Changes in brain glucose metabolism and connectivity in somatoform disorders: an 18F-FDG PET study.

Somatoform disorders (SFD) are defined as a syndrome characterized by somatic symptoms which cannot be explained by organic reasons. Chronic or recurrent forms of somatization lead to heavy emotional and financial burden to the patients and their families. However, the underlying etiology of SFD is largely unknown. The purpose of this study is to investigate the changed brain glucose metabolic pattern in SFD. In this study, 18 SFD patients and 21 matched healthy controls were enrolled and underwent an 18F-FDG PET scan. First, we explored the altered brain glucose metabolism in SFD. Then, we calculated the mean 18F-FDG uptake values for 90 AAL regions, and detected the changed brain metabolic connectivity between the most significantly changed regions and all other regions. In addition, the Pearson coefficients between the neuropsychological scores and regional brain 18F-FDG uptake values were computed for SFD patients. We found that SFD patients showed extensive hypometabolism in bilateral superolateral prefrontal cortex, insula, and regions in bilateral temporal gyrus, right angular gyrus, left gyrus rectus, right fusiform gyrus, right rolandic operculum and bilateral occipital gyrus. The metabolic connectivity between right insula and prefrontal areas, as well as within prefrontal areas was enhanced in SFD. And several brain regions were associated with the somatic symptoms, including insula, putamen, middle temporal gyrus, superior parietal gyrus and orbital part of inferior frontal gyrus. Our study revealed widespread alterations of the brain glucose metabolic pattern in SFD patients. Those findings might elucidate the neuronal mechanisms with glucose metabolism and shed light on the pathology of SFD.

Epigenetics-by-sex interaction for somatization conferred by methylation at the promoter region of SLC6A4 gene.

BACKGROUND: Depression, anxiety and somatoform disorders are all more prevalent in women than in men. However, specific biological mechanisms contributing to such sex differences remain unknown. Serotonergic pathways are involved in mood and behavior regulation and thus have been suggested to be altered in several psychiatric disorders. The serotonin transporter (SERT), encoded by SLC6A4 gene, has received major attention due to its crucial role in serotonergic transmission. METHODS: 148 monozygotic twin subjects were assessed for (i) lifetime categorical diagnosis of anxious-depressive disorders, following SCID-I-based DSM-IV criteria, and (ii) current psychiatric symptomatology, from a dimensional approach, by means of the Brief Symptom Inventory (BSI). SLC6A4 gene methylation was analyzed by means of Infinium HumanMethylation450 in a subset of the sample. CpG-specific methylation at the promoter region of SLC6A4 gene was further analyzed by means of pyrosequencing technology in the total sample. RESULTS: SLC6A4 methylation was found to be significantly higher in women when compared to men independent of DSM-IV diagnosis. SLC6A4 methylation was further associated with the BSI-derived somatization dimension. CONCLUSIONS: Female hypermethylation of a discrete region located within SLC6A4 promoter region could underlie differential SERT expression in women when compared to men and could be one of the causative mechanisms by which women exhibit increased prevalence of somatic symptoms.

Couvade Syndrome - Custom, Behavior or Disease?

The custom of Couvade and Couvade syndrome is a phenomenon observed since ancient times. Whether it constitutes a disease entity or it should be considered a ritual or custom remains a matter of debate. Historical transcripts shed light into the distinct origins and inclinations of couvade behaviors, some of them having religious inclinations. Currently, there are several views on this phenomenon including medical, psychoanalytic, and psychological. Some explain this syndrome as part of men's preparation and participation in pregnancy and post-partum period. Others see it as men rivalling with women for procreative ability or ability to carry an unborn child in the womb. There are a set of criteria that can be used in diagnosing Couvade syndrome, which may be helpful in standardizing clinical detection and management of patients. It is important to embed this syndrome in contemporary society to understand the complexity of male involvement in pregnancy and fatherhood, which at the end may not be a disease. In this review, the authors will guide the reader through history, possible etiologies, and clinical aspects of Couvade syndrome.

Evaluation of hair cortisol and cortisone change during pregnancy and the association with self-reported depression, somatization, and stress symptoms.

