Changes in SLITRK1 Level in the Amygdala Mediate Chronic Neuropathic Pain-Induced Anxio-Depressive Behaviors in Mice.

BACKGROUND: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. METHODS: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. RESULTS: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. CONCLUSION: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity.

Generalization gradients for fear and disgust in human associative learning.

Previous research indicates that excessive fear is a critical feature in anxiety disorders; however, recent studies suggest that disgust may also contribute to the etiology and maintenance of some anxiety disorders. It remains unclear if differences exist between these two threat-related emotions in conditioning and generalization. Evaluating different patterns of fear and disgust learning would facilitate a deeper understanding of how anxiety disorders develop. In this study, 32 college students completed threat conditioning tasks, including conditioned stimuli paired with frightening or disgusting images. Fear and disgust were divided into two randomly ordered blocks to examine differences by recording subjective US expectancy ratings and eye movements in the conditioning and generalization process. During conditioning, differing US expectancy ratings (fear vs. disgust) were found only on CS-, which may demonstrated that fear is associated with inferior discrimination learning. During the generalization test, participants exhibited greater US expectancy ratings to fear-related GS1 (generalized stimulus) and GS2 relative to disgust GS1 and GS2. Fear led to longer reaction times than disgust in both phases, and the pupil size and fixation duration for fear stimuli were larger than for disgust stimuli, suggesting that disgust generalization has a steeper gradient than fear generalization. These findings provide preliminary evidence for differences between fear- and disgust-related stimuli in conditioning and generalization, and suggest insights into treatment for anxiety and other fear- or disgust-related disorders.

Astrocytes in the Ventromedial Hypothalamus Involve Chronic Stress-Induced Anxiety and Bone Loss in Mice.

Chronic stress is one of the main risk factors of bone loss. While the neurons and neural circuits of the ventromedial hypothalamus (VMH) mediate bone loss induced by chronic stress, the detailed intrinsic mechanisms within the VMH nucleus still need to be explored. Astrocytes in brain regions play important roles in the regulation of metabolism and anxiety-like behavior through interactions with surrounding neurons. However, whether astrocytes in the VMH affect neuronal activity and therefore regulate chronic stress-induced anxiety and bone loss remain elusive. In this study, we found that VMH astrocytes were activated during chronic stress-induced anxiety and bone loss. Pharmacogenetic activation of the Gi and Gq pathways in VMH astrocytes reduced and increased the levels of anxiety and bone loss, respectively. Furthermore, activation of VMH astrocytes by optogenetics induced depolarization in neighboring steroidogenic factor-1 (SF-1) neurons, which was diminished by administration of N-methyl-D-aspartic acid (NMDA) receptor blocker but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker. These results suggest that there may be a functional "glial-neuron microcircuit" in VMH nuclei that mediates anxiety and bone loss induced by chronic stress. This study not only advances our understanding of glial cell function but also provides a potential intervention target for chronic stress-induced anxiety and bone loss therapy.

Real-life dental examination elicits physiological responses different to visual and auditory dental-related stimuli.

BACKGROUND: Previous studies on dental anxiety have examined the psychophysiological responses evoked in dentally anxious subjects by dental-related stimuli, but not during a real-life dental examination, which was achieved in the present study. METHODS: The heart rate, skin conductance level, and heart rate variability of 25 subjects with dental anxiety and 25 healthy controls were examined. Anxiety was determined by the Modified Dental Anxiety Scale and the Dental Anxiety Scale-Revised. The psychophysiological reactions of the two groups were compared during exposure to dental-related pictures, dental-related sounds, and an actual examination in a dental surgery. RESULTS: All the dental-related stimuli provoked an increase in heart rate, i.e. visual stimuli (p<0.001; 95% CI 0.98-3.95 bpm), auditory stimuli (p<0.001; 95% CI 1.34-4.99 bpm), and a dental examination (p<0.001; 95% CI 1.26-5.39 bpm). Dental-related pictures provoked inferior skin conductance level changes compared to dental-related sounds and the dental examination (visual modality vs auditory p<0.001; 95% CI 0.039-0.152; visual modality vs examination p<0.001; 95% CI 0.083-0.275). Heart rate variability manifested in a complex pattern of responses to the dental examination. However, when exposed to all three dental-related stimuli presentation conditions, the heart rate (F = 0.352, p = 0.556), skin conductance level (F = 0.009, p = 0.926), and heart rate variability parameters of subjects with dental anxiety did not differ in comparison to the healthy controls. CONCLUSIONS: This pilot study represents an evaluation of psychophysiological reactions during a real-life dental examination compared to single modality stimuli, and shows that a real-life dental examination provokes an increase in heart rate, heart rate variability and skin conductance level. Additionally, autonomic responses did not differ between the experimental and control groups. The key issue for future studies is the effect of real-life situations on the physiological and psychological state of the subjects, which should be considered when planning new research and studied in depth.

