Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain.

UNLABELLED: Maternal inflammation during pregnancy affects placental function and is associated with increased risk of neurodevelopmental disorders in the offspring. The molecular mechanisms linking placental dysfunction to abnormal fetal neurodevelopment remain unclear. During typical development, serotonin (5-HT) synthesized in the placenta from maternal l-tryptophan (TRP) reaches the fetal brain. There, 5-HT modulates critical neurodevelopmental processes. We investigated the effects of maternal inflammation triggered in midpregnancy in mice by the immunostimulant polyriboinosinic-polyribocytidylic acid [poly(I:C)] on TRP metabolism in the placenta and its impact on fetal neurodevelopment. We show that a moderate maternal immune challenge upregulates placental TRP conversion rapidly to 5-HT through successively transient increases in substrate availability and TRP hydroxylase (TPH) enzymatic activity, leading to accumulation of exogenous 5-HT and blunting of endogenous 5-HT axonal outgrowth specifically within the fetal forebrain. The pharmacological inhibition of TPH activity blocked these effects. These results establish altered placental TRP conversion to 5-HT as a new mechanism by which maternal inflammation disrupts 5-HT-dependent neurogenic processes during fetal neurodevelopment. SIGNIFICANCE STATEMENT: The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.

Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.

STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.

Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration.

We believe there are serious problems with a recently published and highly publicized paper entitled "Serotonin reduction in post-acute sequelae of viral infection." The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the "Discussion" section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, "Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment", it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs' effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

Specification of human regional brain lineages using orthogonal gradients of WNT and SHH in organoids.

The repertory of neurons generated by progenitor cells depends on their location along antero-posterior and dorso-ventral axes of the neural tube. To understand if recreating those axes was sufficient to specify human brain neuronal diversity, we designed a mesofluidic device termed Duo-MAPS to expose induced pluripotent stem cells (iPSC) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison of single cell transcriptomes with fetal human brain revealed that Duo-MAPS-patterned organoids generated the major neuronal lineages of the forebrain, midbrain, and hindbrain. Morphogens crosstalk translated into early patterns of gene expression programs predicting the generation of specific brain lineages. Human iPSC lines from six different genetic backgrounds showed substantial differences in response to morphogens, suggesting that interindividual genomic and epigenomic variations could impact brain lineages formation. Morphogen gradients promise to be a key approach to model the brain in its entirety.

Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives.

Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests.

Determination of Indolepropionic Acid and Related Indoles in Plasma, Plasma Ultrafiltrate, and Saliva.

The microbial metabolite indolepropionic acid (IPA) and related indolic metabolites, including indolecarboxylic acid (ICA), indolelactic acid (ILA), indoleacetic acid (IAA), indolebutyric acid (IBA), indoxylsulfate (ISO4), and indole, were determined in human plasma, plasma ultrafiltrate (UF), and saliva. The compounds were separated on a 150 × 3 mm column of 3 µm Hypersil C18 eluted with a mobile phase of 80% pH 5 0.01 M sodium acetate containing 1.0 g/L of tert-butylammonium chloride/20% acetonitrile and then detected fluorometrically. Levels of IPA in human plasma UF and of ILA in saliva are reported for the first time. The determination of IPA in plasma UF enables the first report of free plasma IPA, the presumed physiologically active pool of this important microbial metabolite of tryptophan. Plasma and salivary ICA and IBA were not detected, consistent with the absence of any prior reported values. Observed levels or limits of detection for other indolic metabolites usefully supplement limited prior reports.

Systematic review of studies using platelet serotonin content to assess bioeffect of serotonin reuptake inhibitors at the serotonin transporter.

