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. 2014 Jul;67:1-8.
doi: 10.1016/j.nbd.2014.02.007. Epub 2014 Mar 13.

Diffusion fMRI Detects White-Matter Dysfunction in Mice With Acute Optic Neuritis

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Free PMC article

Diffusion fMRI Detects White-Matter Dysfunction in Mice With Acute Optic Neuritis

Tsen-Hsuan Lin et al. Neurobiol Dis. .
Free PMC article

Abstract

Optic neuritis is a frequent and early symptom of multiple sclerosis (MS). Conventional magnetic resonance (MR) techniques provide means to assess multiple MS-related pathologies, including axonal injury, demyelination, and inflammation. A method to directly and non-invasively probe white-matter function could further elucidate the interplay of underlying pathologies and functional impairments. Previously, we demonstrated a significant 27% activation-associated decrease in the apparent diffusion coefficient of water perpendicular to the axonal fibers (ADC⊥) in normal C57BL/6 mouse optic nerve with visual stimulation using diffusion fMRI. Here we apply this approach to explore the relationship between visual acuity, optic nerve pathology, and diffusion fMRI in the experimental autoimmune encephalomyelitis (EAE) mouse model of optic neuritis. Visual stimulation produced a significant 25% (vs. baseline) ADC⊥ decrease in sham EAE optic nerves, while only a 7% (vs. baseline) ADC⊥ decrease was seen in EAE mice with acute optic neuritis. The reduced activation-associated ADC⊥ response correlated with post-MRI immunohistochemistry determined pathologies (including inflammation, demyelination, and axonal injury). The negative correlation between activation-associated ADC⊥ response and visual acuity was also found when pooling EAE-affected and sham groups under our experimental criteria. Results suggest that reduction in diffusion fMRI directly reflects impaired axonal-activation in EAE mice with optic neuritis. Diffusion fMRI holds promise for directly gauging in vivo white-matter dysfunction or therapeutic responses in MS patients.

Keywords: Diffusion fMRI; EAE; Optic neuritis; Visual acuity; White matter.

Figures

Figure 1
Figure 1
Two diffusion-weighted images (DWI), which were zero-filled to 512 × 512, with diffusion-sensitizing gradients applied in the phase-encoding direction (left-to-right) with b values of 0.1 ms/μm2 (or 100 s/mm2) (A) and 1.4 (B) ms/μm2 (or 1400 s/mm2) were used to generate the resulting ADC map (C). The red box in panel B highlights the location of optic nerves (bright) and surrounding cerebrospinal fluid, which is highly suppressed. ADC values in the optic nerves are considerably lower than in other brain tissues. The regular (nearly circular) shape of the optic nerves suggests good orthogonality between the nerve axes and the slice plane, which minimizes partial volume effects.
Figure 2
Figure 2
Group-averaged visual acuity was significantly decreased by 58% (p < 0.005, vs. sham) in affected EAE eyes (n=7) compared with the normal vision of sham eyes (n=7); the visual acuity of contralateral blocked (n=14) eyes was in the normal range (A). In this mouse model of EAE optic neuritis, visual deficits typically develop asymmetrically, beginning in only one eye. An activation-associated ADC decrease was observed in both EAE and sham eyes but not in blocked eyes (B, C, and Table 1), suggesting that the decreased ADC in stimulated EAE and sham optic nerves was caused by axonal activity. When compared to its own baseline and stimulus-off, ADC significantly decreased in sham optic nerves by 25 and 22%, respectively (both p < 0.005, B, C, and Table 1), with visual stimulation. In contrast, only a slight and non-significant ADC decrease (7%, p = 0.45, vs. baseline and 10 %, p = 0.13, vs. stimulus-off) was observed in EAE optic nerves (B, C and, Table 1). Group ADC maps of EAE (n=7) and sham (n=7) optic nerves were generated by averaging stacked ADC maps, which were interpolated to 1024 × 1024 (C). * indicates p < 0.005
Figure 3
Figure 3
Representative 60× immunohistochemistry staining images of phosphorylated neurofilaments (SMI-31, intact axons), myelin basic protein (MBP, myelin sheath), and 4′, 6-dianidino-2-phenylindole (DAPI, nuclei) from EAE-affected (A, D, and G,) and sham (B, E, and H) optic nerves. EAE optic nerves with optic neuritis demonstrated obvious axonal beading, lower axonal density (A), reduced myelin area (D), and more cell nuclei (G). Group-averaged IHC counts of EAE (n=7) and sham (n=6) optic nerves (Table 2) revealed significant SMI-31 (C) and MBP (F) decrease (p < 0.005) and significant DAPI (I) increase (p < 0.05) in the EAE-affected group. IHC results suggested that axonal impairment, demyelination, and inflammatory infiltration all contribute to visual deficits in acute-stage optic neuritis in this EAE mouse model. Scale Bar: 25 μm * indicates p < 0.005 ** indicates p< 0.05
Figure 4
Figure 4
The activation-associated ADC change (decrease in ADC with stimulation expressed as a percentage of baseline ADC) correlated well with visual function (A, r = 0.76, p = 0.0015) and the density of intact axons (B, r = 0.92, p < 0.0001) and myelination (C, r = 0.76, p = 0.0023). Reduced activation-associated ADC response was associated with the severity of inflammation (D, r = 0.60, p = 0.03). These data suggest that axonal impairment and dysfunction can be assessed by diffusion fMRI.

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