Takayuki Obata

Discrepancies between BOLD and flow dynamics in primary and supplementary motor areas: application of the balloon model to the interpretation of BOLD transients.

The blood-oxygen-level-dependent (BOLD) signal measured in the brain with functional magnetic resonance imaging (fMRI) during an activation experiment often exhibits pronounced transients at the beginning and end of the stimulus. Such transients could be a reflection of transients in the underlying neural activity, or they could result from transients in cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), or cerebral blood volume (CBV). These transients were investigated using an arterial spin labeling (ASL) method that allows simultaneous measurements of BOLD and CBF responses. Responses to a finger-tapping task (40-s stimulus, 80-s rest) were measured in primary motor area (M1) and supplementary motor area (SMA) in five healthy volunteers. In SMA, the average BOLD response was pronounced near the beginning and end of the stimulus, while in M1, the BOLD response was nearly flat. However, CBF responses in the two regions were rather similar, and did not exhibit the same transient features as the BOLD response in SMA. Because this suggests a hemodynamic rather than a neural origin for the transients of the BOLD response in SMA, we used a generalization of the balloon model to test the degree of hemodynamic transients required to produce the measured curves. Both data sets could be approximated with modest differences in the shapes of the CMRO2 and CBV responses. This study illustrates the utility and the limitations of using theoretical models combined with ASL techniques to understand the dynamics of the BOLD response.

Nonlinear temporal dynamics of the cerebral blood flow response.

The linearity of the cerebral perfusion response relative to stimulus duration is an important consideration in the characterization of the relationship between regional cerebral blood flow (CBF), cerebral metabolism, and the blood oxygenation level dependent (BOLD) signal. It is also a critical component in the design and analysis of functional neuroimaging studies. To study the linearity of the CBF response to different duration stimuli, the perfusion response in primary motor and visual cortices was measured during stimulation using an arterial spin labeling technique with magnetic resonance imaging (MRI) that allows simultaneous measurement of CBF and BOLD changes. In each study, the perfusion response was measured for stimuli lasting 2, 6, and 18 sec. The CBF response was found in general to be nonlinearly related to stimulus duration, although the strength of nonlinearity varied between the motor and visual cortices. In contrast, the BOLD response was found to be strongly nonlinear in both regions studied, in agreement with previous findings. The observed nonlinearities are consistent with a model with a nonlinear step from stimulus to neural activity, a linear step from neural activity to CBF change, and a nonlinear step from CBF change to BOLD signal change. Hum. Brain Mapping 13:1–12, 2001.

Age-related degeneration of corpus callosum measured with diffusion tensor imaging.

The corpus callosum is the major commissure connecting the cerebral hemispheres, and there is evidence of its change with aging. The sub-regions of the corpus callosum (genu, rostral body, anterior midbody, posterior midbody, isthmus, splenium) respectively comprise fibers connecting heteromodal- and unimodal-associated cortical regions, and it is known that abnormalities of the corpus callosum are correlated with abnormalities in cognition and behavior. Yet, little is known about changes in the tissue characteristics of its sub-regions. We assessed age-related changes in fractional anisotropy and mean diffusivity in the sub-regions of the corpus callosum using diffusion tensor imaging. We studied 42 healthy right-handed individuals aged 21-73 years. There were no significant interactions of sex x region. Age has significant negative correlation with fractional anisotropy in the genu (P < 0.001), rostral body (P < 0.001), and isthmus (P = 0.005). Fractional anisotropy of the anterior midbody was correlated negatively with age at a trend level (P = 0.022). Age was significantly positively correlated with mean diffusivity in the genu (P = 0.001), rostral body (P = 0.002), anterior midbody (P = 0.001), and isthmus (P = 0.001). Age-related changes were detected in the sub-regions where their projection areas are thought to be vulnerable to normal aging. This suggested that fractional anisotropy and mean diffusivity values of the corpus callosum sub-regions could serve as markers of disturbance across the respective projection areas.

