A healthy dietary pattern is associated with microbiota diversity in recently diagnosed bipolar patients: The Bipolar Netherlands Cohort (BINCO) study.

BACKGROUND: Diet largely impacts the gut microbiota, and may affect mental and somatic health via the gut-brain axis. As such, the relationship between diet and the microbiota in Bipolar Disorder (BD) could be of importance, but has not been studied before. The aim was therefore to assess whether dietary quality is associated with the gut microbiota diversity in patients with recently diagnosed BD, and whether changes occur in dietary quality and microbiota diversity during their first year of treatment. METHODS: Seventy recently (<1 year) diagnosed patients with BD were included in the "Bipolar Netherlands Cohort" (BINCO), and a total of 45 participants were assessed after one year. A 203-item Food Frequency Questionnaire (FFQ) data yielded the Dutch Healthy index (DHD-15), and the microbiota composition and diversity of fecal samples were characterized by 16S rRNA gene amplicon sequencing at baseline and 1-year follow-up. Associations and changes over time were analyzed using multivariate regression analyses and t-tests for paired samples. RESULTS: Included patients had a mean age of 34.9 years (SD ± 11.2), and 58.6 % was female. Alpha diversity (Shannon diversity index), richness (Chao1 index) and evenness (Pielou's Evenness Index) were positively associated with the DHD-15 total score, after adjustment for sex, age and educational level (beta = 0.55; P < 0.001, beta = 0.39; P = 0.024, beta = 0.54; P = 0.001 respectively). The positive correlations were largely driven by the combined positive effect of fish, beans, fruits and nuts, and inverse correlations with alcohol and processed meats. No significant changes were found in DHD-15 total score, nor in microbiota diversity, richness and evenness indexes during one year follow-up and regular treatment. CONCLUSION: A healthy and varied diet is associated with the diversity of the microbiota in BD patients. Its potential consequences for maintaining mood stability and overall health should be studied further.

Dynamic time warp analysis of individual symptom trajectories in individuals with bipolar disorder.

BACKGROUND: Manic and depressive mood states in bipolar disorder (BD) may emerge from the non-linear relations between constantly changing mood symptoms exhibited as a complex dynamic system. Dynamic Time Warp (DTW) is an algorithm that may capture symptom interactions from panel data with sparse observations over time. METHODS: The Young Mania Rating Scale and Quick Inventory of Depressive Symptomatology were repeatedly assessed in 141 individuals with BD, with on average 5.5 assessments per subject every 3-6 months. Dynamic Time Warp calculated the distance between each of the 27 × 27 pairs of standardized symptom scores. The changing profile of standardized symptom scores of BD participants was analyzed in individual subjects, yielding symptom dimensions in aggregated group-level analyses. Using an asymmetric time-window, symptom changes that preceded other symptom changes (i.e., Granger causality) yielded a directed network. RESULTS: The mean age of the BD participants was 40.1 (SD 13.5) years old, and 60% were female participants. Idiographic symptom networks were highly variable between subjects. Yet, nomothetic analyses showed five symptom dimensions: core (hypo)mania (6 items), dysphoric mania (5 items), lethargy (7 items), somatic/suicidality (6 items), and sleep (3 items). Symptoms of the "Lethargy" dimension showed the highest out-strength, and its changes preceded those of "somatic/suicidality," while changes in "core (hypo)mania" preceded those of "dysphoric mania." CONCLUSION: Dynamic Time Warp may help to capture meaningful BD symptom interactions from panel data with sparse observations. It may increase insight into the temporal dynamics of symptoms, as those with high out-strength (rather than high in-strength) could be promising targets for intervention.

Personality traits and the risk of incident (hypo)mania among subjects initially suffering from depressive and anxiety disorders in a 9-year cohort study.

