Serotonergic Dysfunction Research Articles

Autism spectrum disorder-like behaviors induced by hyper-glutamatergic NMDA receptor signaling through hypo-serotonergic 5-HT1A receptor signaling in the prefrontal cortex in mice exposed to prenatal valproic acid.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT1A receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635-a 5-HT1A receptor antagonist-antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT1A receptors in prenatal VPA mice.

Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Bulimia Nervosa (BN): A Review and Insight into Potential Mechanisms of Action.

Bulimia nervosa (BN) is a disorder primarily affecting adolescent females, characterized by episodes of binge eating followed by inappropriate compensatory behaviors aimed at preventing weight gain, including self-induced vomiting and the misuse of diuretics, laxatives, and insulin. The precise etiology of BN remains unknown, with factors such as genetics, biological influences, emotional disturbances, societal pressures, and other challenges contributing to its prevalence. First-line treatment typically includes pharmacotherapy, which has shown moderate effectiveness. Neuroimaging evidence suggests that altered brain activity may contribute to the development of BN, making interventions that directly target the brain extremely valuable. One such intervention is repetitive transcranial magnetic stimulation (rTMS), a non-invasive stimulation technique that has been garnering interest in the medical community for many years. This review explores the use of rTMS in the treatment of BN. Searches were conducted in the PubMed/Medline, ResearchGate, and Cochrane databases. Twelve relevant studies were identified. Analysis of the results from these studies reveals promising findings, particularly regarding key parameters in the pathophysiology of BN. Several studies assessed the impact of rTMS on binge episodes. While some studies did not find significant reductions, most reported decreases in binge eating and purging behaviors, with some cases showing complete remission. Reductions in symptoms of depression and food cravings were also demonstrated. However, results regarding cognitive improvement were mixed. The discussion focused heavily on potential mechanisms of action, including neuromodulation of brain networks, induction of neuroplasticity, impact on serotonergic dysfunction, anti-inflammatory action, and HPA axis modulation. rTMS was found to be a safe intervention with no serious side effects. rTMS in the treatment of BN appears to be a promising intervention that alleviates some symptoms characteristic of the pathophysiology of this disorder. An additional effect is a significant reduction in depressive symptoms. However, despite these findings, further research is required to confirm its effectiveness and elucidate the mechanisms of action. It is also recommended to further investigate the potential mechanisms of action described in this review.

Early-life manipulation of the serotonergic system exacerbates the harmful effects of sleep deprivation on cognitive functions.

Serotonin is a monoamine neurotransmitter that plays a main role in regulating physiologicaland cognitive functions. Serotonergic system dysfunction is involved in the etiology of various psychiatric and neurological disorders. Therefore, the present study was designed to investigate the effects of early-life serotonin depletion on cognitive disorders caused by sleep deprivation. Serotonin was depleted by para-chlorophenylalanine (PCPA, 100 mg/kg, s.c.) at postnatal days 10-20, followed by sleep deprivation-induced through the multiple platform apparatus for 24 h at PND 60. After the examination of the novel object recognition and passive avoidance memories, the hippocampi and prefrontal cortex were dissected to examine the brain-derived neurotrophic factor (BDNF) mRNA expression by PCR. Our findings showed that postnatal serotonin depletion and sleep deprivation impaired the novel object recognition and passive avoidance memories and changed the BDNF levels. In the same way, the serotonin depletion in early life before sleep deprivation exacerbated the harmful effects of sleep deprivation on cognitive function and BDNF levels. It can be claimed that the serotonergic system plays a main role in the modulation of sleep and cognitive functions.

Impact of Serotonin Deficiency on Circadian Dopaminergic Rhythms.

Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain-including those involving serotonin and dopamine-exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.

Examining putamen resting-state connectivity markers of suicide attempt history in depressed adolescents.

