Patrick MacDonald Fisher

• PhD
• Senior Researcher at Center for Integrated Molecular Brain Imaging

Reinforcement learning is a fundamental aspect of adaptive behaviour, since it involves the acquisition and updating of associations between actions and their outcomes based on the rewarding or punishing consequences. Acute experimental manipulations of serotonin have provided compelling evidence for its role in reinforcement learning. However, it...

It has become increasingly common to probe correlations between human brain imaging measures of receptor/protein binding and function using population-level brain maps drawn from independent cohorts, estimating correlations across regions. This strategy raises issues of interpretation that we highlight here with a multimodal brain imaging dataset a...

Background: Premenstrual dysphoric disorder (PMDD) is a depressive disorder linked to the menstrual cycle, notably characterized by the cyclic occurrence of emotional distress. A core symptom is irritability or anger, whose outcome can be aggressiveness. Intermittent selective serotonin reuptake inhibitor (SSRI) treatment has shown promise in allev...

Psilocin, the active metabolite of psilocybin, is a psychedelic and agonist at the serotonin 2A receptor (5-HT2AR) that has shown positive therapeutic effects for brain disorders such as depression. To elucidate the brain effects of psilocybin, we directly compared the acute effects of 5-HT2AR agonist (psilocybin) and antagonist (ketanserin) on cer...

Introduction Patients with mood disorders, especially, major depressive disorder (MDD) and bipolar disorder (BD), are at heightened risk of relapse and psychiatric rehospitalizations. Therefore, there is an urgent need to identify modifiable biomarkers to inform personalized and intensified prevention strategies for those at the greatest risk of re...

Background Using [ ¹⁸ F]altanserin, a serotonin 2A receptor (5-HT 2A R) antagonist Positron Emission Tomography (PET) tracer, a positive association between cortical 5-HT 2A R binding and the inward-directed facets of neuroticism has been demonstrated in healthy individuals. Psilocybin, a 5-HT 2A R agonist, shows promise for the treatment of depres...

Understanding neuromodulatory effects of serotonin 2A receptor (5-HT 2A R) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) t...

Complex behavioral and cognitive processes emerge from coordinated communication between sometimes disparate brain regions, implying a systems-level dynamic synchronization of underlying neural signals. This study presents approaches to multivariate mixture modeling of functional brain imaging data for analyzing phase coherence networks for human b...

Psilocin, the active metabolite of psilocybin, is a psychedelic and agonist at the serotonin 2A receptor (5-HT2AR) that has shown positive therapeutic effects for brain disorders such as depression. To elucidate the brain effects of psilocybin, we directly compared the acute effects of 5-HT2AR agonist (psilocybin) and antagonist (ketanserin) on cer...

Depression is a multifactorial clinical syndrome with a low pharmacological treatment response rate. Therefore, identifying predictors of treatment response capable of providing the basis for future developments of individualized therapies is crucial. Here, we applied model-free and model-based measures of whole-brain turbulent dynamics in resting-...

Being able to distinguish tissues and quantify features in an image is ubiquitous in medical imaging, allowing, for instance, the study of differences between clinical groups or the investigation of the impact of an intervention. Assigning the tissue type is also a fundamental preprocessing step in many neuroimaging applications like image registra...

To investigate patients with disorders of consciousness (DoC) for residual awareness, guidelines recommend quantifying glucose brain metabolism using positron emission tomography. However, this is not feasible in the intensive care unit (ICU). Cerebral blood flow (CBF) assessed by arterial spin labeling magnetic resonance imaging (ASL-MRI) could se...

Objective s This study aimed to investigate the neural underpinnings of emotional cognition subgroups in recently diagnosed patients with bipolar disorder (BD) and change over time over a 15‐month follow‐up period. Methods Patients and healthy controls (HC) underwent emotional and nonemotional cognitive assessments and functional magnetic resonanc...

Background There is a significant contribution of genetic factors to the etiology of bipolar disorder (BD). Unaffected first-degree relatives of patients (UR) with BD are at increased risk of developing mental disorders and may manifest cognitive impairments and alterations in brain functional and connective dynamics, akin to their affected relativ...

Background Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. Aim This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. Methods In this...

Objective To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). Background CCH is an excruciating and difficult‐to‐treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been i...

Brain age prediction algorithms using structural magnetic resonance imaging (MRI) aim to assess the biological age of the human brain. The difference between a person's chronological age and the estimated brain age is thought to reflect deviations from a normal aging trajectory, indicating a slower or accelerated biological aging process. Several p...

Background In intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC), outcome prediction is key to decision-making regarding prognostication, neurorehabilitation, and management of family expectations. Current prediction algorithms are largely based on chronic DoC, whereas multimodal data from acute DoC are scarce....

Background: Bipolar disorder (BD) is commonly associated with cognitive impairments, that directly contribute to patients' functional disability. However, there is no effective treatment targeting cognition in BD. A key reason for the lack of pro-cognitive interventions is the limited insight into the brain correlates of cognitive impairments in t...

