Maturation
Before discussing the results obtained on the OR, a brief overview of the findings relative to other WM tracts is relevant to put into perspective our findings. An increase then decrease of grey matter volume (inverted U-shape) was reported in both cortical and subcortical areas (Gogtay et al.
2004; Luders et al.
2005; Sowell et al.
2003; Thompson et al.
2005), while white matter was shown to continuously increase in volume, roughly linearly (Paus et al.
2001; Bartzokis et al.
2010; Schmithorst and Yuan
2010; Paus
2010). Dissection studies have suggested that WM develops first within posterior sensory areas and at a later stage in anterior and temporal regions (Kinney et al.
1988; Flechsig Of Leipsic
1901; Yakovlev and Lecours
1967). It has been generally found that FA and MD increase and decrease, respectively, with age, especially due to a decrease in λ
⊥ rather than changes in λ
∥ (Schmithorst and Yuan
2010). Such observations from early childhood to the end of adolescence have been demonstrated in the internal capsule, corticospinal tract, inferior longitudinal fasciculus, splenium of the corpus callosum, superior longitudinal fasciculus, cingulum, inferior fronto-occipital fasciculus, uncinate fasciculus, external capsule, cingulum and left arcuate fasciculus (Schmithorst et al.
2002; Bonekamp et al.
2007; Eluvathingal et al.
2007; Schneider et al.
2004; Zhang et al.
2005; Ben Bashat et al.
2005; Lebel et al.
2008).
To the best of our knowledge, the only reference relative to OR maturation using DTI in children is Govindan et al. (
2008) who showed an age effect for FA and MD in a small cohort of 13 children [5 males and 8 females aged 3–18 years (mean 9.1 ± 4.0 years)]. The latter study did not find any significant gender effect and did not investigate lateralization. With respect to adolescents and young adults, the only two studies known to address maturational changes, comparing characteristics of the OR between that group and older volunteers, were a study of FA and MD in 19 subjects aged 19–39 years and 12 subjects aged 40–65 years in Lee et al. (
2009), and FA between 15 subjects aged 14–21 years and 33 subjects aged 22–64 years in Schneiderman et al. (
2007). None of these studies found a significant age effect.
In our cohort of 90 subjects, we observed an increase in FA and a decrease in MD with age, in agreement with maturational changes found in other white matter tracts. We also observed evidence for lateralization and sexual dimorphism in DTI metrics. In addition, we demonstrated for the first time that the decrease in MD in the OR is mainly due to a decrease in λ
⊥, similar to changes reported in other tracts, rather than a decrease in λ
∥. The fact that we did not see an age effect in volume was not surprising. The OR and its direct afferent and efferent structures are known to mature very early in life. By the age of 9 months, the LGN has already reached adult morphology (De Courten and Garey
1982). The primary visual cortex reaches a volume of adult size by the age of 4 months, while synaptic density reaches adult levels after the age of 5 years (Huttenlocher et al.
1982). This is consistent with reports of curing loss of fixation in the squinting eye up to an age of 5–7 years (Assaf
1982; Awaya et al.
1973). Furthermore, the OR has been shown to be myelin mature before the age of 3 years (Kinney et al.
1988).
FA is thought to increase with the organisation and coherence of the underlying tracts, as well as with their density and myelin content (Beaulieu
2002). None of the DTI metrics are direct markers of myelin (Beaulieu and Allen
1994). However, λ
⊥ has shown sensitivity to demyelination in mice (Song et al.
2002,
2005), and MD and FA have been correlated with myelin content according to an ex vivo imaging and histology study (Schmierer et al.
2007). λ
⊥ has also been shown to be positively correlated to axonal caliber (Nair et al.
2005; Song et al.
2005), whilst λ
∥ is thought to also increase with fiber coherence (Dubois et al.
2008b; Takahashi et al.
2000). Since MD is a linear combination of λ
⊥ and λ
∥ (MD = 1/3λ
∥ + 2/3λ
⊥), it is influenced by all these effects. The maturational processes discovered in our study are therefore not likely to be due to myelination but rather to local changes in the extracellular matrix, glial cell morphology (Beaulieu and Allen
1994; Trip et al.
2006) and axonal caliber, as suggested by the decrease in λ
⊥, and also increase in fiber coherence and compactness (McGraw et al.
2002), with which the increase of FA is consistent.
Lateralization
Lateralization has been consistently reported in the cingulum (Gong et al.
2005; Trivedi et al.
2009; Bonekamp et al.
2007; Takao et al.