BACKGROUND: Bipolar disorder (BD) is characterized by the alternating occurrence of (hypo)manic and depressive episodes. The aim of the current study was to determine whether personality traits independently predicted the subsequent development of (hypo)manic episodes within a group of patients who were initially diagnosed with depressive and anxiety disorders. METHODS: The Netherlands Study of Depression and Anxiety is a cohort study with measurements taken at baseline and at 2-, 4-, 6-, and 9-year follow-up. Development of a (hypo)manic episode during follow-up was assessed with the Composite International Diagnostic Interview and (hypo)manic symptoms were evaluated with the Mood Disorder Questionnaire. The Big Five personality traits were the independent variables in multivariable Cox regression analyses. RESULTS: There were 31 incident cases of (hypo)manic episodes (n = 1888, mean age 42.5 years, 68.3% women), and 233 incident cases of (hypo)manic symptoms (n = 1319, mean age 43.1, 71.9% women). In multivariable analyses, low agreeableness was independently associated with an increased risk of developing a (hypo)manic episode, with a hazard ratio (HR) of 0.54 (p = 0.002, 95% CI [0.37, 0.78]). This finding was consistent with the development of (hypo)manic symptoms (HR 0.77, p = 0.001, 95% CI [0.66, 0.89]). LIMITATIONS: The 2-year lag-time analysis reduced the number of participants at risk of a (hypo)manic episode. CONCLUSIONS: We conclude that low agreeableness is a personality-related risk factor for incident (hypo)mania among subjects initially suffering from depressive and anxiety disorders. Increased attention to personality deviances could help to recognize BD at an early stage.

Anatomical demonstration of the suprachiasmatic nucleus-pineal pathway.

A polysynaptic pathway is proposed to transmit light information from the retina through the suprachiasmatic nucleus of the hypothalamus (SCN) to the pineal. In the present study, the powerful transneuronal tracer, pseudorabies virus (PRV), was used to provide a detailed description of this pathway. PRV injected into the pineal subsequently labeled the superior cervical ganglion, the intermediolateral column of the upper thoracic cord, the autonomic division of the paraventricular nucleus of the hypothalamus (PVN), and the SCN. Neurons in the autonomic division of the PVN were the only PRV-labeled neurons in the hypothalamus shown to receive input from the SCN as demonstrated by the presence of vasoactive intestinal polypeptide axonal contacts. This observation concurred with the presence of ventrally placed neurons in the SCN that could only be observed a day after the appearance of PVN-labeled neurons. Nevertheless the majority of the neurons were found in the dorsomedial position of the SCN, associated with the vasopressin-containing population of SCN neurons. Confocal laser scanning microscopy showed double-labeled neurons containing PRV and vasopressin or PRV and vasoactive intestinal polypeptide. Specificity of tracing was also established by prior removal of the superior cervical ganglion, resulting in a complete absence of the tracer but in the pineal. Thus, the present study provides the anatomical basis for circadian control of melatonin secretion.

Effect of NMDA receptor antagonist MK-801 on light-induced Fos expression in the suprachiasmatic nuclei and on melatonin production in the Syrian hamster.

In mammals, circadian rhythms generated by the suprachiasmatic nuclei (SCN) are daily synchronized by a light-dark cycle. Photic information is transmitted to the SCN mainly through the direct retinohypothalamic tract, the neurotransmitters involved being excitatory amino acids. It is also commonly accepted that photoperiodic information coming from the retina via the SCN is transduced by the pineal into a nocturnal signal, i.e. melatonin production. Light exposure at night induces (1) an inhibition of melatonin synthesis and (2) an expression of c-fos in numerous cells of SCN. To determine the role of the NMDA receptor in these effects, we treated Syrian hamsters with ip injections of MK-801, a noncompetitive NMDA receptor antagonist. Several subpopulations of light-sensitive cells in the SCN are affected by MK-801. According to previous studies, MK-801 inhibits light-induced Fos immunoreactivity mainly in the most ventral part of the SCN. However, we observed that numerous other cells are still activated by light. When light is applied in the middle of the night, MK-801 pretreatment does not reduce Fos-ir in the dorsal SCN. At the beginning of the night, labeled cells in this part of the nucleus appear even more numerous after MK-801. We also found that MK-801 fails to reduce the light-induced inhibition of melatonin synthesis. Moreover, in control animals, which received no light stimulation, ip injection of MK-801 induces by itself a dose-dependent inhibition of melatonin production.

Oxytocin innervation of spinal preganglionic neurons projecting to the superior cervical ganglion in the rat.

The paraventricular nucleus of the hypothalamus is a major integrative nucleus for relaying information from the suprachiasmatic nucleus to the autonomic system. The precise pathway by which this information can influence autonomic functions, such as melatonin synthesis in the pineal gland, is not clear. In the present study, we used a retrograde tracer injected in the superior cervical ganglion to identify spinal preganglionic neurons. One of the main neurotransmitters present in descending projections of the paraventricular nucleus of the hypothalamus, oxytocin, was detected with immunocytochemistry to visualise possible contacts with the neurons located in the intermediolateral column of the spinal cord and projecting to the superior cervical ganglion. Although many appositions could be seen at the light-microscopic level, this abundance could not be confirmed at the electron-microscopic level. The implications of these observations for the overall timing message received by the spinal preganglionic neurons are discussed.