Negative correlation between brain glutathione level and negative symptoms in schizophrenia: A 3T 1H-MRS study

Background Glutathione (GSH), a major intracellular antioxidant, plays a role in NMDA receptor-mediated neurotransmission, which is involved in the pathophysiology of schizophrenia. In the present study, we aimed to investigate whether GSH levels are altered in the posterior medial frontal cortex of schizophrenic patients. Furthermore, we examined correlations between GSH levels and clinical variables in patients. Methods and Findings Twenty schizophrenia patients and 16 age- and gender-matched normal controls were enrolled to examine the levels of GSH in the posterior medial frontal cortex by using 3T SIGNA EXCITE 1H-MRS with the spectral editing technique, MEGA-PRESS. Clinical variables of patients were assessed by the Global Assessment of Functioning (GAF), Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), and five cognitive performance tests (Word Fluency Test, Stroop Test, Trail Making Test, Wisconsin Card Sorting Test and Digit Span Distractibility Test). Levels of GSH in the posterior medial frontal cortex of schizophrenic patients were not different from those of normal controls. However, we found a significant negative correlation between GSH levels and the severity of negative symptoms (SANS total score and negative symptom subscore on BPRS) in patients. There were no correlations between brain GSH levels and scores on any cognitive performance test except Trail Making Test part A. Conclusion These results suggest that GSH levels in the posterior medial frontal cortex may be related to negative symptoms in schizophrenic patients. Therefore, agents that increase GSH levels in the brain could be potential therapeutic drugs for negative symptoms in schizophrenia.

Spin-locking versus chemical exchange saturation transfer MRI for investigating chemical exchange process between water and labile metabolite protons

Chemical exchange saturation transfer (CEST) and spin‐locking (SL) experiments were both able to probe the exchange process between protons of nonequivalent chemical environments. To compare the characteristics of the CEST and SL approaches in the study of chemical exchange effects, we performed CEST and SL experiments at varied pH and concentrated metabolite phantoms with exchangeable amide, amine, and hydroxyl protons at 9.4 T. Our results show that: (i) on‐resonance SL is most sensitive to chemical exchanges in the intermediate‐exchange regime and is able to detect hydroxyl and amine protons on a millimolar concentration scale. Off‐resonance SL and CEST approaches are sensitive to slow‐exchanging protons when an optimal SL or saturation pulse power matches the exchanging rate, respectively. (ii) Offset frequency‐dependent SL and CEST spectra are very similar and can be explained well with an SL model recently developed by Trott and Palmer (J Magn Reson 2002;154:157–160). (iii) The exchange rate and population of metabolite protons can be determined from offset‐dependent SL or CEST spectra or from on‐resonance SL relaxation dispersion measurements. (iv) The asymmetry of the magnetization transfer ratio (MTRasym) is highly dependent on the choice of saturation pulse power. In the intermediate‐exchange regime, MTRasym becomes complicated and should be interpreted with care. Magn Reson Med, 2011.

Classification of Intervertebral Disk Degeneration with Axial T2 Mapping

OBJECTIVE The aim of this study was to establish an MRI classification system for intervertebral disks using axial T2 mapping, with a special focus on evaluating early degenerative intervertebral disks. MATERIALS AND METHODS Twenty-nine healthy volunteers (19 men, 10 women; age range, 20-44 years; mean age, 31.8 years) were studied, and axial T2 mapping was performed for the L3-L4, L4-L5, and L5-S1 intervertebral disks. Grading was performed using three classification systems for degenerative disks: our system using axial T2 mapping and two other conventional classification systems that focused on the signal intensity of the nucleus pulposus or the structural morphology in sagittal T2-weighted MR images. We analyzed the relationship between T2, which is known to correlate with change in composition of intervertebral disks, and degenerative grade determined using the three classification systems. RESULTS With axial T2 mapping, differences in T2 between grades I and II were smaller and those between grades II and III, and between grades III and IV, were larger than those with the other grading systems. The ratio of intervertebral disks classified as grade I was higher with the conventional classification systems than that with axial T2 mapping. In contrast, the ratio of intervertebral disks classified as grade II or III was higher with axial T2 mapping than that with the conventional classification systems. CONCLUSION Axial T2 mapping provides a more T2-based classification. The new system may be able to detect early degenerative changes before the conventional classification systems can.