Suicide is a current leading cause of death in adolescents and young adults. The neurobiological underpinnings of suicide risk in youth, however, remain unclear and a brain-based model is lacking. In adult samples, current models highlight deficient serotonin release as a potential suicide biomarker, and in particular, involvement of serotonergic dysfunction in relation to the putamen and suicidal behavior. Less is known about associations among striatal regions and relative suicidal risk across development. The current study examined putamen connectivity in depressed adolescents with (AT) and without history of a suicide attempt (NAT), specifically using resting-state functional magnetic resonance imaging (fMRI) to evaluate patterns in resting-state functional connectivity (RSFC). We hypothesized the AT group would exhibit lower striatal RSFC compared to the NAT group, and lower striatal RSFC would associate with greater suicidal ideation severity and/or lethality of attempt. We examined whole-brain RSFC of six putamen regions in 17 adolescents with depression and NAT (MAge [SD] = 16.4[0.3], 41% male) and 13 with AT (MAge [SD] = 16.2[0.3], 31% male). Only the dorsal rostral striatum showed a statistically significant bilateral between-group difference in RSFC with the superior frontal gyrus and supplementary motor area, with higher RSFC in the group without a suicide attempt compared to those with attempt history (voxel-wise p<.001, cluster-wise p<.01). No significant associations were found between any putamen RSFC patterns and suicidal ideation severity or lethality of attempts among those who had attempted. The results align with recent adult literature and have interesting theoretical and clinical implications. A possible interpretation of the results is a mismatch of the serotonin transport to putamen and to the supplementary motor area and the resulting reduced functional connectivity between the two areas in adolescents with attempt history. The obtained results can be used to enhance the diathesis-stress model and the Emotional paiN and social Disconnect (END) model of adolescent suicidality by adding the putamen. We also speculate that connectivity between putamen and the supplementary motor area may in the future be used as a valuable biomarker of treatment efficacy and possibly prediction of treatment outcome.

Unveiling serotonergic dysfunction of obsessive-compulsive disorder on prefrontal network dynamics: a computational perspective.

Serotonin (5-HT) regulates working memory within the prefrontal cortex network, which is crucial for understanding obsessive-compulsive disorder. However, the mechanisms how network dynamics and serotonin interact in obsessive-compulsive disorder remain elusive. Here, we incorporate 5-HT receptors (5-HT1A, 5-HT2A) and dopamine receptors into a multistable prefrontal cortex network model, replicating the experimentally observed inverted U-curve phenomenon. We show how the two 5-HT receptors antagonize neuronal activity and modulate network multistability. Reduced binding of 5-HT1A receptors increases global firing, while reduced binding of 5-HT2A receptors deepens attractors. The obtained results suggest reward-dependent synaptic plasticity mechanisms may attenuate 5-HT related network impairments. Integrating serotonin-mediated dopamine release into circuit, we observe that decreased serotonin concentration triggers the network into a deep attractor state, expanding the domain of attraction of stable nodes with high firing rate, potentially causing aberrant reverse learning. This suggests a hypothesis wherein elevated dopamine concentrations in obsessive-compulsive disorder might result from primary deficits in serotonin levels. Findings of this work underscore the pivotal role of serotonergic dysregulation in modulating synaptic plasticity through dopamine pathways, potentially contributing to learned obsessions. Interestingly, serotonin reuptake inhibitors and antidopaminergic potentiators can counteract the over-stable state of high-firing stable points, providing new insights into obsessive-compulsive disorder treatment.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part II. Age-associated alterations in serotonin receptor binding profiles within medullary nuclei supporting cardiorespiratory homeostasis.

The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/C receptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1A and/or 5-HT2A/C receptor binding (defined as levels below the 95% confidence interval of controls-a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death. The prevalence and percentage of nuclei with low 5-HT1A and 5-HT2A/C binding in SIDS were twice that of controls. The percentage of nuclei with low 5-HT2A/C binding was greater in older SIDS infants. In >80% of older SIDS infants, low 5-HT2A/C binding characterized the hypoglossal nucleus, vagal dorsal nucleus, nucleus of solitary tract, and nuclei of the olivocerebellar subnetwork (important for blood pressure regulation). Together, our findings from SIDS infants and from animal models of serotonergic dysfunction suggest that some SIDS cases represent a serotonopathy. We present new hypotheses, yet to be tested, about how defects within serotonergic subnetworks may lead to SIDS.

