Koji Matsuo

A voxel-based morphometry study of frontal gray matter correlates of impulsivity†

Impulsivity is a personality trait exhibited by healthy individuals, but excessive impulsivity is associated with some mental disorders. Lesion and functional neuroimaging studies indicate that the ventromedial prefrontal region (VMPFC), including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and medial prefrontal cortex, and the amygdala may modulate impulsivity and aggression. However, no morphometric study has examined the association between VMPFC and impulsivity. We hypothesized that healthy subjects with high impulsivity would have smaller volumes in these brain regions compared with those with low impulsivity. Sixty‐two healthy subjects were studied (age 35.4 ± 12.1 years) using a 1.5‐T MRI system. The Barratt impulsiveness scale (BIS) was used to assess impulsivity. Images were processed using an optimized voxel‐based morphometry (VBM) protocol. We calculated the correlations between BIS scale scores and the gray matter (GM) and white matter (WM) volumes of VMPFC and amygdala. GM volumes of the left and right OFC were inversely correlated with the BIS total score (P = 0.04 and 0.02, respectively). Left ACC GM volumes had a tendency to be inversely correlated with the BIS total score (P = 0.05). Right OFC GM volumes were inversely correlated with BIS nonplanning impulsivity, and left OFC GM volumes were inversely correlated with motor impulsivity. There were no significant WM volume correlations with impulsivity. The results of this morphometry study indicate that small OFC volume relate to high impulsivity and extend the prior finding that the VMPFC is involved in the circuit modulating impulsivity. Hum Brain Mapp 2009.

Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder

The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age±s.d.=34.3±11.5 years) and 15 healthy comparison subjects (37.7±12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.

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.

Decreased cerebral haemodynamic response to cognitive and physiological tasks in mood disorders as shown by near-infrared spectroscopy"

BACKGROUND Hypofrontality has been demonstrated in mood disorders by functional brain imaging methods such as positron emission tomography. However, the neurobiological basis of hypofrontality has not been well clarified. Near-infrared spectroscopy (NIRS) is a non-invasive technique for continuous monitoring of alterations in oxygenated (oxyHb) and deoxygenated (deoxyHb) haemoglobin using near-infrared light, which penetrates biological tissues. METHODS We used NIRS during cognitive and physiological tasks to investigate alterations of haemoglobin oxygenation in the frontal region of euthymic patients with mood disorders (major depressive disorder (MD) and bipolar disorder (BP)) and in controls. RESULTS The increase of oxyHb during a verbal fluency task was significantly less in the MD and the BP groups than in the controls. The MD group showed a significantly smaller decrease of oxyHb during hyperventilation than the controls. The BP group also showed a similar trend. CONCLUSIONS These findings suggest that the hypofrontality in mood disorders may be associated with a poor response in the cerebral blood vessels to neuronal and chemical stimuli.

Amygdala hyperactivation in untreated depressed individuals

The amygdala participates in the detection and control of affective states, and has been proposed to be a site of dysfunction in affective disorders. To assess amygdala processing in individuals with unipolar depression, we applied a functional MRI (fMRI) paradigm previously shown to be sensitive to amygdala function. Fourteen individuals with untreated DSM-IV major depression and 15 healthy subjects were studied using fMRI with a standardized emotion face recognition task. Voxel-level data sets were subjected to a multiple-regression analysis, and functionally defined regions of interest (ROI), including bilateral amygdala, were analyzed with MANOVA. Pearson correlation coefficients between amygdala activation and HAM-D score also were performed. While both depressed and healthy groups showed increased amygdala activity when viewing emotive faces compared to geometric shapes, patients with unipolar depression showed relatively more activity than healthy subjects, particularly on the left. Positive Pearson correlations between amygdala activation and HAM-D score were found for both left and right ROIs in the patient group. This study provides in vivo imaging evidence to support the hypothesis of abnormal amygdala functioning in depressed individuals.

Multiple-time replicability of near-infrared spectroscopy recording during prefrontal activation task in healthy men

Near-infrared spectroscopy (NIRS) has the potential for clinical application in neuropsychiatry because it enables non-invasive and convenient measurement of hemodynamic response to cognitive activation. Using 24-channel NIRS in 12 healthy men, we examined the replicability of oxy- and deoxy-hemoglobin concentration ([oxyHb], [deoxyHb]) changes in the prefrontal cortex during the category fluency task over four repeated sessions (each 1-week apart). Multiple methods were employed to evaluate the replicability of magnitude, location, and time course of the NIRS signals ([oxyHb], [deoxyHb]). Task performances did not differ significantly across sessions, nor were they significantly correlated with NIRS signals. Repeated measures ANOVA and variance component analysis indicated high replicability of magnitude for both NIRS measures, whereas the effect sizes of between-session differences in [oxyHb] were not negligible. The number and spatial location of significantly activated channels were sufficiently replicable for both measures, except that the across-session overlap of significantly activated channels was weak in [deoxyHb]. The time course of the activation was acceptably replicable in both measures. Taken together, these findings suggest there is considerable replicability of multiple-time measurements of prefrontal hemodynamics during cognitive activation in men. Further studies using different conditions or assessing sensitivity to longitudinal changes following interventions are necessary.

Neuronal Correlates of Brain-derived Neurotrophic Factor Val66Met Polymorphism and Morphometric Abnormalities in Bipolar Disorder

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been proposed as a possible candidate for involvement in the pathophysiology of bipolar disorder (BD). To determine whether an association exists between the BDNF Val66Met genotype and morphometric abnormalities of the brain regions involved in memory and learning in BD and healthy subjects. Forty-two BD patients and 42 healthy subjects were studied. Interactions between BDNF Val66Met genotype and diagnosis in gray (GM) volumes were analyzed using an optimized voxel-based morphometry technique. Declarative memory function was assessed with the California Verbal Learning Test II. Left and right anterior cingulate GM volumes showed a significant interaction between genotype and diagnosis such that anterior cingulate GM volumes were significantly smaller in the Val/Met BD patients compared with the Val/Val BD patients (left P=0.01, right P=0.01). Within-group comparisons revealed that the Val/Met carriers showed smaller GM volumes of the dorsolateral prefrontal cortex compared with the Val/Val subjects within the BD patient (P=0.01) and healthy groups (left P=0.03, right P=0.03). The Val/Met healthy subjects had smaller GM volumes of the left hippocampus compared with the Val/Val healthy subjects (P<0.01). There was a significant main effect of diagnosis on memory function (P=0.04), but no interaction between diagnosis and genotype was found (P=0.48). The findings support an association between the BDNF Val66Met genotype and differential gray matter content in brain structures, and suggest that the variation in this gene may play a more prominent role in brain structure differences in subjects affected with BD.

Activation of the prefrontal cortex to trauma-related stimuli measured by near-infrared spectroscopy in posttraumatic stress disorder due to terrorism.

To develop a noninvasive method for psychophysiological assessment of posttraumatic stress disorder (PTSD), 34 victims of the Tokyo Subway Sarin Attack in 1995 including 8 diagnosed as PTSD and 12 controls were examined by a multichannel near-infrared spectroscopy (NIRS) system. Hemodynamic response in the prefrontal cortex was monitored during the presentation of trauma-related and control stimuli by video images. Skin conductance response (SCR) was also examined. Oxygenated hemoglobin significantly increased during the trauma-related image in the victims with or without PTSD. Deoxygenated hemoglobin significantly decreased only in victims with PTSD. No significant alteration was found in controls. Significantly enhanced SCR was also observed in the victims with PTSD during trauma-related stimuli. The findings suggest that measurement of cerebral hemodynamic response by NIRS is useful for psychophysiological assessment of PTSD.

Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy

Accumulated evidence suggests the involvement of vascular factors in late-onset depression. Late-onset depression has characteristics of poor outcome, cognitive decline, and high prevalence rather than early-onset depression. The aim of the present study was to determine whether or not the functional hypofrontality--that is, hypoperfusion and hypometabolism in the frontal lobes-seen in late-onset depression is a trait-dependent abnormality of microvascular regulation. This study was conducted on 10 patients with remitted late-onset major depressive disorder (MDD) and 10 healthy volunteers matched for vascular factors and subcortical, or white matter, hyperintensities (WMH). Using near-infrared spectroscopy combined with magnetic resonance imaging, we investigated the microvascular reactivity in the prefrontal cortex during a cognitive task and during carbon dioxide (CO(2)) inhalation. Activation of the prefrontal cortex during the cognitive task was significantly less in patients as compared with controls, although task performance was not significantly different between the two groups. In the patients, a tendency of negative correlation between the reduced prefrontal activation during a cognitive task and the severity of hyperintensity in periventricular region was observed. Vasomotor reactivity to CO(2) inhalation was significantly lower in the patients than in the controls. Although there was no significant association between the activation during the cognitive and that during the CO(2) inhalation task, the present results suggest that prefrontal microvascular dysregulation as shown by NIRS is involved in the pathophysiological basis of functional hypofrontality in late-onset depression. This finding will provide a new framework for the development of diagnostic methods, treatments, and preventive strategies against late-onset depression.

Prefrontal gray matter increases in healthy individuals after lithium treatment: A voxel-based morphometry study

The objective of this study was to test the hypothesis that 4 weeks of lithium administration would be associated with changes in brain gray and white matter volumes in healthy individuals. Thirteen right-handed healthy volunteers (6 females, mean age=25.9+/-10.0 years) were studied. 3D SPGR MRIs (TR=25 ms, TE=5 ms, slice-thickness=1.5 mm) were acquired using a 1.5 T GE Signa Imaging System, at baseline and after 4 weeks of lithium administration at therapeutically relevant doses. Optimized voxel-based morphometry (VBM) analyses were conducted. Left and right dorsolateral prefrontal cortex and left anterior cingulate gray matter volumes increased significantly following lithium administration. Total white matter volume was increased, whereas total brain volume and total gray matter volume were not significantly changed following 4 weeks of lithium. Lithium treatment resulted in prefrontal regional gray matter volume increases in healthy volunteers, as well as increases in total white matter volume. Whether these changes are mediated by neurotrophic/neuroprotective or osmotic effects remains unknown.