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There are individual effects of alexithymia, childhood maltreatment, impulsivity, and some biological markers on aggression and psychological distress in schizophrenia. However, the combined effects of these psychological and biological markers have not yet been fully studied. This study therefore aimed to investigate the influence of these psychological and biological markers on aggression and psychological distress (e.g., depression and anxiety) in inpatients with schizophrenia (n = 355). Participants completed self-report and clinician-rated scales, and blood samples were collected. There were no significant differences between patients with and without alexithymia regarding biological markers. Patients with childhood maltreatment exhibited higher levels of free triiodothyronine (FT3) and C-reactive protein (CRP), as well as lower total cholesterol (TC) levels, compared to non-traumatized individuals. Aggression was positively predicted by psychological distress, alexithymia, childhood maltreatment, impulsivity, CRP, and FT3, and negatively by TC and low-density lipoprotein cholesterol. Negative symptoms, childhood maltreatment, alexithymia, aggression, and CRP positively, and high-density lipoprotein cholesterol negatively emerged as predictors of psychological distress. The study highlights the connections between childhood maltreatment, alexithymia, impulsivity, and potentially related biological dysregulation in explaining aggression and negative mood states as a bio-psychological model of aggression and mood in schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Early-life social isolation induces emotional and cognitive dysregulation, such as increased aggression and anxiety, and decreases neuron excitability in the medial prefrontal cortex (mPFC). The noradrenergic system in the mPFC regulates emotion and cognitive function via α 1 or α 2A adrenergic receptors, depending on noradrenaline levels. However, social isolation-induced changes in the mPFC noradrenergic system have not been reported. Here, male Wistar rats received post-weaning social isolation for nine consecutive weeks and were administered behavioral tests (novel object recognition, elevated plus maze, aggression, and forced swimming, sequentially). Protein expression levels in the mPFC noradrenergic system (α 1 and α 2A adrenergic receptors, tyrosine hydroxylase, and dopamine-β-hydroxylase used as indices of noradrenaline synthesis and release) were examined through western blotting. Social isolation caused cognitive dysfunction, anxiety-like behavior, and aggression, but not behavioral despair. Socially-isolated rats exhibited increased protein levels of the α 1 adrenergic receptor, tyrosine hydroxylase, and dopamine-β-hydroxylase in the mPFC; there was no significant difference between the groups in the α 2A adrenergic receptor expression levels. Preferential activation of the α 1 adrenergic receptor caused by high noradrenaline concentration in the mPFC may be involved in social isolation-induced emotional and cognitive regulation impairments. Targeting the α 1 adrenergic receptor signaling pathway is a potential therapeutic strategy for psychiatric disorders with symptomatic features such as emotional and cognitive dysregulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Prominent theory suggests that factor one psychopathic traits may develop from increased input from hormones in the hypothalamic pituitary gonadal axis (HPG; i.e., testosterone) and decreased input from the hypothalamic pituitary adrenal axis (HPA; i.e., cortisol). Although there are extensive findings connecting low cortisol to psychopathy, less support has emerged for high levels of testosterone. This study examined whether incorporating the HPG hormone, estradiol, into this model would reveal relationships in line with theory: high levels of estradiol and testosterone in combination with low levels of cortisol would inform psychopathic traits. Baseline and reactive hormone levels were measured and compared to Psychopathy Checklist-Youth Version (PCL-YV) interviews among 66 male justice-involved youth (M age = 15.73) in a Southeastern juvenile detention center. The primary findings of this study were relationships between interacting HPA and HPG axis hormones with facet one and facet two psychopathic traits. Specifically, psychopathy total scores, interpersonal traits, and affective traits related to estradiol and testosterone reactivity, in that psychopathy scores were more likely with decreases in hormone reactivity (i.e., change in hormone level) following a stressor. Moreover, affective traits related to reactivity in all three hormones. These findings support inclusion of estradiol in neurobiological models of psychopathy and consideration of the individual components of psychopathy. This study adds to the growing body of research supporting interactions between variations in functioning of the HPA and HPG axes in relation to psychopathy., (© 2020 Society for Psychophysiological Research.)

Hair cortisol concentrations measured during pregnancy have emerged as a novel biomarker for prenatal stress exposure. However, associations between prenatal stress and distress, broadly defined, and hair cortisol concentrations during pregnancy are inconsistent. We examined relations among hair cortisol concentrations during the third trimester with (a) emotion dysregulation and (b) detailed measures of maternal prenatal stress. We also examined the predictive validity of maternal hair cortisol during pregnancy for adverse newborn health outcomes. Cortisol concentrations were derived from 6 cm of hair during the third trimester of pregnancy. Mothers reported on their emotion dysregulation and stress at this time. A standardized newborn neurobehavioral exam was conducted shortly after birth and newborn birth weight and gestational age were assessed from medical records. All hypotheses were preregistered on the Open Science Framework (osf.io/279ng). High levels of emotion dysregulation, but not stress, were predictive of high hair cortisol concentrations. Maternal prenatal BMI mediated the relation between maternal prenatal emotion dysregulation and hair cortisol concentrations. There was no association between hair cortisol and infant birth outcomes. This research supports the notion that transdiagnostic markers of psychopathology are important correlates of hair cortisol concentrations during pregnancy., (© 2020 Wiley Periodicals, Inc.)

The usefulness of polyunsaturated fatty acids on inflammatory, cardiovascular, and the nervous system was studied in the last decades, but the mechanisms underlying their benefic properties are still partially unknown. These agents seem to express their action on the membrane phospholipid composition and permeability and modulation of second messenger cascades. In psychiatry, the efficacy and tolerability of omega-3 fatty acids were investigated in several psychiatric disorders, including major depression, bipolar disorder, personality disorders, high-risk conditions to develop psychosis, attention-deficit hyperactivity disorder, and autism spectrum disorders. Initial findings in this field are promising, and some relevant questions need to be addressed. In particular, the effects of these agents on the main symptom dimensions have to be investigated in a trans-diagnostic perspective. The present systematic review is aimed to examine the available data on the efficacy of omega-3 fatty acids on domains of psychotic symptoms, affective symptoms, impulsivity, and aggressiveness, and harmful behaviors, and suicide risk.

Background: Previous research showed that automatic emotion regulation is associated with activation of subcortical areas and subsequent feedforward processes to cortical areas. In contrast, cognitive awareness of emotions is mediated by negative feedback from cortical to subcortical areas. Pregenual anterior cingulate cortex (pgACC) is essential in the modulation of both affect and alexithymia. We considered the interplay between these two mechanisms in the pgACC and their relationship with alexithymia., Method: In 68 healthy participants (30 women, age = 26.15 ± 4.22) we tested associations of emotion processing and alexithymia with excitation/inhibition (E/I) balance represented as glutamate (Glu)/GABA in the pgACC measured via magnetic resonance spectroscopy in 7 T., Results: Alexithymia was positively correlated with the Glu/GABA ratio (N = 41, p = 0.0393). Further, cognitive self-awareness showed an association with Glu/GABA (N = 52, p = 0.003), which was driven by a correlation with GABA. In contrast, emotion regulation was only correlated with glutamate levels in the pgACC (N = 49, p = 0.008)., Conclusion: Our results corroborate the importance of the pgACC as a mediating region of alexithymia, reflected in an altered E/I balance. Furthermore, we could specify that this altered balance is linked to a GABA-related modulation of cognitive self-awareness of emotions.

