Dong-Pyo Jang

Alteration of brain metabolites in young alcoholics without structural changes

Using proton magnetic resonance spectroscopy and magnetic resonance imaging, we investigated concentrations of various brain metabolites, including glutamate, and measured brain volumes and neuropsychological performances in 13 recently abstinent young alcoholic men compared with 18 controls. No differences were found in volumetric variables between groups (intracranial volume, white matter, grey matter, anterior cingulate, insula, hippocampus, and amygdala). For the anterior cingulate, choline and creatine levels in the patient group were significantly lower than controls, and the glutamate to creatine ratio was significantly increased. These were correlated with altered short-term memory functions. Thus, neurochemical changes can occur even in the brains of young alcoholic men lacking brain atrophy.

Neural responses in rat brain during acute immobilization stress: A [F-18]FDG micro PET imaging study

We used the [F-18]FDG micro PET neuroimaging technique to investigate changes in brain activity induced by acute stress in rats. Animals were given immobilization stress for 1 or 2 h, or 1-h stress followed by 1-h recovery, after which their brains were scanned. Plasma corticosterone levels measured at various time points in separate groups of rats showed a rapid increase during stress and slower decrease after termination of the stress. Immobilization stress given for an hour activated the hypothalamus, entorhinal and insular/piriform cortices, and raphe pallidus nucleus. At the same time, the dorsal hippocampus, thalamus, other cortical areas (motor, somatosensory and barrel field), striatum, superior colliculus and cerebellum were deactivated. With 2-h immobilization stress, the activity of the hypothalamus, various cortical areas and dorsal hippocampus habituated during the second hour while that of the thalamus and cerebellum did not. During 1-h recovery, the hypothalamic activation and widespread cortical deactivation disappeared, but the dorsal hippocampus, thalamus and cerebellum still remained significantly deactivated. Additional brain areas such as the septum and prelimbic cortex now showed deactivation during recovery. Changes in glucose metabolism in the dorsal hippocampus and hypothalamus exhibited a highly significant negative correlation, supporting the view that the hippocampus is involved in regulating the stress response of the hypothalamo-pituitary-adrenal axis. The advantages and limitations of the [F-18]FDG micro PET used in this study are discussed.

The relationship between brain morphometry and neuropsychological performance in alcohol dependence

The aim of this study was to explore local brain atrophy of patients with alcohol dependence using a voxel-based analysis of magnetic resonance images and to investigate the relationship of those atrophic regions with drinking history and neuropsychological performances. Statistical parametric mapping was applied for the global and regional comparison of segmented gray matter and white matter images from 20 patients with alcohol dependence and with those from 20 controls. The Rey auditory-verbal learning test, Rey-Osterrieth complex figure test, Stroop test, trail-making test, and Wisconsin card sorting test were conducted as neuropsychological evaluations. There was a significant decrease in both gray matter and white matter globally in alcohol dependence. Bilateral parahippocampal white matter areas were reduced in particular. Perseverative responses and perseverative errors in the Wisconsin card sorting test had significant correlation with the decrease of gray matter decrease including the left superior temporal gyri and right postcentral region. The psychological performance measures correlated with gray matter rather than white matter, whereas right temporal white matter correlated with drinking amount for last 4 weeks. This may imply that alcohol consumption in heavy amounts damages both gray matter and white matter, and gray matter atrophy mainly leads to cognitive impairment, whereas white matter is related to drinking history.

BT-11 improves stress-induced memory impairments through increment of glucose utilization and total neural cell adhesion molecule levels in rat brains

In Oriental medicine, roots of Polygala tenuifolia Willdenow have been known to be an important herb that exhibits sedative effects in insomnia, palpitation with anxiety, restlessness, and disorientation in humans. We previously reported that BT‐11, extracted from those roots, improved scopolamine‐induced amnesia in rats and inhibited acetylcholinesterase activities in vitro. Therefore, we proposed that BT‐11 could remedy stress‐induced memory deficits in rats. In this study, the stress‐induced memory impairments in rats were significantly reversed almost to the control level by BT‐11 treatment. To seek an active component of BT‐11 that plays an important role in antipsychotic effects, we compared BT‐11 with 3,4,5‐trimethoxycinnamic acid (TMCA), which is a constituent of those root extracts. However, the effects of TMCA were less or were not consistent with those of BT‐11 in some of tests. In perticular, BT‐11 reversed the stress‐induced reduction of glucose utilization by [18fluorodeoxyglucose]FDG‐PET and the levels of neural cell adhesion molecule (NCAM) in rat brains to the control levels, whereas TMCA did not. Therefore, BT‐11 improved stress‐induced memory impairments through increment of glucose utilization and total NCAM levels in rat brains. In conclusion, BT‐11 may be strongly effective against stress‐induced amnesia in rats, through the combined effects of TMCA and other active components of BT‐11.

Controlled magnetic nanofiber hydrogels by clustering ferritin.

We have fabricated biocompatible nanofiber hydrogels with diverse sizes of ferritin clusters according to the mixing temperature of solutions employing electrospinning. Poly(vinyl alcohol) (PVA) was used as a polymeric matrix for fabricating nanocomposites. By thermal means we controlled the interaction between the host PVA hydrogel and the protein shell on ferritin bionanoparticles to vary the size and concentration of ferritin clusters. The clustering of ferritin was based on the partial unfolding of a protein shell of ferritin. By studying the magnetic properties of the PVA/ferritin nanofibers according to the mixing temperature of the PVA/ferritin solutions, we confirmed that the clustering process of the ferritin was related to changes in the superparamagnetic properties and magnetic resonance imaging (MRI) contrast of the PVA/ferritin nanofibers. PVA/ferritin nanofiber hydrogels with diverse spatial distributions of ferritin nanoparticles are applicable as MRI-based noninvasive detectable cell culture scaffolds and as artificial muscles because of their improved superparamagnetic properties.

Neural responses of rats in the forced swimming test: [F-18]FDG micro PET study

The forced swimming test (FST) is a widely used tool in the assessment of behavioral despair and prediction of response to antidepressants. However, the neural mechanisms underlying behavioral changes between pretest and test sessions of the FST remain unclear. In this study, we investigated changes in rat brain activity during the FST using [F-18]Fluorodeoxyglucose micro PET. In both pretest and test sessions, the activity of the cerebellum and striatum increased, whereas significant deactivation was observed in the hippocampus, inferior colliculus, orbital cortex, and insula. The periaqueductal gray (PAG) region activated markedly in the pretest session, but did not activate in the test session. There was a significant increase in immobility and a decrease in climbing during the behavioral analysis test session. These results suggest that the PAG region may play an important role in the modulation of FST coping strategies subsequent to failure of the escape response during the pretest session.

Spatial Distribution of Glucose Hypometabolism Induced by Intracerebroventricular Streptozotocin in Monkeys

Intracerebroventricular injection of streptozotocin (icv-STZ) in rodents induces cellular and behavioral features mimicking Alzheimers disease (AD). However, the effect of icv-STZ in terms of regional cerebral glucose metabolism has not yet been examined in vivo. Given that regionally specific hypometabolism of glucose is a consistent neuroimaging marker in early AD, we monitored 18F-deoxyglucose uptake using a high-resolution micro-PET after icv-STZ in non-human primates. Two cynomolgus monkeys (Macaca fascicularis) received STZ (2 mg/kg), and another two were given normal saline as controls, at the cerebellomedullary cistern (CM) three times (day 1, 7, and 14). FDG-PET, as well as MRI for structural evaluation, was performed immediately before, six weeks after, and 12 weeks after the first icv injection. In the STZ group, FDG uptake decreased significantly in comparison to the pre-injection baseline, at the precuneus, the posterior cingulate, and medial temporal cortices. Increase in sulcal markings suggesting brain atrophy was observed by MRI at six weeks post-injection. The structural changes normalized at 12 weeks, but the reduced FDG uptake persisted at the same loci. The cortical distribution of glucose hypometabolism was similar to that at early stages of AD patients. The findings demonstrate that the effect of icv-STZ is regionally specific, lending further support for the method as a model of AD pathogenesis.

