Effects of tumor location on cognitive performance of patients with brain tumor are controversial: some studies reported higher risks related to supratentorial locations, some to infratentorial locations, and still others did not find any differences. We aimed to address this issue by comparing school-aged children with supratentorial or infratentorial tumor with respect not only to cognitive outcomes but also to the associations between core cognitive domains and academic abilities.
32 children with infratentorial tumor and 22 with supratentorial tumor participated in the study. To detect relationships among cognitive domains, we tested which neuropsychological variable(s) predicted academic skills, controlling for the effects of radiotherapy and time since diagnosis.
Radiotherapy and time since diagnosis, but not tumor location, predicted cognitive outcomes. Radiotherapy negatively influenced attention and executive functioning, as well as reading speed and arithmetic operations accuracy. Unexpectedly, longer time since diagnosis was associated with improvement in attention and reading speed. Tumor location showed an effect on the relationships between core cognitive domains and academic skills: verbal and visual-spatial memory influenced reading and mathematical performance in supratentorial patients; in infratentorial patients, an only effect of visual-spatial memory on mathematical performance was detected.
Tumor location seems not to influence cognitive performance, while radiotherapy constitutes a key risk factor for cognitive impairment. Attentional and reading abilities may improve over time, possibly due to the weakening of cancer care effects. Different patterns of cognitive associations seem to characterize supratentorial and infratentorial patients, probably associated with different neuroplastic reorganization processes after tumor occurrence.
Neurocognitive impairments are well-known long-term sequelae of brain tumors (BTs) [1,2,3,4], affecting as many as 40 to 100% of surviving children . Attention, memory, executive functioning, processing speed, psychomotor skills, visual-spatial abilities, and global intellectual ability may be variably affected. Cognitive deficits may worsen over time and cause difficulties in acquiring new information and succeeding on academic tasks [5, 6].
Several risk factors, including illness severity grade and tissue invasion, postsurgical primary adjuvant therapies (i.e., radiotherapy and chemotherapy), and demographic characteristics (i.e., age at diagnosis, time since diagnosis and gender), have been associated with neurocognitive decline of pediatric patients with BTs [5, 7,8,9,10,11,12]. In particular, neurocognitive impairment has been documented as one of the most adverse and common effects of treatment toxicity, especially of radiotherapy [1, 13,14,15]. This is due to the disruption of dendritic connections and alterations of growth of myelin around nerve cells during development . Younger patients are exposed to higher risk, as early damage to the central nervous system (CNS) may deviate the normal maturation trajectory of the brain, compromising the acquisition of functional skills [13, 17].
Tumor location has been considered as an additional risk factor for neurocognitive decline, as damage to different parts of the brain may be associated with diverse types and levels of cognitive impairment. However, the impact of tumor location on neurocognitive functioning is still controversial, above all when considering the different effects of supratentorial and infratentorial tumors. Supratentorial and infratentorial tumors affect different neuroanatomical areas (supratentorial tumors are located in the cerebrum and diencephalon, while infratentorial tumors in the cerebellum, fourth ventricle and brain stem) , possibly altering neurocognitive abilities at a different extent. Thus far, reports from extant literature on this issue are discordant: some studies evidenced worse cognitive functioning for supratentorial tumors [19,20,21,22,23], some for infratentorial tumors [18, 24,25,26], and still others failed to detect any differences [27, 28]. Discordances on this issue may have several explanations, most importantly the focus of each study on different core cognitive abilities, the enrollment of patients of different age ranges, and the numerous clinical and demographic variables that may influence neurocognitive performance in this population .
In order to shed light on the still controversial role of tumor location on cognitive functioning, we investigated the presence of differences in cognitive performance in patients with a supratentorial or an infratentorial tumor, by considering a wide spectrum of cognitive domains. For this evaluation, we accounted for well-known risk factors for neurocognitive impairment, such as radiotherapy and time since diagnosis, as previous literature reported worse cognitive outcomes for children who received radiotherapy and a progressive cognitive deterioration over time [5, 13, 17]. We also investigated the associations between cognitive domains in the two tumor locations, testing which neuropsychological variable(s) predicted academic skills. This allowed investigating whether damage to different areas of the CNS influences the structuring of distinct cognitive networks by modifying the organization and development of different neuroanatomical regions.
Materials and method
Compliance with ethical standards
The research project methodology and all related materials were examined and approved by the Ethics Committee of Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco and were in agreement with the principles expressed in the 1964 Declaration of Helsinki. All parents of enrolled patients fulfilled a written informed consent, agreeing with data collection and analysis for research purposes.
Participant recruitment and inclusion and exclusion criteria
Participants of this study were children with a previous diagnosis of BT who referred to the Neuro-oncological and Neuropsychological Rehabilitation Unit of Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco. Patients received a complete neuropsychological assessment, including specific core cognitive abilities, intellectual functioning, and academic skills. Patients were involved in the study if they received neuropsychological assessment between December 2011 and December 2016. For patients who had more than one evaluation in the selected time frame, we considered the most recent evaluation for this study. For patients with tumor types requiring surgery, chemotherapy and/or radiotherapy, the follow-up cognitive evaluations were conducted at least 6 months after the end of postsurgical primary adjuvant therapies.
Patients were included in the study if: their age ranged from 6 years and 5 months to 17 years, as this is the age range covered by administered cognitive tests; Italian was their mother tongue; the cognitive evaluation was conducted at least 1 year after diagnosis; they had no active disease; they received no postsurgical primary adjuvant therapies in the 6 months before the cognitive evaluation. Patients were excluded from the study if they presented: premorbid neurocognitive disabilities or psychological difficulties (as reported in the clinical records by the attending physician); a diagnosis of primary or secondary epilepsy; severe hearing deficits, visual impairment, ataxia, or hemiparesis (as reported in the clinical records filled out by the neurologist). Furthermore, all patients should have not received any neuropsychological interventions in the 6 months before the cognitive evaluation.
Description of participants
Out of the 74 patients satisfying inclusion criteria, 54 underwent all the neuropsychological and academic evaluations considered for this study and were thus considered to be eligible for study inclusion. The remaining 20 patients did not complete all evaluations due to organizational issues, such as scheduling incompatibilities or technical issues with the test software. Among the enrolled patients, the tumor was located supratentorially in 22 patients and infratentorially in 32 patients.
All tests used to evaluate the cognitive outcomes are described in Table 1. For tests available only in Italian language, we reported psychometric properties.
Differences between groups were analyzed by independent sample t tests (two-tailed) for continuous variables and by χ2 for categorical variables. General linear models were used to evaluate the influence of tumor site on each neuropsychological and academic domain, considering radiotherapy and time since diagnosis as covariates, in the acknowledgement that these variables have a key role in determining neurocognitive performance of children with BT [1, 13,14,15,16,17]. To this aim, separate ANCOVA or MANCOVA models for each neuropsychological and academic domain were used, according to whether a given domain was evaluated with a single task or with multiple tasks, respectively. Moreover, independent-sample t tests (two-tailed) were used to evaluate the effects of specific tumor location (cortical vs. subcortical for supratentorial tumors and cerebellum vs. brainstem for infratentorial tumors).
In order to evaluate the associations between core neuropsychological domains and academic abilities, regression analyses were performed with the scores of all neuropsychological domains as independent variables and each academic ability as dependent variable. Even in this case, we controlled for the effects of radiotherapy dose and time since diagnosis. Chemotherapy was not included in these analyses since 92% of patients receiving radiotherapy also received chemotherapy. Regression analyses were conducted both in the whole sample and in each tumor location group, separately. In order to avoid collinearity among independent variables, simple correlations between neuropsychological variables were tested before performing regressions. Among those variables that were highly related with each other within each cognitive domain, we selected the variable with the highest correlation with the other variables pertaining to the same cognitive domain.
Demographic and clinical data
Patients underwent cognitive evaluations at a mean age of 11.03 years (SD = 2.54) and received the diagnosis of BT at a mean age of 6.77 years (SD = 3.93). Supratentorial and infratentorial patients did not differ in any demographic variables. In contrast, infratentorial patients were more likely to receive chemotherapy and radiotherapy as compared to supratentorial patients, while no difference was found for shunt placement. Demographic and clinical data are reported in Table 2. Complete data on tumor-related variables are reported in Supplementary File - A.
The role of tumor site: between-group comparison for neuropsychological and academic abilities
Performance on neuropsychological abilities and academic skills in the whole sample and in the supratentorial and infratentorial groups are depicted in Table 3.
The MANCOVA on executive functioning, with WCST-errors and WCST-perseverations as dependent variables, revealed a main effect of radiotherapy dose, F(2,49) = 5.28, p < 0.01, ηp2 = 0.18, but no effect of tumor site, F(2, 49 = 0.49, p = 0.61, ηp2 = 0.02, and time since diagnosis, F(2,49) = 0.11, p = 0.90, ηp2 = 0.00. A follow-up correlation analysis showed that radiotherapy dose was negatively correlated with both WCST-errors (r = − 0.42, p < 0.01) and WCST-perseverations (r = − 0.36, p < 0.01). Visual-spatial selective attention was influenced by radiotherapy dose, F(1,50) = 4.72, p = 0.03, ηp2 = 0.09, and by time since diagnosis, F(1,50) = 3.88, p = 0.05, ηp2 = 0.07, but not by tumor site, F(1,50) = 0.75, p = 0.39, ηp2 = 0.01. In particular, the correlation with radiotherapy dose was negative, r = − 0.34, p = 0.01, indicating that the higher the irradiation dose the worse the performance. In contrast, the correlation with time since diagnosis was positive, r = 0.33, p = 0.01, with better outcomes at longer time since diagnosis. No effects of tumor site, radiotherapy dose, or time since diagnosis were found for visual-spatial memory, verbal memory, and visual-motor integration, all Fs(1,50) < 2.16, p > 0.15, ηp2 < 0.04. For reading abilities, considering together accuracy, speed and comprehension as dependent variables, no effects of tumor site, F(3,48) = 1.05, p = 0.38, ηp2 = 0.06, or radiotherapy dose, F(3,48) = 1.643, p = 0.25, ηp2 = 0.08, were found. In contrast, reading abilities were significantly influenced by time since diagnosis, F(3,48) = 3.36, p = 0.03, ηp2 = 0.17: a significant positive correlation between time since diagnosis and reading speed was found, r = 0.27, p < 0.05. For arithmetic abilities, considering accuracy and speed together as dependent variables, no influences of tumor site, radiotherapy and time since diagnosis were found, all Fs(2,49) < 2.70, p < 0.08, ηp2 < 0.10.
T tests performed to evaluate the effects of a cortical vs. subcortical tumor location in patients with supratentorial tumor did not reveal any differences in neurocognitive abilities (all t(20) < |1.8|, p > 0.09) and academic abilities (all t(20) < |1.6|, p > 0.1). Also, t tests performed to evaluate the effects of a cerebellar vs. braistem tumor location in patients with infratentorial tumor did not reveal any differences in neurocognitive abilities (all t(30) < |1.7|, p > 0.1) and academic abilities (all t(30) < |1|, p > 0.3).
Control on collinearity of neurocognitive variables
Considering the correlation between WCST-perseverations and WCST-errors (r = 0.88, p < 0.01), the WCST-errors was selected as the preferred measure for the executive functioning domain. For verbal memory, we found a significant correlation between the immediate and delayed verbal recall tasks, r = 0.78, p < 0.01; thus, the more informative immediate verbal recall task was selected. Both the memory and the copy tasks of the Rey-Osterrieth Complex Figure Test were administered to patients and correlation between these two tasks was high, r = 0.63, p < 0.01. Thus, the Copy task was used as an estimate of visual-motor integration, while the memory task was excluded from further analyses. To evaluate the visual-spatial memory domain, we used the visual-spatial memory task of the BVN, which was considered to be a purer measure of visual-spatial memory compared to the Memory task of the Rey-Osterrieth Complex Figure Test.
The influence of specific neuropsychological abilities on academic skills: regression analyses in the whole sample and in each tumor site group
Regression analyses performed to predict academic abilities are presented in Table 4.
In the whole group, radiotherapy and executive functions predicted reading and mathematical speed. Mathematical speed was also predicted by visual-spatial memory. Moreover, verbal memory predicted reading comprehension. In patients with supratentorial tumor, verbal memory positively correlated with reading comprehension, while visual-spatial memory positively correlated with reading speed. Executive functions were negatively associated with reading speed in patients with supratentorial tumor and with mathematical speed in patients with infratentorial tumor. Radiotherapy positively correlated with reading speed in patients with supratentorial tumor and with mathematical speed in patients with infratentorial tumor. In both groups of patients, visual-spatial memory was positively correlated with speed in performing mathematical operations.
Results of this work suggest that tumor location (supratentorial vs. infratentorial) does not affect cognitive outcomes, being in line with studies that failed to detect any differences in neuropsychological performance between patients with supratentorial and infratentorial tumors [27, 28]. Even when considering the specific location of the tumor, namely cortical/subcortical for supratentorial tumors and brainstem/cerebellum for infratentorial tumors, no differences were found in both neuropsychological abilities and academic functioning. This suggests that neurocognitive dysfunctions may be associated at higher extent with brain networks alterations rather than to damage to a specific brain site. However, the limited sample size of this study could have masked some possible effects of tumor location; thus, this hypothesis should be considered with caution. Conversely, differences based on tumor location were found in the associations between core neuropsychological abilities and academic performance, suggesting a distinct reorganization of brain networks after the illness and adjuvant therapies in patients with supratentorial or infratentorial tumor. Worse cognitive outcomes were found to be associated with radiotherapy: the more the dose of irradiation, the more the impairments in executive functions and visual-spatial attention. In contrast, longer time since diagnosis was associated with improvements in visual-spatial attention and reading abilities.
The effects of radiotherapy on executive functioning and visual-spatial attention are in keeping with previous evidence showing that irradiation is one of the most important risk factors for neurocognitive decline, even irrespective of tumor location [13,14,15,16]. In particular, the finding of the influence of radiotherapy on visual-spatial attention is in line with previous studies reporting visual-spatial competence and attention among the abilities most vulnerable to irradiation [13, 14]. The effects of radiotherapy on attention and executive functioning could be explained by the disruption of the cerebro-cerebellar circuits, which can be altered by the treatment of both supratentorial and infratentorial tumors. Although our sample size did not allow testing the effects of radiotherapy within each tumor site group, it is worth noting that about 71% of patients receiving radiotherapy had an infratentorial tumor (27 patients out of 38). Thus, it is unlikely that the influence of radiotherapy on attention and executive functioning was only due to the effects of this treatment on prefrontal areas. In contrast, in accordance with recent research , it is more likely that also damage to cerebellar regions or networks linking prefrontal cortex and cerebellar areas caused such an impairment. The influence of radiotherapy on neurocognitive performance was also confirmed by multiple regression analyses on academic skills, as radiotherapy dose was found to impact on speed in reading texts and performing mathematical tasks. This indicates that such a treatment negatively affects the ability to manipulate complex information in a timely manner, in accordance with previous research .
It is worth noting that our results also pointed to an effect of time since diagnosis on cognitive outcomes, with more attenuated deficits in visual-spatial attention and reading speed longer after diagnosis. In our sample, time since diagnosis was negatively correlated with age at diagnosis (r = − 0.76, p < 0.01), with later evaluated children who were earlier diagnosed. Early age at diagnosis and longer time since diagnosis have often been reported to be associated with worse cognitive performance [13, 14]; thus, expectations based on previous literature would lead to presuppose opposite results. To interpret our data, we may suggest that, considering the parallel hindering effects of radiotherapy on neuropsychological outcomes, the improvement of performance at longer time since diagnosis may reflect the weakening of the acute effects of cancer care programs and associated conditions (i.e., hospitalization, absence from school, isolation from peers, etc.). As long after treatment episodes of fatigue associated with the side-effects of radiotherapy, chemotherapy and medications may decrease, it could be that children exhibit less impaired attentional abilities. The reduced side effects of radiotherapy on attention may be in turn beneficial for reading speed, for either better verbal learning or more attentional resources available to perform the task. Therefore, our study supports findings of a previous study reporting better cognitive functioning at longer time since diagnosis .
The pattern of associations between core neuropsychological variables and academic abilities found by regression analyses revealed that, independently from the influence of radiotherapy and time since diagnosis, math speed was influenced by visual-spatial working memory and reading comprehension by verbal memory. These results are in line with those reported for children with typical development for both the mathematical and verbal domains [43,44,45], suggesting that patients with BT are supported in their higher-level cognitive functioning by the same abilities of children with typical development. However, when exploring the associations between core neurocognitive abilities and academic skills within each tumor site group, we found some discrepancies with respect to the pattern of associations observed in the whole sample. Indeed, in supratentorial patients not only did visual-spatial-working memory predict arithmetic speed, as in the whole sample, but it also predicted reading speed. This indicates a key role of visual-spatial working memory for academic achievement in this group of patients, for both the mathematical and verbal domains. Moreover, considering that the association between verbal memory and reading comprehension was maintained in this group, the findings point to a complementary role of visual-spatial and verbal memory for text reading. This leads to suggest that in supratentorial patients the alterations of specific core cognitive domains may impact at a different extent on the various components of academic abilities. In contrast, in infratentorial patients a unique and selective effect of visual-spatial memory on arithmetic speed was observed, while no core neuropsychological ability significantly predicted reading skills. This probably because a tumor under the tentorium may generate a more general cognitive impairment compared to a supratentorial tumor, thus preventing to detect more specific associations between core neuropsychological abilities and higher-order cognitive skills. The fact that visual-spatial working memory predicted mathematical skills in children with both supratentorial and infratentorial tumors could be due to the contiguity of parietal brain regions that underlie spatial representations for distance and magnitude with those regions that underlie the learning of mathematics [44, 45]. A damage to these regions may still derive from a tumor directly located in the brain cortex or from a tumor located in the posterior fossa, in the latter case especially due to the extended effects of tumor compression or craniospinal radiotherapy on near anatomical regions. In contrast, verbal memory is supported by more anterior regions, in particular the temporo-frontal areas, thus being more likely to be damaged by a supratentorial tumor [46, 47].
Importantly, we found that better executive functioning was associated with reduced speed processing both on reading and mathematical tasks. Although this finding may seem in contrast with the positive role of executive functions on academic achievements, we should consider the peculiar functioning of children and adolescents with BT, who are usually aware of their cognitive difficulties and, thus, may tend to use their cognitive resources in controlling task execution to limit errors. This process, which is strongly related to executive functions, may reduce speed in performing school-related activities, which could explain our results.
Overall, our findings suggest that, also in front of similar cognitive outcome levels, patients with infratentorial and supratentorial tumors may differ in the contribution of core neurocognitive abilities to academic skills, probably due to the development of different neurofunctional organization of cortical and subcortical networks after the ilness and related treatments. Such connectivity differences may affect higher-order tasks, which require the interventions of multiple core cognitive abilities to be performed. This is in line with the hypothesis that characteristics of connectivity in a developing brain may largely influence cognitive development [48, 49], while damage to specific areas per se seems to have only a limited impact on the neuropsychological outcomes of pediatric brain tumors or of other acquired brain disorders occorring in developmental age [48, 50]. At a prognostic level, our data suggest that both the infratentorial and supratentorial patients should be considered at risk for math difficulties in case of deficits in visual-spatial memory abilities. As a consequence, the delivery of rehabilitation interventions aimed at remediating visual-spatial working memory should be considered essential for both patient groups to prevent academic difficulties. Patients with supratentorial tumor may also benefit from rehabilitation interventions on verbal memory due to the contribution of this ability on reading skills. Finally, as speed in performing academic tasks was significantly hindered by radiotherapy, patients who received irradiation should be presented with exercises aimed at improving the rapidity in responding to cognitive tasks, with the aim to limit negative cascade effects on learning.
Study limitations should be acknowledged. First, in this work we could not consider the processing speed parameter with respect to specific cognitive tasks, due to reasons associated with test administering (see the Methods section). Processing speed could be analyzed only for academic abilities, leading us to hypothesize that no difference in this parameter existed between supratentorial and infratentorial patients. However, we cannot rule out that tumor location may affect general processing speed and its relation with academic abilities, thus limiting our conclusions. Second, internal validity of research on pediatric BTs may be affected by biases from history and selection , which may prevent the generalizability of the results to the entire clinical population. Future studies could benefit from our preliminary findings, by narrowing the tested hypotheses, and should limit methodological issues, by using larger sample sizes and stricter control criteria. Finally, data analyzed in this study were collected after adjuvant therapies, as for the most patients no evaluation at the time of diagnosis was available, and this could constitute a limitation for the evaluation of the effects of the tumor itself. We sought to control this aspect through statistics, as the regression analyses allowed us to disentangle the role of tumor location from the effects of radiotherapy and time since diagnosis and no effect of this variable was still detected. Nevertheless, research and clinical practice would benefit from collecting data on neurocognitive functioning also at the time of diagnosis in order to detect the specific effects of the tumor itself independently from the effects of adjuvant therapies.
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This work was supported by Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco Italy (Progetto di Ricerca 5x1000, #111) and by the Italian Ministry of Health (Ricerca Corrente 2019).
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The authors declare that they have no conflict of interest.
All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
In our Scientific Institute, at the moment of the clinical evaluation of children, parents are proposed to sign an informed consent to allow data treatment for research. Informed consent was obtained from all parents of individual participants included in the study.
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Corti, C., Urgesi, C., Massimino, M. et al. Effects of supratentorial and infratentorial tumor location on cognitive functioning of children with brain tumor. Childs Nerv Syst 36, 513–524 (2020). https://doi.org/10.1007/s00381-019-04434-3