Intracortical Myelin in Youths at Risk for Depression.

Background: Major depressive disorder (MDD) is a leading cause of disability. To understand why depression develops, it is important to distinguish between early neural markers of vulnerability that precede the onset of MDD and features that develop during depression. Recent neuroimaging findings suggest that reduced global and regional intracortical myelination (ICM), especially in the lateral prefrontal cortex, may be associated with depression, but it is unknown whether it is a precursor or a consequence of MDD. The study of offspring of affected parents offers the opportunity to distinguish between precursors and consequences by examining individuals who carry high risk at a time when they have not experienced depression. Methods: We acquired 129 T1-weighted and T2-weighted scans from 56 (25 female) unaffected offspring of parents with depression and 114 scans from 63 (34 female) unaffected offspring of parents without a history of depression (ages 9 to 16 years). To assess scan quality, we calculated test-retest reliability. We used the scan ratios to calculate myelin maps for 68 cortical regions. We analyzed data using mixed-effects modeling. Results: ICM did not differ between high and low familial risk youths in global (B = 0.06, SE = 0.03, p = .06) or regional (B = 0.05, SE = 0.03, p = .08) analyses. Our pediatric sample had high ICM reliability (intraclass correlation coefficient = 0.79; 95% CI, 0.55-0.88). Conclusions: Based on our results, reduced ICM does not appear to be a precursor of MDD. Future studies should examine ICM in familial high-risk youths across a broad developmental period.

The Developmental Brain Age Is Associated With Adversity, Depression, and Functional Outcomes Among Adolescents.

BACKGROUND: Most psychiatric disorders emerge in the second decade of life. In the present study, we examined whether environmental adversity, developmental antecedents, major depressive disorder, and functional impairment correlate with deviation from normative brain development in adolescence. METHODS: We trained a brain age prediction model using 189 structural magnetic resonance imaging brain features in 1299 typically developing adolescents (age range 9-19 years, mean = 13.5, SD = 3.04), validated the model in a holdout set of 322 adolescents (mean = 13.5, SD = 3.07), and used it to predict age in an independent risk-enriched cohort of 150 adolescents (mean = 13.6, SD = 2.82). We tested associations between the brain age gap and adversity, early antecedents, depression, and functional impairment. RESULTS: We accurately predicted chronological age in typically developing adolescents (mean absolute error = 1.53 years). The model generalized to the validation set (mean absolute error = 1.55 years, 1.98 bias adjusted) and to the independent at-risk sample (mean absolute error = 1.49 years, 1.86 bias adjusted). The brain age estimate was reliable in repeated scans (intraclass correlation = 0.94). Experience of environmental adversity (ß = 0.18; 95% CI, 0.04 to 0.31; p = .02), diagnosis of major depressive disorder (ß = 0.61; 95% CI, 0.23 to 0.99; p = .01), and functional impairment (ß = 0.16; 95% CI, 0.05 to 0.27; p = .01) were associated with a positive brain age gap. CONCLUSIONS: Risk factors, diagnosis, and impact of mental illness are associated with an older-appearing brain during development.

Toward individualized prediction of seizure recurrence: Hippocampal neuroimaging features in a cohort of patients from a first seizure clinic.

