Cognition and Brain System Segregation in Pediatric Brain Tumor Patients Treated with Proton Therapy.

Purpose: Pediatric brain tumor patients often experience significant cognitive sequelae. Resting-state functional MRI (rsfMRI) provides a measure of brain network organization, and we hypothesize that pediatric brain tumor patients treated with proton therapy will demonstrate abnormal brain network architecture related to cognitive outcome and radiation dosimetry. Participants and Methods: Pediatric brain tumor patients treated with proton therapy were enrolled on a prospective study of cognitive assessment using the NIH Toolbox Cognitive Domain. rsfMRI was obtained in participants able to complete unsedated MRI. Brain system segregation (BSS), a measure of brain network architecture, was calculated for the whole brain, the high-level cognition association systems, and the sensory-motor systems. Results: Twenty-six participants were enrolled in the study for cognitive assessment, and 18 completed rsfMRI. There were baseline cognitive deficits in attention and inhibition and processing speed prior to radiation with worsening performance over time in multiple domains. Average BSS across the whole brain was significantly decreased in participants compared with healthy controls (1.089 and 1.101, respectively; P = 0.001). Average segregation of association systems was significantly lower in participants than in controls (P < 0.001) while there was no difference in the sensory motor networks (P = 0.70). Right hippocampus dose was associated with worse attention and inhibition (P < 0.05) and decreased segregation in the dorsal attention network (P < 0.05). Conclusion: Higher mean dose to the right hippocampus correlated with worse dorsal attention network segregation and worse attention and inhibition cognitive performance. Patients demonstrated alterations in brain network organization of association systems measured with rsfMRI; however, somatosensory system segregation was no different from healthy children. Further work with preradiation rsfMRI is needed to assess the effects of surgery and presence of a tumor on brain network architecture.

Individual-specific functional connectivity of the amygdala: A substrate for precision psychiatry.

The amygdala is central to the pathophysiology of many psychiatric illnesses. An imprecise understanding of how the amygdala fits into the larger network organization of the human brain, however, limits our ability to create models of dysfunction in individual patients to guide personalized treatment. Therefore, we investigated the position of the amygdala and its functional subdivisions within the network organization of the brain in 10 highly sampled individuals (5 h of fMRI data per person). We characterized three functional subdivisions within the amygdala of each individual. We discovered that one subdivision is preferentially correlated with the default mode network; a second is preferentially correlated with the dorsal attention and fronto-parietal networks; and third subdivision does not have any networks to which it is preferentially correlated relative to the other two subdivisions. All three subdivisions are positively correlated with ventral attention and somatomotor networks and negatively correlated with salience and cingulo-opercular networks. These observations were replicated in an independent group dataset of 120 individuals. We also found substantial across-subject variation in the distribution and magnitude of amygdala functional connectivity with the cerebral cortex that related to individual differences in the stereotactic locations both of amygdala subdivisions and of cortical functional brain networks. Finally, using lag analyses, we found consistent temporal ordering of fMRI signals in the cortex relative to amygdala subdivisions. Altogether, this work provides a detailed framework of amygdala-cortical interactions that can be used as a foundation for models relating aberrations in amygdala connectivity to psychiatric symptoms in individual patients.

Dynamic patterns of cortical expansion during folding of the preterm human brain.

During the third trimester of human brain development, the cerebral cortex undergoes dramatic surface expansion and folding. Physical models suggest that relatively rapid growth of the cortical gray matter helps drive this folding, and structural data suggest that growth may vary in both space (by region on the cortical surface) and time. In this study, we propose a unique method to estimate local growth from sequential cortical reconstructions. Using anatomically constrained multimodal surface matching (aMSM), we obtain accurate, physically guided point correspondence between younger and older cortical reconstructions of the same individual. From each pair of surfaces, we calculate continuous, smooth maps of cortical expansion with unprecedented precision. By considering 30 preterm infants scanned two to four times during the period of rapid cortical expansion (28-38 wk postmenstrual age), we observe significant regional differences in growth across the cortical surface that are consistent with the emergence of new folds. Furthermore, these growth patterns shift over the course of development, with noninjured subjects following a highly consistent trajectory. This information provides a detailed picture of dynamic changes in cortical growth, connecting what is known about patterns of development at the microscopic (cellular) and macroscopic (folding) scales. Since our method provides specific growth maps for individual brains, we are also able to detect alterations due to injury. This fully automated surface analysis, based on tools freely available to the brain-mapping community, may also serve as a useful approach for future studies of abnormal growth due to genetic disorders, injury, or other environmental variables.

The Brain Analysis Library of Spatial maps and Atlases (BALSA) database.

We report on a new neuroimaging database, BALSA, that is a repository for extensively analyzed neuroimaging datasets from humans and nonhuman primates. BALSA is organized into two distinct sections. BALSA Reference is a curated repository of reference data accurately mapped to brain atlas surfaces and volumes, including various types of anatomically and functionally derived spatial maps as well as brain connectivity. BALSA Studies is a repository of extensively analyzed neuroimaging and neuroanatomical datasets associated with specific published studies, as voluntarily submitted by authors. It is particularly well suited for sharing of neuroimaging data as displayed in published figures. Uploading and downloading of data to BALSA involves 'scene' files that replicate how datasets appear in Connectome Workbench visualization software. Altogether, BALSA offers efficient access to richly informative datasets that are related to but transcend the images available in scientific publications.

The relationship of cortical folding and brain arteriovenous malformations.

BACKGROUND: The pathogenesis of human intracranial arteriovenous malformations (AVMs) is not well understood; this study aims to quantitatively assess cortical folding in patients with these lesions. METHODS: Seven adult participants, 4 male and 3 female, with unruptured, surgically unresectable intracranial AVMs were prospectively enrolled in the study, with a mean age of 42.1 years and Spetzler-Martin grade range of II-IV. High-resolution brain MRI T1 and T2 sequences were obtained. After standard preprocessing, segmentation and registration techniques, three measures of cortical folding, the depth difference index (DDI), coordinate distance index (CDI) and gyrification index (GI)), were calculated for the affected and unaffected hemispheres of each subject as well as a healthy control subject set. RESULTS: Of the three metrics, CDI, DDI and GI, used for cortical folding assessment, none demonstrated significant differences between the participants and previously studied healthy adults. There was a significant negative correlation between the DDI ratio between affected and unaffected hemispheres and AVM volume (correlation coefficient r = -0.74, p = 0.04). CONCLUSION: This study is the first to quantitatively assess human brain cortical folding in the presence of intracranial AVMs and no significant differences between AVM-affected versus unaffected hemispheres were found in a small dataset. We suggest longitudinal, larger human MRI-based cortical folding studies to assess whether AVMs are congenital lesions of vascular development or de novo, dynamic lesions.

Canonical genetic signatures of the adult human brain.

The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure and function. We applied a correlation-based metric called differential stability to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization. The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations. Using genes with high differential stability, we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely patterned genes displayed marked shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry.

Cortical structural abnormalities in very preterm children at 7 years of age.

We analyzed long-lasting alterations in brain morphometry associated with preterm birth using volumetric and surface-based analyses applied to children at age 7 years. Comparison of 24 children born very preterm (VPT) to 24 healthy term-born children revealed reductions in total cortical gray matter volume, white matter volume, cortical surface area and gyrification index. Regional cortical shape abnormalities in VPT children included the following: shallower anterior superior temporal sulci, smaller relative surface area in the inferior sensori-motor cortex and posterior superior temporal cortex, larger relative surface area and a cingulate sulcus that was shorter or more interrupted in medial frontoparietal cortex. These findings indicate a complex pattern of regional vulnerabilities in brain development that may contribute to the diverse and long-lasting neurobehavioral consequences that can occur after very premature birth.

Analysis of cortical shape in children with simplex autism.

We used surface-based morphometry to test for differences in cortical shape between children with simplex autism (n = 34, mean age 11.4 years) and typical children (n = 32, mean age 11.3 years). This entailed testing for group differences in sulcal depth and in 3D coordinates after registering cortical midthickness surfaces to an atlas target using 2 independent registration methods. We identified bilateral differences in sulcal depth in restricted portions of the anterior-insula and frontal-operculum (aI/fO) and in the temporoparietal junction (TPJ). The aI/fO depth differences are associated with and likely to be caused by a shape difference in the inferior frontal gyrus in children with simplex autism. Comparisons of average midthickness surfaces of children with simplex autism and those of typical children suggest that the significant sulcal depth differences represent local peaks in a larger pattern of regional differences that are below statistical significance when using coordinate-based analysis methods. Cortical regions that are statistically significant before correction for multiple measures are peaks of more extended, albeit subtle regional differences that may guide hypothesis generation for studies using other imaging modalities.

Regional impairments of cortical folding in premature infants.