Hair cortisol levels are used to measure long-term stress, while its inactive metabolite cortisone is often not assessed. We measured hair cortisol concentrations (HCC) and hair cortisone concentrations (HCNC) via liquid chromatography quadrupole linear ion trap mass spectrometry (LC-MS3) in 62 pregnant women who participated in the LIFE CHILD STUDY in their 2nd and 3rd trimester between 12/2011 and 11/2014. Sociodemographic factors, pregnancy-related factors, and hair characteristics were assessed. Degree of severity of depression, somatization, and stress were evaluated in both trimesters with a self-reported Patient Health Questionnaire (PHQ). Multivariate regression analyses were conducted between HCC and potential influencing factors, as well as with subscales of the PHQ, with HCNC and with the ratio of HCNC to HCC. Spearman correlation coefficients were calculated between steroid concentrations and subscale scores of the PHQ, as well as between the log2-fold change in HCC and HCNC and the change in PHQ subscale scores. HCC increased 1.3-fold and HCNC increased 1.5-fold by the 3rd trimester. HCNC was more than three times higher than HCC in both trimesters. We found significant associations of PHQ subscores with HCNC. The PHQ depression score was negatively correlated with HCNC in the 2nd trimester (p < .05). The PHQ stress score change was negatively correlated with the fold change of HCNC (p < .05) and with the change in the ratio of HCNC to HCC (p < .001). Our study suggests an association of cortisol/cortisone metabolism with self-reported stress in the 2nd and 3rd trimester of pregnancy. Since associations with PHQ subscores were only found with cortisone or the ratio of cortisone to cortisol, but not with cortisol alone, both cortisone and cortisol should be used as a marker for stress in pregnant woman.

Increased Glutamate in Somatosensory Cortex in Functional Dyspepsia.

Functional Dyspepsia-Post-prandial Distress Syndrome (FD-PDS) was associated with mood-related increases in resting activity and lowered activation threshold in the somatosensory cortex (SSC), insula and perigenual anterior cingulate cortex(pgACC) in functional imaging studies. The underlying cortical neurochemical changes are unknown. We performed proton Magnetic Resonance Spectroscopy (1H-MRS) on 17 consecutive tertiary clinic-recruited psychotropic-naïve Rome III FD-PDS female and 17 age-sex matched healthy controls. Voxels were placed on bilateral pgACC, left insula and SSC. Water-suppressed spectra were acquired using PRESS with short echo time (TE) (T = 24 ms) to separately quantify glutamate (Glu) and glutamine (Gln). Main outcome measure was regional Glu/Cr + PCr. Severity of depression, anxiety, somatization, and dyspepsia were also assessed. We found significantly increased SSC Glu/Cr + PCr in FD-PDS subjects compared to controls. SSC Glu/Cr + PCr correlated significantly with postprandial distress chronicity, dyspeptic symptoms severity and anxiety. The SSC Glu/Cr + PCr - dyspepsia correlations became insignificant after controlling for anxiety but were independent of depression. Gln/Glu ratio, which indicates glial Glu cycling failure, was unchanged. No between-group differences were noted in other regional metabolite concentrations. Our findings suggested enhanced SSC glutamate transmission in FD-PDS that was linked to post-prandial distress chronicity and severity and anxiety.

Saliva amylase as a measure of sympathetic change elicited by autogenic training in patients with functional somatic syndromes.

The aim of this study was to discuss the effect of autogenic training (AT) on patients with functional somatic syndrome (FSS) using salivary amylase, the skin temperature of the finger, subjective severity of symptoms, and psychological characteristics as measures. We assessed 20 patients with FSS and 23 healthy controls before and after AT. Baseline levels of salivary amylase prior to an AT session were significantly higher in the FSS group than in the control group. However, this difference was not significant after AT. The skin temperature of the finger increased after AT in both the FSS and control groups. AT contributed to the improvement of somatic symptoms in patients with FSS. Our results regarding psychological characteristics suggest that mood disturbances are deeply involved in the pathology of FSS. Individuals with FSS exhibited elevated levels of sympathetic activity compared with healthy controls. Our data indicates that AT eased dysregulation of the autonomic nervous system in patients with FSS. Thus, salivary amylase may be a useful index of change induced by AT in patients with FSS.

Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome.

OBJECTIVE: Somatization is a symptom cluster characterized by 'psychosomatic' symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of 'psychosomatic' symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms. METHOD: This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune (CMI). RESULTS: The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc. CONCLUSION: Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.

Somatization severity associated with postero-medial complex structures.

Somatisation is a frequent problem in various psychiatric disorders, yet the cerebral mechanisms of somatisation remain unexamined. To test if somatisation is susceptible to emotional states, we investigated relationships between somatisation severity, neural effective connectivity, and autonomic responses to emotional facial expressions. Volunteering participants (N = 20) were presented with facial expressions of happy and sad emotion at three intensity levels (0%-50%-100%) in a fast implicit ER-fMRI design with concurrent derivation of skin conductance levels (SCL). Self-reported somatisation severity as assessed with Rief's SOMS-2 index was correlated with neural response controlling for other clinical traits to ascertain brain bases of somatisation. Regression analyses estimated effective connectivity of main clusters so determined with peripheral autonomic responses. Regions in which magnitude of activity correlated with somatisation severity consisted in both happy and sad conditions of the anterior ventral precuneus (BA7), along with posterior cingulate gyrus (PCC, BA23, sad condition) and anteromedial thalamus (happy condition).

Increased soluble interleukin-2 receptor levels are related to somatic but not to cognitive-affective features in major depression.

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.

Brain dysfunction in fibromyalgia and somatization disorder using proton magnetic resonance spectroscopy: a controlled study.

OBJECTIVE: To evaluate the brain metabolite patterns in patients with fibromyalgia (FM) and somatization disorder (STD) compared with healthy controls through spectroscopy techniques and correlate these patterns with psychological variables. METHOD: Design. Controlled, cross-sectional study. Sample. Patients were recruited from primary care in Zaragoza, Spain. The control group was recruited from hospital staff. Patients were administered questionnaires on pain catastrophizing, anxiety, depression, pain, quality of life, and cognitive impairment. All patients underwent Magnetic Resonance Imaging and magnetic resonance spectroscopy (MRS). RESULTS: A significant increase was found in the glutamate + glutamine (Glx) levels in the posterior cingulate cortex (PCC): 10.73 (SD: 0.49) for FM and 9.67 (SD: 1.10) for STD 9.54 (SD: 1.46) compared with controls (P = 0.043). In the FM + STD group, a correlation between Glx and pain catastrophizing in PCC (r = 0.397; P = 0.033) and between quality of life and the myo-inositol/creatine ratio in the left hippocampus (r = -0.500; P = 0.025) was found. To conclude Glutamate seems to be relevant in the molecular processes involved in FM and STD. It also opens the door for Proton MRS ((1) H-MRS) in STD and suggests that reducing glutamatergic activity through pharmacological treatment could improve the outcome of patients with FM and STD. CONCLUSION: Glutamate seems to be relevant in the molecular processes involved in FM and STD. It also opens the door for Proton MRS ((1) H-MRS) in STD and suggests that reducing glutamatergic activity through pharmacological treatment could improve the outcome of patients with FM and STD.

Symptom-specific associations between low cortisol responses and functional somatic symptoms: the TRAILS study.