Background: Response rates to first-line treatments for depression and anxiety remain unsatisfactory. Identification of predictors or moderators that can optimize treatment matching is of scientific and clinical interest. This study examined the role of prolonged laboratory-induced stress cortisol reactivity as a predictor of outcome for a treatment of affective dimensions (TAD). Patients received 15-sessions of a treatment targeting reductions in negative affect or increases in positive affect (Craske et al., 2019). A second aim was to examine whether treatment type would moderate the association between cortisol reactivity and treatment outcome., Methods: Thirty-five participants underwent a 36-minute intermittent stress induction task composed of a mental arithmetic task and a fear-potentiated startle task one week before treatment initiation. Cortisol was collected at five-time points with reactivity being quantified as peak during the task minus basal level of cortisol the evening before the assessment. Using multilevel modeling, we examined the associations between cortisol reactivity and slopes of symptom improvement., Results: Cortisol reactivity was related to treatment outcome, with average and higher levels of stress-induced cortisol response predicting greater decreases in symptoms throughout treatment and 6-month follow-up. Treatment condition differences (moderation) were not observed in the effect of cortisol reactivity on symptoms., Conclusion: Our findings demonstrate the impact of greater cortisol stress reactivity on treatment outcome. Future studies should investigate how to enhance this therapeutic benefit through capitalizing on endogenous diurnal fluctuations or exogenous cortisol manipulation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy, and irritability occur in prodromal phases of clinical Alzheimer's disease (AD), which might be an increased risk for later developing AD. Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor (SSRI) paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress., Methods: To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress, we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age. Next, we tested the cognitive, biochemical and pathological, effects of long term administration of paroxetine at 6 months old., Results: Our results showed that AD mice displayed emotional dysfunction in the early stage. Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice., Conclusion: Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice. These neuroprotective effects are attributable to functional restoration of glutamate receptor (GluN2A) in AD mice.

Sleep disturbances and chronic pain are considered public health concerns. They are frequently associated, and the direction of its relationship and possible mechanisms underlying it are frequently debated. The exploration of the sleep-pain association is of great clinical interest to explore in order to steer potential therapeutic avenues, accommodate the patient's experience, and adapt the common practice of health professionals. In this review, the direction between sleep-pain in adult and pediatric populations will be discussed. Moreover, the possible mechanisms contributing to this relationship as endogenous pain modulation, inflammation, affect, mood and other states, the role of different endogenous substances (dopamine, orexin, melatonin, vitamin D) as well as other lesser known such as cyclic alternating pattern among others, will be explored. Finally, directions for future studies on this area will be discussed, opening up to the addition of tools such as brain imaging (e.g., fMRI), electrophysiology and non-invasive brain stimulation techniques. Such resources paired with artificial intelligence are key to personalized medicine management for patients facing pain and sleep interacting conditions.

Combined oral contraceptive (COC) use is associated with small, albeit significant, increases in mental symptom scores, predominantly irritability, depressed mood, and anxiety. Yet, randomized prospective trials are needed to better characterize the women at risk for COC-induced negative mood change. Thus, the primary aim of this sub-study to a placebo-controlled randomized trial was to determine whether COC use influences emotional interference by negative and positive stimuli. Secondly, we wanted to evaluate what factors would predict depressive symptoms at the end of the trial, taking personality factors, history of mental disorders and other demographic factors into account. Sixty-nine women were included, randomized to three cycles of treatment with a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo. An emotional verbal Stroop task was used to measure interference of emotional stimuli, in which participants were asked to only name the color of a presented word, while ignoring the meaning of the word. Four different word categories were used; neutral, positive, depression, and anxiety. For the second aim of the study, rating on the Montgomery-Åsberg Depression Rating Scale during the final days of the trial was used as outcome. We found no interaction between emotional verbal Stroop word category and treatment, indicating that COC treatment did not evoke any differences in emotional interference to the three word categories. Significant predictors for depressive symptoms at the end of the trial were trait anxiety at baseline and prior adverse mood effects by hormonal contraceptive use. Treatment (i.e. whether women had been treated with the COC or placebo) did not play a role in predicting depression scores at the end of the trial. In conclusion, we found no evidence that combined oral contraceptive use is associated with impaired cognitive-emotional processing. Instead, the main predictors of self-rated depression at the end of the trial were baseline trait anxiety and previous mental symptoms during hormonal contraceptive use., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Adolescence marks a key developmental window during which emotion dysregulation increases, along with risk for the onset of anxiety and other affect-related pathologies. Although emotion dysregulation and related pathologies normatively decline during the transition into adulthood, this does not occur for a sizable minority of individuals. Finally, sex differences in anxiety emerge during adolescence, with females developing a 2-fold increase in risk relative to males. Unfortunately, a neurobiological model of the mechanisms that cause these changes during adolescence has yet to be proposed. In the present work, we first provide brief reviews of relevant literature. Next, we outline a dual-mechanism model focused on (i) the influence of pubertal testosterone on key emotion-regulation circuitry (i.e., orbitofrontal cortex-amygdala coupling) and (ii) myelination of the fiber bundles connecting such circuitry (i.e., uncinate fasciculus). The proposed model offers a set of specific, testable hypotheses that will hopefully spur much needed cross-disciplinary research., (Copyright © 2019. Published by Elsevier Inc.)

Chronic stress-induced emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory GABAergic system in the prefrontal cortex (PFC). However, the precise nature and trajectory of excitatory/inhibitory (E/I) imbalances in these conditions is not clear, with the literature reporting glutamatergic and GABAergic findings that are at times contradictory and inconclusive. Here we propose and discuss the hypothesis that chronic stress-induced emotional dysfunction involves hypoactivity of the PFC due to increased inhibition. We will also discuss E/I imbalances in the context of sex differences. In this review, we will synthesize research about how glutamatergic and GABAergic systems are perturbed by chronic stress and in related emotional disorders like anxiety and depression and propose ideas for reconciling contradictory findings in support of the hypothesis of over-inhibition. We will also discuss evidence for how aspects of the GABAergic system such as parvalbumin (PV) cells can be targeted therapeutically for reinstating activity and plasticity in the PFC and treating stress-related disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Altered neural mechanisms are well-acknowledged in irritable bowel syndrome (IBS), a disorder of brain-gut-communication highly comorbid with anxiety and depression. As a key hub in corticolimbic inhibition, medial prefrontal cortex (mPFC) may be involved in disturbed emotion regulation in IBS. However, aberrant mPFC excitatory and inhibitory neurotransmission potentially contributing to psychological symptoms in IBS remains unknown. Using quantitative magnetic resonance spectroscopy (qMRS), we compared mPFC glutamate + glutamine (Glx) and γ-aminobutyric acid (GABA+) concentrations in 64 women with IBS and 32 age-matched healthy women (HCs) and investigated their association with anxiety and depression in correlational and subgroup analyses. Applying functional magnetic resonance imaging (fMRI), we explored whether altered neurotransmission was paralleled by aberrant mPFC resting-state functional connectivity (FC). IBS patients did not differ from HCs with respect to mPFC GABA+ or Glx levels. Anxiety was positively associated with mPFC GABA+ concentrations in IBS, whereas Glx was unrelated to psychological or gastrointestinal symptoms. Subgroup comparisons of patients with high or low anxiety symptom severity and HCs revealed increased GABA+ in patients with high symptom severity, and lower mPFC FC with adjacent anterior cingulate cortex (ACC), a crucial region of emotion modulation. Our findings provide novel evidence that altered prefrontal inhibitory neurotransmission may be linked to anxiety in IBS.

Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia. The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs. Here, we evaluated the expression of CB 1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats - WRs). The following drugs were used: AM404 (anandamide uptake/metabolism inhibitor), WIN55-212,2 (non-selective CB 1 agonist), capsaicin (TRPV1 agonist), and capsazepine (TRPV1 antagonist). SHRs displayed increased CB 1 expression in prelimbic cortex and cingulate cortex area 1 and in CA3 region of the dorsal hippocampus. Conversely, SHRs exhibited decreases in TRPV1 expression in prelimbic and CA1 region of dorsal hippocampus and increases in the basolateral amygdala. AM404, WIN 55,212-2 and capsaicin attenuated SHRs CFC deficit, although WIN 55,212-2 worsened SHRs CFC deficit in higher doses. WRs and SHRs CFC were modulated by distinct doses, suggesting that these strains display different responsiveness to cannabinoid and vanilloid drugs. Treatment with capsazepine did not modify CFC in either strains. The effects of AM404 on SHRs CFC deficit was not blocked by pretreatment with rimonabant (CB 1 antagonist) or capsazepine. These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia., (Copyright © 2019. Published by Elsevier Ltd.)

In 2016 the World Health Organization reported 39% of the world's adult population (over 18 y) was overweight, with western countries such as Australia and the United States of America at 64.5% and 67.9% respectively. Overconsumption of high fat/sugar containing food and beverages contribute to the development of obesity. Neural plasticity that occurs as a result of long term sugar consumption has been shown to reduce impulse control and therefore lower the ability to resist the high fat/sugar foods contributing to the obesity epidemic. There is significant overlap between the neural pathways involved in emotions that guide behavioural responses to survival situations with those regulating overconsumption of highly palatable food. This suggests that having a clearer understanding of the role of stress and emotions in the development of obesity will lead to the development of novel therapeutic strategies. Sucrose consumption activates the mesocorticolimbic system in a manner synonymous with substances of abuse. There is overwhelming evidence to support the hypothesis that sucrose consumption results in pathophysiological consequences such as morphological neuronal changes, altered emotional processing and modified behaviour in rodent and human models. In this comprehensive review, we examined >300 studies investigating the interaction between sugar consumption, stress and emotions. Preclinical and clinical trials investigating highly palatable foods and stress, anxiety, depression and fear are reviewed. Importantly, the synergy between sugar consumption and neurobiology is addressed. This review summarizes the neurochemical changes and neural adaptations ö including changes in the dopaminergic system ö that influence emotion and behaviour following sugar consumption., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess by magnetic resonance spectroscopy (MRS) the N -acetylaspartate, myo-inositol, choline, sum of glutamate and glutamine (Glx), and creatine (Cr) content in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) and in the occipital cortex (OCC) (control region) in patients with functional motor symptoms (FMS) and healthy controls, and to determine whether neurochemical limbic changes as estimated by MRS correlate with FMS-related motor symptom severity, alexithymia, anxiety, depression, and quality of life., Methods: This case-control study enrolled 10 patients with FMS and 10 healthy controls. Participants underwent MRS and were tested with the Mini-Mental State Examination, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, 20-Item Toronto Alexithymia Scale, and EuroQol 5D., Results: In patients with FMS, MRS showed increased Glx/Cr in the ACC/mPFC but normal content in the control OCC. All the other metabolites tested were normal in both regions. The increased Glx/Cr content in the ACC/mPFC correlated with alexithymia, anxiety, and severity of symptoms., Conclusions: The abnormal limbic Glx increase could have a crucial pathophysiologic role in FMS, possibly by altering limbic-motor interactions, ultimately leading to abnormal movements., (© 2019 American Academy of Neurology.)

Patients with type-2 diabetes, obesity, and metabolic syndrome have a significantly increased risk of developing depression. Dysregulated metabolism may contribute to the etiology of depression by affecting neuronal activity in key limbic areas. The basolateral amygdala (BLA) acts as a critical emotional valence detector in the brain's limbic circuit, and shows hyperactivity and abnormal glucose metabolism in depressed patients. Furthermore, administering a periadolescent high-fructose diet (HFrD; a model of metabolic syndrome) to male Wistar rats increases anxiety- and depressive-like behavior. Repeated shock stress in Sprague Dawley rats similarly increases anxiety-like behavior and increases BLA excitability. We therefore investigated whether a metabolic stressor (HFrD) would have similar effects as shock stress on BLA excitability in Sprague Dawley rats. We found that a HFrD did not affect the intrinsic excitability of BLA neurons. Fructose-fed Sprague Dawley rats had elevated body fat mass, but did not show increases in metabolic efficiency and fasting blood glucose relative to control. Finally unlike Wistar rats, fructose-fed Sprague Dawley rats did not show increased anxiety- and depressive-like behavior. These results suggest that genetic differences between rat strains may affect susceptibility to a metabolic insult. Collectively, these data show that a periadolescent HFrD disrupts metabolism, but does not change affective behavior or BLA excitability in Sprague Dawley rats., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode., Methods: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects., Results: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects., Conclusions: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain's eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a G q -DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders.

There has been a recent growth in investigations into the neural mechanisms underlying the problems recalling specific autobiographical events that are a core feature of emotional disorders. In this review we provide the first synthesis of this literature, taking into account brain as well as cognitive mechanisms. We suggest that these problems are driven by idiosyncratic activation in areas of the brain associated with assigning salience and self-relevance to emotional memories. Other areas associated with inhibiting distraction and constructing vivid memory representations are also important. Each of these mechanisms may work independently or in concert with one another. Importantly, this interaction between mechanisms may differ between diagnostic and demographic groups such that similar problems in specificity may be characterised by different mechanisms. Given this challenge, neuroimaging may prove useful in identifying patient-specific biomarkers for interventions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neuroplastin 65 (Np65) is an immunoglobulin superfamily cell adhesion molecule involved in synaptic formation and plasticity. Our recent study showed that Np65-knockout (KO) mice exhibit abnormal cognition and emotional disorders. However, the underlying mechanisms remain unclear. In this study, we found 588 differentially-expressed genes in Np65-KO mice by microarray analysis. RT-PCR analysis also revealed the altered expression of genes associated with development and synaptic structure, such as Cdh1, Htr3a, and Kcnj9. In addition, the expression of Wnt-3, a Wnt protein involved in development, was decreased in Np65-KO mice as evidenced by western blotting. Surprisingly, MRI and DAPI staining showed a significant reduction in the lateral ventricular volume of Np65-KO mice. Together, these findings suggest that ablation of Np65 influences gene expression, which may contribute to abnormal brain development. These results provide clues to the mechanisms underlying the altered brain functions of Np65-deficient mice.

Background: Individuals with a borderline personality disorder (BPD) suffer from a constellation of rapidly shifting emotional, interpersonal, and behavioral symptoms. The menstrual cycle may contribute to symptom instability among females with this disorder., Methods: Fifteen healthy, unmedicated females with BPD and without dysmenorrhea reported daily symptoms across 35 days. Urine luteinizing hormone and salivary progesterone (P4) were used to confirm ovulation and cycle phase. Cyclical worsening of symptoms was evaluated using (1) phase contrasts in multilevel models and (2) the Carolina Premenstrual Assessment Scoring System (C-PASS), a protocol for evaluating clinically significant cycle effects on symptoms., Results: Most symptoms demonstrated midluteal worsening, a perimenstrual peak, and resolution of symptoms in the follicular or ovulatory phase. Post-hoc correlations with person-centered progesterone revealed negative correlations with most symptoms. Depressive symptoms showed an unexpected delayed pattern in which baseline levels of symptoms were observed in the ovulatory and midluteal phases, and exacerbations were observed during both the perimenstrual and follicular phases. The majority of participants met C-PASS criteria for clinically significant (⩾30%) symptom exacerbation. All participants met the emotional instability criterion of BPD, and no participant met DSM-5 criteria for premenstrual dysphoric disorder (PMDD)., Conclusions: Females with BPD may be at elevated risk for perimenstrual worsening of emotional symptoms. Longitudinal studies with fine-grained hormonal measurement as well as hormonal experiments are needed to determine the pathophysiology of perimenstrual exacerbation in BPD.

