Sujung J. Yoon

Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study.

Preclinical studies suggest that lithium may exert neurotrophic effects that counteract pathological processes in the brain of patients with bipolar disorder (BD). To describe and compare the course and magnitude of gray matter volume changes in patients with BD who are treated with lithium or valproic acid (VPA) compared to healthy comparison subjects, and to assess clinical relationships to gray matter volume changes induced by lithium in patients with BD, we conducted longitudinal brain imaging and clinical evaluations of treatment response in 22 mood-stabilizing and antipsychotic medications-naive patients with BD who were randomly assigned to either lithium or VPA treatment after baseline assessment. Fourteen healthy comparison subjects did not take any psychotropic medications during follow-up. Longitudinal data analyses of 93 serial magnetic resonance images revealed lithium-induced increases in gray matter volume, which peaked at week 10–12 and were maintained through 16 weeks of treatment. This increase was associated with positive clinical response. In contrast, VPA-treated patients with BD or healthy comparison subjects did not show gray matter volume changes over time. Results suggest that lithium induces sustained increases in cerebral gray matter volume in patients with BD and that these changes are related to the therapeutic efficacy of lithium.

The neurobiological role of the dorsolateral prefrontal cortex in recovery from trauma. Longitudinal brain imaging study among survivors of the South Korean subway disaster.

CONTEXTnA multiwave longitudinal neuroimaging study in a cohort of direct survivors of a South Korean subway disaster, most of whom recovered from posttraumatic stress disorder 5 years after trauma, provided a unique opportunity to investigate the brain correlates of recovery from a severe psychological trauma.nnnOBJECTIVESnTo investigate region-specific brain mobilization during successful recovery from posttraumatic stress disorder by assessing cortical thickness multiple times from early after trauma to recovery, and to examine whether a brain-derived neurotrophic factor gene polymorphism was associated with this brain mobilization.nnnDESIGNnFive-year follow-up case-control study conducted from 2003-2007.nnnSETTINGnSeoul National University and Hospital.nnnPARTICIPANTSnThirty psychologically traumatized disaster survivors and 36 age- and sex-matched control group members recruited from the disaster registry and local community, respectively, who contributed 156 high-resolution brain magnetic resonance images during 3 waves of assessments.nnnMAIN OUTCOME MEASURESnCerebral cortical thickness measured in high-resolution anatomic magnetic resonance images using a validated cortical thickness analysis tool and its prospective changes from early after trauma to recovery in trauma-exposed individuals and controls.nnnRESULTSnTrauma-exposed individuals had greater dorsolateral prefrontal cortical (DLPFC) thickness 1.42 years after trauma (right DLPFC, 5.4%; left superior frontal cortex, 5.8%; and left inferior frontal cortex, 5.3% [all clusters, Pxa0≤xa0.01]) relative to controls. Thicknesses gradually normalized over time during recovery. We found a positive linear trend, with trauma-exposed individuals with a valine/valine genotype having the greatest DLPFC cortical thickness, followed by those with a methionine genotype and controls (Pxa0<xa0.001 for trend). Greater DLPFC thickness was associated with greater posttraumatic stress disorder symptom reductions and better recovery.nnnCONCLUSIONnThe DLPFC region might play an important role in psychological recovery from a severely traumatic event in humans.

Brain Structural Abnormalities and Mental Health Sequelae in South Vietnamese Ex–Political Detainees Who Survived Traumatic Head Injury and Torture

CONTEXTnA pilot study of South Vietnamese ex-political detainees who had been incarcerated in Vietnamese reeducation camps and resettled in the United States disclosed significant mental health problems associated with torture and traumatic head injury (THI).nnnOBJECTIVESnTo identify structural brain alterations associated with THI and to investigate whether these deficits are associated with posttraumatic stress disorder and depression.nnnDESIGNnCross-sectional neuroimaging study.nnnSETTINGnMassachusetts General Hospital and McLean Hospital.nnnPARTICIPANTSnA subsample of Vietnamese ex-political detainees (n = 42) and comparison subjects (n = 16) selected from a community study of 337 ex-political detainees and 82 comparison subjects.nnnMAIN OUTCOME MEASURESnScores on the Vietnamese versions of the Hopkins Symptom Checklist-25 (HSCL) and Harvard Trauma Questionnaire for depression and posttraumatic stress disorder, respectively; cerebral regional cortical thickness; and manual volumetric morphometry of the amygdala, hippocampus, and thalamus.nnnRESULTSnEx-political detainees exposed to THI (n = 16) showed a higher rate of depression (odds ratio, 10.2; 95% confidence interval, 1.2-90.0) than those without THI exposure (n = 26). Ex-political detainees with THI had thinner prefrontotemporal cortices than those without THI exposure (P < .001 by the statistical difference brain map) in the left dorsolateral prefrontal and bilateral superior temporal cortices, controlling for age, handedness, and number of trauma/torture events (left superior frontal cortex [SFC], P = .006; left middle frontal cortex, P = .01; left superior temporal cortex [STC], P = .007; right STC, P = .01). Trauma/torture events were associated with bilateral amygdala volume loss (left, P = .045; right, P = .003). Cortical thinning associated with THI in the left SFC and bilateral STC was related to HSCL depression scores in THI-exposed (vs non-THI-exposed) ex-political detainees (left SFC, P for interaction = .007; left STC, P for interaction = .03; right STC, P for interaction = .02).nnnCONCLUSIONSnStructural deficits in prefrontotemporal brain regions are linked to THI exposures. These brain lesions are associated with the symptom severity of depression in Vietnamese ex-political detainees.