RATIONALE: Assessment of the bioeffect of serotonin reuptake inhibitors (SRIs, including both selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)) at the serotonin transporter (SERT) in patients and healthy controls can have important theoretical and clinical implications. OBJECTIVES: Bioeffect at SERT has been assessed by neuroimaging of brain SERT occupancy, through in vitro measurements of platelet serotonin (5-HT) uptake, and by measuring platelet 5-HT content pre- and post-initiation of SRI administration. Studies of platelet 5-HT content were reviewed in order to (1) determine the overall apparent bioeffect of SRIs; (2) compare bioeffect across types of SRIs; (3) compare the three approaches to assessing SRI bioeffect; and (4) determine how the findings might inform clinical practice. METHODS: We performed a systematic review of the published studies that measured platelet 5-HT content to assess SRI bioeffect at the platelet SERT. Studies using neuroimaging and in vitro platelet 5-HT uptake to assess SRI bioeffect were reviewed for comparison purposes. RESULTS: Clinical doses of SRIs typically resulted in 70-90% reductions in platelet 5-HT content. The observed bioeffect at the platelet SERT appeared similar among different SSRIs and SNRIs. The bioeffect estimations based on platelet 5-HT content were consistent with those obtained using neuroimaging to assess brain SERT occupancy and those based on the in vitro measurement of platelet 5-HT uptake. CONCLUSIONS: In general, excellent agreement was seen in the apparent SRI bioeffect (70-90% inhibition) among the platelet 5-HT content studies and across the three bioeffect approaches. Theoretical and practical clinical implications are discussed.

Baseline platelet serotonin in a multi-site treatment study of depression in veterans administration patients: Distribution and effects of demographic variables and serotonin reuptake inhibitors.

BACKGROUND: The objectives of the study were: (1) to examine the overall distribution of baseline platelet serotonin (5-hydroxytryptamine, 5-HT) values in patients seeking treatment for depression and to define subgroups based on the apparent presence or absence of drug exposure; (2) to assess the bioeffect of 5-HT reuptake inhibitors (SRIs) at the platelet 5-HT transporter; and (3) to examine the relationships of demographic variables including population (ancestry), sex, age, and season of sampling to platelet 5-HT concentration. METHODS: Platelet 5-HT levels were measured in a cross-sectional study of 1433 Veterans Administration (VA) patients participating in a pragmatic multi-site pharmacogenomic treatment study of depression. Patients were characterized medically and demographically using VA health records and self-report. RESULTS: A clearly bimodal distribution was observed for platelet 5-HT levels with the lower mode associated with patients exposed to SRIs at baseline. Median transporter blockade bioeffects were similar across the various selective 5-HT reuptake inhibitors (SSRIs) and 5-HT/norepinephrine reuptake inhibitors (SNRIs). In a subset of patients apparently not exposed to an SRI, significant effects of population and sex were observed with group mean platelet 5-HT levels being 25 % greater (p < 0.001) in African-American (AA) individuals compared to European-Americans (EAs). The female group mean was 14 % (p < 0.001) greater than male group mean. An effect of age was observed (r = -0.11, p < 0.001) and no effect of season or month of sampling was seen. CONCLUSIONS: Further research is warranted to understand the bases and clinical implications of the population and sex differences. The apparent similarity in bioeffect at the 5-HT transporter across SSRIs and when comparing SSRIs and SNRIs informs discussions about initiating, dose adjustment and switching of 5-HT reuptake inhibitors.

Network Structure of Autism Spectrum Disorder Behaviors and Its Evolution in Preschool Children: Insights from a New Longitudinal Network Analysis Method.

Network modeling of the social, communication and restrictive/repetitive behaviors (RRBs) included in the definition of Autism Spectrum Disorder was performed. The Autism Diagnostic Interview-Revised (ADI-R) assessed behaviors in 139 pre-school cases at two cross-sections that averaged 34.8 months apart. Cross-sectional networks were based on the correlation matrix of the ADI-R behavioral items and the "bootCross" method was developed and enabled the estimation of a longitudinal network. At both stages, RRB items/nodes formed a consistent peripheral cluster, while social and communication nodes formed a core cluster that diverged with time. These differences in the nature and evolution of the RRB and socio-communicative dimensions indicate that their inter-behavior dynamics are very different. The most central behaviors across stages are proposed as prime targets for efficient therapeutic intervention.

Robotic Spine Surgery in Rhode Island.

Surgical robots were first proposed in the 1960s with subsequent development and clinical implementation in the 1980s and 1990s. Recent advances in technology have led to widespread utilization of robots in many surgical subspecialties. In spine surgery, robots are primarily utilized for pedicle screw placement, with several studies highlighting the potential benefits of improved accuracy and reduction in radiation exposure. Once streamlined, robotic spine surgery (RSS) can provide financial renumeration through potential cost savings and marketing benefits, and in the future will likely aid in more complex surgeries. In Rhode Island, this technology has been implemented and has the potential to deliver optimized outcomes for patients. Robotic spine surgery is not a substitute for a skilled spine surgeon however, and careful diagnosis, care planning, and surgical execution are still mandatory to deliver the best possible patient outcomes. In this review, we chronicle the history of RSS, outline currently available RSS platforms, describe the efficacy, risks, and complications of RSS procedures, and explain the current and future utilization of RSS in Rhode Island.

Development of an Endoscopic Spine Surgery Program: Overview and Basic Considerations for Implementation.

Endoscopic spine surgery (ESS) is an innovative technique allowing for minimally invasive, direct visualization of spinal abnormalities. The growth of ESS in the United States has been stunted by high start-up costs, low reimbursement rates, and the steep learning curve associated with mastering endoscopic techniques. Hergrae, we describe the current state and future direction of ESS and provide key action items for ESS program implementation.

Utilization of Antibiotic Bone Cement in Spine Surgery: Pearls, Techniques, and Case Review.

Vertebral osteomyelitis (VO) encompasses a spectrum of spinal infections ranging from isolated mild vertebral osteomyelitis to severe diffuse infection with associated epidural abscess and fracture. Although patients can often be treated with an initial course of intravenous antibiotics, surgery is sometimes required in patients with sepsis, spinal instability, neurological compromise, or failed medical treatment. Antibiotic bone cement (ABC) has been widely used in orthopedic extremity surgery for more than 150 years, both for prophylaxis and treatment of bacterial infection. However, relatively little literature exists regarding its utilization in spine surgery. This article describes ABC utilization in orthopedic surgery and explains the technique of ABC utilization in spine surgery. Surgeons can choose from multiple premixed ABCs with variable viscosities, setting times, and antibiotics or can mix in antibiotics to bone cements themselves. ABC can be used to fill large defects in the vertebral body or disc space or in some cases to coat instrumentation. Surgeons should be wary of complications such as ABC extravasation as well as an increased difficulty with revision. With a thorough understanding of the properties of the cement and the methods of delivery, ABC is a powerful adjunct in the treatment of spinal infections.

Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings.

BACKGROUND: Stress, alcohol cues, and dysregulated stress responses increase alcohol craving and relapse susceptibility, but few pharmacologic agents are known to decrease stress- and cue-induced alcohol craving and associated stress dysregulation in humans. Here we report findings from a preliminary efficacy study of the alpha-1 receptor antagonist, prazosin, in modulating these relapse-relevant factors in alcohol-dependent individuals. METHODS: Seventeen early abstinent, treatment-seeking alcohol-dependent individuals (12 men and 5 women) were randomly assigned to receive either placebo or 16 mg daily prazosin in a double-blind, placebo-controlled manner over 4 weeks. During week 4, all patients participated in a 3-day laboratory experiment involving 5-minute guided imagery exposure to stress, alcohol cue, and neutral-relaxing/control conditions, 1 exposure per day, on consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, negative emotion, cardiovascular measures, and plasma hypothalamic-pituitary-adrenal (HPA; cortisol, adenocorticotropic hormone) were assessed repeatedly in each session. RESULTS: The prazosin group (n = 9) versus the placebo group (n = 8) showed significantly lower alcohol craving, anxiety, and negative emotion following stress exposure. The placebo group also showed significantly increased stress- and cue-induced alcohol craving, anxiety, negative emotion, and blood pressure (BP), as well as a blunted HPA response relative to the neutral condition, while the prazosin group showed no such increases in craving, anxiety, negative emotion, and BP, and no blunted HPA response to stress and alcohol cue exposure. CONCLUSIONS: Prazosin appears efficacious in decreasing stress- and cue-induced alcohol craving and may normalize the stress dysregulation associated with early recovery from alcoholism. Further research to assess the efficacy of prazosin in reducing alcohol craving and stress-related relapse risk is warranted.

