Effects of trace element dietary supplements on voice parameters and some physiological and psychological parameters related to stress.

Trace elements, often used as dietary supplements, are widely accessible without prescription at pharmacies. Pronutri has pioneered Nutripuncture®, a methodology that utilizes orally consumed trace elements to elicit a physiological response akin to that of acupuncture. Pronutri has empirically observed that the user's voice becomes deeper following an exclusive ingestion procedure. Given that alterations in vocal characteristics are often linked to stress, the Pronutri researchers postulated that the pills have the capacity to promptly alleviate stress upon ingestion. Nevertheless, there is a lack of scientific substantiation about the impact of these supplements on voice (or stress) indicators. The aim of this research was to determine whether there is a consistent impact of trace element ingestion on vocal characteristics, namely the fundamental frequency of the voice, as well as other physiological and psychological stress measurements. In order to achieve this objective, we have devised a unique methodology to examine this hypothesis. This involves conducting a monocentric crossover, randomized, triple-blind, placebo-controlled trial with a sample size of 43 healthy individuals. This study demonstrates that compared to placebo tablets, consuming 10 metal traces containing tablets at once is enough to cause noticeable changes in the vocal spectrum in the direction of an improvement of the voice timbre "richness", and a decrease in the occurrence of spontaneous electrodermal activity, suggesting a stress reduction. However, there were no significant changes observed in the other parameters that were tested. These parameters include vocal measures such as voice frequency F0, standard deviation from this frequency, jitter, and shimmer. Additionally, physiological measures such as respiratory rate, oxygenation and heart rate variability parameters, as well as psychological measures such as self-assessment analogic scales of anxiety, stress, muscle tension, and nervous tension, did not show any significant changes. Ultimately, our research revealed that the ingestion of 10 trace elements pills may promptly elicit a targeted impact on both vocal spectrum and electrodermal activity. Despite the limited impact, these findings warrant more research to explore the long-term effects of trace elements on voice and stress reduction.

Eye movements in response to different cognitive activities measured by eyetracking: a prospective study on some of the neurolinguistics programming theories.

The eyes are in constant movement to optimize the interpretation of the visual scene by the brain. Eye movements are controlled by complex neural networks that interact with the rest of the brain. The direction of our eye movements could thus be influenced by our cognitive activity (imagination, internal dialogue, memory, etc.). A given cognitive activity could then cause the gaze to move in a specific direction (a brief movement that would be instinctive and unconscious). Neuro Linguistic Programming (NLP), which was developed in the 1970s by Richard Bandler and John Grinder (psychologist and linguist respectively), issued a comprehensive theory associating gaze directions with specific mental tasks. According to this theory, depending on the visual path observed, one could go back to the participant's thoughts and cognitive processes. Although NLP is widely used in many disciplines (communication, psychology, psychotherapy, marketing, etc), to date, few scientific studies have examined the validity of this theory. Using eye tracking, this study explores one of the hypotheses of this theory, which is one of the pillars of NLP on visual language. We created a protocol based on a series of questions of different types (supposed to engage different brain areas) and we recorded by eye tracking the gaze movements at the end of each question while the participants were thinking and elaborating on the answer. Our results show that 1) complex questions elicit significantly more eye movements than control questions that necessitate little reflection, 2) the movements are not random but are oriented in selected directions, according to the different question types, 3) the orientations observed are not those predicted by the NLP theory. This pilot experiment paves the way for further investigations to decipher the close links between eye movements and neural network activities in the brain.

Episodic Memory formation: A review of complex Hippocampus input pathways.

Memories of everyday experiences involve the encoding of a rich and dynamic representation of present objects and their contextual features. Traditionally, the resulting mnemonic trace is referred to as Episodic Memory, i.e. the "what", "where" and "when" of a lived episode. The journey for such memory trace encoding begins with the perceptual data of an experienced episode handled in sensory brain regions. The information is then streamed to cortical areas located in the ventral Medio Temporal Lobe, which produces multi-modal representations concerning either the objects (in the Perirhinal cortex) or the spatial and contextual features (in the parahippocampal region) of the episode. Then, this high-level data is gated through the Entorhinal Cortex and forwarded to the Hippocampal Formation, where all the pieces get bound together. Eventually, the resulting encoded neural pattern is relayed back to the Neocortex for a stable consolidation. This review will detail these different stages and provide a systematic overview of the major cortical streams toward the Hippocampus relevant for Episodic Memory encoding.

Reconstruction of Extensive Composite Parotid Region Oncologic Defects with Immediate Facial Nerve Reconstruction Using a Chimeric Scapulodorsal Vascularized Nerve Free Flap.

BACKGROUND: Cancer involving the parotid gland region may originates from parotid parenchyma itself or from locoregional organs and in rare cases, the facial nerve (FN) has to be sacrificed during tumor resection. In these cases, cancer extension often goes beyond the parotid compartment and requires extensive local resection responsible for complex multitissular defects. The goals of reconstruction may be summarized in the following two components: (1) restoration of the volumetric tissue defect and (2) FN reconstruction. The aim of this study is to describe our surgical technique and our cosmetic results using the chimeric scapulodorsal vascularized nerve (SDVN) flap to reconstruct extensive maxillofacial defects associated with FN sacrifice. METHODS: All patients undergone an extensive maxillofacial resection with FN sacrifice and primarily reconstructed with a SDVN flap were included. We classified the maxillofacial defects into six groups based on the type of resection. Intraoperative data including flap composition, topography of FN injury, length of nerve gap, and number of nervous anastomosis were recorded. RESULTS: Twenty-nine patients were included. Mean follow-up was 38.7 months. The harvested flaps included the SDVN combined with different components according to the defect group. A satisfactory volumetric restoration was obtained in 93% of cases. The mean number of distal nervous anastomosis was 4.5. The length of the vascularized grafted nerve ranged from 7 to 10 cm. CONCLUSION: This is largest series presented in literature on primary FN reconstruction utilizing a vascularized nerve graft. We believe that the chimeric SDVN flap should be highly considered for these cases due to its versatility. The surgeon is able to use single donor site available soft and hard tissues components along with a vascular motor nerve graft, which offers a great length and number of distal branches, and easily matches with the extracranial FN trunk and its peripheral ramifications.

Pancreatic nerve electrostimulation inhibits recent-onset autoimmune diabetes.

Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in ß-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.

CD4+ T Cells Affect the Thyroid Hormone Transport at the Choroid Plexus in Mice Raised in Enriched Environment.

BACKGROUND: Others and we have shown that T cells have an important role in hippocampal synaptic plasticity, including neurogenesis in the dentate gyrus, spinogenesis, and glutamatergic synaptic function in the CA of the hippocampus. Hippocampus plasticity is particularly involved in the brain effects of the enriched environment (EE), and interestingly CD4+ and CD8+ T cells play essential and differential roles in these effects. However, the precise mechanisms by which they act on the brain remain elusive. OBJECTIVES: We searched for a putative mechanism of action by which CD4+ T cells could influence brain plasticity and hypothesized that they could regulate protein transport at the level of the blood-CSF barrier in the choroid plexus. METHOD: We compared mice housed in EE and deprived of CD4+ T cells using a depleting antibody with a control group injected with the control isotype. We analyzed in the hippocampus the gene expression profiles using the Agilent system, and the expression of target proteins in plasma, CSF, and the choroid plexus using ELISA. RESULTS: We show that CD4+ T cells may influence EE-induced hippocampus plasticity via thyroid hormone signaling by regulating in the choroid plexus the expression of transthyretin, the major transporter of thyroxine (T4) to the brain parenchyma. CONCLUSIONS: Our study highlights the contribution of close interactions between the immune and neuroendocrine systems in brain plasticity and function.

Adiporon, an adiponectin receptor agonist acts as an antidepressant and metabolic regulator in a mouse model of depression.

Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.

CD4+ T Cells Have a Permissive Effect on Enriched Environment-Induced Hippocampus Synaptic Plasticity.

Living in an enriched environment (EE) benefits health by acting synergistically on various biological systems including the immune and the central nervous systems. The dialog between the brain and the immune cells has recently gained interest and is thought to play a pivotal role in beneficial effects of EE. Recent studies show that T lymphocytes have an important role in hippocampal plasticity, learning, and memory, although the precise mechanisms by which they act on the brain remain elusive. Using a mouse model of EE, we show here that CD4+ T cells are essential for spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. However, CD4+ lymphocytes do not influence EE-induced neurogenesis in the DG of the hippocampus, by contrast to what we previously demonstrated for CD8+ T cells. Importantly, CD4+ T cells located in the choroid plexus have a specific transcriptomic signature as a function of the living environment. Our study highlights the contribution of CD4+ T cells in the brain plasticity and function.

[Adiponectin: an endogenous molecule with anti-inflammatory and antidepressant properties?] / L'adiponectine - Un anti-inflammatoire et anti-dépresseur endogène ?

Adiponectin (ApN) is a hormone produced by adipose tissue, yet the plasma level of ApN is decreased in overweight and obese people, as well as in people with diabetes. In the periphery, this decrease in circulating levels of ApN induces the establishment of a chronic low-grade inflammatory state and is involved in the development of insulin resistance and atheromas. Conversely, "favorable" living conditions, weight loss and regular physical exercise increase ApN blood concentration. Some forms of ApN can reach the brain parenchyma through the cerebrospinal fluid. In the brain, the increase in ApN exerts powerful antidepressant and anxiolytic effects, in particular by fighting against neuroinflammation.

CD8+ T cells are essential for the effects of enriched environment on hippocampus-dependent behavior, hippocampal neurogenesis and synaptic plasticity.

Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4+ T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8+ T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8+ T cells. In addition, we show that spleen CD8+ T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFα release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8+ CD44+ CD62Llow and CD62Lhi T cells repartition 4) transcriptomic signature as revealed by RNA sequencing. CD8+ T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8+ T cells are essential mediators of beneficial EE effects on brain plasticity and cognition. Additionally, we propose that EE differentially primes CD8+ T cells leading to behavioral improvement.