Effects of chewing in working memory processing

It has been generally suggested that chewing produces an enhancing effect on cognitive performance-related aspects of memory by the test battery. Furthermore, recent studies have shown that chewing is associated with activation of various brain regions, including the prefrontal cortex. However, little is known about the relation between cognitive performances affected by chewing and the neuronal activity in specified regions in the brain. We therefore examined the effects of chewing on neuronal activities in the brain during a working memory task using fMRI. The subjects chewed gum, without odor and taste components, between continuously performed two- or three-back (n-back) working memory tasks. Chewing increased the BOLD signals in the middle frontal gyrus (Brodmanns areas 9 and 46) in the dorsolateral prefrontal cortex during the n-back tasks. Furthermore, there were more prominent activations in the right premotor cortex, precuneus, thalamus, hippocampus and inferior parietal lobe during the n-back tasks after the chewing trial. These results suggest that chewing may accelerate or recover the process of working memory besides inducing improvement in the arousal level by the chewing motion.

Lung as reservoir for antidepressants in pharmacokinetic drug interactions

BACKGROUND Although high-affinity imipramine binding sites have been reported in both rat and human lung, the role of the lungs in the pharmacokinetics of antidepressants has not received much attention. Substantial accumulation of selective serotonin-reuptake inhibitors (SSRIs) in the lungs has been reported. We have investigated the role of the lungs in pharmacokinetic drug interactions between tricyclic antidepressants and SSRIs. METHODS We used a carbon-11-labelled form of the imipramine derivative cyanoimipramine to measure uptake in the lungs and brain of healthy volunteers by positron emission tomography. Clomipramine (50 mg) was administered to measure the effect of antidepressants with high affinity for the serotonin transporter on lung and brain uptake. FINDINGS A large proportion of the injected 11C-cyanoimipramine (68-86% in the four volunteers) was extracted by the lungs. Clomipramine decreased the lung uptake from 68% to 35% and from 81% to 54% in the two volunteers studied. By contrast, whole-brain uptake was low in control studies (1.7-2.0% in three volunteers) and increased after clomipramine administration (to 4.5-4.9%). Plasma radioactivity was also higher after clomipramine than in control studies. INTERPRETATION The lungs may function as a reservoir for antidepressants with high affinity to the serotonin transporter. The accumulated antidepressants may be displaced by other antidepressants, and this displacement would substantially increase plasma concentrations and thus cause toxic effects.

T2 mapping of hip articular cartilage in healthy volunteers at 3T: A study of topographic variation†

To perform baseline T2 mapping of the hips of healthy volunteers, focusing on topographic variation, because no detailed study has involved hips. T2 mapping is a quantitative magnetic resonance imaging (MRI) technique that evaluates cartilage matrix components.

Specific metabolites in the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia: A preliminary study

We measured brain metabolites in the medial prefrontal cortex of 19 schizophrenic patients and 18 healthy controls by 3 T proton magnetic resonance spectroscopy ((1)H MRS), and examined the relationship between prefrontal cortex-related neurocognitive functions and brain metabolites in the medial prefrontal cortex. The patients with schizophrenia exhibited deficits on the verbal fluency, Wisconsin card sorting test (WCST), trail making test, Stroop test and digit span distraction test (DSDT), but not on the Iowa gambling test. The patients showed statistical significant changes in the ratio of glutamine/glutamate, the ratio of N-acetyl-l-aspartate (NAA)/glycerophosphorylcholine plus phosphorylcholine (GPC+PC) and the levels of taurine in the medial prefrontal cortex compared with normal controls. Furthermore, we found significant correlations of the ratio of glutamine/glutamate with WCST and DSDT scores, the ratio of NAA/(GPC+PC) with verbal fluency and WCST scores, and the levels of taurine with scores on the Stroop test and Trail making test A among the participants. The ratios of NAA/(GPC+PC) and (GPC+PC)/(Cr+PCr) had significant relationships with the duration of untreated psychosis of the schizophrenic patients. The glutamine/glutamate ratio and levels of taurine were significantly related to the duration of illness of the patients. These data suggest that specific metabolites of the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia.