Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates

Male bonnet monkeys (Macaca radiata) were subjected to the variable foraging demand (VFD) early stress paradigm as infants, MRI scans were completed an average of 4 years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of interest (ROI) hippocampus and whole brain voxel-based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. The animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.     

Cognitive deficits precede motor deficits in a slowly progressing model of parkinsonism in the monkey

Five adult Macaca fascicularis monkeys were trained to perform tests of cognitive and motor functioning that included a complex visual pattern discrimination task, an object retrieval task, a test of task persistence, and a timed motor task. Once stable baseline performance was achieved, monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at doses of 0.05 to 0.075 mg/kg, 2 to 3 times per week for a total of 24 weeks. Animals were assessed weekly for performance on the previously learned tasks. All monkeys developed performance deficits in a predictable pattern with behavioural and cognitive deficits (i.e. deficits in task persistence and the cognitive component of object retrieval) appearing in advance of measurable motor deficits. Deficits in visual pattern discrimination never appeared. These results show that specific cognitive dysfunction pre-dates motor dysfunction in a chronic, slowly progressing parkinson model in monkeys and support the contention that cognitive deficits in Parkinson's disease may precede the motor signs of the disorder and may not be caused by them.     

Repeated isoflurane in adult male mice leads to acute and persistent motor decrements with long-term modifications in corpus callosum microstructural integrity

Isoflurane is a commonly used inhalational anesthetic, clinically and in animal experimental studies. Although it has been reported as safe, recent findings suggest that despite widespread use, isoflurane-induced inhalational anesthesia can lead to various pathophysiological and cognitive alterations. Therefore, we aimed to investigate the long-term behavioral and white matter consequences of repeated isoflurane exposure. Twenty 3-month-old C57BL/6J male mice received one exposure of isoflurane for 40 min or 2 exposures to isoflurane separated by 3 days. Behavioral paradigms (open field, balance beam, foot fault, rotarod, elevated zero maze, tail suspension, water maze, and social recognition tests) were administered at 1, 3, 5, 7, and 90 days post exposure. Animals exposed to repeated isoflurane showed significant motor deficits on the balance beam and increased anxiety-like behavior. Animals exposed to single isoflurane showed impaired performance on the foot fault test. Diffusion tensor imaging showed that repeated isoflurane exposure led to long-term disruption of water diffusivity in corpus callosum (CC) white matter. Furthermore, 2-D structure-tensor analysis from stained brain sections showed differences in the microstructural organization of CC white matter in mice with single versus repeated isoflurane exposures. These results suggest that behavioral deficits observed up to 90 days after repeated isoflurane exposure resulted from, at least in part, altered CC white matter microstructural integrity.     

Interhemispheric transfer of visuomotor conditional learning via the anterior corpus callosum of monkeys

Two experiments examined interhemispheric transfer of learning across the anterior corpus callosum in monkeys (Macaca fascicularis). The animals learned a series of visuomotor conditional discrimination problems for food reward. Within each problem the animals were first trained using one hand to make the motor responses, and were then required to use the opposite hand in order to test for intermanual transfer of the initial learning. In Exp. 1, a group of animals with surgical section of the entire corpus callosum and anterior commissure showed a complete absence of intermanual transfer of learning. A second group, in which only the anterior commissure and the posterior part of the corpus callosum were sectioned, leaving the anterior corpus callosum intact, showed good intermanual transfer. Thus, intermanual transfer in the second group represented interhemispheric information transfer via the anterior portions of the corpus callosum. However, in Expt. 2, normal intermanual transfer was seen in a group of animals in which the anterior corpus callosum alone had been sectioned. We conclude that the anterior corpus callosum can mediate interhemispheric transfer of visuomotor conditional learning, but is not the only available route for such transfer in the present task.     

Effects of the nicotinic acetylcholine receptor agonist SIB-1508Y on object retrieval performance in MPTP-Treated monkeys: Comparison with levodopa treatment

This study assessed the relative potencies of levodopa/benserazide and the nicotinic acetylcholine receptor agonist SIB-1508Y on reversal of cognitive and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–treated monkeys performing an object retrieval task. Monkeys previously taught to perform this task developed significant cognitive deficits after chronic low-dose MPTP exposure. These monkeys then received additional MPTP treatment to superimpose a parkinsonian movement disorder on their preexisting cognitive deficits. Levodopa/benserazide treatment significantly improved motor aspects of object retrieval performance but did not significantly improve cognition. SIB-1508Y (1 mg/kg) alone did not result in a statistically significant improvement in cognition or motor function in symptomatic MPTP-lesioned animals with deficits in both of these areas. However, the combination of SIB-1508Y and levodopa/benserazide caused significant improvements in both cognition and motor aspects of task performance, and did so at one third to one sixth of the levodopa dose necessary to improve only motor function. These results suggest the potential usefulness of SIB-1508Y and levodopa as adjunctive therapies to improve at least some of the cognitive and motor deficits associated with Parkinson's disease.     

Task persistence and learning ability in normal and chronic low dose MPTP-treated monkeys

Monkeys exposed to low doses of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) develop cognitive deficits in the absence of gross motor dysfunction. Attentional deficits and task impersistence are now also described in these animals. The task impersistence correlated with no-response errors (i.e. errors of omission) on a delayed response task and improved with dopamine agonist therapy. In parallel studies, it was observed that there were significant differences in the ability of normal monkeys to learn to perform cognitive tasks. We found that monkeys classified as poor learners had similar deficits in task persistence as did MPTP-exposed monkeys, suggesting a relationship between poor cognitive performance and task impersistence in untreated as well as MPTP-treated monkeys. The possible significance of these results for two clinical disorders, early Parkinson's disease and attention deficit hyperactivity disorder is discussed. Cognitive and behavioral similarities between chronic low dose MPTP-treated monkeys, early Parksinson's disease patients and people with attention deficit hyperactivity disorder may suggest the existence of related pathophysiological mechanisms in these disorders.     

Body mass index correlates negatively with white matter integrity in the fornix and corpus callosum: A diffusion tensor imaging study

Overweight or obese body habitus is associated with cognitive deficits, impaired brain function, gray matter atrophy, and white matter (WM) hyperintensities. However, few diffusion tensor imaging (DTI) studies have assessed WM integrity in relation to overweight or obese status. This study assessed relationships between body mass index (BMI) and values of DTI parameters among 51 normal weight (lean), overweight, and obese participants who were otherwise healthy. BMI correlated negatively with fractional anisotropy and axial eigenvalues (λ₁) in the body of corpus callosum (CC), positively with mean diffusivity and radial eigenvalues (λ_?) in the fornix and splenium of CC, and positively with λ₁ in the right corona radiata (CR) and superior longitudinal fasciculus (SLF). These data indicate that BMI correlates negatively with WM integrity in the fornix and CC. Furthermore, the different patterns of BMI‐related differences in DTI parameters at the fornix, body, and splenium of the CC, and the right CR and SLF suggest that different biological processes may underlie BMI‐related impairments of WM integrity in different brain regions. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Sex and environmental influences on the size and ultrastructure of the rat corpus callosum

A contested report of sex differences in the size of the splenium of the corpus callosum in humans prompted the present examination of the corpus callosum in the rat. We have previously found that sex differences can vary with the rearing environment. Consequently, male and female rats were raised from weaning to 55 days of age in either a complex or an isolated environment. There were no sex differences in the size of the corpus callosum in sagittal cross section in these rats; however, rats of both sexes had a larger posterior third of the corpus callosum if they were raised in the complex environment. Because the corpus callosum continues to grow in size past 55 days of age, we examined socially housed rats at 113 days and again found no sex differences. The splenium was examined with electron microscopy in complex and isolation reared rats at 55 days of age. The ultrastructural analysis revealed differences at were not apparent from gross size measures. Females had more unmyelinated axons regardless of environment, and females from the complex environment had more myelinated axons than comparably housed males. In contrast, males in the complex environment had larger myelinated axons than females. Rats of both sexes from the complex environment had larger and more unmyelinated axons than isolated rats. In addition in myelinated axons, plasticity in the females occurred through changes in axon number and in males, through axon size. Thus sex differences exist in axonal number and size and the environment influences these differences.     

