Publications by authors named "Gerard Martínez-Vilavella"

24 Publications

  • Page 1 of 1

Dysfunctional Brain Reward System in Child Obesity.

Cereb Cortex 2021 Apr 16. Epub 2021 Apr 16.

ISGlobal, 08003 Barcelona, Spain.

Eating habits leading to obesity may reflect nonhomeostatic behavior based on excessive immediate-reward seeking. However, it is currently unknown to what extent excess weight is associated with functional alterations in the brain's reward system in children. We tested the integrity of reward circuits using resting-state functional connectivity magnetic resonance imaging in a population of 230 children aged 8-12 years. The major components of the reward system were identified within the ventral striatum network defined on the basis of the nucleus accumbens connectivity pattern. The functional structure of the cerebral cortex was characterized using a combination of local functional connectivity measures. Higher body mass index was associated with weaker connectivity between the cortical and subcortical elements of the reward system, and enhanced the integration of the sensorimotor cortex to superior parietal areas relevant to body image formation. Obese children, unlike WHO-defined overweight condition, showed functional structure alterations in the orbitofrontal cortex and amygdala region similar to those previously observed in primary obsessive-compulsive disorder and Prader-Willi syndrome associated with obsessive eating behavior. Results further support the view that childhood obesity is not simply a deviant habit with restricted physical health consequences but is associated with reward system dysfunction characterizing behavioral control disorders.
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http://dx.doi.org/10.1093/cercor/bhab092DOI Listing
April 2021

Mapping the Synchronization Effect of Gamma-Aminobutyric Acid Inhibition on the Cerebral Cortex Using Magnetic Resonance Imaging.

Brain Connect 2021 Apr 1. Epub 2021 Apr 1.

MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.

Functional magnetic resonance imaging (fMRI) of spontaneous brain activity permits the identification of functional networks on the basis of region synchrony. The functional coupling between the elements of a neural system increases during brain activation. However, neural synchronization may also be the effect of inhibitory gamma-aminobutyric acid (GABA) neurons in states of brain inhibition such as sleep or pharmacological sedation. We investigated the effects of an oral dose of alprazolam, a classical benzodiazepine known to enhance inhibitory neurotransmission, using recently developed measures of local functional connectivity. In a randomized, double-blind, placebo-controlled, crossover design, 32 non-treatment-seeking individuals with social anxiety underwent two identical resting-state fMRI sessions on separate days after receiving 0.75 mg of alprazolam and placebo. Functional connectivity maps of the cerebral cortex were generated by using multidistance functional connectivity measures defined within iso-distant local areas. Relative to placebo, increased intracortical functional connectivity was observed in the alprazolam condition in visual, auditory, and sensorimotor cortices, and in areas of sensory integration such as the posterior insula and orbitofrontal cortex (OFC). Alprazolam significantly reduced subjective arousal compared with placebo, and the change was associated with variations in multidistance functional connectivity measures in the OFC. In conclusion, we report evidence that alprazolam significantly modifies neural activity coupling at rest in the form of functional connectivity enhancement within the cerebral cortex. The effect of alprazolam was particularly evident in the cortical sensory system, which would further suggest a differentiated effect of GABA inhibition on sensory processing.
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http://dx.doi.org/10.1089/brain.2020.0844DOI Listing
April 2021

Brain Functional Connectivity Correlates of Subclinical Obsessive-Compulsive Symptoms in Healthy Children.

J Am Acad Child Adolesc Psychiatry 2020 Sep 18. Epub 2020 Sep 18.

Hospital Universitari de Bellvitge, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; Instituto de Salud Carlos III-Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

Objective: Commonly observed subclinical obsessive-compulsive symptoms in healthy children may predispose to obsessive-compulsive disorder (OCD). Therefore, investigating the underlying neurobiology may be relevant to identify alterations in specific brain circuits potentially accounting for clinical heterogeneity in OCD without the confounding effects of clinical samples. We analyzed the brain correlates of different obsessive-compulsive symptoms in a large group of healthy children using functional connectivity measures.

