Drinking severity mediates the relationship between hypothalamic connectivity and rule-breaking/intrusive behavior differently in young women and men: an exploratory study.

Background: The hypothalamus is a key hub of the neural circuits of motivated behavior. Alcohol misuse may lead to hypothalamic dysfunction. Here, we investigated how resting-state hypothalamic functional connectivities are altered in association with the severity of drinking and clinical comorbidities and how men and women differ in this association. Methods: We employed the data of the Human Connectome Project. A total of 870 subjects were included in data analyses. The severity of alcohol use was quantified for individual subjects with the first principal component (PC1) identified from principal component analyses of all drinking measures. Rule-breaking and intrusive scores were evaluated with the Achenbach Adult Self-Report Scale. We performed a whole-brain regression of hypothalamic connectivities on drinking PC1 in all subjects and men/women separately and evaluated the results at a corrected threshold. Results: Higher drinking PC1 was associated with greater hypothalamic connectivity with the paracentral lobule (PCL). Hypothalamic PCL connectivity was positively correlated with rule-breaking score in men (r=0.152, P=0.002) but not in women. In women but not men, hypothalamic connectivity with the left temporo-parietal junction (LTPJ) was negatively correlated with drinking PC1 (r=-0.246, P<0.001) and with intrusiveness score (r=-0.127, P=0.006). Mediation analyses showed that drinking PC1 mediated the relationship between hypothalamic PCL connectivity and rule-breaking score in men and between hypothalamic LTPJ connectivity and intrusiveness score bidirectionally in women. Conclusions: We characterized sex-specific hypothalamic connectivities in link with the severity of alcohol misuse and its comorbidities. These findings extend the literature by elucidating the potential impact of problem drinking on the motivation circuits.

Neural correlates of proactive avoidance deficits and alcohol use motives in problem drinking.

Physical pain and negative emotions represent two distinct drinking motives that contribute to harmful alcohol use. Proactive avoidance, in contrast, can reduce consumption in response to these motives but appears to be impaired in those with problem drinking. Despite such evidence, proactive avoidance and its underlying neural deficits have not been assessed experimentally. How these deficits inter-relate with drinking motives to influence alcohol use also remains unclear. The current study leveraged neuroimaging data in forty-one problem and forty-one social drinkers who performed a probabilistic learning go/nogo task featuring proactive avoidance of painful outcomes. We identified the brain responses to proactive avoidance and contrasted the neural correlates of drinking to avoid negative emotions vs. physical pain. Behavioral results confirmed proactive avoidance deficits in problem drinking individuals' learning rate and performance accuracy, both which were associated with greater alcohol use. Imaging findings in the problem drinking group showed that negative emotions as a drinking motive predicted attenuated right anterior insula activation during proactive avoidance. In contrast, physical pain motive predicted reduced right putamen response. These regions' activations as well as functional connectivity with the somatomotor cortex also demonstrated a negative relationship with drinking severity and positive relationship with proactive avoidance performance. Path modeling further delineated the pathways through which physical pain and negative emotions influenced the neural and behavioral measures of proactive avoidance. Taken together, the current findings provide experimental evidence for proactive avoidance deficits in alcohol misuse and establish the link between their neural underpinnings and drinking behavior.

Progressive alterations of resting-state hypothalamic dysconnectivity in schizophrenia.

BACKGROUND: The hypothalamus may be involved in the pathogenesis of schizophrenia. Investigating hypothalamus dysfunction in schizophrenia and probing how it is related to symptoms and responds to antipsychotic medication is crucial for understanding the potential mechanism of hypothalamus dysfunction under the long-term illness. METHODS: We recruited 216 patients with schizophrenia, including 140 antipsychotic-naïve first-episode patients (FES, including 44 patients with 1-year follow-up data), 76 chronically treated schizophrenia (CTS), and 210 healthy controls (HC). Hypothalamic seed-based functional connectivity (FC) was calculated and compared among the FES, CTS, and HC groups using analysis of covariance. Exploratory analysis was conducted between the FES patients at baseline and after 1-year follow-up. Significantly altered hypothalamic FCs were then related to clinical symptomology, while age- and illness-related regression analyses were also conducted and compared between diagnostic groups. RESULTS: The FES patients showed decreased hypothalamic FCs with the midbrain and right thalamus, whereas the CTS patients showed more severe decreased hypothalamic FCs with the midbrain, right thalamus, left putamen, right caudate, and bilateral anterior cingulate cortex compared to HCs. These abnormalities were not correlated to the symptomology or illness duration, or not reversed by the antipsychotic treatment. Age-related hypothalamic FC decrease was also identified in the abovementioned regions, and a faster age-related decline of the hypothalamic FC was observed with the left putamen and bilateral anterior cingulate cortex. CONCLUSION: Age-related hypothalamic FC decrease extends the functional alterations that characterize the neurodegenerative nature of schizophrenia. Future studies are required to further probe the hormonal or endocrinal underpinnings of such alterations and trace the precise progressive trajectories.

Androgen deprivation increases frontopolar cortical thickness in prostate cancer patients: an effect of early neurodegeneration?

Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT leads to altered testosterone levels that may affect brain morphology as well as cognition. Considering the reliability of cortical thickness (CT) as a marker of cognitive and brain changes, e.g., in Alzheimer's disease, we assessed the impacts of ADT on CT and working memory. Thirty men with non-metastatic prostate cancer receiving ADT and 32 patients not receiving ADT (controls or CON), matched in age and years of education, participated in N-back task and quality-of-life (QoL) assessments as well as brain imaging at baseline and prospectively at 6 months. Imaging data were processed with published routines to estimate CT and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold. ADT and CON did not differ in N-back performance or QoL across time points. Relative to CON, patients receiving ADT showed significantly higher frontopolar cortex (FPC) CT at 6-month follow-up vs. baseline. Follow-up vs. baseline FPC CT change correlated negatively with changes in 2-back correct response rate and in testosterone levels across all participants. In mediation analysis, FPC CT change mediated the association between testosterone level change and 2-back accuracy rate change. Increases in FPC CT following 6 months of ADT may reflect early neurodegenerative changes in response to androgen deprivation. While no significant impact on working memory or QoL was observed over 6 months, further research of longer duration of treatment is warranted to unravel the full spectrum of cognitive and neural consequences of ADT in prostate cancer patients.

The inter-related effects of alcohol use severity and sleep deficiency on semantic processing in young adults.

BACKGROUND: Both alcohol misuse and sleep deficiency are associated with deficits in semantic processing. However, alcohol misuse and sleep deficiency are frequently comorbid and their inter-related effects on semantic processing as well as the underlying neural mechanisms remain to be investigated. METHODS: We curated the Human Connectome Project data of 973 young adults (508 women) to examine the neural correlates of semantic processing in link with the severity of alcohol use and sleep deficiency. The latter were each evaluated using the first principal component (PC1) of principal component analysis of all drinking metrics and the Pittsburgh Sleep Quality Index (PSQI). We employed path modeling to elucidate the interplay among clinical, behavioral, and neural variables. RESULTS: Among women, we observed a significant negative correlation between the left precentral gyrus (PCG) and PSQI scores. Mediation analysis revealed that the left PCG activity fully mediated the relationship between PSQI scores and word comprehension in language tasks. In women alone also, the right middle frontal gyrus (MFG) exhibited a significant negative correlation with PC1. The best path model illustrated the associations among PC1, PSQI scores, PCG activity, and MFG activation during semantic processing in women. CONCLUSIONS: Alcohol misuse may lead to reduced MFG activation while sleep deficiency hinder semantic processing by suppressing PCG activity in women. The pathway model underscores the influence of sleep quality and alcohol consumption severity on semantic processing in women, suggesting that sex differences in these effects need to be further investigated.

Sex differences in dorsolateral prefrontal cortical and superior colliculus activities support the impact of alcohol use severity and sleep deficiency on two-back memory.

