Orientation Dispersion Index [ODI, estimate = 0.023, p = 2.22 × 10-3]) and thalamopremotor tracts (higher mid-tract mean kurtosis [estimate = 0.064, p = 7.56 × 10-4], lower Neurite Density Index [estimate = 0.062, p = 2.1 × 10-3], higher distal tract ODI [estimate = 0.062, p = 3.1 × 10-3], lower f [estimate = -0.1, p = 2.3 × 10-3], and striatopremotor tracts [proximal lower f: estimate = -0.075, p = 1.06 × 10-3]). These measures correlated with clinical measures: dystonia duration (right thalamopremotor distal ODI: r = -0.9, p = 1.29 × 10-14), psychiatric symptoms (obsessive compulsive symptoms: left anterior thalamic radiation p2 r = 0.92, p = 2.797 × 10-11), sleep quality (Sleep Disorders Questionnaire Score: left anterior thalamic radiation ODI: r = -0.84, p = 4.84 × 10-11), pain (left anterior thalamic radiation ODI: r = -0.89, p = 1.4 × 10-13), and cognitive functioning (paired associated learning task p2, r = 0.94, p = 6.68 × 10-20).

Discussion: Overall, localized microstructural differences were identified within tracts linking the prefrontal and premotor cortices with thalamic and basal ganglia regions, suggesting pathophysiologic processes involve microstructural aberrances of motor system modulatory pathways, particularly involving intra-axonal and fiber orientation dispersion measures.

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Conflict of interest statement

C.M.W. Tax was supported by a Veni grant (17331) from the Dutch Research Council (NWO) and the Wellcome Trust (215944/Z/19/Z). K.J. Peall is funded by an MRC Clinician-Scientist Fellowship & Transition Award (MR/P008593/1, MR/V036084/1). Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Schematic of Methodological Approaches and Recruitment
(A) Overview of analysis methodology. (B) Schematic of measured parameters. (C) Recruitment flowchart. AK = axial kurtosis; Da = intra-axonal diffusivity; Depar = extra-axonal parallel diffusivity; Deperp = extra-axonal perpendicular diffusivity; DKI = diffusion kurtosis imaging; f = intraneurite signal fraction; FA = fractional anisotropy; FWF = free water fraction; MD = mean diffusivity; MK = mean kurtosis; NDI = Neurite Density Index; NODDI = neurite orientation dispersion and density index; ODI = Orientation Distribution Index; p2 = orientation coherence; R0 = rotationally invariant signal for order = 0, b = 6,000 s/mm2; RK = radial kurtosis; SM = standard model.
Figure 2
Figure 2. Along-Tract Profiles for the Anterior Thalamic Radiations
Parameters are shown only where significant differences were demonstrated in any analyses, with median tract value and standard error displayed for each tract. Green-shaded regions represent those significantly different after multiple comparison correction, and yellow-shaded regions are significant before correction. Deperp = extra-axonal perpendicular diffusivity; DKI = diffusion kurtosis imaging; DTI = diffusion tensor imaging; f = intraneurite signal fraction; FA = fractional anisotropy; MK = mean kurtosis; NDI = Neurite Density Index; NODDI = neurite orientation dispersion and density imaging; ODI = Orientation Dispersion Index; p2 = orientational coherence; R0 = rotationally invariant signal for order = 0, b = 6,000 s/mm2; RISH = rotationally invariant spherical harmonics; RK = radial kurtosis; SM = standard model.
Figure 3
Figure 3. Along-Tract Profiles for the Thalamopremotor Tracts
Parameters are shown only where significant differences were demonstrated in any analyses, with median tract value and standard error displayed for each tract. Green-shaded regions represent those significantly different after multiple comparison correction, and yellow-shaded regions are significant before correction. FA = fractional anisotropy; DKI = diffusion kurtosis imaging; DTI = diffusion tensor imaging; MK = mean kurtosis; RK = radial kurtosis; NODDI = neurite orientation dispersion and density imaging; SM = standard model; ODI = Orientation Dispersion Index; p2 = orientational coherence; NDI = Neurite Density Index; f = intraneurite signal fraction; RISH = rotationally invariant spherical harmonics; R0 = rotationally invariant signal for order = 0, b = 6,000 s/mm2; Deperp = extra-axonal perpendicular diffusivity.
Figure 4
Figure 4. Along-Tract Profiles for the Striatopremotor Tracts
Parameters are shown only where significant differences were demonstrated in any analyses, with median tract value and standard error displayed for each tract. Green-shaded regions represent those significantly different after multiple comparison correction, and yellow-shaded regions are significant before correction. FA = fractional anisotropy; DKI = diffusion kurtosis imaging; DTI = diffusion tensor imaging; MK = mean kurtosis; RK = radial kurtosis; NODDI = neurite orientation dispersion and density imaging; SM = standard model; ODI = Orientation Dispersion Index; p2 = orientational coherence; NDI = Neurite Density Index; f = intraneurite signal fraction; RISH = rotationally invariant spherical harmonics; R0 = rotationally invariant signal for order = 0, b = 6,000 s/mm2; Deperp = extra-axonal perpendicular diffusivity.
Figure 5
Figure 5. Summary of Pearson Correlation Analyses Within the Dystonia Cohort for Clinical Characteristics and Imaging Features That Were Significantly Different in the Dystonia Cohort Compared With Controls
Correlations marked with x were not statistically significant after correction for multiple comparisons. TWSTR = Toronto West Spasmodic Torticollis Rating Scale; MINI = modified Mini International Neuropsychiatric Interview; SCID = Structured Clinical Interview for DSM-V Personality Disorders Questionnaire; OCD = Yale-Brown Obsessive-Compulsive Scale; SF36 = Short Form 36 Health Survey; PSQI = Pittsburgh Sleep Quality Index; SWM = spatial working memory; PAL = paired associated learning; ERT = emotional recognition task; OTS = One Touch Stockings of Cambridge; FA = fractional anisotropy; MK = mean kurtosis; RK = radial kurtosis; ODI = Orientation Dispersion Index; p2 = orientational coherence; NDI = Neurite Density Index; f = intraneurite signal fraction; R0 = rotationally invariant signal for L = 0, b = 6,000 s/mm2; Deperp = extra-axonal perpendicular diffusivity.
Figure 6
Figure 6. Summary of Key Findings
FA = fractional anisotropy; MK = mean kurtosis; RK = radial kurtosis; ODI = Orientation Dispersion Index; p2 = orientational coherence; NDI = Neurite Density Index; f = intraneurite signal fraction; R0 = rotationally invariant signal for L = 0, b = 6,000 s/mm2; Deperp = extra-axonal perpendicular diffusivity.
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