Haruyasu Yamada

Normal aging in the central nervous system: quantitative MR diffusion-tensor analysis.

The purpose of this study is to elucidate changes in mean diffusivity (ADC) and fractional anisotropy (FA) using MR diffusion tensor imaging (DTI) in the central nervous system during normal aging. We studied 50 normal volunteers (30 men, 20 women; mean age 44.8 +/- 14.0; age range, 21-69 years) without disorders affecting the central nervous system. The frontal, parietal white matter, lentiform nucleus, posterior limb of internal capsule, thalamus, genu and splenium of the corpus callosum were selected for investigation. There was no significant difference in ADC or FA between male and female or between the right and left hemisphere. A significant ADC increase with advancing age was observed in frontal white matter (P = 0.010) and lentiform nucleus (P = 0.022). A significant FA decline was found only in the genu of the corpus callosum (P < 0.001) with advancing age. Quantitative diffusion tensor analysis correlate with normal aging and may help in assessing normal age-related changes and serve as a standard for comparison with neurodegenerative disorders.

Aging in the CNS: Comparison of gray/white matter volume and diffusion tensor data

This study investigated the global and regional effects of aging on brain volume, mean diffusivity (MD), and fractional anisotropy (FA) in 73 normal female subjects using voxel-based analysis. On a global scale, gray matter volume and FA were negatively correlated, whereas MD was positively correlated with age. Voxel-wise analyses showed brain volume and FA were negatively correlated predominantly in anterior structures, whereas MD was positively correlated in the cortical gray matter and periventricular white matter. Volume preservation was observed in the cingulate gyrus and subjacent white matter. FA increase was observed in the putamen. Voxel-based direct comparisons of volume and diffusion properties showed FA was more strongly negatively correlated in the fronto-temporal white matter, compared with volume and MD. Stronger positive correlation of MD was observed in the thalamus, caudate nucleus, and midbrain and stronger negative correlation of brain volume was observed in the frontal lobe and basal ganglia, compared with the other. These results indicate that diffusion properties and brain volume are complementary markers to the effects of aging.

Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study

Functional and structural abnormalities of the anterior cingulate gyrus (ACG) in patients with schizophrenia have been repeatedly reported. However, one remaining issue is whether gray matter volume reduction in ACG exists to an extent comparable with, or even in excess of, that in other prefrontal and temporolimbic regions. High-spatial-resolution magnetic resonance imaging was performed on patients with schizophrenia (n=27) and on age-, gender-, and parental socioeconomic-status-matched healthy control subjects (n=27). After the gray and white matter were semiautomatically segmented, whole prefrontal and temporal lobes were manually parceled into 15 subregions-by-two hemispheres (30 regions of interest) constituting seven prefrontal gray matter regions, six temporal gray matter regions, the prefrontal white matter, and the temporal white matter. Compared with healthy subjects, schizophrenic patients showed significant gray matter volume reduction in the bilateral ACG, this being the largest effect size (left, 0.84; right, 0.56) among all the regions examined. There were also significant gray matter volume reductions in the bilateral posterior STG, bilateral inferior frontal gyrus, left posterior amygdala-hippocampal complex (mostly hippocampus), and the left insula. These results suggest that gray matter volume reductions in the ACG are prominent among prefrontal and temporolimbic regions in patients with schizophrenia. These findings indicate the importance of ACG abnormalities in the pathophysiology of schizophrenia.

Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression

The purpose of this study is to use voxel-based analysis to simultaneously elucidate regional changes in gray/white matter volume, mean diffusivity (MD), and fractional anisotropy (FA) in patients with unipolar major depressive disorder. We studied 21 right-handed patients and 42 age- and gender-matched right-handed normal subjects. Local areas showing significant gray matter volume reduction in depressive patients compared with controls were observed in the right parahippocampal gyrus, hippocampus, bilateral middle frontal gyri, bilateral anterior cingulate cortices, left parietal and occipital lobes, and right superior temporal gyrus. Local areas showing an increase of MD in depressive patients were observed in the bilateral parahippocampal gyri, hippocampus, pons, cerebellum, left frontal and temporal lobes, and right frontal lobe. There was no significant difference between the two groups for FA and white matter volume in the entire brain. Although there was no local area where brain volume and MD were significantly correlated with disease severity, FA tended to correlate negatively with total days depressed in the right anterior cingulate and the left frontal white matter. These results suggest that the frontolimbic neural circuit might play an important role in the neuropathology of patients with major depressive disorder.

Association between the oxytocin receptor gene and amygdalar volume in healthy adults.

BACKGROUND Recent studies have suggested that oxytocin affects social cognition and behavior mediated by the oxytocin receptor (OXTR) in amygdala in humans as well as in experimental animals. Genetic studies have revealed a link between the OXTR gene and the susceptibility to autism spectrum disorders (ASD), especially in the social dysfunctional feature of ASD. METHODS We examined the relationship between amygdala volume measured with manual tracing methodology and seven single nucleotide polymorphisms and one haplotype-block in OXTR, which were previously reported to be associated with ASD, in 208 socially intact Japanese adults with no neuropsychiatric history or current diagnosis. RESULTS The rs2254298A allele of OXTR was significantly associated with larger bilateral amygdala volume. The rs2254298A allele effect on amygdala volume varied in proportion to the dose of this allele. The larger the number of rs2254298A alleles an individual had, the larger their amygdala volume. Such an association was not observed with hippocampal volume or with global brain volumes, including whole gray, white matter, and cerebrospinal-fluid space. Furthermore, two three-single nucleotide polymorphism haplotypes, including rs2254298G allele, showed significant associations with the smaller bilateral amygdala volume. CONCLUSIONS The present results suggest that OXTR might be associated with the susceptibility to ASD, especially in its aspects of social interaction and communication mediated by a modulation of amygdala development, one of the most distributed brain regions with high density of OXTR. Furthermore, amygdala volume measured with magnetic resonance imaging could be a useful intermediate phenotype to uncover the complex link between OXTR and social dysfunction in ASD.

