Proof of mechanism investigation of Transcutaneous auricular vagus nerve stimulation through simultaneous measurement of autonomic functions: a randomized controlled trial protocol.

BACKGROUND: The autonomic nervous system plays a vital role in regulating physiological functions. Transcutaneous auricular vagus nerve stimulation (taVNS) is a method that provides insights into autonomic nerve modulation. This paper presents a research protocol investigating proof of mechanism for the impact of taVNS on autonomic functions and aims to both deepen theoretical understanding and pave the way for clinically relevant applications. METHODS: This protocol employs a single-blind, randomized cross-over design involving 10 healthy male participants. Simultaneous assessment of both the afferent and efferent aspects of the vagus nerve will be performed by integrating physiological measures, magnetic resonance imaging, and a questionnaire survey. Electrocardiogram will be measured to assess changes in heart rate, as a primary outcome, and heart rate variability. Active taVNS and sham stimulation will be compared, which ensures precision and blinding. Electrical stimulation will be applied to the left concha cymba and the left lobule for the active and sham conditions, respectively. The specific parameters of taVNS involve a pulse width of 250 µs, a frequency of 25 Hz, and a current adjusted to the perception threshold (0.1 mA ≤ 5 mA), delivered in cycles of 32 s on and 28 s off. CONCLUSIONS: This research investigates proof of mechanism for taVNS to elucidate its modulatory effects on the central and peripheral components of the autonomic nervous system. Beyond theoretical insights, the findings will provide a foundation for designing targeted neuromodulation strategies, potentially benefiting diverse patient populations experiencing autonomic dysregulation. By elucidating the neural mechanisms, this study contributes to the evolution of personalized and effective clinical interventions in the field of neuromodulation. TRIAL REGISTRATION: JRCT, jRCTs032220332, Registered 13 September 2022; https://jrct.niph.go.jp/latest-detail/jRCTs032220332 .

Comprehensive elucidation of resting-state functional connectivity in anorexia nervosa by a multicenter cross-sectional study.

BACKGROUND: Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs). METHODS: We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons. RESULTS: Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus (p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type (p < 0.01, FDR correction). CONCLUSION: Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.

Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Endogenous oxytocin levels in extracted saliva elevates during breastfeeding correlated with lower postpartum anxiety in primiparous mothers.

BACKGROUND: Breastfeeding in the early postpartum period is expected to have mental benefits for mothers; however, the underlying psychobiological mechanisms remain unclear. Previously, we hypothesized that the release of oxytocin in response to the suckling stimuli during breastfeeding would mediate a calming effect on primiparous mothers, and we examined salivary oxytocin measurements in primiparous mothers at postpartum day 4 using saliva samples without extraction, which was erroneous. Thus, further confirmation of this hypothesis with a precise methodology was needed. METHODS: We collected saliva samples at three time points (baseline, feeding, and post-feeding) to measure oxytocin in 24 primiparous mothers on postpartum day 2 (PD2) and 4 (PD4) across the breastfeeding cycle. Salivary oxytocin levels using both extracted and unextracted methods were measured and compared to determine the qualitative differences. State and trait anxiety and clinical demographics were evaluated to determine their association with oxytocin changes. RESULTS: Breastfeeding elevated salivary oxytocin levels; however, it was not detected to a significant increase in the extraction method at PD4. We found a weak but significant positive correlation between changes in extracted and unextracted oxytocin levels during breastfeeding (feeding minus baseline); there were no other significant positive correlations. Therefore, we used the extracted measurement index for subsequent analysis. We showed that the greater the increase in oxytocin during breastfeeding, the lower the state anxiety, but not trait anxiety. Mothers who exclusively breastfed at the 1-month follow-up tended to be associated with slightly higher oxytocin change at PD2 than those who did not. CONCLUSIONS: Breastfeeding in early postpartum days could be accompanied by the frequent release of oxytocin and lower state anxiety, potentially contributing to exclusive breastfeeding.

Eating Disorder Neuroimaging Initiative (EDNI): a multicentre prospective cohort study protocol for elucidating the neural effects of cognitive-behavioural therapy for eating disorders.

