Population-wide cerebellar growth models of children and adolescents.

In the past, the cerebellum has been best known for its crucial role in motor function. However, increasingly more findings highlight the importance of cerebellar contributions in cognitive functions and neurodevelopment. Using a total of 7240 neuroimaging scans from 4862 individuals, we describe and provide detailed, openly available models of cerebellar development in childhood and adolescence (age range: 6-17 years), an important time period for brain development and onset of neuropsychiatric disorders. Next to a traditionally used anatomical parcellation of the cerebellum, we generated growth models based on a recently proposed functional parcellation. In both, we find an anterior-posterior growth gradient mirroring the age-related improvements of underlying behavior and function, which is analogous to cerebral maturation patterns and offers evidence for directly related cerebello-cortical developmental trajectories. Finally, we illustrate how the current approach can be used to detect cerebellar abnormalities in clinical samples.

Longitudinal changes of deep gray matter shape in multiple sclerosis.

OBJECTIVE: This study aimed to investigate longitudinal deep gray matter (DGM) shape changes and their relationship with measures of clinical disability and white matter lesion-load in a large multiple sclerosis (MS) cohort. MATERIALS AND METHODS: A total of 230 MS patients (179 relapsing-remitting, 51 secondary progressive; baseline age 44.5 ±â€¯11.3 years; baseline disease duration 12.99 ±â€¯9.18) underwent annual clinical and MRI examinations over a maximum of 6 years (mean 4.32 ±â€¯2.07 years). The DGM structures were segmented on the T1-weighted images using the "Multiple Automatically Generated Templates" brain algorithm. White matter lesion-load was measured on T2-weighted MRI. Clinical examination included the expanded disability status scale, 9-hole peg test, timed 25-foot walk test, symbol digit modalities test and paced auditory serial addition test. Vertex-wise longitudinal analysis of DGM shapes was performed using linear mixed effect models and evaluated the association between average/temporal changes of DGM shapes with average/temporal changes of clinical measurements, respectively. RESULTS: A significant shrinkage over time of the bilateral ventrolateral pallidal and the left posterolateral striatal surface was observed, whereas no significant shape changes over time were observed at the bilateral thalamic and right striatal surfaces. Higher average lesion-load was associated with an average inwards displacement of the global thalamic surface with relative sparing on the posterior side (slight left-side predominance), the antero-dorso-lateral striatal surfaces bilaterally (symmetric on both sides) and the antero-lateral pallidal surface (left-side predominance). There was also an association between shrinkage of large lateral DGM surfaces with higher clinical motor and cognitive disease severity. However, there was no correlation between any DGM shape changes over time and measurements of clinical progression or lesion-load changes over time. CONCLUSIONS: This study showed specific shape change of DGM structures occurring over time in relapse-onset MS. Although these shape changes over time were not associated with disease progression, we demonstrated a link between DGM shape and the patients' average disease severity as well as white matter lesion-load.

Open science datasets from PREVENT-AD, a longitudinal cohort of pre-symptomatic Alzheimer's disease.

To move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old ± 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information, sensitive by nature, is accessible by qualified researchers at https://registeredpreventad.loris.ca. In addition to being a living resource for continued data acquisition, PREVENT-AD offers opportunities to facilitate understanding of AD pathogenesis.

Maternal cafeteria diet exposure primes depression-like behavior in the offspring evoking lower brain volume related to changes in synaptic terminals and gliosis.

Maternal nutritional programming by caloric exposure during pregnancy and lactation results in long-term behavioral modification in the offspring. Here, we characterized the effect of maternal caloric exposure on synaptic and brain morphological organization and its effects on depression-like behavior susceptibility in rats' offspring. Female Wistar rats were exposed to chow or cafeteria (CAF) diet for 9 weeks (pre-pregnancy, pregnancy, and lactation) and then switched to chow diet after weaning. By postnatal day 60, the male Wistar rat offspring were tested for depressive-like behavior using operational conditioning, novelty suppressed feeding, sucrose preference, and open-field test. Brain macro and microstructural morphology were analyzed using magnetic resonance imaging deformation-based morphometry (DBM) and western blot, immunohistochemistry for NMDA and AMPA receptor, synaptophysin and myelin, respectively. We found that the offspring of mothers exposed to CAF diet displayed deficient motivation showing decrease in the operant conditioning, sucrose preference, and suppressed feeding test. Macrostructural DBM analysis showed reduction in the frontomesocorticolimbic circuit volume including the nucleus accumbens (NAc), hippocampus, and prefrontal cortex. Microstructural analysis revealed reduced synaptic terminals in hippocampus and NAc, whereas increased glial fibrillary acidic protein in hippocampus and lateral hypothalamus, as well as a decrease in the hippocampal cell number and myelin reduction in the dentate gyrus and hilus, respectively. Also, offspring exhibited increase of the GluR1 and GLUR2 subunits of AMPA receptor, whereas a decrease in the mGluR2 expression in hippocampus. Our findings reveal that maternal programming might prime depression-like behavior in the offspring by modulating macro and micro brain organization of the frontomesocorticolimbic circuit.

