Programme

Sex differences exist in the prevalence and symptoms of a number of neuropsychiatric and neurodegenerative disorders. Anytime a sex difference is seen this suggests that sex chromosomes or steroid hormones such as estrogens and androgens are involved, and examples will be explored. Understanding these sex differences can give us clues on how a disease develops, the manifestation of the disease, and eventually treatment of the disease. Furthermore, studying the underlying sex differences in disease will lead to better preclinical models of the disease. I will present examples from the literature to show different instances of how sex can influence the neural response to treatments. I will use examples from the schizophrenia, depression and Alzheimer’s disease literature to show how attention to sex can lead to a better understanding of those diseases. The integrity of the hippocampus is compromised in depression perhaps differentially in men versus women. In this talk I explore these sex differences to better understand the neural manifestation of depression with an eye towards an understanding of how treatment of depression in men and women may need to be tailored. I discuss findings from post-mortem tissue, and in animal models capitalising on gonadal hormone manipulations, in both males and females to determine if there is a difference in hippocampal neuroplasticity and vulnerability to depressive-like endophenotypes. In addition, the postpartum is associated with increased risk to develop anxiety and depression in women and I discuss how natural changes during pregnancy and the postpartum may increase susceptibility to neuropsychiatric disease and influence response to pharmacological antidepressants. These findings emphasize the importance of studying biological sex on brain function and neural plasticity and have implications for brain disorders that show sex differences in prevalence or manifestation. I will end on best practices for studying sex differences in neuroscience highlighting promises and pitfalls in the study of sex as a biological variable.

Psychiatric and neurological disorders are debilitating and even deadly for millions of men and women all over the world. Neuroscience research has the potential to identify the biological basis of disease risk and resilience, as well as inform the development of novel therapeutics. However, the vast majority of relevant preclinical science - from humans to invertebrates - are conducted only in male subjects. This imbalance is a public health problem, because the mechanisms that underlie mental illnesses in men and women may be different. This talk will address the history of the sex bias in neuroscience research and discuss examples of fundamental sex differences in brain structure and function that affect the way we think about psychiatric illnesses. In particular, we will examine behavioral tests designed to tap into emotional or motivational states related to mood and anxiety disorders, and how their development in male animals may make them inadequate for assessing the same states in females. We will also discuss when and when not to consider gonadal hormones as a potential source of variability in experimental outcomes.

Women are twice as likely as men to be diagnosed with major depression, clinical anxiety disorders, and posttraumatic stress disorder (PTSD). Despite decades of research dedicated to sex differences in risk for neuropsychiatric disorders, our understanding remains incomplete. Data from the field of psychoneuroimmunology may be able to shed light on these sex differences. Accumulating data indicate that inflammation profoundly impacts the brain and may contribute to the pathophysiology of neuropsychiatric disorders, including depression, anxiety and PTSD. For example, administration of agents that promote inflammation, both acutely and chronically, appears to elicit symptoms of depression and anxiety. Moreover, large-scale studies and meta-analyses have demonstrated elevated levels of inflammatory proteins in individuals with depression, anxiety and PTSD. Importantly, there are robust sex differences in immune function and inflammation and in some immune-related disorders. For example, women have substantially increased risk for many autoimmune disorders compared to men. There is now also a growing appreciation that the effects of inflammation on the brain and neuropsychiatric symptoms may differ between men and women. In this session, you will learn about sex differences in neuropsychiatric disorders and inflammation, and about differential effects of inflammation on the brain and behavior in men and women. You will also learn about potential implications of this literature for treating depression, anxiety and PTSD and for furthering our understanding of links between neuropsychiatric disorders and other chronic physical diseases.

Posttraumatic stress disorder (PTSD) is common in youth, with a lifetime prevalence of 5% or greater by the age of 18. Females are particularly vulnerable to the development of PTSD following trauma, with a roughly 2-fold greater risk compared to males even after controlling for trauma type. These findings suggest that the neurobiological effects of trauma are more severe in females, and that the underlying neurobiology of PTSD may also differ by sex. However, little research has examined sex differences in the neurobiology of pediatric PTSD. Such studies are particularly important for better understanding illness risk and progression in girls and boys and may allow for more personalized and novel treatment interventions. In this presentation, I will review emerging findings from the Youth PTSD Study, a longitudinal neuroimaging study examining structural and functional neurodevelopment in pediatric PTSD as compared to healthy youth (N=91, 58 females). Preliminary analyses of sex differences show that girls with PTSD present with greater illness severity, though have similar illness duration to males. In our neuroimaging analyses, findings to date suggest notable sex differences in the frontoparietal network, which has been heavily implicated in cognitive control and emotion regulation. I will place these findings in the context of the broader literature on sex differences in the neurobiology of trauma and PTSD and highlight directions for future study, including more precise matching of girls and boys based on age, pubertal stage, trauma exposure type, and PTSD severity.

