Kee Namkoong

Dopamine transporter density of the basal ganglia assessed with [123I]IPT SPECT in drug-naive children with Tourette's disorder

There is evidence that abnormalities in the dopaminergic system involving the dopamine transporter (DAT) are involved in the pathophysiology of Tourettes disorder (TD) from previous studies using [(123)I]2beta-carbomethoxy-3-(4-iodophenyl)tropane ([(123)I]beta-CIT) and single photon emission tomography (SPECT). However, because those studies were performed in medicated adult patients with TD, we decided to compare DAT densities in nine drug-naive children with TD and eight normal children. The children with TD did not suffer from associated psychiatric problems such as obsessive-compulsive symptoms, attention deficit hyperactivity disorder, anxiety, depression and developmental difficulties. We performed brain SPECT 2 h after the intravenous administration of I-123N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)tropane ([(123)I]IPT) and carried out both quantitative and qualitative analyses using the obtained SPECT data, which were reconstructed for the assessment of the specific/non-specific DAT binding ratio in the basal ganglia. We then investigated the correlation between the severity of tics in children with TD assessed with the Yale Global Tic Severity Scale (YGTSS) and the specific/non-specific DAT binding ratio of the basal ganglia. Drug-naive children with TD showed a significantly increased specific/non-specific DAT binding ratio in the basal ganglia compared with normal children that did not correlate significantly with the severity of tics. Our results with drug-naive children with TD between the ages of 6 and 12 may help to clarify previous findings concerning DAT binding in adult patients with TD and suggest that DAT densities may be associated directly with the pathophysiology of TD, regardless of disease progress or drug effect.

Increased P3 amplitudes induced by alcohol-related pictures in patients with alcohol dependence.

BACKGROUND Alcohol craving, a key element in alcohol dependence, is recognized as being a kind of motivational or emotional state. It is meaningful in research and clinical practice involving alcohol dependence to explore ways of measuring alcohol craving. The aim of this study was to measure the P3 event-related potentials induced by alcohol-related pictures in patients with alcohol dependence; these potentials are considered to constitute a neuronal correlate of alcohol craving. METHODS On the basis of our previous study, six alcohol-related pictures and six neutral pictures were chosen as the visual stimuli. Each set of stimuli consisted of alcohol-related or neutral pictures as the target stimuli and same-sized checkerboards as the nontarget stimuli. The stimuli were presented by using the oddball paradigm for 300 msec, with an interstimulus interval of 1000 msec, in 12 controls and 16 abstinent patients with alcohol dependence. Each electroencephalography session consisted of three blocks: a practice block, a neutral block, and an alcohol-craving block. RESULTS The amplitudes of P3 elicited by the alcohol-related pictures were significantly larger than those elicited by the neutral pictures in the patients with alcohol dependence, whereas there was no significant difference according to the stimuli in the P3 amplitudes of controls. Repeated-measures ANOVA on the amplitudes of P3 revealed that there was a significant interaction effect of block by subject group. CONCLUSIONS These results suggest that event-related potentials can be used as a neuronal correlate of alcohol craving in alcohol-dependent patients. Future investigations will be needed to assess the frequency of relapse in the patients included in this study, to elucidate the meaning of the observed results with regard to the therapeutic outcomes.

A randomized controlled study of sequentially applied repetitive transcranial magnetic stimulation in obsessive-compulsive disorder.

