Alcohol use associated alterations in the circulating metabolite profile in the general population and in individuals with major depressive disorder.

Our aim was to evaluate whether alcohol use is associated with changes in the circulating metabolite profile similar to those present in persons with depression. If so, these findings could partially explain the link between alcohol use and depression. We applied a targeted liquid chromatography mass spectrometry method to evaluate correlates between concentrations of 86 circulating metabolites and self-reported alcohol use in a cohort of the non-depressed general population (GP) (n = 247) and a cohort of individuals with major depressive disorder (MDD) (n = 99). Alcohol use was associated with alterations in circulating concentrations of metabolites in both cohorts. Our main finding was that self-reported alcohol use was negatively correlated with serum concentrations of hippuric acid in the GP cohort. In the GP cohort, consumption of six or more doses per week was associated with low hippuric acid concentrations, similar to those observed in the MDD cohort, but in these individuals it was regardless of their level of alcohol use. Reduced serum concentrations of hippuric acid suggest that already moderate alcohol use is associated with depression-like changes in the serum levels of metabolites associated with gut microbiota and liver function; this may be one possible molecular level link between alcohol use and depression.

Cortical thickness is inversely associated with transcranial magnetic stimulation-evoked N45 potential among young adults whose heavy drinking began in adolescence.

BACKGROUND: Adolescence is a particularly vulnerable stage of development in terms of the deleterious effects of alcohol. Both lower gray matter (GM) volume and greater GABAergic activity have been associated with chronic alcohol consumption during adolescence. However, the association between these measures has not been investigated. METHODS: In this exploratory study, we compared 26 young adults with a 10year history of heavy alcohol consumption with 21 controls who used little or no alcohol. Simultaneous transcranial magnetic stimulation and electroencephalography were used to assess transcranial magnetic stimulation-evoked N45 potentials, reflecting a balance between GABAergic inhibition and N-methyl-D-aspartate (NMDA) receptor-mediated glutaminergic excitation in the brain. GM thickness was measured from magnetic resonance images and GM and N45 potentials were then correlated. RESULTS: Cortical thickness was significantly lower in several brain regions in the heavy-drinking group than the light-drinking group. The N45 amplitude was significantly larger frontally in the heavy-drinking group. Among heavy drinkers, there were several statistically significant correlations between thinner GM and larger frontal N45 amplitudes that were not detectable in the light-drinking group. The strongest correlations were detected in the frontal and parietal lobes, especially in the left superior frontal gyrus and the left supramarginal gyrus, and in both hemispheres in the superior parietal lobes. CONCLUSIONS: These findings show that a thinner cortex and greater inhibitory neurotransmission are correlated in certain brain regions among young, long-term heavy alcohol users. Studies are needed to explore the possible causal mechanisms underlying these effects.

Depression and dissociation mediate the association between bullying victimization and self-cutting.

BACKGROUND: Bullying victimization is experienced by more than 10% of children and adolescents worldwide and has been associated with numerous negative mental health consequences, such as depression and dissociation. AIMS: We investigated the association between bullying victimization and self-cutting in a Finnish adolescent population and whether depression and dissociation act as mediators in this association. METHODS: We used cross-sectional questionnaire data from Finnish students (age 13-18; N = 3345; boys n = 1454; girls n = 1891). Logistic regression and mediation analyses were performed. RESULTS: Bullying victimized adolescents were younger, more likely to be afraid to go to school, had fewer friends, felt lonelier, and had a poorer relationship with family members, as well as higher level of depressive and dissociative symptoms compared to non-bullied adolescents. According to logistic regression analysis, the association between bullying and self-cutting remained significant despite all other adjustments besides those for depressive symptoms. In serial mediation analysis, depressive and dissociative symptoms mediated the effect of bullying victimization on self-cutting, regardless of their order in the model. CONCLUSIONS: Self-cutting is more common among bullying victimized adolescents than their peers. The association is mediated by depressive and dissociative symptoms. More studies are needed to clarify the exact mechanisms via which depressive and dissociative symptoms interact with the association between bullying and self-harm.

The associations between metabolic profiles and sexual and physical abuse in depressed adolescent psychiatric outpatients: an exploratory pilot study.

Background: Sexual and physical abuse have been associated with long-term systemic alterations such as low-grade inflammation and changes in brain morphology that may be reflected in the metabolome. However, data on the metabolic consequences of sexual and physical abuse remain scarce.Objective: This pilot study sought to investigate changes in the metabolite profile related to sexual and physical abuse in depressed adolescent psychiatric outpatients.Method: The study included 76 patients aged 14-18 years, whose serum samples were analysed with a targeted metabolite profiling methodology. We estimated the associations between metabolite concentrations and the Trauma and Distress Scale (TADS) Sexual and Physical Abuse factor scores using three linear regression models (one unadjusted and two adjusted) per metabolite and trauma type pair. Additional variables in the two adjusted models were 1) the lifestyle indicators body mass index, tobacco use, and alcohol use, and 2) depression scores and the chronicity of depression.Results: TADS Sexual Abuse scores associated positively with homogentisic acid, as well as cystathionine, and negatively with choline in linear regression analysis, whereas TADS Physical Abuse scores associated negatively with AMP, choline, γ-glutamyl cysteine and succinate, and positively with D-glucuronic acid.Conclusions: This pilot study did not include a healthy control group for comparison and the cohort was relatively small. Nevertheless, we observed alterations in metabolites related to one-carbon metabolism, mitochondrial dysfunction, oxidative stress, and inflammation in depressed patients with a history of sexual or physical abuse.

Metabolomic profiles associate with sexual or physical abuse.Metabolites relate to mitochondria, one-carbon, oxidative stress, and inflammation.Metabolomics a possible tool for precision psychiatry in the future.

Externally oriented thinking style increases primary health care use in adolescence.

BACKGROUND: Alexithymia has been related to adult health care use. We investigated the association between alexithymia and the utilization of primary health care services by adolescents and young adults. METHODS: The participants (n = 751, aged 13-18 years) in this 5-year follow-up study were assessed with the 20-item Toronto Alexithymia Scale (TAS-20) and its three subscales, difficulty identifying feelings (DIF), difficulty describing feelings (DDF) and externally oriented thinking (EOT), and the 21-item Beck Depression Inventory (BDI). Primary health care data were gathered from health care centre registers in 2005-10. Generalized linear models and mediation analyses were used. RESULTS: An increase in the TAS-20 total score correlated with a higher number of primary health care and emergency care visits, but in multivariate general linear models, TAS-20 total scores were no longer significant. Younger age, female gender and an increase in the baseline EOT score are associated with a higher number of both primary health care and emergency room visits. In females, a smaller change in the EOT score from baseline to follow-up was associated with a higher number of primary health care visits. In mediation analyses, EOT had a direct effect on a higher number of primary health care and emergency room visits, whereas the BDI score mediated the incremental effect of DIF and DDF on visit numbers. CONCLUSIONS: The results suggest that an EOT style independently increases health care use by adolescents, whereas the effects of difficulties identifying and describing feelings on health care use are mediated by symptoms of depression.

Stability of alexithymia is low from adolescence to young adulthood, and the consistency of alexithymia is associated with symptoms of depression and dissociation.