2011a,
b; Verhoeven et al.
2010), superior longitudinal fasciculus (Buchel et al.
2004; Makris et al.
2005; Nucifora et al.
2005; Verhoeven et al.
2010; Takao et al.
2011a; Thiebaut de Schotten et al.
2011a) and arcuate fasciculus (Lebel and Beaulieu
2009; Barrick et al.
2007; Buchel et al.
2004; Catani et al.
2007; Parker et al.
2005; Takao et al.
2011a,
b; Thiebaut de Schotten et al.
2011b; Verhoeven et al.
2010) while for other tracts the findings are inconsistent (Takao et al.
2011a). No significant age effect in lateralization is known to have been shown in specific WM tracts. A significant sex effect in lateralization has only been demonstrated in the left-lateralised arcuate fasciculus by Catani et al. (
2007) (with significantly more streamlines in males).
To our knowledge, lateralization of DTI metrics in the OR has only been previously reported for FA. Left lateralization characterised by higher FA was shown by Xie et al. (
2007) in children (10 males and 4 females aged 3.5–9 years) in which age effects were not investigated. The same leftward assymmetry in FA was demonstrated in a cluster of voxels within the OR by Park et al. (
2004) in 32 adult males (aged 30–55 years, mean 44 ± 6.2 years) and by Kang et al. (
2011) in 56 subjects (aged 21–37 years). Both left and right lateralization were found in different parts of the OR in a Tract-Based Spatial Statistics (TBSS) study conducted by Takao et al. (
2011a) on 857 subjects (436 subjects with mean age 56.6 ± 9.8 years on one scanner and 421 subjects with mean age 55.6 ± 9.9 years on another), while Thiebaut de Schotten et al. (
2011b) reported a rightward asymmetry in FA after tractography of the OR in 40 subjects (aged 18–22 years). In contrast with all these studies, we not only investigated lateralization but also analysed if it was characterised by an age or gender effect. The only study known to have undertaken such an analysis is Takao et al. (
2011a), which did not find any significant effect. Hence, no age or gender effect in lateralization has been shown in the OR so far.
We found a significant hemisphere effect in all DTI metrics (FA, MD, λ
∥ and λ
⊥). We observed a left lateralization in FA and for the first time a significant gender effect with respect to this lateralization, females demonstrating more left lateralization than males. Interestingly, this lateralization was not found to be dependent on age. We also observed left lateralization of λ
∥. This finding and the fact that λ
⊥ was shown to be higher in the left OR (in addition with decreasing λ
⊥ with age in the right OR) suggest lower axon density in the left hemisphere. For example, the findings of Schwartz et al. (
2004) showed that anisotropy and parallel and perpendicular diffusivities were negatively correlated to axon counts and axon spacing in histology data of rat spinal cord.
Sexual dimorphism
With respect to sexual dimorphism in specific WM tracts, positive findings are reported in the literature notably for the cingulum (Schneiderman et al.
2007; Bonekamp et al.
2007; Lebel and Beaulieu
2011), inferior longitudinal fasciculus (Eluvathingal et al.
2007; Bava et al.
2011; Choi et al.
2010a), superior longitudinal fasciculus (Bava et al.
2011; Lebel and Beaulieu
2011), right arcuate fasciculus (Schmithorst et al.
2008), splenium of the corpus callosum (Schmithorst et al.
2008; Lebel and Beaulieu
2011), fornix (Perrin et al.
2009) and corticospinal tract (Perrin et al.
2009; Schmithorst et al.
2008; Bava et al.
2011; Lebel and Beaulieu
2011), while discrepancies exist for other tracts. To our knowledge, there is no report of sexual dimorphism for DTI metrics within the OR.
In addition to the gender effect already discussed in the lateralization of FA, we also found for the first time sexual dimorphism for λ
∥ in the right hemisphere with this metric being lower for females than males. Also in the same hemisphere, MD was shown to significantly decrease with age for males, but no such effect was found for females. This is similar to what has been found recently in other WM tracts by Clayden et al. (
2011). It has been shown that WM volume increases more rapidly in males than females (Giedd et al.
1999; De Bellis et al.
2001; Lenroot and Giedd
2006), especially in the occipital lobe and may be more related to increasing axonal diameters than myelination (Perrin et al.
2008). The results we obtained would suggest that the same process is occurring within the OR, as shown by decreasing MD whilst lower values of λ
∥ in females also supports the conclusions of Perrin et al. (
2009) that WM may be more dense and with axons of smaller diameter in females.