National Institute of Mental Health (NIMH)

The scholar will work on a project integrating neuroimaging and genetics across the entire lifespan with the goal of gaining a more fine-grained understanding of the biological mechanisms driving brain morphological changes across the lifespan in health and disease.

What sets the brain apart from other organs is its complex connectivity. In order to study brain function, we need techniques for measuring brain connections with high precision in living humans. The goal of this project is to develop new methods for measuring brain connections using magnetic resonance imaging (MRI).

The project focuses on the cortex, a thin sheet of grey matter surrounding the brain. The cortex is well developed in primates, particularly humans, and plays a key role in cognition. It has a characteristic layered structure; each layer containing different varieties of neurons and connections. The input and output of a cortical region is determined by the connections of the layers. Thus, measuring layer connectivity can give us key insight into information flow in the brain. But these detailed anatomical patterns have only been studied in animal brains, where it is possible to precisely delineate connections.

This project aims to develop new methodology to study layered connectivity in the human brain using MRI. The incredible flexibility of MRI allows us to sensitise the measured signals to multiple aspects of tissue microstructure. We will use this flexibility to create MRI measurements that are sensitive to cortical lamination and integrate these measurements with computational models of laminar connectivity.

This project will open the door to addressing new questions about human brain organisation, such as whether brain areas are organized hierarchically, how information flows across the brain during cognition, learning, and memory; and what happens in diseases that disrupt brain connections

The laboratory of Prof Bridge in Oxford focusses on understanding the pathways in the human visual system that can process residual vision after someone has had a stroke that affects the primary visual cortex.

The laboratory of Prof Leopold combines neuroimaging, behaviour and neurophysiology in a non-human primate model to better understand computation in the visual system, particularly relating to conscious perception.

The proposed PhD project would have 3 main objectives:

1. Quantitatively compare changes in retinotopic maps and population receptive fields in humans and non-human primates with damage to primary visual cortex.
2. Determine the visual pathways in the two species that are necessary and/or sufficient to provide residual vision within the blind region of the visual field.
3. Investigate the neural changes that occur as a result of visual training following the damage to the visual system in order to inform rehabilitation programmes for people who have suffered a stroke to the visual system.
   
   During the training programme, the student would have the opportunity to learn about multi-modal human neuroimaging approaches applied to both the healthy and the damaged visual system. This would be complemented by training in both neuroimaging and neurophysiology in the non-human primate.

During development, brains grow rapidly as behaviors develop. Impairment in early brain development often leads to neurodevelopmental conditions, including a number of neuropsychiatric disorders. From early postnatal period throughout adulthood, learning leads to important and dynamic changes in brain circuitry, and in an animals’ behaviors to adapt and sense the environment. The hierarchical yet reciprocal interaction between thalamus and cortex is one of the key brain circuits that are involved in learning-related changes from early development to adulthood.

To investigate the development of thalamocortical connection in the context of sensory learning, this project aims to understand 1) the specificity and plasticity in the interaction between thalamus and cortex during both early development and later life, and 2) how the impairment in this functional connection during early development results in long lasting effects on the capacity for learning in the adult brain. Specifically, we will study how different neuronal types and neuromodulators play a role in the developmental and adult plasticity of thalamocortical connectivity.

To address these questions, we will use the rodent whisker-related sensory-motor system because it is ecologically relevant and critical to the animal’s abilities to navigate and engage in goal-directed behavior. We will apply a multidisciplinary approach that combines molecular and genetic techniques with in vivo intracellular and extracellular electrophysiology, in vivo longitudinal calcium imaging, viral tracing, optogenetic and pharmacogenetic methods, and quantitative behavior and anatomical analyses.

Lee’s lab at NIH will focus on early developmental studies and Bruno’s lab at Oxford will focus on adult plasticity. The two labs will use complementary approaches. A student working with Drs. Lee and Bruno will have a unique opportunity to learn conceptual perspectives from both labs, as well as a wide range of experimental and analytical methodologies in the field of system neuroscience. 

