The relationship between cognition and white matter tract damage after mild traumatic brain injury in a premorbidly healthy, hospitalised adult cohort during the post-acute period.

Introduction: Recent developments in neuroimaging techniques enable increasingly sensitive consideration of the cognitive impact of damage to white matter tract (WMT) microstructural organisation after mild traumatic brain injury (mTBI). Objective: This study investigated the relationship between WMT microstructural properties and cognitive performance. Participants setting and design: Using an observational design, a group of 26 premorbidly healthy adults with mTBI and a group of 20 premorbidly healthy trauma control (TC) participants who were well-matched on age, sex, premorbid functioning and a range of physical, psychological and trauma-related variables, were recruited following hospital admission for traumatic injury. Main measures: All participants underwent comprehensive unblinded neuropsychological examination and structural neuroimaging as outpatients 6-10 weeks after injury. Neuropsychological examination included measures of speed of processing, attention, memory, executive function, affective state, pain, fatigue and self-reported outcome. The WMT microstructural properties were estimated using both diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) modelling techniques. Tract properties were compared between the corpus callosum, inferior longitudinal fasciculus, uncinate fasciculus, anterior corona radiata and three segmented sections of the superior longitudinal fasciculus. Results: For the TC group, in all investigated tracts, with the exception of the uncinate fasciculus, two DTI metrics (fractional anisotropy and apparent diffusion coefficient) and one NODDI metric (intra-cellular volume fraction) revealed expected predictive linear relationships between extent of WMT microstructural organisation and processing speed, memory and executive function. The mTBI group showed a strikingly different pattern relative to the TC group, with no relationships evident between WMT microstructural organisation and cognition on most tracts. Conclusion: These findings indicate that the predictive relationship that normally exists in adults between WMT microstructural organisation and cognition, is significantly disrupted 6-10 weeks after mTBI and suggests that WMT microstructural organisation and cognitive function have disparate recovery trajectories.

Association of Acute Infarct Topography With Development of Cerebral Palsy and Neurologic Impairment in Neonates With Stroke.

BACKGROUND AND OBJECTIVES: Research investigating neonatal arterial ischemic stroke (NAIS) outcomes have shown that combined cortical and basal ganglia infarction or involvement of the corticospinal tract predict cerebral palsy (CP). The research question was whether voxel-based lesion-symptom mapping (VLSM) on acute MRI can identify brain regions associated with CP and neurodevelopmental impairments in NAIS. METHODS: Newborns were recruited from prospective Australian and Swiss pediatric stroke registries. CP diagnosis was based on clinical examination. Language and cognitive-behavioral impairments were assessed using the Pediatric Stroke Outcome Measure, dichotomized to good (0-0.5) or poor (≥1), at ≥18 months of age. Infarcts were manually segmented using diffusion-weighted imaging, registered to a neonatal-specific brain template. VLSM was conducted using MATLAB SPM12 toolbox. A general linear model was used to correlate lesion masks with motor, language, and cognitive-behavioral outcomes. Voxel-wise t-statistics were calculated, correcting for multiple comparisons using family-wise error (FWE) rate. RESULTS: Eighty-five newborns met the inclusion criteria. Infarct lateralization was left hemisphere (62%), right (8%), and bilateral (30%). At a median age of 2.1 years (interquartile range 1.9-2.6), 33% developed CP and 42% had neurologic impairments. Fifty-four grey and white matter regions correlated with CP (t > 4.33; FWE < 0.05), including primary motor pathway regions, such as the precentral gyrus, and cerebral peduncle, and regions functionally connected to the primary motor pathway, such as the pallidum, and corpus callosum motor segment. No significant correlations were found for language or cognitive-behavioral outcomes. DISCUSSION: CP after NAIS correlates with infarct regions directly involved in motor control and in functionally connected regions. Areas associated with language or cognitive-behavioral impairment are less clear.