The effect of second-generation antipsychotics on basal ganglia and thalamus in first-episode psychosis patients.

Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients.

Cortical abnormalities in episodic migraine: A multi-center 3T MRI study.

BACKGROUND: Several previous studies have investigated cortical abnormalities, specifically cortical thickness, in patients with migraine, with variable results. The relatively small sample sizes of most previous studies may partially explain these inconsistencies. OBJECTIVE: To investigate differences of cortical thickness between control subjects and migraineurs in a large cohort. METHODS: Three Tesla MRI data of 131 patients (38 with and 93 without aura) and 115 control subjects were analysed. A vertex-wise linear model was applied controlling for age, gender and MRI scanner to investigate differences between groups and determine the impact of clinical factors on cortical thickness measures. RESULTS: Migraineurs showed areas of thinned cortex compared with controls bilaterally in the central sulcus, in the left middle-frontal gyrus, in left visual cortices and the right occipito-temporal gyrus. Frequency of migraine attacks and the duration of the disorder had a significant impact on cortical thickness in the sensorimotor cortex and middle-frontal gyrus. Patients without aura showed thinner cortex than controls bilaterally in the central sulcus and in the middle frontal gyrus, in the left primary visual cortices, in the left supramarginal gyrus and in the right cuneus. Patients with aura showed clusters of thinner cortex bilaterally in the subparietal sulcus (between the precuneus and posterior cingulate cortex), in the left intraparietal sulcus and in the right anterior cingulate. CONCLUSION: These results indicate cortical abnormalities in specific brain regions in migraineurs. Some of the observed abnormalities may reflect a genetic susceptibility towards developing migraine attacks, while others are probably a consequence of repeated head pain attacks.

Dissecting genetic cross-talk between ADHD and other neurodevelopmental disorders: Evidence from behavioural, pharmacological and brain imaging investigations.

Several epidemiological and genetic studies have provided evidence of an overlap between neurodevelopmental disorders. However, the details of the etiological pathways remain to be elucidated. In this study, we garnered the findings of previous GWAS, conducted with schizophrenia and bipolar disorder. We conducted an exploratory study to examine the association between these SNPs and quantitative clinical/ behavioural/ cognitive/ structural brain parameters, as well as response to treatment with a fixed dose of methylphenidate, in a relatively large sample of children with ADHD. Family-based association tests were conducted with nine tag SNPs with 602 nuclear families. In addition, structural magnetic resonance imaging (sMRI) was conducted in a subset of children with ADHD (n = 76). Of the 9 tag SNPs examined, rs1602565 showed a significant association with ADHD, several dimensional measures and response to treatment. An association was also observed between rs1006737 (CACNA1C) and performance IQ. In addition, significant reductions in cortical thickness measurements were observed with the risk allele in rs1006737. These results provide preliminary evidence for putative shared genetic vulnerability between childhood ADHD and other neurodevelopmental disorders.

Classification of suicide attempters in schizophrenia using sociocultural and clinical features: A machine learning approach.

OBJECTIVE: Suicide is a major concern for those afflicted by schizophrenia. Identifying patients at the highest risk for future suicide attempts remains a complex problem for psychiatric interventions. Machine learning models allow for the integration of many risk factors in order to build an algorithm that predicts which patients are likely to attempt suicide. Currently it is unclear how to integrate previously identified risk factors into a clinically relevant predictive tool to estimate the probability of a patient with schizophrenia for attempting suicide. METHODS: We conducted a cross-sectional assessment on a sample of 345 participants diagnosed with schizophrenia spectrum disorders. Suicide attempters and non-attempters were clearly identified using the Columbia Suicide Severity Rating Scale (C-SSRS) and the Beck Suicide Ideation Scale (BSS). We developed four classification algorithms using a regularized regression, random forest, elastic net and support vector machine models with sociocultural and clinical variables as features to train the models. RESULTS: All classification models performed similarly in identifying suicide attempters and non-attempters. Our regularized logistic regression model demonstrated an accuracy of 67% and an area under the curve (AUC) of 0.71, while the random forest model demonstrated 66% accuracy and an AUC of 0.67. Support vector classifier (SVC) model demonstrated an accuracy of 67% and an AUC of 0.70, and the elastic net model demonstrated and accuracy of 65% and an AUC of 0.71. CONCLUSION: Machine learning algorithms offer a relatively successful method for incorporating many clinical features to predict individuals at risk for future suicide attempts. Increased performance of these models using clinically relevant variables offers the potential to facilitate early treatment and intervention to prevent future suicide attempts.

Microstructural Integrity of Hippocampal Subregions Is Impaired after Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) affects a large number of individuals and diffusion tensor imaging can be used to investigate microstructural integrity of brain tissue after mTBI. However, results have varied considerably between studies and gray matter (GM) integrity has been largely neglected in these investigations. Given impaired working memory processing after mTBI and its possible association with Alzheimer's disease, we investigated hippocampal integrity and parcellated this structure into five subregions: subiculum, cornu ammonis (CA) 1, CA 2/3, CA 4/dentate gyrus, and stratum radiatum/lacunosum-moleculare. We also employed shape analysis of bilateral hippocampi to explore whether morphological changes had occurred due to the traumatic injury and conducted neuropsychological memory tests. The sample comprised 15 subjects with mTBI (18-55 years, nine female) and 13 age- and sex-matched healthy control subjects (19-57 years, nine female). Voxelwise analyses showed significantly increased mean diffusivity in patients, compared with controls, in the right hippocampus and three of its five subregions (family-wise error corrected p < 0.05). Additionally, results from probabilistic tractography indicated impaired CA 1 connectivity after mTBI (Benjamini-Hochberg false discovery rate [FDR] corrected p < 0.05). Shape of bilateral hippocampi did not significantly differ between groups (Benjamini-Hochberg FDR corrected p > 0.05). Subjects with mTBI reported more symptoms and performed worse in a non-standard verbal working memory task. Based on these preliminary findings, we were able to demonstrate altered diffusivity of hippocampal subregions following mTBI, indicating impaired GM microstructural integrity. These differences highlight the potential of diffusion imaging for investigation of subtle yet relevant changes in GM microstructure not detected otherwise following mTBI.

Erratum: The developing human brain: age-related changes in cortical, subcortical, and cerebellar anatomy.

[This corrects the article DOI: 10.1002/brb3.457.].

Cortical thickness and low insight into symptoms in enduring schizophrenia.

Poor insight is a common, multidimensional phenomenon in patients with schizophrenia, associated with poorer outcomes and treatment non-adherence. Yet scant research has investigated the neuronal correlates of insight into symptoms (IS), a dimension of insight that may be particularly significant in enduring schizophrenia. Sixty-six patients with enduring schizophrenia (duration >4years) and 33 healthy controls completed MRI scanning and IQ, depression, and anxiety assessments. The Scale to Assess Insight-Expanded (SAI-E) measured insight into patients' four most prominent symptoms and patients were classified into two groups: low IS (0-2; n=33), and high IS (>2; n=33). We evaluated the association between cortical thickness (CT) and insight into symptoms using two methods: (1) a between-patients region-of-interest analysis in the insula, superior temporal gyrus (STG) and frontal lobe; and (2) a whole-brain exploratory regression between patient and controls. Brain regions were segmented using a neuroanatomical atlas and vertex-wise CT analyses were conducted with CIVET, covaried for age and sex. ROI analysis revealed thinner insula cortex in patients with low IS (p<0.05, surviving FDR correction). Patients with low IS also showed significantly thinner right insula, STG, and parahippocampal cortex compared to healthy controls (p<0.05, surviving FDR correction). Regions of observed CT reductions have been hypothesized to subserve self-monitoring, error awareness, and ability to identify hallucinations. Results highlight an important association between right insula abnormalities and impaired IS in schizophrenia. The diverse clinical presentation of patients further suggests an independent relationship between symptomology and insight-related differences in CT that has been previously unexplored in enduring schizophrenia.

Neuroimaging predictors of functional outcomes in schizophrenia at baseline and 6-month follow-up.

PURPOSE: Studies show that deficit syndrome schizophrenia patients, characterized by primary negative symptoms and poor functional outcome, have impairment in specific neural circuits. We assessed whether these same neural circuits are directly linked to functional outcomes across schizophrenia patients. METHODS: T1- and diffusion-weighted MR images were obtained for schizophrenia (n=30) and matched healthy control participants (n=30). Negative symptoms and functional outcome were assessed at baseline and 6-month follow-up. Cortical thickness and tract-wise fractional anisotropy (FA) were compared between groups. To assess relationships of neuroimaging measures with functional outcome, principal component analysis (PCA) was performed on tract-wise FA values and components were entered into a multiple regression model for schizophrenia participants. RESULTS: Consistent with the literature, schizophrenia participants showed frontotemporal reductions in cortical thickness and tract-wise FA compared to controls. The top two components from PCA explained 71% of the variance in tract-wise FA values. The second component (associated with inferior longitudinal and arcuate fasciculus FA) was significantly correlated with functional outcome (baseline: ß=0.54, p=0.03; follow-up: ß=0.74, p=0.047); further analysis revealed this effect was mediated by negative symptoms. Post-hoc network analysis revealed increased cortical coupling between right inferior frontal and supramarginal gyri (connected by the arcuate fasciculus) in schizophrenia participants with poorer functional outcome. CONCLUSIONS: Our findings indicate that impairment in the same neural circuitry susceptible in deficit syndrome schizophrenia predicts functional outcome in a continuous manner in schizophrenia participants. This relationship was mediated by negative symptom burden. Our findings provide novel evidence for brain-based biomarkers of longitudinal functional outcome in people with schizophrenia.

Automatic segmentation of the hippocampus for preterm neonates from early-in-life to term-equivalent age.

INTRODUCTION: The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life. METHODS: First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth from early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression. RESULTS: The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice's Kappa > 0.79 and Euclidean distance <1.3 mm between centroids). Using this method, we demonstrate that the average volume of the hippocampus is significantly different (p < 0.0001) in early-in-life (621.8 mm(3)) and term-equivalent age (958.8 mm(3)). Using these differences, we generalize the hippocampal growth rate to 38.3 ± 11.7 mm(3)/week and 40.5 ± 12.9 mm(3)/week for the left and right hippocampi respectively. Not surprisingly, younger gestational age at birth is associated with smaller volumes of the hippocampi (p = 0.001). CONCLUSIONS: MAGeT-Brain is capable of segmenting hippocampi accurately in preterm neonates, even at early-in-life. Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images, suggesting that this phenomenon has its onset in the 3rd trimester of gestation. Hippocampal volume assessed at the time of early-in-life and term-equivalent age is linearly associated with GA at birth, whereby smaller volumes are associated with earlier birth.

The complexities of pain after stroke--a review with a focus on central post-stroke pain.

Pain is frequently reported following stroke, but seems to be an underemphasized phenomenon since it can importantly impact rehabilitation and long-term outcomes. Two major forms of pain have to be distinguished in patients with post-stroke pain: central, neuropathic pain, arising from the vascular lesion defined as central post-stroke pain (CPSP) and pain primarily triggered by peripheral mechanisms such as hemiplegic shoulder pain and spasticity-related pain. Headache after stroke is difficult to classify since the pathophysiology is unclear. The suggested underlying mechanisms as well as treatment strategies of post-stroke pain differ according to the origin (peripheral versus central). This article aims at reviewing the pertinent evidence regarding clinical characteristics and mechanisms of post-stroke pain generation with a focus on CPSP. We discuss possible treatment options and highlight current pathophysiological concepts.

Neuroanatomical consequences of very preterm birth in middle childhood.

Individuals born preterm can demonstrate reductions in brain volume, cortical surface area and thickness. However, the extent of these neuroanatomical deficits and the relation among these measures in middle childhood, a critical developmental period, have not been determined. We assessed differences in brain structure by acquiring high-resolution T(1)-weighted scans in 25 children born very preterm (<32 weeks gestational age) without significant post-natal neurological sequelae and 32 age-matched term-born children (7-10 years). Children born very preterm had decreased brain volume, surface area and cortical thickness compared to term-born children. Furthermore, children born preterm did not display the robust relation between total brain volume and basal ganglia and thalamic volume apparent in the term-born children. Cortical thickness analyses revealed that the cortex was thinner for children born preterm than term-born children in the anterior cingulate cortex/supplementary motor area, isthmus of the cingulate gyrus, right superior temporal sulcus, right anterior insula, postcentral gyrus and precuneus. Follow-up analyses revealed that right precuneus thickness was correlated with gestational age. Thus, even without significant postnatal medical sequelae, very preterm-born children showed atypical brain structure and developmental patterns in areas related to higher cognitive function. Disruptions of the typical neurodevelopmental trajectory in the third trimester of pregnancy likely underlie these differences persisting into middle childhood.