7,683 research outputs found

    Cerebral blood flow predicts differential neurotransmitter activity

    Get PDF
    Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans

    Dopamine-induced dissociation of BOLD and neural activity in macaque visual cortex

    Get PDF
    Neuromodulators determine how neural circuits process information during cognitive states such as wakefulness, attention, learning, and memory [1]. fMRI can provide insight into their function and dynamics, but their exact effect on BOLD responses remains unclear [2, 3 and 4], limiting our ability to interpret the effects of changes in behavioral state using fMRI. Here, we investigated the effects of dopamine (DA) injections on neural responses and haemodynamic signals in macaque primary visual cortex (V1) using fMRI (7T) and intracortical electrophysiology. Aside from DA’s involvement in diseases such as Parkinson’s and schizophrenia, it also plays a role in visual perception [5, 6, 7 and 8]. We mimicked DAergic neuromodulation by systemic injection of L-DOPA and Carbidopa (LDC) or by local application of DA in V1 and found that systemic application of LDC increased the signal-to-noise ratio (SNR) and amplitude of the visually evoked neural responses in V1. However, visually induced BOLD responses decreased, whereas cerebral blood flow (CBF) responses increased. This dissociation of BOLD and CBF suggests that dopamine increases energy metabolism by a disproportionate amount relative to the CBF response, causing the reduced BOLD response. Local application of DA in V1 had no effect on neural activity, suggesting that the dopaminergic effects are mediated by long-range interactions. The combination of BOLD-based and CBF-based fMRI can provide a signature of dopaminergic neuromodulation, indicating that the application of multimodal methods can improve our ability to distinguish sensory processing from neuromodulatory effects

    Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring

    Get PDF
    Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia

    The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

    Get PDF
    Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

    Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition.

    Get PDF
    Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits

    An approach for identifying brainstem dopaminergic pathways using resting state functional MRI.

    Get PDF
    Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks

    Dopaminergic basis for signalling belief updates, but not surprise, and the link to paranoia

    Get PDF
    Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine’s role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based functional magnetic resonance imaging (fMRI) task designed to separate the neural processing of meaningful and meaningless sensory information. We modelled participant behaviour using a normative Bayesian observer model, and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired positron emission tomography (PET) imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioural sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans, and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted

    Hallucinogens: mechanisms and medical complications

    Full text link
    Thesis (M.A.)--Boston UniversityHallucinogens are drugs that alter consciousness by distorting primarily auditory and visual perception but they can affect any sensory system. Hallucinogens also affect judgment, orientation, memory, or emotion. Despite the profound alteration in perception, adverse effects are minimal and hallucinogens are not addictive. Hallucinogen use has its roots in shamanic practices of indigenous cultures and is even incorporated in today’s religions like the Native American Church. By putting a person in an altered state of consciousness, many religions believed that the user was able to see beyond the boundaries of reality and reach out to mythical beings. Hallucinogen use in scientific research was not popular until the 1950’s when Albert Hoffman discovered lysergic acid diethylamide (LSD). The discovery of drug encouraged further research into understanding its mechanisms and its relationship with mental diseases like schizophrenia. Unfortunately, the Comprehensive Drug Abuse Prevention and Control Act of 1970 significantly limited hallucinogenic research and human research for the last 42 years. However, animal research in the last 20 years has determined the importance of serotonergic mechanisms and more specifically the 5-HT2A receptors in mediating LSD’s hallucinogenic effects. Researchers continue to identify mechanisms of LSD action. In addition to serotonergic actions, LSD is active with dopaminergic and metabotropic glutamate receptors. PET scans and fMRI’s have also revealed the importance of the prefrontal cortical region and its interaction with other areas during a hallucinogenic state. The relationship between LSD and acute psychosis is also being explored via animal models. Although human clinical research is limited, recent research sees a much deeper relationship by linking LSD brain activity and neurotransmitter levels to psychotic behaviors. This further understanding of hallucinogens on a physiological and psychological level has led to possible psychotherapeutic areas of research in anxiety and substance abuse. This thesis describes a brief history of hallucinogenic research, the pharmacology and neuroanatomy of serotonergic hallucinogens, the acute and chronic adverse effects of serotonergic hallucinogens, the possible treatments for complications of hallucinogens, the epidemiology, the relationship between hallucinogens and schizophrenia, and possible therapeutic uses of serotonergic hallucinogens. With its minimal adverse effects in humans and its powerful influence on the human psyche, serotonergic hallucinogens are invaluable tools for understanding the human mind

    Internet and gaming addiction: a systematic literature review of neuroimaging studies

    Get PDF
    In the past decade, research has accumulated suggesting that excessive Internet use can lead to the development of a behavioral addiction. Internet addiction has been considered as a serious threat to mental health and the excessive use of the Internet has been linked to a variety of negative psychosocial consequences. The aim of this review is to identify all empirical studies to date that used neuroimaging techniques to shed light upon the emerging mental health problem of Internet and gaming addiction from a neuroscientific perspective. Neuroimaging studies offer an advantage over traditional survey and behavioral research because with this method, it is possible to distinguish particular brain areas that are involved in the development and maintenance of addiction. A systematic literature search was conducted, identifying 18 studies. These studies provide compelling evidence for the similarities between different types of addictions, notably substance-related addictions and Internet and gaming addiction, on a variety of levels. On the molecular level, Internet addiction is characterized by an overall reward deficiency that entails decreased dopaminergic activity. On the level of neural circuitry, Internet and gaming addiction led to neuroadaptation and structural changes that occur as a consequence of prolonged increased activity in brain areas associated with addiction. On a behavioral level, Internet and gaming addicts appear to be constricted with regards to their cognitive functioning in various domains. The paper shows that understanding the neuronal correlates associated with the development of Internet and gaming addiction will promote future research and will pave the way for the development of addiction treatment approaches
    corecore