A versatile fluorescent probe for hydrogen peroxide in serotonergic neurons of living brains of mice with depression.

Depression, a prevalent mental illness, is intricately linked with the neurotransmitters in the brain, while serotonin as a crucial regulator of mood, energy levels, and memory, has been implicated in depression. So, the release of serotonin by serotonergic neurons plays a significant role in the development of depression. Notably, the foremost marker of oxidative stress, hydrogen peroxide (H2O2), can interfere with the functioning of serotonergic neurons and potentially contribute to depression. Investigating the impact of H2O2 on serotonergic neurons could offer valuable insights into the mechanisms underlying depression. However, there have been no effective tools for selectively imaging H2O2 in these neurons so far. To address this gap, we created a small molecular fluorescent probe, PF-H2O2, designed specifically for imaging H2O2 in serotonergic neurons under oxidative stress. PF-H2O2 exerts excellent serotonergic neuron-targetability and notable selectivity for H2O2. Furthermore, we discovered increased H2O2 in serotonergic neurons of mice with depressive symptoms. Altogether, this endeavour unveils a pioneering tool for exploring pathophysiology linked to serotonergic neuronal dysfunction.

Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expressionin mice. Here,we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.

An experimental platform for stochastic analyses of single serotonergic fibers in the mouse brain.

The self-organization of the serotonergic matrix, a massive axon meshwork in all vertebrate brains, is driven by the structural and dynamical properties of its constitutive elements. Each of these elements, a single serotonergic axon (fiber), has a unique trajectory and can be supported by a soma that executes one of the many available transcriptional programs. This "individuality" of serotonergic neurons necessitates the development of specialized methods for single-fiber analyses, both at the experimental and theoretical levels. We developed an integrated platform that facilitates experimental isolation of single serotonergic fibers in brain tissue, including regions with high fiber densities, and demonstrated the potential of their quantitative analyses based on stochastic modeling. Single fibers were visualized using two transgenic mouse models, one of which is the first implementation of the Brainbow toolbox in this system. The trajectories of serotonergic fibers were automatically traced in the three spatial dimensions with a novel algorithm, and their properties were captured with a single parameter associated with the directional von Mises-Fisher probability distribution. The system represents an end-to-end workflow that can be imported into various studies, including those investigating serotonergic dysfunction in brain disorders. It also supports new research directions inspired by single-fiber analyses in the serotonergic matrix, including supercomputing simulations and modeling in physics.

5-HT4 Receptor is Protective for MPTP-induced Parkinson's Disease Mice Via Altering Gastrointestinal Motility or Gut Microbiota.

Serotonergic dysfunction is related to both motor and nonmotor symptoms in Parkinson's disease (PD). As a 5-HT receptor, 5-HT4 receptor (5-HT4R) is well-studied and already-used in clinical therapy of constipation, which is a typical non-motor symptom in PD. In this study, we investigated the role of 5-HT4R as a regulator of gut function in MPTP-induced acute PD mice model. Daily intraperitoneal injection of GR 125487 (5-HT4R antagonist) was administered 3 days before MPTP treatment until sacrifice. Seven days post-MPTP treatment, feces were collected and gastrointestinal transit time (GITT) was measured, 8 days post-MPTP treatment, behavioral tests were performed, and then animals were sacrificed for the further analysis. We found GR 125487 pretreatment not only increased GITT, but also aggravated MPTP-induced motor bradykinesia. In addition, GR 125487 pretreatment exacerbated the loss of dopaminergic neurons probably by suppressing JAK2/PKA/CREB signaling pathway and increased reactive glia and neuroinflammation in the striatum. 16S rRNA sequencing of fecal microbiota showed that GR 125487 pretreatment altered the composition of gut microbiota, in which the abundance of Akkermansia muciniphila and Clostridium clostridioforme was increased, whereas that of Parabacteroides distasonis and Bacteroides fragilis was decreased, which are closely associated with inflammation condition. Taken together, we demonstrated that GR 125487 pretreatment exacerbates MPTP-induced striatal neurodegenerative processes possibly via the JAK2/PKA/CREB pathway and neuroinflammation by altering gut microbiota composition. In the microbiota-gut-brain axis of PD, 5-HT4R should be further explored and might serve as a target for PD diagnosis and treatment.