The BrainDrugs-Epilepsy Study is part of the established Lundbeck Foundation-funded BrainDrugs research alliance (braindrugs.nru.dk). The study aims to identify biomarkers of treatment outcome as well as cognitive and psychiatric comorbidity in patients with a first epileptic seizure and epilepsy. Our goal is to provide a patient-level prediction o...

Background: Using the [18F]altanserin tracer to image serotonin 2A receptors (5-HT2AR), we previously showed that there exists a positive association between cortical 5-HT2AR binding and the inward facets of neuroticism, namely depression, anxiety, self-consciousness, and vulnerability. Fairly recently, the [11C]Cimbi-36 tracer was also shown to be...

The serotonin 2A receptor (5HT 2A R) and personality factors indexing stress coping mechanisms are implicated in the pathophysiology of depression. Cross-sectional studies performed in individuals with high familial risk for depression suggest that the coupling between 5-HT 2A R and the inward-directed facets of neuroticism may be associated with a...

Brain serotonergic (5-HT) signaling is posited to modulate neural responses to emotional stimuli. Dysfunction in 5-HT signaling is implicated in major depressive disorder (MDD), a disorder associated with significant disturbances in emotion processing. In MDD, recent evidence points to altered 5-HT4 receptor (5-HT4R) levels, a promising target for...

Background: Persistent cognitive deficits are prevalent in patients with bipolar disorder (BD) and unipolar disorder (UD), but treatments effectively targeting cognition in these mood disorders are lacking. This is partly due to poor insight into the neuronal underpinnings of cognitive deficits. Methods: The aim of this functional magnetic reson...

Background: Neurocognitive impairments are associated with poor clinical and employment outcomes in individuals with affective disorders. However, little is known about their associations with long-term clinical outcomes such as psychiatric hospitalizations, and with socio-demographic indicators other than employment. In the largest longitudinal s...

Bipolar disorder (BD) and major depressive disorder (MDD) are associated with cognitive and functional impairment. Cognitive impairment is often associated with dorsal prefrontal cortex (dPFC) hypo-activity, but the neuronal correlates of functional disability is largely unknown. In this study, 91 patients with affective disorders in full or partia...

Background: In intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC), outcome prediction is key to decision-making regarding prognostication, neurorehabilitation, and management of family expectations. Current prediction algorithms are largely based on chronic DoC, while multimodal data from acute DoC are scarce. T...

Background: Brain age prediction algorithms using structural magnetic resonance imaging (MRI) aim to assess the biological age of the human brain. The difference between a person's chronological age and the estimated brain age is thought to reflect deviations from a normal aging trajectory, indicating a slower, or accelerated, biological aging proc...

Background: Severe health anxiety is a disorder characterized by a persistent preoccupation with one's health. In behavioral studies, biases in the processing of health-related stimuli (e.g., pictures, words) are consistently associated with health anxiety symptoms. The neural correlates of the observed behavioral abnormalities remain however poor...

BACKGROUND. Alcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patie...

Brain morphology has been suggested to be predictive of drug treatment outcome in major depressive disorders (MDD). The current study aims at evaluating the performance of pretreatment structural brain magnetic resonance imaging (MRI) measures in predicting the outcome of a drug treatment of MDD in a large single-site cohort, and, importantly, to a...

Background Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state time-varying functional c...

Functional MRI (fMRI) and EEG may reveal residual consciousness in patients with disorders of consciousness (DoC), as reflected by a rapidly expanding literature on chronic DoC. However, acute DoC is rarely investigated, although identifying residual consciousness is key to clinical decision-making in the intensive care unit (ICU). Therefore, the o...

Objectives Understanding the dynamics of reorganized network-level brain functions after hemispherectomy is important for treatment, prognostication, and rehabilitation of brain injury, but also for investigating questions of fundamental neurobehavioral interest: How does the brain promote consciousness despite loss of one hemisphere? Methods We s...

Cognitive affective biases describe the tendency to process negative information or positive information over the other. These biases can be modulated by changing extracellular serotonin (5-HT) levels in the brain, for example, by pharmacologically blocking and downregulating the 5-HT transporter (5-HTT), which remediates negative affective bias. T...

Background: Major depressive disorder (MDD) is a prevalent neuropsychiatric illness for which it is important to resolve underlying brain mechanisms. Current treatments are often unsuccessful, precipitating a need to identify predictive markers. Aim: We evaluated (1) alterations in brain responses to an emotional faces functional magnetic resona...

Background Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state dynamic functional connec...

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacol...

The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain ne...

Background Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aim Evaluate changes in resting-state functional connectivity (RSFC) at 1 week and 3...

Clinical research into classical psychedelic drugs including psilocybin, LSD and N,N-DMT (ayahuasca)is expanding rapidly and clinical trials across a range of psychiatric conditions have shown promisingefficacy, with larger trials ongoing. Resting-state functional magnetic resonance imaging (fMRI) hasemerged as a commonly used brain imaging strateg...

