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Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.
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The extent of changes in functional connectivity (FC) within functional networks as a common feature across hallucinogenic drug classes is under-explored. This work utilized fMRI to assess the dissociative hallucinogens Psilocybin, a classical serotonergic psychedelic, and Salvinorin-A, a kappa-opioid receptor (KOR) agonist, on resting-state FC in nonhuman primates. We highlight overlapping and differing influence of these substances on FC relative to the thalamus, claustrum, prefrontal cortex (PFC), default mode network (DMN), and DMN subcomponents. Analysis was conducted on a within-subject basis. Findings support the cortico-claustro-cortical network model for probing functional effects of hallucinogens regardless of serotonergic potential, with a potential key paradigm centered around the claustrum, PFC, anterior cingulate cortices (ACC), and angular gyrus relationship. Thalamo-cortical networks are implicated but appear dependent on 5-HT2AR activation. Acute desynchronization relative to the DMN for both drugs was also shown. Our findings provide a framework to understand broader mechanisms at which hallucinogens in differing classes may impact subjects regardless of the target receptor.
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Diterpenos Clerodânicos , Alucinógenos , Imageamento por Ressonância Magnética , Psilocibina , Alucinógenos/farmacologia , Diterpenos Clerodânicos/farmacologia , Animais , Psilocibina/farmacologia , Masculino , Imageamento por Ressonância Magnética/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Macaca mulatta , Rede de Modo Padrão/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Vias Neurais/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/diagnóstico por imagemRESUMO
ABSTRACT: Epigenetics has gained considerable interest as potential mediators of molecular alterations that could underlie the prolonged sensitization of nociceptors, neurons, and glia in response to various environmental stimuli. Histone acetylation and deacetylation, key processes in modulating chromatin, influence gene expression; elevated histone acetylation enhances transcriptional activity, whereas decreased acetylation leads to DNA condensation and gene repression. Altered levels of histone deacetylase (HDAC) have been detected in various animal pain models, and HDAC inhibitors have demonstrated analgesic effects in these models, indicating HDACs' involvement in chronic pain pathways. However, animal studies have predominantly examined epigenetic modulation within the spinal cord after pain induction, which may not fully reflect the complexity of chronic pain in humans. Moreover, methodological limitations have previously impeded an in-depth study of epigenetic changes in the human brain. In this study, we employed [11C]Martinostat, an HDAC-selective radiotracer, positron emission tomography to assess HDAC availability in the brains of 23 patients with chronic low back pain (cLBP) and 11 age-matched and sex-matched controls. Our data revealed a significant reduction of [11C]Martinostat binding in several brain regions associated with pain processing in patients with cLBP relative to controls, highlighting the promising potential of targeting HDAC modulation as a therapeutic strategy for cLBP.
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Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.
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United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma. Higher blast exposure was associated with increased cortical thickness in the left rostral anterior cingulate cortex (rACC), a finding that remained significant after multiple comparison correction. In uncorrected analyses, higher blast exposure was associated with worse health-related quality of life, decreased functional connectivity in the executive control network, decreased TSPO signal in the right rACC, and increased cortical thickness in the right rACC, right insula, and right medial orbitofrontal cortex-nodes of the executive control, salience, and default mode networks. These observations suggest that the rACC may be susceptible to blast overpressure and that a multimodal, network-based diagnostic approach has the potential to detect brain injury associated with RBE in active-duty SOF.
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Traumatismos por Explosões , Militares , Humanos , Traumatismos por Explosões/diagnóstico por imagem , Adulto , Masculino , Estados Unidos , Imageamento por Ressonância Magnética , Feminino , Tomografia por Emissão de Pósitrons , Cognição/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Adulto JovemRESUMO
Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.
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Transtorno do Espectro Autista , Encéfalo , Tomografia por Emissão de Pósitrons , Receptores de GABA , Humanos , Feminino , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/diagnóstico por imagem , Projetos Piloto , Receptores de GABA/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Adulto , Adulto Jovem , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Caracteres Sexuais , Adolescente , MasculinoRESUMO
Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18â kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90â min normalized standardized uptake value ratios sampled at mid-cortical depth and â¼3â mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.
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Meninges , Esclerose Múltipla , Tomografia por Emissão de Pósitrons , Receptores de GABA , Humanos , Receptores de GABA/metabolismo , Receptores de GABA/genética , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Tomografia por Emissão de Pósitrons/métodos , Meninges/metabolismo , Meninges/diagnóstico por imagem , Meninges/patologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Idoso , Córtex Cerebral/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/patologia , Acetamidas , PiridinasRESUMO
United States Special Operations Forces (SOF) personnel are frequently exposed to explosive blasts in training and combat. However, the effects of repeated blast exposure on the human brain are incompletely understood. Moreover, there is currently no diagnostic test to detect repeated blast brain injury (rBBI). In this "Human Performance Optimization" article, we discuss how the development and implementation of a reliable diagnostic test for rBBI has the potential to promote SOF brain health, combat readiness, and quality of life.
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Traumatismos por Explosões , Militares , Humanos , Estados Unidos , Qualidade de Vida , Encéfalo/diagnóstico por imagem , Traumatismos por Explosões/diagnóstico , Traumatismos por Explosões/terapia , ExplosõesRESUMO
We report a method that enables the fast incorporation of carbon isotopes into the ipso carbon of phenols. Our approach relies on the synthesis of a 1,5-dibromo-1,4-pentadiene precursor, which upon lithium-halogen exchange followed by treatment with carbonate esters results in a formal [5 + 1] cyclization to form the phenol product. Using this strategy, we have prepared 12 1-13C-labeled phenols, show proof-of-concept for the labeling of phenols with carbon-14, and demonstrate phenol synthesis directly from cyclotron-produced [11C]CO2.
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Neuroplasticity is a term that is increasingly permeating mainstream discourse and being used by the popular press to simplify descriptions of how the brain changes in response to stimuli such as exercise, sleep, food, drugs of abuse, and medicines, among others. However, it is a complex, multifaceted concept representing a continuum connecting molecular, cellular, and circuit-level changes and their effects on human behavior. In this Viewpoint, we examine neuroplasticity from several perspectives to construct a holistic view of this ambiguous term. By engaging experts across various scientific disciplines, we attempt to provide an easy entry point to the concept of neuroplasticity for readers of ACS Chemical Neuroscience. By highlighting how neuroplasticity changes in both health and disease, we demonstrate that the concept is applicable to both adaptive and maladaptive responses to stimuli, underscoring its significance in chemical neuroscience.
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Encéfalo , Neurociências , Humanos , Alimentos , Plasticidade Neuronal , SonoRESUMO
In aerobic glycolysis, oxygen is abundant, and yet cells metabolize glucose without using it, decreasing their ATP per glucose yield by 15-fold. During task-based stimulation, aerobic glycolysis occurs in localized brain regions, presenting a puzzle: why produce ATP inefficiently when, all else being equal, evolution should favor the efficient use of metabolic resources? The answer is that all else is not equal. We propose that a tradeoff exists between efficient ATP production and the efficiency with which ATP is spent to transmit information. Aerobic glycolysis, despite yielding little ATP per glucose, may support neuronal signaling in thin (< 0.5 µm), information-efficient axons. We call this the efficiency tradeoff hypothesis. This tradeoff has potential implications for interpretations of task-related BOLD "activation" observed in fMRI. We hypothesize that BOLD "activation" may index local increases in aerobic glycolysis, which support signaling in thin axons carrying "bottom-up" information, or "prediction error"-i.e., the BIAPEM (BOLD increases approximate prediction error metabolism) hypothesis. Finally, we explore implications of our hypotheses for human brain evolution, social behavior, and mental disorders.
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Trifosfato de Adenosina , Glicólise , Humanos , Glicólise/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Glucose/metabolismo , NeuroimagemRESUMO
Williams syndrome (WS) is a genetic disorder affecting multiple organ systems. Cardinal features include cardiovascular disease, distinct facies, and a unique cognitive profile characterized by intellectual disability, hypersociability, and visuospatial weaknesses. Here, we synthesize neuroimaging research in WS with a focus on how the current literature and future work may be leveraged to improve health and quality of life in WS. More than 80 neuroimaging studies in WS have been conducted, the vast majority of which have focused on identifying morphometric brain differences. Aside from decreased volume of the parieto-occipital region and increased cerebellar volume, morphometric findings have been variable across studies. fMRI studies investigating the visuospatial deficit have identified dorsal stream dysfunction and abnormal activation of the hippocampal formation. Minimal work has been done using PET or MRS. Future approaches that conduct neuroimaging in tandem with clinical phenotyping, utilize novel imaging techniques to visualize brain vasculature or provide biochemical and molecular information, and include more homogenous age groups across the lifespan, have significant potential to advance clinical care.
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While cognitive behavioral therapy (CBT) is a first-line treatment for anxiety, it is not typically offered to those with intellectual disability (ID). In this article, we provide a historical perspective on the treatment of mental health concerns in adults with ID, describe an adapted CBT treatment for anxiety in adults with Williams syndrome (WS) and mild to moderate ID, and discuss general modifications to CBT for adults with ID. Strategies used to successfully adapt CBT for adults with WS that may generalize for adults with ID more broadly include: (a) using child-based CBT manuals as a framework; (b) involving a caregiver as a therapy partner; (c) incorporating a high level of repetition; (d) simplifying language; (e) slowing the pace of instruction; and (f) incorporating specific examples and adaptations for WS.
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BACKGROUND: Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample. METHODS: Participants with (n = 25) and without (n = 12) clinically impairing anhedonia completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with [11C]raclopride, a DA D2/D3 receptor antagonist that selectively binds to striatal DA receptors. RESULTS: Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC. CONCLUSIONS: Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia.
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Transtorno Depressivo Maior , Dopamina , Humanos , Racloprida , Dopamina/metabolismo , Anedonia , Tomografia por Emissão de Pósitrons , Imageamento por Ressonância MagnéticaRESUMO
Several naturally occurring molecules exhibit unique potential in treating certain elements of psychiatric illnesses and are being actively pursued in therapeutic development. Among these are molecules termed entheogens, a preferred name for plant-derived compounds that alter human consciousness for religious or spiritual purposes, which are especially important to various Indigenous groups, and their use within these cultures precedes that of the contemporary medicalized use. Here, we acknowledge that some entheogens were included in the DARK Classics issues of ACS Chemical Neuroscience and that the label of "DARK" may perpetuate harmful and misguided labels and stigmas. We acknowledge that these compounds should really be framed in the light and beauty of their histories and uses culturally. Thus, in this Viewpoint, we consider the language used surrounding entheogens specifically and psychedelics more broadly and attempt to reframe the way we describe psychoactive, especially entheogenic, compounds in ACS Chemical Neuroscience.
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Alucinógenos , Transtornos Mentais , Humanos , Alucinógenos/uso terapêutico , Transtornos Mentais/tratamento farmacológicoRESUMO
Voltage-gated sodium channels (Navs) play a crucial electrical signaling role in neurons. Nav-isoforms present in peripheral sensory neurons and dorsal root ganglia of the spinal cord are critically involved in pain perception and transmission. While these isoforms, particularly Nav1.7, are implicated in neuropathic pain disorders, changes in the functional state and expression levels of these channels have not been extensively studied in vivo. Radiocaine, a fluorine-18 radiotracer based on the local anesthetic lidocaine, a non-selective Nav blocker, has previously been used for cardiac Nav1.5 imaging using positron-emission tomography (PET). In the present study, we used Radiocaine to visualize changes in neuronal Nav expression after neuropathic injury. In rats that underwent unilateral spinal nerve ligation, PET/MR imaging demonstrated significantly higher uptake of Radiocaine into the injured sciatic nerve, as compared to the uninjured sciatic nerve, for up to 32 days post-surgery. Radiocaine, due to its high translational potential, may serve as a novel diagnostic tool for neuropathic pain conditions using PET imaging.
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Neuralgia , Canais de Sódio Disparados por Voltagem , Ratos , Animais , Ratos Sprague-Dawley , Nervos Espinhais/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Neuralgia/diagnóstico por imagem , Neuralgia/metabolismo , Gânglios Espinais/metabolismo , Células Receptoras Sensoriais/metabolismoRESUMO
Activation of microglial cells accompanies the progression of many neurodegenerative disorders, including Alzheimer's disease (AD). Development of molecular imaging tools specific to microglia can help elucidate the mechanism through which microglia contribute to the pathogenesis and progression of neurodegenerative disorders. Through analysis of published genetic, transcriptomic, and proteomic data sets, we identified 19 genes with microglia-specific expression that we then ranked based on association with the AD characteristics, change in expression, and potential druggability of the target. We believe that the process we used to identify and rank microglia-specific genes is broadly applicable to the identification and evaluation of targets in other disease areas and for applications beyond molecular imaging.