OBJECTIVE: This study was undertaken to evaluate the influence of preterm birth and other factors on cerebral cortical maturation. METHODS: We have evaluated the effects of preterm birth on cortical folding by applying cortical cartography methods to a cohort of 52 preterm infants (<31 weeks gestation, mild or no injury on conventional magnetic resonance imaging) and 12 term-born control infants. All infants were evaluated at term-equivalent postmenstrual age. RESULTS: Preterm infants had lower values for the global measures of gyrification index (GI; 2.06 ± 0.07 vs 1.80 ± 0.12, p < 0.001; control vs preterm) and cortical surface area (CSA; 316 ± 24 cm(2) vs 257 ± 40 cm(2) , p < 0.001). Regional analysis of sulcal depth and cortical shape showed the greatest impact of preterm birth on the insula, superior temporal sulcus, and ventral portions of the pre- and postcentral sulci in both hemispheres. Although CSA and GI are related, CSA was more sensitive to antenatal and postnatal factors than GI. Both measures were lower in preterm infants of lower birth weight standard deviation scores and smaller occipitofrontal circumference at time of scan, whereas CSA alone was lower in association with smaller occipitofrontal circumference at birth. CSA was also lower in infants with higher critical illness in the first 24 hours of life, exposure to postnatal steroids, and prolonged endotracheal intubation. INTERPRETATION: Preterm birth disrupts cortical development in a regionally specific fashion with abnormalities evident by term-equivalent postmenstrual age. This disruption is influenced by both antenatal growth and postnatal course.

Parcellations and hemispheric asymmetries of human cerebral cortex analyzed on surface-based atlases.

We report on surface-based analyses that enhance our understanding of human cortical organization, including its convolutions and its parcellation into many distinct areas. The surface area of human neocortex averages 973 cm(2) per hemisphere, based on cortical midthickness surfaces of 2 cohorts of subjects. We implemented a method to register individual subjects to a hybrid version of the FreeSurfer "fsaverage" atlas whose left and right hemispheres are in precise geographic correspondence. Cortical folding patterns in the resultant population-average "fs_LR" midthickness surfaces are remarkably similar in the left and right hemispheres, even in regions showing significant asymmetry in 3D position. Both hemispheres are equal in average surface area, but hotspots of surface area asymmetry are present in the Sylvian Fissure and elsewhere, together with a broad pattern of asymmetries that are significant though small in magnitude. Multiple cortical parcellation schemes registered to the human atlas provide valuable reference data sets for comparisons with other studies. Identified cortical areas vary in size by more than 2 orders of magnitude. The total number of human neocortical areas is estimated to be ∼150 to 200 areas per hemisphere, which is modestly larger than a recent estimate for the macaque.

Automated landmark identification for human cortical surface-based registration.

Volume-based registration (VBR) is the predominant method used in human neuroimaging to compensate for individual variability. However, surface-based registration (SBR) techniques have an inherent advantage over VBR because they respect the topology of the convoluted cortical sheet. There is evidence that existing SBR methods indeed confer a registration advantage over affine VBR. Landmark-SBR constrains registration using explicit landmarks to represent corresponding geographical locations on individual and atlas surfaces. The need for manual landmark identification has been an impediment to the widespread adoption of Landmark-SBR. To circumvent this obstacle, we have implemented and evaluated an automated landmark identification (ALI) algorithm for registration to the human PALS-B12 atlas. We compared ALI performance with that from two trained human raters and one expert anatomical rater (ENR). We employed both quantitative and qualitative quality assurance metrics, including a biologically meaningful analysis of hemispheric asymmetry. ALI performed well across all quality assurance tests, indicating that it yields robust and largely accurate results that require only modest manual correction (<10 min per subject). ALI largely circumvents human error and bias and enables high throughput analysis of large neuroimaging datasets for inter-subject registration to an atlas.

Cortical parcellations of the macaque monkey analyzed on surface-based atlases.

Surface-based atlases provide a valuable way to analyze and visualize the functional organization of cerebral cortex. Surface-based registration (SBR) is a primary method for aligning individual hemispheres to a surface-based atlas. We used landmark-constrained SBR to register many published parcellation schemes to the macaque F99 surface-based atlas. This enables objective comparison of both similarities and differences across parcellations. Cortical areas in the macaque vary in surface area by more than 2 orders of magnitude. Based on a composite parcellation derived from 3 major sources, the total number of macaque neocortical and transitional cortical areas is estimated to be about 130-140 in each hemisphere.

Multiple parietal operculum subdivisions in humans: tactile activation maps.

We focused the present analysis on blood-oxygen-level-dependent responses evoked in four architectonic subdivisions of human posterior parietal operculum (PO) during two groups of tasks involving either vibrotactile stimulation or rubbing different surfaces against the right index finger pad. Activity localized in previously defined parietal opercular subdivisions, OP 1-4, was co-registered to a standard cortical surface-based atlas. Four vibrotactile stimulation tasks involved attention to the parameters of paired vibrations: (1) detect rare target trials when vibration frequencies matched; (2) select the presentation order of the vibration with a higher frequency or (3) longer duration; and (4) divide attention between frequency and duration before selecting stimulus order. Surface stimulation tasks involved various discriminations of different surfaces: (1) smooth surfaces required no discrimination; (2) paired horizontal gratings required determination of the direction of roughness change; (3) paired shapes entailed identifying matched and unmatched shapes; (4) raised letters involved letter recognition. The results showed activity in multiple somatosensory subdivisions bilaterally in human PO that are plausibly homologues of somatosensory areas previously described in animals. All tasks activated OP 1, but in vibrotactile tasks foci were more restricted compared to moving surface tasks. Greater spatial extents of activity especially in OP 1 and 4 when surfaces rubbed the finger pad did not support previously reported somatotopy of the second finger representation in "S2". The varied activity distributions across OP subdivisions may reflect low-level perceptual and/or cognitive processing differences between tasks.

Symmetric abnormalities in sulcal patterning in schizophrenia.

To compare the morphology of the cerebral cortex and its characteristic pattern of gyri and sulci in individuals with and without schizophrenia, T1-weighted magnetic resonance scans were collected, along with clinical and cognitive information, from 33 individuals with schizophrenia and 30 healthy individuals group-matched for age, gender, race and parental socioeconomic status. Sulcal depth was measured across the entire cerebral cortex by reconstructing surfaces of cortical mid-thickness (layer 4) in each hemisphere and registering them to the human PALS cortical atlas. Group differences in sulcal depth were tested using methods for cluster size analysis and interhemispheric symmetry analysis. A significant group difference was found bilaterally in the parietal operculum, where the average sulcal depth was shallower in individuals with schizophrenia. In addition, group differences in sulcal depth showed significant bilateral symmetry across much of the occipital, parietal, and temporal cortices. In individuals with schizophrenia, sulcal depth in the left hemisphere was correlated with the severity of impaired performance on tests of working memory and executive function.

Comparing surface-based and volume-based analyses of functional neuroimaging data in patients with schizophrenia.

A major challenge in functional neuroimaging is to cope with individual variability in cortical structure and function. Most analyses of cortical function compensate for variability using affine or low-dimensional nonlinear volume-based registration (VBR) of individual subjects to an atlas, which does not explicitly take into account the geometry of cortical convolutions. A promising alternative is to use surface-based registration (SBR), which capitalizes on explicit surface representations of cortical folding patterns in individual subjects. In this study, we directly compare results from SBR and affine VBR in a study of working memory in healthy controls and patients with schizophrenia (SCZ). Each subject's structural scan was used for cortical surface reconstruction using the SureFit method. fMRI data were mapped directly onto individual cortical surface models, and each hemisphere was registered to the population-average PALS-B12 atlas using landmark-constrained SBR. The precision with which cortical sulci were aligned was much greater for SBR than VBR. SBR produced superior alignment precision across the entire cortex, and this benefit was greater in patients with schizophrenia. We demonstrate that spatial smoothing on the surface provides better resolution and signal preservation than a comparable degree of smoothing in the volume domain. Lastly, the statistical power of functional activation in the working memory task was greater for SBR than for VBR. These results indicate that SBR provides significant advantages over affine VBR when analyzing cortical fMRI activations. Furthermore, these improvements can be even greater in disorders that have associated structural abnormalities.

Surface-based and probabilistic atlases of primate cerebral cortex.

Brain atlases play an increasingly important role in neuroimaging, as they are invaluable for analysis, visualization, and comparison of results across studies. For both humans and macaque monkeys, digital brain atlases of many varieties are in widespread use, each having its own strengths and limitations. For studies of cerebral cortex there is particular utility in hybrid atlases that capitalize on the complementary nature of surface and volume representations, are based on a population average rather than an individual brain, and include measures of variation as well as averages. Linking different brain atlases to one another and to online databases containing a growing body of neuroimaging data will enable powerful forms of data mining that accelerate discovery and improve research efficiency.