Characteristics of diffusion-tensor imaging for healthy adult rhesus monkey brains

Diffusion-tensor imaging can be used to observe the microstructure of brain tissue. Fractional ani- sotropy reflects the integrity of white matter fibers. Fractional anisotropy of a young adult brain is low in gray matter, high in white matter, and highest in the splenium of the corpus callosum. Thus, we selected the anterior and posterior limbs of the internal capsule, head of the caudate nucleus, semioval center, thalamus, and corpus callosum （splenium and genu） as regions of interest when using diffusion-tensor imaging to observe fractional anisotropy of major white matter fiber tracts and the deep gray matter of healthy rhesus monkeys aged 4-8 years. Results showed no laterality dif- ferences in fractional anisotropy values. Fractional anisotropy values were low in the head of cau- date nucleus and thalamus in gray matter. Fractional anisotropy values were highest in the sple- nium of corpus callosum in the white matter, followed by genu of the corpus callosum and the pos- terior limb of the internal capsule. Fractional anisotropy values were lowest in the semioval center and posterior limb of internal capsule. These results suggest that fractional anisotropy values in major white matter fibers and the deep gray matter of 4-8-year-old rhesus monkeys are similar to those of healthy young people.     

Localization of function in corpus callosum: tactual information transmission in Macaca mulatta.

Different portions of the corpus callosum were transected in 28 juvenile rhesus monkeys. These animals were then taught a tactual roughness discrimination task while using their right hands and tested for transfer of training while using their left. Animals with some part of the posterior body region of the corpus callosum preserved exhibited intermediate or high levels of transfer of training. Animals with other portions of the commissures preserved, including the splenium, the anterior body, the genu, and/or the anterior commissure but with the posterior body region transected generally failed to show such transfer. It is concluded that tactual information is transmitted between the hemispheres through the posterior body region of the corpus callosum.     

Mechanisms of interhemispheric transfer and patterns of cognitive function in acallosal patients of normal intelligence.

We investigated interhemispheric transfer and cognitive function in two boys with normal intelligence in whom agenesis of the corpus callosum was identified following minor head trauma. In patient 1, magnetic resonance imaging scan showed agenesis of the corpus callosum and absent anterior commissure. Results of visual interhemispheric transfer tasks suggested degradation in transfer of information to the left hemisphere. Results of a tactile interhemispheric transfer task suggested degradation of access to the right hemisphere. In patient 2, magnetic resonance imaging scan showed agenesis of the corpus callosum and enlarged anterior commissure. Results for both visual and tactile interhemispheric transfer tasks were normal. Dichotic listening tests showed a slight left ear advantage in both patients. These results support the hypothesis that hypertrophy of the anterior commissure is an important mechanism of functional compensation in agenesis of the corpus callosum. However, the relative subtlety of deficits in patient 1 and results of dichotic listening tests support use of other mechanisms as well. No consistent pattern of cognitive deficits was observed.     

Chronic neurological deficits in mice after perinatal hypoxia and ischemia correlate with hemispheric tissue loss and white matter injury detected by MRI

We investigated the effects of perinatal hypoxia-ischemia (HI) on brain injury and neurological functional outcome at postnatal day (P)30 through P90. HI was induced by exposing P9 mice to 8% O(2) for 55 min using the Vannucci HI model. Following HI, mice were treated with either vehicle control or Na(+)/H(+) exchanger isoform 1 (NHE1) inhibitor HOE 642. The animals were examined by the accelerating rotarod test at P30 and the Morris water maze (MWM) test at P60. T(2)-weighted MRI was conducted at P90. Diffusion tensor imaging (DTI) was subsequently performed in ex vivo brains, followed by immunohistochemical staining for changes in myelin basic protein (MBP) and neurofilament protein expression in the corpus callosum (CC). Animals at P30 after HI showed deficits in motor and spatial learning. T(2) MRI detected a wide spectrum of brain injury in these animals. A positive linear correlation was observed between learning deficits and the degree of tissue loss in the ipsilateral hemisphere and hippocampus. Additionally, CC DTI fractional anisotropy (FA) values correlated with MBP expression. Both FA and MBP values correlated with performance on the MWM test. HOE 642-treated mice exhibited improved spatial learning and memory, and less white matter injury in the CC. These findings suggest that HI-induced cerebral atrophy and CC injury contribute to the development of deficits in learning and memory, and that inhibition of NHE1 is neuroprotective in part by reducing white matter injury. T(2)-weighted MRI and DTI are useful indicators of functional outcome after perinatal HI.     

Morphometric evaluation of the hydrocephalic brain: relationships with cognitive development

The effects of early hydrocephalus and related brain anomalies on cognitive skills are not well understood. In this study, magnetic resonance scans were obtained from 99 children aged from 6 to 13 years with either shunted hydrocephalus (n=42) or arrested (unshunted) hydrocephalus (n=19), from patient controls with no hydrocephalus (n=23), and from normal, nonpatient controls (n=15). Lateral ventricle volumes and area measurements of the internal capsules and centra semiovale in both hemispheres were obtained from these scans, along with area measurements of the corpus callosum. Results revealed reductions in the size of the corpus callosum in the shunted hydrocephalus group. In addition, lateral ventricle volumes were larger and internal capsule areas were smaller in both hemispheres in children with shunted and arrested hydrocephalus. The centra semiovale measurements did not differentiate the groups. Correlating these measurements with concurrent assessments of verbal and nonverbal cognitive skills, motor abilities, and executive functions revealed robust relationships only between the area of the corpus callosum and nonverbal cognitive skills and motor abilities. These results support the theory of a prominent role for the corpus callosum defects characteristic of many children with shunted hydrocephalus in the spatial cognition deficits commonly observed in these children.     

Degeneration of corpus callosum and recovery of motor function after stroke: A multimodal magnetic resonance imaging study

Animal models of stroke demonstrated that white matter ischemia may cause both axonal damage and myelin degradation distant from the core lesion, thereby impacting on behavior and functional outcome after stroke. We here used parameters derived from diffusion magnetic resonance imaging (MRI) to investigate the effect of focal white matter ischemia on functional reorganization within the motor system. Patients (n = 18) suffering from hand motor deficits in the subacute or chronic stage after subcortical stroke and healthy controls (n = 12) were scanned with both diffusion MRI and functional MRI while performing a motor task with the left or right hand. A laterality index was employed on activated voxels to assess functional reorganization across hemispheres. Regression analyses revealed that diffusion MRI parameters of both the ipsilesional corticospinal tract (CST) and corpus callosum (CC) predicted increased activation of the unaffected hemisphere during movements of the stroke‐affected hand. Changes in diffusion MRI parameters possibly reflecting axonal damage and/or destruction of myelin sheath correlated with a stronger bilateral recruitment of motor areas and poorer motor performance. Probabilistic fiber tracking analyses revealed that the region in the CC correlating with the fMRI laterality index and motor deficits connected to sensorimotor cortex, supplementary motor area, ventral premotor cortex, superior parietal lobule, and temporoparietal junction. The results suggest that degeneration of transcallosal fibers connecting higher order sensorimotor regions constitute a relevant factor influencing cortical reorganization and motor outcome after subcortical stroke. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Corpus callosum size in schizophrenia – a magnetic resonance imaging analysis

