NEUROTRANSMITTERS AND RESTING STATE NETWORKS: CLINICAL IMPLICATION FOR MAJOR PSYCHIATRIC DISORDER

Alterations in brain intrinsic activity \u2013 as organized in resting-state networks (RSNs) such as sensorimotor network (SMN), salience network (SN) and default-mode network (DMN) \u2013 and in neurotransmitters signaling \u2013 such as dopamine (DA) and serotonin (5-HT) \u2013 have been independently detected in psychiatric disorders like bipolar disorder and schizophrenia. Thus, the aim of this work was to investigate the relationship between such neurotransmitters and RSNs in healthy, by reviewing the relevant work on this topic and performing complementary analyses, in order to better understand their physiological link as well as their alterations in psychiatric disorders. According to the reviewed data, neurotransmitters nuclei diffusively project to subcortical and cortical regions of RSNs. In particular, the dopaminergic substantia nigra (SNc)-related nigrostriatal pathway is structurally and functionally connected with core regions of the SMN, while the ventral tegmental area (VTA)-related mesocorticolimbic pathway with core regions of the SN. The serotonergic raphe nuclei (RNi) connections involve regions of the SMN and DMN. Coherently, changes in neurotransmitters activity impact the functional configuration and level of activity of RSNs, as measured by functional connectivity (FC) and amplitude of low-frequency fluctuations/temporal variability of BOLD signal. Specifically, DA signaling is associated with increase in FC and activity in the SMN (hypothetically via the SNc-related nigrostriatal pathway) and SN (hypothetically via the VTA-related mesocorticolimbic pathway), as well as concurrent decrease in FC and activity in the DMN. By contrast, 5-HT signaling (via the RNi-related pathways) is associated with decrease in SMN activity along with increase in DMN activity. Complementally, our empirical data showed a positive correlation between SNc-related FC and SMN activity, while a negative correlation between RNi-related FC and SMN activity (along with tilting of networks balance toward the DMN). According to these data, we hypothesize that the activity of neurotransmitters-related neurons synchronize the low-frequency oscillations within different RSNs regions, thus affecting the baseline level of RSNs activity and their balancing. In our model, DA signaling favors the predominance of SMN-SN activity, while 5-HT signaling favors the predominance of DMN activity, manifesting in distinct behavioral patterns. In turn, alterations in neurotransmitters signaling (or its disconnection) may favor a correspondent functional reorganization of RSNs, manifesting in distinct psychopathological states. The here suggested model carries important implications for psychiatric disorders, providing novel and well testable hypotheses especially on bipolar disorder and schizophrenia

Diminished Posterior Precuneus Connectivity with the Default Mode Network Differentiates Normal Aging from Alzheimer's Disease

Multivariate analysis of psychological dat

A small number of abnormal brain connections predicts adult autism spectrum disorder

abstract: Although autism spectrum disorder (ASD) is a serious lifelong condition, its underlying neural mechanism remains unclear. Recently, neuroimaging-based classifiers for ASD and typically developed (TD) individuals were developed to identify the abnormality of functional connections (FCs). Due to over-fitting and interferential effects of varying measurement conditions and demographic distributions, no classifiers have been strictly validated for independent cohorts. Here we overcome these difficulties by developing a novel machine-learning algorithm that identifies a small number of FCs that separates ASD versus TD. The classifier achieves high accuracy for a Japanese discovery cohort and demonstrates a remarkable degree of generalization for two independent validation cohorts in the USA and Japan. The developed ASD classifier does not distinguish individuals with major depressive disorder and attention-deficit hyperactivity disorder from their controls but moderately distinguishes patients with schizophrenia from their controls. The results leave open the viable possibility of exploring neuroimaging-based dimensions quantifying the multiple-disorder spectrum.The final version of this article, as published in Nature Communications, can be viewed online at: https://www.nature.com/articles/ncomms1125