Sex difference in cognitive function have been reported quite frequently and show a long tradition, with abilities ranging from the so-called „male-favoring“ spatial processes to assumed more „female-favoring“ social cognitive competencies. Within this talk, the general assumption that women are more social and emotional will be reviewed using recent neuroimaging as well as self-report, behavioral , psychophysiological, and hormonal findings. I will particularly focus on social cognitive processes such as empathy and stress responsivity as these competencies pose high relevance for social coherence as well as mental health. As highlighted throughout the talk, sex differences can be observed in these processes, however need to be framed across the different levels of granularity.

The question of whether males and females differ in their cognitive abilities, and if so, what factors contribute to these differences, has received substantial attention in the research literature. Sex differences favoring males have been reported on a number of spatial tasks like mental rotation, navigation, discrimination of line orientation, and Piaget’s water level task. Of these, the largest sex difference has been found for mental rotation. On the other hand, women generally perform better than men on verbal tasks, like verbal recall and verbal fluency, but the female verbal advantage extends into tasks of spatial and autobiographical abilities, and general episodic memory. Overall, the effect sizes for these sex differences are generally small and the individual variability much greater, meaning that sex differences play a minor role at the individual level. Some of these sex differences have also been attributed to organizational and activational effects of sex hormones. It has been suggested that sexually dimorphic cognitive skills that favor men are improved during menstrual cycle phases with low estrogen and that cognitive skills that favor women are improved during cycle phases with increased estrogen and/or progesterone. However, at present there is insufficient evidence to support any of these hypotheses.

Functional cerebral asymmetries (FCAs) are a basic principle of functional brain organization in humans and many other non-human species. However, the degree of FCAs shows large inter-individual differences and can dynamically change within relative short time periods. For example, while FCAs are relatively stable in men, they can change dynamically across the menstrual cycle in women, suggesting that sex hormones play an important role in modulating FCAs. Sex hormones modulate neuronal actions and affect the interaction between functionally linked cortical areas within and across cerebral hemispheres. However, the underlying mechanisms are not well understood. Here I propose that sex hormones modulate interhemispheric interaction via the corpus callosum due to their neuromodulatory properties, which can diminish cortico-cortical transmission, and thus reduce FCAs. Menstrual cycle-related fluctuations in FCAs and interhemispheric crosstalk have been shown to be a useful experimental model to investigate the activating effects of sex hormones on functional connectivity in the brain. Apart from a better understanding of sex hormonal effects on cognitive brain functions, this research may also contribute to addressing the question of whether sex differences in cognitive brain functioning truly exist and where they originate from.

Sex hormone transition may trigger severe mental health disorders, including depressive episodes in some women. Changes in brain chemistry, particular in sensitive individuals, is likely to be involved in the underlying mechanisms. In this talk I will cover work that has mapped mechanisms related to such psychopathological phenomena. This will include insights from a pharmacological preclinical human model using sex-hormone manipulation with Gonadotrophin Releasing Hormone agonist (GnRHa) in a placebo controlled design in a population of healthy women. This work points to an estradiol dependent depressive response in healthy women undergoing short term sex hormone manipulation, which is linked to serotonin transporter changes (a key regulator of synaptic serotonin), a disengagement of hippocampus, and overengagement of brain networks recruited when processing emotional salient information. Further, key regions in the reward circuit appear to be less engaged in positive stimuli when undergoing sex-hormone manipulation, which may drive anhedonia. Also, this work supports that enhanced sensitivity to estrogen signalling at the level of gene-expression may drive increased risk for depressive symptoms when exposed to sex-steroid hormone fluctuations. Taken together, this talk will cover current knowledge of brain signatures of rapid and profound changes in sex-steroid hormone milieu, which reflect plausible mechanisms by which risk for psychiatric disorders works. The talk will point to the role of estrogen dynamics and sensitivity and discuss prospects for personalized prevention in hormonal transition phases, e.g. pregnancy to postpartum transition, perimenopause and hormone treatments, which can hopefully move into clinical translation to protect mental and cognitive health.

