Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization

Functional brain imaging in the dog : Single Photon Emission Tomography as a research and clinical tool for the investigation of canine brain physiology and pathophysiology

summary of doctoral dissertatio

Neurobiological Correlates of Personality Traits: A Study on Harm Avoidance and Neuroticism

Harm Avoidance and Neuroticism are traits that predispose to mental illnesses. Studying them provides a unique way to study predisposition of mental illnesses. Understanding the biological mechanisms that mediate vulnerability could lead to improvement in treatment and ultimately to pre-emptive psychiatry. These personality traits describe a tendency to feel negative emotions such as fear, shyness and worry. Previous studies suggest these traits are regulated by serotonin and opiate pathways. The aim of this thesis was to test the following hypotheses using personality trait measures and positron emission tomography (PET): 1) Brain serotonin transporter density in vivo is associated with Harm Avoidance and Neuroticism traits. 2) μ-opioid receptor binding is associated with Harm Avoidance. In addition, we developed a methodology for studying neurotransmitter interactions in the brain using the opiate and serotonin pathways. 32 healthy subjects who were consistently in either the highest or lowest quartile of the Harm Avoidance trait were recruited from a population-based cohort. Each subject underwent two PET scans, serotonin transporter binding was measured with [11C] MADAM and μ-opioid receptor binding with [11C]carfentanil. We found that the serotonin transporter is not associated with anxious personality traits. However, Harm Avoidance positively correlated with μ-opioid receptor availability. Particularly the tendency to feel shy and the inability to cope with stress were associated μ-opioid receptor availability. We also demonstrated that serotonin transporter binding correlates with μ-opioid receptor binding, suggesting interplay between the two systems. These findings shed light on the neurobiological correlates of personality and have an impact on etiological considerations of affective disorders.Persoonallisuuden neurobiologiset taustatekijät Turvallisuushakuisuus ja neuroottisuus ovat persoonallisuuden piirteitä, joihin liittyy ahdistustaipumus ja joiden on osoitettu altistavan mielenterveyshäiriöille. Tutkimalla näitä persoonallisuuspiirteitä on mahdollisuus saada ainutlaatuista tietoa myös alttiudesta sairastua mielenterveyshäiriöön. Tällaista tietoa voitaisiin käyttää hyväksi psykiatrisen hoidon ja sairauksien ennaltaehkäisyn kehittämiseen. Turvallisuushakuisuus ja neuroottisuus kuvaavat taipumusta kokea negatiivisia tunteita kuten pelkoa, ujoutta ja huolta. Aikaisempien tutkimusten perusteella aivojen serotoniini ja opioidijärjestelmien ajatellaan olevan yhteydessä näihin persoonallisuuden piirteisiin. Tässä väitöskirjatyössä käytettiin positroniemissiotomografia (PET) –tekniikkaa aivojen välittäjäainejärjestelmien toiminnan mittaamiseen ja persoonallisuuskyselyjä (TCI, NEO) persoonallisuuspiirteiden määrittelyyn. Tutkimuksessa testattiin seuraavia hypoteeseja: serotoniinin takaisinottajaproteiini on yhteydessä turvallisuushakuisuuteen, serotoniinin takaisinottajaproteiini on yhteydessä neuroottisuuteen ja μ-opioidireseptori on yhteydessä turvallisuushakuisuuteen. Lisäksi tutkimuksessa kehitettiin menetelmä välittäjäaineverkoston tutkimiseen PET menetelmällä. Tutkimukseen värvättiin laajasta väestöpohjaisesta kohorttitutkimuksesta 32 tervettä koehenkilöä, jotka olivat toistettujen mittausten perusteella turvallisuushakuisuuden suhteen joko ylimmässä tai alimmassa kvartiilissa. Kaikille koehenkilöille tehtiin kaksi PET-kuvausta saman päivän aikana. Ensimmäisessä kuvauksessa käytettiin [11C]MADAM–merkkiainetta mittaamaan serotoniinin takaisinottajaproteiinisitoutumista. Toisessa kuvauksessa käytettiin [11C]karfentaniili–merkkiainetta mittaamaan μ-opioidireseptorisitoutumista. Tämän tutkimuksen perusteella serotoniinin takaisinottajaproteiini ei ollut yhteydessä turvallisuushakuisuuteen eikä neuroottisuuteen. Tutkimuksessa havaittiin kuitenkin positiivinen korrelaatio turvallisuushakuisuuden ja μ-opioidireseptorin välillä. Erityisesti ujous ja taipumus tuntea itsensä turvattomaksi vieraiden ihmisten seurassa sekä kyky selvitä stressistä olivat yhteydessä μ-opioidireseptoriin. Lisäksi serotoniinin takaisinottajaproteiinin havaittiin olevan yhteydessä μ-opioidireseptoriin tietyillä aivoalueilla, jotka liittyvät mieliala- ja ahdistuneisuushäiriöihin. Näitä löydöksiä voidaan tulevaisuudessa hyödyntää mielenterveyshäiriöiden etiologisessa ja mahdollisesti ennaltaehkäisevässä tutkimuksessa.Siirretty Doriast

