Sujung Yoon

The Role of Oxidative Stress in Neurodegenerative Diseases.

Oxidative stress is induced by an imbalanced redox states, involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system. The brain is one of organs especially vulnerable to the effects of ROS because of its high oxygen demand and its abundance of peroxidation-susceptible lipid cells. Previous studies have demonstrated that oxidative stress plays a central role in a common pathophysiology of neurodegenerative diseases such as Alzheimers disease and Parkinsons disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases, although the results with regard to their efficacy of treating neurodegenerative disease have been inconsistent. In this review, we will discuss the role of oxidative stress in the pathophysiology of neurodegenerative diseases and in vivo measurement of an index of damage by oxidative stress. Moreover, the present knowledge on antioxidant in the treatment of neurodegenerative diseases and future directions will be outlined.

A Randomized, Double-Blind Placebo-Controlled Trial of Oral Creatine Monohydrate Augmentation for Enhanced Response to a Selective Serotonin Reuptake Inhibitor in Women With Major Depressive Disorder

OBJECTIVE Antidepressants targeting monoaminergic neurotransmitter systems, despite their immediate effects at the synaptic level, usually require several weeks of administration to achieve clinical efficacy. The authors propose a strategy of adding creatine monohydrate (creatine) to a selective serotonin reuptake inhibitor (SSRI) in the treatment of patients with major depressive disorder. Such augmentation may lead to a more rapid onset of antidepressant effects and a greater treatment response, potentially by restoring brain bioenergetics at the cellular level. METHOD Fifty-two women with major depressive disorder were enrolled in an 8-week double-blind placebo-controlled clinical trial and randomly assigned to receive escitalopram in addition to either creatine (5 g/day, N=25) or placebo (N=27). Efficacy was primarily assessed by changes in the Hamilton Depression Rating Scale (HAM-D) score. RESULTS In comparison to the placebo augmentation group, patients receiving creatine augmentation showed significantly greater improvements in HAM-D score, as early as week 2 of treatment. This differential improvement favoring creatine was maintained at weeks 4 and 8. There were no differences between treatment groups in the proportion of patients who discontinued treatment prematurely (creatine: N=8, 32.0%; placebo: N=5, 18.5%) or in the overall frequency of all reported adverse events (creatine: 36 events; placebo: 45 events). CONCLUSIONS The current study suggests that creatine augmentation of SSRI treatment may be a promising therapeutic approach that exhibits more rapid and efficacious responses in women with major depressive disorder.

THE EFFECTS OF ALCOHOL HANGOVER ON COGNITIVE FUNCTIONS IN HEALTHY SUBJECTS

A hangover is characterized by the constellation of unpleasant physical and mental symptoms that occur between 8 and 16 h after drinking alcohol. We evaluated the effects of experimentally-induced alcohol hangover on cognitive functions using the Luria-Nebraska Neuropsychological Battery. A total of 13 normal adult males participated in this study. They did not have any previous histories of psychiatric or medical disorders. We defined the experimentally-induced hangover condition at 13 h after drinking a high dose of alcohol (1.5 g/kg of body weight). We evaluated the changes of cognitive functions before drinking alcohol and during experimentally-induced hangover state. The Luria-Nebraska Neuropsychological Battery was administrated in order to examine the changes of cognitive functions. Cognitive functions, such as visual, memory, and intellectual process functions, were decreased during the hangover state. Among summary scales, the profile elevation scale was also increased. Among localization scales, the scores of left frontal, sensorimotor, parietal-occipital dysfunction, and right parietal-occipital scales were increased during the hangover state. These results indicate that alcohol hangovers have a negative effect on cognitive functions, particularly on the higher cortical and visual functions associated with the left hemisphere and right posterior hemisphere.

