Sleep is crucial for overall well-being and normal cognitive function [1], with acute decreases in several cognitive functions after sleep loss [2,3]. Despite an increased attention to the general health benefits of sleep [4], the physiology of sleep remains poorly understood. The glymphatic system is a mechanism that regulates interstitial fluid flow and waste clearance by means of cerebrospinal fluid (CSF). Recent evidence proposes a close relationship between the glymphatic system and sleep [5,6,7], possibly through slow rhythmic contractions and relaxations of brain vasculature termed vasomotion [8,9,10]. In human non-rapid eye movement (NREM) sleep, neural low-frequency electroencephalographic oscillations have been linked to hemodynamic oscillations, which are in turn coupled to CSF oscillations [11]. Although low-frequency CSF oscillations have become an area of increasing interest [12,13], little has been done to look at what drives the coupling between vasomotion and the glymphatic system in humans. The impact of sleep deprivation on the glymphatic system poses a particularly interesting subject, as it may provide insight into the underlying mechanisms linking sleep loss to cognitive decline and neurodegenerative disorders [14].
This study will be part of a multi-center study, contributing to build the EBRAINS 2.0 database. It will be part of the planned “penta-model or 5M Healthy Connectome”, which will include multimodal within-subject data in healthy controls from simultaneously obtained structural and functional MRI, PET, EEG, and neuropsychological testing, giving the opportunity to tackle the question of intra- and intersubject variability. In total, more than 200 healthy volunteers from Denmark, Germany, Austria, and Italy are participating in the project, divided into different age groups ranging from 20 to 80 years. Approximately 60 participants are from Denmark and the acquired data will be integrated in the EBRAINS atlases. The novelty of our research project lies in the fact that, by studying a large number of individuals, we can gain much deeper insight into how the brain functions on multiple levels and understand what this means for aspects like memory and reactions.
Aging is associated with a wide range of molecular and structural changes throughout an individual's lifespan, resulting in the deterioration of physical abilities and increased risk of disease [1]–[3]. In the brain, aging results in cognitive decline [4] and predisposes to neurodegenerative disorders like Alzheimer’s disease and Parkinson’s disease [5]. Therefore, developing biomarkers capable of robustly capturing age-related biological changes is necessary to understand the pathophysiology of various disorders and potentially assess the effects of interventions that target aging [2], [6].
ADHD is a disabling neuropsychiatric disorder with high prevalence and a detailed pathogenesis that remains to be elucidated. All medications currently approved to treat ADHD are thought to exert therapeutic effects by manipulation of norepinephrine and/or dopamine. Given the efficacy of ADHD psychostimulant treatment, dopaminergic and noradrenergic neurotransmission is thought to be the main biological substrate of ADHD. However, several lines of evidence also suggest an involvement of serotonin in aspects of the disorder. For example, emotional dysregulation with mood swings and irritability, closely linked to serotonergic pathways, has lately been discussed as an additional core symptom of ADHD, and impulsivity, which is a core diagnostic feature in ADHD, is modulated by serotonin signaling. The serotonin 1B (5-HT1B) receptor is a likely substrate through which serotonin may influence reward and impulsive action. Striatal 5-HT1B receptors are critical for the modulation of impulsive action, possibly through modulation of reward value by interactions with dopamine signaling. This raises the question whether the attenuated dopamine function and reward processing in ADHD can be attributed to alterations in 5-HT1B receptor levels.
Although many women with ADHD report a premenstrual worsening of symptoms, not much research have been made on the subject. Studies show heterogenous results on the influence of sex hormones on cognitive functions across the menstrual cycle, but several studies show that sex hormones, especially estrogen, can interact with the neurotransmitter systems related to cognitive functions that are affected in ADHD. Therefore, it may be reasonable to believe that women with ADHD experience fluctuations in the severity of their ADHD-symptoms during the menstrual cycle.
Psychedelic drugs such as LSD and psilocybin are showing promising efficacy in clinical trials for the treatment of mood and addictive disorders as well as providing a new tool for investigating altered states of consciousness in the human brain. As with other psychedelic compounds, LSD produces profound psychological effects, and possibly therapeutic effects via agonism of the 5-HT2A receptor.
Currently, the degree to which LSD occupies its primary site of action at each dose is unknown. As such, it is not known what doses of LSD should be considered low, medium or high for use in clinical trials. By using positron emission tomography and the novel radioligand CIMBI-36, an agonist at the 5-HT2A receptor, we will be able to establish the relation between LSD doses and % occupancy at this site.
The overall aim of BrainDrugs is to establish which key features predict drug response in patients with epilepsy or major depression disorder (MDD).
Depression is the leading cause of disability worldwide. Meanwhile, there is growing evidence that Major Depressive Disorder (MDD) describes not just one but several subtypes of brain disorders, each with potentially different biological and psychological causes and disease mechanisms. Possibly, why almost one in three patients do not respond to standard treatment with first- or second-line antidepressants.
Establishing the deep phenotyping depression cohort is part of the BrainDrugs thematic research alliance within precision medicine in epilepsy and depression funded by the Lundbeck Foundation. The project is in collaboration with the Mental Health services in the Capital Region, by Professor Martin Balslev Jørgensen and PhD-student Kristian Reveles Jensen.
Epilepsy is traditionally classified as a disease with recurrent epileptic seizures. However, for many patients psychiatric symptoms, cognitive decline and behavioral change affect quality of life more than seizures, and symptoms may even be present before the first seizure. This could imply a common pathophysiological mechanism, that translates into changes in brain anatomical pathways and functional networks early in the disease process.
As part of the BrainDrugs research alliance, in the BrainDrugs-Epilepsy study, we aim to establish cohorts of newly diagnosed drug naïve epilepsy patients along with patients, who experienced their first epileptic seizure. We will follow the patients for 5 years in an open, longitudinal, cohort study and collect a wide range of markers that may cause, modify or label the pathphysiological processes that determine the course of epilepsy in individual patients. These factors include biomarkers of brain morphology and networks using neuroimaging and high-definition EEG, and variety of other factors including demographics, life style, personality traits and cognition (see Figure 1).
The ultimate goal is to predict patient-level treatment response that can aid early implementation of preventive strategies and treatment decisions in the clinical setting and thereby improve patient care and quality of life.
The Maternal Mental Health (MAMA) trial is a placebo-controlled trial evaluating the preventive effect of transdermal estradiol treatment in the immediate postpartum on depressive episodes. The trial is conducted in a multi-center setting involving maternity wards at three university hospitals in the Capital Region of Denmark.
Evidence from National Health Registers in several countries has shown that starting on oral contraceptives is associated with an increased risk of developing depressive episodes. We do not know why this is, but changes in the internal communication in the brain via the serotonergic brain system might play a role. Intriguingly, we have found a lower level of the serotonin 4 receptor globally in the brain of healthy women using oral contraceptives compared to non-users, however this is a cross-sectional observation that cannot directly inform on causality. The difference between OC users and non-users is comparable to what we see in depressed individuals compared to healthy controls.
In The Pill Project we will apply a longitudinal study design to determine if starting on oral contraceptives induces a reduction in the serotonin 4 receptor in healthy women and whether such changes are related to changes in cognition as well as mood/affect and sexual desire.
It is standard procedure in Danish hospitals to employ general anesthesia when small children (< 8-10 years) are in need of medical imaging procedures, such as an MRI. The anesthesia reduces motion artefacts and is useful when dealing with anxious children. Although complications directly related to general anesthesia are rare, there is an increasing concern about the potential neurotoxic effects of general anesthesia. Additionally, there are logistic and financial challenges associated with the use of general anesthesia. In the MoCo project we want to test the clinical efficacy a new approach of imaging children, including preparation and training and introducing a novel marker-less motion tracking device “Tracoline” that can register children’s movements while scanning.
The OCD-project is a double-blind placebo-controlled study of individuals with the Obsessive-Compulsive Disorder (OCD) and healthy individuals matched on sex and age. Here, we evaluate how a three-week treatment with the drug selective serotonin reuptake inhibitor (SSRI) affects the serotonin receptor 4, measured with Positron Emission Tomography (PET), and compulsive behaviour, measured with functional Magnetic Resonance Imaging (fMRI) and sophisticated neuropsychological testing (Cambridge Neuropsychological Test Automated Battery and EMOTICOM). The project is a collaboration between NRU and Professor and cognition expert Trevor Robbins and post doc Paula Banca from The University of Cambridge, UK.
Synapses are the points of communication between neurons and they are subject to adaptations to the extent to which they are used, i.e., synaptic plasticity, which is key to enforce learning or rehabilitation. In this project, we will investigate synaptic plasticity with a novel radioligand 11C-UCB-J and positron emission tomography (PET). This enables neuroimaging of the presynaptic marker, synaptic vesicle glycoprotein 2A (SV2A).