In vivo imaging of dopamine and serotonin release: response to psychopharmacological challenges

De neurotransmitters dopamine en serotonine zijn betrokken bij vele processen waaronder de regulatie van beloningsmechanismen (dopamine) en de stemming (serotonine). Ook is gevonden dat deze neurotransmitters betrokken zijn bij het ontstaan en de behandeling van verschillende psychiatrische en neurologische ziektebeelden. Het is echter nog steeds niet bekend wat de precieze rol van deze neurotransmitters hierbij is. Met behulp van neuroimaging technieken zoals PET (positron emission tomography) is het mogelijk om hierin meer inzicht te krijgen. In dit proefschrift werden een aantal methoden onderzocht die gericht zijn op het meten van de serotonerge en dopaminerge transmissie. In de eerste studies van dit proefschrift werd onderzocht of PET gebruikt kan worden om veranderingen in serotonine afgifte te meten. Hierbij werd gebruik gemaakt van de serotonine-1A ligand 18F-MPPF. Het principe van deze methode berust op het gegeven dat de binding van een radioligand wordt beïnvloed door veranderingen in de neurotransmitterconcentratie. Deze studies werden uitgevoerd bij gezonde vrijwilligers en proefdieren. Helaas bleek de binding van 18F-MPPF niet gevoelig voor veranderingen in de serotonineconcentratie. In een volgende studie werd het effect van een verhoging van de dopamineconcentratie onderzocht met behulp van de dopamine D2 ligand 11C-raclopride, bij gezonde vrijwilligers. Hierbij werd ondermeer een verband gevonden tussen de mate van dopamineafgifte en emoties zoals angst en euforie. In de laatste studie werd het effect van een dopamine toename op de hersenactiviteit gemeten met behulp van 15O-H2O PET. In deze studie werd een relatie gevonden tussen de dopamine-geïnduceerde toename in activiteit in de “anterior cingulate cortex” en de mate van euforie. Deze laatste twee methoden kunnen mogelijk worden toegepast bij patiëntenonderzoek en onderzoek naar het werkingsmechanisme van geneesmiddelen.

The Molecular-enriched Functional Circuits Underlying Consciousness and Cognition

Homo Sapiens consist of trillions of atoms, each inanimate, yet somehow collectively constituting a conscious being. The fundamental question of how organisms are organised to beget consciousness and cognition has largely been approached through independent examination of the structure and function of the nervous system at varying levels of granularity. As neuroscience progresses, it has thus increasingly fragmented into separate streams of research which study the brain at these different scales. This has resulted in the field becoming “data rich, but theory poor”, which is largely attributable to the paucity of methods which bridge these levels of analysis to provide novel trans-hierarchical insights and inform unified theories. The research in this doctoral thesis therefore aims to explore how a specific type of multimodal analysis - Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) – can begin to bridge the theoretic void between molecular level mechanisms and systems levels dynamics to provide novel perspectives on the function and dysfunction of the brain. First, I provide a narrative synthesis of the challenges precluding a meaningful understanding of the human brain utilising conventional functional neuroimaging and outlining how incorporation of molecular information may help overcome these limitations. Specifically, by embedding functional dynamics in the molecular landscape of the brain, we can begin to move from the simple characterisation of “where” cognitive phenomena may be within the brain towards mechanistic accounts of “how” they are produced. Additionally, this offers enticing opportunities to link pharmacological treatments to novel molecular-network based biomarkers. Second, I explore how networks enriched with the spatial configurations of serotonergic and dopaminergic receptor subtypes are modulated by lysergic acid diethylamide (LSD) as compared to placebo in healthy participants. The results highlight the challenges of disentangling pharmacodynamics of drugs exhibiting rich pharmacology as well as identifying differential relationship between serotonergic and dopaminergic networks and phenomenological sub- components of psychedelic state. Third, I expand the remit of molecular-enriched network analyses beyond pure psychopharmacology to examine the direct and indirect actions of propofol anaesthesia on inhibitory and modulatory neurotransmission at both rest as well as during a naturalistic listening task. This work demonstrates for the first time that these molecular-networks can capture broader perceptual and cognitive-driven network reconfigurations as well as indirect pharmacological actions on neuromodulatory systems. Moreover, it provides evidence that the effects of propofol on consciousness are enacted through both direct inhibitory as well as indirect neuromodulatory mechanisms.Finally, I produce normative models of networks enriched with the principal neuromodulatory, excitatory, and inhibitory transmitter systems, testing their capacity to characterise neural dysfunction within and across several neuropsychiatric disorders. This work provides a computational foundation for large scale integration of molecular mechanisms and functional imaging to provide novel individualised biomarkers for neuropsychiatric disorders. Collectively, this thesis offers methodological and theoretical progress towards a trans-hierarchical characterisation of the human brain, providing insights into the neural correlates of both conscious contents and level as well as the perturbations underlying key neuropsychiatric conditions