Method: We evaluated 227 healthy children (52% girls; mean [SD] age 9.71 [0.86] years; range, 8-12.1 years). Participants underwent clinical assessment with the Obsessive-Compulsive Inventory-Child Version and a resting-state functional magnetic resonance imaging examination. Total and symptom-specific severity were correlated with voxelwise global functional connectivity degree values. Significant clusters were then used as seeds of interest in seed-to-voxel analyses. Modulating effects of age and sex were also assessed.

Results: Global functional connectivity of the left ventral putamen and medial dorsal thalamus correlated negatively with total obsessive-compulsive symptom severity. Seed-to-voxel analyses revealed specific negative correlations from these clusters with limbic, sensorimotor, and insular regions in association with obsessing, ordering, and doubt-checking symptoms, respectively. Hoarding symptoms were associated with negative correlations between the left medial dorsal thalamus and a widespread pattern of regions, with such associations modulated by sex and age.

Conclusion: Our findings concur with prevailing neurobiological models of OCD on the importance of cortico-striato-thalamo-cortical dysfunction to account for symptom severity. Notably, we showed that changes in cortico-striato-thalamo-cortical connectivity are present at subclinical stages, which may result in an increased vulnerability for OCD. Moreover, we mapped different symptom dimensions onto specific cortico-striato-thalamo-cortical circuit attributes.
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http://dx.doi.org/10.1016/j.jaac.2020.08.435DOI Listing
September 2020

Largest scale dissociation of brain activity at propofol-induced loss of consciousness.

Sleep 2021 01;44(1)

Department of Anesthesiology, Hospital del Mar-IMIM, Barcelona, Spain.

The brain is a functional unit made up of multilevel connected elements showing a pattern of synchronized activity that varies in different states. The wake-sleep cycle is a major variation of brain functional condition that is ultimately regulated by subcortical arousal- and sleep-promoting cell groups. We analyzed the evolution of functional MRI (fMRI) signal in the whole cortex and in a deep region including most sleep- and wake-regulating subcortical nuclei at loss of consciousness induced by the hypnotic agent propofol. Optimal data were obtained in 21 of the 30 healthy participants examined. A dynamic analysis of fMRI time courses on a time-scale of seconds was conducted to characterize consciousness transition, and functional connectivity maps were generated to detail the anatomy of structures showing different dynamics. Inside the magnet, loss of consciousness was marked by the participants ceasing to move their hands. We observed activity synchronization after loss of consciousness within both the cerebral cortex and subcortical structures. However, the evolution of fMRI signal was dissociated, showing a transient reduction of global cortico-subcortical coupling that was restored during the unconscious state. An exception to cortico-subcortical decoupling was a brain network related to self-awareness (i.e. the default mode network) that remained connected to subcortical brain structures. Propofol-induced unconsciousness is thus characterized by an initial, transitory dissociated synchronization at the largest scale of brain activity. Such cortico-subcortical decoupling and subsequent recoupling may allow the brain to detach from waking activity and reorganize into a functionally distinct state.
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http://dx.doi.org/10.1093/sleep/zsaa152DOI Listing
January 2021

Brain activity during traditional textbook and audiovisual-3D learning.

Brain Behav 2019 10 30;9(10):e01427. Epub 2019 Sep 30.

MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.

Introduction: Audiovisual educational tools have increasingly been used during the past years to complement and compete with traditional textbooks. However, little is known as to how the brain processes didactic information presented in different formats. We directly assessed brain activity during learning using both traditional textbook and audiovisual-3D material.

Methods: A homogeneous sample of 30 young adults with active study habits was assessed. Educational material on the subject of Cardiology was adapted to be presented during the acquisition of functional MRI.

Results: When tested after image acquisition, participants obtained similar examination scores for both formats. Evoked brain activity was robust during both traditional textbook and audiovisual-3D lessons, but a greater number of brain systems were implicated in the processing of audiovisual-3D information, consistent with its multisource sensory nature. However, learning was not associated with group mean brain activations, but was instead predicted by distinct functional MRI signal changes in the frontal lobes and showed distinct cognitive correlates. In the audiovisual-3D version, examination scores were positively correlated with late-evoked prefrontal cortex activity and working memory, and negatively correlated with language-related frontal areas and verbal memory. As for the traditional textbook version, the fewer results obtained suggested the opposite pattern, with examination scores negatively correlating with prefrontal cortex activity evoked during the lesson.

Conclusions: Overall, the results indicate that a similar level of knowledge may be achieved via different cognitive strategies. In our experiment, audiovisual learning appeared to benefit from prefrontal executive resources (as opposed to memorizing verbal information) more than traditional textbook learning.
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http://dx.doi.org/10.1002/brb3.1427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790317PMC
October 2019

Effects of prenatal exposure to particulate matter air pollution on corpus callosum and behavioral problems in children.

Environ Res 2019 11 7;178:108734. Epub 2019 Sep 7.

ISGLOBAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Pompeu Fabra University, Barcelona, Catalonia, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Institut Hospital del Mar d'Investigacions Mèdiques-Parc de Salut Mar, Barcelona, Catalonia, Spain.

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 (PM) 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 PM 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 PM levels ranged from 11.8 to 39.5 μg/m during the third trimester of pregnancy. An interquartile range increase in PM level (7 μg/m) was significantly linked to a decrease in the body CC volume (mm) (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 mm 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 PM may be associated with CC volume decrease in children. The consequences might be an increase in behavioral problems.
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http://dx.doi.org/10.1016/j.envres.2019.108734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892268PMC
November 2019

Testing the effects of gentle vibrotactile stimulation on symptom relief in fibromyalgia.

Arthritis Res Ther 2019 06 14;21(1):148. Epub 2019 Jun 14.

MRI Research Unit, Department of Radiology, Hospital del Mar, Passeig Marítim 25-29, 08003, Barcelona, Spain.

Background: Sensory disturbances in fibromyalgia extend beyond nociception. It has been proposed that imbalance in the mutual competition between painful input and non-painful sensory activity may, to a significant extent, account for the augmented subjective perception of pain. In this context, non-nociceptive somatosensory stimulation could arguably attenuate fibromyalgia symptoms by restoring the sensory balance. We specifically tested the effect of vibrotactile stimulation on symptom relief in fibromyalgia patients with a randomized, double-blind, sham-controlled, crossover clinical trial.

Methods: Seventy-seven female patients were randomized and data from 63 valid cases were analyzed. Active intervention involved extensive body stimulation with gentle mechanical vibrations administered during 3 h at night for 3 weeks, and the placebo effect was controlled using identical instruments to simulate an alternative treatment option. The primary outcome measure combined pain, fatigue, and complaints of poor cognition.

Results: Vibrotactile stimulation was significantly superior to sham in alleviating fibromyalgia symptoms globally. However, univariate analyses showed that the effect was not universal. Benefits were perceived on unpleasant somatic sensations such as generalized pain and fatigue, but not on poor cognition, anxiety, and depression. Vibrotactile stimulation was notably well tolerated and sleep quality significantly improved despite the fact that vibrations were administered at night.

Conclusions: Results thus provide new evidence that non-nociceptive somatosensory stimulation may favorably act upon altered somatosensory balance in fibromyalgia. From a clinical perspective, both the degree of improvement and the easy application of our proposal would seem to support a potential role for vibrotactile stimulation in the symptomatic treatment of fibromyalgia.

Trial Registration: ClinicalTrials.gov registration number NCT03227952 . Registered 24 July, 2017.
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http://dx.doi.org/10.1186/s13075-019-1932-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570892PMC
June 2019

Brain Structure and Function in School-Aged Children With Sluggish Cognitive Tempo Symptoms.