INTRODUCTION: Anorexia nervosa is a refractory psychiatric disorder with a mortality rate of 5.9% and standardised mortality ratio of 5.35, which is much higher than other psychiatric disorders. The standardised mortality ratio of bulimia nervosa is 1.49; however, it is characterised by suicidality resulting in a shorter time to death. While there is no current validated drug treatment for eating disorders in Japan, cognitive-behavioural therapy (CBT) is a well-established and commonly used treatment. CBT is also recommended in the Japanese Guidelines for the Treatment of Eating Disorders (2012) and has been covered by insurance since 2018. However, the neural mechanisms responsible for the effect of CBT have not been elucidated, and the use of biomarkers such as neuroimaging data would be beneficial. METHODS AND ANALYSIS: The Eating Disorder Neuroimaging Initiative is a multisite prospective cohort study. We will longitudinally collect data from 72 patients with eating disorders (anorexia nervosa and bulimia nervosa) and 70 controls. Data will be collected at baseline, after 21-41 sessions of CBT and 12 months later. We will assess longitudinal changes in neural circuit function, clinical data, gene expression and psychological measures by therapeutic intervention and analyse the relationship among them using machine learning methods. ETHICS AND DISSEMINATION: The study was approved by The Ethical Committee of the National Center of Neurology and Psychiatry (A2019-072). We will obtain written informed consent from all patients who participate in the study after they had been fully informed about the study protocol. All imaging, demographic and clinical data are shared between the participating sites and will be made publicly available in 2024. TRIAL REGISTRATION NUMBER: UMIN000039841.

Oxytocin Mediates a Calming Effect on Postpartum Mood in Primiparous Mothers.

OBJECTIVES: The current study sought to characterize changes in salivary oxytocin (OT) secretion patterns across the breastfeeding cycle, and to evaluate whether breastfeeding has a positive effect on mood disturbances related to postpartum depression, via endogenous OT release. MATERIALS AND METHODS: Twenty-four primiparous mothers who delivered vaginally at term and were exclusively breastfeeding were examined 4-5 days postpartum. Salivary OT was measured using enzyme immunoassays at 30 minutes before breastfeeding (baseline), during breastfeeding (feeding), and 30 minutes after completing breastfeeding (postfeeding). In addition, maternal mood changes were evaluated at baseline and postfeeding using the Profile of Mood States (POMS) questionnaire. RESULTS: OT levels rose significantly during feeding (pcorr < .05) and postfeeding (pcorr < 0.05), compared with baseline. POMS scores for Tension-Anxiety were decreased postfeeding compared with baseline (p < 0.001). This decrease was significantly associated with increased OT (feeding minus baseline: r = -0.52, rpart = -0.51, postfeeding minus baseline: r = -0.53, rpart = -0.52, ps < 0.05). POMS scores for Fatigue and Confusion also decreased, while Vigor significantly increased. Significant correlations were found between Fatigue decreases and OT increases (feeding minus baseline: r = -0.48, rpart = -0.53, postfeeding minus baseline: rpart = -0.60, ps < 0.05). This result partially contradicted with the finding of no correlation between increased Vigor and increased OT. CONCLUSIONS: OT is released across the breastfeeding cycle and can be detected with salivary measurement. This OT release exhibited a temporary anxiolytic-like calming effect on postpartum maternal mood disturbances.

Genetic variants in oxytocin receptor and arginine-vasopressin receptor 1A are associated with the neural correlates of maternal and paternal affection towards their child.

There is extensive evidence in animal studies, particularly in vole species (Microtus), that oxytocin (OT) receptor and arginine-vasopressin (AVP) receptor 1a is critical for the regulation of maternal and paternal behavior, respectively. Human studies have gained insight into the relationship between both hormone receptor gene variants and behavior, but not between the variants and the underlying brain activity. To study this, we investigated the association between neural activation of the anterior prefrontal cortex (APFC) in mothers and fathers in response to their child smiling video stimuli to induce the positive affect related to attachment with their child, and genetic variants of OT receptor (OXTR) and AVP receptor 1A (AVPR1A). Overall, 43 mothers and 41 fathers participated, and each parent's child smiling was video recorded. Participants were then genotyped and underwent near-infrared spectroscopy to measure neural activation of the APFC while observing their own child smiling compared with an unfamiliar child. We found that the right inferior APFC was activated in response to child video stimuli in mothers and differential hemispheric activation of the inferior APFC in OXTR rs2254298-G/G mothers compared with -A carrier mothers, but not in fathers. Furthermore, we found a difference in the left inferior APFC activation between AVPR1A RS3-non-334 and -334 carrier fathers, but not mothers. Our results indicate a sex-dependent association between the genetic variants and the inferior APFC activations of maternal and paternal positive affect, analogous to the results reported in voles.

