Physical activity and neurodevelopment in children

This thesis aims to study the determinants and trajectories of cognitive development, as well as the role of physical activity on cognitive and brain development in children aged 4 to 14 years old. We used data from two Spanish cohorts (INMA and BREATHE) and one Dutch cohort (Generation R). Teachers reported Attention Deficit and Hyperactivity Disorder (ADHD) symptoms of the participants through questionnaires. Cognitive development, specifically of attention and working memory, was tested by using computerized-based tasks. Growth trajectories were constructed based on four repeated cognitive measurements during a 1-year period in 7- to 11-year-old children. Physical activity was reported by parents through questionnaires. Magnetic Resonance Imaging data was collected in Generation R when children were 6-to-10 years old. Age, gender and ADHD symptoms were identified as important determinants of cognitive development. The use of cognitive growth trajectories in epidemiological research was supported. Physical activity during childhood was positively associated with brain maturation and promoted cognitive development.Aquesta tesi pretén estudiar els determinants i les trajectòries del desenvolupament cognitiu, així com el paper de l’activitat física en el desenvolupament cognitiu i cerebral en nens entre 4 i 14 anys. Vam utilitzar dades de dues cohorts espanyoles (INMA i BREATHE) i una cohort holandesa (Generation R). Els mestres van avaluar els símptomes de Trastorn per Dèficit d’Atenció i Hiperactivitat (TDAH) dels participants a través de qüestionaris. El desenvolupament cognitiu, en concret d’atenció i memòria de treball, es va avaluar amb tasques computeritzades. Les trajectòries de creixement es van generar a partir de quatre mesures cognitives repetides durant un període d’un any en nens de 7 a 11 anys. L’activitat física va ser informada pels pares a través de qüestionaris. Es van recollir dades de ressonància magnètica a Generation R quan els nens tenien de 6 a 10 anys. L’edat, el sexe i els símptomes de TDAH es van identificar com a determinants importants del desenvolupament cognitiu. L’ús de les trajectòries de creixement cognitiu en recerca epidemiològica va ser recolzat. L’activitat física durant la infantesa es va associar positivament amb la maduració del cervell i va promoure el desenvolupament cognitiu

Physical activity and neurodevelopment in children

This thesis aims to study the determinants and trajectories of cognitive development, as well as the role of physical activity on cognitive and brain development in children aged 4 to 14 years old. We used data from two Spanish cohorts (INMA and BREATHE) and one Dutch cohort (Generation R). Teachers reported Attention Deficit and Hyperactivity Disorder (ADHD) symptoms of the participants through questionnaires. Cognitive development, specifically of attention and working memory, was tested by using computerized-based tasks. Growth trajectories were constructed based on four repeated cognitive measurements during a 1-year period in 7- to 11-year-old children. Physical activity was reported by parents through questionnaires. Magnetic Resonance Imaging data was collected in Generation R when children were 6-to-10 years old. Age, gender and ADHD symptoms were identified as important determinants of cognitive development. The use of cognitive growth trajectories in epidemiological research was supported. Physical activity during childhood was positively associated with brain maturation and promoted cognitive development.Aquesta tesi pretén estudiar els determinants i les trajectòries del desenvolupament cognitiu, així com el paper de l’activitat física en el desenvolupament cognitiu i cerebral en nens entre 4 i 14 anys. Vam utilitzar dades de dues cohorts espanyoles (INMA i BREATHE) i una cohort holandesa (Generation R). Els mestres van avaluar els símptomes de Trastorn per Dèficit d’Atenció i Hiperactivitat (TDAH) dels participants a través de qüestionaris. El desenvolupament cognitiu, en concret d’atenció i memòria de treball, es va avaluar amb tasques computeritzades. Les trajectòries de creixement es van generar a partir de quatre mesures cognitives repetides durant un període d’un any en nens de 7 a 11 anys. L’activitat física va ser informada pels pares a través de qüestionaris. Es van recollir dades de ressonància magnètica a Generation R quan els nens tenien de 6 a 10 anys. L’edat, el sexe i els símptomes de TDAH es van identificar com a determinants importants del desenvolupament cognitiu. L’ús de les trajectòries de creixement cognitiu en recerca epidemiològica va ser recolzat. L’activitat física durant la infantesa es va associar positivament amb la maduració del cervell i va promoure el desenvolupament cognitiu

Neurodevelopmental effects of low dose ionizing radiation exposure: A systematic review of the epidemiological evidence

Background: The neurodevelopmental effects of high doses of ionizing radiation (IR) in children are well established. To what extent such effects exist at low-to-moderate doses is unclear. Considering the increasing exposure of the general population to low-to-moderate levels of IR, predominantly from diagnostic procedures, the study of these effects has become a priority for radiation protection. Objectives: We conducted a systematic review of the current evidence for possible effects of low-to-moderate IR doses received during gestation, childhood and adolescence on different domains of neurodevelopment. Data sources: Searches were performed in PubMed, Scopus, EMBASE and Psychinfo on the 6th of June 2017 and repeated in December 2018. Study eligibility criteria: We included studies evaluating the association between low-to-moderate IR doses received during gestation, childhood and adolescence, and neurodevelopmental functions. Study appraisal and synthesis methods: Studies were evaluated using the Cochrane Collaboration's risk of bias tool adapted to environmental sciences. A qualitative synthesis was performed. Results: A total of 26 manuscripts were finally selected. Populations analyzed in these publications were exposed to the following sources of IR: atomic bomb (Hiroshima and Nagasaki), diagnostic/therapeutic radiation, and Chernobyl and nuclear weapon testing fallout. There was limited evidence for an association between low-to-moderate doses of IR and a decrease in general cognition and language abilities, that is, a causal interpretation is credible, but chance or confounding cannot not be ruled out with reasonable confidence. Evidence for a possible stronger effect when exposure occurred early in life, in particular, during the fetal period, was inadequate. Evidence for an association between IR and other specific domains, including attention, executive function, memory, processing speed, visual-spatial abilities, motor and socio-emotional development, was inadequate, due to the very limited number of studies found. Limitations, conclusions, and implications of key findings: Overall, depending on the domain, there was limited to inadequate evidence for an effect of low-to-moderate IR doses on neurodevelopment. Heterogeneity across studies in terms of outcome and exposure assessment hampered any quantitative synthesis and any stronger conclusion. Future research with adequate dosimetry and covering a range of specific neurodevelopmental outcomes would likely contribute to improve the body of evidence. Systematic review registration number: The systematic review protocol was registered in PROSPERO (registration number CRD42018091902)

Polygenic risk for ADHD and ASD and their relation with cognitive measures in school children

Background: Attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are child-onset neurodevelopmental disorders frequently accompanied by cognitive difficulties. In the current study, we aim to examine the genetic overlap between ADHD and ASD and cognitive measures of working memory (WM) and attention performance among schoolchildren using a polygenic risk approach. Methods: A total of 1667 children from a population-based cohort aged 7-11 years with data available on genetics and cognition were included in the analyses. Polygenic risk scores (PRS) were calculated for ADHD and ASD using results from the largest GWAS to date (N = 55 374 and N = 46 351, respectively). The cognitive outcomes included verbal and numerical WM and the standard error of hit reaction time (HRTSE) as a measure of attention performance. These outcomes were repeatedly assessed over 1-year period using computerized version of the Attention Network Test and n-back task. Associations were estimated using linear mixed-effects models. Results: Higher polygenic risk for ADHD was associated with lower WM performance at baseline time but not over time. These findings remained significant after adjusting by multiple testing and excluding individuals with an ADHD diagnosis but were limited to boys. PRS for ASD was only nominally associated with an increased improvement on verbal WM over time, although this association did not survive multiple testing correction. No associations were observed for HRTSE. Conclusions: Common genetic variants related to ADHD may contribute to worse WM performance among schoolchildren from the general population but not to the subsequent cognitive-developmental trajectory assessed over 1-year period.This work was supported by the European Research Council under the Grant Agreement number 268479 - the BREATHE project. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the ‘Centro de Excelencia Severo Ochoa 2019-2023’ Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. S.Alemany and N.Vilor-Tejedor are funded by Juan de la Cierva Programme (Ministry of Science, Innovation and Universities - Spanish State Research Agency, ref. IJCI-2017-34068, and ref. FJC-2018-038085-I)

Sleeping, TV, cognitively stimulating activities, physical activity, and attention-deficit hyperactivity disorder symptom incidence in children: a prospective study

Objective: To analyze associations between time spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity, all at 4 years, and (1) attention-deficit/hyperactivity disorder (ADHD) symptoms and (2) behavior problems, both assessed at 7 years, in ADHD-free children at baseline. Method: In total, 817 participants of the Infancia y Medio Ambiente birth cohort, without ADHD at baseline, were included. At the 4-year follow-up, parents reported the time that their children spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity. At the 7-year follow-up, parents completed the Conners' Parent Rating Scales and the Strengths and Difficulties Questionnaire, which measure ADHD symptoms and behavior problems, respectively. Negative binomial regression models were used to assess associations between the activities at 4 years and ADHD symptoms and behavior problems at 7 years. Results: Children (48% girls) spent a median (p25-p75) of 10 (10-11) hours per day sleeping, 1.5 (0.9-2) hours per day watching TV, 1.4 (0.9-1.9) hours per day engaging in cognitively stimulating activities, and 1.5 (0.4-2.3) hours per day engaging in physical activity. Longer sleep duration (>10 hours per day) was associated with a lower ADHD symptom score (adjusted incidence rate ratio = 0.97, 95% confidence interval, 0.95-1.00). Longer time spent in cognitively stimulating activities (>1 hours per day) was associated with lower scores of both ADHD symptoms (0.96, 0.94-0.98) and behavior problems (0.89, 0.83-0.97). Time spent watching TV and engaging in physical activity were not associated with either outcomes. Conclusion: A shorter sleep duration and less time spent in cognitively stimulating activities were associated with an increased risk of developing ADHD symptoms and behavior problems

Exposure to traffic-related air pollution and noise during pregnancy and childhood, and functional brain connectivity in preadolescents

Background: The amount of people affected by traffic-related air pollution and noise is continuously increasing, but limited research has been conducted on the association between these environmental exposures and functional brain connectivity in children. Objective: This exploratory study aimed to analyze the associations between the exposure to traffic-related air pollution and noise during pregnancy and childhood, and functional brain connectivity amongst a wide-swath of brain areas in preadolescents from 9 to 12 years of age. Methods: We used data of 2,197 children from the Generation R Study. Land use regression models were applied to estimate nitrogen oxides and particulate matter levels at participant's homes for several time periods: pregnancy, birth to 3 years, 3 to 6 years, and 6 years of age to the age at magnetic resonance imaging (MRI) assessment. Existing noise maps were used to estimate road traffic noise exposure at participant's homes for the same time periods. Resting-state functional MRI was obtained at 9-12 years of age. Pair-wise correlation coefficients of the blood-oxygen-level-dependent signals between 380 brain areas were calculated. Linear regressions were run and corrected for multiple testing. Results: Preadolescents exposed to higher levels of NO2, NOx, and PM2.5 absorbance, from birth to 3 years, and from 3 to 6 years of age showed higher correlation coefficients among several brain regions (e.g. from 0.16 to 0.19 higher correlation coefficient related to PM2.5 absorbance exposure, depending on the brain connection). Overall, most identified associations were between brain regions of the task positive and task negative networks, and were mainly inter-network (20 of 26). Slightly more than half of the connections were intra-hemispheric (14 of 26), predominantly in the right hemisphere. Road traffic noise was not associated with functional brain connectivity. Conclusions: This exploratory study found that exposure to traffic-related air pollution during the first years of life was related to higher functional brain connectivity predominantly in brain areas located in the task positive and task negative networks, in preadolescents from 9 to 12 years of age. These results could be an indicator of differential functional connectivity in children exposed to higher levels of air pollution.Air pollution exposure assessment was possible by funding from the European Community’s Seventh Framework Program (GA#211250, GA#243406). In addition, the study was made possible by financial support from the Netherlands Organization for Health Research and Development (ZonMW Geestkracht Program 10.000.1003 & ZonMw TOP 40–00812-98–11021). The neuroimaging and neuroimaging infrastructure was funded via TOP project number 91,211,021 to Tonya White and and Sophia Foundation S18-20 awarded to Ryan Muetzel. Supercomputing computations for imaging processing were supported by the NWO Physical Sciences Division (Exacte Wetenschappen) and SURFsara (Cartesius compute cluster, https://www.surfsara.nl). Mònica Guxens received funding from the Spanish Institute of Health Carlos III (CPII18/00018, PI17/01340). Henning Tiemeier received funding from the Netherlands Organization for Health Research and Development (NWO-grant 016.VICI.170.200). Maria Foraster is a beneficiary of an AXA Research Fund grant. Mónica López-Vicente was funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 707404