Classic Psychedelic Drugs: Update on Biological Mechanisms

Renewed interest in the effects of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. During the past two decades, state-of-the-art studies of animals and humans have yielded new important insights into the molecular, cellular, and systems-level actions of psychedelic drugs. These efforts have revealed that psychedelics affect primarily serotonergic receptor subtypes located in cortico-thalamic and cortico-cortical feedback circuits of information processing. Psychedelic drugs modulate excitatory-inhibitory balance in these circuits and can participate in neuroplasticity within brain structures critical for the integration of information relevant to sensation, cognition, emotions, and the narrative of self. Neuroimaging studies showed that characteristic dimensions of the psychedelic experience obtained through subjective questionnaires as well as alterations in self-referential processing and emotion regulation obtained through neuropsychological tasks are associated with distinct changes in brain activity and connectivity patterns at multiple-system levels. These recent results suggest that changes in self-experience, emotional processing, and social cognition may contribute to the potential therapeutic effects of psychedelics

Effect of Pharmacological Interventions on the Fronto-Cingulo-Parietal Cognitive Control Network in Psychiatric Disorders: A Transdiagnostic Systematic Review of fMRI Studies

Executive function deficits such as working memory, decision-making, and attention problems are a common feature of several psychiatric disorders for which no satisfactory treatment exists. Here, we transdiagnostically investigate the effects of pharmacological interventions (other than methylphenidate) on the fronto-cingulo-parietal cognitive control network, in order to identify functional brain markers for future pro-cognitive pharmacological interventions. 29 manuscripts investigated the effect of pharmacological treatment on executive function-related brain correlates in psychotic disorders (n=11), depression (n=4), bipolar disorder (n=4), ADHD (n=4), OCD (n=2), smoking dependence (n=2), alcohol dependence (n=1) and pathological gambling (n=1). In terms of impact on the fronto-cingulo-parietal networks, the preliminary evidence for catechol-o-methyl-transferase inhibitors, nicotinic receptor agonists and atomoxetine suggested was relatively consistent, the data for atypical antipsychotics and anticonvulsants moderate, and interpretation of the data for antidepressants was hampered by the employed study designs. Increased activity in task-relevant areas and decreased activity in task-irrelevant areas were the most common transdiagnostic effects of pharmacological treatment. These markers showed good positive and moderate negative predictive value. It is concluded that fronto-cingulo-parietal activity changes can serve as a marker for future pro-cognitive interventions. Future recommendations include the use of randomized double-blind designs and selective cholinergic and glutamatergic compounds

Default mode network modulation by psychedelics : a systematic review

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics

Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity

Neuro Imaging Researc

Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity

The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity. We used this non-invasive neuroimaging technique to measure acute pharmacological effects of the selective serotonin reuptake inhibitor sertraline (75 mg) in 12 healthy volunteers. In this randomized, double blind, placebo-controlled, crossover study, RS-fMRI scans were repeatedly acquired during both visits (at baseline and 3, 5, 7 and 9 h after administering sertraline or placebo). Within-group comparisons of voxelwise functional connectivity with ten functional networks were examined (p < 0.005, corrected) using a mixed effects model with cerebrospinal fluid, white matter, motion parameters, heart rate and respiration as covariates. Sertraline induced widespread effects on functional connectivity with multiple networks; the default mode network, the executive control network, visual networks, the sensorimotor network and the auditory network. A common factor among these networks was the involvement of the precuneus and posterior cingulate cortex. Cognitive and subjective measures were taken as well, but yielded no significant treatment effects, emphasizing the sensitivity of RS-fMRI to pharmacological challenges. The results are consistent with the existence of an extensive serotonergic system relating to multiple brain functions with a possible key role for the precuneus and cingulate

Human brain effects of DMT assessed via EEG-fMRI.

Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT's effects. The present findings advance on previous work by confirming a predominant action of DMT-and likely other 5-HT2AR agonist psychedelics-on the brain's transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors