Cerebral Cortical Structures Research Articles

Causal association among glaucoma, cerebral cortical structures, and Alzheimer's disease: insights from genetic correlation and Mendelian randomization.

Glaucoma and Alzheimer's disease are critical degenerative neuropathies with global impact. Previous studies have indicated that glaucomatous damage could extend beyond ocular structures, leading to brain alterations potentially associated with Alzheimer's disease risk. This study aimed to explore the causal associations among glaucoma, brain alterations, and Alzheimer's disease. We conducted a comprehensive investigation into the genetic correlation and causality between glaucoma, glaucoma endophenotypes, cerebral cortical surficial area and thickness, and Alzheimer's disease (including late-onset Alzheimer's disease, cognitive performance, and reaction time) using linkage disequilibrium score regression and Mendelian randomization. This study showed suggestive genetic correlations between glaucoma, cortical structures, and Alzheimer's disease. The genetically predicted all-caused glaucoma was nominally associated with a decreased risk of Alzheimer's disease (OR = 0.96, 95% CI: 0.93-0.99, P = 0.013). We found evidence for suggestive causality between glaucoma (endophenotypes) and 20 cortical regions and between 29 cortical regions and Alzheimer's disease (endophenotypes). Four cortical regions were causally associated with cognitive performance or reaction time at a significant threshold (P < 6.2E-04). Thirteen shared cortical regions between glaucoma (endophenotypes) and Alzheimer's disease (endophenotypes) were identified. Our findings complex causal relationships among glaucoma, cerebral cortical structures, and Alzheimer's disease. More studies are required to clarify the mediation effect of cortical alterations in the relationship between glaucoma and Alzheimer's disease.

No changes in cerebral cortical and subcortical structures before and after SARS-CoV-2 infection: Case reports of a patient with schizophrenia and a patient with major depressive disorder.

No changes in cerebral cortical and subcortical structures before and after SARS-CoV-2 infection: Case reports of a patient with schizophrenia and a patient with major depressive disorder.

Inflammatory bowel diseases, interleukin-6 and interleukin-6 receptor subunit alpha in causal association with cerebral cortical structure: a Mendelian randomization analysis.

Neurological involvement and psychiatric manifestations have been documented in clinical cases of inflammatory bowel disease (IBD); however, the presence of a causal relationship remains elusive. The objective of this study is to investigate the modifications occurring in the cerebral cortex as a result of IBD. A compendium of data extracted from a genome-wide association study (GWAS) involving a maximum of 133,380 European subjects. A series of Mendelian random analyses were applied to exclude heterogeneity and pleiotropy, ensuring the stability of the results. Neither IBDs nor inflammatory cytokines (IL-6/IL-6Rα) were found to have a significant causality with surface area (SA) and thickness (TH) at the global level. At the regional functional brain level, Crohn's disease (CD) significantly decreased the TH of pars orbitalis (β=-0.003mm, Se=0.001mm, pivw =4.85×10-4). IL-6 was observed to reduce the SA of middle temporal (β=-28.575mm2, Se=6.482mm2, pivw=1.04×10-5) and increase the TH of fusiform (β=0.008mm, Se=0.002mm, pivw=8.86×10-5) and pars opercularis (β=0.009mm, Se=0.002mm, pivw=2.34×10-4). Furthermore, a causal relationship between IL-6Rα and an increase in the SA of superior frontal (β=21.132mm2, Se=5.806mm2, pivw=2.73×10-4) and the TH of supramarginal (β=0.003mm, Se=0.0002mm, pivw=7.86×10-37). All results passed sensitivity analysis and no heterogeneity and pleiotropy were detected. The correlation between IBD and changes in cerebral cortical structures implies the existence of a gut-brain axis at the organismal level. It is recommended that clinical patients with IBD prioritize long-term management of inflammation, as changes at the organismal level can lead to functional pathologies. Magnetic resonance imaging (MRI) may be considered as an additional screening option for IBD.

Cerebellar control of thalamocortical circuits for cognitive function: A review of pathways and a proposed mechanism.

There is general agreement that cerebrocerebellar interactions via cerebellothalamocortical pathways are essential for a cerebellar cognitive and motor functions. Cerebellothalamic projections were long believed target mainly the ventral lateral (VL) and part of the ventral anterior (VA) nuclei, which project to cortical motor and premotor areas. Here we review new insights from detailed tracing studies, which show that projections from the cerebellum to the thalamus are widespread and reach almost every thalamic subnucleus, including nuclei involved in cognitive functions. These new insights into cerebellothalamic pathways beyond the motor thalamus are consistent with the increasing evidence of cerebellar cognitive function. However, the function of cerebellothalamic pathways and how they are involved in the various motor and cognitive functions of the cerebellum is still unknown. We briefly review literature on the role of the thalamus in coordinating the coherence of neuronal oscillations in the neocortex. The coherence of oscillations, which measures the stability of the phase relationship between two oscillations of the same frequency, is considered an indicator of increased functional connectivity between two structures showing coherent oscillations. Through thalamocortical interactions coherence patterns dynamically create and dissolve functional cerebral cortical networks in a task dependent manner. Finally, we review evidence for an involvement of the cerebellum in coordinating coherence of oscillations between cerebral cortical structures. We conclude that cerebellothalamic pathways provide the necessary anatomical substrate for a proposed role of the cerebellum in coordinating neuronal communication between cerebral cortical areas by coordinating the coherence of oscillations.

Cerebellar Coordination of Neuronal Communication in Cerebral Cortex.

Cognitive processes involve precisely coordinated neuronal communications between multiple cerebral cortical structures in a task specific manner. Rich new evidence now implicates the cerebellum in cognitive functions. There is general agreement that cerebellar cognitive function involves interactions between the cerebellum and cerebral cortical association areas. Traditional views assume reciprocal interactions between one cerebellar and one cerebral cortical site, via closed-loop connections. We offer evidence supporting a new perspective that assigns the cerebellum the role of a coordinator of communication. We propose that the cerebellum participates in cognitive function by modulating the coherence of neuronal oscillations to optimize communications between multiple cortical structures in a task specific manner.

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t=2.1, p=.04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t=2.7, p=.01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Accurate Image-guided (Re)Placement of NIRS Probes

Background and Objective: Functional near-infrared spectroscopy (fNIRS) has become an attractive choice to neuroscience because of its high temporal resolution, ease of use, non-invasiveness, and affordability. With the advent of wearable fNIRS technology, on-the-spot studies of brain function have become viable. However, the lack of within-subject reproducibility is one of the barriers to the full acceptability of fNIRS. To support the validation of the claim that within-subject reproducibility of fNIRS could benefit from accurate anatomical information, we present in this paper a method to develop an image-based system that improves the placement of the sensors on the scalp at interactive rates.Methods: The proposed solution consists of an electromagnetic digitizer and an interactive visualization system that allows monitoring the movements of the digitizer on a real head with respect to the underlying cerebral cortical structures. GPU-based volume raycasting rendering is applied to unveil these structures from the corresponding magnetic resonance imaging volume. Scalp and cortical surface are estimated from the scanned volume to improve depth perception. An alignment algorithm between the real and scanned heads is devised to visually feedback the position of the stylus of the digitizer. Off-screen rendering of the depthmaps of the visible surfaces makes spatial positioning of a 2D interaction pointer possible.Results: We evaluated the alignment accuracy using four to eight anatomical landmarks and found seven to be a good compromise between precision and efficiency. Next, we evaluated reproducibility in positioning five arbitrarily chosen points on three volunteers by four operators over five sessions. In every session, seven anatomical landmarks were applied in the alignment of the real and the scanned head. For the same volunteer, one-way analysis of variance (ANOVA) revealed no significant differences within the five points digitized by the same operator over five sessions (α = 0.05). In addition, preliminary study of motor cortex activation by right-hand finger tapping showed the potential of our approach to increase functional fNIRS reproducibility.Conclusions: Results of experiments suggest that the enhancement of the visualization of the location of the probes on the scalp, relative to the underlying cortical structures, improves reproducibility of fNIRS measurements. As further work, we plan to study the fNIRS reproducibility in other cortical regions and in clinical settings using the proposed system.

Long-term high-resolution in vivo imaging of cerebral cortical structures following ischemic stroke

The development of multi-photon microscopic technique has made it possible to image submicron structures deep in biological tissues. This technique is widely used for imaging of cortical structures in developing and adult animals, and there have been detail descriptions of in vivo imaging of synaptic structures in normal animals through a thinned-skull or open-skull cranial window. However, several challenges should be considered carefully for high-resolution imaging of cortical structures under pathological conditions. Here we describe a protocol for in vivo imaging of dendritic structures following ischemic stroke through thinned skull. This protocol can also be applied for acute or chronic imaging of neuronal structural plasticity, glial activation, cerebral microcirculation, or synaptic functions in other pathological conditions.

Inner retinal thinning as a biomarker for cognitive impairment in de novo Parkinson\u2019s disease

We investigated the association between retinal changes measured using optical coherence tomography (OCT) and diverse clinical grading scales in patients with Parkinson’s disease (PD). Seventy-four eyes of 74 patients with de novo PD and 53 eyes of age-matched control subjects were included. The thickness of the peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL) were measured. We analyzed the correlations between the clinical PD grading scales and OCT parameters, and between the OCT parameters and volumetric data in the cerebral cortical and subcortical structures. The area under the receiver operating characteristic curve (AUC) was calculated for diagnosing cognitive impairment in patients with PD. Statistically significant reductions in the thickness of average, temporal, and inferior pRNFL and overall mGCIPL were observed in patients with PD. The Montreal Cognitive Assessment score was significantly associated with mGCIPL thinning. The AUC of the mGCIPL parameters for diagnosing cognitive impairment in patients with PD ranged from 0.651 to 0.760. Moreover, thinning of the mGCIPL was significantly associated with the volumetric parameters of associated brain structures. Our findings highlight the clinical implications of OCT measurements as a potential biomarker for early detection of cognitive impairment in patients with PD.

Quantitative analysis of forebrain pallial morphology in monotremes and comparison with that in therians

We have made quantitative volumetric analyses of cerebral cortical (pallial) structures in the brains of three species of monotreme (Ornithorhynchus anatinus, Tachyglossus aculeatus, Zaglossus bruijni) and compared the findings with similar measurements in a range of therian mammals (6 marsupials and 50 placentals). We have found that although the iso- and periallocortical grey matter volume of the monotremes is about what would be expected for their brain size, the proportion of iso- and periallocortical white matter in monotremes is substantially lower than that in the forebrains of therians. This suggests that the forebrains of the three monotremes have fewer association, commissural and/or projection connections than those of similarly sized forebrains of therian mammals. We also found that the iso- and periallocortex of the platypus is relatively smooth-surfaced compared to similarly sized brains of therian mammals, with a distinct caudal shift in the positioning of cortical white matter in the forebrain, consistent with expansion of the posterior thalamic radiation. Central laminated olfactory structures (anterior olfactory nucleus and piriform cortex) are large in the tachyglossid monotremes (Tachyglossus aculeatus and Zaglossus bruijni) and large in xenarthran placental mammals, suggesting convergence of the forebrain structure of monotreme formivores with that of similarly specialized therians like the xenarthrans Myrmecophaga tridactyla and Dasypus novemcinctus.

Reduced cortical thickness related to single nucleotide polymorphisms in the major histocompatibility complex region in antipsychotic-naive schizophrenia.

Instructions The aim of this study was to explore the relationships between changes in cortical thickness and single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) region in a group of antipsychotic‐naive schizophrenia (AN‐SCZ) patients.MethodsTwenty‐five AN‐SCZ patients and 51 healthy controls (HCs) participated in this study. General linear models were used to identify associations between the average cortical thicknesses of each brain region (N = 68) and each of the 11 SNPs in the MHC region in the AN‐SCZ patients and HCs. Next, we performed independent‐sample t tests to investigate whether cortical thickness was significantly lower in the AN‐SCZ patients than in HCs in the brain regions that were significantly associated with the SNPs. Finally, we examined the correlations between clinical symptoms and cortical thickness in the above brain areas in the whole AN‐SCZ group using Pearson correlation tests.ResultsSeven of the 11 SNPs within the MHC region were significantly associated with cortical thickness only in the AN‐SCZ patients; these included rs1635, rs1736913, rs2021722, rs204999, rs2523722, rs3131296, and rs9272105. The AN‐SCZ patients had significantly thinner cortical thicknesses in the above brain regions, especially the prefrontal cortex. Furthermore, the left entorhinal region was negatively correlated with Positive and Negative Symptom Scale (PANSS) activation scores in the AN‐SCZ group (r = −0.601, p = 0.03).ConclusionsThis study provides evidence demonstrating the potential effects of MHC risk variants in cortical thickness deficits in AN‐SCZ. These data also support the notion that the immune system plays critical roles in the pathology of schizophrenia, which is mediated via the modulation of the development of cerebral cortical structures.

An Alternative Transcranial Motor Evoked Potential Montage to Minimize Ipsilateral “Crossover” Motor Responses

ABSTRACTTranscranial electrical motor evoked potential (TcMEP) is a modality utilized in intraoperative neurophysiological monitoring to assess the integrity of the corticospinal tract. Traditionally, TcMEPs are obtained by anodal stimulation of the scalp over the motor cortex of the selected hemisphere and referenced to the contralateral hemisphere. Subsequent compound motor action potential responses (CMAPs) are recorded at various muscles. The muscle responses of interest are usually those recorded in the limb contralateral to the hemisphere of stimulation. However, TcMEPs may elicit simultaneous muscle responses in the limbs ipsilateral to the hemisphere of stimulation, otherwise defined as “crossover” responses. Crossover TcMEPs are thought to be generated when electrical stimulation reaches the corticospinal tract at intracranial structures as deep as the medullary pyramids. If electrical stimulation penetrates deeper than the at-risk structures, false negatives motor evoked potential monitoring may occur. Therefore, in surgeries where cerebral cortical structures may be at risk, TcMEPs may be elicited so that contralateral CMAP responses are present without crossover responses. We present three cases using an alternative TcMEP montage in which anodal stimulation of the target hemisphere is referenced to Fpz at midline. Compared with the C3-C4/C4-C3 montage, crossover responses are minimized with the modified montage. C3-Fpz/C4-Fpz TcMEP stimulation may be a potential tool to implement in certain intraoperative neuromonitoring cases.

Modulation of Cerebellar Cortical Plasticity Using Low-Intensity Focused Ultrasound for Poststroke Sensorimotor Function Recovery

Background. Stroke affects widespread brain regions through interhemispheric connections by influencing bilateral motor activity. Several noninvasive brain stimulation techniques have proved their capacity to compensate the functional loss by manipulating the neural activity of alternative pathways. Over the past few decades, brain stimulation therapies have been tailored within the theoretical framework of modulation of cortical excitability to enhance adaptive plasticity after stroke. Objective. However, considering the vast difference between animal and human cerebral cortical structures, it is important to approach specific neuronal target starting from the higher order brain structure for human translation. The present study focuses on stimulating the lateral cerebellar nucleus (LCN), which sends major cerebellar output to extensive cortical regions. Methods. In this study, in vivo stroke mouse LCN was exposed to low-intensity focused ultrasound (LIFU). After the LIFU exposure, animals underwent 4 weeks of rehabilitative training. Results. During the cerebellar LIFU session, motor-evoked potentials (MEPs) were generated in both forelimbs accompanying excitatory sonication parameter. LCN stimulation group on day 1 after stroke significantly enhanced sensorimotor recovery compared with the group without stimulation. The recovery has maintained for a 4-week period in 2 behavior tests. Furthermore, we observed a significantly decreased level of brain edema and tissue swelling in the affected hemisphere 3 days after the stroke. Conclusions. This study provides the first evidence showing that LIFU-induced cerebellar modulation could be an important strategy for poststroke recovery. A longer follow-up study is, however, necessary in order to fully confirm the effects of LIFU on poststroke recovery.

Age-specific gray and white matter DTI atlas for human brain at 33, 36 and 39 postmenstrual weeks

During the 3rd trimester, dramatic structural changes take place in the human brain, underlying the neural circuit formation. The survival rate of premature infants has increased significantly in recent years. The large morphological differences of the preterm brain at 33 or 36 postmenstrual weeks (PMW) from the brain at 40PMW (full term) make it necessary to establish age-specific atlases for preterm brains. In this study, with high quality (1.5 × 1.5 × 1.6 mm3 imaging resolution) diffusion tensor imaging (DTI) data obtained from 84 healthy preterm and term-born neonates, we established age-specific preterm and term-born brain templates and atlases at 33, 36 and 39PMW. Age-specific DTI templates include a single-subject template, a population-averaged template with linear transformation and a population-averaged template with nonlinear transformation. Each of the age-specific DTI atlases includes comprehensive labeling of 126 major gray matter (GM) and white matter (WM) structures, specifically 52 cerebral cortical structures, 40 cerebral WM structures, 22 brainstem and cerebellar structures and 12 subcortical GM structures. From 33 to 39 PMW, dramatic morphological changes of delineated individual neural structures such as ganglionic eminence and uncinate fasciculus were revealed. The evaluation based on measurements of Dice ratio and L1 error suggested reliable and reproducible automated labels from the age-matched atlases compared to labels from manual delineation. Applying these atlases to automatically and effectively delineate microstructural changes of major WM tracts during the 3rd trimester was demonstrated. The established age-specific DTI templates and atlases of 33, 36 and 39 PMW brains may be used for not only understanding normal functional and structural maturational processes but also detecting biomarkers of neural disorders in the preterm brains.

Structural Covariance of Sensory Networks, the Cerebellum, and Amygdala in Autism Spectrum Disorder.

Sensory dysfunction is a core symptom of autism spectrum disorder (ASD), and abnormalities with sensory responsivity and processing can be extremely debilitating to ASD patients and their families. However, relatively little is known about the underlying neuroanatomical and neurophysiological factors that lead to sensory abnormalities in ASD. Investigation into these aspects of ASD could lead to significant advancements in our general knowledge about ASD, as well as provide targets for treatment and inform diagnostic procedures. Thus, the current study aimed to measure the covariation of volumes of brain structures (i.e., structural magnetic resonance imaging) that may be involved in abnormal sensory processing, in order to infer connectivity of these brain regions. Specifically, we quantified the structural covariation of sensory-related cerebral cortical structures, in addition to the cerebellum and amygdala by computing partial correlations between the structural volumes of these structures. These analyses were performed in participants with ASD (n = 36), as well as typically developing peers (n = 32). Results showed decreased structural covariation between sensory-related cortical structures, especially between the left and right cerebral hemispheres, in participants with ASD. In contrast, these same participants presented with increased structural covariation of structures in the right cerebral hemisphere. Additionally, sensory-related cerebral structures exhibited decreased structural covariation with functionally identified cerebellar networks. Also, the left amygdala showed significantly increased structural covariation with cerebral structures related to visual processing. Taken together, these results may suggest several patterns of altered connectivity both within and between cerebral cortices and other brain structures that may be related to sensory processing.

Alterations in inter-alpha inhibitor protein expression after hypoxic-ischemic brain injury in neonatal rats

Hypoxic-ischemic (HI) brain injury is frequently associated with premature and/or full-term birth-related complications that reflect widespread damage to cerebral cortical structures. Inflammation has been implicated in the long-term evolution and severity of HI brain injury. Inter-Alpha Inhibitor Proteins (IAIPs) are immune modulator proteins that are reduced in systemic neonatal inflammatory states. We have shown that endogenous IAIPs are present in neurons, astrocytes and microglia and that exogenous treatment with human plasma purified IAIPs decreases neuronal injury and improves behavioral outcomes in neonatal rats with HI brain injury. In addition, we have shown that endogenous IAIPs are reduced in the brain of the ovine fetus shortly after ischemic injury. However, the effect of HI on changes in circulating and endogenous brain IAIPs has not been examined in neonatal rats. In the current study, we examined changes in endogenous IAIPs in the systemic circulation and brain of neonatal rats after exposure to HI brain injury. Postnatal day 7 rats were exposed to right carotid artery ligation and 8% oxygen for 2h. Sera were obtained immediately, 3, 12, 24, and 48h and brains 3 and 24h after HI. IAIPs levels were determined by a competitive enzyme-linked immunosorbent assay (ELISA) in sera and by Western immunoblots in cerebral cortices. Serum IAIPs were decreased 3h after HI and remained lower than in non-ischemic rats up to 7days after HI. IAIP expression increased in the ipsilateral cerebral cortices 24h after HI brain injury and in the hypoxic contralateral cortices. However, 3h after hypoxia alone the 250kDa IAIP moiety was reduced in the contralateral cortices. We speculate that changes in endogenous IAIPs levels in blood and brain represent constituents of endogenous anti-inflammatory neuroprotective mechanism(s) after HI in neonatal rats.

Learning as a Functional State of the Brain: Studies in Wild-Type and Transgenic Animals.

Contemporary neuroscientists are paying increasing attention to subcellular, molecular, and electrophysiological mechanisms underlying learning and memory processes. Recent studies have examined the development of transgenic mice affected at different stages of the learning process, or have emulated in animals various human pathological conditions involving cognition and motor learning. However, a parallel effort is needed to develop stimulating and recording techniques suitable for use in behaving mice in order to understand activity-dependent synaptic changes taking place during the very moment of the learning process. The in vivo models should incorporate information collected from different molecular and in vitro approaches. Long-term potentiation (LTP) has been proposed as the neural mechanism underlying synaptic plasticity, and NMDA receptors have been proposed as the molecular substrate of LTP. It now seems necessary to study the relationship of both LTP and NMDA receptors to functional changes in synaptic efficiency taking place during actual learning in selected cerebral cortical structures. Here, we review data collected in our laboratory during the past 10years on the involvement of different hippocampal synapses in the acquisition of the classically conditioned eyelid responses in behaving mice. Overall the results indicate a specific contribution of each cortical synapse to the acquisition and storage of new motor and cognitive abilities. Available data show that LTP, evoked by high-frequency stimulation of Schaffer collaterals, disturbs both the acquisition of conditioned eyelid responses and the physiological changes that occur at hippocampal synapses during learning. Moreover, the administration of NMDA-receptor antagonists is able not only to prevent LTP induction in vivo, but also to hinder both the formation of conditioned eyelid responses and functional changes in the strength of the CA3-CA1 synapse. Nevertheless, many other neurotransmitter receptors, intracellular mediators, and transcription factors are also involved in learning and memory processes. In summary, it can be proposed that learning and memory in behaving mammals are the result of the activation of complex and distributed functional states involving many different cerebral cortical synapses, with the participation also of various neurotransmitter systems.

Volume transmission signalling via astrocytes.

The influence of astrocytes on synaptic function has been increasingly studied, owing to the discovery of both gliotransmission and morphological ensheathment of synapses. While astrocytes exhibit at best modest membrane potential fluctuations, activation of G-protein coupled receptors (GPCRs) leads to a prominent elevation of intracellular calcium which has been reported to correlate with gliotransmission. In this review, the possible role of astrocytic GPCR activation is discussed as a trigger to promote synaptic plasticity, by affecting synaptic receptors through gliotransmitters. Moreover, we suggest that volume transmission of neuromodulators could be a biological mechanism to activate astrocytic GPCRs and thereby to switch synaptic networks to the plastic mode during states of attention in cerebral cortical structures.

Neuroanatomical Assessment of Biological Maturity

Structural MRI allows unparalleled in vivo study of the anatomy of the developing human brain. For more than two decades, MRI research has revealed many new aspects of this multifaceted maturation process, significantly augmenting scientific knowledge gathered from postmortem studies. Postnatal brain development is notably protracted and involves considerable changes in cerebral cortical, subcortical, and cerebellar structures, as well as significant architectural changes in white matter fiber tracts (see [12]). Although much work has described isolated features of neuroanatomical development, it remains a critical challenge to characterize the multidimensional nature of brain anatomy, capturing different phases of development among individuals. Capitalizing on key advances in multisite, multimodal MRI, and using cross-validated nonlinear modeling, we demonstrate that developmental brain phase can be assessed with much greater precision than has been possible using other biological measures, accounting for more than 92% of the variance in age. Further, our composite metric of morphology, diffusivity, and signal intensity shows that the average difference in phase among children of the same age is only about 1 year, revealing for the first time a latent phenotype in the human brain for which maturation timing is tightly controlled.

Predicting Regional Neurodegeneration from the Healthy Brain Functional Connectome

Neurodegenerative diseases target large-scale neural networks. Four competing mechanistic hypotheses have been proposed to explain network-based disease patterning: nodal stress, transneuronal spread, trophic failure, and shared vulnerability. Here, we used task-free fMRI to derive the healthy intrinsic connectivity patterns seeded by brain regions vulnerable to any of five distinct neurodegenerative diseases. These data enabled us to investigate how intrinsic connectivity in health predicts region-by-region vulnerability to disease. For each illness, specific regions emerged as critical network "epicenters" whose normal connectivity profiles most resembled the disease-associated atrophy pattern. Graph theoretical analyses in healthy subjects revealed that regions with higher total connectional flow and, more consistently, shorter functional paths to the epicenters, showed greater disease-related vulnerability. These findings best fit a transneuronal spread model of network-based vulnerability. Molecular pathological approaches may help clarify what makes each epicenter vulnerable to its targeting disease and how toxic protein species travel between networked brain structures.