Prenatal exposures to higher levels of maternal cortisol and depression have been linked to a variety of adverse physiological, neurological, and behavioral outcomes, such as dysregulated cortisol production, structural and functional differences in limbic areas of the brain, and greater negative emotionality. This study investigated prospective associations between maternal prepartum depression/cortisol levels and offspring emotional reactivity in 163 mother-child pairs. Women were assessed repeatedly during pregnancy, and later participated in a laboratory visit with their preschool-aged children. Mothers self-reported on depressive symptomatology during pregnancy and provided saliva samples for cortisol assay. Offspring emotional reactivity was assessed through multiple measures, including caregiver reports, cortisol response following a stressor, and laboratory observations of behavior. The findings suggest potential prenatal timing effects, with depression and maternal cortisol measured in the first and second trimesters being more strongly associated with child emotional reactivity. Sex was found to moderate associations between maternal prepartum depression/cortisol and child emotional reactivity, with the general pattern reflecting positive associations in girls, and negative associations in boys., (© 2018 Wiley Periodicals, Inc.)

The endocannabinoid (EC) system influences a wide variety of neurobiological processes including affect and emotionality as well as other neuropsychiatric functions. In this study we examined the relationship of circulating endocannabinoids [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] with affect and emotionality in 175 individuals with (n = 115) and without (n = 60) mood, anxiety, and/or personality disorders. Circulating AEA levels displayed a modest, though statistically significant, inverse relationship with a composite measure of affect regulation (β = - 0.264, p = 0.009), due to its relationship with affect intensity (β = - 0.225, p = 0.021) across all study participants. Neither AEA nor 2-AG level differed as a function of any syndromal/personality disorder and neither correlated significantly with state depression or state anxiety scores. These data suggest that circulating levels endocannabinoids may play a role in emotionality across individuals regardless of defined psychiatric disorder., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Despite the high prevalence of panhypopituitarism and diabetes insipidus in patients with craniopharyngioma (CP), little is known about the functioning of the neuropeptide oxytocin in these patients. This is of special interest as tumor-associated lesions often impair sites critical for oxytocin production and release, and affective dysfunction in CP links with elsewhere reported prosocial, antidepressant and anxiolytic oxytocin effects. Using a prospective study-design, we tested whether oxytocin is reduced in CP-patients, and whether altered oxytocin levels account for affective and emotional dysfunction. 26 adult CP-patients and 26 healthy controls matched in sex and age underwent physical exercise, a stimulus previously shown to induce oxytocin release. Baseline and stimulated salivary oxytocin levels, as well as empathy, depression and anxiety scores were measured. Results showed that patients overall did not present with lower baseline oxytocin levels than controls (F[1,30]=0.21, p=0.649), but baseline oxytocin levels were indeed reduced in patients with hypothalamic damage, as assessed by MRI-based grading (F[2,9.79]=4.54, p=0.040). In response to exercise-induced stimulation, all CP-patients showed a blunted oxytocin-release compared to controls (F[1,30]=9.36, p=0.005). DI was not associated with oxytocin levels. Regarding affective function, unexpectedly, higher baseline oxytocin was related to higher trait anxiety (b=2.885, t(43)=2.421, p=0.020, CI[.478; 5.292]); the positive link with higher depression failed to reach statistical significance (b=1.928, t(43)=1.949, p=0.058, CI[-0.070; 3.927]). A blunted oxytocin-release was linked with higher state anxiety (b=-0.133, t(43)=-2.797, p=0.008, CI[-0.230; -0.037]). Empathy was not associated with oxytocin measures. In conclusion, we observed reduced baseline oxytocin levels only in CP-patients with hypothalamic damage. Exercise-induced stimulation de-masked an oxytocin-deficiency in all CP-patients. Baseline oxytocin levels and stimulated OT-responses might have different effects on affective function, which should be considered in future substitution paradigms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Increased prevalence of depression is found in both type 2 diabetes (T2D) and type 1 diabetes (T1D). Melancholia and atypical depression differ by cortisol secretion and clinical features. The aim was to compare the clinical presentation of T1D and T2D patients in relation to self-reported depression, self-reported anxiety, alexithymia, obesity, and midnight salivary cortisol (MSC)., Methods: Comparative cross-sectional design. The participants were consecutively recruited from one hospital diabetes outpatient clinic: 24 T2D patients (31-59 years) and 148 T1D patients (32-59 years). Self-reported depression, anxiety and alexithymia were assessed by Hospital Anxiety and Depression scale and Toronto Alexithymia Scale-20. MSC, HbA1c, anthropometrics and data from medical records were collected. Multiple logistic regression analyses were performed., Results: Comparisons of prevalence between diabetes types showed for T2D/T1D: depression 25%/12% (P = 0.10); high MSC (≥9.3 nmol/L) 38%/22% (P = 0.13); alexithymia 25%/13% (P = 0.12); anxiety 38%/35% (P = 0.82). The prevalence of high MSC did not differ between depressed and non-depressed T2D patients (17% vs. 44%, P = 0.35), but differed between depressed and non-depressed T1D patients (53% vs. 18%, P = 0.003). The alexithymia prevalence differed between depressed and non-depressed T2D patients (67% vs.11%, P = 0.018), and between depressed and non-depressed T1D patients (47% vs. 11%, P < 0.001). The anxiety prevalence did not differ between depressed and non-depressed T2D patients (67% vs. 28%, P = 0.15), but differed between depressed and non-depressed T1D patients (76% vs. 30%, P < 0.001). The obesity prevalence (BMI ≥30 kg/m 2 ) was 83% for depressed T2D patients and 6% for depressed T1D patients. In the T2D patients, depression was associated with alexithymia (Adjusted odds ratio (AOR) 15.0). In the T1D patients, depression was associated with anxiety (AOR 11.0), foot complications (AOR 8.5), HbA1C >70 mmol/mol (AOR 6.4), and high MSC (≥9.3 nmol/L) (AOR 4.8)., Conclusions: The depressed T2D patients had traits of atypical depression, without associated high MSC (≥9.3 nmol/L) and anxiety, but the association with alexithymia was strong. The depressed T1D patients had traits of melancholia with associated high MSC and anxiety. The obesity prevalence was high in depressed T2D patients and low in depressed T1D patients.

Some patients suffering from the same neuropsychiatric disorder may have no overlapping symptoms whilst others may share symptoms common to other distinct disorders. Therefore, the Research Domain Criteria initiative recognises the need for better characterisation of the individual symptoms on which to focus symptom-based treatment strategies. Many of the disorders involve dysfunction within the prefrontal cortex (PFC) and so the marmoset, due to their highly developed PFC and small size, is an ideal species for studying the neurobiological basis of the behavioural dimensions that underlie these symptoms.Here we focus on a battery of tests that address dysfunction spanning the cognitive (cognitive inflexibility and working memory), negative valence (fear generalisation and negative bias) and positive valence (anhedonia) systems pertinent for understanding disorders such as ADHD, Schizophrenia, Anxiety, Depression and OCD. Parsing the separable prefrontal and striatal circuits and identifying the selective neurochemical modulation (serotonin vs dopamine) that underlie cognitive dysfunction have revealed counterparts in the clinical domain. Aspects of the negative valence system have been explored both at individual- (trait anxiety and genetic variation in serotonin transporter) and circuit-based levels enabling the understanding of generalisation processes, negative biases and differential responsiveness to SSRIs. Within the positive valence system, the combination of cardiovascular and behavioural measures provides a framework for understanding motivational, anticipatory and consummatory aspects of anhedonia and their neurobiological mechanisms. Together, the direct comparison of experimental findings in marmosets with clinical studies is proving an excellent translational model to address the behavioural dimensions and neurobiology of neuropsychiatric symptoms. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 328-353, 2017., (© 2016 Wiley Periodicals, Inc.)