Lower loss rate of serotonergically modulated neuronal accumulator for time in patients with major depressive disorder

Major depressive disorder (MDD) is characterized by dramatic and persistent worsening of mood, as well as a subjective feeling of time slowing. However, experimental data on time perception are inconsistent. As serotonergic dysfunction implicated in MDD etiology, we aim to examine time perception in MDD through the framework of lossy temporal integration model, previously also related to serotonergic transmission. Thirty-one patients with recurrent depressive disorder in partial remission and thirty control participants, without a history of psychiatric and neurological disorders, performed duration discrimination of visual stimuli (duration ranges from 3.2 to 6.4 s) and subjective minute production tasks. To infer about central serotonergic transmission, an electroencephalogram in response to the 1000 Hz tone of different intensity (50, 60, 70 and 80 dB SPL) was recorded. Patients with MDD shorten the past durations in the duration discrimination task significantly less than controls, thus being more objective. No difference in the subjective minute production was recorded. Patients with MDD have also exhibited larger auditory evoked potentials in response to the tones of high intensity (70 and 80 dB SPL) when compared with the controls. This resulted in a steeper slope of auditory evoked potentials by intensity function. These converging findings suggest a lower loss rate of neuronal temporal accumulator modulated by serotonergic transmission in patients with MDD.

Serotonin sensing by microglia conditions the proper development of neuronal circuits and of social and adaptive skills.

The proper maturation of emotional and sensory circuits requires fine-tuning of serotonin (5-HT) level during early postnatal development. Consistently, dysfunctions of the serotonergic system have been associated with neurodevelopmental psychiatric diseases, including autism spectrum disorders (ASD). However, the mechanisms underlying the developmental effects of 5-HT remain partially unknown, one obstacle being the action of 5-HT on different cell types. Here, we focused on microglia, which play a role in brain wiring refinement, and we investigated whether the control of these cells by 5-HT is relevant for neurodevelopment and spontaneous behaviors in mice. Since the main 5-HT sensor in microglia is the 5-HT2B receptor subtype, we prevented 5-HT signaling specifically in microglia by conditional invalidation of the Htr2b gene in these cells. We observed that abrogating the serotonergic control of microglia during early postnatal development affects the phagolysosomal compartment of these cells and their proximity to dendritic spines and perturbs neuronal circuits maturation. Furthermore, this early ablation of microglial 5-HT2B receptors leads to adult hyperactivity in a novel environment and behavioral defects in sociability and flexibility. Importantly, we show that these behavioral alterations result from a developmental effect, since they are not observed when microglial Htr2b invalidation is induced later, at P30 onward. Thus, a primary alteration of 5-HT sensing in microglia, during a critical time window between birth and P30, is sufficient to impair social and flexibility skills. This link between 5-HT and microglia may explain the association between serotonergic dysfunctions and behavioral traits like impaired sociability and inadaptability to novelty, which are prominent in psychiatric disorders such as ASD.

Association of two variable number of tandem repeats in the monoamine oxidase A gene promoter with suicide completion: The present study and meta-analysis.

