Brain morphometry in former American football players: findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE), which currently can be diagnosed only at post-mortem. American football players are at higher risk of developing CTE given their exposure to repetitive head impacts. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at post-mortem in living individuals using structural MRI. MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 54, age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each traumatic encephalopathy syndrome (TES) diagnosis, core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula, temporal pole and superior frontal gyrus. Post hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus, amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe Age × Group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggested that MRI morphometrics detect abnormalities in individuals with a history of repetitive head impact exposure that resemble the anatomic distribution of pathological findings from post-mortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggested that brain morphometry must be complemented by other types of measures to characterize individuals with repetitive head impacts.

Revisiting 'brain modes' in a new computational era: approaches for the characterization of brain-behavioural associations.

The study of brain-function relationships is undergoing a conceptual and methodological transformation due to the emergence of network neuroscience and the development of multivariate methods for lesion-deficit inferences. Anticipating this process, in 1998 Godefroy and co-workers conceptualized the potential of four elementary typologies of brain-behaviour relationships named 'brain modes' (unicity, equivalence, association, summation) as building blocks able to describe the association between intact or lesioned brain regions and cognitive processes or neurological deficits. In the light of new multivariate lesion inference and network approaches, we critically revisit and update the original theoretical notion of brain modes, and provide real-life clinical examples that support their existence. To improve the characterization of elementary units of brain-behavioural relationships further, we extend such conceptualization with a fifth brain mode (mutual inhibition/masking summation). We critically assess the ability of these five brain modes to account for any type of brain-function relationship, and discuss past versus future contributions in redefining the anatomical basis of human cognition. We also address the potential of brain modes for predicting the behavioural consequences of lesions and their future role in the design of cognitive neurorehabilitation therapies.

Prenatal malnutrition leads to deficits in attentional set shifting and decreases metabolic activity in prefrontal subregions that control executive function.

Globally, over 25% of all children under the age of 5 years experience malnutrition leading to cognitive and emotional impairments that can persist into adulthood and beyond. We use a rodent model to determine the impact of prenatal protein malnutrition on executive functions in an attentional set-shifting task and metabolic activity in prefrontal cortex (PFC) subregions critical to these behaviors. Long-Evans dams were provided with a low (6% casein) or adequate (25% casein) protein diet 5 weeks before mating and during pregnancy. At birth, the litters were culled to 8 pups and fostered to control dams on the 25% casein diet. At postnatal day 90, prenatally malnourished rats were less able to shift attentional set and reverse reward contingencies than controls, demonstrating cognitive rigidity. Naive same-sexed littermates were assessed for regional brain activity using the metabolic marker (14)C-2-deoxyglucose (2DG). The prenatally malnourished rats had lower metabolic activity than controls in prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices, but had comparable activity in the nearby piriform cortex and superior colliculus. This study demonstrates that prenatal protein malnutrition in a well-described animal model produces cognitive deficits in tests of attentional set shifting and reversal learning, similar to findings of cognitive inflexibility reported in humans exposed to early childhood malnutrition.

Volumetric Analysis of Amygdala and Hippocampal Subfields for Infants with Autism.

Previous studies have demonstrated abnormal brain overgrowth in children with autism spectrum disorder (ASD), but the development of specific brain regions, such as the amygdala and hippocampal subfields in infants, is incompletely documented. To address this issue, we performed the first MRI study of amygdala and hippocampal subfields in infants from 6 to 24 months of age using a longitudinal dataset. A novel deep learning approach, Dilated-Dense U-Net, was proposed to address the challenge of low tissue contrast and small structural size of these subfields. We performed a volume-based analysis on the segmentation results. Our results show that infants who were later diagnosed with ASD had larger left and right volumes of amygdala and hippocampal subfields than typically developing controls.

Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study.

BACKGROUND: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. METHODS: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. RESULTS: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. CONCLUSIONS: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.

Anatomically curated segmentation of human subcortical structures in high resolution magnetic resonance imaging: An open science approach.