Maternal circulating Vitamin D3 levels during pregnancy and behaviour across childhood

Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D3, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D3 was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D3, children obtained higher social competence scores (coefficient = 0.77; 95% CI = 0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D3 and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed.We thank all the investigators who have collected information and samples from the participants. Menorca: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263. Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CPII/00018), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundació La marató de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Valencia: This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663; Miguel Servet-FEDER CP11/00178, CP15/00025, and MSII16/00051), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), and Alicia Koplowitz Foundation 2017. Asturias: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), FIS-PI042018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI18/00909, CIBERESP, Obra Social Cajastur/Fundación Liberbank and UNIVERSIDAD DE OVIEDO. Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090 and FIS-PI13/02187), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain)

Maternal circulating Vitamin D3 levels during pregnancy and behaviour across childhood

Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D3, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D3 was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D3, children obtained higher social competence scores (coefficient = 0.77; 95% CI = 0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D3 and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed.We thank all the investigators who have collected information and samples from the participants. Menorca: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263. Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CPII/00018), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundació La marató de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Valencia: This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663; Miguel Servet-FEDER CP11/00178, CP15/00025, and MSII16/00051), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), and Alicia Koplowitz Foundation 2017. Asturias: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), FIS-PI042018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI18/00909, CIBERESP, Obra Social Cajastur/Fundación Liberbank and UNIVERSIDAD DE OVIEDO. Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090 and FIS-PI13/02187), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain)

Association between early life exposure to air pollution and working memory and attention

Background: Although previous studies have reported negative associations between exposure to air pollution and cognition, studies of the effects of prenatal and postnatal exposures in early childhood have been limited. Objectives: We sought to assess the role exposure to fine particulate matter ([Formula: see text]) during different prenatal and postnatal windows may play in children's cognitive development at school age. Methods: Within the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) Project, we estimated residential [Formula: see text] exposures by land use regression for the prenatal period and first seven postnatal years of 2,221 children from Barcelona, Spain. The participants ([Formula: see text]) completed computerized tests assessing working memory, attentiveness, and conflict network during four visits in 2012–2013. We used linear mixed effects and distributed lag models to assess the period of exposure to [Formula: see text] in association with cognitive development. Results: Inverse associations were identified between [Formula: see text] exposure during the fifth and sixth postnatal years and working memory, with boys showing much higher vulnerability. Regarding attention functions, exposure to higher [Formula: see text] levels during the prenatal period and from the fourth postnatal year were associated with a reduction in conflict network performance, though we found no association with attentiveness. The overall estimated cumulative effect of a [Formula: see text] increase in [Formula: see text] resulted in a reduction in the working memory [Formula: see text] score of [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] points and an increase in the conflict attentional network of 11.31 (95% CI: 6.05, 16.57) milliseconds, indicating a poorer performance. Conclusions: Early life exposure to [Formula: see text] was associated with a reduction in fundamental cognitive abilities, including working memory and conflict attentional network. https://doi.org/10.1289/EHP3169.The research leading to these results has received funding from the European Research Council (ERC-Advanced Grant) under grant agreement number 268479—the BREATHE project. We are grateful to A. Dalmau-Bueno for his help in estimating exposure to air pollution. We thank all the families participating in the study and particularly to the schools. P.D. is funded by a Juan de la Cierva fellowship (JCI-2011-09937) awarded by the Spanish Ministry of Science and Innovation

Exposure to road traffic noise and cognitive development in schoolchildren in Barcelona, Spain: a population-based cohort study

Background: road traffic noise is a prevalent and known health hazard. However, little is known yet about its effect on children's cognition. We aimed to study the association between exposure to road traffic noise and the development of working memory and attention in primary school children, considering school-outdoor and school-indoor annual average noise levels and noise fluctuation characteristics, as well as home-outdoor noise exposure. Methods and findings: we followed up a population-based sample of 2,680 children aged 7 to 10 years from 38 schools in Barcelona (Catalonia, Spain) between January 2012 to March 2013. Children underwent computerised cognitive tests 4 times (n = 10,112), for working memory (2-back task, detectability), complex working memory (3-back task, detectability), and inattentiveness (Attention Network Task, hit reaction time standard error, in milliseconds). Road traffic noise was measured indoors and outdoors at schools, at the start of the school year, using standard protocols to obtain A-weighted equivalent sound pressure levels, i.e., annual average levels scaled to human hearing, for the daytime (daytime LAeq, in dB). We also derived fluctuation indicators out of the measurements (noise intermittency ratio, %; and number of noise events) and obtained individual estimated indoor noise levels (LAeq) correcting for classroom orientation and classroom change between years. Home-outdoor noise exposure at home (Lden, i.e., EU indicator for the 24-hour annual average levels) was estimated using Barcelona's noise map for year 2012, according to the European Noise Directive (2002). We used linear mixed models to evaluate the association between exposure to noise and cognitive development adjusting for age, sex, maternal education, socioeconomical vulnerability index at home, indoor or outdoor traffic-related air pollution (TRAP) for corresponding school models or outdoor nitrogen dioxide (NO2) for home models. Child and school were included as nested random effects. The median age (percentile 25, percentile 75) of children in visit 1 was 8.5 (7.8; 9.3) years, 49.9% were girls, and 50% of the schools were public. School-outdoor exposure to road traffic noise was associated with a slower development in working memory (2-back and 3-back) and greater inattentiveness over 1 year in children, both for the average noise level (e.g., ‒4.83 points [95% CI: ‒7.21, ‒2.45], p-value < 0.001, in 2-back detectability per 5 dB in street levels) and noise fluctuation (e.g., ‒4.38 [‒7.08, ‒1.67], p-value = 0.002, per 50 noise events at street level). Individual exposure to the road traffic average noise level in classrooms was only associated with inattentiveness (2.49 ms [0, 4.81], p-value = 0.050, per 5 dB), whereas indoor noise fluctuation was consistently associated with all outcomes. Home-outdoor noise exposure was not associated with the outcomes. Study limitations include a potential lack of generalizability (58% of mothers with university degree in our study versus 50% in the region) and the lack of past noise exposure assessment. Conclusions: we observed that exposure to road traffic noise at school, but not at home, was associated with slower development of working memory, complex working memory, and attention in schoolchildren over 1 year. Associations with noise fluctuation indicators were more evident than with average noise levels in classrooms.This research received funding from the following sources: European Research Council under the ERC Grant Agreement number 268479 (FP7 Ideas) – BREATHE project (JS) and the ERC Grant agreement number 785994 (H2020) - AirNB project (JS), https://erc.europa.eu/. Project "PI16/00118", funded by Instituto de Salud Carlos III and co-funded by European Union (European Regional Development Fund) "A way to make Europe" (JS), www.isciii.es. Agència de Gestió d’Ajuts Universitaris (Beatriu de Pinós fellowship, 2017 BP 00173, MF), https://agaur.gencat.cat/en/Beatriu-de-Pinos. MF is currently supported by an AXA Research Fund grant, https://www.axa-research.org/. We also acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S, https://www.ciencia.gob.es/site-web/en/Organismos-y-Centros/Centros-y-Unidades-de-Excelencia.html, and the Generalitat de Catalunya through the CERCA Program (https://cerca.cat/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript