Search

Large-scale recordings of neural activity over days and weeks have revealed that neural representations of familiar tasks, precepts and actions continually evolve without obvious changes in behaviour. We hypothesise that this steady drift in neural activity and accompanying physiological changes is due in part to the continuous application of a learning rule at the cellular and population level. Explicit predictions of this drift can be found in neural network models that use iterative learning to optimise weights. Drift therefore provides a measurable signal that can reveal systems-level properties of biological plasticity mechanisms, such as their precision and effective learning rates.

Abstract. Emotion recognition ability of emotions expressed by other people (ERA-O) can be important for job performance, leadership, bargaining, and career success. Traditional personnel assessment tools of this ability, however, are contaminated by linguistic skills. In a time of global work migration, more and more people speak a language at work that is not their mother tongue. Consequently, we developed and validated the Face-Based Emotion Matching Test (FEMT), a nonlinguistic objective test of ERA-O in gainfully employed adults. We demonstrate the FEMT’s validity with psychological constructs (cognitive and emotional intelligence, Big Five personality traits) and its criterion validity and interethnic fit.

Neurons utilize plasticity of dendritic arbors as part of a larger suite of adaptive plasticity mechanisms. This explicitly manifests with motoneurons in the Drosophila embryo and larva, where dendritic arbors are exclusively postsynaptic and are used as homeostatic devices, compensating for changes in synaptic input through adapting their growth and connectivity. We recently identified reactive oxygen species (ROS) as novel plasticity signals instrumental in this form of dendritic adjustment. ROS correlate with levels of neuronal activity and negatively regulate dendritic arbor size. Here, we investigated NADPH oxidases as potential sources of such activity-regulated ROS and implicate Dual Oxidase (but not Nox), which generates hydrogen peroxide extracellularly. We further show that the aquaporins Bib and Drip, but not Prip, are required for activity-regulated ROS-mediated adjustments of dendritic arbor size in motoneurons. These results suggest a model whereby neuronal activity leads to activation of the NADPH oxidase Dual Oxidase, which generates hydrogen peroxide at the extracellular face; aquaporins might then act as conduits that are necessary for these extracellular ROS to be channeled back into the cell where they negatively regulate dendritic arbor size.

This scientific commentary refers to ‘Physiological alterations of pineal recess crowding in symptomatic non-hydrocephalic pineal cysts’ by Eide et al. (https://doi.org/10.1093/braincomms/fcad078).

Cerebral vasculature plays an important role in maintaining brain function and homeostasis. In ageing, a number of genetic and environmental risk factors can compromise brain vascular health and contribute to multiple neurological disorders. White matter (WM) is more vulnerable in cerebrovascular ageing compared with grey matter. With the development of automated and reproducible neuroimaging techniques, there is an opportunity to detect many ageing-related or diseases-related WM changes at an early stage with greater sensitivity. The overall objective of this PhD project is, therefore, to develop reliable neuroimaging biomarkers for characterising WM integrity and examine their relationships with cerebrovascular burden. Four separate studies were carried out to investigate this topic in depth. In the first study, a new diffusion-weighted imaging (DWI) measure, Difference in Distribution Functions (DDF), was developed to overcome the limitations of existing DWI measures in characterising the white matter (WM) microstructural integrity. DDF showed a stronger correlation with age and cognition than other DWI measures investigated. The second study extended the first study by employing longitudinal datasets to examine the effects of various risk factors on WM microstructural integrity over time. Results showed that older age is the primary risk factor for decline in WM integrity in a healthy general population sample. In the third study, a new imaging metric, WM brain age, was introduced to comprehensively assess the health of WM and cerebrovascular disease burdens for each individual. WM brain age was calculated by using a three-dimensional convolutional neural network (3D-CNN) deep learning model. Findings showed that WM brain age is sensitive to most vascular risk factors and cognitive domains related to vascular dysfunction. In the fourth study, the impacts of high blood pressure on grey matter (GM) and WM, respectively, were examined using 3D-CNN to construct GM and WM ages. Findings revealed that hypertension is associated with both GM and WM impairment, and that WM integrity is more vulnerable to hypertension. In conclusion, by developing novel neuroimaging biomarkers for the changes in cerebrovascular ageing, this thesis provides novel contributions to the existing literature. These findings have the potential to better quantify the vascular burden in future research work and in clinical practice.