Posterior cerebellar vermal deficits in bipolar disorder

BACKGROUND Based on growing evidence of the crucial role of the cerebellum in emotional regulation, we sought to identify cerebellar structural deficits in a large sample of patients with bipolar disorder (BD). METHODS Cerebellar gray matter density was examined in 49 BD patients (24 medication-naive and 25 medication-treated) and 50 carefully matched healthy individuals, using voxel-based morphometry with a high-resolution spatially unbiased atlas template of the human cerebellum. This recently developed methodology is specifically optimized for the assessment of cerebellar structures. We further explored whether antimanic treatment could attenuate cerebellar structural deficits. RESULTS BD patients showed a greater reduction in gray matter density of the posterior cerebellar regions, including the bilateral vermi and the right crus relative to healthy individuals (corrected p<.05). A stepwise linear reduction in gray matter density was observed in bilateral vermal regions between healthy individuals, medication-treated, and medication-naive BD patients. Furthermore, positive correlations of longer duration of illness with bilateral vermal gray matter deficits were observed only in medication-naive BD patients, but not in patients with medication history. LIMITATIONS This study adopted a cross-sectional design. The automatic intensity-normalization method for the measurement of cerebellar gray matter density may have a limitation in providing detailed anatomical information at a cerebellar folia level. CONCLUSIONS The current findings suggest that BD-related deficits in the posterior cerebellar regions, which appear to progress over the course of illness, could potentially be ameliorated by proper treatment with mood stabilizers.

Morphometric Changes in Lateral Ventricles of Patients with Recent-Onset Type 2 Diabetes Mellitus

It is becoming increasingly evident that type 2 diabetes mellitus can have effects on global and regional brain morphology. Ventricular enlargement reflecting cerebral atrophy has been reported particularly in elderly type 2 diabetes patients. However, little is known about its timing through the disease course and morphological variability. Using the combined volumetric and advanced three-dimensional morphological approach, we identified differences in size and shape of the lateral ventricles between recent-onset type 2 diabetes patients and healthy individuals. High-resolution T1-weighted images were obtained from 23 type 2 diabetes patients whose illness duration was less than 1 year and 23 carefully matched healthy individuals. By volume measurement, we found enlarged lateral and third ventricles in type 2 diabetes patients, relative to healthy individuals (F 1,41 = 7.96, P = 0.007; F 1,41 = 11.16, P = 0.002, respectively). Morphological analysis revealed that the expansion of lateral ventricles in the diabetic brain was prominent in the bilateral frontal horns. The current findings suggest that atrophic changes particularly of the anterior frontal lobe can occur as early as the first year after the clinical diagnosis of type 2 diabetes mellitus.

Ghrelin precursor gene polymorphism and methamphetamine dependence in the Korean population

Ghrelin is a recently isolated brain-gut peptide that has growth hormone-releasing and appetite-inducing activities. Several recent studies have suggested that ghrelin plays a major role in the pathophysiology of drug-seeking behavior and anxiety. Therefore, we assessed the effect of the ghrelin precursor polymorphism on methamphetamine dependence in the Korean population. One hundred and eighteen patients with methamphetamine dependence, according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria, and the 144 healthy controls were enrolled in this study. Genotyping for the ghrelin precursor polymorphism was performed by the polymerase chain reaction-restriction fragment length polymorphism-based technique. The genotypic and allelic distributions of the ghrelin precursor polymorphism in the patients with methamphetamine dependence were not significantly different from those of the control subjects. However, the Met72 carriers were associated with the emotional problems of methamphetamine dependence. The patients with the Met72 allele were more depressed and anxious than the homozygous patients with the wild Leu72 allele. The present study suggests that the ghrelin precursor polymorphism may not confer a susceptibility to the development of methamphetamine dependence in the Korean population. However, the Leu72Met polymorphism could have a potential role in the emotional problems that are associated with this disease.

Network-level structural abnormalities of cerebral cortex in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion.