We will examine synaptic plasticity in healthy people exposed to two different antidepressants, i.e., serotonin transporter inhibitors (SSRI) and the psychedelic drug psilocybin, both known to increase synaptic density in animals. Next, in a longitudinal setup in patients, we will follow the regeneration of synapses following stroke.
The overall aim of this project is to investigate whether brain pulsations, as measured by ultra-fast magnetic resonance imaging (UFMR), are influenced by dynamic and chronic changes in intracranial pressure. If this is the case, the UFMR-method could be a valuable non-invasive tool for diagnosing and monitoring conditions with increased intracranial pressure (ICP), such as Normal Pressure Hydrocephalus (iNPH) and Idiopathic Intracranial Hypertension (IIH).
The project is a hospital-based prospective, observational cohort study, in which we will assess UFMR-detected brain pulsations in patients suffering from IIH and iNPH.
We will include patients who, on clinical indication and as part of their existing clinical course of treatment, undergo MR imaging and are
1) referred to a diagnostic tap test (iNPH)
2) diagnosed with a lumbar opening pressure above 250 mmCSF (IIH)
3) referred to an implantation of an intracranial ICP device and shunt operation (iNPH)
The aim of this study is to perform a systematic evaluation of [123I]FP-CIT SPECT DAT scan with the new brain-dedicated pin-hole collimator AnyScan SPECT-CT, including establishing an age-adjusted healthy group, and to perform a 'head-to-head' comparison with [18F]FE-PE2I PET-CT. Furthermore, the aim is to evaluate the usefulness of adding MR-based neuromelanin measurements.
The aim of Connect-Me is to facilitate individualized assessment of unresponsive patients in the intensive care unit for signs of preserved consciousness after acute brain injury. Connect-Me is a project led by Dr. Daniel Kondziella, a neurologist from Dept of Neurology, Rigshospitalet. We assess intensive care patients with acute brain injury for preserved consciousness. Through this collaboration, we acquire and examine resting-state fMRI to identify brain imaging features that are clinically informative in assessing consciousness level at the time of scan and prognosis of recovery.
The intraoperative MRI project is a collaboration between departments of radiology, neurosurgery, and NRU. The scanner (GE Signa 1.5T) was installed last year and is already in use for standard perioperative structural imaging with contrast, as well as during laser interstitial thermotherapy (LITT) surgery of tumors and epilepsy seizure sources. Our goal is to expand the usage to include intraoperative functional brain mapping (fMRI) to delineate eloquent areas, which is a desired in vivo tool for optimal resection of tumors.
More than 40% of patients with obsessive compulsive disorders (OCD) are resistant to treatment. Untreated OCD is highly disabling and costy for society, yet advancement in treatment options are almost on a standstill. Studies show that the functional connectivity between cortical and striatal brain regions are altered in patients with OCD, and that these changes can lead to compulsive behaviors. However, we do not fully understand the underlying neuronal dysfunctions. In this project, we use chemogenetics to selectively activate cortical inputs to the striatum, creating an animal model of OCD-like compulsive behavior. We will investigate how activation of these inputs alter functional connectivity and OCD-like compulsive behavior, and the effectiveness of a novel serotonergic drug treatment. This is a high-risk/high-gain project with great clinical translational value and potential to redefine our understanding and treatment of OCD, which will ultimately benefit patients.
Alcohol use disorder (AUD) is a widespread burden on public health across the world and constitutes a major risk factor for disability and mortality. In Denmark, approximately 15% of the population has a harmful use of alcohol and 3% fulfill the criteria for AUD and excessive consumption of alcohol cost the Danish society 1.7 billion EUR per year. Unfortunately, AUD has a chronic and progressive course and is inefficiently treated. In the 1950s through the 1960s, before the Controlled Substance Act of 1970, several studies were carried out evaluating the effects of classic psychedelics such as psilocybin and LSD on addiction. A recent meta-analysis reviewed six randomized controlled trials in AUD from the 1950-1970s (n = 536) and found odds in favor of abstinence (OR 19.6) after a single administration of LSD. Recently in 2015, a small (n=10) proof of concept study in patients with AUD evaluated the effects of psilocybin and found significant and persisting reductions in drinking days and heavy drinking days. While these preliminary results are certainly encouraging, a larger placebo-controlled study is needed to evaluate treatment efficacy of psilocybin for AUD.
The 7 Tesla (7T) MRI projects are focused on the benefit of 7T MRI in the clinic. Among other promising contributions when compared to conventional clinical MRI (1.5 or 3T), structural images from 7T MRI have the benefit of increased spatial resolution and contrast, which may help radiologists detect and delineate smaller and more precise details.