Direct vasoactive intestinal polypeptide-containing projection from the suprachiasmatic nucleus to spinal projecting hypothalamic paraventricular neurons.

In mammals, photoperiodic information is conveyed from the retina to the pineal through a polysynaptic pathway, which includes the suprachiasmatic nucleus (SCN), the paraventricular nucleus of the hypothalamus (PVN), the spinal preganglionic neurons and, finally, the superior cervical ganglion. Precise data on the site in the PVN or which SCN transmitters are involved in the transmission of information in this pathway is lacking. In the present experiment we investigated whether SCN efferents containing vasoactive intestinal polypeptide (VIP) innervate PVN neurons that project to the spinal cord. A combination of retrograde tracing and immunocytochemistry with the aid of a confocal laser scanning microscope allowed us to assess possible interaction of SCN efferents and spinal cord projecting neurons in the PVN. Approximately 30% of identified autonomic projecting neurons in the dorsal PVN and 40% in the ventral PVN received VIP innervation mainly on their dendrites. These results provide further evidence for the involvement of SCN-derived VIP in the transmission of circadian information to the pineal.

In Syrian and European hamsters, the duration of sensitive phase to light of the suprachiasmatic nuclei depends on the photoperiod.

Light induction of the expression of Fos protein in the suprachiasmatic nuclei was used to investigate the photosensitive state of the clock in Syrian and European hamster kept under different photoperiods. We observed that the duration of the photosensitive phase is variable and tied to the length of the night. A maximal extension has been determined in both species studied. Finally, a 4 h lengthening of the phase of photosensitivity take approximately 3 weeks, while 3 days only are needed for its shortening.

Time course of neuronal sensitivity to light in the circadian timing system of the golden hamster.

The mammalian suprachiasmatic nuclei of the hypothalamus (SCN) have been identified as containing the pacemaker for circadian rhythms. Photic stimulation is known to induce the expression of the immediate early gene c-fos in the SCN of rodents during the subjective night. In order to determine the exact time course of the light sensitivity in the different cell subgroups of the SCN, we have investigated the effect of a light pulse every hour of the subjective night in golden hamsters kept in constant darkness for 3 days. Three neuronal populations inside and outside the SCN have been identified as sensitive to light at different times of the subjective night. These findings indicate (1) that there are neurons outside the SCN that are activated by light which might be part of the pacemaker system, and (2) that the switch from light-induced phase delays to phase advances as illustrated by phase-response curves is linked to the appearance of sensitivity to light in the three cell populations defined here.

Efferent projections of the suprachiasmatic nucleus in the golden hamster (Mesocricetus auratus).

The efferent projections of the suprachiasmatic nucleus (SCN) in the golden hamster have been examined by using the anterograde tracer Phaseolus vulgaris leucoagglutinin (Pha-L). SCN projections were further localized through a combination of restricted SCN-lesions and immunocytochemistry for three well-known peptidergic transmitters contained in SCN neurons, viz. vasopressin (VP), vasoactive intestinal peptide (VIP), and gastrin-releasing peptide (GRP). Thus, major terminal fields of SCN-derived VP were detected in the medial preoptic nucleus, the anterior part of the paraventricular nucleus of the thalamus (PVA), the medial parvicellular part of the paraventricular nucleus of the hypothalamus (PVN), and the medial part of the dorsomedial nucleus of the hypothalamus (DMH). VIP-containing projections from the SCN were discovered in the PVA, anterior and dorsal parvicellular divisions of the PVN, subparaventricular area, and medial DMH. Efferent fibers from the SCN containing GRP were restricted to the subparaventricular area, medial DMH, and supraoptic nucleus. In addition, Pha-L tracing indicated the existence of SCN projections which could not be ascribed to one of the presently investigated peptides. Furthermore, a pronounced innervation of the contralateral SCN was observed, of which the neurotransmitter remains to be established. The results of the present study indicate that the different neuronal populations in the SCN, as characterized by their transmitter content, also show a clear diversity in their preferential target areas.