BACKGROUND: The aims of this study were to investigate the stability of alexithymia from adolescence to young adulthood, as well as the association between alexithymia, peer relationships, and symptoms of depression and dissociation. METHODS: The participants (n = 755, aged 13-18 years) were assessed with self-rated questionnaires and the 20-item Toronto Alexithymia Scale (TAS-20) at baseline in 2005 and on follow-up in 2011. RESULTS: The changes in the TAS-20 total score (t = -12.26) and the scores for its subscales, difficulty identifying feelings (DIF) (t = -4.04), difficulty describing feelings (DDF) (t = -5.10), and externally oriented thinking (EOT) (t = -18.23), were statistically significant (p < 0.001). Effect sizes (Cohen's d) for the change indicating absolute stability were small for DIF (-0.15) and DDF (-0.19), medium for TAS-20 total (-0.45), and large for EOT (-0.66) scores. Moderate correlations in test-retests with Spearman's ρ (TAS-20 total 0.46, DIF 0.41, DDF 0.39, EOT 0.43) indicated relative stability, whereas low intraclass correlation coefficients (ICCs) (respectively 0.41, 0.39, 0.37, 0.37) indicated poor reliability of test-retests. In regression analyses, poor relationships with peers, loneliness, and symptoms of depression and dissociation at baseline associated with alexithymia at baseline and on follow-up. Unlike EOT, increases in the TAS-20 total, DIF, and DDF scores during the 6-year follow-up associated with baseline symptoms of depression and dissociation. CONCLUSIONS: Alexithymia in adolescence is not always a reliable predictor of alexithymia in young adulthood. Mental health symptoms appear to affect the consistency of alexithymia during adolescent development.

Social support may prevent self-cutting in adolescence: A 5-year follow-up study.

Self-cutting is common among adolescents. However, studies examining protective factors are rare. It has been suggested that social support may protect against self-cutting in adolescence. The aim of this study was to investigate the possible association of social relationships with the initiation of self-cutting. METHODS: The participants were community-dwelling Finnish adolescents (N = 4171) aged 13-18 years at baseline. The follow-up assessment was conducted 5 years later (N = 794). Those adolescents who had self-cut before the baseline assessment (N = 134) were excluded from the analysis, leaving a total of 660 participants to be analyzed. In this group, 37 adolescents initiated self-cutting during the 5-year follow-up period and 623 did not. Cox's proportional hazards models were used with several adjustments for possible confounding factors. FINDINGS: A higher age, male gender, good relationships with siblings, weekly meetings with friends, and personal experience of not being lonely associated with the noninitiation of self-cutting during the follow-up period. Good relationships with parents or peers had no association with the initiation of self-cutting. Depressive symptoms mediated the effect of subjective loneliness on initiating self-cutting. CONCLUSIONS: Social support produced by friends may have a protective effect against self-cutting.

Heavy drinking from adolescence to young adulthood is associated with an altered cerebellum.

Excessive alcohol use results in cerebellar damage in adults, but there has been less research on how alcohol use during adolescence affects the cerebellum. In this study, we observed that heavy drinking from adolescence to young adulthood was associated with altered volumes of cerebellar lobules. The study included two groups consisting of 33 heavy-drinking and 25 light-drinking participants. The heavy-drinking participants were highly functional young adults without alcohol use disorder, but with a history of regular heavy alcohol consumption. The participants were 13-18 years old at baseline and were followed for 10 years. At the age of 21-28 years, the participants underwent magnetic resonance imaging (MRI). From the MR images, the cerebellum was segmented into 12 lobules using the CERES pipeline. Heavy drinking did not influence the absolute cerebellar volume, but changes were observed in posterior cerebellar lobules associated with motor and cognitive functions. The absolute volume (p = 0.038) and gray matter volume (p = 0.034) of Crus II (hemispheres combined) were smaller in the heavy-drinking group. Furthermore, the relative volume of the right VIIIB lobule was larger in the HD group (p = 0.036). However, there were no differences in the absolute right VIIIB volumes (p = 0.198) between the groups. Our results suggest changes in the cerebellum in healthy young adults with a history of heavy drinking from adolescence. The exact implications and significance of these findings require further research.

Repeated Transcranial Magnetic Stimulation-Induced Motor Evoked Potentials Correlate With the Subject-Specific Serum Metabolic Profile of Creatine.

PURPOSE: Transcranial magnetic stimulation-induced motor responses have been considered to mainly reflect the electrophysiological characteristics of the central motor system. However, certain motor phenomena, such as the magnitude of repetition suppression measured with motor evoked potentials (MEPs), could also in part be influenced by metabolic processes in the peripheral muscles and in both the peripheral and central nervous system. Repetition suppression is an inhibitory phenomenon in which the amplitude of MEP decreases in comparison to that of the first MEP in a train of transcranial magnetic stimulation pulses. This study aimed to identify possible metabolic processes influencing repetition suppression. METHODS: The metabolic profiles from serum samples and repetition suppression from the right abductor pollicis brevis muscle were measured in 73 subjects (37 female subjects). Repetition suppression was measured using trains of transcranial magnetic stimulation stimuli consisting of 4 identical single pulses at 1-second intervals. The trains were repeated every 20 seconds, and 30 trains were given with a stimulation intensity of 120% of the resting motor threshold of the abductor pollicis brevis. Thus, a total of 120 stimuli were administered. RESULTS: The main finding was a significant negative relationship between serum creatine levels and the magnitude of repetition suppression (standardized ß coefficient (ß) = -0.43; P < 0.001). In other words, higher creatine levels corresponded to a smaller decrement in the MEP amplitude in response to repetition. When MEPs were not repeated, no relationship was observed (ß = 0.09; P = 0.454). Creatine is used to form phosphocreatine, which in turn is needed to resynthesize adenosine triphosphate from adenosine diphosphate in situations requiring high amounts of energy in muscles and neural cells. CONCLUSIONS: For the first time, this study demonstrated a connection between repeated MEPs and peripheral serum metabolites linked to muscle function. These findings could explain some of the intersubject variability commonly observed in MEPs when the pulses are repeated.

Changes in the serum metabolite profile correlate with decreased brain gray matter volume in moderate-to-heavy drinking young adults.

Our aim was to analyze metabolite profile changes in serum associated with moderate-to-heavy consumption of alcohol in young adults and to evaluate whether these changes are connected to reduced brain gray matter volumes. These study population consisted of young adults with a 10-year history of moderate-to-heavy alcohol consumption (n = 35) and light-drinking controls (n = 27). We used the targeted liquid chromatography mass spectrometry method to measure concentrations of metabolites in serum, and 3.0 T magnetic resonance imaging to assess brain gray matter volumes. Alterations in amino acid and energy metabolism were observed in the moderate-to-heavy drinking young adults when compared to the controls. After correction for multiple testing, the group of moderate-to-heavy drinking young adults had increased serum concentrations of 1-methylhistamine (p = 0.001, d = 0.82) when compared to the controls. Furthermore, concentrations of 1-methylhistamine (r = -0.48, p = 0.004) and creatine (r = -0.52, p = 0.001) were negatively correlated with the brain gray matter volumes in the females. Overall, our results show association between moderate-to-heavy use of alcohol and altered metabolite profile in young adults as well as suggesting that some of these changes could be associated with the reduced brain gray matter volume.

Association of the N100 TMS-evoked potential with attentional processes: A motor cortex TMS-EEG study.

The most thoroughly studied transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) potential (TEP), N100, is often defined as a measure of cortical inhibition. We explored the association of the N100 amplitude with attention in 51 young healthy adults. Navigated TMS with simultaneous EEG registering was applied over the left primary motor cortex at the intensity of 110% of the resting motor threshold. Attention was assessed with the Paced Auditory Serial Addition Test (PASAT). We found a negative Pearson correlation (p = .023, r = -0.317) between the left centroparietal N100 amplitude and the PASAT score. Of the participants, the 17 with the highest PASAT scores and 17 with the lowes scores were selected for further analysis, in which a significant between-group difference in the left centroparietal N100 was found (p = .017). The topographic specificity of this finding was further confirmed with linear mixed model (LMM) analysis, in which significant differences were detected in the N100 amplitude; most prominently in the left centroparietal region (p = .001). A smaller N100 amplitude was associated with better performance in the attention task. Our findings suggest that the GABA-B-ergic TEP N100 is associated with attentional processes and thus represents cortical inhibition beyond motor inhibition.

Heavy alcohol use in adolescence is associated with altered cortical activity: a combined TMS-EEG study.

Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS-EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.

Alcohol consumption during adolescence is associated with reduced grey matter volumes.

BACKGROUND AND AIMS: Cognitive impairment has been associated with excessive alcohol use, but its neural basis is poorly understood. Chronic excessive alcohol use in adolescence may lead to neuronal loss and volumetric changes in the brain. Our objective was to compare the grey matter volumes of heavy- and light-drinking adolescents. DESIGN: This was a longitudinal study: heavy-drinking adolescents without an alcohol use disorder and their light-drinking controls were followed-up for 10 years using questionnaires at three time-points. Magnetic resonance imaging was conducted at the last time-point. SETTING: The area near Kuopio University Hospital, Finland. PARTICIPANTS: The 62 participants were aged 22-28 years and included 35 alcohol users and 27 controls who had been followed-up for approximately 10 years. MEASUREMENTS: Alcohol use was measured by the Alcohol Use Disorders Identification Test (AUDIT)-C at three time-points during 10 years. Participants were selected based on their AUDIT-C score. Magnetic resonance imaging was conducted at the last time-point. Grey matter volume was determined and compared between heavy- and light-drinking groups using voxel-based morphometry on three-dimensional T1-weighted magnetic resonance images using predefined regions of interest and a threshold of P < 0.05, with small volume correction applied on cluster level. FINDINGS: Grey matter volumes were significantly smaller among heavy-drinking participants in the bilateral anterior cingulate cortex, right orbitofrontal and frontopolar cortex, right superior temporal gyrus and right insular cortex compared to the control group (P < 0.05, family-wise error-corrected cluster level). CONCLUSIONS: Excessive alcohol use during adolescence appears to be associated with an abnormal development of the brain grey matter. Moreover, the structural changes detected in the insula of alcohol users may reflect a reduced sensitivity to alcohol's negative subjective effects.

Psychosocial problems in adolescents associated with frequent health care use.

BACKGROUND: The prevalence of somatic, mental and behavioural problems increases in puberty. Nevertheless, compared to adults, health service utilization by adolescents, and associated factors such as risky health behaviours, have been poorly explored. In order to improve health care services, there is a need for further research on adolescents frequently using primary health care. OBJECTIVES: We aimed to investigate adolescents who seek help for health issues, and examine whether particular socio-economic or psychological factors predict frequent primary health care use. METHODS: Finnish adolescents aged 13-18 years (N = 793) attending comprehensive, upper secondary and vocational schools participated in the study in 2005. Data were collected using a questionnaire that included the Youth Self Report (YSR), as well as questions on the psychosocial background of the adolescents and substance use. Data regarding the frequency of use of health services were gathered from medical records of the local public health care services. RESULTS: Altogether, 288 in the sample had used primary health care services making a combined total of 1411 health care visits. Female gender associated with frequent primary health care use. Furthermore, a high level of alcohol consumption and mental health symptoms in girls, and increased self-reported somatic complaints in the YSR in boys were associated with frequent primary health care use. Attending upper secondary school was related to less frequent primary health care use. CONCLUSION: Few adolescents frequently use primary health care, but they account for a considerable proportion of all adolescent health care visits. There are higher levels of alcohol consumption, as well as socio-economic, educational and gender differences among adolescent frequent primary health care users.

Alcohol use among adolescents, aggressive behaviour, and internalizing problems.

Alcohol use is common among adolescents, but its association with behavioural and emotional problems is not well understood. This study aimed to investigate how self-reported psychosocial problems were associated with the use of alcohol in a community sample consisting of 4074 Finnish adolescents aged 13-18 years. Aggressive behaviour associated with alcohol use and a high level of alcohol consumption, while internalizing problems did not associate with alcohol use. Having problems in social relationships associated with abstinence and lower alcohol consumption. Tobacco smoking, early menarche and attention problems also associated with alcohol use.