PURPOSE: We performed an exploratory analysis of electroencephalography (EEG) and neuroimaging data from a cohort of 51 patients with first seizure (FS) and new-onset epilepsy (NOE) to identify variables, or combinations of variables, that might discriminate between clinical trajectories over a one-year period and yield potential biomarkers of epileptogenesis. METHODS: Patients underwent EEG, hippocampal and whole brain structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) within six weeks of the index seizure, and repeat neuroimaging one year later. We classified patients with FS as having had a single seizure (FS-SS) or having converted to epilepsy (FS-CON) after one year and performed logistic regression to identify combinations of variables that might discriminate between FS-SS and FS-CON, and between FS-SS and the combined group FS-CON + NOE. We performed paired t-tests to assess changes in quantitative variables over time. RESULTS: Several combinations of variables derived from hippocampal structural MRI, DTI, and MRS provided excellent discrimination between FS-SS and FS-CON in our sample, with areas under the receiver operating curve (AUROC) ranging from 0.924 to 1. They also provided excellent discrimination between FS-SS and the combined group FS-CON + NOE in our sample, with AUROC ranging from 0.902 to 1. After one year, hippocampal fractional anisotropy (FA) increased bilaterally, hippocampal radial diffusivity (RD) decreased on the side with the larger initial measurement, and whole brain axial diffusivity (AD) increased in patients with FS-SS; hippocampal volume decreased on the side with the larger initial measurement, hippocampal FA increased bilaterally, hippocampal RD decreased bilaterally and whole brain AD, FA and mean diffusivity increased in the combined group FS-CON + NOE (corrected threshold for significance, q = 0.017). CONCLUSION: We propose a prospective, multicenter study to develop and test models for the prediction of seizure recurrence in patients after a first seizure, based on hippocampal neuroimaging. Further longitudinal neuroimaging studies in patients with a first seizure and new-onset epilepsy may provide clues to the microstructural changes occurring at the earliest stages of epilepsy and yield biomarkers of epileptogenesis.

Reliability of multimodal MRI brain measures in youth at risk for mental illness.

INTRODUCTION: A new generation of large-scale studies is using neuroimaging to investigate adolescent brain development across health and disease. However, imaging artifacts such as head motion remain a challenge and may be exacerbated in pediatric clinical samples. In this study, we assessed the scan-rescan reliability of multimodal MRI in a sample of youth enriched for risk of mental illness. METHODS: We obtained repeated MRI scans, an average of 2.7 ± 1.4 weeks apart, from 50 youth (mean age 14.7 years, SD = 4.4). Half of the sample (52%) had a diagnosis of an anxiety disorder; 22% had attention-deficit/hyperactivity disorder (ADHD). We quantified reliability with the test-retest intraclass correlation coefficient (ICC). RESULTS: Gray matter measurements were highly reliable with mean ICCs as follows: cortical volume (ICC = 0.90), cortical surface area (ICC = 0.89), cortical thickness (ICC = 0.82), and local gyrification index (ICC = 0.85). White matter volume reliability was excellent (ICC = 0.98). Diffusion tensor imaging (DTI) components were also highly reliable. Fractional anisotropy was most consistently measured (ICC = 0.88), followed by radial diffusivity (ICC = 0.84), mean diffusivity (ICC = 0.81), and axial diffusivity (ICC = 0.78). We also observed regional variability in reconstruction, with some brain structures less reliably reconstructed than others. CONCLUSIONS: Overall, we showed that developmental MRI measures are highly reliable, even in youth at risk for mental illness and those already affected by anxiety and neurodevelopmental disorders. Yet, caution is warranted if patterns of results cluster within regions of lower reliability.

Psychotic symptoms are associated with lower cortical folding in youth at risk for mental illness

Background: Cortical folding is essential for healthy brain development. Previous studies have found regional reductions in cortical folding in adult patients with psychotic illness. It is unknown whether these neuroanatomical markers are present in youth with subclinical psychotic symptoms. Methods: We collected MRIs and examined the local gyrification index in a sample of 110 youth (mean age ± standard deviation 14.0 ± 3.7 yr; range 9­25 yr) with a family history of severe mental illness: 48 with psychotic symptoms and 62 without. Images were processed using the Human Connectome Pipeline and FreeSurfer. We tested for group differences in local gyrification index using mixed-effects generalized linear models controlling for age, sex and familial clustering. Sensitivity analysis further controlled for intracranial volume, IQ, and stimulant and cannabis use. Results: Youth with psychotic symptoms displayed an overall trend toward lower cortical folding across all brain regions. After adjusting for multiple comparisons and confounders, regional reductions were localized to the frontal and occipital lobes. Specifically, the medial (B = ­0.42, pFDR = 0.04) and lateral (B = ­0.39, pFDR = 0.04) orbitofrontal cortices as well as the cuneus (B = ­0.47, pFDR = 0.03) and the pericalcarine (B = ­0.45, pFDR = 0.03) and lingual (B = ­0.38, pFDR = 0.04) gyri. Limitations: Inference about developmental trajectories was limited by the cross-sectional data. Conclusion: Psychotic symptoms in youth are associated with cortical folding deficits, even in the absence of psychotic illness. The current study helps clarify the neurodevelopmental basis of psychosis at an early stage, before medication, drug use and other confounds have had a persistent effect on the brain.

Complete recovery following transorbital penetrating head injury traversing the brainstem: case report.

Transorbital penetration accounts for one-quarter of the penetrating head injuries (PHIs) in adults and half of those in children. Injuries that traverse (with complete penetration of) the brainstem are often fatal, with survivors rarely seen in clinical practice. Here, the authors describe the case of a 16-year-old male who suffered and recovered from an accidental transorbital PHI traversing the brainstem-the first case of complete neurological recovery following such injury. Neuroimaging captured the trajectory of the initial injury. A delayed-onset carotid cavernous fistula and the subsequent development of internal carotid artery pseudoaneurysms were managed by endovascular embolization.The authors also review the relevant literature. Sixteen cases of imaging-confirmed PHI traversing the brainstem have been reported, 14 involving the pons and 12 penetrating via the transorbital route. Management and outcome of PHI are informed by object velocity, material, entry point, trajectory, relationship to neurovascular structures, and the presence of a retained foreign body. Trauma resuscitation is followed by a careful neurological examination and appropriate neuroimaging. Ophthalmological examination is performed if transorbital penetration is suspected, as injuries may be occult; the potential for neurovascular complications highlights the value of angiography. The featured case shows that complete recovery is possible following injury that traverses the brainstem.

Visual and Auditory fMRI Paradigms for Presurgical Language Mapping: Convergent Validity and Relationship to Individual Variables.

Functional MRI (fMRI) has emerged as a safe alternative to invasive procedures for determining hemispheric language dominance prior to neurosurgery. Despite this, there are currently no standardized fMRI protocols that have been explored in healthy controls to determine the influence of individual patient variables on the results, which poses challenges in clinical interpretation of ambiguous findings in patient populations. In addition, most fMRI protocols are not suitable for individuals with visual or intellectual disabilities (IQ<70). In the current study, 61 healthy adults (ages: 18-74 years) completed two fMRI paradigms for language mapping. One paradigm used visually based stimuli and has shown good face validity to date in our center. The second paradigm used auditory stimuli presented at slowed speed and was designed for individuals with visual or cognitive dysfunction but has not yet been used clinically. The paradigms demonstrated 97% agreement in classifying individuals as left-hemisphere, right-hemisphere, and bilaterally dominant. Cases that were classified differently showed bilateral dominance in response to either paradigm. Dominance classification rates for right- and left-handed individuals were largely in keeping with published data. Within the left-handed group, IQ and education were positively correlated with laterality indices generated by both paradigms (r values range: 0.44-0.95, p<0.01), suggesting that individuals with higher IQ and formal education were more likely to be classified as left-hemisphere dominant in the current sample. This study will help improve clinical interpretation of language fMRI maps by identifying factors that might impact results (like IQ). It also offers an alternative paradigm to make this procedure more accessible to a broader range of patients. Future studies will replicate results with a sample of patients with epilepsy across a broad range of intellectual abilities.

Role of neuroimaging in first seizure diagnosis.

The primary goal of neuroimaging in a first, unprovoked seizure is to identify a lesion that can explain the seizure. Secondarily, neuroimaging may be used to predict seizure recurrence and assist with the diagnosis of epilepsy. However, the events leading from a first seizure to epilepsy, with or without an identifiable epileptogenic lesion, are not well understood, and it is not always clear which lesions are epileptogenic as opposed to incidental. Much neuroimaging research to date has focused on findings in chronic epilepsy, rather than first seizure. Dedicated epilepsy imaging with high quality MRI protocols maximizes the likelihood of a diagnosis. However, a significant proportion of patients are MRI-negative, prompting researchers in the field to continue the search for better imaging strategies. Here we describe the role of neuroimaging in the assessment of a first seizure, the current state of the art and possible future directions.

Childhood exposure to ionizing radiation from computed tomography imaging in Nova Scotia.

BACKGROUND: Examining radiation dose in the paediatric population is particularly important due to the vulnerability of paediatric patients (increased radiosensitive tissues and postexposure life-years) and risk for future radiogenic malignancy. OBJECTIVES: To evaluate trends in paediatric computed tomography (CT) use and ionizing radiation exposure using population-based data from Nova Scotia. METHODS: A retrospective, population-based cohort study of CT use in patients <20 years of age, from January 1, 2004 to December 31, 2011, was performed in Nova Scotia. CT examination data were retrieved from a provincial imaging repository. Trends in CT use were described, and both annual and cumulative effective dose exposures were calculated. RESULTS: In total, 29,452 CT events, involving up to 22,867 individuals were retrieved. Overall annual paediatric CT examination rates remained static (range 17.4 to 18.8 per 1000 per year). However, use in children <10 years of age decreased by >50% (P<0.001); this was counterbalanced by a steady increase among 15- to 19-year-olds (P<0.0001). Overall, 15.4% of scanned patients underwent ≥2 examinations, of which 58 patients (1.6%) exceeded 50 mSv of exposure. CONCLUSIONS: Despite a static rate in CT imaging among the entire cohort, children <15 years of age and, particularly, those <10 years of age displayed marked reductions in CT use. This may reflect increased awareness of campaigns emphasizing judicious CT use, revised clinical practice guidelines and increased availability of alternative modalities. A small subgroup demonstrated high-dose exposure (>50 mSv), and rates in individuals >15 years of age steadily increased, suggesting further exposure reduction efforts are necessary.

HISTORIQUE: Il est particulièrement important d'examiner les doses de rayonnement dans la population pédiatrique en raison de sa vulnérabilité (augmentation des tissus radiosensibles et années de vie postexposition) et du risque de future tumeur radiogénique. OBJECTIFS: Évaluer les tendances d'utilisation de la tomodensitométrie (TD) en pédiatrie et l'exposition ionisante au moyen de données en population provenant de la Nouvelle-Écosse. MÉTHODOLOGIE: Les chercheurs ont réalisé une étude de cohorte rétrospective en population sur l'usage de la TD chez des patients de moins de 20 ans en Nouvelle-Écosse, entre le 1er janvier 2004 et le 31 décembre 2011. Ils ont extrait les données d'examen de la TD d'un registre d'imagerie provincial. Ils ont décrit les tendances d'utilisation de la TD et calculé à la fois les expositions aux doses efficaces annuelles et cumulatives. RÉSULTATS: Les chercheurs ont extrait 29 452 TD effectuées auprès de 22 867 personnes. Dans l'ensemble, les taux annuels d'examens TD en pédiatrie sont demeurés inchangés (plage de 17,4 à 18,8 sur 1 000 enfants par année). Cependant, l'utilisation chez les enfants de moins de dix ans a diminué de plus de 50 % (P<0,001), ce qui était compensé par une augmentation régulière chez les 15 à 19 ans (P<0,0001). Au total, 15,4 % des patients ont subi au moins deux examens, et 58 d'entre eux (1,6 %) ont été exposés à plus de 50 mSv. CONCLUSIONS: Malgré un taux inchangé de TD dans l'ensemble de la cohorte, l'utilisation de la TD a beaucoup diminué chez les enfants de moins de 15 ans, et particulièrement ceux de moins de dix ans. Ce résultat reflète peut-être la sensibilisation accrue aux campagnes prônant une utilisation judicieuse de la TD, des guides de pratique clinique révisés et un meilleur accès à d'autres modalités. Un petit sous-groupe a présenté une exposition à de fortes doses (plus de 50 mSv), et les taux chez les personnes de plus de 15 ans augmentaient régulièrement, ce qui démontre la nécessité de poursuivre les efforts pour réduire l'exposition.

Evaluation of whole brain health in aging and Alzheimer's disease: a standard procedure for scoring an MRI-based brain atrophy and lesion index.

BACKGROUND: The Brain Atrophy and Lesion Index (BALI), a semi-quantitative rating scale, has been developed to evaluate whole brain structural changes in aging and Alzheimer's disease (AD). OBJECTIVE: This study describes a standard procedure to score the BALI and train new raters for reliable BALI evaluation following this procedure. METHODS: Structural MRI of subjects in the Alzheimer's Disease Neuroimaging Initiative dataset who had 3.0T, T1, and T2 weighted MRI scans at baseline and at 6, 12, and 24 month follow-ups were retrieved (n = 122, including 24 AD, 51 mild cognitive impairment patients, and 47 healthy control subjects). Images were evaluated by four raters following training with a step-by-step BALI process. Seven domains of structural brain changes were evaluated, and a total score was calculated as the sum of the sub-scores. RESULTS: New raters achieved >90% accuracy after two weeks of training. Reliability was shown in both intra-rater correlation coefficients (ICC ≥ 0.92, p < 0.001) and inter-rater correlation coefficients (ICC ≥0.88, p < 0.001). Mean BALI total scores differed by diagnosis (F ≥ 2.69, p ≤ 0.049) and increased consistently over two years. CONCLUSION: The BALI can be introduced using a standard procedure that allows new users to achieve highly reliable evaluation of structural brain changes. This can advance its potential as a robust method for assessing global brain health in aging, AD, and mild cognitive impairment.

A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy.

Twenty percent to 49% of newly treated patients with epilepsy will develop pharmacoresistance (PR). The mechanisms leading to PR are unclear. There is currently no unifying theory to explain the variety of presentations of PR and the diversity of potential contributing factors. Etiology of seizures seems to play a critical role in at least a subset of PR. Many magnetic resonance imaging (MRI) studies in the advanced stages of epilepsy suggest a strong association between lesions such as hippocampal sclerosis and focal cortical dysplasia and PR. Unfortunately, almost all of these studies are cross-sectional and retrospective. There is a need for a new perspective on the role of preexisting lesions in the evolution of epilepsy and PR. We propose in this article to study a unique population of drug-naive patients with either first seizure or new-onset epilepsy longitudinally with advanced MRI imaging techniques, including magnetic resonance spectroscopy and diffusion tensor imaging. We hope to be able to monitor imaging findings and the development of PR early in the course of the disease in a subset of these patients with temporal lobe epilepsy (TLE). Our goal is to understand the pathogenesis of PR, to dissect changes associated with the development of PR from changes associated with chronic seizures and medication, and ultimately to predict PR at the onset of disease.

Sensitivity to white matter FMRI activation increases with field strength.

Functional magnetic resonance imaging (fMRI) activation in white matter is controversial. Given that many of the studies that report fMRI activation in white matter used high field MRI systems, we investigated the field strength dependence of sensitivity to white matter fMRI activation. In addition, we evaluated the temporal signal to noise ratio (tSNR) of the different tissue types as a function of field strength. Data were acquired during a motor task (finger tapping) at 1.5 T and 4 T. Group and individual level activation results were considered in both the sensorimotor cortex and the posterior limb of the internal capsule. We found that sensitivity increases associated with field strength were greater for white matter than gray matter. The analysis of tSNR suggested that white matter might be less susceptible to increases in physiological noise related to increased field strength. We therefore conclude that high field MRI may be particularly advantageous for fMRI studies aimed at investigating activation in both gray and white matter.

Overlapping compared with end-to-end repair of complete third-degree or fourth-degree obstetric tears: three-year follow-up of a randomized controlled trial.

OBJECTIVE: To report on a 3-year follow-up of women who underwent overlapping repair of a complete third-degree or fourth-degree obstetric tear. METHODS: Primiparous women sustaining a complete third-degree or a fourth-degree tear of the perineum were randomized to a primary sphincter repair using either an end-to-end or an overlapping surgical technique. At 1, 2, and 3 years, questionnaires on rates of flatal and fecal incontinence were mailed to participants. RESULTS: At 1 year, women who underwent an end-to-end repair reported lower rates of flatal and fecal incontinence than women who had an overlapping repair. For flatal incontinence the rates were 31% compared with 56% (95% confidence interval for the rate difference 6-43%, P=.012). For fecal incontinence, the rates were 7% compared with 16% (95% confidence interval for the rate difference -4% to 21%, P=.17). The difference between the two methods of surgical repair had largely disappeared by the end of year 2. CONCLUSION: At 1-year follow-up, end-to-end repair of complete third-degree or fourth-degree obstetric anal sphincter tears is associated with significantly lower rates of anal incontinence when compared with overlapping repair. There is no long-term benefit associated with either technique over the other. CLINICAL TRIAL REGISTRATION: ISRCTN Register, http://isrctn.org, ISRCTNO 4149919. LEVEL OF EVIDENCE: I.

Neuroimaging in epilepsy: the state of the art.

Our understanding of epileptogenesis is still limited. Knowledge is increasing with regard to structural and functional changes in chronic stages of epilepsy. At the same time, we have to appreciate that there is a significant lack of such information in new-onset epilepsy. The First Halifax International Epilepsy Conference tried to fill this gap, focusing on the contribution of advanced neuroimaging in early stages of epilepsy. The following article aims to synthesize the themes that emerged from this meeting. Participants agreed that (1) there is a need for a unified theory of epileptogenesis, addressing the interplay of functional and structural brain changes; (2) neuroimaging reveals widespread brain alterations in epilepsy; (3) advances in neuroimaging challenge the concept of "MRI-negative" (magnetic resonance imaging negative) focal epilepsy; (4) methodologic limitations and potential confounders must be considered in the translation of innovative imaging approaches to clinical practice; and (5) there is an urgent need for longitudinal studies that begin early in the disease process.

Overlapping compared with end-to-end repair of third- and fourth-degree obstetric anal sphincter tears: a randomized controlled trial.

OBJECTIVE: To compare overlapping repair with end-to-end repair of obstetric tears and to investigate which procedure results in a higher rate of flatal incontinence. METHODS: One-hundred forty-nine primiparous women sustaining a complete third- or a fourth-degree tear of the perineum were assigned randomly to a primary sphincter repair using either an end-to-end (n=75) or an overlapping surgical technique (n=74) using 3-0 polyglyconate. Outcome measures at 6 months included rates of flatal and fecal incontinence, quality-of-life scores, integrity of the internal and external anal sphincters by anal ultrasonography, and anal sphincter function as reflected by anal manometry. RESULTS: Women who underwent overlapping repair compared with end-to-end repair had higher rates of flatal incontinence, 61% compared with 39% (odds ratio [OR] 2.44, confidence interval [CI] 1.2-5.0). The rate of fecal incontinence was also higher, 15% compared with 8% (OR 1.97, CI 0.62-6.3) but did not attain statistical significance. Rates of internal and external anal sphincter defects did not differ significantly between groups and did not correlate with anal incontinence symptoms. Fecal incontinence was higher when there was a defect in both sphincter muscles. Anal sphincter function as assessed by manometry did not differ significantly between groups. CONCLUSION: End-to-end repair of third- or fourth-degree obstetric anal sphincter tears is associated with lower rates of anal incontinence when compared with overlapping repair. CLINICAL TRIAL REGISTRATION: ISRCTN Register, isrctn.org, ISRCTN04149919. LEVEL OF EVIDENCE: I.

Wavelet-based image registration and segmentation framework for the quantitative evaluation of hydrocephalus.

Hydrocephalus, characterized by increased fluid in the cerebral ventricles, is traditionally evaluated by a visual assessment of serial CT scans. The complex shape of the ventricular system makes accurate visual comparison of CT scans difficult. The current research developed a quantitative method to measure the change in cerebral ventricular volume over time. Key elements of the developed framework are: adaptive image registration based on mutual information and wavelet multiresolution analysis; adaptive segmentation with novel feature extraction based on the Dual-Tree Complex Wavelet Transform; volume calculation. The framework, when tested on physical phantoms, had an error of 2.3%. When validated on clinical cases, results showed that cases deemed to be normal/stable had a calculated volume change less than 5%. Those with progressive/treated hydrocephalus had a calculated change greater than 20%. These findings indicate that the framework is reasonable and has potential for development as a tool in the evaluation of hydrocephalus.