Hydroxyurea maintains working memory function in pediatric sickle cell disease.

Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in neurocognitive deficits. Hydroxyurea is the standard treatment for SCD; however, whether hydroxyurea influences such effects is unclear. A key area of SCD-associated neurocognitive impairment is working memory, which is implicated in other cognitive and academic skills. The neural correlates of working memory can be tested using n-back tasks. We analyzed functional magnetic resonance imaging (fMRI) data of patients with SCD (20 hydroxyurea-treated patients and 11 controls, aged 7-18 years) while they performed n-back tasks. Blood-oxygenation level-dependent (BOLD) signals were assessed during working memory processing at 2 time points: before hydroxyurea treatment and ~1 year after treatment was initiated. Neurocognitive measures were also assessed at both time points. Our results suggested that working memory was stable in the treated group. We observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- >0-back contrast. Searchlight-pattern classification of the 2 time points of the 2-back tasks identified greater changes in the pattern and magnitude of BOLD signals, especially in the posterior regions of the brain, in the control group than in the treated group. In the control group at 1-year follow-up, 2-back BOLD signals increased across time points in several clusters (e.g., right inferior temporal lobe, right angular gyrus). We hypothesize that these changes resulted from increased cognitive effort during working memory processing in the absence of hydroxyurea. In the treated group, 0- to 2-back BOLD signals in the right angular gyrus and left cuneus increased continuously with increasing working memory load, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. These findings suggest that hydroxyurea treatment helps maintain working memory function in SCD.

Cerebellar Mutism Syndrome and Dentato-Thalamo-Cortical Tract Disruption in Diffusion Tractography Following Surgery for Medulloblastoma.

Background Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentato-thalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS-related symptoms has not been investigated. Purpose To investigate the association between severity of CMS-related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods This retrospective case-control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma. CMS was divided into types 1 (CMS1) and 2 (CMS2). Multivariable logistic regression was used to investigate the relationship between CMS likelihood and DTCT injury. Results Overall, 82 participants with medulloblastoma (mean age, 11.0 years ± 5.2 [SD]; 53 male) and 35 healthy controls (mean age, 18.0 years ± 3.06; 18 female) were included. In participants with medulloblastoma, DTCT was absent bilaterally (AB), absent on the right side (AR), absent on the left side (AL), or present bilaterally (PB), while it was PB in all healthy controls. Odds of having CMS were associated with higher degree of DTCT damage (AB, odds ratio = 272.7 [95% CI: 269.68, 275.75; P < .001]; AR, odds ratio = 14.40 [95% CI: 2.84, 101.48; P < .001]; and AL, odds ratio = 8.55 [95% CI: 1.15, 74.14; P < .001). Left (coefficient = -0.07, χ2 = 12.4, P < .001) and right (coefficient = -0.15, χ2 = 33.82, P < .001) DTCT volumes were negatively associated with the odds of CMS. More participants with medulloblastoma with AB showed CMS1; unilateral DTCT absence prevailed in CMS2. Lower DTCT volumes correlated with more severe ataxia. Unilateral DTCT injury caused ipsilateral dysmetria; AB caused symmetric dysmetria. PB indicated better neurologic outcome. Conclusion The severity of CMS-associated mutism, ataxia, and dysmetria was associated with DTCT damage severity. DTCT damage patterns differed between CMS1 and CMS2. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Dorigatti Soldatelli and Ertl-Wagner in this issue.

Secondary cerebro-cerebellar and intracerebellar dysfunction in cerebellar mutism syndrome.

BACKGROUND: Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebrocerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebrocerebellar dysfunction may be related to chronic, rather than transient, symptomatology. METHODS: We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma. Surgical lesions were mapped to the infratentorial anatomy, and connectivity with cerebral cortex was tested for statistical dependence on extent of cerebellar outflow pathway injury. RESULTS: CMS diagnosis was associated with an increase in connectivity between the right cerebellar and left cerebral hemisphere, maximally between cerebellum and ventromedial prefrontal cortex (VM-PFC). Connectivity dependence on cerebellar outflow was significant for some speech nodes but not for VM-PFC, suggesting altered input to the cerebellum. Connectivity between posterior regions of cerebellar cortex and ipsilateral dentate nuclei was abnormal in CMS participants, maximally within the right cerebellar hemisphere. CONCLUSIONS: The functional abnormalities we identified are notably upstream of where causal surgical injury is thought to occur, indicating a secondary phenomenon. The VM-PFC is involved in several functions that may be relevant to the symptomatology of CMS, including emotional control and motor learning. We hypothesize that these abnormalities may reflect maladaptive learning within the cerebellum consequent to disordered motor and limbic function by the periaqueductal grey and other critical midbrain targets.

Hydroxyurea maintains working memory function in pediatric sickle cell disease.

Pediatric patients with sickle cell disease (SCD) have decreased oxygen-carrying capacity in the blood and reduced or restricted cerebral blood flow resulting in neurocognitive deficits and cerebral infarcts. The standard treatment for children with SCD is hydroxyurea; however, the treatment-related neurocognitive effects are unclear. A key area of impairment in SCD is working memory, which is implicated in other cognitive and academic skills. N-back tasks are commonly used to investigate neural correlates of working memory. We analyzed functional magnetic resonance imaging (fMRI) of patients with SCD while they performed n-back tasks by assessing the blood-oxygenation level-dependent (BOLD) signals during working memory processing. Twenty hydroxyurea-treated and 11 control pediatric patients with SCD (7-18 years old) performed 0-, 1-, and 2-back tasks at 2 time points, once before hydroxyurea treatment (baseline) and ~1 year after treatment (follow-up). Neurocognitive measures (e.g., verbal comprehension, processing speed, full-scale intelligence quotient, etc.) were assessed at both time points. Although no significant changes in behavior performance of n-back tasks and neurocognitive measures were observed in the treated group, we observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- > 0-back contrast. Through searchlight-pattern classifications in the treated and control groups to identify changes in brain activation between time points during the 2-back task, we found more brain areas, especially the posterior region, with changes in the pattern and magnitude of BOLD signals in the control group compared to the treated group. In the control group, increases in 2-back BOLD signals were observed in the right crus I cerebellum, right inferior parietal lobe, right inferior temporal lobe, right angular gyrus, left cuneus and left middle frontal gyrus at 1-year follow-up. Moreover, BOLD signals elevated as the working memory load increased from 0- to 1-back but did not increase further from 1- to 2-back in the right inferior temporal lobe, right angular gyrus, and right superior frontal gyrus. These observations may result from increased cognitive effort during working memory processing with no hydroxyurea treatment. In contrast, we found fewer changes in the pattern and magnitude of BOLD signals across time points in the treated group. Furthermore, BOLD signals in the left crus I cerebellum, right angular gyrus, left cuneus and right superior frontal gyrus of the treated group increased continuously with increasing working memory load from 0- to 2-back, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. Collectively, these findings suggest that hydroxyurea treatment helped maintain working memory function in SCD.

Cerebellar mutism is linked to midbrain volatility and desynchronization from speech cortices.

Cerebellar mutism syndrome is a disorder of speech, movement and affect that can occur after tumour removal from the posterior fossa. Projections from the fastigial nuclei to the periaqueductal grey area were recently implicated in its pathogenesis, but the functional consequences of damaging these projections remain poorly understood. Here, we examine functional MRI data from patients treated for medulloblastoma to identify functional changes in key brain areas that comprise the motor system for speech, which occur along the timeline of acute speech impairment in cerebellar mutism syndrome. One hundred and twenty-four participants, all with medulloblastoma, contributed to the study: 45 with cerebellar mutism syndrome, 11 patients with severe postoperative deficits other than mutism, and 68 without either (asymptomatic). We first performed a data-driven parcellation to spatially define functional nodes relevant to the cohort that align with brain regions critical for the motor control of speech. We then estimated functional connectivity between these nodes during the initial postoperative imaging sessions to identify functional deficits associated with the acute phase of the disorder. We further analysed how functional connectivity changed over time within a subset of participants that had suitable imaging acquired over the course of recovery. Signal dispersion was also measured in the periaqueductal grey area and red nuclei to estimate activity in midbrain regions considered key targets of the cerebellum with suspected involvement in cerebellar mutism pathogenesis. We found evidence of periaqueductal grey dysfunction in the acute phase of the disorder, with abnormal volatility and desynchronization with neocortical language nodes. Functional connectivity with periaqueductal grey was restored in imaging sessions that occurred after speech recovery and was further shown to be increased with left dorsolateral prefrontal cortex. The amygdalae were also broadly hyperconnected with neocortical nodes in the acute phase. Stable connectivity differences between groups were broadly present throughout the cerebrum, and one of the most substantial differences-between Broca's area and the supplementary motor area-was found to be inversely related to cerebellar outflow pathway damage in the mutism group. These results reveal systemic changes in the speech motor system of patients with mutism, centred on limbic areas tasked with the control of phonation. These findings provide further support for the hypothesis that periaqueductal grey dysfunction (following cerebellar surgical injury) contributes to the transient postoperative non-verbal episode commonly observed in cerebellar mutism syndrome but highlights a potential role of intact cerebellocortical projections in chronic features of the disorder.