Intraoperative Pain Sensation During Cataract Surgery: Why Does Timing Matter?

Purpose: To investigate whether timing influences pain perception during cataract surgery and to investigate the possible mechanisms.Methods: Patients scheduled for cataract surgery both in the morning and afternoon were consecutively enrolled. Questionnaires to evaluate anxiety, including the Simplified State-Trait Anxiety Inventory, Amsterdam Preoperative Anxiety and Information Scale, and a visual analogue scale (VAS) for anxiety, were completed preoperatively, whereas a VAS for pain and the Wong-Baker FACES® Pain Rating Scale questionnaire were completed after surgery. Preoperative blood pressure and heart rate were recorded. Blood samples were acquired before surgery, and plasma cortisol, adrenocorticotropic hormone, adrenalin, and noradrenalin were tested.Results: Fifty-five patients underwent uneverntful cataract surgery (28 in the morning and 27 in the afternoon) were included in the final analysis. Greater intraoperative pain perception during cataract surgery was reported in the afternoon than in the morning. Overall anxiety levels were significantly higher in the afternoon. Plasma adrenalin levels were significantly higher in the afternoon. Cortisol levels were higher in the afternoon. Preoperative anxiety levels were closely related to intraoperative pain perception. Both adrenalin and cortisol correlated positively with preoperative anxiety, but only adrenalin correlated significantly with the pain scores.Conclusions: Patients undergoing cataract surgery in the afternoon showed more preoperative anxiety, which may have increased their relevant stress hormones. Both the patient's emotional state and hormone levels may together aggravate his/her perceived pain in the afternoon. Monitoring preoperative anxiety levels, blood pressure, and heart rate should help to identify patients at higher risk of perceived intraoperative pain.Clinical trial registration:Trial registration number: NCT02182921Registration site: clinicaltrials.gov.

Disentangling comorbidity in chronic pain: A study in primary health care settings from India.

OBJECTIVES: The study examined the prevalence, sociodemographic, and clinical correlates of chronic pain among primary care patients in the state of Kerala, India. It also examined the patterns and relationships of chronic physical and mental health conditions with chronic pain. METHODS: This study is a cross-sectional survey conducted among 7165 adult patients selected randomly by a multi-stage stratified design from 71 primary health centers. The questionnaires administered included Chronic pain screening questionnaire, self-reported Chronic physical health condition checklist, Patient Health Questionnaire-SADS, The Alcohol Use Disorders Identification Test, Fagerström Test for Nicotine Dependence, WHO Disability Assessment Schedule and WHOQOL- BREF for Quality/Satisfaction with Life. The prevalence and comorbid patterns of chronic pain were determined. Logistic regression analysis and generalized linear mixed-effects model was employed to examine the relationship of chronic pain to socio-demographic variables and examined physical and mental health conditions. RESULTS: A total of 1831 (27%) patients reported chronic pain. Among those with chronic pain, 28.3% reported no co-occurring chronic mental or physical illness, 35.3% reported one, and 36.3% reported multi-morbidity. In the multivariate analysis, patients with chronic pain when compared to those without had higher odds of being older, female, having lower education, not living with their family, greater disability, and poor satisfaction with life. Chronic pain was independently associated with both medical (hypertension, diabetes mellitus, tuberculosis, arthritis, and other medical illnesses) and mental health conditions (depressive disorders, anxiety disorders, and tobacco dependence). It showed a varying strength of association and additive effect with increasing number of co-occurring physical and mental illnesses. CONCLUSIONS: Chronic pain is a common condition among primary care attendees associated with significant burden of medical and mental health comorbidity. The findings highlight the need to incorporate treatment models that will ensure appropriate management to improve outcomes within the resource constraints.