Background: Working memory refers to a process of temporary storage and manipulation of information to support planning, decision-making, and action. Frequently comorbid alcohol misuse and sleep deficiency have both been associated with working memory deficits. However, how alcohol misuse and sleep deficiency interact to impact working memory remains unclear. In this study, we aim to investigate the neural processes inter-relating alcohol misuse, sleep deficiency and working memory. Methods: We curated the Human Connectome Project (HCP) dataset and investigated the neural correlation of working memory in link with alcohol use severity and sleep deficiency in 991 young adults (521 women). The two were indexed by the first principal component (PC1) of principal component analysis of all drinking metrics and Pittsburgh Sleep Quality Index (PSQI) score, respectively. We processed the imaging data with published routines and evaluated the results with a corrected threshold. We used path model to characterize the inter-relationship between the clinical, behavioral, and neural measures, and explored sex differences in the findings. Results: In whole-brain regression, we identified ß estimates of dorsolateral prefrontal cortex response (DLPFC ß) to 2- vs. 0-back in correlation with PC1. The DLPFC showed higher activation in positive correlation with PC1 across men and women (r=0.16, P<0.001). Path analyses showed the model PC1 → DLPFC ß â†’ differences in reaction time (2- minus 0-back; RT2-0) of correct trials → differences in critical success index (2- minus 0-back; CSI2-0) with the best fit. In women alone, in addition to the DLPFC, a cluster in the superior colliculus (SC) showed a significant negative correlation with the PSQI score (r=-0.23, P<0.001), and the path model showed the inter-relationship of PC1, PSQI score, DLPFC and SC ß's, and CSI2-0 in women. Conclusions: Alcohol misuse may involve higher DLPFC activation in functional compensation, whereas, in women only, sleep deficiency affects 2-back memory by depressing SC activity. In women only, path model suggests inter-related impact of drinking severity and sleep deficiency on 2-back memory. These findings suggest potential sex differences in the impact of drinking and sleep problems on working memory that need to be further investigated.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia.

BACKGROUND: Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). METHODS: The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). RESULTS: The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. CONCLUSIONS: These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

Age-related reduction in anxiety and neural encoding of negative emotional memory.

Introduction: Older adults experience less anxiety. We examined how memory of negative emotional images varied with age and may reflect age-related differences in anxiety. Methods: Fifty-one adults, age 22-80 years, underwent imaging with a memory task where negative and neutral images were displayed pseudo-randomly. They were queried post-scan about the images inter-mixed with an equal number of images never displayed. Sensitivity (d') and reporting bias (Z-score of false alarm rate; Z[FAR]) were quantified with signal detection theory. Results: Age was negatively correlated with both Spielberg State Trait Anxiety Inventory (STAI) state score and d' (negative - neutral) and positively with Z[FAR] (negative - neutral). However, STAI score and d' or Z[FAR] (negative - neutral) were not significantly correlated. In whole-brain regression, STAI score was correlated with higher activity of the right middle/superior temporal gyri/temporal parietal junction (MTG/STG/TPJ) for "negative correct - incorrect" - "neutral correct - incorrect" trials. Further, the MTG/STG/TPJ activity (ß) was also negatively correlated with age. Mediation analyses supported a complete mediation model of age → less anxiety → less MTG/STG/TPJ ß. Discussion: Together, the findings demonstrated age-related changes in negative emotional memory and how age-related reduction in anxiety is reflected in diminished temporoparietal cortical activities during encoding of negative emotional memory.

Gray matter volumetric correlates of the polygenic risk of depression: A study of the Human Connectome Project data.

Genetic factors confer risks for depression. Understanding the neural endophenotypes, including brain morphometrics, of genetic predisposition to depression would help in unraveling the pathophysiology of depression. We employed voxel-based morphometry (VBM) to examine how gray matter volumes (GMVs) were correlated with the polygenic risk score (PRS) for depression in 993 young adults of the Human Connectome Project. The phenotype of depression was quantified with a DSM-oriented scale of the Achenbach Adult Self-Report. The PRS for depression was computed for each subject using the Psychiatric Genomics Association Study as the base sample. In multiple regression with age, sex, race, drinking severity, and total intracranial volume as covariates, regional GMVs in positive correlation with the PRS were observed in bilateral hippocampi and right gyrus rectus. Regional GMVs in negative correlation with the PRS were observed in a wide swath of brain regions, including bilateral frontal and temporal lobes, anterior cingulate cortex, thalamus, lingual gyri, cerebellum, and the left postcentral gyrus, cuneus, and parahippocampal gyrus. We also found sex difference in anterior cingulate volumes in manifesting the genetic risk of depression. In addition, the GMV of the right cerebellum crus I partially mediated the link from PRS to depression severity. These findings add to the literature by highlighting 1) a more diverse pattern of the volumetric markers of depression, with most regions showing lower but others higher GMVs in association with the genetic risks of depression, and 2) the cerebellar GMV as a genetically informed neural phenotype of depression, in neurotypical individuals.

Functional Networks of Reward and Punishment Processing and Their Molecular Profiles Predicting the Severity of Young Adult Drinking.

Alcohol misuse is associated with altered punishment and reward processing. Here, we investigated neural network responses to reward and punishment and the molecular profiles of the connectivity features predicting alcohol use severity in young adults. We curated the Human Connectome Project data and employed connectome-based predictive modeling (CPM) to examine how functional connectivity (FC) features during wins and losses are associated with alcohol use severity, quantified by Semi-Structured Assessment for the Genetics of Alcoholism, in 981 young adults. We combined the CPM findings and the JuSpace toolbox to characterize the molecular profiles of the network connectivity features of alcohol use severity. The connectomics predicting alcohol use severity appeared specific, comprising less than 0.12% of all features, including medial frontal, motor/sensory, and cerebellum/brainstem networks during punishment processing and medial frontal, fronto-parietal, and motor/sensory networks during reward processing. Spatial correlation analyses showed that these networks were associated predominantly with serotonergic and GABAa signaling. To conclude, a distinct pattern of network connectivity predicted alcohol use severity in young adult drinkers. These "neural fingerprints" elucidate how alcohol misuse impacts the brain and provide evidence of new targets for future intervention.

Immunosenescence-related T cell phenotypes and white matter in schizophrenia patients with tardive dyskinesia.

Schizophrenia patients with tardive dyskinesia (TD) are associated with accelerated biological aging, immunological dysfunction, and premature morbidity and mortality. Older individuals are particularly vulnerable to TD development. As a characteristic of immunosenescence, alterations in the relative proportions of naïve or memory T cell subpopulations may be negatively or positively associated with brain structure abnormalities; however, whether these changes are correlated with TD remains unclear. In this study, we investigated correlations between distributions of T cell phenotypes and brain structure abnormalities (especially white matter) in schizophrenia patients with (TD) and without (NTD) TD (n = 50 and 58, respectively) relative to healthy controls (HC, n = 41). Immune markers, including naïve (CD45RA+), memory (CD45RO+), and apoptotic (CD95+) CD4+ and CD8+ T cells, were examined by flow cytometry, as were the intracellular levels of cytokines (interferon (IFN)-γ, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α) in CD8 + CD45RA + CD95+ and CD8 + CD45RO + CD95+ T cells. MRI was employed to evaluate the fractional anisotropy (FA) of white matter tracts and subcortical volumes, following published routines. The percentage of CD8 + CD45RO + CD95+ T cells was higher in TD compared with NTD and HC groups and correlated with the choroid plexus volume in TD group. The intracellular level of IFN-γ in CD8 + CD45RO + CD95+ T cells, the FA of the fornix/stria terminalis, and the pallidum volume were correlated with orofacial TD, whereas the FAs of the inferior fronto-occipital fasciculus, cingulum, and superior longitudinal fasciculus were correlated with limb-truncal TD. These findings provide preliminary evidence that the association between immunosenescence-related T cell subpopulations and brain structure may underline the pathological process of TD.

Tripod transcranial alternating current stimulation at 5-Hz to alleviate anxiety symptoms: A preliminary report.

INTRODUCTION: One of the most common applications of transcranial electrical stimulation (tES) at low current intensity is to induce a relaxed state or reduce anxiety. With technical advancement, different waveforms, montages, and parameters can be incorporated into the treatment regimen. We developed a novel protocol to treat individuals with anxiety disorders by transcranial alternating current stimulation (tACS). METHODS: A total of 27 individuals with anxiety disorders underwent tACS treatment for 12 sessions, with each session lasting 25 min. tACS at 5 Hz was applied to F4 (1.0 mA), P4 (1.0 mA), and T8 (2.0 mA) EEG lead positions (tripod), with sinewave oscillation between T8 and F4/P4. We evaluated the primary and secondary outcomes using the Beck Anxiety Inventory (BAI) and neuropsychological assessments. RESULTS: Of the 27 patients, 19 (70.4 %) experienced a reduction in symptom severity >50 %, with an average reduction of BAI 58.5 %. All reported side effects were mild, with itching or tingling being the most common complaint. No significant differences were noted in attention, linguistic working memory, visuospatial working memory, or long-term memory in neuropsychological assessments. CONCLUSION: The results suggest the potential of this novel tripod tACS design as a rapid anxiety alleviator and the importance of a clinical trial to verify its efficacy.

Premature Ovarian Insufficiency Is Associated with Increased Risk of Depression, Anxiety, and Poor Life Quality: A Systematic Review and Meta-analysis.

Background: Premature ovarian insufficiency (POI) seriously affects the reproductive health of women. Several studies have been conducted to show that POI appears to be associated with psychological and psychosocial problems, but whether POI increases the risk of mental health problems has not been identified. Therefore, this meta-analysis provides a preliminary systematic assessment of the studies published to date on the impact of POI on women's mental health. Methods: We implemented a systematic search for studies on this topic up to October 2022. Pooled odds ratios (ORs) and 95% confident intervals (CIs) of prevalence were used to assess the impacts of POI on various psychological factors, and the publication bias was assessed by Egger's test. Results: A total of 15 articles comprising 5820 participants were included in this meta-analysis. POI was found to be related to higher risk of 13 psychological and psychosocial problems identified and classified into 3 domains: depression (OR = 1.61; 95% CI: 1.11-2.33), anxiety (OR = 3.74; 95% CI: 1.78-7.87), and poor life quality (OR = 2.55, 95% CI: 1.63-3.97). Conclusion: This meta-analysis reveals that women with POI have an increased risk of depression, anxiety, and poor life quality. The marital status of POI may be a possible influencing factor for depression, meaning that the unmarried status in POI is at high risk of psychological and psychosocial problems. We should pay attention to the mental health of women with POI who were unmarried.

Deficient sleep, altered hypothalamic functional connectivity, depression and anxiety in cigarette smokers.

Background: Deficient sleep is implicated in nicotine dependence as well as depressive and anxiety disorders. The hypothalamus regulates the sleep-wake cycle and supports motivated behavior, and hypothalamic dysfunction may underpin comorbid nicotine dependence, depression and anxiety. We aimed to investigate whether and how the resting state functional connectivities (rsFCs) of the hypothalamus relate to cigarette smoking, deficient sleep, depression and anxiety. Methods: We used the data of 64 smokers and 198 age- and sex-matched adults who never smoked, curated from the Human Connectome Project. Deficient sleep and psychiatric problems were each assessed with Pittsburgh Sleep Quality Index (PSQI) and Achenbach Adult Self-Report. We processed the imaging data with published routines and evaluated the results at a corrected threshold, all with age, sex, and the severity of alcohol use as covariates. Results: Smokers vs. never smokers showed poorer sleep quality and greater severity of depression and anxiety. In smokers only, the total PSQI score, indicating more sleep deficits, was positively associated with hypothalamic rsFCs with the right inferior frontal/insula/superior temporal and postcentral (rPoCG) gyri. Stronger hypothalamus-rPoCG rsFCs were also associated with greater severity of depression and anxiety in smokers but not never smokers. Additionally, in smokers, the PSQI score completely mediated the relationships of hypothalamus-rPoCG rsFCs with depression and anxiety severity. Conclusions: These findings associate hypothalamic circuit dysfunction to sleep deficiency and severity of depression and anxiety symptoms in adults who smoke. Future studies may investigate the roles of the hypothalamic circuit in motivated behaviors to better characterize the inter-related neural markers of smoking, deficient sleep, depression and anxiety.