Previous MRI studies have shown differences in corpus callosum size between schizophrenic patients and controls. The corpus callosum (CC), as the main interhemispheric fiber tract, plays an important role in interhemispheric integration and communication. Though MRI studies suggest smaller CC in schizophrenia, there are still conflicting findings. Using in vivo magnetic resonance imaging, it was investigated whether the midsagittal area of CC differs between twenty-three right-handed male schizophrenic patients and twenty-three matched controls. Total CC area, five subregions of CC, total brain volume, gray and white matter were measured. No differences between schizophrenic patients and controls were found regarding all CC measurements, total brain volume, and gray matter tissue. However, a significant reduction of white matter tissue in the patient group emerged. There was no correlation between CC morphology and clinical variables such as age of onset, length of illness or symptom severity. Interestingly, five schizophrenic patients with a positive family history of schizophrenia showed significant reduction of the subregion C3, associated with a reduced total brain and gray and white matter volume. Significant reduction in the CC and its subregions was not confirmed in this group of patients with schizophrenia. In the subgroup of schizophrenic patients with a positive family history of schizophrenia, a significant reduction of the subregion corresponding to a part of the trunk of the CC was found. Received: 16 August 1999 / Accepted: 5 October 1999     

White matter integrity and math performance in pediatric multiple sclerosis: a diffusion tensor imaging study

Multiple sclerosis is associated with reduced white matter integrity and deficits in key cognitive processes important for arithmetic. This study examined the relationship between white matter microstructure and academic ability in 31 youths with multiple sclerosis (aged 11-19 years) and 34 demographically matched controls. Using diffusion tensor imaging, fractional anisotropy was calculated in corpus callosum and in lateralized hemispheric lobes. Difficulties with written arithmetic ability were observed in 26% of patients. Arithmetic ability correlated with fractional anisotropy values across all segments of the corpus callosum and in right frontal and parietal regions, controlling for age (r values >0.5, P<0.005). Findings highlight the functional impact of compromised white matter microstructure across diffuse regions of the brain on mathematical ability.     

Bimanual coordination in alcohol-exposed children: role of the corpus callosum.

The corpus callosum (CC) is one of several brain structures affected in children prenatally exposed to alcohol. This structure plays a major role in coordinating motor activity from opposite sides of the body, and deficits in bimanual coordination have been documented in individuals with agenesis of or damage to the CC, particularly when the task is performed without visual feedback. The Bimanual Coordination Test was used to assess speed and accuracy on a task where both hands must coordinate to guide a cursor through angled pathways providing measures of interhemispheric interaction or the ability of the two hemispheres to coordinate activity via the corpus callosum. Twenty-one children with fetal alcohol spectrum disorders (FASD) and 17 non-exposed control children (CON), matched closely in age, sex, and ethnicity were tested. For trials with visual feedback (WV), children with FASD were slower than CON children but were equally accurate. Although statistically significant group differences were not observed on most trials completed without visual feedback (WOV), accuracy of the FASD group on WOV trials was highly variable. Group differences in accuracy on WOV angles approached significance after accounting for performance on the WV angles, and children with FASD were significantly less accurate on an individual angle believed to be particularly sensitive to interhemispheric interaction. These results indicate that children with FASD are slower than CON children but equally accurate on basic visuomotor tasks. However, as task complexity and reliance on interhemispheric interaction increases, children with FASD demonstrate variable and inaccurate performance.     

Isolation rearing induces recognition memory deficits accompanied by cytoskeletal alterations in rat hippocampus

Social isolation from weaning affects hippocampal structure and function in the rat. The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal development and organization. Accordingly, the present paper investigated the effects of social isolation on hippocampal levels of alpha-tubulin isoforms associated with microtubule dynamics, the dendritic marker MAP-2 and alterations in locomotor activity and recognition memory. Male Lister Hooded rats (postnatal day 25-28) were housed either in groups or singly (isolated animals) for 30 days. Locomotor activity in a novel arena and novel object recognition were monitored in activity boxes. The hippocampus was dissected out 18 h after the novel object recognition task. Levels of alpha-tubulin isoforms and MAP-2 were analysed using Western blots. The experiments were conducted in duplicate, using two batches of rats obtained from different suppliers. Isolated animals were hyperactive and showed recognition memory deficits in the novel object recognition task. These behavioural alterations were accompanied by specific alterations in hippocampal alpha-tubulin isoforms and decreased MAP-2 expression. The results confirm that rearing rats in isolation produces hyperactivity and cognitive deficits. The behavioural alterations were accompanied by hippocampal cytoskeletal changes consistent with microtubule stabilization, and by decreased MAP-2 expression. These findings are indicative of an abnormal development of synaptic connections and/or reductions in neuronal cell number. The developmental structural abnormalities in the hippocampus may contribute to the cognitive impairments which result from isolation rearing in rats.     

Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study

Background

Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions.

Objective

To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age‐related white matter hyperintensities (WMH).

Methods

In the Leukoaraiosis and Disability Study, 567 subjects with age‐related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors.

Results

Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing—namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion.

Conclusions

Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal‐lobe‐mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.Corpus callosum is the largest commissural structure consisting of white matter tracts that connect the cerebral hemispheres according to an anterior–posterior topographical organisation. Recent research using diffusion tensor magnetic resonance imaging (MRI) has augmented earlier postmortem findings of corpus callosum topography and has shown that the anterior parts of corpus callosum (rostrum and genu) connect the orbitofrontal, lateral and medial frontal cortices, whereas the body and splenium connect parietal, temporal and occipital homotopic regions.¹ In neurodegenerative diseases, the corpus callosum area is markedly reduced, indicating marked axonal loss.^2,3,4,5 In Alzheimer''s disease, the severity and pattern of corpus callosum atrophy have been associated with cortical neuronal loss⁶ independently of white matter hyperintensities (WMH).⁷ In vascular dementia and other ischaemic conditions, however, corpus callosum atrophy is correlated with WMH and hence may result from subcortical ischaemic damage.^8,9Earlier studies have shown that corpus callosum atrophy is associated with global cognitive status,^5,6,10 but, to date, few studies have investigated the role of regional corpus callosum atrophy in specific cognitive processes. Based on the topographical organisation of corpus callosum, the integrity of its subregions may reflect distinct cognitive deficits. In particular, anterior corpus callosum atrophy may be related to the frontal‐lobe‐mediated executive deficits. Previous work of the Leukoaraiosis and Disability (LADIS) Study has shown that age‐related WMH are associated with cognitive impairment in elderly subjects without dementia.¹¹ Moreover, in these subjects, the corpus callosum area has been found to be inversely related to motor deficits and global cognitive decline.¹² This study examined the independent contribution of regional corpus callosum atrophy to deficits in mental speed, attention and executive functions in a large sample of elderly subjects with WMH by using quantitative MRI analysis and targeted neuropsychological test methods. The demographic and medical background variables, and coexisting WMH were controlled by using multivariate analysis.     

Diffusion tensor imaging of cocaine-treated rodents

Studies in cocaine-dependent human subjects have shown differences in white matter on diffusion tensor imaging (DTI) compared with non-drug-using controls. It is not known whether the differences in fractional anisotropy (FA) seen on DTI in white matter regions of cocaine-dependent humans result from a pre-existing predilection for drug use or purely from cocaine abuse. To study the effect of cocaine on brain white matter, DTI was performed on 24 rats after continuous infusion of cocaine or saline for 4 weeks, followed by brain histology. Voxel-based morphometry analysis showed an 18% FA decrease in the splenium of the corpus callosum (CC) in cocaine-treated animals relative to saline controls. On histology, significant increase in neurofilament expression (125%) and decrease in myelin basic protein (40%) were observed in the same region in cocaine-treated animals. This study supports the hypothesis that chronic cocaine use alters white matter integrity in human CC. Unlike humans, where the FA in the genu differed between cocaine users and non-users, the splenium was affected in rats. These differences between rodent and human findings could be due to several factors that include differences in the brain structure and function between species and/or the dose, timing, and duration of cocaine administration.