Predisposition to and effects of methamphetamine use on the adolescent brain

Adolescence is a period of heightened vulnerability both to addictive behaviors and drug-induced brain damage. Yet, only limited information exists on the brain mechanisms underlying these adolescent-specific characteristics. Moreover, distinctions in brain correlates between predisposition to drug use and effects of drugs in adolescents are unclear. Using cortical thickness and diffusion tensor image analyses, we found greater and more widespread gray and white matter alterations, particularly affecting the frontostriatal system, in adolescent methamphetamine (MA) users compared with adult users. Among adolescent-specific gray matter alterations related to MA use, smaller cortical thickness in the orbitofrontal cortex was associated with family history of drug use. Our findings highlight that the adolescent brain, which undergoes active myelination and maturation, is more vulnerable to MA-related alterations than the adult brain. Furthermore, MA-use-related executive dysfunction was greater in adolescent MA users than in adult users. These findings may provide explanation for the severe behavioral complications and relapses that are common in adolescent-onset drug addiction. Additionally, these results may provide insights into distinguishing the neural mechanisms that underlie the predisposition to drug addiction from effects of drugs in adolescents.

Altered cortical gyrification patterns in panic disorder: Deficits and potential compensation

Abnormal gyrification patterns may reflect aberrant cortical connectivity during an early period of brain maturation. We here investigated anatomical distribution of cortical gyrification deficits underlying panic disorder and the relationships of these potential neurodevelopmental markers with panic symptom severity. High-resolution three-dimensional T1-weighted structural images were obtained from 23 patients with panic disorder and 33 matched healthy individuals. Local gyrification indices were measured in each genetically-based parcellated cortical subregion and regional gyrification patterns were compared between groups. Cortical areas in which gyrification patterns were associated with panic symptom severity were also determined. Significant reductions in cortical gyrification were observed in panic patients compared with healthy individuals, which were mainly distributed in the lateral brain extending from the fronto-parietal to the temporal areas. In contrast, hyper-gyrification in the posteromedial cortical regions which exert interconnecting roles in the default mode network, was associated with less severe panic symptoms. Post-hoc analysis for the inter-regional covariance of local gyrification indices revealed that interconnections of the posteromedial cortical regions with other cortical areas which belong to the default mode network were reduced in panic patients with severe symptoms relative to either less severe patients or healthy individuals. Our findings suggest not only substantial perturbation in cortical gyrification patterns in panic disorder but also potential contribution of integrated cortical folding pattern of the default mode network to alleviated panic severity.

Complexity Changes of the EEG Induced by Alcohol Cue Exposure in Alcoholics and Social Drinkers

BACKGROUND An understanding of the neurophysiological mechanisms underlying alcohol craving is important in the effective treatment of alcohol dependence. The aim of this study was to examine the utility of the electroencephalogram (EEG) to measure the changes in electrical brain activity of alcoholics when exposed to alcohol-specific cues. METHODS Fifteen adult alcoholic subjects (four women) with a mean age of 35 (SD = 4.5) and 10 healthy social drinking controls (three women) with a mean age of 34 (SD = 5.6) were recruited. Subjects were serially rated for alcohol craving after presentations of pictures of control nonalcoholic and alcohol beverages. After the picture presentation, the EEG was recorded (16,384 data points for each epoch) with eyes closed. The dimensional complexity (D2) was estimated as a measure of complexity of the EEG. RESULTS Alcoholic subjects exhibited a significant increase in the D2 values of the EEG in frontal (F3, F4), right posterior temporal (T6), and occipital (O1, O2) regions after viewing alcohol cues compared with viewing other beverage cues. These results indicate that more complex (or higher) cortical activity is induced over specific brain regions of alcoholic subjects by alcohol-specific cues. Changes in subscale of alcohol craving between nonalcoholic and alcohol pictures were correlated with changes in D2 values in the left frontal (F3) region in alcoholic subjects. CONCLUSIONS These findings suggest that, when subjects are exposed to alcohol cues, changes in the EEG complexity are induced in frontal, right posterior temporal, and occipital areas, which may be key brain structures for alcohol craving. In addition, nonlinear measures like the D2 are useful in evaluating alcohol cue-induced brain activity from the EEG.