Magnetic resonance imaging (MRI)-based brain segmentation has recently been revolutionized by deep learning methods. These methods use large numbers of annotated segmentations to train algorithms that have the potential to perform brain segmentations reliably and quickly. However, training data for these algorithms are frequently obtained from automated brain segmentation systems, which may contain inaccurate neuroanatomy. Thus, the neuroimaging community would benefit from an open source database of high quality, neuroanatomically curated and manually edited MRI brain images, as well as the publicly available tools and detailed procedures for generating these curated data. Manual segmentation approaches are regarded as the gold standard for brain segmentation and parcellation. These approaches underpin the construction of neuroanatomically accurate human brain atlases. In addition, neuroanatomically precise definitions of MRI-based regions of interest (ROIs) derived from manual brain segmentation are essential for accuracy in structural connectivity studies and in surgical planning for procedures such as deep brain stimulation. However, manual segmentation procedures are time and labor intensive, and not practical in studies utilizing very large datasets, large cohorts, or multimodal imaging. Automated segmentation methods were developed to overcome these issues, and provide high data throughput, increased reliability, and multimodal imaging capability. These methods utilize manually labeled brain atlases to automatically parcellate the brain into different ROIs, but do not have the anatomical accuracy of skilled manual segmentation approaches. In the present study, we developed a custom software module for manual editing of brain structures in the freely available 3D Slicer software platform that employs principles and tools based on pioneering work from the Center for Morphometric Analysis (CMA) at Massachusetts General Hospital. We used these novel 3D Slicer segmentation tools and techniques in conjunction with well-established neuroanatomical definitions of subcortical brain structures to manually segment 50 high resolution T1w MRI brains from the Human Connectome Project (HCP) Young Adult database. The structural definitions used herein are associated with specific neuroanatomical ontologies to systematically interrelate histological and MRI-based morphometric definitions. The resulting brain datasets are publicly available and will provide the basis for a larger database of anatomically curated brains as an open science resource.

In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia.

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

MRI-based Parcellation and Morphometry of the Individual Rhesus Monkey Brain: the macaque Harvard-Oxford Atlas (mHOA), a translational system referencing a standardized ontology.

Investigations of the rhesus monkey (Macaca mulatta) brain have shed light on the function and organization of the primate brain at a scale and resolution not yet possible in humans. A cornerstone of the linkage between non-human primate and human studies of the brain is magnetic resonance imaging, which allows for an association to be made between the detailed structural and physiological analysis of the non-human primate and that of the human brain. To further this end, we present a novel parcellation method and system for the rhesus monkey brain, referred to as the macaque Harvard-Oxford Atlas (mHOA), which is based on the human Harvard-Oxford Atlas (HOA) and grounded in an ontological and taxonomic framework. Consistent anatomical features were used to delimit and parcellate brain regions in the macaque, which were then categorized according to functional systems. This system of parcellation will be expanded with advances in technology and, like the HOA, will provide a framework upon which the results from other experimental studies (e.g., functional magnetic resonance imaging (fMRI), physiology, connectivity, graph theory) can be interpreted.

Perturbation-driven paradoxical facilitation of visuo-spatial function: Revisiting the 'Sprague effect'.

The 'Sprague Effect' described in the seminal paper of James Sprague (Science 153:1544-1547, 1966a) is an unexpected paradoxical effect in which a second brain lesion reversed functional deficits induced by an earlier lesion. It was observed initially in the cat where severe and permanent contralateral visually guided attentional deficits generated by the ablation of large areas of the visual cortex were reversed by the subsequent removal of the superior colliculus (SC) opposite to the cortical lesion or by the splitting of the collicular commissure. Physiologically, this effect has been explained in several ways-most notably by the reduction of the functional inhibition of the ipsilateral SC by the contralateral SC, and the restoration of normal interactions between cortical and midbrain structures after ablation. In the present review, we aim at reappraising the 'Sprague Effect' by critically analyzing studies that have been conducted in the feline and human brain. Moreover, we assess applications of the 'Sprague Effect' in the rehabilitation of visually guided attentional impairments by using non-invasive therapeutic approaches such as transcranial magnetic stimulation (TMS) and transcranial direct-current stimulation (tDCS). We also review theoretical models of the effect that emphasize the inhibition and balancing between the two hemispheres and show implications for lesion inference approaches. Last, we critically review whether the resulting inter-hemispheric rivalry theories lead toward an efficient rehabilitation of stroke in humans. We conclude by emphasizing key challenges in the field of 'Sprague Effect' applications in order to design better therapies for brain-damaged patients.