Genetic variants, neurocognitive outcomes, and functional neuroimaging in survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Genetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: Long-term ALL survivors (n = 212; mean = 14.3 [SD = 4.77] years; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging. Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based functional neuroimaging. Statistical tests were 2-sided. RESULTS: Survivors exhibited higher rates of impaired attention (20.8%), motor skills (42.2%), visuo-spatial memory (49.3%-58.3%), processing speed (20.1%), and executive function (24.3%-26.1%) relative to population norms (10%; P < .001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25, F(2,172) = 4.07, P = .019) and motor skills (monoamine oxidase A, F(2,125) = 5.25, P = .007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165) = 3.48, P = .033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135) = 3.8, P = .025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158) = 3.95, P = .021; MTHFD1rs1950902, F(2,154) = 5.55, P = .005) and glucocorticoid regulation (vitamin D receptor, F(2,158) = 3.29, P = .039; FKBP prolyl isomerase 5, F(2,154) = 5.6, P = .005). Additionally, MTHFD1rs2236225 and FKBP prolyl isomerase 5 were associated with altered brain function during attention and working memory (P < .05; family wise error corrected). CONCLUSIONS: Results extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.

Automatic detection and segmentation of postoperative cerebellar damage based on normalization.

Background: Surgical resection is the gold standard in the treatment of pediatric posterior fossa tumors. However, surgical damage is often unavoidable and its association with postoperative complications is not well understood. A reliable localization and measure of cerebellar damage is fundamental to study the relationship between the damaged cerebellar regions and postoperative neurological outcomes. Existing cerebellum normalization methods are likely to fail on postoperative scans, therefore current approaches to measure postoperative damage rely on manual labelling. In this work, we develop a robust algorithm to automatically detect and measure cerebellum damage in postoperative 3D T1 magnetic resonance imaging (MRI). Methods: In our approach, normal brain tissues are first segmented using a Bayesian algorithm customized for postoperative scans. Next, the cerebellum is isolated by nonlinear registration of a whole-brain template to the native space. The isolated cerebellum is then normalized into the spatially unbiased atlas (SUIT) space using anatomical information derived from the previous step. Finally, the damage is detected in the atlas space by comparing the normalized cerebellum and the SUIT template. Results: We evaluated our damage detection tool on postoperative scans of 153 patients with medulloblastoma based on inspection by human experts. We also designed a simulation to evaluate performance without human intervention and with an explicitly controlled and defined ground truth. Our results show that the approach performs adequately under various realistic conditions. Conclusions: We develop an accurate, robust, and fully automatic localization and measurement of cerebellar damage in the atlas space using postoperative MRI.

Fastigial nuclei surgical damage and focal midbrain disruption implicate PAG survival circuits in cerebellar mutism syndrome.

BACKGROUND: Pediatric postoperative cerebellar mutism syndrome (CMS) is a rare but well-known complication of medulloblastoma (Mb) resection with devastating effects on expressive language, mobility, cognition, and emotional regulation that diminishes quality of life for many Mb survivors. The specific anatomical and neuronal basis of CMS remains obscure. We address this issue by identifying patterns of surgical damage and secondary axonal degeneration in Mb survivors with CMS. METHODS: Children with Mb deemed high risk for CMS based on intraventricular location of the tumor had T1 images analyzed for location(s) of surgical damage using a specially developed algorithm. We used three complementary methods of spatial analysis to identify surgical damage linked to CMS diagnosis. Magnetization transfer ratio (MTR) images were analyzed for evidence of demyelination in anatomic regions downstream of the cerebellum, indicating neuronal dysfunction. RESULTS: Spatial analyses highlighted damage to the fastigial nuclei and their associated cerebellar cortices as the strongest predictors of CMS. CMS-related MTR decrease was greatest in the ventral periaqueductal gray (PAG) area and highly consistent in the left red nucleus. CONCLUSION: Our evidence points to disruption of output from the fastigial nuclei as a likely causal trigger for CMS. We propose that core CMS symptoms result from a disruption in the triggering of survival behaviors regulated by the PAG, including the gating of vocalization and volitional movement. The fastigial nuclei provide the densest output to the PAG from the cerebellum, thus sparing these structures may provide a greater likelihood of CMS prevention.

Assessment of Fat Fractions in the Tongue, Soft Palate, Pharyngeal Wall, and Parapharyngeal Fat Pad by the GOOSE and DIXON Methods.

OBJECTIVE: The 2-point DIXON method is widely used to assess fat fractions (FFs) in magnetic resonance images (MRIs) of the tongue, pharyngeal wall, and surrounding tissues in patients with obstructive sleep apnea (OSA). However, the method is semiquantitative and is susceptible to B0 field inhomogeneities and R2* confounding factors. Using the method, although several studies have shown that patients with OSA have increased fat deposition around the pharyngeal cavity, conflicting findings was also reported in 1 study. This discrepancy necessitates that we examine the FF estimation method used in the earlier studies and seek a more accurate method to measure FFs. MATERIALS AND METHODS: We examined the advantages of using the GOOSE (globally optimal surface estimation) method to replace the 2-point DIXON method for quantifying fat in the tongue and surrounding tissues on MRIs. We first used phantoms with known FFs (true FFs) to validate the GOOSE method and examine the errors in the DIXON method. Then, we compared the 2 methods in the tongue, soft palate, pharyngeal wall, and parapharyngeal fat pad of 63 healthy participants to further assess the errors caused by the DIXON method. Six participants were excluded from the comparison of the tongue FFs because of technical failures. Paired Student t tests were performed on FFs to detect significant differences between the 2 methods. All measures were obtained using 3 T Siemens MRI scanners. RESULTS: In the phantoms, the FFs measured by GOOSE agreed with the true FF, with only a 1.2% mean absolute error. However, the same measure by DIXON had a 10.5% mean absolute error. The FFs obtained by DIXON were significantly lower than those obtained by GOOSE (P < 0.0001) in the human participants. We found strong correlations between GOOSE and DIXON in the tongue (R2 = 0.90), soft palate (R2 = 0.66), and parapharyngeal fat pad (R2 = 0.88), but the correlation was weaker in the posterior pharyngeal walls (R2 = 0.32) in participants. CONCLUSIONS: The widely used 2-point DIXON underestimated FFs, relative to GOOSE, in phantom measurements and tissues studied in vivo. Thus, an advanced method, such as GOOSE, that uses multiecho complex data is preferred for estimating FF.

Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.

Sex-Based Differences in Functional Brain Activity During Working Memory in Survivors of Pediatric Acute Lymphoblastic Leukemia.

BACKGROUND: Long-term survivors of pediatric acute lymphoblastic leukemia are at elevated risk for neurocognitive deficits and corresponding brain dysfunction. This study examined sex-based differences in functional neuroimaging outcomes in acute lymphoblastic leukemia survivors treated with chemotherapy alone. METHODS: Functional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors (46% male; median [min-max] age = 14.2 years [8.3-26.5 years]; time since diagnosis = 7.7 years [5.1-12.5 years]) treated on the St. Jude Total XV treatment protocol. Participants performed the n-back working memory task in a 3 T scanner. Functional neuroimaging data were processed (realigned, slice time corrected, normalized, smoothed) and analyzed using statistical parametric mapping with contrasts for 1-back and 2-back conditions, which reflect varying degrees of working memory and task load. Group-level fMRI contrasts were stratified by sex and adjusted for age and methotrexate exposure. Statistical tests were 2-sided (P < .05 statistical significance threshold). RESULTS: Relative to males, female survivors exhibited less activation (ie, reduced blood oxygen dependent-level signals) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and bilateral superior frontal medial gyrus during increased working memory load (family-wise error-corrected P = .004 to .008, adjusting for age and methotrexate dose). Female survivors were slower to correctly respond to the 2-back condition than males (P < .05), though there were no differences in overall accuracy. Performance accuracy was negatively correlated with fMRI activity in female survivors (Pearson's r = -0.39 to -0.29, P = .001 to .02), but not in males. CONCLUSIONS: These results suggest the working memory network is more impaired in female survivors than male survivors, which may contribute to ongoing functional deficits.

CT-Based Modeling of the Dentition for Craniomaxillofacial Surgical Planning.

ABSTRACT: Historically, the accuracy of imaging teeth by computed tomography (CT) has been suboptimal and deemed inadequate for surgical planning of orthognathic procedures. However, recent advances in CT hardware and software have significantly improved the accuracy of imaging occlusal anatomy. This technical note describes a quantitative means of evaluating the accuracy of CT-based modeling of teeth. Three-dimensional models of the dentition were created from a CT scan obtained of a craniomaxillofacial skeleton. Multiple reconstruction algorithms and modeling parameters were applied. The dentition of the same skeleton was scanned using a handheld optical scanning device to serve as the "gold standard." Semi-automated registrations of CT and optically acquired models were performed and deviation analysis was conducted. On average, the deviation of the CT model with the optical scan measured 0.19 to 0.25 mm across the various reconstruction and modeling parameters, with a mean of 0.22 mm. Computed tomography underestimated contours at cusp tips, while overestimating contours in occlusal groves. The use of bone reconstruction algorithms and decreased model smoothing resulted in more accurate models, though greater surface noise. Future studies evaluating the clinical effectiveness of CT-based occlusal splints should take this finding into account.

Structural and Functional Brain Imaging in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia Treated With Chemotherapy: A Systematic Review.

Background: The effect of chemotherapy on brain development in long-term survivors of pediatric acute lymphoblastic leukemia (ALL) was systematically reviewed. Methods: A systematic search of Pubmed, Scopus, and PsycINFO databases was conducted to identify articles published between January 2000 and February 2020 that implemented magnetic resonance imaging to assess brain structure and function in pediatric ALL survivors (diagnosed younger than 21 years of age). The review included articles that were published on children diagnosed with ALL between 0 and 21 years of age and treated with chemotherapy-only protocols. Articles meeting the inclusion criteria described survivors on average of 5 years or more from diagnosis and were peer-reviewed articles and original studies. Results: The search yielded 1975 articles with 23 articles meeting inclusion criteria. The review revealed that survivors had statistically significant alterations in brain anatomy, most commonly a smaller hippocampus and impaired microstructural white matter integrity in frontal brain regions. Survivors also had impaired brain function including lower brain network efficiency and altered resting state connectivity. Survivors also displayed widespread reductions in brain activation (ie, frontal, temporal, parietal brain regions) during cognitive tasks. Conclusion: Although the neurotoxic effects of cancer treatment are reduced in the absence of cranial radiation, survivors treated on chemotherapy-only protocols still display long-term alterations in brain structure and function, which contribute to lifelong neurocognitive late effects.

Developmental patterns of CBF and BOLD responses to visual stimulus.

To investigate the developmental changes of cerebral blood flow (CBF) and hemodynamic responses to changing neural activity, we used the arterial spin label (ASL) technique to measure resting CBF and simultaneous CBF / blood-oxygen-level dependent (BOLD) signal changes during visual stimulation in 97 typically developing children and young adults (age 13.35 [6.02, 25.25] (median [min, max]) years old at the first time point). The longitudinal study protocol included three MRIs (2.7 ± 0.06 obtained), one year apart, for each participant. Mixed-effect linear and non-linear statistical models were used to analyze age effects on CBF and BOLD signals. Resting CBF decreased exponentially with age (p = 0.0001) throughout the brain, and developmental trajectories differed across brain lobes. The absolute CBF increase in visual cortex during stimulation was constant over the age range, but the fractional CBF change increased with age (p = 0.0001) and the fractional BOLD signal increased with age (p = 0.0001) correspondingly. These findings suggest that the apparent neural hemodynamic coupling in visual cortex does not change after age six years, but age-related BOLD signal changes continue through adolescence primarily due to the changes with age in resting CBF.

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.

Importance: Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). Objective: To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. Design, Setting, and Participants: This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. Exposure: ALL treatment using chemotherapy-only protocols. Main Outcomes and Measures: This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. ß values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Results: Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: ß = 55.54; SE = 25.55; P = .03; right cerebellum: ß = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: ß = 82.71; SE = 31.04; P = .009; right cerebellum: ß = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (ß = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (ß = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. Conclusions and Relevance: These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.

Cerebral microbleeds in adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation.

Cranial radiation therapy is associated with white matter-specific brain injury, cortical volume loss, mineralization, microangiopathy and neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia. In this retrospective cross-sectional analysis, neurocognitive testing and 3 T brain MRI's were obtained in 101 survivors treated with cranial radiation. Small focal intracerebral hemorrhages only visible on exquisitely sensitive MRI sequences were identified and localized using susceptibility weighted imaging. Modified Poisson regression was used to assess the effect of cranial radiation on cumulative number and location of microbleeds in each brain region, and multiple linear regression was used to evaluate microbleeds on neurocognitive outcomes, adjusting for age at diagnosis and sex. At least one microbleed was present in 85% of survivors, occurring more frequently in frontal lobes. Radiation dose of 24 Gy conveyed a 5-fold greater risk (95% CI 2.57-10.32) of having multiple microbleeds compared to a dose of 18 Gy. No significant difference was found in neurocognitive scores with either the absence or presence of microbleeds or their location. Greater prevalence of microbleeds in our study compared to prior reports is likely related to longer time since treatment, better sensitivity of SWI for detection of microbleeds and the use of a 3 T MRI platform.

Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex-stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long-term problems with learning may be related to residual posttreatment brain differences.

Cognitive Performance, Aerobic Fitness, Motor Proficiency, and Brain Function Among Children Newly Diagnosed With Craniopharyngioma.

OBJECTIVES: Craniopharyngioma survivors experience cognitive deficits that negatively impact quality of life. Aerobic fitness is associated with cognitive benefits in typically developing children and physical exercise promotes recovery following brain injury. Accordingly, we investigated cognitive and neural correlates of aerobic fitness in a sample of craniopharyngioma patients. METHODS: Patients treated for craniopharyngioma [N=104, 10.0±4.6 years, 48% male] participated in fitness, cognitive and fMRI (n=51) assessments following surgery but before proton radiation therapy. RESULTS: Patients demonstrated impaired aerobic fitness [peak oxygen uptake (PKVO2)=23.9±7.1, 41% impaired (i.e., 1.5 SD<normative mean)], motor proficiency [Bruininks-Oseretsky (BOT2)=38.6±9.0, 28% impaired], and executive functions (e.g., WISC-IV Working Memory Index (WMI)=96.0±15.3, 11% impaired). PKVO2 correlated with better executive functions (e.g., WISC-IV WMI r=.27, p=.02) and academic performance (WJ-III Calculation r=.24, p=.04). BOT2 correlated with better attention (e.g., CPT-II omissions r=.26, p=.04) and executive functions (e.g., WISC-IV WMI r=.32, p=.01). Areas of robust neural activation during an n-back task included superior parietal lobule, dorsolateral prefrontal cortex, and middle and superior frontal gyri (p<.05, corrected). Higher network activation was associated with better working memory task performance and better BOT2 (p<.001). CONCLUSIONS: Before adjuvant therapy, children with craniopharyngioma demonstrate significantly reduced aerobic fitness, motor proficiency, and working memory. Better aerobic fitness and motor proficiency are associated with better attention and executive functions, as well as greater activation of a well-established working memory network. These findings may help explain differential risk/resiliency with respect to acute cognitive changes that may portend cognitive late effects. (JINS, 2019, 25, 413-425).

Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated. METHODS: Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided. RESULTS: Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate. CONCLUSIONS: Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standard/high- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p = 0.037) and poor separation between sensorimotor, executive/attention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.