Globular Adiponectin Limits Microglia Pro-Inflammatory Phenotype through an AdipoR1/NF-κB Signaling Pathway.

We recently reported that increased levels of Adiponectin (ApN) in the brain led to microglia phenotype and activation state regulation, thus reducing both global brain inflammation and depressive-like behaviors in mice. Apart from this, little is known on ApN molecular effects on microglia, although these cells are crucial in both physiological and pathological processes. Here we fill this gap by studying the effects and targets of ApN toward neuroinflammation. Our findings suggest that ApN deficiency in mice leads to a higher sensitivity of mice to neuroinflammation that is due to enhanced microglia responsiveness to a pro-inflammatory challenge. Moreover, we show that globular ApN (gApN) exerts direct in vivo anti-inflammatory actions on microglia by reducing IL-1ß, IL-6, and TNFα synthesis. In vitro, gApN anti-inflammatory properties are confirmed in brain-sorted microglia, primary cultured and microglia cell line (BV2), but are not observed on astrocytes. Our results also show that gApN blocks LPS-induced nitrosative and oxidative stress in microglia. Finally, we demonstrate for the first time that these anti-inflammatory and anti-oxidant actions of gApN on microglia are mediated through an AdipoR1/NF-κB signaling pathway.

Retrospective Outcome Analysis of 39 Patients Who Underwent Lip Surgery for Cutaneous Carcinoma.

PURPOSE: The treatment of lip carcinomas needs tumor surgical resection with safety margins respect. The aim of this study was to report the oncologic and aesthetic/functional outcomes of a retrospective monocentric case series of 39 patients treated for cutaneous lip cancer. METHODS: This retrospective study assessed 56 patients who were treated for a lip carcinoma between 2008 and 2012 and included 39 patients with cutaneous lip basal cell carcinoma or squamous cell carcinoma. Clinical, surgical and pathological data were reviewed, and patients were interviewed for follow-up data. A comparison was made between the marked surgical margins and the margins observed under microscopy after histologic process. RESULTS: The most frequent tumor type was basal cell carcinoma in 69.2 %. The measured surgical margins were superior to the histological margins in 24 cases (61.5 %) and were inferior in 13 cases (33.3 %). Overall survival and recurrence-free survival rates at 1 year were 97.5 and 95 % respectively. CONCLUSION: Differences between the surgical margins and the final histologic margins were the main finding of this retrospective study. These differences were attributed to surgical practices and modification during the histological process. Nevertheless, we did not observe a higher rate of recurrence or death in our study than in literature.

Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation.

Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior.

TRH modulates glutamatergic synaptic inputs on CA1 neurons of the mouse hippocampus in a biphasic manner.

Thyrotropin Releasing Hormone (TRH) is a tripeptide that induces the release of Thyroid Stimulating Hormone (TSH) in the blood. Besides its role in the thyroid system, TRH has been shown to regulate several neuronal systems in the brain however its role in hippocampus remains controversial. Using electrophysiological recordings in acute mouse brain slices, we show that TRH depresses glutamate responses at the CA3-CA1 synapse through an action on NMDA receptors, which, as a consequence, decreases the ability of the synapse to establish a long term potentiation (LTP). TRH also induces a late increase in AMPA/kainate responses. Together, these results suggest that TRH plays an important role in the modulation of hippocampal neuronal activities, and they contribute to a better understanding of the mechanisms by which TRH impacts synaptic function underlying emotional states, learning and memory processes.

A family of photoswitchable NMDA receptors.

NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity.

Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior.

Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1ß, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice.

Differential neuronal plasticity in mouse hippocampus associated with various periods of enriched environment during postnatal development.

Enriched environment (EE) is characterized by improved conditions for enhanced exploration, cognitive activity, social interaction and physical exercise. It has been shown that EE positively regulates the remodeling of neural circuits, memory consolidation, long-term changes in synaptic strength and neurogenesis. However, the fine mechanisms by which environment shapes the brain at different postnatal developmental stages and the duration required to induce such changes are still a matter of debate. In EE, large groups of mice were housed in bigger cages and were given toys, nesting materials and other equipment that promote physical activity to provide a stimulating environment. Weaned mice were housed in EE for 4, 6 or 8 weeks and compared with matched control mice that were raised in a standard environment. To investigate the differential effects of EE on immature and mature brains, we also housed young adult mice (8 weeks old) for 4 weeks in EE. We studied the influence of onset and duration of EE housing on the structure and function of hippocampal neurons. We found that: (1) EE enhances neurogenesis in juvenile, but not young adult mice; (2) EE increases the number of synaptic contacts at every stage; (3) long-term potentiation (LTP) and spontaneous and miniature activity at the glutamatergic synapses are affected differently by EE depending on its onset and duration. Our study provides an integrative view of the role of EE during postnatal development in various mechanisms of plasticity in the hippocampus including neurogenesis, synaptic morphology and electrophysiological parameters of synaptic connectivity. This work provides an explanation for discrepancies found in the literature about the effects of EE on LTP and emphasizes the importance of environment on hippocampal plasticity.