Variations in neuronal connectivity occur widely in nervous systems from invertebrates to mammals. Yet, it is unclear how neuronal variability originates, to what extent and at what time scales it exists, and what functional consequences it might carry. To assess inter- and intraindividual neuronal variability, it would be ideal to analyze the same identified neuron across different brain hemispheres and individuals. Here, using genetic labeling and electron microscopy connectomics, we show that an identified inhibitory olfactory local interneuron, TC-LN, exhibits extraordinary variability in its glomerular innervation patterns. Moreover, TC-LN’s innervation of the VL2a glomerulus, which processes food signals and modulates mating behavior, is sexually dimorphic, is influenced by female’s courtship experience, and correlates with food intake in mated females. Mating also affects output connectivity of TC-LN to specific local interneurons. We propose that mating-associated variability of TC-LNs regulates how food odor is interpreted by an inhibitory network to modulate feeding.

The interaction of descending neocortical outputs and subcortical premotor circuits is critical for shaping skilled movements. Two broad classes of motor cortical output projection neurons provide input to many subcortical motor areas: pyramidal tract (PT) neurons, which project throughout the neuraxis, and intratelencephalic (IT) neurons, which project within the cortex and subcortical striatum. It is unclear whether these classes are functionally in series or whether each class carries distinct components of descending motor control signals. Here, we combine large-scale neural recordings across all layers of motor cortex with cell type–specific perturbations to study cortically dependent mouse motor behaviors: kinematically variable manipulation of a joystick and a kinematically precise reach-to-grasp. We find that striatum-projecting IT neuron activity preferentially represents amplitude, whereas pons-projecting PT neurons preferentially represent the variable direction of forelimb movements. Thus, separable components of descending motor cortical commands are distributed across motor cortical projection cell classes.

Introduction: Prediagnostic features of Parkinson’s Disease are well described but prediagnostic Progressive Supranuclear Palsy (PSP) is less understood. The diagnosis of PSP is delayed by an average of three years after symptom onset. Understanding the changes that occur in the prediagnostic period will aid earlier diagnosis, clarify the natural history, and may aid the design of early disease-modifying therapy trials. We set out to identify motor and cognitive markers of prediagnostic PSP, with Parkinson’s disease as a comparator condition, in a large prospective cohort. Methods: Baseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinson’s disease cases were identified from primary and secondary care electronic health records’ diagnostic coding data and death registry, with 5,404 matched controls. Results: 176 PSP cases (time to diagnosis 7.8±2.8 years) and 2,526 Parkinson’s disease cases (time to diagnosis 7.8±2.9 years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, prospective memory, self-rated health scores and digit recall than controls. Reaction times were correlated with time to diagnosis. The PSP group had higher mortality than both Parkinson’s disease and control groups. Conclusions: Motor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP that are typically symptomatic three years before diagnosis. Objective markers of these features were evident on average 7.8 years before diagnosis. Our findings suggest the existence of a long prediagnostic phase in PSP, with subtle changes in motor and cognitive function.

This thesis focuses on the development and applications of magnetic resonance electrical properties tomography (MREPT), which is an emerging imaging modality to noninvasively obtain the electrical properties of tissues, such as conductivity and permittivity. Chapter 2 describes the general information about human research ethics, MRI scanner, MR sequence and the method of phase-based MREPT implemented in this thesis. Chapter 3 examines the repeatability of phase-based MREPT in the brain conductivity measurement using balanced fast field echo (bFFE) and turbo spin echo (TSE) sequences, and investigate the effects of compressed SENSE, whole-head B_1 shimming and video watching during scan on the measurement precision. Chapter 4 investigates the conductivity signal in response to short-duration visual stimulus, compares the signal and functional activation pathway with that of BOLD, and tests the consistency of functional conductivity imaging (funCI) with visual stimulation across participants. Chapter 5 extends the use of functional conductivity imaging to somatosensory stimulation and trigeminal nerve stimulation to evaluate the consistency of functional conductivity activation across different types of stimuli. In addition, visual adaptation experiment is performed to test if the repetition suppression effect can be observed using funCI. Chapter 6 explores if resting state conductivity networks can be reliably constructed using resting state funCI, evaluates the consistency of persistent homology architectures, and compares the links between nodes in the whole brain. Chapter 7 investigates the feasibility of prostate conductivity imaging using MREPT, and distinctive features in the conductivity distribution between healthy participants and participants with suspected abnormalities.