Childhood trauma and dysregulation of multiple biological stress systems in adulthood: Results from the Netherlands Study of Depression and Anxiety (NESDA).

BACKGROUND: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive. METHODS: In the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood. RESULTS: Almost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems' activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, ß = .088, p = .007; AUCi, ß = .084, p = .010), cumulative HPA-axis markers (ß = .115, p = .001), C-reactive protein (ß = .055, p = .032), interleukin-6 (ß = .053, p = .038), cumulative inflammation (ß = .060, p = .020), and cumulative markers across all systems (ß = .125, p = .0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases. CONCLUSION: While our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health.

Toxic effect of calcium/calmodulin kinase II on anxiety behavior, neuronal firing and plasticity in the male offspring of morphine-abstinent rats.

Studies have shown that epigenetic changes such as alteration in histone acetylation and DNA methylation in various brain regions play an essential role in anxiety behavior. According to the critical role of calcium/calmodulin protein kinaseII (CaMKII) in these processes, the present study examined the effect of CaMKII inhibitor (KN93) on neuronal activity and level of c-fos in the amygdala and nucleus accumbens (NAC) in the offspring of morphine-exposed parents. Adult male and female Wistar rats received morphine orally (for 21 days). After the washout period (10 days), rats were mated with either drug-naïve or morphine-exposed rats. KN93 was microinjected into the brain of male offspring. The anxiety-like behavior, the neuronal firing rate in the NAC and the amygdala and level of c-fos were assessed by related techniques. Data showed the offspring with one and/or two morphine-abstinent parent(s) had more anxiety-like behavior than the control group. However, the administration of KN-93 decreased anxiety in the offspring of morphine-exposed rats compared with saline-treated groups. The expression level of the c-fos was not significantly altered by the inhibition of CaMKII in the amygdala, but the c-fos level was reduced in the NAC. The neuronal firing rate of these groups was associated with an increase in the amygdala in comparison to the saline groups but was decreased in the NAC. Results showed that CaMKII had a role in anxiety-like behavior in the offspring of morphine-exposed parents, and changes in neuronal firing rate and c-fos level in the NAC might be involved in this process.

Inducible nitric oxide synthase plays a role in depression- and anxiety-like behaviors chronically induced by lipopolysaccharide in rats: Evidence from inflammation and oxidative stress.

OBJECTIVE: The effects of aminoguanidine (AG) were investigated in a rat model of lipopolysaccharide (LPS)-induced anxiety- and depression-like behaviors. MATERIALS AND METHODS: The animals were allocated to five groups (n = 10 in each) and treated by: (1) saline as a control group, (2) LPS 1 mg/kg injected two hours before behavioral tests, (3-5) AG 50, 100 or 150 mg/kg before LPS. The open-field test (OFT), elevated plus maze test (EPT), and forced swimming (FS) tests were performed. The brains and blood were then collected to examine oxidative stress and inflammation criteria. RESULTS: LPS increased the immobility while decreased the active time in the FS test. In EPT, LPS decreased the time spent in the open arms, whereas it increased the time spent in the closed arms. In OFT, LPS decreased the time spent in the central zone compared with the controls. A higher dose of selenium improved the performances of the rats in behavioral tests. LPS injection also increased malondialdehyde (MDA) while it decreased thiol, superoxide dismutase (SOD), and catalase. LPS also increased interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), but decreased IL-10 in the LPS group. AG protected the brain from inflammation and oxidative damage. CONCLUSION: It was demonstrated that AG improves the behaviors of depression and anxiety in a rat model of LPS-induced anxiety- and depression-like behaviors. Moreover, the effects of AG were accompanied by improved inflammation and oxidative damage biomarkers in brain tissues.

