Tien-Wen Lee

Serotonin Dysfunction and Suicide Attempts in Major Depressives: An Auditory Event-Related Potential Study

Background: Serotonergic dysfunction is believed to be involved in suicide attempts. The loudness-dependent auditory evoked potential (LDAEP) is one of the validated indicators of the activity of the central serotonin system in humans. Objectives: This study was designed to investigate possible differences in the LDAEP and P300 between those depressed patients who attempted suicide and those who did not. Methods: The LDAEP and P300 levels were recorded for 66 depressive patients (among which 16 had attempted suicide). Results: Those who had attempted suicide showed a sharper slope of the LDAEP and increased frontal P300 amplitude. A high correlation between the LDAEP and P300, and a gender difference were also noted. Conclusions: Our results are concordant with previous assumptions about serotonin dysfunction in depressives who attempt suicide.

The implication of functional connectivity strength in predicting treatment response of major depressive disorder: a resting EEG study.

Predicting treatment response in major depressive disorder (MDD) has been an important clinical issue given that the initial intent-to-treat response rate is only 50 to 60%. This study was designed to examine whether functional connectivity strengths of resting EEG could be potential biomarkers in predicting treatment response at 8 weeks of treatment. Resting state 3-min eyes-closed EEG activity was recorded at baseline and compared in 108 depressed patients. All patients were being treated with selective serotonin-reuptake inhibitors. Baseline coherence and power series correlation were compared between responders and non-responders evaluated at the 8th week by Hamilton Depression Rating Scale. Pearson correlation and receiver operating characteristic (ROC) analyses were applied to evaluate the performance of connectivity strengths in predicting/classifying treatment responses. The connectivity strengths of right fronto-temporal network at delta/theta frequencies differentiated responders and non-responders at the 8th week of treatment, such that the stronger the connectivity strengths, the poorer the treatment response. ROC analyses supported the value of these measures in classifying responders/non-responders. Our results suggest that fronto-temporal connectivity strengths could be potential biomarkers to differentiate responders and slow responders or non-responders in MDD.

The effects of catechol-O-methyl-transferase polymorphism Val158Met on functional connectivity in healthy young females: a resting EEG study.

The catechol-O-methyl-transferase (COMT) gene has been linked to a wide spectrum of human phenotypes, including cognition, affective response, pain sensitivity, anxiety and psychosis. This study examined the modulatory effects of COMT Val158Met on neural interactions, indicated by connectivity strengths. Blood samples and resting state eyes-closed EEG signals were collected in 254 healthy young females. The COMT Val158Met polymorphism was decoded into 3 groups: Val/Val, Val/Met and Met/Met. The values of mutual information of 20 frontal-related channel pairs across delta, theta, alpha and beta frequencies were analyzed based on the time-frequency mutual information method. Our one-way ANOVA analyses revealed that the significant connection-frequency pairs were relatively left lateralized (P<0.01) and included F7-T3 and F7-C3 at delta frequency, and F3-F4, F7-T3, F7-C3, F7-P3, F3-C3, F3-F7 and F4-F8 at theta frequency. The F-test at F7-T3 and F7-C3 theta surpassed the statistical threshold of P<0.003 (after Bonferroni correction). For all the above connection-frequency pairs, there was a dose-dependent trend in the connectivity strengths of the alleles as follows: Val/Val>Val/Met>Met/Met. Our analyses complemented previous literature regarding neural modulation by the COMT Val158Met polymorphism. The implication to the pathogenesis in schizophrenia was also discussed. Further studies are needed to clarify whether there is gender difference on this gene-brain interaction.

Resting network is composed of more than one neural pattern: An fMRI study

In resting state, the dynamics of blood oxygen level-dependent signals recorded by functional magnetic resonance imaging (fMRI) showed reliable modular structures. To explore the network property, previous research used to construct an adjacency matrix by Pearsons correlation and prune it using stringent statistical threshold. However, traditional analyses may lose useful information at middle to moderate high correlation level. This resting fMRI study adopted full connection as a criterion to partition the adjacency matrix into composite sub-matrices (neural patterns) and investigated the associated community organization and network features. Modular consistency across subjects was assessed using scaled inclusivity index. Our results disclosed two neural patterns with reliable modular structures. Concordant with the results of traditional intervention, community detection analysis showed that neural pattern 1, the sub-matrix at highest correlation level, was composed of sensory-motor, visual associative, default mode/midline, temporal limbic and basal ganglia structures. The neural pattern 2 was situated at middle to moderate high correlation level and comprised two larger modules, possibly associated with mental processing of outer world (such as visuo-associative, auditory and sensory-motor networks) and inner homeostasis (such as default-mode, midline and limbic systems). Graph theoretical analyses further demonstrated that the network feature of neural pattern 1 was more local and segregate, whereas that of neural pattern 2 was more global and integrative. Our results suggest that future resting fMRI research may take the neural pattern at middle to moderate high correlation range into consideration, which has long been ignored in extant literature. The variation of neural pattern 2 could be relevant to individual characteristics of self-regulatory functions, and the disruption in its topology may underlie the pathology of several neuropsychiatric illnesses.

The influence of serotonin transporter polymorphisms on cortical activity: A resting EEG study

BackgroundThe serotonin transporter gene (5-HTT) is a key regulator of serotonergic neurotransmission and has been linked to various psychiatric disorders. Among the genetic variants, polymorphisms in the 5-HTT gene-linked polymorphic region (5-HTTLPR) and variable-number-of-tandem-repeat in the second intron (5-HTTVNTR) have functional consequences. However, their genetic impact on cortical oscillation remains unclear. This study examined the modulatory effects of 5-HTTLPR (L-allele carriers vs. non-carriers) and 5-HTTVNTR (10-repeat allele carriers vs. non-carriers) polymorphism on regional neural activity in a young female population.MethodsBlood samples and resting state eyes-closed electroencephalography (EEG) signals were collected from 195 healthy women and stratified into 2 sets of comparisons of 2 groups each: L-allele carriers (N = 91) vs. non-carriers for 5-HTTLPR and 10-repeat allele carriers (N = 25) vs. non-carriers for 5-HTTVNTR. The mean power of 18 electrodes across theta, alpha, beta, gamma, gamma1, and gamma2 frequencies was analyzed. Between-group statistics were performed by an independent t-test, and global trends of regional power were quantified by non-parametric analyses.ResultsAmong 5-HTTVNTR genotypes, 10-repeat allele carriers showed significantly low regional power at gamma frequencies across the brain. We noticed a consistent global trend that carriers with low transcription efficiency of 5-HTT possessed low regional powers, regardless of frequency bands. The non-parametric analyses confirmed this observation, with P values of 3.071 × 10-8 and 1.459 × 10-12 for 5-HTTLPR and 5-HTTVNTR, respectively.Conclusions and LimitationsOur analyses showed that genotypes with low 5-HTT activity are associated with less local neural synchronization during relaxation. The implication with respect to genetic vulnerability of 5-HTT across a broad range of psychiatric disorders is discussed. Given the low frequency of 10-repeat allele of 5-HTTVNTR in our research sample, the possibility of false positive findings should also be considered.

The Influence of Apolipoprotein E Epsilon4 Polymorphism on qEEG Profiles in Healthy Young Females: A Resting EEG Study

The epsilon4 allele of the Apolipoprotein E (ApoE) gene has been linked to various neurological conditions and the aging process in the elderly. However, evidence has suggested that the influence of ApoE epsilon4 may commence in early life. This study examined the modulatory effects of ApoE epsilon4 on regional neural activity as well as inter-regional neural interactions in a young population aged 19–21. Blood samples and resting state eyes-closed EEG signals were collected from 265 healthy females, and stratified into two groups: epsilon4 carriers and non-carriers. The values of the log-transformed mean power of 18 electrodes and the mutual information of 20 channel pairs across delta, theta, alpha and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group statistics were performed by independent t-test. We notice a consistent trend across the brain, in which ApoE epsilon4 carriers possess lower regional power at the alpha band. The epsilon4 allele is also associated with lower regional power at the theta frequency in the left frontal and posterior brain regions. Functional connectivity analyses reveal a right-lateralized network that differentiates epsilon4 carriers and non-carriers, with lower connectivity strengths for the former. Our tonic EEG analyses complement those of previous reports in that the ApoE epsilon4 allele has a negative impact on regional neural synchronization and inter-regional neural interaction.

Effect of age and global function score on schizophrenic p300 characteristics.

The relationship between function level and P300 has long been ignored and awaits clarification. Further, previous Western studies have discussed the trait/state markers of schizophrenic P300; this has not been assessed for an analogous Chinese population. P300 was recorded and compared in 153 schizophrenic patients and 101 normal controls. Reduced and delayed P300 was demonstrated for the schizophrenic group. Regression analysis was performed to determine the factors contributing to P300 amplitude and latency variation. Global Assessment of Functioning score and age had a significant influence on P300 latency prolongation. Amplitude decrement was not affected by age, duration of illness, education, psychotic status, antipsychotic dosage, or function level. Our results were grossly concordant with analogous Western reports and provided evidence that function level is an important variable contributing to P300 latency change in Chinese schizophrenics. Besides, the effect of gender on P300 amplitude was noted in normal population.

Cortical mechanisms of the symptomatology in major depressive disorder: a resting EEG study.

BACKGROUND Diagnosis and treatment rely on symptom criteria in modern psychiatry. However, the cortical mechanisms of symptomatology in major depressive disorder (MDD) are still not clear. This study examined neural correlates of symptom clusters of MDD by electroencephalography (EEG). METHODS Resting state eye-closed EEG signals were recorded in 196 depressive patients. Quantitative EEG (qEEG) of regional power, coherence and power series correlation across delta, theta, alpha and beta frequencies were used to correlate with overall depression severity evaluated by the Hamilton Depression Rating Scale (HDRS). Further, statistical comparisons between patients with high vs. low qEEG indices (median-split) were undertaken regarding symptom severity of core depression, sleep, activity, psychic anxiety, somatic anxiety, and delusion. RESULTS None of the qEEG indices significantly correlated with overall depression severity or differentiated symptom severity of core depression, sleep, activity and psychic anxiety. A higher symptom severity of somatic anxiety was associated with higher regional power over widespread cortical regions and lower strengths at bi-temporal, temporo-parietal and fronto-parietal connections. A higher symptom severity of delusion was associated with higher regional power in the frontal and temporal regions, and lower strengths at inter-hemispheric (frontal, temporal and parietal) and fronto-temporo-parietal connections. LIMITATIONS Our EEG recording with sampling rate of 128Hz and 20 electrodes may provide restricted spatial and temporal precision. CONCLUSIONS Our results suggest that cortical mechanisms play important roles in the symptom manifestation of cognitive distortion (sub-score of delusion) and somatic anxiety in MDD. Our findings further imply that psychic anxiety and somatic anxiety are distinct entities.

The Influence of Dopamine Receptor D4 Polymorphism on Resting EEG in Healthy Young Females

The polymorphism of variable number of tandem repeat (VNTR) in dopamine receptor D4 (DRD4) gene exon III has been linked to various neuro-psychiatric conditions with disinhibition/impulsivity as one of the core features. This study examined the modulatory effects of long-allele variant of DRD4 VNTR on the regional neural activity as well as inter-regional neural interactions in a young female population. Blood sample and resting state eyes-closed EEG signals were collected in 233 healthy females, stratified into two groups by polymerase chain reaction: long-allele carriers (>4- repeat) and non-carriers (<=4-repeat/<=4-repeat). The values of mean power of 18 electrodes and mutual information of 38 channel pairs across theta, alpha, and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group differences of regional power and connectivity strength were quantified by independent t-test, while between-group differences in global trends were examined by non-parametric analyses. We noticed that DRD4 VNTR long-allele was associated with decreased global connectivity strength (from non-parametric analysis), especially over bi-frontal, biparietal and right fronto-parietal and right fronto-temporal connections (from independent t-tests). The between-group differences in regional power were not robust. Our findings fit with the networks of response inhibition, providing evidence bridging DRD4 long-allele and disinhibition/impulsivity in neuropsychiatric disorders. We suggest future DRD4 studies of imaging genetics incorporate connectivity analysis to unveil its impact on cerebral network.