OBJECTIVE The present study investigated possible therapeutic effects and safety of sequentially combined low-frequency repetitive transcranial magnetic stimulation (rTMS) to the right dorsolateral prefrontal cortex and supplementary motor area in patients with treatment-resistant obsessive-compulsive disorder. METHOD Between February 2007 and January 2008, we carried out a study with a rater-blinded, sham-controlled design in which 20 patients with treatment-resistant obsessive-compulsive disorder, confirmed by a psychiatrist after use of the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version, were randomly assigned to either active rTMS (n = 10) or sham treatment (n = 10). Over 10 days, rTMS of 1 Hz was given at 110% of the motor threshold for 20 minutes over the right dorsolateral prefrontal cortex and sequentially at 1 Hz at 100% of the motor threshold for 20 minutes over the supplementary motor area. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS) score. RESULTS For the between-group analyses, there were no significant differences over 4 weeks between the active and sham groups on the YBOCS (F = 0.01, P = .92) and the Montgomery-Asberg Depression Rating Scale (MADRS; F = 0.39, P = .54). In repeated-measures analyses on all subjects, there was a significant effect of time on the YBOCS (F = 5.48, P = .009) and the MADRS (F = 6.55, P = .004). There were no significant group-by-time interactions for the YBOCS (F = 0.03, P = .94) or the MADRS (F = 0.09, P = .67). CONCLUSIONS These findings suggest that 10 sessions of sequential rTMS of the right dorsolateral prefrontal cortex and the supplementary motor area at low frequency had no therapeutic effect on obsessive-compulsive symptoms. However, rTMS was a safe method of treatment, and there was no significant change in cognitive function after rTMS. Further controlled studies using a more sophisticated sham system in larger samples are required to confirm the effect of rTMS in obsessive-compulsive disorder. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00932204.

Reduced P3 amplitudes by negative facial emotional photographs in schizophrenia

Event-related potentials (ERPs), mostly P3, were measured in 20 schizophrenia and 20 healthy control subjects, in order to determine whether patients with schizophrenia have greater impairment in the processing of negative emotions. Study subjects were instructed to feel and respond to rare targets of facial photographs placed between frequent nontarget checkerboards. We found that P3 amplitudes associated with negative emotional photographs, in normal controls, were significantly larger than those of positive stimuli. Unlike the controls, in patients with schizophrenia, P3 amplitudes generated by negative emotional targets were significantly smaller than those of positive stimuli. We conclude that schizophrenia patients might be neurophysiologically different from healthy controls in terms of the manner in which they process facial emotion. Our findings are in line with previous neurobehavioral studies, in which patients with schizophrenia showed greater impairment in the recognition of negative emotions.

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.

Organotypic hippocampal slice culture from the adult mouse brain: A versatile tool for translational neuropsychopharmacology

One of the most significant barriers towards translational neuropsychiatry would be an unavailability of living brain tissues. Although organotypic brain tissue culture could be a useful alternative enabling observation of temporal changes induced by various drugs in living brain tissues, a proper method to establish a stable organotypic brain slice culture system using adult (rather than neonatal) hippocampus has been still elusive. In this study, we evaluated our simple method using the serum-free culture medium for successful adult organotypic hippocampal slice culture. Several tens of hippocampal slices from a single adult mouse (3-5 months old) were cultured in serum-free versus serum-containing conventional culture medium for 30 days and underwent various experiments to validate the effects of the existence of serum in the culture medium. Neither the excessive regression of neuronal viability nor metabolic deficiency was observed in the serum-free medium culture in contrast to the serum-containing medium culture. Despite such viability, newly generated immature neurons were scarcely detected in the serum-free culture, suggesting that the original neurons in the brain slice persist rather than being replaced by neurogenesis. Key structural features of in vivo neural tissue constituting astrocytes, neural processes, and pre- and post-synapses were also well preserved in the serum-free culture. In conclusion, using the serum-free culture medium, the adult hippocampal slice culture system will serve as a promising ex vivo tool for various fields of neuroscience, especially for studies on aging-related neuropsychiatric disorders or for high throughput screening of potential agents working against such disorders.

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.

Mirtazapine for patients with alcohol dependence and comorbid depressive disorders: A multicentre, open label study

Major depressive disorder and alcohol dependence are common and serious mental illnesses. There is a great interest in discovering useful treatments for both mood symptoms and alcohol abuse in those patients with depressive disorders and comorbid alcohol dependence. The primary purpose of this study was to evaluate the effectiveness and tolerability of mirtazapine for the treatment of patients with alcohol dependence comorbid with a depressive disorder in an open label, naturalistic multicentre treatment setting. The 17-item Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS) and the Clinical Global Impression-Severity (CGI-S) scale were measured at baseline and at weeks 4 and 8 for the assessment of treatment effectiveness. Alcohol craving was measured using the Obsessive Compulsive Drinking Scale (OCDS) and the Visual Analog Scale for Craving (VAS). This study showed a statistically significant reduction of the scores on the HDRS (13.9+/-7.3, p<0.0001), HARS (10.8+/-7.2, p<0.0001) and the CGI-S (1.7+/-1.0, p<0.0001) from baseline to the endpoint (week 8). The OCDS and VAS scores were also decreased significantly by 42.3% and 53.2% (9.0+/-10.0, p<0.0001; 2.5+/-2.4, p<0.0001, respectively). The number of patients with a 50% reduction or more in the HDRS and HARS scores was 103 (72.0%) and 106 (74.1%) at the endpoint, respectively. Adverse events related to mirtazapine were observed in 10% or more of the patients in this study. In conclusion, the results from this naturalistic study suggest that the use of mirtazapine for the patients with alcohol dependence comorbid with depressive disorder is accompanied by clinical improvement in their mood and alcohol craving.

Resting-state synchrony between anterior cingulate cortex and precuneus relates to body shape concern in anorexia nervosa and bulimia nervosa

Cortical areas supporting cognitive control and salience demonstrate different neural responses to visual food cues in patients with eating disorders. This top-down cognitive control, which interacts with bottom-up appetitive responses, is tightly integrated not only in task conditions but also in the resting-state. The dorsal anterior cingulate cortex (dACC) is a key node of a large-scale network that is involved in self-referential processing and cognitive control. We investigated resting-state functional connectivity of the dACC and hypothesized that altered connectivity would be demonstrated in cortical midline structures involved in self-referential processing and cognitive control. Seed-based resting-state functional connectivity was analyzed in women with anorexia nervosa (N=18), women with bulimia nervosa (N=20) and age matched healthy controls (N=20). Between group comparisons revealed that the anorexia nervosa group exhibited stronger synchronous activity between the dACC and retrosplenial cortex, whereas the bulimia nervosa group showed stronger synchronous activity between the dACC and medial orbitofrontal cortex. Both groups demonstrated stronger synchronous activity between the dACC and precuneus, which correlated with higher scores of the Body Shape Questionnaire. The dACC-precuneus resting-state synchrony might be associated with the disorder-specific rumination on eating, weight and body shape in patients with eating disorders.

Abnormalities of emotional awareness and perception in patients with obsessive–compulsive disorder

BACKGROUND Emotional awareness deficit may play a critical role in the production and maintenance of obsessive-compulsive symptoms and social dysfunction in patients with obsessive-compulsive disorder (OCD). The aim of this study was to investigate characteristics of emotional awareness such as empathy and alexithymia in OCD patients. In addition, we examined whether impaired emotional awareness measured by self-assessment questionnaires was associated with emotional facial recognition ability in OCD patients. METHODS Study participants included 107 patients with OCD and 130 healthy age- and sex-matched volunteers. The Interpersonal Reactivity Index (IRI) and Toronto Alexithymia Scale-20 were applied as measures of empathy and alexithymia. A subset of 56 patients with OCD additionally performed the emotional perception task of face expression. RESULTS Patients with OCD scored significantly lower for perspective taking, and significantly higher for personal distress of IRI, and significantly higher for alexithymia compared to normal controls. Impaired emotional awareness such as lower perspective taking and fantasy seeking had a perception bias towards disgust in response to ambiguous facial expressions in OCD patients. LIMITATIONS The OCD group consisted of patients in different stages of the illness and with different degrees of severity. CONCLUSIONS OCD involves the impairment of emotional awareness and perception and it may relate to social dysfunction and to impairments in the ability to shift naturally from obsessive thoughts to other thoughts in response to social situations in patients with OCD.