Development of a Robotic Spine Surgery Program: Rationale, Strategy, Challenges, and Monitoring of Outcomes After Implementation.

ABSTRACT: Surgical robots were invented in the 1980s, and since then, robotic-assisted surgery has become commonplace. In the field of spine surgery, robotic assistance is utilized mainly to place pedicle screws, and multiple studies have demonstrated that robots can increase the accuracy of screw placement and reduce radiation exposure to the patient and the surgeon. However, this may be at the cost of longer operative times, complications, and the risk of errors in mapping the patient's anatomy.

Analysis of Patients' Online Reviews of Orthopaedic Surgeons.

INTRODUCTION: Physician rating websites (PRWs) are an increasingly popular interface between patient and surgeon. Despite the growing popularity of PRWs, little guidance exists for orthopaedic surgeons regarding online reviews. We analyzed online ratings and comments to provide a better understanding of patients' values and expectations so that surgeons can tailor their practice accordingly to enhance their clinical care and online reputation. METHODS: Three common PRWs (Vitals, HealthGrades, and RateMDs) were queried from January 1, 2006, to May 18, 2020. Publicly available ratings, both quantitative (1 to 5 stars) and qualitative (free text comments), were collected. Comments were qualitatively tabulated as having positive or negative assessments for categories including outcome, personality, staff, surgical skill, visit time, bedside manner, wait time, diagnosis, knowledge, treatment, and advanced practice providers and analyzed using chi square goodness of fit. Quantitative comparisons of star ratings were made across surgeon years in practice, sex, practice setting, and PRW and compared using chi square independence testing. RESULTS: In total, 81% of patient comments were found to have a positive assessment. Comments regarding outcome (P < 0.001), staff (P = 0.001), surgical skill (P < 0.001), or knowledge (P = 0.001) were more likely to be positive. Reviews regarding bedside manner (P < 0.001), wait time (P < 0.001), diagnosis (P < 0.001), treatment (P < 0.001), or advanced practice providers (P < 0.001) were more likely to be negative. Surgeon sex was not associated with a difference in quantitative ratings (P = 0.131), unlike practice setting (P < 0.001) and PRW (P < 0.001). DISCUSSION: PRWs are a growing interface between surgeon and patient with a considerable effect on surgeon marketability. This study reveals a statistical association between certain patient-centered medical practices and positive patient reviews. This emphasizes the importance of ensuring that high standards are maintained throughout a physician's practice of maintaining a constant awareness of the fundamentals for effective patient care and of taking care to curate a physician's online presence.

Antibiotic Cement Utilization for the Prophylaxis and Treatment of Infections in Spine Surgery: Basic Science Principles and Rationale for Clinical Use.

Antibiotic bone cement (ABC) is an effective tool for the prophylaxis and treatment of osteomyelitis due to the controlled, sustained release of local antibiotics. ABC has been proven to be effective in the orthopedic fields of arthroplasty and extremity trauma, but the adoption of ABC in spine surgery is limited. The characteristics of ABC make it an optimal solution for treating vertebral osteomyelitis (VO), a serious complication following spine surgery, typically caused by bacterial and sometimes fungal and parasitic pathogens. VO can be devastating, as infection can result in pathogenic biofilms on instrumentation that is dangerous to remove. New techniques, such as kyphoplasty and novel vertebroplasty methods, could amplify the potential of ABC in spine surgery. However, caution should be exercised when using ABC as there is some evidence of toxicity to patients and surgeons, antibiotic allergies, bone cement structural impairment, and possible development of antibiotic resistance. The purpose of this article is to describe the basic science of antibiotic cement utilization and review its usage in spine surgery.