Cognitive Sparing in Proton versus Photon Radiotherapy for Pediatric Brain Tumor Is Associated with White Matter Integrity: An Exploratory Study.

Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging >7 years post-radiotherapy. A healthy comparison group (n = 23) was also recruited. Participants completed age-appropriate measures of intellectual functioning, visual-motor integration, and motor coordination. Tractography was conducted using automated fiber quantification (AFQ). Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 12 tracts of interest. Overall, both white matter integrity (FA) and neuropsychological performance were lower in XRT patients while PRT patients were similar to healthy control participants with respect to both FA and cognitive functioning. These findings support improved long-term outcomes in PRT versus XRT. This exploratory study is the first to directly support for white matter integrity as a mechanism of cognitive sparing in PRT.

A Preliminary DTI Tractography Study of Developmental Neuroplasticity 5-15 Years After Early Childhood Traumatic Brain Injury.

Plasticity is often implicated as a reparative mechanism when addressing structural and functional brain development in young children following traumatic brain injury (TBI); however, conventional imaging methods may not capture the complexities of post-trauma development. The present study examined the cingulum bundles and perforant pathways using diffusion tensor imaging (DTI) in 21 children and adolescents (ages 10-18 years) 5-15 years after sustaining early childhood TBI in comparison with 19 demographically-matched typically-developing children. Verbal memory and executive functioning were also evaluated and analyzed in relation to DTI metrics. Beyond the expected direction of quantitative DTI metrics in the TBI group, we also found qualitative differences in the streamline density of both pathways generated from DTI tractography in over half of those with early TBI. These children exhibited hypertrophic cingulum bundles relative to the comparison group, and the number of tract streamlines negatively correlated with age at injury, particularly in the late-developing anterior regions of the cingulum; however, streamline density did not relate to executive functioning. Although streamline density of the perforant pathway was not related to age at injury, streamline density of the left perforant pathway was significantly and positively related to verbal memory scores in those with TBI, and a moderate effect size was found in the right hemisphere. DTI tractography may provide insight into developmental plasticity in children post-injury. While traditional DTI metrics demonstrate expected relations to cognitive performance in group-based analyses, altered growth is reflected in the white matter structures themselves in some children several years post-injury. Whether this plasticity is adaptive or maladaptive, and whether the alterations are structure-specific, warrants further investigation.

Developmental Alterations in Cortical Organization and Socialization in Adolescents Who Sustained a Traumatic Brain Injury in Early Childhood.

This study investigated patterns of cortical organization in adolescents who had sustained a traumatic brain injury (TBI) during early childhood to determine ways in which early head injury may alter typical brain development. Increased gyrification in other patient populations is associated with polymicrogyria and aberrant development, but this has not been investigated in TBI. Seventeen adolescents (mean age = 14.1 ± 2.4) who sustained a TBI between 1-8 years of age, and 17 demographically-matched typically developing children (TDC) underwent a high-resolution, T1-weighted 3-Tesla magnetic resonance imaging (MRI) at 6-15 years post-injury. Cortical white matter volume and organization was measured using FreeSurfer's Local Gyrification Index (LGI). Despite a lack of significant difference in white matter volume, participants with TBI demonstrated significantly increased LGI in several cortical regions that are among those latest to mature in normal development, including left parietal association areas, bilateral dorsolateral and medial frontal areas, and the right posterior temporal gyrus, relative to the TDC group. Additionally, there was no evidence of increased surface area in the regions that demonstrated increased LGI. Higher Vineland-II Socialization scores were associated with decreased LGI in right frontal and temporal regions. The present results suggest an altered pattern of expected development in cortical gyrification in the TBI group, with changes in late-developing frontal and parietal association areas. Such changes in brain structure may underlie cognitive and behavioral deficits associated with pediatric TBI. Alternatively, increased gyrification following TBI may represent a compensatory mechanism that allows for typical development of cortical surface area, despite reduced brain volume.

Acute pediatric traumatic brain injury severity predicts long-term verbal memory performance through suppression by white matter integrity on diffusion tensor imaging.

Mediation analysis was used to investigate the role of white matter integrity in the relationship between injury severity and verbal memory performance in participants with chronic pediatric traumatic brain injury (TBI). DTI tractography was used to measure fractional anisotropy (FA) within the corpus callosum, fornix, cingulum bundles, perforant pathways, and uncinate fasciculi. Injury severity was indexed using Glasgow Coma Scale (GCS) scores obtained at the time of the injury. Verbal memory was measured by performance on the long-delay free recall (LDFR) trial of the California Verbal Learning Test-Children's version. Participants were between the ages of 10-18 and included 21 children with TBI (injured before age 9) and 19 typically-developing children (TDC). Children with TBI showed lower FA across all pathways and poorer LDFR performance relative to TDC. Within the TBI group, mediation analysis revealed neither a significant total effect of GCS on LDFR nor significant direct effects of GCS on LDFR across pathways; however, the indirect effects of GCS on LDFR through FA of the corpus callosum, left perforant pathway, and left uncinate fasciculus were significant and opposite in sign to their respective direct effects. These results suggests that the predictive validity of GCS for LDFR is initially suppressed by the substantial variance accounted for by FA, which is uncorrelated with GCS, and the predictive validity of GCS increases only when FA is considered, and the opposing path is controlled. These findings illustrate the complex associations between acute injury severity, white matter pathways, and verbal memory several years following pediatric TBI.

A Preliminary High-Definition Fiber Tracking Study of the Executive Control Network in Blast-Induced Traumatic Brain Injury.

Blast-induced traumatic brain injury (bTBI) is common in veterans of the Iraq- and Afghanistan-era conflicts. However, the typical subtlety of neural alterations and absence of definitive biomarkers impede clinical detection on conventional imaging. This preliminary study examined the structure and functional correlates of executive control network (ECN) white matter in veterans to investigate the clinical utility of using high-definition fiber tracking (HDFT) to detect chronic bTBI. Demographically similar male veterans (N = 38) with and without bTBI (ages 24 to 50 years) completed standardized neuropsychological testing and magnetic resonance imaging. Quantitative HDFT metrics of subcortical-dorsolateral prefrontal cortex (DLPFC) tracts were derived. Moderate-to-large group effects were observed on HDFT metrics. Relative to comparisons, bTBI demonstrated elevated quantitative anisotropy (QA) and reduced right hemisphere volume of all examined tracts, and reduced fiber count and increased generalized fractional anisotropy in the right DLPFC-putamen tract and DLPFC-thalamus, respectively. The Group × Age interaction effect on DLPFC-caudate tract volume was large; age negatively related to volume in the bTBI group, but not comparison group. Groups performed similarly on the response inhibition measure. Performance (reaction time and commission errors) robustly correlated with HDFT tract metrics (QA and tract volume) in the comparison group, but not bTBI group. Results support anomalous density and integrity of ECN connectivity, particularly of the right DLPFC-putamen pathway, in bTBI. Results also support exacerbated aging in veterans with bTBI. Similar ECN function despite anomalous microstructure could reflect functional compensation in bTBI, although alternate interpretations are explored.

Neurological outcome scale for traumatic brain injury: III. Criterion-related validity and sensitivity to change in the NABIS hypothermia-II clinical trial.

The neurological outcome scale for traumatic brain injury (NOS-TBI) is a measure assessing neurological functioning in patients with TBI. We hypothesized that the NOS-TBI would exhibit adequate concurrent and predictive validity and demonstrate more sensitivity to change, compared with other well-established outcome measures. We analyzed data from the National Acute Brain Injury Study: Hypothermia-II clinical trial. Participants were 16-45 years of age with severe TBI assessed at 1, 3, 6, and 12 months postinjury. For analysis of criterion-related validity (concurrent and predictive), Spearman's rank-order correlations were calculated between the NOS-TBI and the glasgow outcome scale (GOS), GOS-extended (GOS-E), disability rating scale (DRS), and neurobehavioral rating scale-revised (NRS-R). Concurrent validity was demonstrated through significant correlations between the NOS-TBI and GOS, GOS-E, DRS, and NRS-R measured contemporaneously at 3, 6, and 12 months postinjury (all p<0.0013). For prediction analyses, the multiplicity-adjusted p value using the false discovery rate was <0.015. The 1-month NOS-TBI score was a significant predictor of outcome in the GOS, GOS-E, and DRS at 3 and 6 months postinjury (all p<0.015). The 3-month NOS-TBI significantly predicted GOS, GOS-E, DRS, and NRS-R outcomes at 6 and 12 months postinjury (all p<0.0015). Sensitivity to change was analyzed using Wilcoxon's signed rank-sum test of subsamples demonstrating no change in the GOS or GOS-E between 3 and 6 months. The NOS-TBI demonstrated higher sensitivity to change, compared with the GOS (p<0.038) and GOS-E (p<0.016). In summary, the NOS-TBI demonstrated adequate concurrent and predictive validity as well as sensitivity to change, compared with gold-standard outcome measures. The NOS-TBI may enhance prediction of outcome in clinical practice and measurement of outcome in TBI research.

Psychiatric disorders after pediatric traumatic brain injury: a prospective, longitudinal, controlled study.

The objective was to examine the effects of traumatic brain injury (TBI), as compared with orthopedic injury (OI), relative to the risk for psychiatric disorder. There has only been one previous prospective study of this nature. Participants were age 7-17 years at the time of hospitalization for either TBI (complicated mild-to-severe) or OI. The study used a prospective, longitudinal, controlled design, with standardized psychiatric assessments conducted at baseline (reflecting pre-injury functioning) and 3 months post-injury. Assessments of pre-injury psychiatric, adaptive functioning, family adversity, and family psychiatric history status were conducted. Severity of injury was assessed by standard clinical scales. The outcome measure was the presence of a psychiatric disorder not present before the injury ("novel"), during the first 3 months after TBI. Enrolled participants (N=141) included children with TBI (N=75) and with OI (N=66). The analyses focused on 118 children (84%) (TBI: N=65; OI: N=53) who returned for follow-up assessment at 3 months. Novel psychiatric disorder (NPD) occurred significantly more frequently in the TBI (32/65; 49%) than the OI (7/53; 13%) group. This difference was not accounted for by pre-injury lifetime psychiatric status; pre-injury adaptive functioning; pre-injury family adversity, family psychiatric history, socioeconomic status, injury severity, or age at injury. Furthermore, none of these variables significantly discriminated between children with TBI who developed, versus those who did not develop, NPD. These findings suggest that children with complicated mild-to-severe TBI are at significantly higher risk than OI-controls for the development of NPD in the first 3 months after injury.

Neuroimaging correlates of novel psychiatric disorders after pediatric traumatic brain injury.

OBJECTIVE: To study magnetic resonance imaging (MRI) correlates of novel (new-onset) psychiatric disorders (NPD) after traumatic brain injury (TBI) and orthopedic injury (OI). METHOD: Participants were 7 to 17 years of age at the time of hospitalization for either TBI or OI. The study used a prospective, longitudinal, controlled design with standardized psychiatric assessments conducted at baseline (reflecting pre-injury function) and 3 months post-injury. MRI assessments including diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), volumetric measures of gray and white matter regions, volumetric measures of lesions, and cortical thickness were conducted. Injury severity was assessed by standard clinical scales. The outcome measure was the presence of an NPD identified during the first 3 months after injury. RESULTS: There were 88 participants (TBI, 44; OI, 44). NPD occurred more frequently in the TBI (21/44; 48%) versus the OI (6/44; 14%) group (Fisher's exact test, p = .001). NPD in TBI participants was not related to injury severity. Multivariate analysis of covariance of the relationship between FA in hypothesized regions of interest (bilateral frontal and temporal lobes, bilateral centrum semiovale, bilateral uncinate fasciculi) and NPD and group (TBI versus OI) was significant, and both variables (NPD, p < .05; group, p < .001) were jointly significantly related to FA. NPD was not significantly related to volumetric measures of white or gray matter structures, volumetric measures of lesions, or cortical thickness measures. CONCLUSIONS: Lowered white matter integrity may be more important in the pathophysiology of NPD than indices of gray matter or white matter atrophic changes, macroscopic lesions, and injury severity.

Diffusion tensor imaging and volumetric analysis of the ventral striatum in adults with traumatic brain injury.

OBJECTIVES: The aim was to determine if there are changes in the integrity and volume of the ventral striatum following severe traumatic brain injury (TBI) and if these changes relate to executive functioning. METHODS: This study recruited 14 participants with severe TBI (mean age: 22 years) and 15 demographically-matched controls. All participants underwent magnetic resonance imaging with diffusion tensor imaging (DTI) and volumetric analysis at 6 months post-injury. Participants with TBI underwent neuropsychological testing and the relation between imaging data and cognitive performance was examined. RESULTS: Differences in DTI parameters (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) were found between participants with TBI and controls. Correlations between right and left ventral striatum ADC and the executive functioning factor of the Neurobehavioural Rating Scale-Revised (NRS-R) were found. Correlations between right ventral striatum FA and the Controlled Oral Word Association Test, Trails Making Test Part B (TMT-B) time and NRS-R executive functioning factor were also found. Volumetric analysis showed a difference only in left nucleus accumbens between TBI and control groups. CONCLUSIONS: The integrity of the ventral striatum is affected following severe TBI. Decreases in executive functioning are related to damage to the ventral striatum and its associated structures.

Diffusion tensor imaging of the perforant pathway zone and its relation to memory function in patients with severe traumatic brain injury.

Based on the importance of the perforant pathway (PP) for normal hippocampal function, the vulnerability of temporal structures, and significant memory impairment in patients with traumatic brain injury (TBI), we investigated in vivo changes in the PP zone, hippocampus, and temporal lobe white and gray matter using diffusion tensor imaging (DTI) and volumetric analysis, and any specific relations with memory performance (Verbal Selective Reminding Test, Rey-Osterrieth Complex Figure Test), in 14 patients with severe TBI. Compared to a demographically-similar control group, our patients had significantly decreased fractional anisotropy (FA) and higher apparent diffusion coefficient (ADC) for the PP zone bilaterally, and higher ADC bilaterally in the hippocampus. Volumetric analysis revealed significantly decreased volumes in both hippocampi and temporal gray matter bilaterally. Consistent long-term retrieval (CLTR) and delayed recall were significantly related to (1) right and left PP zone ADC, (2) left hippocampus ADC, and (3) left hippocampal volume. Nonverbal memory (immediate and delayed recall) was significantly associated with (1) right and left PP zone ADC, (2) left hippocampal volume, and (3) gray (immediate recall) and white (immediate recall, bilaterally; delayed recall, left) matter temporal volumes. Advanced neuroimaging analysis can detect in vivo changes in the PP zone and temporal structures in patients with severe TBI, with these changes being highly associated with memory impairment.

The temporal stem in traumatic brain injury: preliminary findings.

The temporal stem (TS) of the temporal lobe is a major white matter (WM) region containing several major pathways that connect the temporal lobe with the rest of the brain. Because of its location, it may be particularly vulnerable to shear-strain effects resulting from traumatic brain injury (TBI). A case vignette is presented in a patient with severe brain injury and focal TS pathology. Also, 12 severe TBI subjects unselected for TS pathology were compared to demographically matched, neurologically-intact controls using diffusion tensor imaging (DTI) to examine white matter tracts associated with the TS, including the inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), arcuate fasciculus (AF), cingulum bundle (CB) and the uncinate fasciculus (UF). For each tract, fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and compared between the two groups and also examined in relationship to memory performance in the TBI subjects. Significant FA and ADC differences were observed in all tracts in the TBI patients compared to controls, with several relationships with memory outcome noted in the IFOF, ILF and AF. Based on these preliminary findings, the potential role of TBI-induced WM disconnection involving the TS is discussed as well as the relationship of TS damage to neurobehavioral outcome. The need for future studies specifically examining the role of TS injury in TBI is emphasized.