One potential cause of suicide is serotonergic dysfunction. Sex differences have been reported to modulate the effects of serotonergic polymorphisms. Monoamine oxidase A (MAOA) is an enzyme that degrades serotonin and is located on the X chromosome. A previous study indicated that the upstream (u) variable number of tandem repeat (VNTR) in the MAOA gene promoter may be associated with suicide. However, a meta-analysis showed that this polymorphism may not be related to suicide. According to a recent study, compared with the uVNTR, the distal (d)VNTR and the haplotypes of the two VNTRs modulate MAOA expression. We examined the two VNTRs in the MAOA gene promoter in 1007 subjects who committed suicide and 844 healthy controls. We analyzed the two VNTRs using fluorescence-based polymerase chain reaction assays. We conducted a meta-analysis for the two VNTRs to update it. Our results demonstrated that neither the genotype-based associations nor allele/haplotype frequencies of the two VNTRs were significantly associated with suicide. In the meta-analysis, we did not indicate relationships between uVNTR and suicide nor did we identify articles analyzing dVNTR in suicide. Overall, we did not find a relationship between the two VNTRs in the MAOA promoter and suicide completion; thus, warranting further studies are required.

Insomniac symptoms and suicidality-link and management

Alink between insomniac symptoms and suicidality has long been suspected and deserves specific attention. We examine the current evidence for this relationship from epidemiology and neurobiology in order to propose atargeted management. Clinical example and selective Medline-literature research for insomnia symptoms and suicidality. Epidemiological data and statistical analysis show that symptoms of insomnia are independent risk factors for suicidality. Neurobiological factors associated with combined insomnia symptoms and suicidality are: serotonergic dysfunction and circadian rhythm disorder leading to hypofrontality with reduced problem solving capacity and impaired emotional and impulse-control. Social isolation, recurrent rumination, comorbid psychiatric disorders, access to potentially lethal drugs or weapons need urgent evaluation in patients with acombination of suicidality and symptoms of insomnia. patients with insomnia and further risk factors for suicide need to be treated resolutely and at an early stage. Modern sleep-promoting antidepressants with low toxicity and antipsychotics must be preferred in the treatment of patients with insomniac sleep disorders and suicidality. Multimodal anti-insomnia and anti-depressive therapy adapted to the circadian rhythm can exert afavorable influence both on depressive-suicidal and insomnia symptoms and their inherent risks.

Seizures Cause Prolonged Impairment of Ventilation, CO2 Chemoreception and Thermoregulation.

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1a R1407X/+ (Dravet syndrome; DS) and Scn8a N1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with para-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone.SIGNIFICANCE STATEMENT There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO2 chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.

Reduced platelet 5-HT content is associated with rest tremor in Parkinson's disease

IntroductionParkinson's disease (PD) is highly heterogeneous in manifestations and pathogenesis. Serotonergic neurotransmitter system dysfunction is frequently implicated in PD tremor. Serotonin (5-HT) content in platelets is highly correlated with that in cerebrospinal fluid. In this study, we aimed to understand whether and how platelet 5-HT content reflects tremor in PD. MethodA total of 139 Chinese PD patients met with inclusion criteria were recruited. Motor and non-motor scores, and disease severity were evaluated. Patients were classified into subtypes of tremor-dominant (TD) and non-tremor-dominant (NTD). Peripheral platelets were isolated, and platelet 5-HT levels were measured. ResultsPlatelet 5-HT content was lower in PD patients of TD subtype than in NTD subtype. Multifactor risk analysis showed that this lower content was independently associated with the TD phenotype. Platelet 5-HT level was inversely correlated with total tremor score, rest tremor amplitude score, rest tremor constancy score, and index of rest tremor, but not with postural tremor score, and kinetic tremor score. ConclusionThe cross-sectional study demonstrates that reduced platelet 5-HT content is associated with PD rest tremor. Our results support the involvement of serotonergic disturbance in PD rest tremor and indicate that 5-HT reduction can be manifested in peripheral platelets.

Hypoechogenicity of the raphe nuclei as a biomarker of migraine: A case-control study, review, and meta-analysis.

Hypoechogenicity of the raphe nuclei (hR) has been related to major depression. Comorbidity between migraine and depression is bidirectional postulating a common mechanism of serotonergic dysfunction. We aimed to investigate the association between migraine and hR and its role as biomarker of migraine-associated depression and disease severity. This is a single-center cross-sectional descriptive study. We included consecutive patients with episodic (EM) and chronic migraine (CM). We collected their comorbidities, analgesic consumption, hospital anxiety and depression scale (HADS), disability, and impact on quality of life associated with migraine. We also included a group of control subjects, matched for age and sex with the patients. In both groups, hR was assessed by means of transcranial sonography. We performed a meta-analysis of the studies investigating the association between migraine and hR. A total of 107 subjects were included (57 cases and 50 controls). hR rate was lower in controls than in migraine patients(22.2% vs. 42.9%, p=.02) with a progressive increase in EM and CM groups respect to the control group (33.3% and 50% vs. 22.2%, respectively; p=.03). Among patients, hR was not associated with depression, higher HADS score, greater migraine-related disability, or higher consumption of analgesic medication. The meta-analysis showed a significant association between migraine and hR (odds ratio =2.16; 95% confidence interval: 1.42-3.29). hR is more prevalent in migraine patients than in controls and, in our population, its prevalence increases in a stepwise manner in patients with EM and CM. These findings support the role of raphe nuclei in migraine pathophysiology.

Association between the loudness dependence of auditory evoked potentials and age in patients with schizophrenia and depression.

ObjectiveAlthough serotonergic dysfunction is significantly associated with major depressive disorder (MDD) and schizophrenia (SCZ), comparison of serotonergic dysfunction in both diseases has received little attention. Serotonin hypotheses have suggested diminished and elevated serotonin activity in MDD and SCZ, respectively. However, the foundations underlying these hypotheses are unclear regarding changes in serotonin neurotransmission in the aging brain. The loudness dependence of auditory evoked potentials (LDAEP) reflects serotonin neurotransmission. The present study compared the LDAEP between patients with SCZ or MDD and healthy controls (HCs). We further examined whether age was correlated with the LDAEP and clinical symptoms.MethodsThis prospective clinical study included 105 patients with SCZ (n = 54) or MDD (n = 51). Additionally, 35 HCs were recruited for this study. The LDAEP was measured on the midline channels via 62 electroencephalography channels.ResultsPatients with SCZ or MDD showed a significantly smaller mean LDAEP than those in HCs. The LDAEP was positively correlated with age in patients with SCZ or MDD.ConclusionsChanges in central serotonergic activity could be indicated by evaluating the LDAEP in patients with SCZ or MDD. Age-related reductions in serotonergic activity may be screened using the LDAEP in patients with SCZ or MDD.

Migraine With Comorbid Depression: Pathogenesis, Clinical Implications, and Treatment.

Migraine is a neurological disorder that strongly relates to psychiatric conditions like depression. Lately, the increased prevalence of depression in migraineurs has come to attention. This article compiled various literature to explore the association between migraine and depression. Genetic overlap of various gene segments was studied, and heritability patterns were explored. Shared mechanisms such as serotonergic dysfunction, methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and hormonal effects were investigated, and commonalities like comorbidities, stress, and environmental factors were analyzed. Migraine with comorbid depression (MID) affects various aspects of life and its clinical impact on migraine disability, quality of life (QOL), progression, and medication overuse was investigated. We further inspected several types of research in order to provide options on various treatment modalities. Pharmacotherapy such as antidepressants and anti-Calcitonin Gene-Related Peptide (CGRP) monoclonal antibodies like fremanezumab were studied. Alternative treatment options such as onabotulinumtoxinA (OBTA) injections, cognitive behavioral therapy (CBT), and vagal nerve stimulations (VNS) were also appraised and the efficacies of each were compared.