Serum neuroactive metabolites of the tryptophan pathway in patients with acute phase of affective disorders.

Background: Many studies showed disrupted tryptophan metabolism in patients with affective disorders. The aims of this study were to explore the differences in the metabolites of tryptophan pathway (TP) and the relationships between TP metabolites and clinical symptoms, therapeutic effect in patients with bipolar disorder with acute manic episode (BD-M), depressive episode (BD-D) and major depressive disorder (MDD). Methods: Patients with BD-M (n=52) and BD-D (n=39), MDD (n=48) and healthy controls (HCs, n=49) were enrolled. The serum neuroactive metabolites levels of the TP were measured by liquid chromatography-tandem mass spectrometry. Hamilton Depression Scale-17 item (HAMD-17) and Young Mania Rating Scale (YMRS) were used to evaluate depressive and manic symptoms at baseline and after 8 weeks of antidepressants, mood stabilizers, some also received antipsychotic medication. Results: The levels of tryptophan (TRP) and kynurenic acid (KYNA) were significantly lower and the ratios of tryptophan/kynurenine (TRP/KYN), 5-hydroxytryptamine/tryptophan (5-HT/TRP), quinolinic acid/kynurenic acid (QUIN/KYNA) were higher in BD-M, BD-D, MDD vs. HC. The levels of QUIN and the ratios of QUIN/KYNA were higher in BD-M than in BD-D, MDD, and HCs. The 5-hydroxyindoleacetic acid (5-HIAA) levels of patients with MDD were significantly higher than those in BD-M and BD-D. Binary logistic regression analysis showed the lower peripheral KYNA, the higher the QUIN level, and the higher the risk of BD-M; the lower peripheral KYNA and the higher KYN/TRP and 5-HT/TRP, the higher the risk of BD-D; and the lower the peripheral KYNA level and the higher the KYN/TRP and 5-HT/TRP, the higher the risk of MDD. Correlation analysis, showing a significant association between tryptophan metabolites and improvement of clinical symptoms, especially depression symptoms. Conclusions: Patients with affective disorders had abnormal tryptophan metabolism, which involved in 5-HT and kynurenine pathway (KP) sub-pathway. Tryptophan metabolites might be potential biomarkers for affective disorders and some metabolites have been associated with remission of depressive symptoms.

Ligand-gated ion channels as potential biomarkers for ADT-mediated cognitive decline in prostate cancer patients.

Men with prostate cancer are at increased risk of developing cognitive decline by the use of second-generation androgen signaling inhibitors. To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high-throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements-cytoscape, and bioinformatic analyses employing Advaita® iPathwayGuide and DisGeNET for identification of disease-related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real-time polymerase chain reaction assay. Our systematic analysis of androgen deprivation-associated genes involved multiple biological processes, including neuroactive ligand-receptor interaction, axon guidance, cytokine-cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma-aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein-protein interaction network analysis highlighted the role of ligand-gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene-disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type-1 angiotensin II receptor, brain-derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5-hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT-mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.

Cannabis Dependence is Associated with Reduced Hippocampal Subregion Volumes Independently of Sex: Findings from an ENIGMA Addiction Working Group Multi-Country Study.

Background: Males and females who consume cannabis can experience different mental health and cognitive problems. Neuroscientific theories of addiction postulate that dependence is underscored by neuroadaptations, but do not account for the contribution of distinct sexes. Further, there is little evidence for sex differences in the neurobiology of cannabis dependence as most neuroimaging studies have been conducted in largely male samples in which cannabis dependence, as opposed to use, is often not ascertained. Methods: We examined subregional hippocampus and amygdala volumetry in a sample of 206 people recruited from the ENIGMA Addiction Working Group. They included 59 people with cannabis dependence (17 females), 49 cannabis users without cannabis dependence (20 females), and 98 controls (33 females). Results: We found no group-by-sex effect on subregional volumetry. The left hippocampal cornu ammonis subfield 1 (CA1) volumes were lower in dependent cannabis users compared with non-dependent cannabis users (p<0.001, d=0.32) and with controls (p=0.022, d=0.18). Further, the left cornu ammonis subfield 3 (CA3) and left dentate gyrus volumes were lower in dependent versus non-dependent cannabis users but not versus controls (p=0.002, d=0.37, and p=0.002, d=0.31, respectively). All models controlled for age, intelligence quotient (IQ), alcohol and tobacco use, and intracranial volume. Amygdala volumetry was not affected by group or group-by-sex, but was smaller in females than males. Conclusions: Our findings suggest that the relationship between cannabis dependence and subregional volumetry was not moderated by sex. Specifically, dependent (rather than non-dependent) cannabis use may be associated with alterations in selected hippocampus subfields high in cannabinoid type 1 (CB1) receptors and implicated in addictive behavior. As these data are cross-sectional, it is plausible that differences predate cannabis dependence onset and contribute to the initiation of cannabis dependence. Longitudinal neuroimaging work is required to examine the time-course of the onset of subregional hippocampal alterations in cannabis dependence, and their progression as cannabis dependence exacerbates or recovers over time.

Correlation of allostatic load and perceived stress with clinical features in first-episode schizophrenia.

BACKGROUND: Stress plays an important role in the etiology of schizophrenia. However, the mechanisms by which chronic physiological stress and perceived stress relate to the clinical features of schizophrenia may differ. We aimed to elucidate the relationships among chronic physiological stress indexed by allostatic load (AL), perceived stress, and clinical symptoms in individuals with first-episode schizophrenia (FES). METHODS: Individuals with FES (n = 90, mean age = 28.26years old, 49%female) and healthy controls (111, 28.88, 51%) were recruited. We collected data of 13 biological indicators to calculate the AL index, assessed subjective stress with the Perceived Stress Scale-14 (PSS-14), and compared AL and perceived stress between groups. Patients with FES were also evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). RESULTS: Individuals with FES had higher AL and PSS score than healthy controls. There were no significant correlations between AL and PSS score in either patients or controls. Among individuals with FES, the AL index was associated with the severity of positive symptoms, while the PSS score was positively associated with CDSS score. Both elevated AL and PSS were correlated with the occurrence of schizophrenia. CONCLUSIONS: Physiological stress, as reflected by AL, may be more related to positive symptoms, while perceived stress appear to be associated with depressive symptoms in individuals with FES. Longitudinal studies are necessary to explore the relationships between interventions for different stressor types and specific clinical outcomes in FES.

Deficits in proactive avoidance and neural responses to drinking motives in problem drinkers.

Physical pain and negative emotions represent two distinct drinking motives that contribute to harmful alcohol use. Proactive avoidance which can reduce problem drinking in response to these motives appears to be impaired in problem drinkers. However, proactive avoidance and its underlying neural deficits have not been assessed experimentally. How these deficits inter-relate with drinking motives to influence alcohol use also remains unclear. The current study leveraged neuroimaging data collected in forty-one problem and forty-one social drinkers who performed a probabilistic learning go/nogo task that involved proactive avoidance of painful outcomes. We characterized the regional brain responses to proactive avoidance and identified the neural correlates of drinking to avoid physical pain and negative emotions. Behavioral results confirmed problem drinkers' proactive avoidance deficits in learning rate and performance accuracy, both which were associated with greater alcohol use. Imaging findings in problem drinkers showed that negative emotions as a drinking motive predicted attenuated right insula activation during proactive avoidance. In contrast, physical pain motive predicted reduced right putamen response. These regions' activations as well as functional connectivity with the somatomotor cortex also demonstrated a negative relationship with drinking severity and positive relationship with proactive avoidance performance. Path modeling further delineated the pathways through which physical pain and negative emotions, along with alcohol use severity, influenced the neural and behavioral measures of proactive avoidance. Taken together, the current findings provide experimental evidence for proactive avoidance deficits in problem drinkers and establish the link between their neural underpinnings and alcohol misuse.