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There is ample evidence from basic research in neuroscience of the importance of local corticocortical networks. Millimetric resolution is achievable with current functional magnetic resonance imaging (fMRI) scanners and sequences, and consequently a number of "local" activity similarity measures have been defined to describe patterns of segregation and integration at this spatial scale. We have introduced the use of IsoDistant Average Correlation (IDAC), easily defined as the average fMRI temporal correlation of a given voxel with other voxels placed at increasingly separated isodistant intervals, to characterize the curve of local fMRI signal similarities. IDAC curves can be statistically compared using parametric multivariate statistics. Furthermore, by using red-green-blue color coding to display jointly IDAC values belonging to three different distance lags, IDAC curves can also be displayed as multidistance IDAC maps. We applied IDAC analysis to a sample of 41 subjects scanned under two different conditions, a resting state and an auditory-visual continuous stimulation. Multidistance IDAC mapping was able to discriminate between gross anatomofunctional cortical areas and, moreover, was sensitive to modulation between the two brain conditions in areas known to activate and deactivate during audiovisual tasks. Unlike previous fMRI local similarity measures already in use, our approach draws special attention to the continuous smooth pattern of local functional connectivity. ; This work was supported in part by the Carlos III Health Institute grant PI10/02206 and the I+D+I grant PSI2014-53524-P. We thank the Agency of University and Research Funding Management of the Catalonia Government for their participation in the context of Research Group SGR SGR2017-1198.

Introduction: Children are more vulnerable to the effects of environmental elements. A variety of air pollutants are among the identified factors causing neural damage at toxic concentrations. It is not obvious, however, to what extent the tolerated high levels of air pollutants are able to alter brain development. We have specifically investigated the neurotoxic effects of airborne copper exposure in school environments. Methods: Speed and consistency of motor response were assessed in 2836 children aged from 8 to 12 years. Anatomical MRI, diffusion tensor imaging, and functional MRI were used to directly test the brain repercussions in a subgroup of 263 children. Results: Higher copper exposure was associated with poorer motor performance and altered structure of the basal ganglia. Specifically, the architecture of the caudate nucleus region was less complete in terms of both tissue composition and neural track water diffusion. Functional MRI consistently showed a reciprocal connectivity reduction between the caudate nucleus and the frontal cortex. Conclusions: The results establish an association between environmental copper exposure in children and alterations of basal ganglia structure and function. © 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. ; This work was supported by the European Research Council under the ERC (grant number 268479) ?the BREATHE project. The Agency of University and Research Funding Management of the Catalonia Government participated in the context of Research Group SGR2014-1673. We acknowledge C. Persavento, J. Gonz?lez, L. Bouso, M. L?pez, and P. Figueras their contribution to the field work. We also acknowledge all the families and schools participating in the study. ; Peer reviewed

A relevant aspect in osteoarthritic pain is neural sensitization. This phenomenon involves augmented responsiveness to painful stimulation and may entail a clinically worse prognosis. We used functional magnetic resonance imaging (fMRI) to study pain sensitization in patients with knee osteoarthritis. Sixty patients were recruited and pain sensitization was clinically defined on the basis of regional spreading of pain (spreading sensitization) and increased pain response to repeated stimulation (temporal summation). Functional magnetic resonance imaging testing involved assessing brain responses to both pressure and heat stimulation. Thirty-three patients (55%) showed regional pain spreading (simple sensitization) and 19 patients (32%) showed both regional spreading and temporal summation. Sensitized patients were more commonly women. Direct painful pressure stimulation of the joint (articular interline) robustly activated all of the neural elements typically involved in pain perception, but did not differentiate sensitized and nonsensitized patients. Painful pressure stimulation on the anterior tibial surface (sensitized site) evoked greater activation in sensitized patients in regions typically involved in pain and also beyond these regions, extending to the auditory, visual, and ventral sensorimotor cortices. Painful heat stimulation of the volar forearm did not discriminate the sensitization phenomenon. Results confirm the high prevalence of pain sensitization secondary to knee osteoarthritis. Relevantly, the sensitization phenomenon was associated with neural changes extending beyond strict pain-processing regions with enhancement of activity in general sensory, nonnociceptive brain areas. This effect is in contrast to the changes previously identified in primary pain sensitization in fibromyalgia patients presenting with a weakening of the general sensory integration. ; This study was supported in part by the Ministry of Economy and Competitiveness of Spain (grant PSI2014- 53524-P) and the Merck Investigator Studies Program (grant MISP-IISP41059). We thank to the Agency of University and Research Funding Management of the Catalonia Government for their participation in the context of Research Group SGR2014-1673. BJH is supported by a National Health and Medical Research Council of Australia (NHMRC) Clinical Career Development Award (1124472).

