Detailed mapping of the complex fiber structure and white matter pathways of the chimpanzee brain

Long-standing questions about human brain evolution may only be resolved through comparisons with close living evolutionary relatives, such as chimpanzees. This applies in particular to structural white matter (WM) connectivity, which continuously expanded throughout evolution. However, due to legal restrictions on chimpanzee research, neuroscience research currently relies largely on data with limited detail or on comparisons with evolutionarily distant monkeys. Here, we present a detailed magnetic resonance imaging resource to study structural WM connectivity in the chimpanzee. This open-access resource contains (1) WM reconstructions of a postmortem chimpanzee brain, using the highest-quality diffusion magnetic resonance imaging data yet acquired from great apes; (2) an optimized and validated method for high-quality fiber orientation reconstructions; and (3) major fiber tract segmentations for cross-species morphological comparisons. This dataset enabled us to identify phylogenetically relevant details of the chimpanzee connectome, and we anticipate that it will substantially contribute to understanding human brain evolution

Methods for analysis of brain connectivity : An IFCN-sponsored review

The goal of this paper is to examine existing methods to study the "Human Brain Connectome" with a specific focus on the neurophysiological ones. In recent years, a new approach has been developed to evaluate the anatomical and functional organization of the human brain: the aim of this promising multimodality effort is to identify and classify neuronal networks with a number of neurobiologically meaningful and easily computable measures to create its connectome. By defining anatomical and functional connections of brain regions on the same map through an integrated approach, comprising both modern neurophysiological and neuroimaging (i.e. flow/metabolic) brain-mapping techniques, network analysis becomes a powerful tool for exploring structural-functional connectivity mechanisms and for revealing etiological relationships that link connectivity abnormalities to neuropsychiatric disorders. Following a recent IFCN-endorsed meeting, a panel of international experts was selected to produce this current state-of-art document, which covers the available knowledge on anatomical and functional connectivity, including the most commonly used structural and functional MRI, EEG, MEG and non-invasive brain stimulation techniques and measures of local and global brain connectivity. (C) 2019 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.Peer reviewe

Micro-, Meso- and Macro-Connectomics of the Brain

Neurosciences, Neurolog

Principles of organisation within the pathways in the brainstem and thalamus

There are few detailed studies on the pathways through the human brainstem and even fewer on those through the pons. This thesis aims to address this lack of fine detail, and used ultra-high-field magnetic resonance imaging (MRI) of human and macaque brains to identify and characterise fibre tracts connecting cortical and spinal areas as they traverse through brainstem and thalamic structures. The material in this thesis is based on a unique dataset of ultra-high-field (7 Tesla – Duke and 11, 7 Tesla – Johns Hopkins) MRI scans on postmortem specimens, on which deterministic tractography has been applied based on high-angular-resolution diffusion imaging (HARDI) and subsequently higher order tensor glyph models. The first results section of the thesis (Chapter 3) maps the descending fibre bundles associated with movement. From the motor cortical areas, the fibres of the internal capsule are traced through the crus cerebri, basilar pons and pyramids in three dimensions to reveal their organisation into functional and topographic subdivisions. While human cortico-pontine, -bulbar and -spinal tracts were traditionally considered to be dispersed, or a “melange”, I show here a much more discrete and defined organisation of these descending fibre bundles. Nine descending fibre bundles are identified and their anatomical location and terminations are described. A hitherto unknown pathway at the midline of the pons has been discovered and named herein as the Stria Pontis which connects the neocortex to the pontine tegmentum. Ten transverse fibre bundles connecting the pontine nuclei to the cerebellum are also identified. The second results section (Chapter 4) analyses the sensory pathways; the dorsal column - medial lemniscus pathway, the spinothalamic tract, the spinal trigeminal tract and the trigeminothalamic tracts. The third results section (Chapter 5) analyses the dentato-rubro-thalamic tract. The mapping identifies the superior cerebellar peduncle, the patterning of the fibres within the superior cerebellar decussation, the patterning of the fibres within the red nucleus and finally the projection of the dentato-rubro-thalamic tract from the red nucleus to the ventral lateral nucleus of the thalamus. Finally, I characterised 117 already known anatomical parts, areas and structures of the brainstem and thalamus in 3D

Brain connectivity mapping with diffusion MRI across individuals and species

The human brain is a highly complex organ that integrates functionally specialised subunits. Underpinning this complexity and functional specialisation is a network of structural connections, which may be probed using diffusion tractography, a unique, powerful and non-invasive MRI technique. Estimates of brain connectivity derived through diffusion tractography allow for explorations of how the brain’s functional subunits are inter-linked to subsequently produce experiences and behaviour. This thesis develops new diffusion tractography methodology for mapping brain connectivity, both across individuals and also across species; and explores frameworks for discovering associations of such brain connectivity features with behavioural traits. We build upon the hypothesis that connectional patterns can probe regions of functional equivalence across brains. To test this hypothesis we develop standardised and automated frameworks for mapping these patterns in very diverse brains, such as from human and non-human primates. We develop protocols to extract homologous fibre bundles across two species (human and macaque monkeys). We demonstrate robustness and generalisability of these protocols, but also their ability to capture individual variability. We also present investigations into how structural connectivity profiles may be used to inform us of how functionally-related features can be linked across different brains. Further, we explore how fully data-driven tractography techniques may be utilised for similar purposes, opening the door for future work on data-driven connectivity mapping. Subsequently, we explore how such individual variability in features that probe brain organisation are associated with differences in human behaviour. One approach to performing such explorations is the use of powerful multivariate statisitical techniques, such as canonical correlation analysis (CCA). After identifying issues in out-of-sample replication using multi-modal connectivity information, we perform comprehensive explorations into the robustness of such techniques and devise a generative model for forward predictions, demonstrating significant challlenges and limitations in their current applications. Specifically, we predict that the stability and generalisability of these techniques requires an order of magnitude more subjects than typically used to avoid overfitting and mis-interpretation of results. Using population-level data from the UK Biobank and confirmations from independent imaging modalities from the Human Connectome Project, we validate this prediction and demonstrate the direct link of CCA stability and generalisability with the number of subjects used per considered feature

Brain connectivity mapping with diffusion MRI across individuals and species

The human brain is a highly complex organ that integrates functionally specialised subunits. Underpinning this complexity and functional specialisation is a network of structural connections, which may be probed using diffusion tractography, a unique, powerful and non-invasive MRI technique. Estimates of brain connectivity derived through diffusion tractography allow for explorations of how the brain’s functional subunits are inter-linked to subsequently produce experiences and behaviour. This thesis develops new diffusion tractography methodology for mapping brain connectivity, both across individuals and also across species; and explores frameworks for discovering associations of such brain connectivity features with behavioural traits. We build upon the hypothesis that connectional patterns can probe regions of functional equivalence across brains. To test this hypothesis we develop standardised and automated frameworks for mapping these patterns in very diverse brains, such as from human and non-human primates. We develop protocols to extract homologous fibre bundles across two species (human and macaque monkeys). We demonstrate robustness and generalisability of these protocols, but also their ability to capture individual variability. We also present investigations into how structural connectivity profiles may be used to inform us of how functionally-related features can be linked across different brains. Further, we explore how fully data-driven tractography techniques may be utilised for similar purposes, opening the door for future work on data-driven connectivity mapping. Subsequently, we explore how such individual variability in features that probe brain organisation are associated with differences in human behaviour. One approach to performing such explorations is the use of powerful multivariate statisitical techniques, such as canonical correlation analysis (CCA). After identifying issues in out-of-sample replication using multi-modal connectivity information, we perform comprehensive explorations into the robustness of such techniques and devise a generative model for forward predictions, demonstrating significant challlenges and limitations in their current applications. Specifically, we predict that the stability and generalisability of these techniques requires an order of magnitude more subjects than typically used to avoid overfitting and mis-interpretation of results. Using population-level data from the UK Biobank and confirmations from independent imaging modalities from the Human Connectome Project, we validate this prediction and demonstrate the direct link of CCA stability and generalisability with the number of subjects used per considered feature

