Several lines of evidence link the pathophysiology of mood and anxiety symptoms to white matter abnormalities. For instance, macroscopic white matter lesions that affect prefrontal-subcortical circuits are highly associated with post-stroke depression [26
]. Diffusion tensor imaging (DTI), a modality of MRI technology, quantifies fractional anisotropy (FA), a measure of the directionality of diffusion of water molecules within white matter tracts of the brain. FA is relatively high in white matter, and is reduced in demyelinating conditions [2
]. Reduced FA in the absence of gross pathology of white matter may represent a subtle impairment of normative structural organization of axons [10
]. Molecular abnormalities in frontal white matter tracts are observed in late-life depression [20
] and adolescent bipolar disorder [1
], suggesting an association of white matter changes with depression independent of age and depressive subtype. Moreover, treatment with electroconvulsive therapy in late-life depression normalizes FA of frontal white matter tracts [20
Deep brain stimulation (DBS) of white matter, particularly the anterior limb of the internal capsule (ALIC) and the closely associated subcallosal cingulate white matter may be effective in treating depression [13
]. Using DTI tractography techniques, the ALIC demonstrates widespread projections to frontal pole, medial temporal lobe, cerebellum, nucleus accumbens, thalamus, hypothalamus, and brainstem [13
]. Moreover, the ALIC has been reported to be involved in multiple psychiatric disorders, particularly schizophrenia [19
] and obsessive compulsive disorder [3
]. Furthermore, the ALIC is involved in two important circuits, the medial and the basolateral limbic circuits [29
]. Thus, abnormalities of the ALIC may result in a dysfunction of the connectivity between the temporal and frontal regions as well as in an impairment of neural circuits involved in depression. To our knowledge, there is no report that examines the integrity of white matter of the ALIC in association with early life stress either in humans or in translational animal models.
More recently, using DTI, parental verbal abuse was found to reduce integrity of white matter in the 1) left superior temporal gyrus, 2) cingulum bundle by the posterior tail of the left hippocampus, and 3) the left body of the fornix. White matter integrity in these areas was strongly associated with parental verbal abuse. Fractional anisotropy in region 2 was inversely associated with ratings of depression, whereas fractional anisotropy in region 3 was inversely correlated with ratings of anxiety [4
]. These data support the view that early life stressors may impair white matter integrity with affective consequences.
In the nonhuman primate, we have previously modeled persistent susceptibility to anxiety and mood disorders following early life stressors [7
]. In bonnet macaques, exposure to early life stress in the infant is achieved through imposing unpredictable foraging conditions on the mother – a procedure termed “variable foraging demand” (VFD). VFD rearing disrupts normative patterns of maternal rearing and infant attachment, and exposed infants exhibit persistent abnormalities in neuroanatomical and neurochemical systems implicated in the etiology of mood and anxiety disorders [7
]. Animal models can complement human studies by experimental control of early life stress while also providing a post-stress environment free of confounding variables [12
Human myelination of the internal capsule progresses rostrally. Most of the myelination in the posterior limb of the internal capsule is complete shortly after birth, whereas myelination of the anterior limb of the internal capsule is ongoing until about a year postnatally (4-5 months on T1W MRI and 8-12 months on T2W MRI) – approximately the period in development when the VFD paradigm was implemented [8
]. There is a paucity of data on white matter maturation during the first year of life in nonhuman primates. However, those studies that have examined postnatal brain development in rhesus monkeys showed a similarity in white matter mylelination and growth between human and nonhuman primates with the exception that white matter growth was 3-4 times faster in monkeys [16
]. The purpose of the current study was to examine white matter integrity of the anterior limb of the internal capsule using DTI, given its emerging role in human mood and anxiety states [28
]. We hypothesized that early life stress may affect white matter formation in nonhuman primates and would be associated with reduced FA in the anterior limb of the internal capsule.