Cerebral microhaemorrhage count is related to processing speed, but not level of symptom reporting, independently of age, psychological status and premorbid functioning, after first-ever mild traumatic brain injury.

Cerebral microhaemorrhage is a commonly identified neuropathological consequence of mild traumatic brain injury (mTBI) and can be identified in vivo using susceptibility weighted imaging (SWI). This study aimed to determine whether SWI-detected microhaemorrhages are more common in individuals after a single, first-ever, mTBI event relative to trauma controls (TC) and to investigate whether a linear relationship exists between microhaemorrhage numbers and cognition or symptom reporting in the post-acute period after injury, independently of age, psychological status and premorbid level of functioning. Microhaemorrhagic lesions were identified by expert clinical examination of SWI for 78 premorbidly healthy adult participants who were admitted to hospital after a traumatic injury and had suffered a first-ever mTBI (n = 47) or no head strike (n = 31). Participants underwent objective cognitive examination of processing speed, attention, memory, and executive function as well as self-reported post-concussion symptomatology. Bootstrapping analyses were used as data were not normally distributed. Analyses revealed that the mTBI group had significantly more microhaemorrhages than the TC group (Cohen's d = 0.559). These lesions were only evident in 28% of individuals. The mTBI participants demonstrated a significant linear association between number of microhaemorrhages and processing speed, independently of age, psychological status, or premorbid level of functioning. This study shows that a single mTBI causes cerebral microhaemorrhages to occur in a minority of premorbidly healthy individuals. Greater microhaemorrhage count is independently associated with slower processing speed, but not symptom reporting, during the post-acute injury period.

Exercise as therapy for neurodevelopmental and cognitive dysfunction in people with a Fontan circulation: A narrative review.

People with a Fontan circulation are at risk of neurodevelopmental delay and disability, and cognitive dysfunction, that has significant implications for academic and occupational attainment, psychosocial functioning, and overall quality of life. Interventions for improving these outcomes are lacking. This review article discusses current intervention practices and explores the evidence supporting exercise as a potential intervention for improving cognitive functioning in people living with a Fontan circulation. Proposed pathophysiological mechanisms underpinning these associations are discussed in the context of Fontan physiology and avenues for future research are recommended.

Intrinsic and secondary epileptogenicity in focal cortical dysplasia type II.

OBJECTIVE: Favorable seizure outcome is reported following resection of bottom-of-sulcus dysplasia (BOSD). We assessed the distribution of epileptogenicity and dysplasia in and around BOSD to better understand this clinical outcome and the optimal surgical approach. METHODS: We studied 27 children and adolescents with magnetic resonance imaging (MRI)-positive BOSD who underwent epilepsy surgery; 85% became seizure-free postresection (median = 5.0 years follow-up). All patients had resection of the dysplastic sulcus, and 11 had additional resection of the gyral crown (GC) or adjacent gyri (AG). Markers of epileptogenicity were relative cortical hypometabolism on preoperative 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and spiking, ripples, fast ripples, spike-high-frequency oscillation cross-rate, and phase amplitude coupling (PAC) on preresection and postresection electrocorticography (ECoG), all analyzed at the bottom-of-sulcus (BOS), top-of-sulcus (TOS), GC, and AG. Markers of dysplasia were increased cortical thickness on preoperative MRI, and dysmorphic neuron density and variant allele frequency of somatic MTOR mutations in resected tissue, analyzed at similar locations. RESULTS: Relative cortical metabolism was significantly reduced and ECoG markers were significantly increased at the BOS compared to other regions. Apart from spiking and PAC, which were greater at the TOS compared to the GC, there were no significant differences in PET and other ECoG markers between the TOS, GC, and AG, suggesting a cutoff of epileptogenicity at the TOS rather than a tapering gradient on the cortical surface. MRI and tissue markers of dysplasia were all maximal in the BOS, reduced in the TOS, and mostly absent in the GC. Spiking and PAC reduced significantly over the GC after resection of the dysplastic sulcus. SIGNIFICANCE: These findings support the concept that dysplasia and intrinsic epileptogenicity are mostly limited to the dysplastic sulcus in BOSD and support resection or ablation confined to the MRI-visible lesion as a first-line surgical approach. 18 F-FDG PET and ECoG abnormalities in surrounding cortex seem to be secondary phenomena.