Memory and language impairments are associated with anxiety disorder severity in childhood

Abstract Introduction Children with anxiety disorders have been suggested to possess deficits in verbal fluency, shifting and attention, with inconsistent results regarding working memory and its subcomponents. This study extends previous findings by analyzing the performance of children with anxiety disorders in a wide range of neuropsychological functions. Methods We evaluated 54 children with a primary diagnosis of an anxiety disorder according to diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) using subtests of a neuropsychological battery. The severity of anxiety disorders was assessed using the Pediatric Anxiety Rating Scale (PARS). We calculated the frequency of neuropsychological impairments (-1.5 standard deviation of the normative sample). Comparisons between groups were performed based on the severity of anxiety symptoms, as well as in the presence of one vs. more diagnoses of anxiety disorder. Results We found higher impairment in visuospatial working memory (23.1%), semantic memory (27.8%), oral language (35.4%) and word writing (44.4%) in anxious children. Moreover, children with higher anxiety severity presented lower performance in visuospatial working memory, inferential processing, word reading, writing comprehension, copied writing, and semantic verbal fluency (d = 0.49 to 0.96 [Cohen's d]). The higher the number of anxiety diagnoses, the lower the performance in episodic memory and oral and written language (d = 0.56 to 0.77). Conclusion Our data suggested the presence of memory (visuospatial working memory and semantic memory) and language deficits (oral and writing) in some children with an anxiety disorder. Severity and number of anxiety diagnoses were associated with lower performance in memory and language domains in childhood.

Physical and mental fatigue across the menstrual cycle in women with and without generalised anxiety disorder.

Subjective, disabling fatigue is a common complaint and a key feature of numerous medical conditions, and is a transdiagnostic feature of psychiatric disorders. Despite physical and mental fatigue being associated with functional impairment and reduced quality of life, little is understood about its underlying mechanisms or modulating factors. Women commonly experience exacerbation of other (non-fatigue related) psychiatric symptoms during the luteal phase of the menstrual cycle, and report greater fatigue prevalence compared to men. It is therefore plausible that subjective fatigue may similarly fluctuate across the menstrual cycle. Here we compared physical and mental fatigue in the early-follicular (lower ovarian hormones) and mid-luteal (higher ovarian hormones) phases of a single menstrual cycle, while controlling for sleep disruption, in women with (n = 18) and without (non-anxious; n = 20) generalised anxiety disorder (GAD). As expected, women with GAD reported greater physical and mental fatigue than healthy women. Further, although there were no changes in physical fatigue from the early-follicular to mid-luteal phases in both groups, mental fatigue in non-anxious women increased to levels equivalent to those experienced by their GAD counterparts in the mid-luteal phase. Although salivary levels of estradiol and progesterone increased from the early-follicular to mid-luteal phase, hormones did not significantly predict fatigue in either phase. These findings are consistent with the exacerbations of state anxiety and mood disturbance recognised to occur in the luteal phase of the menstrual cycle. We speculate that increased mental fatigue in the luteal phase may represent a vulnerable period for the development and maintenance of psychiatric disorders, potentially via compromised emotional regulation.

Adiposity, depression and anxiety: interrelationship and possible mediators.

OBJECTIVES: To explore the association between adiposity, major depressive disorder and generalized anxiety disorder, and to assess the role of inflammation, diet quality and physical activity in this association. METHODS: We used data from 2,977 individuals from the 1993 Pelotas Cohort (Brazil) who attended the 18- and 22-year follow-ups. We assessed general obesity using body mass index, fat mass index, and abdominal obesity using waist circumference. Major Depressive Disorder and generalized anxiety disorder were assessed using the mini-international neuropsychiatric interview. C-reactive protein and interleukin-6 (IL-6) levels were used as a measure of inflammation; diet quality was estimated using the revised diet quality index, and physical activity was assessed by the International physical activity questionnaire (IPAQ, min/day). The association between adiposity and major depressive disorder and generalized anxiety disorder was assessed using logistic regression, and the natural indirect effect via the mediators was estimated using G-computation. RESULTS: General obesity assessed by body mass index (OR: 2.3; 95% CI:1.13; 4.85), fat mass index (OR: 2.6; 95%CI: 1.37; 4.83), and abdominal obesity (OR: 2.5; 95%CI: 1.18; 5.39) were associated with higher odds of major depressive disorder, whereas major depressive disorder was only associated with obesity assessed by body mass index (OR=1.9; 95% CI: 1.09; 3.46). Obesity and generalized anxiety disorder were not associated. C-reactive protein, diet quality and physical activity did not mediate the effect of obesity on major depressive disorder, and C-reactive protein mediated about 25% of the effect of major depressive disorder on adiposity. CONCLUSIONS: Depression, but not generalized anxiety disorder, is associated with adiposity in both directions, with a stronger evidence for the direction obesity-depression. Inflammation explains part of the effect of major depressive disorder on obesity but not the other way around. Further research should explore other mechanisms that could be involved in the association between obesity and depression.

Mediating Roles of Anxiety, Self-Efficacy, and Sleep Quality on the Relationship Between Patient-Reported Physician Empathy and Inflammatory Markers in Ulcerative Colitis Patients.

BACKGROUND Empathy between doctor and patient has an important bearing on patient health. The purpose of this study was to assess whether anxiety, sleep quality, and self-efficacy of patients have mediating effects in the relationship of patient-reported physician empathy and inflammatory factor in ulcerative colitis (UC) patients. MATERIAL AND METHODS This study included 242 patients attended by 45 doctors. Self-reported doctors' empathy ability was measured at patient admission (T1), and patient-reported physician empathy was measured 3 months later (T2). Patient anxiety, general self-efficacy, sleep, and inflammatory factor (IL-6) were measured on T1 and T2. Pearson correlation analysis was used to assess the relationships between self-reported doctor empathy ability and patient indices on T1 and T2. The relationships between anxiety, sleep quality, self-efficacy, IL-6, and patient-reported physician empathy were measured by Pearson correlation analysis and structural equation modeling. RESULTS On T1, no significant correlation was reported between self-reported doctors' empathy ability and indices of the patients (P>0.05). On T2, self-reported doctors' empathy ability was significantly positively correlated with patient sleep and self-efficacy (P<0.01), and significantly negatively correlated with patient anxiety and IL-6 (P<0.01). Moreover, on T2, patient-reported physician empathy was negatively correlated with anxiety and IL-6 and was positively correlated with self-efficacy and sleep quality. The effect of patient-reported physician empathy on IL-6 was mediated by anxiety, sleep quality, and self-efficacy. CONCLUSIONS The anxiety, self-efficacy, and sleep quality of UC patients had mediating effects in the relationship between patient-reported physician empathy and IL-6.

Structural and functional neuroimaging studies in generalized anxiety disorder: a systematic review

Objectives: Brain imaging studies carried out in patients suffering from generalized anxiety disorder (GAD) have contributed to better characterize the pathophysiological mechanisms underlying this disorder. The present study reviews the available functional and structural brain imaging evidence on GAD, and suggests further strategies for investigations in this field. Methods: A systematic literature review was performed in PubMed, PsycINFO, and Google Scholar, aiming to identify original research evaluating GAD patients with the use of structural and functional magnetic resonance imaging as well as diffusion tensor imaging. Results: The available studies have shown impairments in ventrolateral and dorsolateral prefrontal cortex, anterior cingulate, posterior parietal regions, and amygdala in both pediatric and adult GAD patients, mostly in the right hemisphere. However, the literature is often tentative, given that most studies have employed small samples and included patients with comorbidities or in current use of various medications. Finally, different methodological aspects, such as the type of imaging equipment used, also complicate the generalizability of the findings. Conclusions: Longitudinal neuroimaging studies with larger samples of both juvenile and adult GAD patients, as well as at risk individuals and unaffected relatives, should be carried out in order to shed light on the specific biological signature of GAD.

Meta-Analysis of Anxiety in Parents of Young People with Chronic Health Conditions.

OBJECTIVE: Chronic health conditions are often associated with uncertainty and threats which may cause anxiety in the family members. The present meta-analysis analyzed whether parents of children with chronic physical diseases and/or sensory/physical disabilities show higher anxiety levels than parents of healthy/nondisabled children or test norms. METHODS: The databases PSYCINFO, MEDLINE, Google Scholar, CINAHL, and PSYNDEX were searched for relevant studies. In total, 486 studies were identified that fulfilled the inclusion criteria. RESULTS: We found moderate elevations of anxiety symptoms in parents of young people with chronic conditions (g = .54 standard deviation units). About 16% of the parents fulfilled the criteria for an anxiety disorder. Parents of young people with neuromuscular disorders, HIV-infection/AIDS, and cancer during active treatment showed large elevations of anxiety symptoms. Elevations of anxiety symptoms were smaller in the cases of longer lasting chronic conditions, longer time since the end of active treatment, in families of older children, in samples with lower percentages of mothers, and in studies from economically developed countries compared to less developed countries. CONCLUSION: Measures for preventing and reducing anxiety symptoms in parents of young people with neuromuscular disorders, HIV-infection/AIDS, and those undergoing cancer treatments are particularly needed.