Estradiol and progesterone fluctuate along the menstrual cycle and affect a variety of neurotransmitter systems. However, few studies have addressed menstrual cycle dependent changes in the brain connectivity. In two large scale studies, each including 36 naturally cycling women, we investigate menstrual cycle variations in brain activation and connectivity patterns underlying cognition. In the first study, women completed a stop-signal task to study inhibitory control and an n-back task to study working memory functions. In the second study, women completed a spatial navigation and verbal fluency task. All women were scanned three times along the menstrual cycle: (i) during menses, (ii) during the pre-ovulatory estradiol peak, (iii) during the mid-luteal progesterone peak. Performance changes along the menstrual cycle were minimal. However, we observed strikingly similar patterns of activation and connectivity changes along the menstrual cycle. Irrespective of the task, progesterone boosts right-hemispheric fronto-striatal activation during the luteal cycle phase. Connectivity analyses suggest that the increase in right-hemispheric frontal activation is the result of inter-hemispheric decoupling and is involved in the down-regulation of hippocampal activation. We will also explore, whether similar connectivity patterns can be observed in a sample of 36 healthy young men, who also completed the spatial navigation and verbal fluency task.

There is plenty of evidence showing sex differences in individuals suffering from mental disorders. For example, women suffer significantly more frequently from depression and anxiety disorders than men, while men are more affected by au-tism or substance-related disorders. Are there biological causes that lead to such differences? Structural and functional brain differences as well as genetic and hormonal disparities might create sex-specific vulnerabilities for certain disorders. Or does society and its gender roles play a decisive role in the development of sex differences in mental disorders as society promotes different behavior and coping strategies in women and men? This talk will give an overview of the cur-rent research on sex differences in mental disorders, thereby critically discussing influencing factors as well as implications of future research.

The number of women in science, technology, engineering, and mathematics (commonly abbreviated STEM) has significantly increased over the past years. However, women still remain the minority in STEM disciplines and the disparity widens along the educational-vocational continuum, starting at school and gradually increasing during professional (academic) life. There is an ongoing de-bate as to the source of this disparity and there seems to be a tenacious belief that “innate” sex differences in cognitive abilities may partly account for it, or at least that these differences can partly explain why significantly fewer females than males appear at the upper end of higher cognitive abilities that are required in STEM areas (e.g. Summers, 2005, January 14). This talk will give an overview of current research on neurocognitive sex differences and critically addresses this issue within a psychobiosocial approach.

Human language surpasses all other animal communication systems in its complexity and generative power. In my group, we use a combination of behavioral, brain imaging, and computational approaches to illuminate the functional architecture of language, with the ultimate goal of deciphering the representations and computations that enable us to understand and produce language. In this talk, I will ask whether language processing shares mechanisms with other aspects of high-level cognition, such as arithmetic, music perception, executive functions, and Theory of Mind. I will present evidence from neuroimaging studies showing that healthy adults strongly engage the brain’s language areas when they understand a sentence, but not when they add and subtract, listen to music, hold information in working memory, or think about another person’s thoughts. I will further talk about individuals with severe aphasia, who, despite their near-total loss of language, are nonetheless able to perform a wide range of complex non-linguistic cognitive tasks. Together, these two complementary lines of evidence demonstrate that many aspects of thought engage distinct brain regions from, and do not depend on, language.

From the age of 25 onwards, we have on average a 25% chance of suffering a stroke at some point in our lives; there are more than 7 million stroke survivors in the USA alone. Approximately a third of stroke survivors suffer language impairments, or aphasia, but current medicine cannot predict which patients might hope to recover. To bridge this gap, we are accumulating a dataset associating demographic and structural brain imaging data with language outcomes for an ever-larger sample of stroke patients. One objective of this work is to predict language outcomes for new patients by generalising trends learned from patients whose outcomes are known. Another objective is to explain why some patients recover so much more quickly and fully than others. In this talk, I describe how my colleagues and I have pursued these objectives in recent years. First, I show that we can predict hundreds of patients’ language outcomes after stroke with high accuracy, and use these predictions to identify a ‘bilingual disadvantage’ in those outcomes: a surprising counterpoint to the much-reported ‘bilingual advantages’ in cognitive control. I will also describe results which: (a) show that brain structural adaptation in the preserved right-hemisphere predicts longitudinal change in aphasic symptoms over years after stroke onset; and (b) demonstrate that prognostic models that take account of that preserved neural tissue make more accurate predictions than those that do not. In a field still dominated by lesion-symptom analyses, results like this are encouraging us to look beyond the lesion, to the way the brain uses preserved tissue to recover after stroke.