Karawun: a software package for assisting evaluation of advances in multimodal imaging for neurosurgical planning and intraoperative neuronavigation.

PURPOSE: The neuroimaging research community-which includes a broad range of scientific, medical, statistical, and engineering disciplines-has developed many tools to advance our knowledge of brain structure, function, development, aging, and disease. Past research efforts have clearly shaped clinical practice. However, translation of new methodologies into clinical practice is challenging. Anything that can reduce these barriers has the potential to improve the rate at which research outcomes can contribute to clinical practice. In this article, we introduce Karawun, a file format conversion tool, that has become a key part of our work in translating advances in diffusion imaging acquisition and analysis into neurosurgical practice at our institution. METHODS: Karawun links analysis workflows created using open-source neuroimaging software, to Brainlab (Brainlab AG, Munich, Germany), a commercially available surgical planning and navigation suite. Karawun achieves this using DICOM standards supporting representation of 3D structures, including tractography streamlines, and thus offers far more than traditional screenshot or color overlay approaches. RESULTS: We show that neurosurgical planning data, created from multimodal imaging data using analysis methods implemented in open-source research software, can be imported into Brainlab. The datasets can be manipulated as if they were created by Brainlab, including 3D visualizations of white matter tracts and other objects. CONCLUSION: Clinicians can explore and interact with the results of research neuroimaging pipelines using familiar tools within their standard clinical workflow, understand the impact of the new methods on their practice and provide feedback to methods developers. This capability has been important to the translation of advanced analysis techniques into practice at our institution.

Assessment of intraoperative diffusion EPI distortion and its impact on estimation of supratentorial white matter tract positions in pediatric epilepsy surgery.

The effectiveness of correcting diffusion Echo Planar Imaging (EPI) distortion and its impact on tractography reconstruction have not been adequately investigated in the intraoperative MRI setting, particularly for High Angular Resolution Diffusion Imaging (HARDI) acquisition. In this study, we evaluated the effectiveness of EPI distortion correction using 27 legacy intraoperative HARDI datasets over two consecutive surgical time points, acquired without reverse phase-encoded data, from 17 children who underwent epilepsy surgery at our institution. The data was processed with EPI distortion correction using the Synb0-Disco technique (Schilling et al., 2019) and without distortion correction. The corrected and uncorrected b0 diffusion-weighted images (DWI) were first compared visually. The mutual information indices between the original T1-weighted images and the fractional anisotropy images derived from corrected and uncorrected DWI were used to quantify the effect of distortion correction. Sixty-four white matter tracts were segmented from each dataset, using a deep-learning based automated tractography algorithm for the purpose of a standardized and unbiased evaluation. Displacement was calculated between tracts generated before and after distortion correction. The tracts were grouped based on their principal morphological orientations to investigate whether the effects of EPI distortion vary with tract orientation. Group differences in tract distortion were investigated both globally, and regionally with respect to proximity to the resecting lesion in the operative hemisphere. Qualitatively, we observed notable improvement in the corrected diffusion images, over the typically affected brain regions near skull-base air sinuses, and correction of additional distortion unique to intraoperative open cranium images, particularly over the resection site. This improvement was supported quantitatively, as mutual information indices between the FA and T1-weighted images were significantly greater after the correction, compared to before the correction. Maximum tract displacement between the corrected and uncorrected data, was in the range of 7.5 to 10.0 mm, a magnitude that would challenge the safety resection margin typically tolerated for tractography-informed surgical guidance. This was particularly relevant for tracts oriented partially or fully in-line with the acquired diffusion phase-encoded direction. Portions of these tracts passing close to the resection site demonstrated significantly greater magnitude of displacement, compared to portions of tracts remote from the resection site in the operative hemisphere. Our findings have direct clinical implication on the accuracy of intraoperative tractography-informed image guidance and emphasize the need to develop a distortion correction technique with feasible intraoperative processing time.

Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.

Intraoperative magnetic resonance imaging in epilepsy surgery: A systematic review and meta-analysis.

This systematic review investigated the added value of intraoperative magnetic resonance imaging (iMRI)-guidance in epilepsy surgery, compared to conventional non-iMRI surgery, with respect to the rate of gross total resection (GTR), postoperative seizure freedom, neurological deficits, non-neurological complications and reoperations. A comprehensive literature search was conducted using Medline, Embase, PubMed, and Cochrane Reviews databases. Randomized control trials, case control or cohort studies, and surgical case series published from January 1993 to February 2021 that reported on iMRI-guided epilepsy surgery outcomes for either adults or children were eligible for inclusion. Studies comparing iMRI-guided epilepsy surgery to non-iMRI surgery controls were selected for meta-analysis using random-effects models. Forty-two studies matched the selection criteria and were used for qualitative synthesis and ten of these were suitable for meta-analysis. Overall, studies included various 0.2-3.0 Tesla iMRI systems, contained small numbers with heterogenous clinical characteristics, utilized subjective GTR reporting, and had variable follow-up durations. Meta-analysis demonstrated that the use of iMRI-guidance led to statistically significant higher rates of GTR (RR = 1.31 [95% CI = 1.10-1.57]) and seizure freedom (RR = 1.44 [95% CI = 1.12-1.84]), but this was undermined by moderate to significant statistical heterogeneity between studies (I2 = 55% and I2 = 71% respectively). Currently, there is only level III-2 evidence supporting the use of iMRI-guidance over conventional non-iMRI epilepsy surgery, with respect to the studied outcomes.

Automated Perfusion-Diffusion Magnetic Resonance Imaging in Childhood Arterial Ischemic Stroke.

Background and Purpose: Recent studies using automated perfusion imaging software have identified adults most likely to benefit from reperfusion therapies in extended time windows. The time course of penumbral tissue is poorly characterized in childhood arterial ischemic stroke (AIS). We explore the feasibility of using automated perfusion-diffusion imaging software to characterize penumbra in childhood AIS. Methods: An observational cohort study of children with acute unilateral AIS presenting to our institution. Diffusion-weighted imaging and dynamic susceptibility contrast perfusion magnetic resonance imaging performed within 72 hours of symptom onset were necessary for inclusion. Perfusion-diffusion mismatch was estimated using RAPID software. Ischemic core was defined as apparent diffusion coefficient <620×10−6 mm2/s and hypoperfusion as Tmax >6 seconds. Favorable mismatch profile was defined as core volume <70 mL, mismatch volume ≥15 mL, and a mismatch ratio ≥1.8. Results: Twenty-nine children (median 8 years old, interquartile range, 4.4­14.6) were included (26 unilateral middle cerebral artery and 3 unilateral cerebellar infarcts). Median Pediatric National Institutes of Health Stroke Scale was 4 (interquartile range, 3­11). Most cases had cryptogenic (n=11) or focal cerebral arteriopathy (n=9) causes. Median time-to-imaging =13.7 hours (interquartile range, 7.5­25.3). RAPID detected an ischemic core in 19 (66%) patients. In the remaining cases, the mean apparent diffusion coefficient values were mostly higher than the threshold as the majority of these presentations were delayed (median >21 hours) and infarct volumes were small (<3.5 mL). Overall, 3 children, imaged at 3.75, 11, and 23.5 hours had favorable mismatch profiles. Conclusions: This study demonstrates it is feasible to rapidly assess perfusion-diffusion mismatch in childhood AIS using automated software. Favorable mismatch profiles, using adult-based parameters, persisted beyond the standard 4.5 hours window for thrombolysis, suggesting potential therapeutic benefit of RAPID use. Further work is required to determine the utility of perfusion-based imaging to guide clinical decision making, whether adult thresholds require modification in childhood AIS, and to investigate the effect of time-delay and cause on mismatch characteristics.