No evidence of attentional bias toward angry faces in patients with obsessive-compulsive disorder

Objective: Although attentional bias (AB) toward angry faces is well established in patients with anxiety disorders, it is still poorly studied in obsessive-compulsive disorder (OCD). We investigated whether OCD patients present AB toward angry faces, whether AB is related to symptom severity and whether AB scores are associated with specific OCD symptom dimensions. Method: Forty-eight OCD patients were assessed in clinical evaluations, intelligence testing and a dot-probe AB paradigm that used neutral and angry faces as stimuli. Analyses were performed with a one-sample t-test, Pearson correlations and linear regression. Results: No evidence of AB was observed in OCD patients, nor was there any association between AB and symptom severity or dimension. Psychiatric comorbidity did not affect our results. Conclusion: In accordance with previous studies, we were unable to detect AB in OCD patients. To investigate whether OCD patients have different brain activation patterns from anxiety disorder patients, future studies using a transdiagnostic approach should evaluate AB in OCD and anxiety disorder patients as they perform AB tasks under functional neuroimaging protocols.

Age-specific associations among functional COMT Val158Met polymorphism, resting parasympathetic nervous control and generalized anxiety disorder.

The functional Val158Met polymorphism (rs4680) of the Catechol-O-Methyltransferase (COMT) gene has been implicated in generalized anxiety disorder (GAD); however, the underlying neural mechanisms remain unexamined. Recent evidence reveals that low resting parasympathetic (vagal) control is an endophenotypic predictor of anxiety, while the effect of COMT rs4680 differs at different ages. Thus, we examined whether the COMT Val158Met variant could increase the risk of GAD through decreased resting parasympathetic nervous control in an age-specific manner. COMT rs4680 polymorphism was genotyped in 1,655 Han Chinese adults (1,142 healthy subjects and 513 patients with GAD; age: 20-65). High-frequency power (HF) of heart rate variability (HRV) was used to measure resting state parasympathetic nervous regulation. Non-genetic factors, such as gender, smoking status, medication use and comorbidity conditions, were treated as covariates. After adjusting for relevant covariates, there was a significant age x COMT genotype interaction on resting HF of HRV. In younger adults, Met allele carriers had a significantly lower HF index; however, older adults exhibited the opposite pattern, with Val/Val homozygotes exhibiting decreased HF values. Moreover, reduced HF-HRV is associated with increased risk of GAD. Finally, pathway analysis revealed a significant indirect effect of COMT on the risk of GAD via reduced resting HF-HRV, in the aforementioned age-dependent manner. Our findings are the first to demonstrate that COMT Val158Met polymorphism is associated with risk of GAD via reduced resting parasympathetic nervous control, an age-specific risk pathway.

Adult social isolation leads to anxiety and spatial memory impairment: Brain activity pattern of COx and c-Fos.

Social isolation during adulthood is a frequent problem that leads to a large variety of adverse emotional and cognitive effects. However, most of the social isolation rodent procedures begin the separation early post-weaning. This work explores locomotor activity, anxiety-like behaviour, and spatial working memory after twelve weeks of adult social isolation. In order to study the functional contribution of selected brain areas following a working memory task, we assessed neuronal metabolic activity through quantitative cytochrome oxidase histochemistry and c-Fos immunohistochemistry. Behaviourally, we found that isolated animals (IS) showed anxiety-like behaviour and worse working memory than controls, whereas motor functions were preserved. Moreover, IS rats showed lower levels of learning-related c-Fos immunoreactivity, compared to controls, in the medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and nucleus accumbens shell. In addition, the IS group showed lower neuronal metabolic activity in the mPFC, VTA, and CA1 subfield of the hippocampus. These results indicate that twelve weeks of social isolation in adult rats leads to different behavioural and brain alterations, and they highlight the importance of social support, not only in development, but also in adulthood.

The role of long-term psychodynamic psychotherapy in improving attachment patterns, defense styles, and alexithymia in patients with depressive/anxiety disorders / O papel da psicoterapia psicodinâmica de longo prazo na melhora de padrões de apego, estilos de defesa e alexitimia em pacientes com transtornos depressivos e de ansiedade

Abstract Introduction Long-term psychodynamic psychotherapy (LTPP) emphasizes the centrality of intrapsychic and unconscious conflicts and their relation to development. Although there is evidence supporting the efficacy of LTPP in mental disorders, little research has been published on the efficacy of LTPP for depressive and anxiety disorders. Objective To examine whether patients with anxiety and depressive disorders demonstrate improvement in their attachment styles, defense styles, psychiatric symptoms, anxiety/depressive symptoms, and alexithymia with LTPP. Methods In this retrospective, descriptive study, the psychological outcomes of patients who were treated at the psychoanalytic clinic of Babol University of Medical Sciences were assessed. Fourteen patients diagnosed with depressive or anxiety disorder participated in the study of LTPP using the self-psychology approach. The Beck Depression Inventory II, Beck Anxiety Inventory, Adult Attachment Scale, 40-item Defense Style Questionnaire, and the 20-item Toronto Alexithymia Scale were administered at pre-treatment, post-treatment, and 6-month follow-up. Generalized estimating equations were used to analyze changes in psychological outcomes after each of the three assessments. Results The mean scores of depression and anxiety and secure attachment improved significantly after LTPP with self-psychology approach from baseline to post-treatment and follow-up. Also, the mean scores of neurotic and immature defenses, difficulty in identifying feelings, difficulty in describing feelings, externally oriented thinking, and total alexithymia scores decreased significantly from baseline to post-treatment and follow-up. Conclusion Symptoms of anxiety disorders, depressive disorders, insecure attachment styles, alexithymia, and neurotic/immature defense styles improved after the LTPP with self-psychology approach. Moreover, the improvements persisted at the 6-month follow-up.

Resumo Introdução A psicoterapia psicodinâmica de longo prazo (PPLP) enfatiza a centralidade dos conflitos intrapsíquicos e inconscientes e sua relação com o desenvolvimento. Apesar da evidência em favor da eficácia da PPLP em transtornos mentais, há poucos dados sobre a eficácia da PPLP em transtornos de depressão/ansiedade. Objetivo Examinar se pacientes com transtornos de depressão/ansiedade demonstram melhora em seus estilos de apego, estilos defensivos, sintomas psiquiátricos, sintomas de ansiedade/depressão e alexitimia com PPLP. Métodos Neste estudo retrospectivo, descritivo, os desfechos psicológicos de pacientes tratados na clínica psicanalítica da Babol University of Medical Sciences foram avaliados. Quatorze pacientes com diagnóstico de transtorno de depressão ou ansiedade participaram do estudo sobre PPLP com abordagem de psicologia do self. O Inventário de Depressão de Beck II, o Inventário de Ansiedade de Beck, a Escala de Apego do Adulto, o Questionário de Estilo de Defesa-40 e a Escala de Alexitimia de Toronto-20 foram administrados antes e após o tratamento e no seguimento de 6 meses. Equações de estimação generalizadas foram usadas para analisar mudanças nos desfechos psicológicos após cada avaliação. Resultados Os escores médios de depressão/ansiedade e apego seguro melhoraram significativamente após PPLP com abordagem de psicologia do self do início do estudo ao pós-tratamento e seguimento. Além disso, os escores médios de defesas neuróticas e imaturas, dificuldade em identificar sentimentos, dificuldade em descrever sentimentos, pensamentos orientados externamente e escores totais de alexitimia diminuíram significativamente do início do estudo ao pós-tratamento e seguimento. Conclusão Sintomas de transtornos de ansiedade, transtornos depressivos, estilos de apego inseguro, alexitimia e estilos de defesa neuróticos/imaturos melhoraram após PPLP com abordagem de psicologia do self. Além disso, as melhoras persistiram no seguimento de 6 meses.