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BACKGROUND: Overgeneralised self-blame and worthlessness are key symptoms of major depressive disorder (MDD) and have previously been associated with self-blame-selective changes in connectivity between right superior anterior temporal lobe (rSATL) and subgenual frontal cortices. Another study showed that remitted MDD patients were able to modulate this neural signature using functional magnetic resonance imaging (fMRI) neurofeedback training, thereby increasing their self-esteem. The feasibility and potential of using this approach in symptomatic MDD were unknown. METHOD: This single-blind pre-registered randomised controlled pilot trial probed a novel self-guided psychological intervention with and without additional rSATL-posterior subgenual cortex (BA25) fMRI neurofeedback, targeting self-blaming emotions in people with insufficiently recovered MDD and early treatment-resistance (n = 43, n = 35 completers). Participants completed three weekly self-guided sessions to rebalance self-blaming biases. RESULTS: As predicted, neurofeedback led to a training-induced reduction in rSATL-BA25 connectivity for self-blame v. other-blame. Both interventions were safe and resulted in a 46% reduction on the Beck Depression Inventory-II, our primary outcome, with no group differences. Secondary analyses, however, revealed that patients without DSM-5-defined anxious distress showed a superior response to neurofeedback compared with the psychological intervention, and the opposite pattern in anxious MDD. As predicted, symptom remission was associated with increases in self-esteem and this correlated with the frequency with which participants employed the psychological strategies in daily life. CONCLUSIONS: These findings suggest that self-blame-rebalance neurofeedback may be superior over a solely psychological intervention in non-anxious MDD, although further confirmatory studies are needed. Simple self-guided strategies tackling self-blame were beneficial, but need to be compared against treatment-as-usual in further trials. https://doi.org/10.1186/ISRCTN10526888.
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Trastorno Depresivo Mayor , Neurorretroalimentación , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Mayor/patología , Proyectos Piloto , Neurorretroalimentación/métodos , Depresión , Imagen por Resonancia Magnética , Método Simple CiegoRESUMEN
BACKGROUND: Inflammation rapidly reorients motivational state, mood is impaired, pleasurable activities avoided and sensitivity to negative stimuli enhanced. When sustained, this can precipitate major depressive episodes. In humans, this has been linked to opposing actions of inflammation on striatal/insula reward/punishment learning signals while in rodents, motivational impairments can be attenuated with minocycline, implicating a mechanistic role for microglia. Here we investigated whether minocycline also inhibits the reorienting effects of lipopolysaccharide (LPS) on reward/punishment sensitivity in humans. Methods Using a crossover design, fifteen healthy volunteers underwent two experimental sessions in which they each received LPS (1 ng/kg) and placebo. Half (N = 8) received minocycline (100 mg bd) and half (N = 7) an identical looking placebo for 3½ days before each session. Six hours post-injection participants completed a probabilistic instrumental learning task in which they had to learn to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli to maximise their gains and minimize losses. Physiological and sickness responses were sampled hourly and blood sampled at baseline, 3 and 6 h post-injection. Results LPS induced robust peripheral physiological: temperature, heart rate and immune: differential white cell, IL-6, TNF-α, IL-8, IL-10 responses (all condition × time interactions: p < 0.005), none were significantly modulated by minocycline (p > 0.1). LPS also biased behavior, enhancing punishment compared with reward sensitivity (F(1,13) = 6.10, p = 0.028). Minocycline significantly attenuated this inflammation-induced shift in reward versus punishment sensitivity (F(1,13) = 4.28, p = 0.033). Conclusions These data replicate the previous finding that systemic inflammation rapidly impairs sensitivity to rewards versus punishments in humans and extend this by implicating activated microglia in this acute motivational reorientation with implications for the development of microglial-targeted immune-modulatory therapies in depression.