Diffusion MRI tractography for neurosurgery: the basics, current state, technical reliability and challenges.

Diffusion magnetic resonance imaging (dMRI) tractography is currently the only imaging technique that allows for non-invasive delineation and visualisation of white matter (WM) tractsin vivo,prompting rapid advances in related fields of brain MRI research in recent years. One of its major clinical applications is for pre-surgical planning and intraoperative image guidance in neurosurgery, where knowledge about the location of WM tracts nearby the surgical target can be helpful to guide surgical resection and optimise post-surgical outcomes. Surgical injuries to these WM tracts can lead to permanent neurological and functional deficits, making the accuracy of tractography reconstructions paramount. The quality of dMRI tractography is influenced by many modifiable factors, ranging from MRI data acquisition through to the post-processing of tractography output, with the potential of error propagation based on decisions made at each and subsequent processing steps. Research over the last 25 years has significantly improved the anatomical accuracy of tractography. An updated review about tractography methodology in the context of neurosurgery is now timely given the thriving research activities in dMRI, to ensure more appropriate applications in the clinical neurosurgical realm. This article aims to review the dMRI physics, and tractography methodologies, highlighting recent advances to provide the key concepts of tractography-informed neurosurgery, with a focus on the general considerations, the current state of practice, technical challenges, potential advances, and future demands to this field.

Clinical seizure manifestations in the absence of synaptic connections.

We report a child with a history of temporal-parietal-occipital disconnection for epilepsy secondary to posterior quadrantic dysplasia who developed recurrent and prolonged bouts of distress and autonomic disturbance associated with EEG and PET evidence of status epilepticus confined to his disconnected cortex. These bouts were refractory to antiseizure medications but resolved following resection of the disconnected cortex. In the absence of synaptic connections, we hypothesise that his seizure-related symptoms were mediated either by neurochemical transmission in preserved vascular and lymphatic channels or by ephaptic transmission to trigeminal nerve fibres in overlying dura, producing symptoms akin to migraine. The case highlights potential means by which seizures may manifest clinically, without synaptic connections, and adds to the differential for symptoms post-disconnection surgery.

Individual Differences in Intrinsic Brain Networks Predict Symptom Severity in Autism Spectrum Disorders.

The neurobiology of heterogeneous neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) is still unknown. We hypothesized that differences in subject-level properties of intrinsic brain networks were important features that could predict individual variation in ASD symptom severity. We matched cases and controls from a large multicohort ASD dataset (ABIDE-II) on age, sex, IQ, and image acquisition site. Subjects were matched at the individual level (rather than at group level) to improve homogeneity within matched case-control pairs (ASD: n = 100, mean age = 11.43 years, IQ = 110.58; controls: n = 100, mean age = 11.43 years, IQ = 110.70). Using task-free functional magnetic resonance imaging, we extracted intrinsic functional brain networks using projective non-negative matrix factorization. Intrapair differences in strength in subnetworks related to the salience network (SN) and the occipital-temporal face perception network were robustly associated with individual differences in social impairment severity (T = 2.206, P = 0.0301). Findings were further replicated and validated in an independent validation cohort of monozygotic twins (n = 12; 3 pairs concordant and 3 pairs discordant for ASD). Individual differences in the SN and face-perception network are centrally implicated in the neural mechanisms of social deficits related to ASD.

Investigating White Matter Tract Microstructural Changes at Six-Twelve Weeks following Mild Traumatic Brain Injury: A Combined Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging Study.