Developmental changes in the neural responses to own and unfamiliar mother's smiling face throughout puberty.

An attachment relationship between boys and their mother is important for subsequent development of the ability to sustain peer relationships. Affective responses to attachment figure, especially mother, is supposed to change drastically during puberty. To elucidate the neural correlates underlying this behavioral change, we compared the neural response of boys at three different developmental stages throughout puberty to visual image of their own mothers. Subjects included 27 pre-puberty boys (9.0 ± 0.6 years), 31 middle puberty boys (13.5 ± 1.2 years), and 27 post-puberty boys (20.8 ± 1.9 years), and their mother's smile was video recorded. We measured their neural response in the anterior part of the prefrontal cortex (APFC) to their own mother's smile compared with an unfamiliar-mother's. We found that in response to their own mother's smiling, the right inferior and medial part of the APFC (Ch6) was activated in the pre-puberty group. By contrast, the left inferior and medial (Ch4) and superior (Ch2 and Ch5) APFC were activated in the middle-puberty group, which is presumably linked to empathic feelings fostered by memories of mutual experience with own mother. These findings suggest that different patterns of APFC activation are associated with qualitative changes in affective response to own mother around puberty.

I love my grandkid! An NIRS study of grandmaternal love in Japan.

Grandmaternal love is essential for the grandmother­grandchild attachment relationship and thus aids an infant's development and mental health, but the underlying neural mechanism is unknown. Recent studies have shed light on involvement of the prefrontal cortex (PFC) in maternal and romantic love. Here, we investigated the involvement of the PFC in grandmaternal love by examining cerebral hemoglobin concentration changes using near-infrared spectroscopy (NIRS). Seventeen grandmothers viewed video clips which included their own or other's (unknown) grandchild smiling or showing a neutral expression while the oxy-hemoglobin (oxy-Hb) concentration was measured from the anterior prefrontal cortex (APFC). The sight of one's own grandchild activated the inferior and medial APFC irrespective of their expression. In addition, the sight of the smiling grandchild induced an increased activation in the medial APFC involved in reward monitoring and mentalizing and an additional activation in the superior APFC involved in cognitive and attentional control. Both medial and superior activations significantly correlated with emotional mood rating. These findings indicate that the different regions of the APFC are involved in grandmaternal love.

Perceived parental rejection mediates the influence of serotonin transporter gene (5-HTTLPR) polymorphisms on impulsivity in Japanese adults.

This study examined (1) the interrelationships among 5-HTTLPR genotype, perceived parental rejection, and impulsivity, and (2) meditational models in which perceived paternal/maternal rejection mediates the relationship between the 5-HTTLPR genotype and impulsive behaviour. Participants included 403 adults (152 males and 252 females, mean age = 24.20) who provided genetic data and a set of the questionnaires (BIS11; Barratt Impulsiveness Scale-11 and EMBU; Egna Minnen av Bätraffande Uppfostran). Using SEM (Structural Equation Modeling), we evaluated 3 models for both direct and indirect relationships between 5-HTTLPR (5HTT) and Impulsivity (IMP), via maternal/fraternal rejection (MAT/FAT). In model 1, the direct path from 5HTT and IMP was not significant across the mother's and father's analysis. Models 2 and 3 assessed the indirect influence of 5HTT on IMP through MOT/FAT. The paths of models 2 and 3 were all significant and showed a good fit between the hypothesized model and data. Furthermore, the effects of the 5-HTTLPR genotype on impulsiveness in this Japanese sample were particularly accounted for by perceived rejection from the mother or father. The effects from the parents appeared to be robust especially among males. These results may help elucidate the specific pathways of risk in relation to genetic and environment influences on impulsive phenotypes.