The current study supported the hypothesis that healthy anterior white matter tracts, linking frontal regions to the rest of the brain, have lower FA in comparison to caudal white matter tracts or the corpus callosum. To our knowledge, no other studies have directly compared the fractional anisotropy of the anterior white matter to that of the rest of the white matter. However, it has been reported that the corpus callosum has high diffusion anisotropy [5
]. Moreover, inspection of published data of human DTI studies suggests higher fractional anisotropy in the corpus callosum compared to other white matter regions such as the internal capsule [2
], or the frontal and temporal white matter [15
It is of great interest to study the complexity of the ALIC as it has been reported to be involved in multiple psychiatric disorders, particularly schizophrenia [14
] and obsessive compulsive disorder [4
]. Moreover, the ALIC is involved in two important limbic circuits: the medial limbic circuit (consisted of the hippocampal formation, mammillary bodies, anterior thalamic nuclei, and cingulate gyrus) and the basolateral limbic circuit (connecting the orbitofrontal cortex, dorsomedial thalamic nucleus, amygdala, and anterior temporal cortex) [28
]. Furthermore, the ALIC has been increasingly examined as a potential target for deep brain stimulation (DBS) in patients with treatment resistant depression [8
] and treatment resistant obsessive compulsive disorder [23
]. In addition, using DTI tractography techniques, Gutman and colleagues showed that the ALIC demonstrates widespread projections to the frontal pole, the medial temporal lobe, the cerebellum, the nucleus accumbens, the thalamus, the hypothalamus, and the brainstem [8
]. Therefore, the ALIC seems to be part of multiple neural circuits and is subsequently essential to a diversity of normal and pathological brain functions.
In this nonhuman primate study, we demonstrate that FA, a possible measure of white matter complexity, can vary markedly as a function of region of interest. FA is an index ranging from zero to one, with one signifying maximal anisotropy (water diffusion occurring along only one axis). Alternatively, a value of zero means isotropy (water diffusion that is unrestricted and the same in all directions). Though decreased anisotropy can be a biomarker of neuronal pathology, the correlation between neuronal microstructure and anisotropy is multifactorial (for review, see [3
] & [16
]). Since our sample is composed of healthy subjects, it is unlikely that neuronal pathology contributed to the observed FA difference.
Recall that a voxel size is on the scale of millimeters, whereas a single axon is on the order of micrometers. At present, conventional DTI is incapable of resolving multiple fiber orientations within an individual voxel [25
], therefore, we surmise that a higher level of intersections of fiber tracts in the anterior regions of the brain likely accounts for the decrease in the level of anisotropy in these regions. Although a limitation of our DTI protocol might be the 1mm gap between imaging planes. The effects of this would be mainly on smaller tracts or sharp angles; our analysis approach has focused on larger tracts with ROIs well contained inside the tract.
Studies showed flexible changes in the level of anisotropy in multiple brain regions after treatment with different modalities [15
]. Nobuhara and colleagues noticed an increase in the frontal FA after treatment with electroconvulsive therapy of depressed geriatric patients [15
]. Yoo and colleagues observed a decrease in the corpus callosum and the internal capsule FA after treatment with citalopram of patients with obsessive-compulsive disorder [27
]. Scholz and colleagues reported increase in fractional anisotropy in the subcortical white matter around the intraparietal sulcus of healthy adults following visuomotor skill training [19
]. These significant white matter changes, as illustrated by differences in FA, occurred within an interval of 4 to 12 weeks in human adult participants. The authors suggested that these white matter changes may reflect alterations of axonal caliber, myelination, packing density, or directional coherence [19
]. However, other studies confirm that intact membranes are the main determinant of anisotropic water diffusion in the brain's white matter [3
]. In addition, it now appears that axons are capable of communicating with each other, without utilizing classical neurotransmitters, through gap junctions [9
]. Additionally, computational modeling, electrophysiological, and dye coupling studies provided evidence for axo-axonic gap junctions in pyramidal cells [17
]. Gap junctions are membrane proteins that allow for direct electrical and chemical communication between cells. Gap junction channels allow for the transmission of small molecules up to a molecular mass of 1 KDa. Water has a molecular mass of about 18 Da and can be exchanged by passive diffusion through gap junctional conduits [11
]. Thus, axo-axonic water diffusion could potentially contribute to FA reduction. It is therefore highly plausible that at least part of the observed low FA in the anterior brain regions, compared to the posterior regions, may be influenced by the abundant presence of gap junctions in these highly connected brain regions. Furthermore, it has been reported that gap junctions have activity-dependent plasticity and may be modulated by local factors (e.g., voltage, pH, and calcium), neurotransmitters (e.g., dopamine), and medications (e.g., carbenoxolone) [10
]. This raises the possibility that part of the fractional anisotropy changes, noticed in the above mentioned studies, are the result of gap junction coupling modulation and state.
To our knowledge, this is the first study that directly compares the FA among different regions of interest in the brain rather than between same regions of interest in different groups. Examining white matter complexity using DTI in nonhuman primates allows for future neurohistological studies of the same sample, an option not available in human studies. This study provides additional evidence supporting the view that white matter tracts are malleable [19
] and may represent an important primate neuroevolutionary component [18
]. Moreover, although the precise substrate by which axons communicate with each other remains speculative, the findings of this study introduce the hypothesis of high abundance of gap junctions in the increasingly complex anterior white matter, as evidenced by low FA. However, it remains to be demonstrated, either in humans or in animals, whether individual variations in axo-axonal connectivity influence fractional anisotropy or account for functional attributes and psychopathology.