Using diffusion-weighted imaging (DWI), research has demonstrated changes suggestive of damage to white matter tracts (WMT) following mild traumatic brain injury (mTBI). Yet due to the predominant use of the diffusion tensor imaging (DTI) model, which has numerous well-established limitations, it has not yet been possible to clearly examine the nature of changes to WMT microstructure following mTBI. This study used a second DWI-based technique, neurite orientation dispersion and density imaging (NODDI), in combination with DTI to measure microstructural changes within the corpus callosum, three long association and one projection WMTs at 6-12 weeks following mTBI, compared with matched trauma controls (TC). Between-groups differences were identified across all WMT for the DTI metric fractional anisotropy (FA), and the NODDI metrics orientation dispersion index (ODI) and isotropic volume fraction (ISO). No statistically significant between-groups differences were found for other DTI and NODDI metrics. Our study revealed that reduced FA was accompanied by increased ODI, suggesting that mTBI results in reduced coherence of axonal fiber bundles within the studied WMTs. These between-groups differences in WMT microstructure were found at 6-12 weeks post-injury, which suggests that structural recovery is not yet complete towards end of the typical 3-month recovery period.

White matter extension of the Melbourne Children's Regional Infant Brain atlas: M-CRIB-WM.

Brain atlases providing standardised identification of neonatal brain regions are key in investigating neurological disorders of early childhood. Our previously developed Melbourne Children's Regional Infant Brain (M-CRIB) and M-CRIB 2.0 neonatal brain atlases provide standardised parcellation of 100 brain regions including cortical, subcortical, and cerebellar regions. The aim of this study was to extend M-CRIB atlas coverage to include 54 white matter (WM) regions. Participants were 10 healthy term-born neonates that were used to create the initial M-CRIB atlas. WM regions were manually segmented based on T2 images and co-registered diffusion tensor imaging-based, direction-encoded colour maps. Our labelled regions imitate the Johns Hopkins University neonatal atlas, with minor anatomical modifications. All segmentations were reviewed and approved by a paediatric radiologist and a neurosurgery research fellow for anatomical accuracy. The resulting neonatal WM atlas comprises 54 WM regions: 24 paired regions, and six unpaired regions comprising five corpus callosum subdivisions, and one pontine crossing tract. Detailed protocols for manual WM parcellations are provided, and the M-CRIB-WM atlas is presented together with the existing M-CRIB cortical, subcortical, and cerebellar parcellations in 10 individual neonatal MRI data sets. The novel M-CRIB-WM atlas, along with the M-CRIB cortical and subcortical atlases, provide neonatal whole brain MRI coverage in the first multi-subject manually parcellated neonatal atlas compatible with atlases commonly used at older time points. The M-CRIB-WM atlas is publicly available, providing a valuable tool that will help facilitate neuroimaging research into neonatal brain development in both healthy and diseased states.

Optic Radiation Tractography in Pediatric Brain Surgery Applications: A Reliability and Agreement Assessment of the Tractography Method.

BACKGROUND: Optic radiation (OR) tractography may help predict and reduce post-neurosurgical visual field deficits. OR tractography methods currently lack pediatric and surgical focus. PURPOSE: We propose a clinically feasible OR tractography strategy in a pediatric neurosurgery setting and examine its intra-rater and inter-rater reliability/agreements. METHODS: Preoperative and intraoperative MRI data were obtained from six epilepsy and two brain tumor patients on 3 Tesla MRI scanners. Four raters with different clinical experience followed the proposed strategy to perform probabilistic OR tractography with manually drawing anatomical landmarks to reconstruct the OR pathway, based on fiber orientation distributions estimated from high angular resolution diffusion imaging data. Intra- and inter-rater reliabilities/agreements of tractography results were assessed using intraclass correlation coefficient (ICC) and dice similarity coefficient (DSC) across various tractography and OR morphological metrics, including the lateral geniculate body positions, tract volumes, and Meyer's loop position from temporal anatomical landmarks. RESULTS: Good to excellent intra- and inter-rater reproducibility was demonstrated for the majority of OR reconstructions (ICC = 0.70-0.99; DSC = 0.84-0.89). ICC was higher for non-lesional (0.82-0.99) than lesional OR (0.70-0.99). The non-lesional OR's mean volume was 22.66 cm3; the mean Meyer's loop position was 29.4 mm from the temporal pole, 5.89 mm behind of and 10.26 mm in front of the temporal ventricular horn. The greatest variations (± 1.00-3.00 mm) were observed near pathology, at the tract edges or at cortical endpoints. The OR tractography were used to assist surgical planning and guide lesion resection in all cases, no patient had new visual field deficits postoperatively. CONCLUSION: The proposed tractography strategy generates reliable and reproducible OR tractography images that can be reliably implemented in the routine, non-emergency pediatric neurosurgical setting.