Background Polycyclic aromatic hydrocarbons (PAHs) have been proposed as environmental risk factors for attention deficit hyperactivity disorder (ADHD). The effects of these pollutants on brain structures potentially involved in the pathophysiology of ADHD are unknown. Objective The aim of this study was to investigate the effects of PAHs on basal ganglia volumes and ADHD symptoms in school children. Methods We conducted an imaging study in 242 children aged 8–12 years, recruited through a set of representative schools of the city of Barcelona, Spain. Indoor and outdoor PAHs and benzo[a]pyrene (BPA) levels were assessed in the school environment, one year before the MRI assessment. Whole-brain volumes and basal ganglia volumes (caudate nucleus, globus pallidus, putamen) were derived from structural MRI scans using automated tissue segmentation. ADHD symptoms (ADHD/DSM-IV Scales, American Psychiatric Association 2002) were reported by teachers, and inattentiveness was evaluated with standard error of hit reaction time in the attention network computer-based test. Results Total PAHs and BPA were associated with caudate nucleus volume (CNV) (i.e., an interquartile range increase in BPA outdoor level (67 pg/m3) and indoor level (76 pg/m3) was significantly linked to a decrease in CNV (mm3) (β = − 150.6, 95% CI [− 259.1, − 42.1], p = 0.007, and β = − 122.4, 95% CI [− 232.9, − 11.8], p = 0.030 respectively) independently of intracranial volume, age, sex, maternal education and socioeconomic vulnerability index at home). ADHD symptoms and inattentiveness increased in children with higher exposure to BPA, but these associations were not statistically significant. Conclusions Exposure to PAHs, and in particular to BPA, is associated with subclinical changes on the caudate nucleus, even below the legislated annual target levels established in the European Union. The behavioral consequences of this induced brain change were not identified in this study, but given the caudate nucleus involvement in many crucial cognitive and behavior processes, this volume reduction is concerning for the children's neurodevelopment. © 2017 The Authors ; Marion Mortamais is supported by a Marie Sk?odowska-Curie Individual Fellowship (H2020-MSCA-IF-2014; EU project 656294). This work was supported by the European Research Council under the ERC [grant number 268479]?the BREATHE project. The Agency of University and Research Funding Management of the Catalonia Government participated in the context of Research Group SGR2014-1673. We also thank the Caixa Foundation for their financial support in the PAHs analyses. ; Peer reviewed

INTRODUCTION: Children are more vulnerable to the effects of environmental elements. A variety of air pollutants are among the identified factors causing neural damage at toxic concentrations. It is not obvious, however, to what extent the tolerated high levels of air pollutants are able to alter brain development. We have specifically investigated the neurotoxic effects of airborne copper exposure in school environments. METHODS: Speed and consistency of motor response were assessed in 2836 children aged from 8 to 12 years. Anatomical MRI, diffusion tensor imaging, and functional MRI were used to directly test the brain repercussions in a subgroup of 263 children. RESULTS: Higher copper exposure was associated with poorer motor performance and altered structure of the basal ganglia. Specifically, the architecture of the caudate nucleus region was less complete in terms of both tissue composition and neural track water diffusion. Functional MRI consistently showed a reciprocal connectivity reduction between the caudate nucleus and the frontal cortex./nCONCLUSIONS: The results establish an association between environmental copper exposure in children and alterations of basal ganglia structure and function. ; This work was supported by the European Research Council under the ERC (grant number 268479)—the BREATHE project. The Agency of University and Research Funding Management of the Catalonia Government participated in the context of Research Group SGR2014-1673.

Objective: Sluggish cognitive tempo (SCT) is a cluster of symptoms associated with poor function in various domains of major life activities that may comprise a novel attention disorder distinct from attention-deficit/hyperactivity disorder (ADHD). Nevertheless, very little is known about the neural substrate of SCT in children. The present study aimed to examine associations between SCT symptoms and brain structure and function in school-aged children. Method: We performed a cross-sectional MRI study in 178 children 8 to 12 years old from primary schools in Barcelona, Spain. Data were collected between January 2012 and March 2013. Parents completed the Sluggish Cognitive Tempo-Child Behavior Checklist (SCT-CBCL). Participants underwent magnetic resonance imaging to assess regional brain volume, white matter integrity using diffusion tensor imaging, and functional connectivity in major neural networks. Results: SCT symptoms were associated with altered anatomy of the frontal lobe in the form of increased regional volume. The anomalously large cortical regions were less mature in terms of functional connectivity. Importantly, all the anatomical and functional anomalies identified remained significant after adjusting the analyses for ADHD symptom scores. Conclusion: Our results suggest that SCT symptoms are associated with distinct features of brain structure and function that differ from the classical neural substrates described in ADHD. ; This work was supported by the European Research Council under the ERC (grant number 268479)—the BREATHE project. The Agency of University and Research Funding Management of the Catalonia Government part icipated in the context of Research Group SGR2014-167

Background: Polycyclic aromatic hydrocarbons (PAHs) have been proposed as environmental risk factors for attention deficit hyperactivity disorder (ADHD). The effects of these pollutants on brain structures potentially involved in the pathophysiology of ADHD are unknown. Objective: The aim of this study was to investigate the effects of PAHs on basal ganglia volumes and ADHD symptoms in school children. Methods: We conducted an imaging study in 242 children aged 8–12 years, recruited through a set of representative schools of the city of Barcelona, Spain. Indoor and outdoor PAHs and benzo[a]pyrene (BPA) levels were assessed in the school environment, one year before the MRI assessment. Whole-brain volumes and basal ganglia volumes (caudate nucleus, globus pallidus, putamen) were derived from structural MRI scans using automated tissue segmentation. ADHD symptoms (ADHD/DSM-IV Scales, American Psychiatric Association 2002) were reported by teachers, and inattentiveness was evaluated with standard error of hit reaction time in the attention network computer-based test. Results: Total PAHs and BPA were associated with caudate nucleus volume (CNV) (i.e., an interquartile range increase in BPA outdoor level (67 pg/m3) and indoor level (76 pg/m3) was significantly linked to a decrease in CNV (mm3) (β = −150.6, 95% CI [−259.1, −42.1], p = 0.007, and β = −122.4, 95% CI [−232.9, −11.8], p = 0.030 respectively) independently of intracranial volume, age, sex, maternal education and socioeconomic vulnerability index at home). ADHD symptoms and inattentiveness increased in children with higher exposure to BPA, but these associations were not statistically significant. Conclusions: Exposure to PAHs, and in particular to BPA, is associated with subclinical changes on the caudate nucleus, even below the legislated annual target levels established in the European Union. The behavioral consequences of this induced brain change were not identified in this study, but given the caudate nucleus involvement in many crucial cognitive and behavior processes, this volume reduction is concerning for the children's neurodevelopment.

Children are more vulnerable to the effects of environmental elements due to their active developmental processes. Exposure to urban air pollution has been associated with poorer cognitive performance, which is thought to be a result of direct interference with brain maturation. We aimed to assess the extent of such potential effects of urban pollution on child brain maturation using general indicators of vehicle exhaust measured in the school environment and a comprehensive imaging evaluation. A group of 263 children, aged 8 to 12years, underwent MRI to quantify regional brain volumes, tissue composition, myelination, cortical thickness, neural tract architecture, membrane metabolites, functional connectivity in major neural networks and activation/deactivation dynamics during a sensory task. A combined measurement of elemental carbon and NO2 was used as a putative marker of vehicle exhaust. Air pollution exposure was associated with brain changes of a functional nature, with no evident effect on brain anatomy, structure or membrane metabolites. Specifically, a higher content of pollutants was associated with lower functional integration and segregation in key brain networks relevant to both inner mental processes (the default mode network) and stimulus-driven mental operations. Age and performance (motor response speed) both showed the opposite effect to that of pollution, thus indicating that higher exposure is associated with slower brain maturation. In conclusion, urban air pollution appears to adversely affect brain maturation in a critical age with changes specifically concerning the functional domain. ; This work was supported by the European Research Council under the ERC [grant number 268479]—the BREATHE project. The Agency of University and Research Funding Management of the Catalonia Government participated in the context of Research Group SGR2014-1673.

Background: Polycyclic aromatic hydrocarbons (PAHs) have been proposed as environmental risk factors for attention deficit hyperactivity disorder (ADHD). The effects of these pollutants on brain structures potentially involved in the pathophysiology of ADHD are unknown. Objective: The aim of this study was to investigate the effects of PAHs on basal ganglia volumes and ADHD symptoms in school children. Methods: We conducted an imaging study in 242 children aged 8–12 years, recruited through a set of representative schools of the city of Barcelona, Spain. Indoor and outdoor PAHs and benzo[a]pyrene (BPA) levels were assessed in the school environment, one year before the MRI assessment. Whole-brain volumes and basal ganglia volumes (caudate nucleus, globus pallidus, putamen) were derived from structural MRI scans using automated tissue segmentation. ADHD symptoms (ADHD/DSM-IV Scales, American Psychiatric Association 2002) were reported by teachers, and inattentiveness was evaluated with standard error of hit reaction time in the attention network computer-based test. Results: Total PAHs and BPA were associated with caudate nucleus volume (CNV) (i.e., an interquartile range increase in BPA outdoor level (67 pg/m3) and indoor level (76 pg/m3) was significantly linked to a decrease in CNV (mm3) (β = − 150.6, 95% CI [− 259.1, − 42.1], p = 0.007, and β = − 122.4, 95% CI [− 232.9, − 11.8], p = 0.030 respectively) independently of intracranial volume, age, sex, maternal education and socioeconomic vulnerability index at home). ADHD symptoms and inattentiveness increased in children with higher exposure to BPA, but these associations were not statistically significant. Conclusions: Exposure to PAHs, and in particular to BPA, is associated with subclinical changes on the caudate nucleus, even below the legislated annual target levels established in the European Union. The behavioral consequences of this induced brain change were not identified in this study, but given the caudate nucleus involvement in many crucial cognitive and behavior processes, this volume reduction is concerning for the children's neurodevelopment. ; This work was supported by the European Research Council under the ERC [grant number 268479]—the BREATHE project. The Agency of University and Research Funding Management of the Catalonia Government participated in the context of Research Group SGR2014-1673. We also thank the Caixa Foundation for their financial support in the PAHs analyses.

Objective: Air pollution (AP) may affect neurodevelopment, but studies about the effects of AP on the growing human brain are still scarce. We aimed to investigate the effects of prenatal exposure to AP on lateral ventricles (LV) and corpus callosum (CC) volumes in children and to determine whether the induced brain changes are associated with behavioral problems. Methods: Among the children recruited through a set of representative schools of the city of Barcelona, (Spain) in the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) study, 186 typically developing participants aged 8–12 years underwent brain MRI on the same 1.5 T MR unit over a 1.5-year period (October 2012–April 2014). Brain volumes were derived from structural MRI scans using automated tissue segmentation. Behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ) and the criteria of the Attention Deficit Hyperactivity Disorder DSM-IV list. Prenatal fine particle (PM2.5) levels were retrospectively estimated at the mothers' residential addresses during pregnancy with land use regression (LUR) models. To determine whether brain structures might be affected by prenatal PM2.5 exposure, linear regression models were run and adjusted for age, sex, intracranial volume (ICV), maternal education, home socioeconomic vulnerability index, birthweight and mothers' smoking status during pregnancy. To test for associations between brain changes and behavioral outcomes, negative binomial regressions were performed and adjusted for age, sex, ICV. Results: Prenatal PM2.5 levels ranged from 11.8 to 39.5 μg/m3 during the third trimester of pregnancy. An interquartile range increase in PM2.5 level (7 μg/m3) was significantly linked to a decrease in the body CC volume (mm3) (β = −53.7, 95%CI [-92.0, −15.5] corresponding to a 5% decrease of the mean body CC volume) independently of ICV, age, sex, maternal education, socioeconomic vulnerability index at home, birthweight and mothers' smoking status during the third trimester of pregnancy. A 50 mm3 decrease in the body CC was associated with a significant higher hyperactivity subscore (Rate Ratio (RR) = 1.09, 95%CI [1.01, 1.17) independently of age, sex and ICV. The statistical significance of these results did not survive to False Discovery Rate correction for multiple comparisons. Conclusions: Prenatal exposure to PM2.5 may be associated with CC volume decrease in children. The consequences might be an increase in behavioral problems. ; Marion Mortamais is supported by a Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2014; EU project 656294). Natalia Vilor-Tejedor is funded by a pre-doctoral grant from the Agència de Gestió d'Ajuts Universitaris i de Recerca (2017 FI_B 00636). Silvia Alemany thanks the Institute of Health Carlos III for her Sara Borrell postdoctoral grant (CD14/00214). This work was supported by the European Research Council under the ERC [grant number 268479]—the BREATHE project. The Agency of University and Research Funding Management of the Catalonia Government participated in the context of Research Group SGR2014-1673. This project also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 785994).