BACKGROUND: Functional somatic symptoms (FSS), like chronic pain and overtiredness, are often assumed to be stress-related. Altered levels of the stress hormone cortisol could explain the association between stress and somatic complaints. We hypothesized that low cortisol levels after awakening and low cortisol levels during stress are differentially associated with specific FSS. METHODS: This study is performed in a subsample of TRAILS (Tracking Adolescents' Individual Lives Survey) consisting of 715 adolescents (mean age: 16.1 years, SD=0.6, 51.3% girls). Adolescents' cortisol levels after awakening and during a social stress task were assessed. The area under the curve with respect to the ground (AUCg) and the area under the curve above the baseline (AUCab) were calculated for these cortisol levels. FSS were measured using the Youth Self-Report and pain questions. Based upon a factor analysis, FSS were divided into two clusters, one consisting of headache and gastrointestinal symptoms and the other consisting of overtiredness, dizziness and musculoskeletal pain. RESULTS: Regression analyses revealed that the cluster of headache and gastrointestinal symptoms was associated with a low AUCg of cortisol levels during stress (ß=-.09, p=.03) and the cluster of overtiredness, dizziness and musculoskeletal pain with a low AUCg of cortisol levels after awakening (ß=-.15, p=.008). All these analyses were adjusted for the potential confounders smoking, physical activity level, depression, corticosteroid use, oral contraceptive use, gender, body mass index and, if applicable, awakening time. CONCLUSION: Two clusters of FSS are differentially associated with the stress hormone cortisol.

Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7.

BACKGROUND: Sodium channel NaV1.7 is preferentially expressed within dorsal root ganglia (DRG), trigeminal ganglia and sympathetic ganglion neurons and their fine-diamter axons, where it acts as a threshold channel, amplifying stimuli such as generator potentials in nociceptors. Gain-of-function mutations and variants (single amino acid substitutions) of NaV1.7 have been linked to three pain syndromes: Inherited Erythromelalgia (IEM), Paroxysmal Extreme Pain Disorder (PEPD), and Small Fiber Neuropathy (SFN). IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling, and is caused by mutations that hyperpolarize activation, slow deactivation, and enhance the channel ramp response. PEPD is characterized by perirectal, periocular or perimandibular pain, often triggered by defecation or lower body stimulation, and is caused by mutations that severely impair fast-inactivation. SFN presents a clinical picture dominated by neuropathic pain and autonomic symptoms; gain-of-function variants have been reported to be present in approximately 30% of patients with biopsy-confirmed idiopathic SFN, and functional testing has shown altered fast-inactivation, slow-inactivation or resurgent current. In this paper we describe three patients who house the NaV1.7/I228M variant. METHODS: We have used clinical assessment of patients, quantitative sensory testing and skin biopsy to study these patients, including two siblings in one family, in whom genomic screening demonstrated the I228M NaV1.7 variant. Electrophysiology (voltage-clamp and current-clamp) was used to test functional effects of the variant channel. RESULTS: We report three different clinical presentations of the I228M NaV1.7 variant: presentation with severe facial pain, presentation with distal (feet, hands) pain, and presentation with scalp discomfort in three patients housing this NaV1.7 variant, two of which are from a single family. We also demonstrate that the NaV1.7/I228M variant impairs slow-inactivation, and produces hyperexcitability in both trigeminal ganglion and DRG neurons. CONCLUSION: Our results demonstrate intra- and interfamily phenotypic diversity in pain syndromes produced by a gain-of-function variant of NaV1.7.

Posttraumatic oxytocin dysregulation: is it a link among posttraumatic self disorders, posttraumatic stress disorder, and pelvic visceral dysregulation conditions in women?

This article explicates a theory that oxytocin, a sexually dimorphic neurotransmitter and paracrine hormone, is a plausible mechanism linking early relational trauma with posttraumatic self disorders (e.g., dissociation, somatization, and interpersonal sensitivity), posttraumatic stress disorder, and pelvic visceral dysregulation disorders (e.g., irritable bowel syndrome, chronic pelvic pain, interstitial cystitis, and hyperemesis gravidarum). This posttraumatic oxytocin dysregulation disorders theory is consistent with the historical and contemporary literature. It integrates attention to psychological and physical comorbidities and could account for the increased incidence of these disorders among females. Specific propositions are explored in data from studies of traumatic stress and women's health.

Perceived symptoms of psychological distress and salivary cortisol levels in young women with muscular or disk-related temporomandibular disorders.

OBJECTIVE: To assess any differences in psychological and endocrine variables between homogeneous core groups of young women with well-defined muscle- or disk-related temporomandibular disorders (TMDs) and matched controls. MATERIAL AND METHODS: Fifteen women, aged 18-24 years, fulfilling the TMD Research Diagnostic Criteria I a/b (but not II or III) and 15 fulfilling the II a/b and III criteria were consecutively selected from referrals to an orofacial pain/TMD clinic. Thirty consecutive healthy age-matched women attending yearly routine check-ups at a general dental clinic served as controls. All 60 subjects answered a questionnaire, the Profile of Fatigue Related Symptoms (PFRS), and salivary samples on waking were collected for analysis of cortisol levels. RESULTS: Symptom duration and pain levels were similar irrespective of muscle- or disk-related symptoms. Both diagnostic groups obtained scores that were similar and significantly higher than those of controls in all four scales of the PFRS: fatigue, emotional distress, cognitive difficulties and somatic symptoms. Salivary cortisol levels on waking did not differ between patients and controls. CONCLUSIONS: Patients with TMDs, irrespective of diagnosis, appeared to be more psychologically distressed than controls evaluated psychometrically, which is in line with earlier findings. A corresponding difference was not reflected in a single measurement of morning salivary cortisol. A more comprehensive evaluation of endocrine variables is probably necessary to reveal whether any differences actually exist in this respect.

Role of the oestrogen receptors GPR30 and ERalpha in peripheral sensitization: relevance to trigeminal pain disorders in women.

Oestrogen increases facial allodynia through its actions on activation of the MAPK extracellular-signal regulated kinase (ERK) in trigeminal ganglion neurons. This goal of study was to determine which oestrogen receptor is required for behavioural sensitization. Immunohistochemical studies demonstrated the presence of oestrogen receptor alpha (ERalpha) in nuclei of larger neurons and cytoplasm of smaller neurons, and the novel oestrogen receptor G-protein coupled receptor 30 (GPR30) in small diameter neurons that also contained peripherin, a marker of unmyelinated C-fibres. Specific agonists for ERalpha (PPT) and GPR30 (G-1), but not ERbeta (DPN), activated ERK in trigeminal ganglion neurons in vitro. Both G-1 and PPT treatment increased allodynia after CFA injections into the masseter of ovariectomized Sprague-Dawley rats. Treatment with oestrogen increased expression of ERalpha but not GPR30, while masseter inflammation increased GRP30 but not ERalpha. Differential modulation of these ERK-coupled receptors by oestrogen and inflammation may play a role in painful episodes of temporomandibular disorder and migraine.

The relationship between alexithymia and salivary cortisol levels in somatoform disorders.

The purpose of this study was to investigate cortisol levels as a function of the hypothalamic-pituitary-adrenal axis (HPA) in relation to alexithymia in patients with somatoform disorders (SFD). Diurnal salivary cortisol was sampled in 32 patients with SFD who also underwent a psychiatric examination and filled in questionnaires (Toronto Alexithymia Scale, TAS scale; Screening for Somatoform Symptoms, SOMS scale; Hamilton Depression Scale, HAMD). The mean TAS total score in the sample was 55.6+/-9.6, 32% of patients being classified as alexithymic on the basis of their TAS scores. Depression scores were moderate (HAMD=13.2, Beck Depression Inventory, BDI=16.5). The patients' alexithymia scores (TAS scale "Difficulty identifying feelings") correlated significantly positively with their somatization scale scores (Symptom Checklist-90 Revised, SCL-90-R); r=0.3438 (P<0.05) and their scores on the Global Severity Index (GSI) on the SCL-90-R; r=0.781 (P<0.01). Regression analysis was performed with cortisol variables as the dependent variables. Cortisol levels [measured by the area under the curve-ground (AUC-G), area under the curve-increase (AUC-I) and morning cortisol (MCS)] were best predicted in a multiple linear regression model by lower depressive scores (HAMD) and more psychopathological symptoms (SCL-90-R). No significant correlations were found between the patients' alexithymia scores (TAS) and cortisol levels. The healthy control group (n=25) demonstrated significantly higher cortisol levels than did the patients with SFD; in both tests P<0.001 for AUC-G and AUC-I. However, the two groups did not differ in terms of their mean morning cortisol levels (P>0.05). The results suggest that pre-existing hypocortisolism might possibly be associated with SFD.