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Trastorno Depresivo Mayor , Castigo , Humanos , Minociclina/farmacología , Lipopolisacáridos/farmacología , Recompensa , Inflamación/tratamiento farmacológicoRESUMEN
BACKGROUND: Low-dose lipopolysaccharide (LPS) is a well-established experimental method for inducing systemic inflammation and shown by microscopy to activate microglia in rodents. Currently, techniques for in-vivo imaging of glia in humans are limited to TSPO (Translocator protein) PET, which is expensive, methodologically challenging, and has poor cellular specificity. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) sensitizes MR spectra to diffusion of intracellular metabolites, potentially providing cell-specific information about cellular morphology. In this preliminary study, we applied DW-MRS to measure changes in the apparent diffusion coefficients (ADC) of glial and neuronal metabolites to healthy participants who underwent an LPS administration protocol. We hypothesized that the ADC of glial metabolites will be selectively modulated by LPS-induced glial activation. METHODS: Seven healthy male volunteers, (mean 25.3 ± 5.9 years) were each tested in two separate sessions once after LPS (1 ng/Kg intravenously) and once after placebo (saline). Physiological responses were monitored during each session and serial blood samples and Profile of Mood States (POMS) completed to quantify white blood cell (WBC), cytokine and mood responses. DW-MRS data were acquired 5-5½ hours after injection from two brain regions: grey matter in the left thalamus, and frontal white matter. RESULTS: Body temperature, heart rate, WBC and inflammatory cytokines were significantly higher in the LPS compared to the placebo condition (p < 0.001). The ADC of the glial metabolite choline (tCho) was also significantly increased after LPS administration compared to placebo (p = 0.008) in the thalamus which scaled with LPS-induced changes in POMS total and negative mood (Adj R2 = 0.83; p = 0.004). CONCLUSIONS: DW-MRS may be a powerful new tool sensitive to glial cytomorphological changes in grey matter induced by systemic inflammation.
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Imagen de Difusión por Resonancia Magnética , Lipopolisacáridos , Encéfalo/metabolismo , Colina/metabolismo , Colina/farmacología , Imagen de Difusión por Resonancia Magnética/métodos , Humanos , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética/métodos , Masculino , Neuroglía/metabolismo , Receptores de GABA/metabolismoRESUMEN
Addiction has been proposed as a 'reward deficient' state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.
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Alcoholismo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dextroanfetamina/administración & dosificación , Dextroanfetamina/farmacología , Péptidos Opioides/metabolismo , Administración Oral , Adulto , Fentanilo/administración & dosificación , Fentanilo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismoRESUMEN
Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.
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Encéfalo/diagnóstico por imagen , Inflamación/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Acetamidas , Adulto , Atrofia , Encéfalo/patología , Radioisótopos de Carbono , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Microglía , Persona de Mediana Edad , Tamaño de los Órganos , Tomografía de Emisión de Positrones , Piridinas , Receptores de GABA , Sustancia Blanca/patología , Adulto JovenRESUMEN
The 18â kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.
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Hormona Adrenocorticotrópica/farmacología , Proteínas Portadoras/genética , Hidrocortisona/sangre , Polimorfismo de Nucleótido Simple , Receptores de GABA-A/genética , Receptores de GABA/genética , Adolescente , Adulto , Animales , Secuencia de Bases , Proteínas Portadoras/metabolismo , Ésteres del Colesterol/biosíntesis , Ésteres del Colesterol/sangre , Gonadotropina Coriónica/farmacología , Clonación Molecular , Corticosterona/biosíntesis , Corticosterona/sangre , Embrión de Mamíferos , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Humanos , Hidrocortisona/biosíntesis , Masculino , Plásmidos/química , Plásmidos/metabolismo , Pregnanolona/biosíntesis , Pregnanolona/sangre , Ratas , Ratas Transgénicas , Receptores de GABA/metabolismo , Receptores de GABA-A/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Testosterona/biosíntesis , Testosterona/sangre , Dedos de Zinc , Cigoto/efectos de los fármacos , Cigoto/crecimiento & desarrollo , Cigoto/metabolismoAsunto(s)
Trastorno Bipolar/etiología , Enfermedades Mitocondriales/complicaciones , Trastorno Bipolar/genética , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/psicología , Escalas de Valoración Psiquiátrica , Encuestas y CuestionariosRESUMEN
Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
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Encéfalo/efectos de los fármacos , Alucinógenos/farmacología , Imagen por Resonancia Magnética/métodos , Psilocibina/farmacología , Adulto , Arterias/efectos de los fármacos , Arterias/metabolismo , Encéfalo/fisiología , Mapeo Encefálico , Circulación Cerebrovascular/efectos de los fármacos , Femenino , Humanos , Masculino , Oxígeno/sangre , Perfusión , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Marcadores de SpinRESUMEN
This study aimed to replicate a previous study which showed that endogenous opioid release, following an oral dose of amphetamine, can be detected in the living human brain using [11C]carfentanil positron emission tomography (PET) imaging. Nine healthy volunteers underwent two [11C]carfentanil PET scans, one before and one 3 h following oral amphetamine administration (0.5 mg/kg). Regional changes in [11C]carfentanil BPND from pre- to post-amphetamine were assessed. The amphetamine challenge led to significant reductions in [11C]carfentanil BPND in the putamen, thalamus, frontal lobe, nucleus accumbens, anterior cingulate, cerebellum and insula cortices, replicating our earlier findings. None of the participants experienced significant euphoria/'high', supporting the use of oral amphetamine to characterize in vivo endogenous opioid release following a pharmacological challenge. [11C]carfentanil PET is able to detect changes in binding following an oral amphetamine challenge that reflects endogenous opioid release and is suitable to characterize the opioid system in neuropsychiatric disorders.
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Anfetamina/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Estimulantes del Sistema Nervioso Central/farmacología , Péptidos Opioides/metabolismo , Adulto , Anfetamina/sangre , Encéfalo/metabolismo , Mapeo Encefálico , Radioisótopos de Carbono , Estimulantes del Sistema Nervioso Central/sangre , Estudios de Cohortes , Fentanilo/análogos & derivados , Humanos , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
High ventilation breathwork with retention (HVBR) has been growing in popularity over the past decade and might be beneficial for mental and physical health. However, little research has explored the potential therapeutic effects of brief, remotely delivered HVBR and the tolerability profile of this technique. Accordingly, we investigated the effects of a fully-automated HVBR protocol, along with its tolerability, when delivered remotely in a brief format. This study (NCT06064474) was the largest blinded randomised-controlled trial on HVBR to date in which 200 young, healthy adults balanced for gender were randomly allocated in blocks of 2 by remote software to 3 weeks of 20 min daily HVBR (fast breathing with long breath holds) or a placebo HVBR comparator (15 breaths/min with short breath holds). The trial was concealed as a 'fast breathwork' study wherein both intervention and comparator were masked, and only ~ 40% guessed their group assignment with no difference in accuracy between groups. Both groups reported analogous credibility and expectancy of benefit, subjective adherence, positive sentiment, along with short- and long-term tolerability. At post-intervention (primary timepoint) for stress level (primary outcome), we found no significant group × time interaction, F(1,180) = 1.98, p = 0.16, ηp2 = 0.01, d = 0.21), nor main effect of group, (F = 0.35, p = 0.55, ηp2 < 0.01) but we did find a significant main effect of time, (F = 13.0, p < 0.01, ηp2 = 0.07). There was a significant improvement in stress pre-post-intervention in both groups, however there was no significant difference in such improvement between groups. In addition to stress at follow-up, we found no significant group x time interactions for secondary trait outcomes of anxiety, depression, mental wellbeing, and sleep-related impairment. This was also the case for state positive and negative affect after the first session of breathwork and at post-intervention. Brief remote HVBR therefore may not be more efficacious at improving mental health than a well-designed active comparator in otherwise healthy, young adults.
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Salud Mental , Humanos , Masculino , Femenino , Adulto , Adulto Joven , Ejercicios Respiratorios/métodosRESUMEN
BACKGROUND: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability-leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria. METHODS: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus-implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability. RESULTS: A decrease in global CBF and CMRO2 was observed after acutely administrating MB to all participants. Greater regional CMRO2 reductions were observed after MB, in patients compared to controls in FL (mean = -14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = -14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO2 in those regions were primarily driven by patients with longer disease duration and higher mood instability. LIMITATIONS: Sample size; medications potentially impacting on response to MB. CONCLUSIONS: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD.
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Trastorno Bipolar , Imagen por Resonancia Magnética , Azul de Metileno , Humanos , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/fisiopatología , Trastorno Bipolar/metabolismo , Trastorno Bipolar/diagnóstico por imagen , Femenino , Masculino , Adulto , Azul de Metileno/farmacología , Método Simple Ciego , Neuroimagen , Estudios Cruzados , Persona de Mediana Edad , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Giro del Cíngulo/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/diagnóstico por imagen , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacosRESUMEN
Alterations in neurometabolism and mitochondria are implicated in the pathophysiology of psychiatric conditions such as mood disorders and schizophrenia. Thus, developing objective biomarkers related to brain mitochondrial function is crucial for the development of interventions, such as central nervous system penetrating agents that target brain health. Lactate, a major circulatory fuel source that can be produced and utilized by the brain and body, is presented as a theranostic biomarker for neurometabolic dysfunction in psychiatric conditions. This concept is based on three key properties of lactate that make it an intriguing metabolic intermediate with implications for this field: Firstly, the lactate response to various stimuli, including physiological or psychological stress, represents a quantifiable and dynamic marker that reflects metabolic and mitochondrial health. Second, lactate concentration in the brain is tightly regulated according to the sleep-wake cycle, the dysregulation of which is implicated in both metabolic and mood disorders. Third, lactate universally integrates arousal behaviours, pH, cellular metabolism, redox states, oxidative stress, and inflammation, and can signal and encode this information via intra- and extracellular pathways in the brain. In this review, we expand on the above properties of lactate and discuss the methodological developments and rationale for the use of functional magnetic resonance spectroscopy for in vivo monitoring of brain lactate. We conclude that accurate and dynamic assessment of brain lactate responses might contribute to the development of novel and personalized therapies that improve mitochondrial health in psychiatric disorders and other conditions associated with neurometabolic dysfunction.
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Background: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. Methods: Systematic literature searches were conducted in MEDLINE, Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. Results: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life. One study reported baseline erythrocyte sedimentation rate (ESR) predicted LDN response (≥30% reduction in fibromyalgia symptoms) and a second study showed plasma concentrations of inflammatory biomarkers were lower after LDN treatment. To our knowledge, there are no brain imaging studies reporting the effect of LDN in patients with fibromyalgia. All studies were based on small sample sizes, were restricted to women and the risk of bias was assessed to be high. There is also some evidence of publication bias. Conclusion: The strength of evidence from randomized controlled trials to support the use of LDN among patients with fibromyalgia is low. Two small studies suggest ESR and cytokines may be involved in the mechanism by which LDN exerts its effects. Two trials (INNOVA and FINAL) are currently in progress, but further work is needed among men and different ethnic groups.
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High Ventilation Breathwork (HVB) refers to practices employing specific volitional manipulation of breathing, with a long history of use to relieve various forms of psychological distress. This paper seeks to offer a consolidative insight into potential clinical application of HVB as a treatment of psychiatric disorders. We thus review the characteristic phenomenological and neurophysiological effects of these practices to inform their mechanism of therapeutic action, safety profiles and future clinical applications. Clinical observations and data from neurophysiological studies indicate that HVB is associated with extraordinary changes in subjective experience, as well as with profound effects on central and autonomic nervous systems functions through modulation of neurometabolic parameters and interoceptive sensory systems. This growing evidence base may guide how the phenomenological effects of HVB can be understood, and potentially harnessed in the context of such volitional perturbation of psychophysiological state. Reports of putative beneficial effects for trauma-related, affective, and somatic disorders invite further research to obtain detailed mechanistic knowledge, and rigorous clinical testing of these potential therapeutic uses.
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Trastornos Mentales , Yoga , Humanos , Respiración , Sistema Nervioso Autónomo , Trastornos Mentales/terapia , PsicofisiologíaRESUMEN
Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p = 0.02) and rats (F(1,5)26.04, p = 0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p = 0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t = 2.6(16) p = 0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MB's hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MB's ability to enhance cerebral metabolism might be limited.
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Encéfalo , Azul de Metileno , Humanos , Ratas , Animales , Azul de Metileno/farmacología , Azul de Metileno/metabolismo , Encéfalo/irrigación sanguínea , Glucosa/metabolismo , Oxígeno/metabolismo , Consumo de Oxígeno , Circulación CerebrovascularRESUMEN
BACKGROUND: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. METHODS: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. RESULTS: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). CONCLUSIONS: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.
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Trastorno Depresivo Mayor , Serotonina , Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Serotonina/metabolismo , Anfetamina , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/metabolismo , Cinética , Depresión , Receptor de Serotonina 5-HT2A/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodos , DextroanfetaminaRESUMEN
BACKGROUND: There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis. METHODS: We searched "medical cannabis" on June 2019 using google.com and downloaded the first 243 websites. After excluding dead links or websites with no information about cannabis, 176 websites were included. They were then classified for their typology (e.g., commercial, government, news outlets). As an indicator of trustworthiness, we used the Journal of American Medical Association (JAMA) score, which assesses the indication of date, author, ownership of the website, and the presence of references. We also considered if a website is certified by Health-On-the-Net (HON), an independent organization, by displaying a HONCode symbol. Subsequently, we performed a content analysis to assess both the medical cannabis indications mentioned by webpages and the completeness of the information provided (whether they mentioned potential side effects and legal/regulatory issues or not). RESULTS: Analyzing 176 webpages returned by a search engine, we found that 52% of them were news websites. Pain, epilepsy, and multiple sclerosis were the most frequently mentioned therapeutic areas (cited in 92, 84 and 80 webpages, respectively), which did not always match those for which there is regulatory approval. Information was also incomplete, with only 22% of the webpages mentioning potential side effects. Health portal websites provided the most complete information, with all of them (n = 7) reporting side effects. On average, 80% of webpages had a neutral stance on the potential benefits of medical cannabis, with commercial websites having more frequently a positive stance (67%). CONCLUSIONS: We conclude that the information that can be found online is not always aligned in terms of the therapeutic areas for which science-based evidence is often still weak.
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The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks' dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities.
RESUMEN
INTRODUCTION: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including ß-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. METHODS: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. RESULTS: Following sodium acetate administration, 2.5-6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. CONCLUSIONS: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.
Asunto(s)
Encéfalo/metabolismo , Fentanilo/análogos & derivados , Péptidos Opioides/metabolismo , Acetato de Sodio/farmacología , Adulto , Analgésicos Opioides/metabolismo , Encéfalo/efectos de los fármacos , Radioisótopos de Carbono , Fentanilo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Receptores Opioides/metabolismo , Acetato de Sodio/administración & dosificaciónRESUMEN
In the present study we extract clusters of symptoms in acute hospitalized psychotic patients during a re-exacerbation phase, using factor analysis of BPRS-E. We aim to investigate the relative contribution of each symptom dimension in predicting the severity of symptoms at discharge, the length of acute hospitalization, and the occurrence of aggressive behaviours during acute hospitalization. The data are drawn from a prospective, naturalistic, observational study of 183 patients with Psychotic Disorders consecutively admitted to a psychiatric ward, during a re-exacerbation phase. General symptomatology has been measured through BPRS-E at admission and at discharge. Statistical analyses include principal component analysis and multiple linear regression.We found symptoms of acute psychosis disorder to cluster together in four distinct domains, labelled "Excitement/Activation", "Positive symptoms", and "Negative symptoms", and "Depression/Anxiety". Excitement/activation was the dimension most associated with occurrence of aggressive behaviours and severity of psychopathological symptoms at discharge. The negative symptoms dimension, also, predicted the severity of symptoms at discharge. Positive and negative symptoms dimensions were both predictors of duration of hospitalization. The depressive dimension was significantly associated only to self-aggression. These data indicate that during acute hospitalization due to re-exacerbation of psychosis each symptom dimension has a specific impact on distinct measures of outcome.