Disturbances of emotion regulation and depressive symptoms are common during the menopause transition. Reproductive hormone levels are not directly correlated with depressive symptoms, and other factors may influence mood symptoms during menopause. In this study, we sought to determine the role of metabolic function in mood symptoms during menopause, hypothesizing an association with menopause status and long-term glucose load. We studied 54 women across three menopause transition stages (15 premenopause, 11 perimenopause, and 28 postmenopause), examining effects of age, hormones, and metabolism on mood and neural activation during emotional discrimination. We assessed participants using behavioral and functional MRI measures of negative emotion and emotion discrimination, and glycated hemoglobin A1c, to assess long-term glucose load. We found that emotionally unpleasant images activated emotion regulation (amygdala) and cognitive association brain regions (prefrontal cortex, posterior cingulate, temporal-parietal-occipital (TPO) junction, hippocampus). Cognitive association region activity increased with menopause stage. Perimenopausal women had left TPO junction activation, and postmenopausal women had prefrontal cortex, posterior cingulate, and TPO junction activation. Negative affect was associated with decreased amygdala activation, while depression symptoms and negative mood were associated with increased TPO junction activation. Hemoglobin A1c was associated with negative interpretation bias of neutral images and cognitive region recruitment during emotion discrimination. FSH levels, indicating menopause stage, were associated with negative mood. Age was not associated with any behavioral measures or activation patterns during the emotion task. Our results suggest that an interaction between metabolic and hormonal factors may influence emotion regulation, leading to increased risk for depression during menopause., Competing Interests: There are no known conflicts of interest, (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The aim of the present study was to investigate the relationships between alexithymia, suicide ideation, C-Reactive Protein (CRP), and serum lipid levels in adult outpatients with a DSM-IV diagnosis of Generalized Anxiety Disorder (GAD). Seventy consecutive patients with GAD were recruited and evaluated. Measures were the Hamilton Anxiety Scale, the Toronto Alexithymia Scale (TAS-20), the Scale of Suicide Ideation (SSI), and the Montgomery Åsberg Depression Rating Scale (MADRS). All patients were assessed for: CRP, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceridaemia (TG), and very-low-density lipoprotein cholesterol (VLDL-C). TC/HDL-C and LDL-C/HDL-C ratios were also evaluated. Alexithymic patients showed higher scores on almost all rating scales and altered serum CRP and lipid levels vs. non-alexithymics. In the hierarchical regression model, the presence of higher MADRS scores together with higher scores at the Difficulty in Identifying Feelings dimension of TAS-20 were associated with higher rates of suicide ideation. Although alexithymic subjects with GAD may show a CRP and cholesterol dysregulation, this latter seems independent on increased suicide ideation, rather to Difficulty in Identifying Feelings, and subthreshold depressive symptoms. Study limitations and future research implications are discussed.

Prader-Willi syndrome (PWS) is characterized by infantile hypotonia, hypogonadism, small hands and feet, distinct facial features and usually intellectual impairment. The disorder is associated with severe behavioral disturbances which include hyperphagia leading to morbid obesity, temper outbursts, skin-picking, and compulsive behaviors. While the brain mechanisms that underpin these disturbances are unknown these behaviors suggest a lack of inhibition and thus gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter may be implicated. In the present study, we investigated in vivo brain GABA and its relationship with emotion and behavior in individuals with PWS. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed on 15 individuals with PWS and 15 age- and gender-matched typically developing controls. GABA levels were measured in the parieto-occipital lobe. All other metabolite levels (N-acetyl aspartate, myo-Inositol, glutathione, glutamate, and glutamine + glutamate) were measured in the anterior cingulate cortex (ACC). GABA levels were significantly lower in the participants with PWS who had clinically significant emotional and behavioral problems relative to typically developing control participants and participants with PWS who did not have emotional and behavioral problems within the clinically significant range. GABA levels were negatively correlated with total behavioral problem scores as well as temper outbursts, skin-picking, depression, social relating difficulties, and a tendency to be self-absorbed. Our data suggests that alterations of the GABAergic system may play an important role in aspects of the pathophysiology of PWS. Pathological mechanism found in PWS may be relevant to understanding the control of similar behaviors in the general population. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: Cortisol levels have been related to mood disorders at the group level, but not much is known about how cortisol relates to affective states within individuals over time. We examined the temporal dynamics of cortisol and affective states in depressed and non-depressed individuals in daily life. Specifically, we addressed the direction and timing of the effects, as well as individual differences., Methods: Thirty depressed and non-depressed participants (aged 20-50 years) filled out questionnaires regarding their affect and sampled saliva three times a day for 30 days in their natural environment. They were pair-matched on age, gender, smoking behavior and body mass index. The multivariate time series (T=90) of every participant were analyzed using vector autoregressive (VAR) modeling to assess lagged effects of cortisol on affect, and vice versa. Contemporaneous effects were assessed using the residuals of the VAR models. Impulse response function analysis was used to examine the timing of effects., Results: For 29 out of 30 participants, a VAR model could be constructed. A significant relationship between cortisol and positive or negative affect was found for the majority of the participants, but the direction, sign, and timing of the relationship varied among individuals., Conclusion: This approach proves to be a valuable addition to traditional group designs, because our results showed that daily life fluctuations in cortisol can influence affective states, and vice versa, but not in all individuals and in varying ways. Future studies may examine whether these individual differences relate to susceptibility for or progression of mood disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Women show increased risk of depressive symptoms in life phases where ovarian steroid hormone levels fluctuate or decline rapidly. The risk mechanisms may include changes in mental state and affective cognition possibly mediated by serotonergic neurotransmission., Methods: In a randomized controlled double-blinded trial, 61 healthy women (mean age 24.3±4.9 years) were tested with measures of affective verbal memory, reaction time, mental distress, and serotonin transporter binding at baseline and at follow-up after receiving gonadotropin-releasing hormone agonist (GnRHa) or placebo intervention. Women also reported daily mood profiles during intervention. We tested direct effects of intervention and indirect effects through changes in serotonin transporter binding on verbal affective memory, simple reaction time and self-reported measures of mental distress, and further effects of GnRHa on daily mood., Results: GnRHa induced an increase in simple reaction time (p=0.03) and more pronounced fluctuations in daily self-reported mood in a manner dependent on baseline mood (p=0.003). Verbal affective memory recall, overall self-perceived mental distress, and serotonin transporter binding were not affected., Conclusions: In healthy women transient sex-steroid hormone fluctuations decrease speed of information processing and further produce more labile mood only in women with elevated levels of mood disturbances at baseline., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Inter-individual variability in metrics of hypothalamic-pituitary-adrenocortical (HPA) activity, such as the slope of the diurnal decline in cortisol, cortisol awakening response (CAR), and total cortisol output, have been found to associate inversely with trait ratings of extraversion and positive affect (E/PA) and positively with neuroticism and negative affect (N/NA) in some, but not all, investigations. These inconsistencies may partly reflect varied intensity of cortisol sampling among studies and reliance on self-rated traits, which are subject to reporting biases and limitations of introspection. Here, we further examined dispositional correlates of HPA activity in 490 healthy, employed midlife volunteers (M age=43 years; 54% Female; 86% white). Trait ratings were requested from participants and 2 participant-elected informants using the Positive and Negative Affect Schedule (PANAS) and Extraversion and Neuroticism dimensions of NEO personality inventories. CAR was assessed as percent increase in cortisol levels from awakening to 30min after awakening; and the diurnal slope and total output of cortisol [Area Under the Curve (AUC)] were determined from cortisol measurements taken at awakening, +4 and +9h later, and bedtime, across 3 workdays. Structural equation modeling was used to estimate multi-informant E/PA and N/NA factors. We used 3days of measurement as indicators to model each of the three latent cortisol factors (slope, CAR, and AUC). With the two latent emotionality and three latent cortisol indices included there was good fit to the data (χ(2)(200)=278.38, p=0.0002; RMSEA=0.028, 90% CI=0.02-0.04; CFI/TLI=0.97/0.96; SRMR=0.04). After controlling for covariates (age, sex, race), results showed higher latent E/PA associated with a steeper diurnal slope (Standardized β=-0.19, p=0.02) and smaller CAR (Standardized β=-0.26, p=0.004), whereas N/NA did not associate with any cortisol metric (Standardized β's=-0.12 to 0.13, p's=0.10 to 0.53). These findings suggest that positive emotionality may be more closely associated with indices of diurnal cortisol release than negative emotionality., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Individuals with substance-use disorders exhibit emotional problems, including deficits in emotion recognition and processing, and this class of disorders also has been linked to deficits in dopaminergic markers in the brain. Because associations between these phenomena have not been explored, we compared a group of recently abstinent methamphetamine-dependent individuals (n=23) with a healthy-control group (n=17) on dopamine D2-type receptor availability, measured using positron emission tomography with [(18)F]fallypride., Methods: The anterior cingulate and anterior insular cortices were selected as the brain regions of interest, because they receive dopaminergic innervation and are thought to be involved in emotion awareness and processing. The Toronto Alexithymia Scale, which includes items that assess difficulty in identifying and describing feelings as well as externally oriented thinking, was administered, and the scores were tested for association with D2-type receptor availability., Results: Relative to controls, methamphetamine-dependent individuals showed higher alexithymia scores, reporting difficulty in identifying feelings. The groups did not differ in D2-type receptor availability in the anterior cingulate or anterior insular cortices, but a significant interaction between group and D2-type receptor availability in both regions, on self-report score, reflected significant positive correlations in the control group (higher receptor availability linked to higher alexithymia) but nonsignificant, negative correlations (lower receptor availability linked to higher alexithymia) in methamphetamine-dependent subjects., Conclusions: The results suggest that neurotransmission through D2-type receptors in the anterior cingulate and anterior insular cortices influences capacity of emotion processing in healthy people but that this association is absent in individuals with methamphetamine dependence., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Purpose: It is well accepted that emotional content can affect memory, interacting with the encoding and consolidation processes. The aim of the present study was to verify the effects of estrogens in the interplay of cognition and emotion., Methods: Images from the International Affective Pictures System, based on valence (pleasant, unpleasant and neutral), maintaining arousal constant, were viewed passively by two groups of young women in different cycle phases: a periovulatory group (PO), characterized by high level of estrogens and low level of progesterone, and an early follicular group (EF), characterized by low levels of both estrogens and progesterone. The electrophysiological responses to images were measured, and P300 peak was considered. One week later, long-term memory was tested by means of free recall., Findings: Intra-group analysis displayed that PO woman had significantly better memory for positive images, while EF women showed significantly better memory for negative images. The comparison between groups revealed that women in the PO phase had better memory performance for positive pictures than women in the EF phase, while no significant differences were found for negative and neutral pictures. According to the free recall results, the subjects in the PO group showed greater P300 amplitude, and shorter latency, for pleasant images compared with women in the EF group., Conclusion: Our results showed that the physiological hormonal fluctuation of estrogens during the menstrual cycle can influence memory, at the time of encoding, during the processing of emotional information., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Alexithymia, a personality construct marked by difficulties in processing one's emotions, has been linked to the altered activity in the anterior cingulate cortex (ACC). Although longitudinal studies reported sex differences in alexithymia, what mediates them is not known. To investigate sex-specific associations of alexithymia and neuronal markers, we mapped metabolites in four brain regions involved differentially in emotion processing using a point-resolved spectroscopy MRS sequence in 3 Tesla. Both sexes showed negative correlations between alexithymia and N-acetylaspartate (NAA) in pregenual ACC (pgACC). Women showed a robust negative correlation of the joint measure of glutamate and glutamine (Glx) to NAA in posterior cingulate cortex (PCC), whereas men showed a weak positive association of Glx to NAA in dorsal ACC (dACC). Our results suggest that lowered neuronal integrity in pgACC, a region of the default mode network (DMN), might primarily account for the general difficulties in emotional processing in alexithymia. Association of alexithymia in women extends to another region in the DMN-PCC, while in men a region in the salience network (SN) was involved. These observations could be representative of sex specific regulation strategies that include diminished internal evaluation of feelings in women and cognitive emotion suppression in men., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Alexithymia and increased interoceptive awareness have been associated with affective disorders as well as with altered insula and anterior cingulate cortex (ACC) function. Brain imaging studies have demonstrated an association between neurotransmitter function and affective disorders as well as personality traits. Here, we first examined the relationship between alexithymic facets as assessed with the Toronto Alexithymia Scale (TAS-20) and interoceptive awareness (assessed with the Body Perception Questionnaire) in 18 healthy subjects. Second, we investigated their association with glutamate and gamma-aminobutyric acid (GABA) concentrations in the left insula and the ACC using 3-Tesla proton magnetic resonance spectroscopy. Behaviorally, we found a close association between alexithymia and interoceptive awareness. Furthermore, glutamate levels in the left insula were positively associated with both alexithymia and awareness of autonomic nervous system reactivity, while GABA concentrations in ACC were selectively associated with alexithymia. Although preliminary, our results suggest that increased glutamate-mediated excitatory transmission-related to enhanced insula activity-reflects increased interoceptive awareness in alexithymia. Suppression of the unspecific emotional arousal evoked by increased awareness of bodily responses in alexithymics might thus be reflected in decreased neuronal activity mediated by increased GABA concentration in ACC., (© The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Alteration in the HPA axis is a robust biomarker of anxiety and depression in adults, but questions remain about this association in pregnancy. We examined the longitudinal links between diurnal cortisol and mood symptoms from self-report questionnaire and diagnostic interview in an ethnically diverse, psychosocially at-risk sample of 101 women at mid-pregnancy and early third trimester. There were modest but significant associations between depression and elevated cortisol, indexed by a decreased morning level and diminished diurnal decline; the effects were strongest for diagnostic data from clinical interview. These effects were independent of socio-demographic factors and sleep disturbance. Associations with anxiety and trauma were generally non-significant. These findings extend prior work by showing that significant mood symptoms in pregnancy are associated with altered diurnal cortisol in pregnancy, which may have implications for maternal and child health., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: Alexithymia is a personality trait characterized by difficulties in identifying, describing and communicating one's own emotions. It is also associated with several stress-related psychiatric disorders. The aim of the study was to examine the cortisol awakening response (CAR) as a measure of HPA-system function in a community based sample of psychologically and physically healthy adults with alexithymia., Methods: Fourty-one high alexithymic individuals and thirty-seven low alexithymic subjects, well-controlled regarding gender, age and sociodemographic status, provided three saliva cortisol samples each day for three consecutive days for the calculation of mean CAR. Participants filled out questionnaires on alexithymia (TAS-20, BVAQ) and interpersonal reactivity (IRI) prior to cortisol assessment., Results: The mean CAR of three sampling days was significantly lower in the alexithymic group in comparison to control participants. Additionally there was a negative correlation between CAR and perceived stress, which points to lower CAR in alexithymia accompanied by higher perceived stress in socio-emotional situations. CAR was negatively correlated with age in the alexithymic group, indicating to alterations in HPA system over longer time to stress exposure., Conclusion: Alexithymic individuals have a lower CAR. Hence the results of the present study indicate that certain aspects of personality modulate HPA-system functioning., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background and Purpose: The investigation of the relationship between affective symptoms and dopamine transporter (DAT) density provided conflicting data in both Parkinson's disease (PD) and non-PD patients. However, the potential interference of psychoactive as well as anti-parkinsonian drugs on DAT density should be taken into account., Objective: To investigate the relationship between affective symptoms and pre-synaptic dopaminergic function in de novo PD patients., Methods: Forty-four de novo PD consecutive outpatients were recruited, and the severity of anxious symptoms was evaluated with the Hamilton Anxiety Rating Scale (HAM-A), the severity of depressive symptoms with the Hamilton Depression Scale (HAM-D) and the Beck Depression Inventory (BDI). Six patients had a formal diagnosis of depression. All patients performed (123) I-FP-CIT SPECT, and semi-quantitative striatal indices were calculated., Results: Disease severity, as measured by Unified Parkinson's Disease Rating Scale (UPDRSIII), was inversely correlated with bilateral striatal indices. Bilateral striatal uptake was significantly positively correlated with HAM-D (r.329; r.423, respectively, right and left), BDI (r.377; r.360, respectively, right and left) and HAM-A (r.338; r.340, respectively, right and left). After controlling for age, disease duration and severity, and Mini Mental State Examination (MMSE), no significant reduction in r-values was observed (P < 0.05)., Conclusion: Our data support the existence of a relationship between depressive and anxious symptoms and the striatal (123) I-FP-CIT uptake. The finding of an increased DAT density associated with mild affective symptoms could be due to the lack of compensatory mechanisms usually present in early PD, and/or it might have a pathogenic role in affective symptoms by reducing the dopaminergic tone in the synaptic cleft., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders found in women of reproductive age. Differences in hormonal and metabolic profiles are observed in groups of patients with normal and elevated BMI. Cause of disturbances observed in the two groups of patients with PCOS is analyzed. The aim of the study is to assess whether psychological parameters of lean and obese patients with PCOS are comparably significantly different and whether there is a correlation between these characteristics and the concentration of various hormones., Participants and Procedures: The study consisted of 20 patients with diagnosed polycystic ovary syndrome and 20 healthy women of similar age. Both groups were stratified according to BMI. Specific psychological parameters and hormones were estimated in all patients., Results: In our study, we found that patients with BMI <25 represented personality traits associated with lower resistance to stress. We also observed significantly higher ACTH levels in the same group as compared to patients with BMI >25. A correlation between plasma ghrelin and the severity of anxiety experienced by test subjects was also observed., Conclusion: The type of personality and emotional disorders in lean PCOS patients may lead to the activation of the hypothalamic-pituitary-adrenal (HPA) axis and disturbences in hypothalamic-pituitary-ovary (HPO) axis. The results suggest participation of primary hypothalamic dysfunction in the pathogenesis of PCOS in patients with specific fenotype. Ghrelin is a hormone that may affect the symptoms of PCOS in lean patients. Psychological therapy should be considered as a permanent element in the therapeutic plan provided to PCOS patients.

Cell-mediated immune activation may play a role in the pathogenesis of depression as indicated by findings of increased soluble tumor necrosis factor receptor (sTNF-R) levels and meta-analytic evidence for elevated soluble interleukin-2 receptor (sIL-2R) concentrations. However, little research has been done on how these soluble cytokine receptors are differently related to specific features in patients with depression. We measured levels of the soluble cytokine receptors sIL-2R, sTNF-R1 and sTNF-R2 in 25 non-medicated patients with major depression (DSM-IV) and 22 healthy controls. Psychometric measures included cognitive-affective depressive symptoms, somatoform symptoms, somatic and cognitive dimensions of anxiety and current mood states. While patients with depression showed increased levels of sIL-2R (p<0.01), differences in sTNF-R1 (p=0.09) and sTNF-R2 (p=0.08) marginally failed to reach significance. Increased concentrations of sIL-2R were related to somatic measures such as the severity of somatoform symptoms and somatic anxiety symptoms but not to cognitive-affective measures or current mood states. Our findings may suggest some specificity in the relationship between sIL-2R and symptom dimensions and highlight potential pathways by which T cell mediated immune activation may underpin somatic symptoms in depression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Most psychometric evaluations in the postpartum (PP) target depression (PPD) and show an association with thyroid autoantibodies (TAb), not with thyroid function. Three studies evaluated PP alexithymia, but none its relationship with thyroid indices. We tested 74 women aged 31.8±4.64 years, on day 3 PP, by the Edinburgh Postnatal Depression Scale (EPDS), the Montgomery and Asberg Depression Rating Scale (MADRS), and the Toronto Alexithymia Scale (TAS). Concurrently, we measured serum thyrotropin (TSH), free T3 (FT3), free T4 (FT4), thyroperoxidase and thyroglobulin antibodies (TPOAb, TgAb). Using cut-off scores of ≥12 (EPDS), ≥15 (MADRS) and ≥61 (TAS), rates of women with abnormal EPDS and MADRS scores were similar (31%, 30% and 28.4%, respectively). TAS scores were higher and proportions of alexithymics were greater in the abnormal EPDS group or in the abnormal MADRS group than in the normal EPDS or MADRS group. EPDS correlated significantly with TAS. Compared to nonalexithymics, alexythimics had lower FT4, higher FT3, lower FT4:FT3 ratio, and insignificantly higher TPOAb or TgAb levels. Only TPOAb and TgAb were significantly higher in women at risk for PPD compared to women not at risk for PPD, but solely at EPDS cut-off values of ≥13 or ≥14. TAS correlated directly with TPOAb and FT3, and inversely with FT4:FT3 ratio, while EPDS correlated only with TPOAb. Comparing women at risk for depression but nonalexithymics or women alexithymics but not at risk for depression vs. women normal on all scales, the former had lower FT3 and higher FT4:FT3 ratio while the latter had lower both FT4 and FT4:FT3 ratio. We conclude that PPD risk and alexithymia (i) are partly comorbid and directly associated with thyroid autoimmunity; (ii) their association with serum free thyroid hormones and with FT4:FT3 ratio goes in opposite directions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Converging preclinical, and human epidemiological, neuroimaging, and genetic evidence suggests a central role for dopamine neurotransmission in modulating pain perception and analgesia. Dysregulation in dopamine signaling may modulate the experience of pain both directly, by enhancing or diminishing the propagation of nociceptive signals, and indirectly, by influencing affective and cognitive processes, which affect the expectation, experience, and interpretation of nociceptive signals. Hypersensitivity to pain and high rates of comorbid chronic pain are common in disorders linked with deficits in dopamine system function, including disorders of mood and affect, substance abuse, and Parkinson disease. Hyposensitivity to pain, however, is common in patients with schizophrenia, which has been linked with excessive dopamine neurotransmission. Although patients are typically affected most by the primary symptoms of their disorders, alterations in pain perception may further increase the burden of their illness, compromising their quality of life. The present review focuses on this relationship, and discusses clinical and potential therapeutic implications for both patients with dopamine-related disorders and those with chronic pain syndromes., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objective: We examined the links of social relational (family environment and peer victimization) and neuroendocrinological (HPA axis dysregulation) risk factors to children's emotional symptoms. We placed special emphasis on the joint effects of these risk factors with respect to the emergence and course of the emotional symptoms., Methods: One hundred and sixty-six children were interviewed (Berkeley Puppet Interview) at age 5 and 6. Teachers and parents completed the Strengths and Difficulties Questionnaire. Parents completed the Family Environment Scales. Peer victimization was assessed by teacher and child reports. Children's saliva cortisol was measured before and after a highly structured story completion task which targeted their cognitive emotional representations of family conflicts., Results: In the cross-sectional analyses, negative family environment, peer victimization, and cortisol increase during the story completion task independently contributed to the variance of emotional symptoms. There was a significant interaction effect between family environment and cortisol increase: those six-year-olds who had experienced an unfavorable family environment only showed high levels of emotional symptoms if they exhibited a cortisol increase during the story completion task. In the longitudinal analysis, peer victimization at age 5 predicted an increase of emotional symptoms at age 6, but only for those children who exhibited a blunted cortisol response a year earlier., Conclusions: Negative family environment and peer victimization proved to be independently associated with emotional symptoms. HPA axis reactivity differentially moderated these associations. Therapeutic strategies should take the interaction between negative relational experiences and biological susceptibility to stress into account., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Mild traumatic brain injury (cerebral concussion) results in cognitive and emotional dysfunction. These injuries are a significant risk factor for the development of anxiety disorders, including posttraumatic stress disorder. However, because physically traumatic events typically occur in a highly emotional context, it is unknown whether traumatic brain injury itself is a cause of augmented fear and anxiety., Methods: Rats were trained with one of five fear-conditioning procedures (n = 105) 2 days after concussive brain trauma. Fear learning was assessed over subsequent days and chronic changes in fear learning and memory circuitry were assessed by measuring N-methyl-D-aspartate receptor subunits and glutamic acid decarboxylase, 67 kDa isoform protein levels in the hippocampus and basolateral amygdala complex (BLA)., Results: Injured rats exhibited an overall increase in fear conditioning, regardless of whether fear was retrieved via discrete or contextual-spatial stimuli. Moreover, injured rats appeared to overgeneralize learned fear to both conditioned and novel stimuli. Although no gross histopathology was evident, injury resulted in a significant upregulation of excitatory N-methyl-D-aspartate receptors in the BLA. There was a trend toward decreased γ-aminobutyric acid-related inhibition (glutamic acid decarboxylase, 67 kDa isoform) in the BLA and hippocampus., Conclusions: These results suggest that mild traumatic brain injury predisposes the brain toward heightened fear learning during stressful postinjury events and provides a potential molecular mechanism by which this occurs. Furthermore, these data represent a novel rodent model that can help advance the neurobiological and therapeutic understanding of the comorbidity of posttraumatic stress disorder and traumatic brain injury., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aims: To examine associations between personality and abnormal glucose regulation., Methods: This cross-sectional study comprised 2152 men and 3143 women (43-66 years). Oral glucose tolerance test identified 316 men and 213 women with previously unknown impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, or type 2 diabetes. Personality traits antagonism (low agreeableness), impulsivity (low conscientiousness), hedonic capacity (high extraversion), negative affectivity (high neuroticism) and alexithymia (low openness) were measured by a self-report inventory. Based on distribution of scores, responses were divided into "low" (<1 SD), "middle" (±1 SD) and "high" (>1 SD). Middle groups were considered reference groups. Prevalence odds ratios (ORs) and 95% confidence intervals (CIs) were estimated., Results: In men, OR for low antagonism was 0.3 (CI 0.2-0.6) (age- and multi-adjusted models) while in women, neither high nor low antagonism was associated to abnormal glucose regulation. Men and women with high hedonic capacity had ORs 0.5 (0.3-0.9) and 0.6 (0.4-1.0), respectively (age- and multi-adjusted models). The other scales illustrated no significant associations., Conclusions: No elevated risk of abnormal glucose regulation was observed for deviating scores on personality scales. Instead, reduced risks were indicated in men with low antagonism, and in men and women with high hedonic capacity., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The main aim of this study was to use proton Magnetic Resonance Spectroscopy (MRS) to identify brain biomarkers for emotional dysregulation in youth as measured by subscales of the Child Behavior Checklist (CBCL)., Methods: We measured glutamate (Glu) concentrations in the anterior cingulated cortex (ACC) of 37 pediatric subjects (aged 6-17 years) using high field (4.0 Tesla) proton Magnetic Resonance Spectroscopy (MRS). Subjects were grouped based on combined T scores on three subscales (Anxiety/Depression, Aggression and Attention) of the CBCL previously associated with deficits in the regulation of emotion. Subjects were stratified into those with high (> 180) (N=10) and low (< 180) (N=27) scores., Limitations: Limitations include small sample size, wide age range studied, focus on Anterior Cingulate Cortex (ACC) only, and that some subjects received psychopharmacological treatments., Results: We found a statistically significant correlation between Glu levels in the ACC and CBCL dysregulation profile scores among subjects with high dysregulation profile scores., Conclusions: These results suggest that glutamatergic dysregulation in the ACC may represent a useful biomarker of emotional dysregulation in youth. Further investigation into the causality, time line and utility as a predictive metric is warranted.