White matter fibres dissection in the human brain

PhD ThesisIntroduction: lesion to white matter fibres can induce permanent neurological deficits due to the induction of disconnection syndromes. Knowledge of white matter fibre anatomy is therefore relevant to the neurosurgeon in order to minimise the risk of causing neurological damage when approaching lesions in eloquent areas of the brain. Aim: to investigate the 3D anatomy of white matter fibres with particular attention to the associative tracts, including short arcuate fibres and intralobar fibres. The results obtained will be used to provide insights in brain connectivity, delineating networks important for specific brain functions. Methods: The Klingler technique for white matter dissection was followed. Brain specimens were collected and prepared at the Newcastle Brain Tissue Resource, Newcastle University. Brains were initially fixed in 10% formalin for at least 4 weeks. After removing the pia-mater and arachnoid, the brains were frozen at -15C° for 2 weeks. The water crystallisation induced by the freezing process separates the white matter fibres, facilitating the dissection of the tracts. Dissection was performed with wooden spatulas and blunt metallic dissectors, removing the cortex and exposing the white matter. The short associative (U-shaped) fibres were initially exposed. Long associative, commissural and projection fibres were demonstrated as the dissection proceeded. Results: five papers form the main body of the present work: 1) “Raymond de Vieussens and his contribution to the study of white matter anatomy”. This historical paper reviewed the history of white matter dissection, focusing on the work of Raymond de Vieussens, who gave the first account of the centrum ovale and of the continuity of the corticospinal tract from the centrum ovale to the brainstem. 2) “The white matter of the human cerebrum: part I The occipital lobe by Heinrich Sachs “ ; 3) “Intralobar fibres of the occipital lobe: A post mortem dissection study”. These joint papers were dedicated to the white matter anatomy of the occipital lobe. A rich network of association fibres, arranged around the ventricular wall, was demonstrated. A new white matter tract, connecting the cuneus to the lingula, was also described. Our original data I II were compared to the atlas of occipital fibres produced by the German anatomist Heinrich Sachs. 4) “White matter connections of the Supplementary Motor Area (SMA) in humans”. This study demonstrated that the SMA shows a wide range of connections with motor, language and limbic areas. Features of the SMA syndrome (akinesia and mutism) can be better understood on the basis of these findings. 5) “Anatomical connections of the Subgenual Cingulate Region” (SCG). This study showed that the SCG is at the centre of a large network, connecting prefrontal, limbic and mesotemporal regions. The connectivity of this region can help explain the clinical effect of neuromodulaton of the SCG in Deep Brain Stimulation for neuropsychiatric disorders. Conclusions: Klingler dissection provided original data about the connections of different brain regions that are relevant to neurosurgical practice, along with the description of a new white matter tract, connecting the cuneus to the lingula

Investigating the behavioural significance of the claustrum

Sequestered deep beneath the cortex, the claustrum is the most densely connected structure in the brain. This tantalizing anatomy has spawned a wide range of hypotheses regarding the function of the claustrum, but technological and biological constraints have hindered research. In this thesis, I have investigated the activity and behavioural function of the claustrum. I developed a novel preparation for recording claustrum activity using two-photon calcium imaging of claustrum axons in dorsal cortex. I show that claustrum axons display stimulus-locked changes in activity following uni- and multimodal sensory stimuli. While some axons were selective to one sensory modality, most were promiscuously responsive to multiple sensory modalities. I then investigated the behavioural consequences of silencing the claustrum. I detected no effects of claustrum silencing on home-cage activity, circadian behaviour, or a battery of tests assessing a wide range of behavioural domains. Finally, I investigated the impact of claustrum silencing on two behavioural tasks. While I detected no effects on a reversal learning task, I found that claustrum silencing reduced animals’ sensitivity to multimodal stimuli in a classical conditioning-like paradigm. Collectively, these results support the hypothesis that the claustrum may be involved in processing multimodal information and highlight the need for more research into the function of the claustrum