Among emerging technologies developed to interface neuronal signaling, engineering electrodes at the nanoscale would yield more precise biodevices opening to progress in neural circuit investigations and to new therapeutic potential. Despite remarkable progress in miniature electronics for less invasive neurostimulation, most nano-enabled, optically triggered interfaces are demonstrated in cultured cells, which precludes the studies of natural neural circuits. We exploit here free-standing silicon-based nanoscale photodiodes to optically modulate single, identified neurons in mammalian spinal cord explants. With near-infrared light stimulation, we show that activating single excitatory or inhibitory neurons differently affects sensory circuits processing in the dorsal horn. We successfully functionalize nano-photodiodes to target single molecules, such as glutamate AMPA receptor subunits, thus enabling light activation of specific synaptic pathways. We conclude that nano-enabled neural interfaces can modulate selected sensory networks with low invasiveness. The use of nanoscale photodiodes can thus provide original perspective in linking neural activity to specific behavioral outcome. We thank M. Gigante, G. Cellot, S. Mortal, and M. Lazzarino for help with setting up the laser stimulation setup; the group of P. Heppenstall for help with the AAV production; M. Giugliano for MATLAB code optimization; R. Owen for suggestions in antibody nPD characterization; and S. Usmani for help with initial experiments. This project was funded by HFSP program grant RGP0004/2019 (to L.B., B.T., and L.F.).

BACKGROUND: Scientific and societal interest is growing in understanding links between sports concussion and neurodegeneration. When multiple symptoms, such as memory loss, anxiety and headaches, persist after head impact(s), this is defined as post-concussion syndrome (PCS). Aetiology of PCS is poorly understood and there is no specific pharmacological cure. This study aimed to generate a novel sports PCS model in Drosophila melanogaster to facilitate further understanding of the syndrome. METHODS: The HIT device was constructed as per prior methods1 , but with protractor added and impact forces measured with a pancake load cell for repeatable trauma application to fly subgroups at 0° (control), 30°, 45° or 60° release angles, measured as 0N, 1.1N, 1.8N and 2.1N respectively. Hits were repeated five times with 48-72 hour intervals to model multiple traumas contact-sports players experience during their careers. To evaluate effects of impacts, motor ability, survival and reactive oxygen nitrogen species (RONS) levels were measured. Motor ability was reported as a percentage of the number of flies that climbed above 5.5cm in 5.5 seconds. Flies were frozen at 21-22 days post-eclosure (middle-age), heads and bodies separated and homogenised, then post-centrifugation supernatant was assayed with DCF-DA: condensed into highly fluorescent DCF in the presence of RONS, quantified by fluorescence spectroscopy. RESULTS: As with most human mild head trauma cases, fly motor ability was not significantly different acutely or long-term following HIT device impacts. Similarly, with 1.8N impacts, lifespan was not significantly different compared to non-trauma controls. Meanwhile, RONS levels increased in both fly heads (brains) and bodies (periphery) with five 1.8N impacts, representative of physiological stress in contact sportspeople with PCS. CONCLUSIONS: Five 1.8N hits (at 45° release angle) produced the most suitable Drosophila sports PCS model. This novel model offers a rapid, inexpensive drug screening approach for prospective PCS treatments, and shows promise in investigating the oxidative stress mechanisms underlying PCS. Additional analyses, including neurodegeneration biomarker quantification and behavioural monitoring, are currently being explored to validate this model. Reference: 1 Katzenberger RJ et al. (2013) PNAS 110, 4152-4159.