Context: Affective symptoms are poorly understood in polycystic ovary syndrome (PCOS). Clinical signs of hyperandrogenism and high serum androgens are key features in PCOS, and women with PCOS are more likely to be overweight or obese, as well as insulin resistant. Further, PCOS is associated with high sympathetic nerve activity., Objective: To elucidate if self-reported hirsutism, body mass index (BMI) and waistline, circulating sex steroids, sex hormone-binding globulin (SHBG), insulin sensitivity and sympathetic nerve activity are associated with depression and anxiety-related symptoms in women with PCOS., Design and Methods: Seventy-two women with PCOS, aged 21-37 years, were recruited from the community. Hirsutism was self-reported using the Ferriman-Gallway score. Serum estrogens, sex steroid precursors, androgens and glucuronidated androgen metabolites were analyzed by gas and liquid chromatography/mass spectroscopy (GC-MS/LC-MS/MS) and SHBG by chemiluminiscent microparticle immunoassay (CMIA). Insulin sensitivity was measured with euglycemic hyperinsulinemic clamp. Sympathetic nerve activity was measured with microneurography. Symptoms of depression and anxiety were self-reported using the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Brief Scale for Anxiety (BSA-S)., Results: Circulating concentrations of testosterone (T) (P=0.026), free T (FT) (P=0.025), and androstane-3α 17β-diol-3glucuronide (3G) (P=0.029) were lower in women with depression symptoms of potential clinical relevance (MADR-S≥11). The odds of having a MADRS-S score ≥11 were higher with lower FT and 3G. No associations with BSA-S were noted., Conclusion: Lower circulating FT and 3G were associated with worse self-reported depression symptoms. The relationship between mental health, sex steroids and corresponding metabolites in PCOS requires further investigation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)