Repetition priming (RP) is a basic form of memory, whereby prior exposure to a stimulus facilitates or biases subsequent responses to that stimulus. From a neuropsychological perspective, RP is interesting because it can occur without awareness, and despite the damage to the medial temporal lobe (MTL) system that produces amnesia. Many functional neuroimaging studies using fMRI and MEG/EEG have investigated the brain regions and neuronal dynamics associated with RP. However, the results are complex, depending on several important variables, and suggesting multiple underlying neural mechanisms. Recent computational models provide some insight, and the proposed project will extend these models to a broader range of neuroimaging data, including existing data from intracranial recording in human and non-human primates.

Invent and implement new radioactive probes for imaging specific molecular targets in animal and human brain with positron emission tomography

Invent and implement new radioactive probes for imaging specific molecular targets in animal and human brain with positron emission tomography

Light exposure profoundly affects human physiology and behaviour. Light at the wrong time can shift the internal circadian rhythm and suppress the production of the endogenous hormone melatonin. These non-visual effects of light are largely mediated by the recently discovered melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), which are sensitive to short-wavelength (blue) light.

Chronic exposure to light at night can also have long-term consequences for health and well-being. Importantly, however, recent evidence shows that daytime light exposure can improve alertness and also offset the detrimental effects of light at night. Understanding what 'good' light exposure constitutes therefore is a key priority for mitigating circadian disruption by light.

This innovative collaborative research project will combine state-of-the-art laboratory and field assessments of circadian phase, melatonin production, visual and non-visual sensitivity, activity cycles, and other physiological and behavioural measurements. Broad training in a wide variety of techniques spanning circadian and visual neuroscience will be provided.

Humans display robust age-dependent sex differences in diverse domains of motor, language and social development, as well as in risk for developmentally-emergent disorders. There is a robust male-bias in risk for early-emerging impairments of attention, motor control, language and social functioning, vs. a female-bias for adolescent-emergent disorders of mood and eating behaviors.  The stereotyped pattern of these sex biases suggests a role for sex differences in brain development, and further implies that these differences unfold in a spatiotemporally-specific manner. In support of this notion - in vivo structural neuroimaging studies find focal sex differences in brain anatomy that vary over development. However, the mechanisms driving these neurodevelopmental differences remain poorly understood in humans. In particular, we do not know how specific spatial and temporal instances of sex-biased brain development in humans relate to the two foundational biological differences between males and females: gonadal sex-steroid profile (henceforth “gonadal”) and X/Y-chromosome count [henceforth “sex chromosome dosage” (SCD)]. In our prior cross-sectional neuroimaging studies, we have however provided extensive evidence that gonads and SCD can both shape regional anatomy of the human brain, and that similar effects can be observed in mice. However, to date there are no available data on the temporal unfolding of gonadal and SCD effects on regional brain anatomy, and no quantitative frameworks for comparing these effects between observational humans studies and experimental work in mice.

This project will build on a longstanding productive collaboration between Drs. Lerch and Raznahan, with rich existing datasets, to better-specify sex as a neurobiological variable in health and disease. Key questions for the project relate to (i) fine-grained spatiotemporal mapping of sex, SCD and gonadal effects using neuroimaging in transgenic mice and rare patient groups, (ii) computational solutions for comparison of these maps between species, and (iii) “decoding” of imaging data using measures of gene expression in brain tissue and integrative functional genomics. The resulting anatomical, and genomic signatures for sex-biased development will be probed for association with biological bases of sex-biased brain disorders.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

Use experimental medicine and neuroimaging approaches to uncover the mechanisms mood disorders in adolescents and adults. Depression is a leading cause of burden of disease worldwide yet we know little about its pathogenesis. The student is going to work across the NIMH and Oxford laboratories and use neuroimaging (fMRI, EEG and MEG) in patients and controls who undergo experimental treatments.