How Human Is Human Connectional Neuroanatomy?

The structure of the human brain has been studied extensively. Despite all the knowledge accrued, direct information about connections, from origin to termination, in the human brain is extremely limited. Yet there is a widespread misperception that human connectional neuroanatomy is well-established and validated. In this article, we consider what is known directly about human structural and connectional neuroanatomy. Information on neuroanatomical connections in the human brain is derived largely from studies in non-human experimental models in which the entire connectional pathway, including origins, course, and terminations, is directly visualized. Techniques to examine structural connectivity in the human brain are progressing rapidly; nevertheless, our present understanding of such connectivity is limited largely to data derived from homological comparisons, particularly with non-human primates. We take the position that an in-depth and more precise understanding of human connectional neuroanatomy will be obtained by a systematic application of this homological approach.

The composition of the inner nuclear layer of the cat retina.

The cellular composition of the inner nuclear layer (INL) is largely conserved among mammals. Studies of rabbit, monkey, and mouse retinas have shown that bipolar, amacrine, Müller, and horizontal cells make up constant fractions of the INL (42, 35, 20, and 3%, respectively); these proportions remain relatively constant at all retinal eccentricities. The purpose of our study was to test whether the organization of cat retina is similar to that of other mammalian retinas. Fixed retinas were embedded in plastic, serially sectioned at a thickness of 1 microm, stained, and imaged at high power in the light microscope. Bipolar, amacrine, Müller, and horizontal cells were classified and counted according to established morphological criteria. Additional sets of sections were processed for protein kinase C and calretinin immunoreactivity to determine the relative fraction of rod bipolar and AII amacrine cells. Our results show that the organization of INL in the cat retina contains species-specific alterations in the composition of the INL tied to the large fraction of rod photoreceptors. Compared with other mammalian retinas, cat retinas show an expansion of the rod pathway with rod bipolar cells accounting for about 70% of all bipolar cells and AII cells accounting for nearly a quarter of all amacrine cells. Our results suggest that evolutionary pressures in cats over time have refined their retinal organization to suit its ecological niche.

Prenatal Protein Malnutrition Leads to Hemispheric Differences in the Extracellular Concentrations of Norepinephrine, Dopamine and Serotonin in the Medial Prefrontal Cortex of Adult Rats.

Exposure to prenatal protein malnutrition (PPM) leads to a reprogramming of the brain, altering executive functions involving the prefrontal cortex (PFC). In this study we used in vivo microdialysis to assess the effects of PPM on extracellular concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) bilaterally in the ventral portion of the medial prefrontal cortex (vmPFC; ventral prelimbic and infralimbic cortices) of adult Long-Evans rats. Female Long-Evans rats were fed either a low protein (6%) or adequate protein diet (25%) prior to mating and throughout pregnancy. At birth, all litters were culled and fostered to dams fed a 25% (adequate) protein diet. At 120 days of age, 2 mm microdialysis probes were placed into left and right vmPFC. Basal extracellular concentrations of NE, DA, and 5-HT were determined over a 1-h period using HPLC. In rats exposed to PPM there was a decrease in extracellular concentrations of NE and DA in the right vmPFC and an increase in the extracellular concentration of 5-HT in the left vmPFC compared to controls (prenatally malnourished: N = 10, well-nourished: N = 20). Assessment of the cerebral laterality of extracellular neurotransmitters in the vmPFC showed that prenatally malnourished animals had a significant shift in laterality from the right to the left hemisphere for NE and DA but not for serotonin. In a related study, these animals showed cognitive inflexibility in an attentional task. In animals in the current study, NE levels in the right vmPFC of well-nourished animals correlated positively with performance in an attention task, while 5-HT in the left vmPFC of well-nourished rats correlated negatively with performance. These data, in addition to previously published studies, suggest a long-term reprogramming of the vmPFC in rats exposed to PPM which may contribute to attention deficits observed in adult animals exposed to PPM.

Age-dependent sparing of visual function after bilateral lesions of primary visual cortex.

Bilateral lesions of primary visual cortex (PVC) sustained early in life induce the visual system to undergo structural and functional reorganization and produce modified neuronal networks capable of mediating visual abilities that would be impaired if the lesions occurred in adulthood. Reorganization after early lesion is also accompanied by degeneration of the lateral geniculate nucleus of the thalamus, and 90% of beta retinal ganglion cells die via retrograde degeneration. It is unclear whether the high potential of the system to reorganize after early lesion could overcome the effects of beta retinal ganglion cell death. Visual acuity, which depends on an intact beta-cell array, was impaired in cats that underwent PVC lesions on postnatal day 1 and indicated that neuroplastic potential was insufficient to overcome early lesion-induced maladaptive plasticity. Animals with lesions made at 1 month of age, a stage accompanied by high levels of neuroplastic potential but no death of beta cells, achieved acuity measures equivalent to intact animals. The authors conclude that visual signals are rerouted to subserve functionality when the lesion is made at 1 month of age, but not at 1 day of age.

Functional circuitry underlying visual neglect.

Visuospatial neglect is a common neurological syndrome caused by unilateral brain damage to the posterior and inferior parietal cerebral cortex, and is characterized by an inability to respond or orient to stimuli presented in the contralesional hemifield. Neglect has been elicited in experimental models of the rat, cat and monkey, and is thought to result in part from a pathological state of inhibition exerted on the damaged hemisphere by the hyperexcited intact hemisphere. We sought to test this theory by assessing neural activity levels in multiple brain structures during neglect using 2-deoxyglucose (2DG) as a metabolic marker of neural activity. Neglect was induced in two ways: (i) by cooling deactivation of posterior parietal cortex or (ii) in conjunction with broader cortical blindness produced by unilateral lesion of all contiguous visual cortical areas spanning occipital, parietal and temporal regions. The direction and magnitude of changes in 2DG uptake were measured in cerebral cortex and midbrain structures. Finally, the 2DG uptake was assessed in a group of cats in which the lesion-induced neglect component of blindness was cancelled by cooling of either the contralateral posterior parietal cortex or the contralateral superior colliculus (SC). Overall, we found that (i) both lesion- and cooling-induced neglect are associated with decreases in 2DG uptake in specific ipsilateral cortical and midbrain regions; (ii) levels of 2DG uptake in the intermediate and deep layers of the SC contralateral to both cooling and lesion deactivations are increased; (iii) changes in 2DG uptake were not identified in the contralateral cortex; and (iv) reversal of the lesion-induced neglect component of blindness is associated with a reduction of contralesional 2DG uptake to normal or subnormal levels. These data are in accord with theories of neglect that include mutually suppressive mechanisms between the two hemispheres, and we show that these mechanisms operate at the level of the SC, but are not apparent at the level of cortex. These results suggest that the most effective therapies for visual neglect will be those that act to decrease neural activity in the intermediate layers of the SC contralateral to the brain damage.

Motor Cortex Neurostimulation Technologies for Chronic Post-stroke Pain: Implications of Tissue Damage on Stimulation Currents.

Background: Central post stroke pain (CPSP) is a highly refractory syndrome that can occur after stroke. Primary motor cortex (M1) brain stimulation using epidural brain stimulation (EBS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have been explored as potential therapies for CPSP. These techniques have demonstrated variable clinical efficacy. It is hypothesized that changes in the stimulating currents that are caused by stroke-induced changes in brain tissue conductivity limit the efficacy of these techniques. Methods: We generated MRI-guided finite element models of the current density distributions in the human head and brain with and without chronic focal cortical infarctions during EBS, TMS, and tDCS. We studied the change in the stimulating current density distributions' magnitude, orientation, and maxima locations between the different models. Results: Changes in electrical properties at stroke boundaries altered the distribution of stimulation currents in magnitude, location, and orientation. Current density magnitude alterations were larger for the non-invasive techniques (i.e., tDCS and TMS) than for EBS. Nonetheless, the lesion also altered currents during EBS. The spatial shift of peak current density, relative to the size of the stimulation source, was largest for EBS. Conclusion: In order to maximize therapeutic efficiency, neurostimulation trials need to account for the impact of anatomically disrupted neural tissues on the location, orientation, and magnitude of exogenously applied currents. The relative current-neuronal structure should be considered when planning stimulation treatment, especially across techniques (e.g., using TMS to predict EBS response). We postulate that the effects of altered tissue properties in stroke regions may impact stimulation induced analgesic effects and/or lead to highly variable outcomes during brain stimulation treatments in CPSP.

