White matter microstructure in transmasculine and cisgender adolescents: A multiparametric and multivariate study.

Adolescence is a sensitive developmental period for neural sex/gender differentiation. The present study used multiparametric mapping to better characterize adolescent white matter (WM) microstructure. WM microstructure was investigated using diffusion tensor indices (fractional anisotropy; mean, radial, and axial diffusivity [AD]) and quantitative T1 relaxometry (T1) in hormone therapy naïve adolescent cisgender girls, cisgender boys, and transgender boys (i.e., assigned female at birth and diagnosed with gender dysphoria). Diffusion indices were first analyzed for group differences using tract-based spatial statistics, which revealed a group difference in AD. Thus, two multiparametric and multivariate analyses assessed AD in conjunction with T1 relaxation time, and with respect to developmental proxy variables (i.e., age, serum estradiol, pubertal development, sexual attraction) thought to be relevant to adolescent brain development. The multivariate analyses showed a shared pattern between AD and T1 such that higher AD was associated with longer T1, and AD and T1 strongly related to all five developmental variables in cisgender boys (10 significant correlations, r range: 0.21-0.73). There were fewer significant correlations between the brain and developmental variables in cisgender girls (three correlations, r range: -0.54-0.54) and transgender boys (two correlations, r range: -0.59-0.77). Specifically, AD related to direction of sexual attraction (i.e., gynephilia, androphilia) in all groups, and T1 related to estradiol inversely in cisgender boys compared with transgender boys. These brain patterns may be indicative of less myelination and tissue density in cisgender boys, which corroborates other reports of protracted WM development in cisgender boys. Further, these findings highlight the importance of considering developmental trajectory when assessing the subtleties of neural structure associated with variations in sex, gender, and sexual attraction.

Diurnal oscillations of MRI metrics in the brains of male participants.

Regulation of biological processes according to a 24-hr rhythm is essential for the normal functioning of an organism. Temporal variation in brain MRI data has often been attributed to circadian or diurnal oscillations; however, it is not clear if such oscillations exist. Here, we provide evidence that diurnal oscillations indeed govern multiple MRI metrics. We recorded cerebral blood flow, diffusion-tensor metrics, T1 relaxation, and cortical structural features every three hours over a 24-hr period in each of 16 adult male controls and eight adult male participants with bipolar disorder. Diurnal oscillations are detected in numerous MRI metrics at the whole-brain level, and regionally. Rhythmicity parameters in the participants with bipolar disorder are similar to the controls for most metrics, except for a larger phase variation in cerebral blood flow. The ubiquitous nature of diurnal oscillations has broad implications for neuroimaging studies and furthers our understanding of the dynamic nature of the human brain.

Inter-Network Brain Functional Connectivity in Adolescents Assigned Female at Birth Who Experience Gender Dysphoria.

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Brain functional connectivity in adolescents who experience GD may be associated with experienced gender (vs. assigned sex) and/or brain networks implicated in own-body perception. Furthermore, sexual orientation may be related to brain functional organization given commonalities in developmental mechanisms proposed to underpin GD and same-sex attractions. Here, we applied group independent component analysis to resting-state functional magnetic resonance imaging (rs-fMRI) BOLD timeseries data to estimate inter-network (i.e., between independent components) timeseries correlations, representing functional connectivity, in 17 GD adolescents assigned female at birth (AFAB) not receiving gender-affirming hormone therapy, 17 cisgender girls, and 15 cisgender boys (ages 12-17 years). Sexual orientation was represented by degree of androphilia-gynephilia and sexual attractions strength. Multivariate partial least squares analyses found that functional connectivity differed among cisgender boys, cisgender girls, and GD AFAB, with the largest difference between cisgender boys and GD AFAB. Regarding sexual orientation and age, the brain's intrinsic functional organization of GD AFAB was both similar to and different from cisgender girls, and both differed from cisgender boys. The pattern of group differences and the networks involved aligned with the hypothesis that brain functional organization is different among GD AFAB (vs. cisgender) adolescents, and certain aspects of this organization relate to brain areas implicated in own-body perception and self-referential thinking. Overall, brain functional organization of GD AFAB was generally more similar to that of cisgender girls than cisgender boys.

EEG variability: Task-driven or subject-driven signal of interest?