Altered Prefrontal Glutamate–Glutamine–γ-Aminobutyric Acid Levels and Relation to Low Cognitive Performance and Depressive Symptoms in Type 1 Diabetes Mellitus

CONTEXTnNeural substrates for low cognitive performance and depression, common long-term central nervous system-related changes in patients with type 1 diabetes mellitus, have not yet been studied.nnnOBJECTIVEnTo investigate whether prefrontal glutamate levels are higher in patients with type 1 diabetes and whether an elevation is related to lower cognitive performance and depression.nnnDESIGNnCross-sectional study.nnnSETTINGnGeneral clinical research center.nnnPARTICIPANTSnOne hundred twenty-three patients with adult type 1 diabetes with varying degrees of lifetime glycemic control and 38 healthy participants.nnnMAIN OUTCOME MEASURESnWith the use of proton magnetic resonance spectroscopy, prefrontal glutamate-glutamine-gamma-aminobutyric acid (Glx) levels were compared between patients and control subjects. Relationships between prefrontal Glx levels and cognitive function and between Glx levels and mild depressive symptoms were assessed in patients with type 1 diabetes.nnnRESULTSnPrefrontal Glx concentrations were 9.0% (0.742 mmol/L; P = .005) higher in adult patients with type 1 diabetes than in healthy control subjects. There were positive linear trends for the effects of lifetime glycemic control on prefrontal Glx levels (P for trend = .002). Cognitive performances in memory, executive function, and psychomotor speed were lower in patients (P = .003, .01, and <.001, respectively) than in control subjects. Higher prefrontal Glx concentrations in patients were associated with lower performance in assessment of global cognitive function (0.11 change in z score per 1-mmol/L increase in Glx) as well as with mild depression.nnnCONCLUSIONSnThe high prefrontal glutamate levels documented in this study may play an important role in the genesis of the low cognitive performance and mild depression frequently observed in patients with type 1 diabetes. Therapeutic options that alter glutamatergic neurotransmission may be of benefit in treating central nervous system-related changes in patients with adult type 1 diabetes.

Laterobasal Amygdalar Enlargement in 6- to 7-Year-Old Children With Autism Spectrum Disorder

CONTEXTnThere is substantial imaging evidence for volumetric abnormalities of the amygdala in younger children with autism spectrum disorder (ASD). The amygdala can be divided into functionally distinct laterobasal, superficial, and centromedial subregions. To date, we are not aware of any in vivo reports specifically assessing subregional amygdalar abnormalities in individuals with ASD.nnnOBJECTIVESnTo evaluate alterations in subregional amygdalar morphology in children with ASD compared with typically developing (TD) children and to examine the relationships with ASD symptom severity.nnnDESIGNnA cross-sectional study encompassing a narrow age range of children with ASD and age-matched TD children that evaluated magnetic resonance imaging-defined subregional morphology of the amygdala using a novel subregional analytic method.nnnSETTINGnParticipants were recruited and clinically evaluated through the University of Washington Autism Center and imaged at the Diagnostic Imaging Sciences Center at the University of Washington. Imaging data were analyzed through the Brain Imaging Laboratory at the Seoul National University.nnnPARTICIPANTSnFifty-one children 6 to 7 years of age (ASD, n = 31 and TD, n = 20) were assessed using magnetic resonance imaging and behavioral measures.nnnMAIN OUTCOME MEASURESnVolume and subregional measures of the amygdala and measures of social and communication functioning.nnnRESULTSnThe ASD group exhibited larger right and left amygdalae, by 12.7% and 11.0%, respectively, relative to the TD group. Subregional analysis revealed that the ASD group had enlarged laterobasal amygdalar subregions, relative to the TD group, after adjusting for age, sex, and hemispheric cerebral volume (P < .05, false discovery rate corrected and with clustered surface points >15). Exploratory analyses revealed that there were linear trends comparing a strictly defined subgroup of children with autistic disorder, who exhibited the greatest extent of laterobasal enlargement, followed by a subgroup of children with pervasive developmental disorder not otherwise specified and then the group of TD children (P for linear trend <.001). There were linear trends between enlargement of laterobasal subregions and lower levels of social and communication functioning (P < .001, P < .001, and P = .001 for 3 areas in the right laterobasal subregion; P < .001 for 1 area in the left laterobasal subregion).nnnCONCLUSIONnThe current study demonstrates bilateral enlargement of laterobasal subregions of the amygdala in 6- to 7-year-old children with ASD and that subregional alterations are associated with deficits in social and communicative behavior.

Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: a proton magnetic resonance spectroscopy (1H-MRS) study.

The purpose of this study was to investigate the brain gamma-aminobutyric acid (GABA) concentration and its relationship with clinical variables in patients with panic disorder (PD). Single voxel proton magnetic resonance spectroscopy ((1)H-MRS) scan was performed on 22 medicated subjects with PD and 25 age and sex-matched healthy comparison subjects. GABA and other metabolite levels were measured in the anterior cingulate cortex (ACC) and basal ganglia. GABA levels were significantly lower in the ACC and basal ganglia of PD patients relative to comparison subjects. Lactate and choline concentrations in the ACC in PD patients were also higher than in the comparison subjects. Our data suggested in part that alterations of the GABA function and the energy metabolism in ACC and basal ganglia may play an important role in the pathophysiology of panic disorder.

Decreased glutamate/glutamine levels may mediate cytidine's efficacy in treating bipolar depression: a longitudinal proton magnetic resonance spectroscopy study.

Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine’s efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1–4; p=0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p=0.004, 0.004, and 0.02, respectively). Cytidine-related glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p=0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine’s efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.

Decreased N-acetyl-aspartate levels in anterior cingulate and hippocampus in subjects with post-traumatic stress disorder: a proton magnetic resonance spectroscopy study

The purpose of this study was to investigate the concentration of N‐acetyl‐aspartate (NAA) in the brain and its relationship with clinical characteristics in patients with post‐traumatic stress disorder (PTSD). Proton magnetic resonance spectroscopy was performed in order to measure NAA concentrations in the anterior cingulate cortex (ACC) and bilateral hippocampus in 26 subjects with fire‐related PTSD, who were survivors of a subway fire in South Korea, and 25 age‐ and sex‐matched healthy comparison subjects. There were decreased NAA levels in the ACC (tu2003=u2003−3.88, d.f.u2003=u200349, Pu2003<u20030.001) and bilateral hippocampus (right, tu2003=u2003−3.88, d.f.u2003=u200349, Pu2003<u20030.001; left, tu2003=u2003−3.62, d.f.u2003=u200349, Pu2003<u20030.001) in the PTSD group relative to the healthy comparison group. Also, NAA levels of the ACC (ru2003=u2003–0.43, nu2003=u200326, Pu2003=u20030.027) and bilateral hippocampus (right, ru2003=u2003–0.48, nu2003=u200326, Pu2003=u20030.013; left, ru2003=u2003−0.40, nu2003=u200326, Pu2003=u20030.04) were negatively correlated with re‐experience symptom scores in subjects with PTSD. In conclusion, our findings suggest that subjects with PTSD had decreased neuronal viabilities in the ACC and bilateral hippocampus, and that these deficits may play an important role in the pathophysiology of PTSD, especially regarding the re‐experiencing of traumatic events.

Triacetyluridine (TAU) Decreases Depressive Symptoms and Increases Brain pH in Bipolar Patients

Eleven patients with bipolar depression were given doses of up to 18 g per day of triacetyluridine (TAU) over 6 weeks to test the effect of uridine on symptoms of depression via Montgomery-Asberg Depression Rating Scale (MADRS; Asberg, Montgomery, Perris, Schalling, & Sedvall, 1978) scores and on cellular bioenergetics using phosphorus magnetic resonance spectroscopic imaging (31P-MRSI). All patients and comparison participants (n = 9) completed baseline 31P-MRSI scans, and 9 patients completed posttherapy scans. The percentage changes for MADRS scores (Week 2, -23.8; Week 3, -34.9; Week 4, -42.5) and the time effects of TAU on MADRS scores (Week 2, z = -2.07, p = .039; Week 3, z = -4.28, p < .001; Week 4, z = -4.54, p < .001) may reflect TAU effects on early symptom improvement. TAU responders (patients who had a 50% or greater reduction in MADRS scores from baseline at any time) demonstrated a significant difference from nonresponders in pH changes from baseline (effect size = 150). These results suggest that TAU treatment may decrease symptoms of depression and improve mitochondrial functioning.

Gray matter deficits in young adults with narcolepsy

Objectivesu2002–u2002 The aim of this study was to investigate gray matter volume changes in narcolepsy.