Functional impact of primary visual cortex deactivation on subcortical target structures in the thalamus and midbrain.

The functional relationships between the primary visual cortex and its major subcortical target structures have long been a subject of interest. We studied these relationships by using localized cooling deactivation to silence portions of primary visual cortex and measuring 2-deoxyglucose (2DG) uptake to assess neural activity in subcortical and midbrain targets. We focused analysis on the largest subcortical targets of primary visual cortex: the superior colliculus (SC), the dorsal lateral geniculate nucleus of the thalamus (dLGN), and the lateral division of the lateral posterior nucleus of the thalamus (LPL). We found that localized cooling of different regions of primary visual cortex caused specific decreases in 2DG uptake in target structures such that the location of 2DG decrease varied according to joint retinotopy, and the magnitude of the decreases in target structures was associated with the amount of cooled cortex. In addition, we found that the impact of cortical cooling was more profound on the SC than on the dLGN. The functional impact of cortical deactivations on the LPL was weak for small deactivations but approximated the impact on the SC when deactivations were large. We discuss these findings in terms of neural circuits and in terms of drivers and modulators.

Animal models of cerebral neglect and its cancellation.

The purpose of this perspective is twofold: 1) to alert and inform the neurospychology and neurology communities on how animal models can improve our understanding of spatial neglect in humans, and 2) to serve as a guide to rehabilitation strategies. Spatial neglect is a neurological syndrome that is inextricably linked to the ability to overtly or covertly reorient attention to new loci. Literature describing variants of neglect leads to the perception of lesion-induced neglect as a uniquely human syndrome for which there are limited treatment options. To the contrary, neglect has been reversed in laboratory animals, and results show that adequate neural representations and motor mechanisms for reversal are present despite damaged or deactivated cerebral cortex. These results and conclusions provoke thought on strategies that can be employed on humans to cancel neglect, and they suggest that long-term amelioration of neglect can be induced by training of specific bypass circuits.

Neuroplasticity after unilateral visual cortex damage in the newborn cat.

Anatomical, electrophysiological, and behavioral studies implicate extrastriate cortex as a major contributor to the sparing of visually guided behaviors following lesions of primary visual cortex incurred early in life. Here we report considerable sparing of the ability to detect and localize stimuli in the hemifield contralateral to unilateral early lesions of all contiguous visually-responsive primary and extrastriate cortical regions (occipital, visuoparietal, and visuotemporal cortices). In the adult cat this same lesion induces a dense blindness and cats are unable to orient to any visual stimulus introduced into the contralesional hemifield. In the absence of cortical circuits, the neural sparing identified following the neonatal lesion is based on the superior colliculus and it occurs despite massive retrograde transynaptic degeneration of large numbers of retinal ganglion cells.

Functional circuitry underlying natural and interventional cancellation of visual neglect.

A large body of work demonstrates that lesions at multiple levels of the visual system induce neglect of stimuli in the contralesional visual field and that the neglect dissipates as neural compensations naturally emerge. Other studies show that interventional manipulations of cerebral cortex, superior colliculus or deep-lying midbrain structures have the power to attenuate, or cancel, the neglect and reinstate orienting into a neglected hemifield, and even into a profound cortically blind field. These results, and those derived from experiments on the behavioral impacts of unilateral and bilateral lesions, lead us to evaluate the repercussions of unilateral and bilateral deactivations, neural compensations and cancellations of attentional deficits in terms of an overarching hypothesis of neglect. The cancellations can be both striking and enduring, and they suggest that therapeutic strategies can be developed to reverse or ameliorate neglect in human patients. Animal studies show that in many instances of neglect adequate representations and the accompanying motor mechanisms are present despite the lesion and they simply need to be unmasked and brought into use to effect a remedy.