James Kolasinski

Review: the role of vitamin D in nervous system health and disease.

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinsons disease, amyotrophic lateral sclerosis, Alzheimers disease, and is especially strong for multiple sclerosis.

A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology.

Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.

Radial and tangential neuronal migration pathways in the human fetal brain: anatomically distinct patterns of diffusion MRI coherence

Corticogenesis is underpinned by a complex process of subcortical neuroproliferation, followed by highly orchestrated cellular migration. A greater appreciation of the processes involved in human fetal corticogenesis is vital to gaining an understanding of how developmental disturbances originating in gestation could establish a variety of complex neuropathology manifesting in childhood, or even in adult life. Magnetic resonance imaging modalities offer a unique insight into anatomical structure, and increasingly infer information regarding underlying microstructure in the human brain. In this study we applied a combination of high-resolution structural and diffusion-weighted magnetic resonance imaging to a unique cohort of three post-mortem fetal brain specimens, aged between 19 and 22 post-conceptual weeks. Specifically, we sought to assess patterns of diffusion coherence associated with subcortical neuroproliferative structures: the pallial ventricular/subventricular zone and subpallial ganglionic eminence. Two distinct three-dimensional patterns of diffusion coherence were evident: a clear radial pattern originating in ventricular/subventricular zone, and a tangentio-radial patterns originating in ganglionic eminence. These patterns appeared to regress in a caudo-rostral and lateral-ventral to medial-dorsal direction across the short period of fetal development under study. Our findings demonstrate for the first time distinct patterns of diffusion coherence associated with known anatomical proliferative structures. The radial pattern associated with dorsopallial ventricular/subventricular zone and the tangentio-radial pattern associated with subpallial ganglionic eminence are consistent with reports of radial-glial mediated neuronal migration pathways identified during human corticogenesis, supported by our prior studies of comparative fetal diffusion MRI and histology. The ability to assess such pathways in the fetal brain using MR imaging offers a unique insight into three-dimensional trajectories beyond those visualized using traditional histological techniques. Our results suggest that ex-vivo fetal MRI is a potentially useful modality in understanding normal human development and various disease processes whose etiology may originate in aberrant fetal neuronal migration.

Asymmetry of White Matter Pathways in Developing Human Brains

Little is known about the emergence of structural asymmetry of white matter tracts during early brain development. We examined whether and when asymmetry in diffusion parameters of limbic and association white matter pathways emerged in humans in 23 brains ranging from 15 gestational weeks (GW) up to 3 years of age (11 ex vivo and 12 in vivo cases) using high-angular resolution diffusion imaging tractography. Age-related development of laterality was not observed in a limbic connectional pathway (cingulum bundle or fornix). Among the studied cortico-cortical association pathways (inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus, and arcuate fasciculus), only the ILF showed development of age-related laterality emerging as early as the second trimester. Comparisons of ages older and younger than 40 GW revealed a leftward asymmetry in the cingulum bundle volume and a rightward asymmetry in apparent diffusion coefficient and leftward asymmetry in fractional anisotropy in the ILF in ages older than 40 GW. These results suggest that morphometric asymmetry in cortical areas precedes the emergence of white matter pathway asymmetry. Future correlative studies will investigate whether such asymmetry is anatomically/genetically driven or associated with functional stimulation.

Revealing the neural fingerprints of a missing hand

The hand area of the primary somatosensory cortex contains detailed finger topography, thought to be shaped and maintained by daily life experience. Here we utilise phantom sensations and ultra high-field neuroimaging to uncover preserved, though latent, representation of amputees’ missing hand. We show that representation of the missing hand’s individual fingers persists in the primary somatosensory cortex even decades after arm amputation. By demonstrating stable topography despite amputation, our finding questions the extent to which continued sensory input is necessary to maintain organisation in sensory cortex, thereby reopening the question what happens to a cortical territory once its main input is lost. The discovery of persistent digit topography of amputees’ missing hand could be exploited for the development of intuitive and fine-grained control of neuroprosthetics, requiring neural signals of individual digits. DOI: http://dx.doi.org/10.7554/eLife.15292.001

Investigating the Stability of Fine-Grain Digit Somatotopy in Individual Human Participants.

Studies of human primary somatosensory cortex (S1) have placed a strong emphasis on the cortical representation of the hand and the propensity for plasticity therein. Despite many reports of group differences and experience-dependent changes in cortical digit somatotopy, relatively little work has considered the variability of these maps across individuals and to what extent this detailed functional architecture is dynamic over time. With the advent of 7 T fMRI, it is increasingly feasible to map such detailed organization noninvasively in individual human participants. Here, we extend the ability of ultra-high-field imaging beyond a technological proof of principle to investigate the intersubject variability of digit somatotopy across participants and the stability of this organization across a range of intervals. Using a well validated phase-encoding paradigm and an active task, we demonstrate the presence of highly reproducible maps of individual digits in S1, sharply contrasted by a striking degree of intersubject variability in the shape, extent, and relative position of individual digit representations. Our results demonstrate the presence of very stable fine-grain somatotopy of the digits in human S1 and raise the issue of population variability in such detailed functional architecture of the human brain. These findings have implications for the study of detailed sensorimotor plasticity in the context of both learning and pathological dysfunction. The simple task and 10 min scan required to derive these maps also raises the potential for this paradigm as a tool in the clinical setting. SIGNIFICANCE STATEMENT We applied ultra-high-resolution fMRI at 7 T to map sensory digit representations in the human primary somatosensory cortex (S1) at the level of individual participants across multiple time points. The resulting fine-grain maps of individual digits in S1 reveal the stability in this fine-grain functional organization over time, contrasted with the variability in these maps across individuals.

Individual Differences in the Alignment of Structural and Functional Markers of the V5/MT Complex in Primates

Extrastriate visual area V5/MT in primates is defined both structurally by myeloarchitecture and functionally by distinct responses to visual motion. Myelination is directly identifiable from postmortem histology but also indirectly by image contrast with structural magnetic resonance imaging (sMRI). First, we compared the identification of V5/MT using both sMRI and histology in Rhesus macaques. A section-by-section comparison of histological slices with in vivo and postmortem sMRI for the same block of cortical tissue showed precise correspondence in localizing heavy myelination for V5/MT and neighboring MST. Thus, sMRI in macaques accurately locates histologically defined myelin within areas known to be motion selective. Second, we investigated the functionally homologous human motion complex (hMT+) using high-resolution in vivo imaging. Humans showed considerable intersubject variability in hMT+ location, when defined with myelin-weighted sMRI signals to reveal structure. When comparing sMRI markers to functional MRI in response to moving stimuli, a region of high myelin signal was generally located within the hMT+ complex. However, there were considerable differences in the alignment of structural and functional markers between individuals. Our results suggest that variation in area identification for hMT+ based on structural and functional markers reflects individual differences in human regional brain architecture.

A Mechanistic Link from GABA to Cortical Architecture and Perception

Summary Understanding both the organization of the human cortex and its relation to the performance of distinct functions is fundamental in neuroscience. The primary sensory cortices display topographic organization, whereby receptive fields follow a characteristic pattern, from tonotopy to retinotopy to somatotopy [1]. GABAergic signaling is vital to the maintenance of cortical receptive fields [2]; however, it is unclear how this fine-grain inhibition relates to measurable patterns of perception [3, 4]. Based on perceptual changes following perturbation of the GABAergic system, it is conceivable that the resting level of cortical GABAergic tone directly relates to the spatial specificity of activation in response to a given input [5, 6, 7]. The specificity of cortical activation can be considered in terms of cortical tuning: greater cortical tuning yields more localized recruitment of cortical territory in response to a given input. We applied a combination of fMRI, MR spectroscopy, and psychophysics to substantiate the link between the cortical neurochemical milieu, the tuning of cortical activity, and variability in perceptual acuity, using human somatosensory cortex as a model. We provide data that explain human perceptual acuity in terms of both the underlying cellular and metabolic processes. Specifically, higher concentrations of sensorimotor GABA are associated with more selective cortical tuning, which in turn is associated with enhanced perception. These results show anatomical and neurochemical specificity and are replicated in an independent cohort. The mechanistic link from neurochemistry to perception provides a vital step in understanding population variability in sensory behavior, informing metabolic therapeutic interventions to restore perceptual abilities clinically.

Perceptually relevant remapping of human somatotopy in 24 hours

Experience-dependent reorganisation of functional maps in the cerebral cortex is well described in the primary sensory cortices. However, there is relatively little evidence for such cortical reorganisation over the short-term. Using human somatosensory cortex as a model, we investigated the effects of a 24 hr gluing manipulation in which the right index and right middle fingers (digits 2 and 3) were adjoined with surgical glue. Somatotopic representations, assessed with two 7 tesla fMRI protocols, revealed rapid off-target reorganisation in the non-manipulated fingers following gluing, with the representation of the ring finger (digit 4) shifted towards the little finger (digit 5) and away from the middle finger (digit 3). These shifts were also evident in two behavioural tasks conducted in an independent cohort, showing reduced sensitivity for discriminating the temporal order of stimuli to the ring and little fingers, and increased substitution errors across this pair on a speeded reaction time task. DOI: http://dx.doi.org/10.7554/eLife.17280.001

COMPARISON OF HISTOLOGICAL AND DIFFUSION-WEIGHTED MRI TECHNIQUES IN THE ANALYSIS OF POST MORTEM MULTIPLE SCLEROSIS BRAINS

Multiple sclerosis (MS) is a chronic inflammatory neurological condition characterised by both focal and diffuse neurodegeneration and demyelination throughout the central nervous system. However, associations between these individual pathological processes remain poorly defined. Here we present a highly novel combination of whole brain post-mortem diffusion and structural MRI with quantitative histology to assess patterns of MS pathology. Two white matter tracts and their associated grey matter structures were assessed in nine fixed whole brains on the basis of their documented involvement in MS: that running from lateral geniculate nucleus to primary visual cortex, and from mediodorsal nucleus of the thalamus to prefrontal cortex. Cortical thickness was correlated significantly with both tract myelination and thalamic nucleus cell density within the anatomically distinct tract structures. Such correlations were not observed between these markers of neurodegeneration across the two tract types. In addition, diffusion MRI metrics in all tracts were correlated significantly with histologically defined levels of tract myelination. These data demonstrate for the first time the potential relevance of functional anatomical connectivity to the spread of MS pathology in a “tract-specific” pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted MRI and tissue microstructure in fixed samples validates the exciting potential of this imaging modality for future neuropathological studies.