How does hearing ability affect the way our brains process speech? I will review data from behavioral and brain imaging studies that speak to the added cognitive demands associated with acoustic challenge. Evidence from multiple sources is consistent with a shared resource framework of speech comprehension in which domain-general cognitive processes supported by discrete regions of frontal cortex are required for both auditory and linguistic processing. The specific patterns of neural activity depend on the difficulty of the speech being heard, as well as the hearing and cognitive ability of the listeners. Although frequently studied in the context of hearing loss, these principles have broader implications for our understanding of how auditory and cognitive factors interact during spoken language comprehension. I will present neuroimaging data from listeners with normal hearing, age-related hearing loss, and cochlear implants implicating executive attention networks in understanding acoustically challenging speech.

Our environment is replete with statistical structure and similar cause-effect relationships hold across related experiences. By organising relational knowledge efficiently, the brain can predict states and reinforcement that were never directly experienced. In physical space, the relationships between landmarks are organised in a cognitive map. We show that such a map can be used to extrapolate across related states and infer rewards that were never directly experienced when value is distributed smoothly in space. We further demonstrate that a map-like organisation of knowledge can also be observed for discrete relationships between objects that are entirely non-spatial, suggesting that spatial codes may also organise other dimensions of our experiences. When participants need to flexibly switch between cognitive maps characterised by the same underlying structure, but a different distribution of stimuli, structural knowledge is abstracted away from sensory representations in the medial prefrontal cortex over time. Such a separation of structure from stimulus representations may facilitate the generalisation of knowledge across sensory environments and thereby accelerate learning in novel situations. Together, these data suggest a potential neural mechanism underlying the remarkable human ability to draw accurate inferences from little data.

We continue to learn new information across our lifespan which we then use to support flexible behaviour. In this talk I will first examine mechanisms that underlie the stable storage of multiple memories. Using ultra-high field 7T MRI and brain stimulation in humans I will show evidence to suggest that memories are stored in balanced excitatory-inhibitory (EI) ensembles in the neocortex. These balanced EI ensembles provide a means to store multiple memories in a quiescent state, while transient disinhibition facilitates selective memory recall. Having identified a potential mechanism for stable memory storage, I will then ask how these memories may be used for flexible behaviour. Using a parallel cross-species approach in both mice and humans I will examine how memories are used to support inference, an example of model-based decision-making. I will show that at the time of inference, the hippocampus prospectively reinstates memories for predicted sensory cues, thus drawing on memory to provide a logical link between events that have not previously been experienced together. Furthermore, during offline periods, sharp-wave ripple events in the hippocampus show a read-out of inferred relationships, providing a potential means to build a cognitive map that includes relationships between stimuli that have not previously been observed. Together these studies will present a potential mechanism for stable memory storage that can be used to facilitate flexible behaviour.

The fundamental question in cognitive neuroscience—what are the key coding principles of the brain enabling human thinking—still remains largely unanswered. Evidence from neurophysiology suggests that place and grid cells in the hippocampal-entorhinal system provide an internal spatial map, the brain’s SatNav—the most intriguing neuronal coding scheme outside the sensory system. Our framework is concerned with the key idea that this navigation system in the brain—potentially as a result of evolution—provides the blueprint for a neural metric underlying human cognition. Specifically, we propose that the brain maps experience in so-called ‘cognitive spaces’. In this talk, I will give an overview of our theoretical framework and experimental approach and will present show-case examples from our fMRI, MEG and virtual reality experiments identifying cognitive coding mechanisms in the hippocampal-entorhinal system and beyond.

Further reading:
Bellmund, J. L. S., Gärdenfors, P., Moser, E. I., & Doeller, C. F. (2018). Navigating cognition: Spatial codes for human thinking. Science, 362(6415), eaat6766. https://doi.org/10.1126/science.aat6766

Real-time communication between a nervous system and a device is now possible, but full and reliable integration in biohybrid systems to restore function lost to trauma is still far from reality. By focal activation of peripheral nerves and adaptive neuromorphic control, bionic interfaces offer targeted restoration of function lost to neurotrauma. Biohybrid systems of the future are likely to utilize biomimetic machines with multi-channel, high throughput interfaces not only to integrate with the biological system, but to close the loop in a manner that promotes adaptation in the nervous system. This lecture will discuss uses of tools and techniques from computational neuroscience and neural engineering to develop biohybrid systems. We will discuss three applications. 1) A neural model of spinal pattern generating circuitry of lower vertebrates characterized extensively and used to design neuromorphic controllers. These controllers have been interfaced with an active spinal cord and used to adaptively control an orthosis that could allow mobility after lower limb trauma. 2) Neural models for control of breathing used for design of adaptive controllers for diaphragmatic pacing after spinal cord injury, and 3) A system to simulate expected peripheral nerve recordings using longitudinal intrafascicular electrodes in order to develop algorithms to decode motor intent for upper limb neuroprosthetic control.

The normative rules by which brains make decisions, act and interact with their environments can be formally expressed by mathematical and computational principles. This supports neuroscience efforts, for example in neuroimaging, by providing detailed and latent descriptions of behaviour. It further supports the understanding of abnormal behaviour and its treatment e.g. in the context of psychiatric disorders. Under Active Inference (Friston 2009), a decision – such as that to move ones’ eyes - is driven by the imperative to minimise a bound on surprise known as the Free Energy. In the context of partially observable Markov decision processes (POMDPs), a model-based framework in which we can cast naturalistic decision-making tasks; the Free Energy of a policy (a sequence of actions) can be understood as a drive to both minimize cost (maximise the likelihood of achieving a goal) while maximising the information return from a given set of actions. This scheme has been used to model decision making in tasks such as ‘the urn task’ and also in reading. In my talk I will explain technical framework of Free Energy minimization in the context of brain connectivity. I will describe the use of online gaming environments (designed to test artificial intelligence algorithms) and present data from decision-making simulations. For example, how would ‘optimal’ brains play the game ‘Doom’ and compare agents trained under Active Inference to agents trained to maximise reward. Linking these simulations to putative neurobiological substrates I will describe the potential links from brain and neuroimaging to the underlying drives that influence decisions. I will focus on two results from our simulated agents that describe normative rules to understand aging and anhedonia.

Substantial efforts across the fields of computer science, artificial intelligence, statistics, operations research, economics, and control theory have provided us with a psychologically- and neurobiologically-grounded account of how humans and other animals learn to predict rewards and punishments, and choose actions to maximize the former and minimize the latter. It becomes an obvious idea to try and relate disruptions of these models to the discontents of decision-making, as seen in neurological and psychiatric disease. I will describe Bayesian accounts of decision making, along with various reinforcement learning realizations, together with our early attempts to use this to structure an understanding of dysfunction.

The Bayesian analysis

[1] locates potential issues in at least three places. First is the definition of tasks - for example, prior expectations about the availability of rewards and punishments or the controllability of the environment; about likelihoods, which map observations to the underlying states of the person or the environment, or about and utilities. Second is solutions to those tasks, for example the degree of reliance on inflexible model-free or habitual methods

[2]; or on evolutionary pre-programmed or Pavlovian methods

[3], or the functioning of euromodulatory systems. The third concerns the relationship between present and past environments, for instance reflecting path-dependencies that arise over the course of learning and adaptation

[4]. These various issues lead to structurally different flaws, and, although we are currently very far from this, potentially, therapeutic paths. I will touch upon various conditions as examples.

[1] Huys, Q.J.M., Guitart-Masip, M., Dolan, R.J., Dayan, P. 2015. Decision-Theoretic Psychiatry. Clinical Psychological Science, doi:10.1177/2167702614562040

[2] Gillan, C.M., Kosinski, M., Whelan, R., Phelps, E.A., Daw, N.D. 2016. Characterizing a psychiatric symptom dimension related to deficits in goal-directed control. Elife. 2016 Mar 1;5. pii: e11305. doi: 10.7554/eLife.11305

[3] Huys, Q.J., Golzer, M., Friedel, E., Heinz, A., Cools, R., Dayan, P. Dolan, R.J. 2016. The specificity of Pavlovian regulation is associated with recovery from depression. Psychological Medicine, doi: 10.1017/S0033291715002597

[4] Dayan, P., Roiser J.P., Viding, E. 2018. The first steps on long marches: The costs of active observation. In Davies, W., Roache, R., Savulescu, J. Rethinking Biopsychosocial Psychiatry. Oxford University Press.