Sex steroid hormones and brain function:PET imaging as a tool for research

Sex steroid hormones are major regulators of sexual characteristic among species. These hormones, however, are also produced in the brain. Steroidal hormone-mediated signalling via the corresponding hormone receptors can influence brain function at the cellular level and thus affect behaviour and higher brain functions. Altered steroid hormone signalling has been associated with psychiatric disorders, such as anxiety and depression. Neurosteroids are also considered to have a neuroprotective effect in neurodegenerative diseases. So far, the role of steroid hormone receptors in physiological and pathological conditions has mainly been investigated post mortem on animal or human brain tissues. To study the dynamic interplay between sex steroids, their receptors, brain function and behaviour in psychiatric and neurological disorders in a longitudinal manner, however, non-invasive techniques are needed. Positron emission tomography (PET) is a non-invasive imaging tool that is used to quantitatively investigate a variety of physiological and biochemical parameters in vivo. PET uses radiotracers aimed at a specific target (eg, receptor, enzyme, transporter) to visualise the processes of interest. In this review, we discuss the current status of the use of PET imaging for studying sex steroid hormones in the brain. So far, PET has mainly been investigated as a tool to measure (changes in) sex hormone receptor expression in the brain, to measure a key enzyme in the steroid synthesis pathway (aromatase) and to evaluate the effects of hormonal treatment by imaging specific downstream processes in the brain. Although validated radiotracers for a number of targets are still warranted, PET can already be a useful technique for steroid hormone research and facilitate the translation of interesting findings in animal studies to clinical trials in patients

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.</p

The alpha2C-adrenoceptor as a neuropsychiatric drug tar-get - PET studies in human subjects

Positron emission tomography imaging has both academic and applied uses in revealing the distribution and density of different molecular targets in the central nervous system. Following the significant progress made with the dopamine D2 receptor, advances have been made in developing PET tracers to allow analysis of receptor occupancy of many other receptor types as well as evaluating changes in endogenous synaptic transmitter concentrations of transmitters e.g. serotonin and noradrenaline. Noradrenergic receptors are divided into α1-, α2- and β-adrenoceptor subfamilies, in humans each of which is composed of three receptor subtypes. The α2-adrenoceptors have an important presynaptic auto-inhibitory function on noradrenaline release but they also have postsynaptic roles in modulating the release of other neurotransmitters, such as serotonin and dopamine. One of the subtypes, the α2C-adrenoceptor, has been detected at distinct locations in the central nervous system, most notably the dorsal striatum. Several serious neurological conditions causing dementia, Alzheimer’s disease and Parkinson’s disease have been linked to disturbed noradrenergic signaling. Furthermore, altered noradrenergic signaling has also been implicated in conditions like ADHD, depression, anxiety and schizophrenia. In order to benefit future research into these central nervous system disorders as well as being useful in the clinical development of drugs affecting brain noradrenergic neurotransmission, validation work of a novel tracer for positron emission tomography studies in humans was performed. Altogether 85 PET imaging experiments were performed during four separate clinical trials. The repeatability of [11C]ORM-13070 binding was tested in healthy individuals, followed by a study to evaluate the dose-dependent displacement of [11C]ORM-13070 from α2C-adrenoceptors by a competing ligand, and the final two studies examined the sensitivity of [11C]ORM-13070 binding to reflect changes in endogenous noradrenaline levels. The repeatability of [11C]ORM-13070 binding was very high. The binding properties of the tracer allowed for a reliable estimation of α2C-AR occupancy by using the reference tissue ratio method with low test-retest variability. [11C]ORM-13070 was dose-dependently displaced from its specific binding sites by the subtype-nonselective α2-adrenoceptor antagonist atipamezole, and thus it proved suitable for use in clinical drug development of novel α2C-adrenoceptor ligands e.g. to determine the best doses and dosing intervals for clinical trials. Convincing experimental evidence was gained to support the suitability of [11C]ORM-13070 for detecting an increase in endogenous synaptic noradrenaline in the human brain. Tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, although statistical significance was not reached. Thus, the investigation was unable to fully validate [11C]ORM-13070 for the detection of pharmacologically evoked reductions in noradrenaline levels.Siirretty Doriast

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies