Jae-Hon Lee

Different generators in human temporal-parasylvian cortex account for subdural laser-evoked potentials, auditory-evoked potentials, and event-related potentials

In order to localize cortical areas mediating pain we now report subdural cortical potentials evoked by auditory stimulation (auditory-evoked potentials - AEPs) and by cutaneous stimulation with a laser (laser-evoked potentials - LEPs). Stimulation with the laser evokes a pure pain sensation by selective activation of nociceptors. LEPs were maximal over the inferior aspect of the central sulcus and had the same polarity on either side of the sylvian fissure. AEPs were maximal posterior to the LEP maximum and had opposite polarity on opposite sides of the sylvian fissure, consistent with the location of a known generator in the temporal operculum. Auditory P3 (event-related) potentials were maximal over the temporal base. These findings demonstrate that the LEP generator is not in secondary somatosensory cortex on the parietal operculum and is different from the P3 generator.

Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study.

BACKGROUND There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder. METHODS In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. RESULTS Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohens d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohens d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality. LIMITATIONS Small sample size, open-label design, lack of a placebo group. CONCLUSIONS Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein.

Efficacy of antidepressants on measures of workplace functioning in major depressive disorder: a systematic review

INTRODUCTION Work-related disability and productivity loss in Major Depressive Disorder (MDD) are critical determinants of patient quality of life and contribute significantly to the human and economic costs of MDD. Notwithstanding the return to work and pre-morbid levels of functioning as a critical therapeutic objective among individuals with MDD, it is unclear whether antidepressant treatment significantly and reliably improves measures of workplace functioning. Herein, we investigate to what extent antidepressant treatment improves workplace functioning among adults with MDD. METHODS We conducted a systematic review of randomized, double-blind, placebo-controlled or active comparator clinical trials primarily or secondarily investigating the efficacy of antidepressant agents on subjective ratings of workplace functioning and/or measures of work absence. RESULTS Thirteen placebo-controlled and four active comparator clinical trials reported on the efficacy of agomelatine, bupropion, desvenlafaxine, duloxetine, fluoxetine, levomilnacipran, paroxetine, sertraline, venlafaxine, or vortioxetine on subjective measures of workplace impairment. Overall, antidepressant treatment improved standardized measures of workplace functioning (e.g., Sheehan Disability Scale-work item). One placebo-controlled trial of agomelatine and one clinical trial comparing the efficacy of vortioxetine to that of venlafaxine had mixed results on measures of work absence. LIMITATIONS Included interventional trials evaluated work-related disability as a secondary outcome using subjective rating scales. CONCLUSION Extant data suggest that antidepressant treatment improves workplace outcomes in MDD. The capability of antidepressants in improving measures of workplace functioning should be considered in cost-benefit analyses to better inform cost-modelling studies pertaining to antidepressant therapy.

Treatment with a GLP−1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders

Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural/volumetric parameters in adults with a mood disorder. This is the secondary analysis of a 4-week, pilot, proof-of-concept, open-label study. Participants (N=19) exhibiting impairments in executive function with either major depressive disorder (MDD) or bipolar disorder (BD) were recruited. Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. Structural magnetic resonance imaging (MRI) scanning was obtained at baseline and endpoint. Results showed that at endpoint there was significant weight loss (mean: 3.15%; p<0.001). Changes in frontal and striatal volumes were significantly correlated with changes in body mass index (BMI), indicating the weight loss was associated with volume increase in most regions (e.g. r=-0.561, p=0.042 in the left superior frontal area). After adjusting for intracranial volume, age, gender, and BMI, we observed significant changes from baseline to endpoint in multiple regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function.

Sleep duration and quality as related to left ventricular structure and function

Objective Inadequate sleep is associated with increased risk of cardiovascular events; however, the associations between sleep duration or quality and cardiac function or structure are not well understood. This cross-sectional study was conducted to investigate to what extent sleep duration and quality are associated with left ventricular (LV) diastolic dysfunction or structural deterioration. Methods A total of 31,598 healthy Korean adults who received echocardiography and completed the Pittsburg Sleep Quality Index were enrolled in this study. Participants were stratified into three groups by self-reported sleep duration (i.e., <7, 7–9, >9 hours) and into two groups by subjective sleep quality. Sleep duration was also assessed as a continuous variable. The odds ratios for impaired LV diastolic function, increased relative wall thickness, and LV hypertrophy (LVH) were compared between groups using multivariable logistic regression analyses. Results After adjustment for confounding variables (e.g., age, smoking, body mass index), there was a statistically significant association between short sleep duration (<7 hours) and greater LVH (fully adjusted odds ratio = 1.32 [95% confidence interval {CI} = 1.02–1.73]). Short sleep duration was also significantly associated with greater LVH (0.87 per hour [95% CI = 0.78–0.98]) and increased relative wall thickness (0.92 [95% CI = 0.86–0.99]), but there was no significant association between sleep and LV diastolic function. Among individuals with normal sleep duration, poor quality of sleep was not associated with adverse cardiac measures. Conclusions These results indicate that short sleep duration (<7 hours) is associated with unfavorable LV structural characteristics. The association of insufficient sleep with adverse cardiovascular health outcomes may be mediated in part by adverse changes in cardiac structure and function.

Effects of olanzapine and haloperidol on mTORC1 signaling, dendritic outgrowth, and synaptic proteins in rat primary hippocampal neurons under toxic conditions

Recent studies have demonstrated that antipsychotic drugs may activate mammalian target of rapamycin complex 1 (mTORC1) signaling in neurons. However, the relationship between mTORC1 signaling activation and currently prescribed antipsychotic drugs remains incompletely understood. The purpose of this study was to determine whether alterations in the level of mTORC1 signaling occur after rat primary hippocampal neurons are treated with olanzapine and haloperidol under toxic conditions. Additionally, we investigated whether these drugs affect dendritic outgrowth and synaptic protein expression through the mTORC1 signaling pathway. We measured changes in mTORC1-mediated and synaptic proteins by Western blotting assay under toxic conditions induced by B27 deprivation. Dendritic outgrowth was determined by a neurite assay. Olanzapine significantly increased the phosphorylated levels of mTORC1, its downstream effectors, and its upstream activators. The increased mTORC1 phosphorylation induced by olanzapine was significantly blocked by specific PI3K, MEK, or mTORC1 inhibitors. Olanzapine also increased dendritic outgrowth and synaptic proteins levels; all of these effects were blocked by rapamycin. However, haloperidol had none of these effects. We demonstrated that olanzapine, but not haloperidol, activated the mTORC1 signaling pathway and increased dendritic outgrowth and synaptic proteins by activating mTORC1 signaling in rat primary hippocampal neurons. These findings suggest that olanzapine affects neuroplasticity by activating mTORC1 signaling.

Association Between Sleep Duration, Quality and Body Mass Index in the Korean Population

STUDY OBJECTIVES Mounting evidence indicates that sleep disturbance contributes to the increased risk for cardiometabolic diseases. Obesity and underweight are also closely linked to cardiometabolic risk. Thus, the objective of this study was to examine the association between sleep duration, quality, and body mass index (BMI) categories. METHODS Using data from a cohort of 107,718 Korean individuals (63,421 men and 44,297 women), we conducted cross-sectional analysis with sex subgroup analysis. Sleep duration was classified into 3 groups-short (< 7 hours), normal (7-9 hours) and long sleep (> 9 hours)-and Pittsburgh Sleep Quality Index (PSQI) score was used to divide sleep quality into 2 groups-poor (PSQI > 5) and good sleep (PSQI ≤ 5). Compared to normal sleep and good sleep quality, adjusted odds ratios of short and long sleep and poor sleep for BMI categories were calculated. BMI categories included underweight (BMI < 18.5 kg/m2), overweight (BMI 23 to < 25 kg/m2), obesity (BMI 25 to < 30 kg/m2) and severe obesity (BMI ≥ 30 kg/m2). RESULTS Short sleep duration had the dose-dependent relationship with obesity categories from overweight to severe obesity, and inverse relationship with underweight (adjusted odds ratios [95% confidence intervals] for underweight, overweight, obesity, and severe obesity versus normal weight; 0.88 [0.82-0.94], 1.15 [1.11-1.20], 1.31 [1.26-1.37], 1.70 [1.54-1.85]). Poor sleep quality was significantly associated with severe obesity in male subgroup (1.16 [1.05-1.27]) and with obesity (1.18 [1.10-1.25]) and severe obesity in female subgroup (1.66 [1.40-1.98]). CONCLUSIONS Short sleep duration and poor sleep quality was more positively associated with obesity across BMI than underweight.

Liraglutide Activates mTORC1 Signaling and AMPA Receptors in Rat Hippocampal Neurons Under Toxic Conditions

The aim of the present study was to determine whether treatment with liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, would alter mammalian target of rapamycin complex 1 (mTORC1) signaling and/or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor activity under dexamethasone-induced toxic conditions. Western blot analyses were performed to assess changes in mTORC1-mediated proteins, brain-derived neurotrophic factor (BDNF), and various synaptic proteins (PSD-95, synapsin I, and GluA1) in rat hippocampal cultures under toxic conditions induced by dexamethasone, which causes hippocampal cell death. Hippocampal dendritic outgrowth and spine formation were measured using immunostaining procedures. Dexamethasone significantly decreased the phosphorylation levels of mTORC1 as well as its downstream proteins. However, treatment with liraglutide prevented these reductions and significantly increased BDNF expression. The increase in BDNF expression was completely blocked by rapamycin and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Liraglutide also recovered dexamethasone-induced decreases in the total length of hippocampal dendrites and reductions in spine density in a concentration-dependent manner. However, the positive effects of liraglutide on neural plasticity were abolished by the blockade of mTORC1 signaling and AMPA receptors. Furthermore, liraglutide significantly increased the expression levels of PSD-95, synapsin I, and GluA1, whereas rapamycin and NBQX blocked these effects. The present study demonstrated that liraglutide activated mTORC1 signaling and AMPA receptor activity as well as increased dendritic outgrowth, spine density, and synaptic proteins under toxic conditions in rat primary hippocampal neurons. These findings suggest that GLP-1 receptor (GLP-1R) activation by liraglutide may affect neuroplasticity through mTORC1 and AMPA receptors.