Short- and Long-Term Neurodevelopmental Outcomes of Very Preterm Infants with Neonatal Sepsis: A Systematic Review and Meta-Analysis.

Sepsis is commonly experienced by infants born very preterm (<32 weeks gestational age and/or <1500 g birthweight), but the long-term functional outcomes are unclear. The objective of this systematic review was to identify observational studies comparing neurodevelopmental outcomes in very preterm infants who had blood culture-proven neonatal sepsis with those without sepsis. Twenty-four studies were identified, of which 19 used prespecified definitions of neurodevelopmental impairment and five reported neurodevelopmental outcomes as continuous variables. Meta-analysis was conducted using 14 studies with defined neurodevelopmental impairment and demonstrated that very preterm infants with neonatal sepsis were at higher risk of impairments, such as cerebral palsy and neurosensory deficits, compared with infants without sepsis (OR 3.18; 95% CI 2.29-4.41). Substantial heterogeneity existed across the studies (I2 = 83.1, 95% CI 73-89). The five studies that reported outcomes as continuous variables showed no significant difference in cognitive performance between sepsis and non-sepsis groups. Neonatal sepsis in very preterm infants is associated with increased risk of neurodevelopmental disability. Due to the paucity of longitudinal follow-up data beyond 36 months, the long-term cognitive effect of neonatal sepsis in very preterm infants could not be conclusively determined. Effects on the development of minor impairment could not be assessed, due to the small numbers of infants included in the studies.

Caffeine for apnea of prematurity and brain development at 11 years of age.

OBJECTIVE: Caffeine therapy for apnea of prematurity has been reported to improve brain white matter microstructure at term-equivalent age, but its long-term effects are unknown. This study aimed to investigate whether caffeine affects (1) brain structure at 11 years of age, and (2) brain development from term-equivalent age to 11 years of age, compared with placebo. METHODS: Preterm infants born ≤1250 g were randomly allocated to caffeine or placebo. Magnetic resonance imaging (MRI) was performed on 70 participants (33 caffeine, 37 placebo) at term-equivalent age and 117 participants (63 caffeine, 54 placebo) at 11 years of age. Global and regional brain volumes and white matter microstructure were measured at both time points. RESULTS: In general, there was little evidence for differences between treatment groups in brain volumes or white matter microstructure at age 11 years. There was, however, evidence that the caffeine group had a smaller corpus callosum than the placebo group. Volumetric brain development from term-equivalent to 11 years of age was generally similar between treatment groups. However, there was evidence that caffeine was associated with slower growth of the corpus callosum, and slower decreases in axial, radial, and mean diffusivities in the white matter, particularly at the level of the centrum semiovale, over time than placebo. INTERPRETATION: This study suggests any benefits of neonatal caffeine therapy on brain structure in preterm infants weaken over time and are not clearly detectable by MRI at age 11 years, although caffeine may have long-term effects on corpus callosum development.

A systematic evaluation of intraoperative white matter tract shift in pediatric epilepsy surgery using high-field MRI and probabilistic high angular resolution diffusion imaging tractography.

OBJECTIVE Characterization of intraoperative white matter tract (WMT) shift has the potential to compensate for neuronavigation inaccuracies using preoperative brain imaging. This study aimed to quantify and characterize intraoperative WMT shift from the global hemispheric to the regional tract-based scale and to investigate the impact of intraoperative factors (IOFs). METHODS High angular resolution diffusion imaging (HARDI) diffusion-weighted data were acquired over 5 consecutive perioperative time points (MR1 to MR5) in 16 epilepsy patients (8 male; mean age 9.8 years, range 3.8-15.8 years) using diagnostic and intraoperative 3-T MRI scanners. MR1 was the preoperative planning scan. MR2 was the first intraoperative scan acquired with the patient's head fixed in the surgical position. MR3 was the second intraoperative scan acquired following craniotomy and durotomy, prior to lesion resection. MR4 was the last intraoperative scan acquired following lesion resection, prior to wound closure. MR5 was a postoperative scan acquired at the 3-month follow-up visit. Ten association WMT/WMT segments and 1 projection WMT were generated via a probabilistic tractography algorithm from each MRI scan. Image registration was performed through pairwise MRI alignments using the skull segmentation. The MR1 and MR2 pairing represented the first surgical stage. The MR2 and MR3 pairing represented the second surgical stage. The MR3 and MR4 (or MR5) pairing represented the third surgical stage. The WMT shift was quantified by measuring displacements between a pair of WMT centerlines. Linear mixed-effects regression analyses were carried out for 6 IOFs: head rotation, craniotomy size, durotomy size, resected lesion volume, presence of brain edema, and CSF loss via ventricular penetration. RESULTS The average WMT shift in the operative hemisphere was 2.37 mm (range 1.92-3.03 mm) during the first surgical stage, 2.19 mm (range 1.90-3.65 mm) during the second surgical stage, and 2.92 mm (range 2.19-4.32 mm) during the third surgical stage. Greater WMT shift occurred in the operative than the nonoperative hemisphere, in the WMTs adjacent to the surgical lesion rather than those remote to it, and in the superficial rather than the deep segment of the pyramidal tract. Durotomy size and resection size were significant, independent IOFs affecting WMT shift. The presence of brain edema was a marginally significant IOF. Craniotomy size, degree of head rotation, and ventricular penetration were not significant IOFs affecting WMT shift. CONCLUSIONS WMT shift occurs noticeably in tracts adjacent to the surgical lesions, and those motor tracts superficially placed in the operative hemisphere. Intraoperative probabilistic HARDI tractography following craniotomy, durotomy, and lesion resection may compensate for intraoperative WMT shift and improve neuronavigation accuracy.

Automated alignment of perioperative MRI scans: A technical note and application in pediatric epilepsy surgery.

Conventional image registration utilizing brain voxel information may be erroneous in a neurosurgical setting due to pathology and surgery-related anatomical distortions. We report a novel application of an automated image registration procedure based on skull segmentation for magnetic resonance imaging (MRI) scans acquired before, during and after surgery (i.e., perioperative). The procedure was implemented to assist analysis of intraoperative brain shift in 11 pediatric epilepsy surgery cases, each of whom had up to five consecutive perioperative MRI scans. The procedure consisted of the following steps: (1) Skull segmentation using tissue classification tools. (2) Estimation of rigid body transformation between image pairs using registration driven by the skull segmentation. (3) Composition of transformations to provide transformations between each scan and a common space. The procedure was validated using locations of three types of reference structural landmarks: the skull pin sites, the eye positions, and the scalp skin surface, detected using the peak intensity gradient. The mean target registration error (TRE) scores by skull pin sites and scalp skin rendering were around 1 mm and <1 mm, respectively. Validation by eye position demonstrated >1 mm TRE scores, suggesting it is not a reliable reference landmark in surgical scenarios. Comparable registration accuracy was achieved between opened and closed skull scan pairs and closed and closed skull scan pairs. Our procedure offers a reliable registration framework for processing intrasubject time series perioperative MRI data, with potential of improving intraoperative MRI-based image guidance in neurosurgical practice. Hum Brain Mapp 37:3530-3543, 2016. © 2016 Wiley Periodicals, Inc.