The BrainDrugs-Epilepsy Study - Precision medicine in the treatment of epilepsy (BrainDrugs-E)

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.

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Hormonal Sensitivity and Brain Function: Do Oral Contraceptives Distort Serotonergic Brain Signaling? (The Pill Project)

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.

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In the past two decades, we have seen an exponential growth in the scale at which neuroimaging research in psychiatry and neurology takes place in terms of sample size, technology advancements and number of disorders investigated. Yet, many research findings turn out to be hard to replicate, partly because of inconsistencies in data acquisition, preprocessing and analysis. One of our major research themes within NRU is to understand these sources of discrepancies and in a recent consensus paper, we lead an initiative that aims to standardize the way PET neuroimaging data are acquired, documented, analysed, and archived. Such an initiative will also help to establish data sharing of these costly experiments, enabling replications and increasing sample sizes.

Achieving this requires having appropriate research infrastructure and fortunately, The Novo Nordisk Foundation decided in 2020 to fund our ”OpenNeuroPET Archive” which is an infrastructure that will unite the scientific community to enable meta- and mega-analyses of brain imaging data by creating an expertly labelled, shared-access data repository and processing platform. The main ethos of the OpenNeuroPET will be: open, inclusive, participatory, and democratic.

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Molecular neuroimaging of synaptic plasticity in the human brain - Pharmacological modulations and stroke (UCB-J project)

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.

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Intraoperative MRI

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.

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Non-invasive Magnetic Resonance diagnostics of hydrocephalus or increased intracranial pressure (UFMR-project)

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)

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Precision Medicine in the Treatment of First Episode Depression – establishing the BrainDrugs-Depression Cohort (BrainDrugs-D)

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.

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The Quantum Trip Trial study: Can a single administration of psilocybin reduce alcohol intake in patients with alcohol use disorder? (QTT)

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.

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Serotonergic modulation of cognition, emotion and brain activation in healthy volunteers (HC-SSRI project)

The HC-SSRI project is a double-blind placebo-controlled study of healthy individuals. Here, we evaluate how a three-week treatment with the drug selective serotonin reuptake inhibitor (SSRI) affects human’s cognition and emotions, as measured with functional magnetic resonance imaging (fMRI) and sophisticated neuropsychological testing (Cambridge Neuropsychological Test Automated Battery and EMOTICOM), and further affects synaptic plasticity measured with Positron Emission Tomography (PET). The project is a collaboration between NRU and Professor and cognition expert Barbara Sahakian and post doc Christelle Langley from The University of Cambridge, UK.

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Prophylactic effects of psilocybin on chronic cluster headache (EPOCH)

Cluster headache is a debilitating primary headache disorder, where patients experience excruciating headache attacks up 8 times per day. Some patients respond poorly to preventive medication or experience unacceptable side-effects. Thus, there is a need for development of novel medication. In this project, we evaluate effects of thee doses of psilocybin (active compound in "magic mushrooms") on headache in 10 patients with chronic cluster headache. To better understand potential mechanisms of action, patients are also scanned with fMRI before and after the drug intervention. The findings will help determine, whether psilocybin is a viable option for further drug development in cluster headache and also elucidate effects on brain function.

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The role of serotonin in compulsive behaviour in humans (OCD-project)

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.

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Consciousness in Neurocritical Care Cohort Study Using fMRI and EEG (Connect-Me)

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.

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Early detection of cognitive difficulties and psychopathology in survivors of cardiac arrest (REVIVAL)

Cognitive impairment and psychopathology caused by brain hypoxia and the traumatic impact of critical illness are common in cardiac arrest survivors and can lead to negative consequences of everyday life functioning, and further impact mental health in relatives. Most studies have dealt with the mere survival rate after cardiac arrest and not with long-term consequences to mental health in cardiac arrest survivors. Importantly, we face a gap in our knowledge about suitable screening tools in the early post-arrest phase for long-term risk prediction of mental health problems.

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Reducing the need for general anesthesia in children undergoing neuroimaging by preparation and motion correction (MoCo)

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.

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Cognition, risk-related decision making and brain function in entrepreneurs (Entrepreneurship)

This project seeks to disentangle whether entrepreneurs perceive or cognitively process risk and uncertainty differently than comparable others. We use behavioural experiments tapping into decision making under risk and ambiguity as well as reward processing while tracking changes in neural activation in sections of the brain which have been shown to be associated with this type of decision making. Uncovering these differences in the neural processing of risk, ambiguity and reward between entrepreneurs and non-entrepreneurs, could explain the behavioural differences that has been observed in entrepreneurs with regard to decision making in risky and ambiguous settings. We plan to include 70 participants consisting of 3 groups of equal sizes: serial entrepreneurs, one-time entrepreneurs and a control group.

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Brain disorders diagnosed with 7 Tesla MR (7 Tesla)

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.

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Neuronal dysfunction in treatment resistant obsessive compulsive disorder and effectiveness of novel serotonergic drug treatment

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.

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