Parkinson's disease (PD) is caused by progressive neurodegeneration and characterised by motor dysfunction. Neurodegeneration of dopaminergic neurons also causes aberrations within the cortico-striato-thalamo-cortical (CSTC) circuit, which has been hypothesised to lead to non-motor symptoms such as depression. Individuals with PD have both lower sy...

Premenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopreg...

Evaluating associations between the five-factor personality domains and resting-state functional connectivity networks (e.g., default mode network, DMN) highlights distributed neurobiological systems linked to behaviorally relevant phenotypes. Establishing these associations can highlight a potential underlying role for these neural pathways in rel...

Nigro-striatal dopamine transmission in the rat dorsomedial striatum (DMS) engages the cortico-striato-thalamo-cortical (CSTC) circuit. Modulation of the CSTC circuit can emulate behavioral and functional aspects of neuropsychiatric diseases, including obsessive compulsive disorder (OCD). Classical pharmacological and neurotoxic manipulations of br...

The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain ne...

Background Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aims Evaluate changes in resting-state functional connectivity (RSFC) at one-week and...

Major depressive disorder (MDD) is a prevalent brain disorder for which anhedonia is a core symptom, indicating aberrations in the neural processing of reward. The striatum, medial prefrontal cortex (mPFC) and anterior insula (AI) are core reward processing regions. Here we used a reward-related, card-guessing functional magnetic resonance imaging...

Cognitive impairment is prevalent in bipolar disorder (BD) but treatments with pro-cognitive effects are lacking. Insight concerning the neurocircuitry of cognitive improvement could provide a biomarker for pro-cognitive effects to advance treatment development. The dorsal prefrontal cortex (dPFC) is a promising region for such treatment target eng...

Background Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to n...

Introduction: 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 arres...

Endogenous serotonin (5‐HT) release can be measured noninvasively using positron emission tomography (PET) imaging in combination with certain serotonergic radiotracers. This allows us to investigate effects of pharmacological and nonpharmacological interventions on brain 5‐HT levels in living humans. Here, we study the neural responses to a visual...

Background Between 30 and 50% of patients with major depressive disorder (MDD) do not respond sufficiently to antidepressant regimens. The conventional pharmacological treatments predominantly target serotonergic brain signaling but better tools to predict treatment response and identify relevant subgroups of MDD are needed to support individualize...

The serotonin 2A receptor (5‐HT2AR) is implicated in the pathophysiology and treatment of various psychiatric disorders. [¹⁸F]altanserin and [¹¹C]Cimbi‐36 positron emission tomography (PET) allow for high‐resolution imaging of 5‐HT2AR in the living human brain. Cerebral 5‐HT2AR binding is strongly genetically determined, though the impact of specif...

Objective Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signalling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register‐based studies show that starting an OC is associated with increased risk of developing...

Latent variable models are commonly used in psychology and increasingly used for analysing brain imaging data. Such studies typically involve a small number of participants (n<100), where standard asymptotic results often fail to control the type 1 error appropriately. The paper presents two corrections improving the control of the type 1 error of...

A single dose of the serotonin 2A receptor (5-HT2AR) agonist psilocybin can have long-lasting beneficial effects on mood, personality, and potentially on mindfulness, but underlying mechanisms are unknown. Here, we for the first time conduct a study that assesses psilocybin effects on cerebral 5-HT2AR binding with [¹¹C]Cimbi-36 positron emission to...

Latent variable models (LVMs) are commonly used in psychology and increasingly used for analyzing brain imaging data. Such studies typically involve a small number of participants (n<100), where standard asymptotic results often fail to appropriately control the type 1 error. This paper presents two corrections improving the control of the type 1 e...

Rationale The serotonergic system has been repeatedly linked to visual attention in general, but the effects of selective serotonin reuptake inhibitor (SSRI) on specific components of visual attention remain unknown. Changes in distinct perceptual and cognitive processes are not readily evident in most attention paradigms. Objective In this study,...

The original version of this article contained an error in the labelling of Figures 2 and 3. While the captions and figures themselves are correct, in order to correspond with the in-text references, they have now been re-numbered in both the PDF and HTML versions of the article.

Background:: Recent studies have suggested therapeutic benefits of psychedelics for a variety of mental health conditions. The understanding of how single psychedelic administrations can induce long-lasting effects are, in large, still lacking. However, recent studies in both healthy and clinical populations suggest a role for personality changes....

The analysis of structural and functional neuroimaging data using graph theory has increasingly become a popular approach for visualising and understanding anatomical and functional relationships between different cerebral areas. In this work we applied a network-based approach for brain PET studies using population-based covariance matrices, with...

The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between int...

Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5‐HT2AR) agonist psilocybin. However, no studies have investigated whether 5‐HT2AR availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy...

Aims and Objectives: To facilitate individualized assessment of unresponsive patients in the intensive care unit for signs of preserved consciousness after acute brain injury. Background: Physicians and neuroscientists are increasingly recognizing a disturbing dilemma: Brain-injured patients who appear entirely unresponsive at the bedside may show...