Development of Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) Methods to Study Pathophysiology Underlying Neurodegenerative Diseases in Murine Models

Manganese-enhanced magnetic resonance imaging (MEMRI) opens the great opportunity to study complex paradigms of central nervous system (CNS) in freely behaving animals and reveals new pathophysiological information that might be otherwise difficult to gain. Due to advantageous chemical and biological properties of manganese (Mn2+), MEMRI has been successfully applied in the studies of several neurological diseases using translational animal models to assess comprehensive information about neuronal activity, morphology, neuronal tracts, and rate of axonal transport. Although previous studies highlight the potential of MEMRI for brain imaging, the limitations concerning the use of Mn2+ in living animals and applications of MEMRI in neuroscience research are in their infancy. Therefore, development of MEMRI methods for experimental studies remains essential for diagnostic findings, development of therapeutic as well as pharmacological intervention strategies. Our lab has been dedicating to develop novel MEMRI methods to study the pathophysiology underlying neurodegenerative diseases in murine models. In the first study, we investigated the cellular mechanism of MEMRI signal change during neuroinflammation in mice. The roles of neural cells (glia and neurons) in MEMRI signal enhancement were delineated, and ability of MEMRI to detect glial (astrocyte and microglia) and neuronal activation was demonstrated in mice treated with inflammatory inducing agents. In vitro work demonstrated that cytokine-induced glial activation facilitates neuronal uptake of Mn2+,and that glial Mn2+ content was not associated with glial activation. The in vivo work confirmed that MEMRI signal enhancement in the CNS is induced by astrocytic activation by stimulating neuronal Mn2+ uptake. In conclusion, our results supported the notion that MEMRI reflects neuronal excitotoxicity and impairment that can occur through a range of insults that include neuroinflammation. In the second study, we evaluated the efficacy of MEMRI in diagnosing the complexities of neuropathology in an ananimal model of a neurodegenerative disease, neuroAIDS. This study demonstrated that MEMRI reflects brain region specific HIV-1-induced neuropathology in virus-infected NOD/scid-IL-2Rγcnull humanized mice. Altered MEMRI signal intensity was observed in affected brain regions. These included, but were not limited to, the hippocampus, amygdala, thalamus, globus pallidus, caudoputamen, substantia nigra and cerebellum. MEMRI signal was coordinated with levels of HIV-1 infection, neuroinflammation (astro- and micro- gliosis), and neuronal injury. Following the application of MEMRI to assess HIV-1 induced neuropathology in immune deficient mice humanized with lymphoid progenitor cells, our successful collaboration with Dr. Sajja BR (Department of Radiology, UNMC, Omaha, NE) led to the generation of a MEMRI-based NOD/scid-IL-2Rγcnull (NSG) mouse brain atlas. Mouse brain MRI atlases allow longitudinal quantitative analyses of neuroanatomical volumes and imaging metrics. As NSG mice allow human cell transplantation to study human disease, these animals are used to assess brain morphology. MEMRI provided sufficient contrast permitting 41 brain structures to be manually labeled on average brain of 19 mice using alignment algorithm. The developed atlas is now made available to researchers through Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) website (https://www.nitrc.org/projects/memribrainatlas/). Finally, we evaluated the efficacy of N-acetylated-para-aminosalicylic acid (AcPAS) to accelerate Mn2+ elimination from rodent brain, enabling repeated use of MEMRI to follow the CNS longitudinally in weeks or months as well as inhibiting the confounding effects of residual Mn2+ from preceding administrations on imaging results. Two-week treatment with AcPAS (200 mg/kg/dose × 3 daily) accelerated the decline of Mn2+ induced enhancement in MRI. This study demonstrated that AcPAS could enhance MEMRI utility in evaluating brain biology in small animals