Effects of fluoxetine on the rat brain in the forced swimming test: A [F-18]FDG micro-PET imaging study

We used the [F-18]FDG micro-PET neuroimaging to examine the effects of fluoxetine on brain activity in rats and on their behavioral response in the forced swimming test (FST). In the first experiment, the rats were administered doses of fluoxetine (10 or 20mg/kg) 24, 19 and 1h before the rat brains were scanned. Fluoxetine induced strong activation of the dorsal hippocampus and the deactivation of the inferior colliculus, medulla oblongata, and prelimbic cortex in a dose-dependent manner. These results seemed to be related with the changes in 5-HT (5-hydroxytryptamine, serotonin) levels after selective serotonin reuptake-inhibitor treatments. In the second experiment, the changes in glucose metabolism in the test session were measured after fluoxetine was given between pre-test and test sessions of the FST. Fluoxetine administration significantly decreased immobility behavior compared with saline administration. At the same time, the activity of the insular/piriform cortex decreased significantly. In contrast, the extent of cerebellar activation increased. The glucose metabolism of the dorsal hippocampus also increased, which suggests that post-stress changes in the facilitation of hippocampal serotonergic neurotransmission lead to decreased immobilization in the FST.

Canine model of ischemic stroke with permanent middle cerebral artery occlusion: clinical and histopathological findings

The aim of the present study was to assess the clinical and histopathological findings in a canine model of ischemic stroke. Cerebral ischemic stroke was induced by middle cerebral artery occlusion in four healthy beagle dogs using silicone plugs. They showed neurological signs of forebrain dysfunction such as reduced responsiveness, head turning, circling, postural reaction deficits, perceptual deficits, and hemianopsia. These signs gradually regressed within 4 weeks without therapy. On magnetic resonance imaging, T2 hyperintensity and T1 hypointensity were found in the cerebral cortex and basal ganglia. These lesions were well-defined and sharply demarcated from adjacent brain parenchyma with a homogenous appearance. No abnormalities of the cerebrospinal fluid were observed. At necropsy, atrophic and necrotic lesions were observed in the cerebral cortex. The cerebral cortex, basal ganglia, and thalamus were partially unstained with triphenyl-tetrazolium chloride. Histopathologically, typical features of infarction were identified in cortical and thalamic lesions. This study demonstrates that our canine model resembles the conditions of real stroke patients.

Detection of cerebral metabolites in a canine model of ischemic stroke using 1H magnetic resonance spectroscopy.

Proton magnetic resonance spectroscopy ((1)H MRS) provides in vivo biochemical information on tissue metabolites. The purpose of this study was to investigate the serial metabolic changes of (1)H MRS in the cerebrum of ischemic dogs. An ischemic stroke was induced in five health laboratory beagle dogs by permanent middle cerebral artery occlusion using a silicone plug. (1)H MRS was serially performed three times with a 1.5-T MR system: before, three days after and 10days after the stroke. Immunohistochemical staining was performed to determine the expression of neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) at both the ipsilateral and contralateral cerebral cortex. Reduced levels of N-acetyl-asparate (p<0.05), choline (Cho), creatine (Cr) and myo-inositol (mI), and a marked increase in the lactate (Lac) level (p<0.01) were found at three days after the stroke. At 10days after the stroke, the levels of Lac significantly increased (p<0.01); however, the other metabolites were partially elevated. The changes of Cr, Cho and mI were not statistically significant (p>0.05) when the before and after stroke values were compared. There was a significant loss of NeuN and GFAP immunoreactivity at the ischemic core. (1)H MRS may be to a useful diagnostic tool for the evaluation of ischemic stroke in dogs.