Neurons in the brain are seldom perfectly quiet. They continually receive input and generate output, resulting in highly variable patterns of ongoing activity. Yet the functional significance of this variability is not well understood. If brain signal variability is functionally relevant and serves as an important indicator of cognitive function, then it should be highly sensitive to the precise manner in which a cognitive system is engaged and/or relate strongly to differences in behavioral performance. To test this, we examined EEG activity in younger adults as they performed a cognitive skill learning task and during rest. Several measures of EEG variability and signal strength were calculated in overlapping time windows that spanned the trial interval. We performed a systematic examination of the factors that most strongly influenced the variability and strength of EEG activity. First, we examined the relative sensitivity of each measure to across-subject variation (within blocks) and across-block variation (within subjects). We found that the across-subject variation in EEG variability and signal strength was much stronger than the across-block variation. Second, we examined the sensitivity of each measure to different sources of across-block variation during skill acquisition. We found that key task-driven changes in EEG activity were best reflected in changes in the strength, rather than the variability, of EEG activity. Lastly, we examined across-subject variation in each measure and its relationship with behavior. We found that individual differences in response time measures were best reflected in individual differences in the variability, rather than the strength, of EEG activity. Importantly, we found that individual differences in EEG variability related strongly to stable indicators of subject identity rather than dynamic indicators of subject performance. We therefore suggest that EEG variability may provide a more sensitive subject-driven measure of individual differences than task-driven signal of interest.

Fatty acid amide hydrolase levels in brain linked with threat-related amygdala activation.

Background: Preclinical evidence suggests that increasing levels of the major endocannabinoid anandamide decreases anxiety and fear responses potentially through its effects in the amygdala. Here we used neuroimaging to test the hypothesis that lower fatty acid amide hydrolase (FAAH), the main catabolic enzyme for anandamide, is associated with a blunted amygdala response to threat. Methods: Twenty-eight healthy participants completed a positron emission tomography (PET) scan with the radiotracer for FAAH, [11C]CURB, as well as a block-design functional magnetic resonance imaging session during which angry and fearful faces meant to activate the amygdala were presented. Results: [11C]CURB binding in the amygdala as well as in the medial prefrontal cortex, cingulate and hippocampus correlated positively with blood-oxygen-level-dependent (BOLD) signal during processing of angry and fearful faces (pFWE < 0.05). Conclusion: Our finding that lower levels of FAAH in amygdala, medial prefrontal cortex, cingulate and hippocampus was associated with a dampened amygdala response to a threatening social cue aligns with preclinical and neuroimaging studies in humans and suggests the involvement of FAAH in modulating stress and anxiety in humans. The current neuroimaging study also lends support for the potential use of FAAH inhibitors to control amygdala hyperactivity, which is known to be involved in the pathophysiology of anxiety and trauma-related disorders.

Resting state fMRI scanner instabilities revealed by longitudinal phantom scans in a multi-center study.

Quality assurance (QA) is crucial in longitudinal and/or multi-site studies, which involve the collection of data from a group of subjects over time and/or at different locations. It is important to regularly monitor the performance of the scanners over time and at different locations to detect and control for intrinsic differences (e.g., due to manufacturers) and changes in scanner performance (e.g., due to gradual component aging, software and/or hardware upgrades, etc.). As part of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Canadian Biomarker Integration Network in Depression (CAN-BIND), QA phantom scans were conducted approximately monthly for three to four years at 13 sites across Canada with 3T research MRI scanners. QA parameters were calculated for each scan using the functional Biomarker Imaging Research Network's (fBIRN) QA phantom and pipeline to capture between- and within-scanner variability. We also describe a QA protocol to measure the full-width-at-half-maximum (FWHM) of slice-wise point spread functions (PSF), used in conjunction with the fBIRN QA parameters. Variations in image resolution measured by the FWHM are a primary source of variance over time for many sites, as well as between sites and between manufacturers. We also identify an unexpected range of instabilities affecting individual slices in a number of scanners, which may amount to a substantial contribution of unexplained signal variance to their data. Finally, we identify a preliminary preprocessing approach to reduce this variance and/or alleviate the slice anomalies, and in a small human data set show that this change in preprocessing can have a significant impact on seed-based connectivity measurements for some individual subjects. We expect that other fMRI centres will find this approach to identifying and controlling scanner instabilities useful in similar studies.

Fatty acid amide hydrolase binding is inversely correlated with amygdalar functional connectivity: a combined positron emission tomography and magnetic resonance imaging study in healthy individuals.

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control. Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest. Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = -0.38, q = 0.04; dACC: r = -0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05). Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity. Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.

A Multi-Modal MRI Analysis of Cortical Structure in Relation to Gender Dysphoria, Sexual Orientation, and Age in Adolescents.

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Sex-differentiated brain regions are hypothesized to reflect the experienced gender in GD and may play a role in sexual orientation development. Magnetic resonance brain images were acquired from 16 GD adolescents assigned female at birth (AFAB) not receiving hormone therapy, 17 cisgender girls, and 14 cisgender boys (ages 12-17 years) to examine three morphological and microstructural gray matter features in 76 brain regions: surface area (SA), cortical thickness (CT), and T1 relaxation time. Sexual orientation was represented by degree of androphilia-gynephilia and sexual attraction strength. Multivariate analyses found that cisgender boys had larger SA than cisgender girls and GD AFAB. Shorter T1, reflecting denser, macromolecule-rich tissue, correlated with older age and stronger gynephilia in cisgender boys and GD AFAB, and with stronger attractions in cisgender boys. Thus, cortical morphometry (mainly SA) was related to sex assigned at birth, but not experienced gender. Effects of experienced gender were found as similarities in correlation patterns in GD AFAB and cisgender boys in age and sexual orientation (mainly T1), indicating the need to consider developmental trajectories and sexual orientation in brain studies of GD.

Differential levels of prefrontal cortex glutamate+glutamine in adults with antisocial personality disorder and bipolar disorder: A proton magnetic resonance spectroscopy study.

As the main excitatory neurotransmitter in the central nervous system, glutamate, as measured in combination with glutamine (Glx), is implicated in several psychopathologies when levels are aberrant. One illness that shows heightened Glx levels is bipolar disorder (BD), an illness characterized by high impulsivity. In addition, although animal studies have reported elevated levels of Glx in aggressive and impulsive phenotypes, no study, to our knowledge, has reported Glx in the human cortex in relation to aggression. Here, we addressed the question of whether elevated levels of Glx would be present in patients with BD and antisocial personality disorder (ASPD), a condition associated with aggression and, like BD, also presents high impulsivity. We recruited individuals with ASPD (n = 18), individuals with BD (n = 16), and a healthy control group (n = 24). We used proton magnetic resonance spectroscopy to measure relative neurometabolite concentrations in the left dorsolateral prefrontal cortex (dlPFC) and supra-genual anterior cingulate cortex (ACC), two brain regions associated with impulsivity and behavior control. We found significantly elevated levels of Glx in the ASPD group relative to the BD and healthy control groups in the dlPFC (p = .014), and a positive correlation between Glx levels and aggression in the dlPFC in the ASPD group alone (r = .59, p = .026). These findings suggest a link between aggression in ASPD and Glx levels.

Manual segmentation of the fornix, fimbria, and alveus on high-resolution 3T MRI: Application via fully-automated mapping of the human memory circuit white and grey matter in healthy and pathological aging.

Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high-resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at https://github.com/cobralab/atlases. Our segmentation methods demonstrated high inter- and intra-rater reliability, were validated as inputs in automated segmentation, and were used to analyze the trajectory of these regions in both healthy aging (OASIS), and Alzheimer's disease (AD) and mild cognitive impairment (MCI; using ADNI). We observed significant bilateral decreases in the fornix in healthy aging while the alveus and cornu ammonis (CA) 1 were well preserved (all p's<0.006). MCI and AD demonstrated significant decreases in fimbriae and fornices. Many hippocampal subfields exhibited decreased volume in both MCI and AD, yet no significant differences were found between MCI and AD cohorts themselves. Our results suggest a neuroprotective or compensatory role for the alveus and CA1 in healthy aging and suggest that an improved understanding of the volumetric trajectories of these structures is required.

Changes in working memory performance in youth following concussion.

OBJECTIVE: The purpose of this study was to compare the working memory (WM) performance pre- and post-concussion, and investigate the relationships between performance changes and characteristics such as self-reported symptom scores, number of days post-injury and age at injury in 10-14-year-old youth. METHODS: Twenty-one youth (17 males) aged 10-14 years recruited from the community completed verbal and non-verbal WM tasks pre- and post-concussion. Performance was measured using accuracy and performance errors (false alarms and misses). Pre- and post-tests were compared using a Wilcoxon signed rank test, and effect size was determined using matched-pairs rank biserial correlation. RESULTS: Comparisons showed lower verbal WM accuracy at post-test, greater verbal and non-verbal WM false alarm errors at post-test, and greater verbal WM miss errors at post-test (all r ≥ 0.30). Correlations between performance and characteristics revealed associations between younger youth and lower non-verbal WM accuracy and more false alarms at post-test, as well as an association among non-verbal WM miss errors, higher PCS scores and fewer days since injury at post-test. CONCLUSIONS: The current study found lower WM performance in youth following concussion. Furthermore, the findings suggest that false alarm errors may be a useful screening measure acutely post-concussion when assessing WM performance in youth.

Multiregional integration in the brain during resting-state fMRI activity.

Data-driven models of functional magnetic resonance imaging (fMRI) activity can elucidate dependencies that involve the combination of multiple brain regions. Activity in some regions during resting-state fMRI can be predicted with high accuracy from the activities of other regions. However, it remains unclear in which regions activity depends on unique integration of multiple predictor regions. To address this question, sparse (parsimonious) models could serve to better determine key interregional dependencies by reducing false positives. We used resting-state fMRI data from 46 subjects, and for each region of interest (ROI) per subject we performed whole-brain recursive feature elimination (RFE) to select the minimal set of ROIs that best predicted activity in the modeled ROI. We quantified the dependence of activity on multiple predictor ROIs, by measuring the gain in prediction accuracy of models that incorporated multiple predictor ROIs compared to models that used a single predictor ROI. We identified regions that showed considerable evidence of multiregional integration and determined the key regions that contributed to their observed activity. Our models reveal fronto-parietal integration networks, little integration in primary sensory regions, as well as redundancy between some regions. Our study demonstrates the utility of whole-brain RFE to generate data-driven models with minimal sets of ROIs that predict activity with high accuracy. By determining the extent to which activity in each ROI depended on integration of signals from multiple ROIs, we find cortical integration networks during resting-state activity.

High-resolution In Vivo Manual Segmentation Protocol for Human Hippocampal Subfields Using 3T Magnetic Resonance Imaging.

The human hippocampus has been broadly studied in the context of memory and normal brain function and its role in different neuropsychiatric disorders has been heavily studied. While many imaging studies treat the hippocampus as a single unitary neuroanatomical structure, it is, in fact, composed of several subfields that have a complex three-dimensional geometry. As such, it is known that these subfields perform specialized functions and are differentially affected through the course of different disease states. Magnetic resonance (MR) imaging can be used as a powerful tool to interrogate the morphology of the hippocampus and its subfields. Many groups use advanced imaging software and hardware (>3T) to image the subfields; however this type of technology may not be readily available in most research and clinical imaging centers. To address this need, this manuscript provides a detailed step-by-step protocol for segmenting the full anterior-posterior length of the hippocampus and its subfields: cornu ammonis (CA) 1, CA2/CA3, CA4/dentate gyrus (DG), strata radiatum/lacunosum/moleculare (SR/SL/SM), and subiculum. This protocol has been applied to five subjects (3F, 2M; age 29-57, avg. 37). Protocol reliability is assessed by resegmenting either the right or left hippocampus of each subject and computing the overlap using the Dice's kappa metric. Mean Dice's kappa (range) across the five subjects are: whole hippocampus, 0.91 (0.90-0.92); CA1, 0.78 (0.77-0.79); CA2/CA3, 0.64 (0.56-0.73); CA4/dentate gyrus, 0.83 (0.81-0.85); strata radiatum/lacunosum/moleculare, 0.71 (0.68-0.73); and subiculum 0.75 (0.72-0.78). The segmentation protocol presented here provides other laboratories with a reliable method to study the hippocampus and hippocampal subfields in vivo using commonly available MR tools.

Trail Making Test Elucidates Neural Substrates of Specific Poststroke Executive Dysfunctions.

BACKGROUND AND PURPOSE: Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. METHODS: One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute-subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. RESULTS: Multiple linear regression analyses were completed. Although larger infarcts (ß=0.37, P<0.0001) were associated with slower processing speed, cholinergic hyperintensities projections scale severity (ß=0.39, P<0.0001) was associated with all metrics of set shifting. Left superior longitudinal fasciculus damage, however, was only associated with the difference score (ß=0.17, P=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. CONCLUSIONS: In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting.

Multivariate fMRI and Eye Tracking Reveal Differential Effects of Visual Interference on Recognition Memory Judgments for Objects and Scenes.

Recent work has demonstrated that the perirhinal cortex (PRC) supports conjunctive object representations that aid object recognition memory following visual object interference. It is unclear, however, how these representations interact with other brain regions implicated in mnemonic retrieval and how congruent and incongruent interference influences the processing of targets and foils during object recognition. To address this, multivariate partial least squares was applied to fMRI data acquired during an interference match-to-sample task, in which participants made object or scene recognition judgments after object or scene interference. This revealed a pattern of activity sensitive to object recognition following congruent (i.e., object) interference that included PRC, prefrontal, and parietal regions. Moreover, functional connectivity analysis revealed a common pattern of PRC connectivity across interference and recognition conditions. Examination of eye movements during the same task in a separate study revealed that participants gazed more at targets than foils during correct object recognition decisions, regardless of interference congruency. By contrast, participants viewed foils more than targets for incorrect object memory judgments, but only after congruent interference. Our findings suggest that congruent interference makes object foils appear familiar and that a network of regions, including PRC, is recruited to overcome the effects of interference.

Superficial white matter as a novel substrate of age-related cognitive decline.

Studies of diffusion tensor imaging have focused mainly on the role of deep white matter tract microstructural abnormalities associated with aging and age-related cognitive decline. However, the potential role of superficial white matter (SWM) in aging and, by extension, cognitive-aging, is less clear. Healthy individuals (n = 141; F/M: 66/75 years) across the adult lifespan (18-86 years) underwent diffusion tensor imaging and a battery of cognitive testing. SWM was assessed via a combination of probabilistic tractography and tract-based spatial statistics (TBSS). A widespread inverse relationship of fractional anisotropy (FA) values in SWM with age was observed. SWM-FA adjacent to the precentral gyri was associated with fine-motor-speed, whereas performance in visuomotor-attention/processing speed correlated with SWM-FA in all 4 lobes of the left-hemisphere and in right parieto-occipital SWM-FA (family-wise error corrected p < 0.05). Independent of deep white matter-FA, right frontal and right occipital SWM-FA-mediated age effects on motor-speed and visuomotor-attention/processing speed, respectively. Altogether, our results indicate that SWM-FA contributes uniquely to age-related cognitive performance, and should be considered as a novel biomarker of cognitive-aging.

Old wine in new bottles: validating the clinical utility of SPECT in predicting cognitive performance in mild traumatic brain injury.

The neural underpinnings of cognitive dysfunction in mild traumatic brain injury (TBI) are not fully understood. Consequently, patient prognosis using existing clinical imaging is somewhat imprecise. Single photon emission computed tomography (SPECT) is a frequently employed investigation in this population, notwithstanding uncertainty over the clinical utility of the data obtained. In this study, subjects with mild TBI underwent (99m)Tc-ECD SPECT scanning, and were administered a brief battery of cognitive tests and self-report symptom scales of concussion and emotional distress. Testing took place 2 weeks (n=84) and 1 year (n=49) post-injury. Multivariate analysis (i.e., partial least squares analysis) revealed that frontal perfusion in right superior frontal and middle frontal gyri predicted poorer performance on the Stroop test, an index of executive function, both at initial and follow-up testing. Conversely, SPECT scans categorized as normal or abnormal by radiologists did not differentiate cognitively impaired from intact subjects. These results demonstrate the clinical utility of SPECT in mild TBI, but only when data are subjected to blood flow quantification analysis.

Derivation of high-resolution MRI atlases of the human cerebellum at 3T and segmentation using multiple automatically generated templates.

The cerebellum has classically been linked to motor learning and coordination. However, there is renewed interest in the role of the cerebellum in non-motor functions such as cognition and in the context of different neuropsychiatric disorders. The contribution of neuroimaging studies to advancing understanding of cerebellar structure and function has been limited, partly due to the cerebellum being understudied as a result of contrast and resolution limitations of standard structural magnetic resonance images (MRI). These limitations inhibit proper visualization of the highly compact and detailed cerebellar foliations. In addition, there is a lack of robust algorithms that automatically and reliably identify the cerebellum and its subregions, further complicating the design of large-scale studies of the cerebellum. As such, automated segmentation of the cerebellar lobules would allow detailed population studies of the cerebellum and its subregions. In this manuscript, we describe a novel set of high-resolution in vivo atlases of the cerebellum developed by pairing MR imaging with a carefully validated manual segmentation protocol. Using these cerebellar atlases as inputs, we validate a novel automated segmentation algorithm that takes advantage of the neuroanatomical variability that exists in a given population under study in order to automatically identify the cerebellum, and its lobules. Our automatic segmentation results demonstrate good accuracy in the identification of all lobules (mean Kappa [κ]=0.731; range 0.40-0.89), and the entire cerebellum (mean κ=0.925; range 0.90-0.94) when compared to "gold-standard" manual segmentations. These results compare favorably in comparison to other publically available methods for automatic segmentation of the cerebellum. The completed cerebellar atlases are available freely online (http://imaging-genetics.camh.ca/cerebellum) and can be customized to the unique neuroanatomy of different subjects using the proposed segmentation pipeline (https://github.com/pipitone/MAGeTbrain).

Alterations of superficial white matter in schizophrenia and relationship to cognitive performance.

Post-mortem studies have demonstrated alterations in superficial white matter (SWM) in schizophrenia patients. Diffusion tensor imaging (DTI) can be used to assess SWM in vivo, and compare SWM fractional anisotropy (FA) in schizophrenia patients vs healthy controls. The assessment of SWM in vivo also provides an opportunity to identify novel neural correlates of cognitive performance, and potential cognitive impairment in schizophrenia patients. Forty-four patients with schizophrenia and 44 matched healthy controls underwent neuroimaging and cognitive protocols. Using an SWM mask and tract-based spatial statistics, differences in SWM-FA were examined between groups. SWM-FA clusters different between groups were then used to predict cognitive performance with multiple linear regression. The relative contribution of SWM fiber subtypes (deep white matter extensions vs U-fibers and intraregional fibers) from significantly different clusters was examined. Compared to controls, patients with schizophrenia had reduced FA in five SWM clusters: the largest a left posterior parieto-occipital cluster, followed by four clusters in the left frontal lobe. SWM-FA in the frontal lobe clusters predicted attention, working memory, and processing speed performance in healthy controls, but not in patients with schizophrenia. The majority of streamlines tracked from these clusters were restricted to U-fibers and intraregional fibers, rather than deep white matter extensions. Our analyses revealed prominent SWM disruption in patients with schizophrenia compared to controls. SWM-cognition relationships shown in healthy individuals were disrupted in patients with schizophrenia. SWM may be an important neurobiological substrate of cognitive performance and a novel cortical treatment target for cognitive deficits in schizophrenia patients.

A novel in vivo atlas of human hippocampal subfields using high-resolution 3 T magnetic resonance imaging.

The hippocampus is a neuroanatomical structure that has been widely studied in the context of learning, memory, stress, and neurodegeneration. Neuroanatomically, the hippocampus is subdivided into several subfields with intricate morphologies and complex three-dimensional relationships. Recent studies have demonstrated that the identification of different subfields is possible with high-resolution and -contrast image volumes acquired using ex vivo specimens in a small bore 9.4 T scanner and, more recently, in vivo, at 7 T. In these studies, the neuroanatomical definitions of boundaries between subfields are based upon salient differences in image contrast. Typically, the definition of subfields has not been possible using commonly available magnetic resonance (MR) scanners (i.e.: 1.5 or 3T) due to resolution and contrast limitations. To overcome the limited availability of post-mortem specimens and expertise in state-of-the-art high-field imaging, we propose a coupling of MR acquisition and detailed segmentation techniques that allow for the reliable identification of hippocampal anatomy (including subfields). High-resolution and -contrast T1- and T2-weighted image volumes were acquired from 5 volunteers (2 male; 3 female; age range: 29-57, avg. 37) using a clinical research-grade 3T scanner and have final super-sampled isotropic voxel dimensions of 0.3mm. We demonstrate that by using these acquisition techniques, our data results in contrast-to-noise ratios that compare well with high-resolution images acquired with long scan times using post-mortem data at higher field strengths. For the subfields, the cornus ammonis (CA) 1, CA2/CA3, CA4/dentate gyrus, stratum radiatum/stratum lacunosum/stratum moleculare, and subiculum were all labeled as separate structures. Hippocampal volumes are reported for each of the substructures and the hippocampus as a whole (range for hippocampus: 2456.72-3325.02 mm(3)). Intra-rater reliability of our manual segmentation protocol demonstrates high reliability for the whole hippocampus (mean Dice Kappa of 0.91; range 0.90-0.92) and for each of the subfields (range of Dice Kappas: 0.64-0.83). We demonstrate that our reliability is better than the Dice Kappas produced by simulating the following errors: a translation by a single voxel in all cardinal directions and 1% volumetric shrinkage and expansion. The completed hippocampal atlases are available freely online (info2.camh.net/kf-tigr/index.php/Hippocampus) and can be coupled with novel computational neuroanatomy techniques that will allow for them to be customized to the unique neuroanatomy of different subjects, and ultimately be utilized in different analysis pipelines.