Voxel-based diffusion tensor analysis reveals aberrant anterior cingulum integrity in posttraumatic stress disorder due to terrorism

Recent functional neuroimaging work has suggested that interregional functional connectivity between the anterior cingulate cortex (ACC), other limbic, and prefrontal regions may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). However, less attention has been paid to the white matter network. Voxel-based analysis enables an exploration of morphological or functional changes throughout the entire brain. Here we undertook the first application of this technology to diffusion tensor data in patients with PTSD. Participants were 9 victims of the Tokyo subway sarin attack with PTSD and 16 matched victims of the same traumatic event without PTSD. The voxel-based analysis showed a significant fractional anisotropy increase in the left anterior cingulum, subjacent to the left ACC gray matter where we previously found a volume decrement, in PTSD subjects. Moreover, the severity was positively, but not significantly associated with the fractional anisotropy of the left anterior cingulum in the victims with PTSD, using the region of interest defined in the native space with the inverse normalization technique. The present study demonstrated further evidence of abnormalities of both the ACC, a structure that is pivotally involved in attention, emotional regulation, and fear conditioning, and of subjacent white matter in the pathology of PTSD.

Topography of the human corpus callosum using diffusion tensor tractography

Objective: To evaluate the crossing fiber trajectory through the corpus callosum using distortion-corrected diffusion tensor tractography in the human brain. Methods: After correcting distortion associated with large-diffusion gradients, T2-weighted echo planar images (EPIs) acquired from 10 right-handed healthy men were coregistered into T2-weighted fast spin echo images using linear through sixth-order nonlinear, 3-dimensional, polynomial warping functions. The optimal transformation parameters were also applied to the distortion-corrected diffusion-weighted EPIs. Diffusion tensor tractography through the corpus callosum was reconstructed, employing the “1 or 2 regions of interest” method. Results: Compared with the lines through the genu, those through the rostrum ran more inferiorly and seemed to enter the orbital gyrus. Those lines entering posterior temporal white matter (tapetum) crossed through the ventral portion of the splenium and were clearly distinguished from lines that reached parieto-occipital white matter (forceps major). Conclusion: Diffusion tensor tractography is a feasible noninvasive tool to evaluate commissural fiber trajectory.

Smaller amygdala volume and reduced anterior cingulate gray matter density associated with history of post-traumatic stress disorder

Although post-traumatic stress disorder (PTSD) may be seen to represent a failure to extinguish learned fear, significant aspects of the pathophysiology relevant to this hypothesis remain unknown. Both the amygdala and hippocampus are necessary for fear extinction occur, and thus both regions may be abnormal in PTSD. Twenty-five people who experienced the Tokyo subway sarin attack in 1995, nine who later developed PTSD and 16 who did not, underwent magnetic resonance imaging (MRI) with manual tracing to determine bilateral amygdala and hippocampus volumes. At the time of scanning, one had PTSD and eight had a history of PTSD. Results indicated that the group with a history of PTSD had significantly smaller mean bilateral amygdala volume than did the group that did not develop PTSD. Furthermore, left amygdala volume showed a significant negative correlation with severity of PTSD symptomatology as well as reduced gray matter density in the left anterior cingulate cortex. To our knowledge, this is the first observation of an association between PTSD and amygdala volume. Furthermore the apparent interplay between amygdala and anterior cingulate cortex represents support at the level of gross brain morphology for the theory of PTSD as a failure of fear extinction.

Human brain structural change related to acute single exposure to sarin

This study aimed to identify persistent morphological changes subsequent to an acute single‐time exposure to sarin, a highly poisonous organophosphate, and the neurobiological basis of long‐lasting somatic and cognitive symptoms in victims exposed to sarin.

1H-MR spectroscopy and gray matter volume of the anterior cingulate cortex in schizophrenia.

Schizophrenic and normal control subjects were examined using both 1H-magnetic resonance spectroscopy (MRS) and structural MR imaging, in order to accurately assess the partial volume within the spectroscopic volume of interest (VOI) in the anterior cingulate cortex. The gray matter volume within VOI correlated positively with the N-acetyl-aspartate (NAA) to choline (Cho) ratio in schizophrenics only, not in controls. Schizophrenic patients had a reduced NAA/Cho ratio and an elevated Cho/creatine ratio compared to controls after the partial volume effect was eliminated. There was a significant negative correlation between the NAA/Cho ratio and the severity of blunted affect symptom in schizophrenics. These results provide further support to the idea that the measures of 1H-MRS indicate not only neuronal loss but also neuronal dysfunction in schizophrenia.