J Am Acad Child Adolesc Psychiatry 2019 02 26;58(2):256-266. Epub 2018 Nov 26.

Institut de Salut Global de Barcelona (ISGlobal), Barcelona, Spain; Hospital del Mar Research Institute, Barcelona, and the Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.jaac.2018.09.441DOI Listing
February 2019

Mapping Alterations of the Functional Structure of the Cerebral Cortex in Obsessive-Compulsive Disorder.

Cereb Cortex 2019 12;29(11):4753-4762

Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barcelona, Spain.

We mapped alterations of the functional structure of the cerebral cortex using a novel imaging approach in a sample of 160 obsessive-compulsive disorder (OCD) patients. Whole-brain functional connectivity maps were generated using multidistance measures of intracortical neural activity coupling defined within isodistant local areas. OCD patients demonstrated neural activity desynchronization within the orbitofrontal cortex and in primary somatosensory, auditory, visual, gustatory, and olfactory areas. Symptom severity was significantly associated with the degree of functional structure alteration in OCD-relevant brain regions. By means of a novel imaging perspective, we once again identified brain alterations in the orbitofrontal cortex, involving areas purportedly implicated in the pathophysiology of OCD. However, our results also indicated that weaker intracortical activity coupling is also present in each primary sensory area. On the basis of previous neurophysiological studies, such cortical activity desynchronization may best be interpreted as reflecting deficient inhibitory neuron activity and altered sensory filtering.
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http://dx.doi.org/10.1093/cercor/bhz008DOI Listing
December 2019

Lack of response to disgusting food in the hypothalamus and related structures in Prader Willi syndrome.

Neuroimage Clin 2019 4;21:101662. Epub 2019 Jan 4.

Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT- UAB, 08208 Sabadell, Spain.

Objective: To investigate, based on a putative abnormal neural processing of disgusting signals in Prader Willi syndrome (PWS) patients, the brain response to visual representations of disgusting food in PWS using functional MRI (fMRI).

Methods: Twenty-one genetically-confirmed PWS patients, 30 age- and sex-matched and 28 BMI-matched control subjects viewed a movie depicting disgusting food-related scenes interspersed with scenes of appetizing food while fMRI was acquired. Brain activation maps were compared between groups and correlated with disgust and hunger ratings.

Results: At the cortical level, the response to disgusting food representations in PWS patients was qualitatively similar to that of control subjects, albeit less extensive, and engaged brain regions typically related to visually-evoked disgust, such as the anterior insula/frontal operculum, the lateral frontal cortex and visual areas. By contrast, activation was almost absent in limbic structures directly concerned with the regulation of instinctive behavior robustly activated in control subjects, such as the hypothalamus, amygdala/hippocampus and periaqueductal gray.

Conclusions: Our study provides novel insights into the neural substrates of appetite control in a genetically-mediated cause of obesity. The presence of significant cortical changes further indicates that PWS patients consciously process disgusting stimuli, but the virtual absence of response in deep, limbic structures suggests that disgusting signals do not adequately reach the primary brain system for the appetite control.
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http://dx.doi.org/10.1016/j.nicl.2019.101662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412080PMC
January 2020

A longitudinal study of brain anatomy changes preceding dementia in Down syndrome.

Neuroimage Clin 2018 28;18:160-166. Epub 2018 Jan 28.

Specialized Service in Mental Health and Intellectual Disability, Institut Assistència Sanitària (IAS), Parc Hospitalari Martí i Julià, 17190 Girona, Spain.

Background: We longitudinally assessed Down syndrome individuals at the age of risk of developing dementia to measure changes in brain anatomy and their relationship to cognitive impairment progression.

Methods: Forty-two Down syndrome individuals were initially included, of whom 27 (mean age 46.8 years) were evaluable on the basis of completing the 2-year follow-up and success in obtaining good quality MRI exams. Voxel-based morphometry was used to estimate regional brain volumes at baseline and follow-up on 3D anatomical images. Longitudinal volume changes for the group and their relationship with change in general cognitive status and specific cognitive domains were mapped.

Results: As a group, significant volume reduction was identified in the substantia innominata region of the basal forebrain, hippocampus, lateral temporal cortex and left arcuate fasciculus. Volume reduction in the substantia innominata and hippocampus was more prominent in individuals whose clinical status changed from cognitively stable to mild cognitive impairment or dementia during the follow-up. Relevantly, longitudinal memory score change was specifically associated with volume change in the hippocampus, prospective memory with prefrontal lobe and verbal comprehension with language-related brain areas.

Conclusions: Results are notably concordant with the well-established anatomical changes signaling the progression to dementia in Alzheimer's disease, despite the dense baseline pathology that developmentally accumulates in Down syndrome. This commonality supports the potential value of Down syndrome as a genetic model of Alzheimer's neurodegeneration and may serve to further support the view that Down syndrome patients are best candidates to benefit from treatment research in Alzheimer's disease.
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http://dx.doi.org/10.1016/j.nicl.2018.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984600PMC
January 2019

Characterization of the Spatial Structure of Local Functional Connectivity Using Multidistance Average Correlation Measures.

Brain Connect 2018 06 7;8(5):276-287. Epub 2018 Jun 7.

1 MRI Research Unit, Department of Radiology, Hospital del Mar , Barcelona, Spain .

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.
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http://dx.doi.org/10.1089/brain.2017.0575DOI Listing
June 2018

The Association between Lifelong Greenspace Exposure and 3-Dimensional Brain Magnetic Resonance Imaging in Barcelona Schoolchildren.

Environ Health Perspect 2018 02 23;126(2):027012. Epub 2018 Feb 23.

ISGlobal, Barcelona, Catalonia, Spain

Background: Proponents of the biophilia hypothesis believe that contact with nature, including green spaces, has a crucial role in brain development in children. Currently, however, we are not aware of evidence linking such exposure with potential effects on brain structure.

Objective: We determined whether lifelong exposure to residential surrounding greenness is associated with regional differences in brain volume based on 3-dimensional magnetic resonance imaging (3D MRI) among children attending primary school.

Methods: We performed a series of analyses using data from a subcohort of 253 Barcelona schoolchildren from the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) project. We averaged satellite-based normalized difference vegetation index (NDVI) across 100-m buffers around all residential addresses since birth to estimate each participant's lifelong exposure to residential surrounding greenness, and we used high-resolution 3D MRIs of brain anatomy to identify regional differences in voxel-wise brain volume associated with greenness exposure. In addition, we performed a supporting substudy to identify regional differences in brain volume associated with measures of working memory ( from computerized -back tests) and inattentiveness (hit reaction time standard error from the Attentional Network Task instrument) that were repeated four times over one year. We also performed a second supporting substudy to determine whether peak voxel tissue volumes in brain regions associated with residential greenness predicted cognitive function test scores.

Results: Lifelong exposure to greenness was positively associated with gray matter volume in the left and right prefrontal cortex and in the left premotor cortex and with white matter volume in the right prefrontal region, in the left premotor region, and in both cerebellar hemispheres. Some of these regions partly overlapped with regions associated with cognitive test scores (prefrontal cortex and cerebellar and premotor white matter), and peak volumes in these regions predicted better working memory and reduced inattentiveness.

Conclusion: Our findings from a study population of urban schoolchildren in Barcelona require confirmation, but they suggest that being raised in greener neighborhoods may have beneficial effects on brain development and cognitive function. https://doi.org/10.1289/EHP1876.
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http://dx.doi.org/10.1289/EHP1876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066357PMC
February 2018

Brain Structural Correlates of Subclinical Obsessive-Compulsive Symptoms in Healthy Children.

J Am Acad Child Adolesc Psychiatry 2018 01 10;57(1):41-47. Epub 2017 Nov 10.

Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Carlos III Health Institute, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barcelona; Autonomous University of Barcelona. Electronic address:

Objective: Subclinical obsessive-compulsive (OC) symptoms are frequently observed in children and have been reported to predict a subsequent diagnosis of OC disorder (OCD). Therefore, identifying the putative neurobiological signatures of such risk is crucial, because it would allow for the characterization of the underpinnings of OCD without the interfering effects of chronicity, medication, or comorbidities, especially when interpreted within the context of OCD clinical heterogeneity and taking into account normal neurodevelopmental changes. The present study aimed to identify the brain volumetric features associated with subclinical OC symptoms and the potential modulatory effects of sex and age in a large sample of healthy children.

Method: Two hundred fifty-five healthy children were assessed using the Obsessive-Compulsive Inventory-Child Version and underwent a brain structural magnetic resonance examination. The relation between total and symptom-specific scores and regional gray and white matter (GM and WM) volumes was evaluated. Participants were grouped according to sex and age (younger versus older) to assess the effect of these factors on symptom-brain morphometry associations.

Results: Ordering symptoms were negatively related to GM volumes in the ventral caudate. Hoarding symptoms were positively associated with GM and WM volumes in the left inferior frontal gyrus, and obsessing symptoms correlated negatively with GM and WM volumes in the right temporal pole. Doubt-checking symptoms correlated positively with WM volumes in the right inferior fronto-occipital fasciculus and the corpus callosum. Sex and age modulated some of these associations.

Conclusion: Subclinical OC symptoms are associated with specific brain volumetric features, which could be considered potential neural signatures of increased risk for OCD.
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http://dx.doi.org/10.1016/j.jaac.2017.10.016DOI Listing
January 2018

Mapping the sequence of brain events in response to disgusting food.

Hum Brain Mapp 2018 01 11;39(1):369-380. Epub 2017 Oct 11.

Endocrinology and Nutrition Department, Sabadell University Hospital (UAB), Corporació Sanitària Parc Taulí, Sabadell, 08208, Spain.

Warning signals indicating that a food is potentially dangerous may evoke a response that is not limited to the feeling of disgust. We investigated the sequence of brain events in response to visual representations of disgusting food using a dynamic image analysis. Functional MRI was acquired in 30 healthy subjects while they were watching a movie showing disgusting food scenes interspersed with the scenes of appetizing food. Imaging analysis included the identification of the global brain response and the generation of frame-by-frame activation maps at the temporal resolution of 2 s. Robust activations were identified in brain structures conventionally associated with the experience of disgust, but our analysis also captured a variety of other brain elements showing distinct temporal evolutions. The earliest events included transient changes in the orbitofrontal cortex and visual areas, followed by a more durable engagement of the periaqueductal gray, a pivotal element in the mediation of responses to threat. A subsequent core phase was characterized by the activation of subcortical and cortical structures directly concerned not only with the emotional dimension of disgust (e.g., amygdala-hippocampus, insula), but also with the regulation of food intake (e.g., hypothalamus). In a later phase, neural excitement extended to broad cortical areas, the thalamus and cerebellum, and finally to the default mode network that signaled the progressive termination of the evoked response. The response to disgusting food representations is not limited to the emotional domain of disgust, and may sequentially involve a variety of broadly distributed brain networks. Hum Brain Mapp 39:369-380, 2018. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866415PMC
January 2018

Brain imaging of pain sensitization in patients with knee osteoarthritis.

Pain 2017 Sep;158(9):1831-1838

Rheumatology Department, Hospital del Mar, Barcelona, Spain.

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.
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http://dx.doi.org/10.1097/j.pain.0000000000000985DOI Listing
September 2017

Effect of exposure to polycyclic aromatic hydrocarbons on basal ganglia and attention-deficit hyperactivity disorder symptoms in primary school children.

Environ Int 2017 08 5;105:12-19. Epub 2017 May 5.

ISGLOBAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Pompeu Fabra University, Barcelona, Catalonia, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Institut Hospital del Mar d'Investigacions Mèdiques-Parc de Salut Mar, Barcelona, Catalonia, Spain.

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 8-12years, 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 (67pg/m) and indoor level (76pg/m) was significantly linked to a decrease in CNV (mm) (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.
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http://dx.doi.org/10.1016/j.envint.2017.04.011DOI Listing
August 2017

Anomalous White Matter Structure and the Effect of Age in Down Syndrome Patients.

J Alzheimers Dis 2017 ;57(1):61-70

Integrative Pharmacology and Neuroscience Systems Research Group, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Background: Neural tissue alterations in Down syndrome are fully expressed at relatively late developmental stages. In addition, there is an early presence of neurodegenerative changes in the late life stages.

Objective: The aims of this study were both to characterize white matter abnormalities in the brain of adult Down syndrome patients using diffusion tensor imaging (DTI) and to investigate whether degenerative alterations in white matter structure are detectable before dementia is clinically evident.

Methods: Forty-five adult non-demented Down syndrome patients showing a wide age range (18-52 years) and a matched 45-subject control group were assessed. DTI fractional anisotropy (FA) brain maps were generated and selected cognitive tests were administered.

Results: Compared with healthy controls, non-demented Down syndrome patients showed lower DTI FA in white matter involving the major pathways, but with more severe alterations in the frontal-subcortical circuits. White matter FA decreased with age at a similar rate in both DS and control groups.

Conclusions: Our results contribute to characterizing the expression of white matter structural alterations in adult Down syndrome. However, an accelerated aging effect was not demonstrated, which may suggest that the FA measurements used are not sufficiently sensitive or, alternatively, age-related white matter neurodegeneration is not obvious prior to overt clinical dementia.
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http://dx.doi.org/10.3233/JAD-161112DOI Listing
February 2018

A Genome-Wide Association Study of Attention Function in a Population-Based Sample of Children.

PLoS One 2016;11(9):e0163048. Epub 2016 Sep 22.

ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

Background: Attention function filters and selects behaviorally relevant information. This capacity is impaired in some psychiatric disorders and has been proposed as an endophenotype for Attention-Deficit/Hyperactivity Disorder; however, its genetic basis remains largely unknown. This study aimed to identify single nucleotide polymorphism (SNPs) associated with attention function.

Materials And Methods: The discovery sample included 1655 children (7-12 years) and the replication sample included 546 children (5-8 years). Five attention outcomes were assessed using the computerized Attentional Network Test (ANT): alerting, orienting, executive attention, Hit Reaction time (HRT) and the standard error of HRT (HRTSE). A Genome-wide Association Study was conducted for each outcome. Gene set enrichment analyses were performed to detect biological pathways associated with attention outcomes. Additional neuroimaging analyses were conducted to test neural effects of detected SNPs of interest.

Results: Thirteen loci showed suggestive evidence of association with attention function (P<10-5) in the discovery sample. One of them, the rs4321351 located in the PID1 gene, was nominally significant in the replication sample although it did not survive multiple testing correction. Neuroimaging analysis revealed a significant association between this SNP and brain structure and function involving the frontal-basal ganglia circuits. The mTOR signaling and Alzheimer disease-amyloid secretase pathways were significantly enriched for alerting, orienting and HRT respectively (FDR<5%).

Conclusion: These results suggest for the first time the involvement of the PID1 gene, mTOR signaling and Alzheimer disease-amyloid secretase pathways, in attention function during childhood. These genes and pathways have been proposed to play a role in neuronal plasticity, memory and neurodegenerative disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033492PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163048PLOS
September 2016

Video gaming in school children: How much is enough?

Ann Neurol 2016 09 22;80(3):424-33. Epub 2016 Aug 22.

Center for Research in Environmental Epidemiology, Barcelona, Spain.

Objective: Despite extensive debate, the proposed benefits and risks of video gaming in young people remain to be empirically clarified, particularly as regards an optimal level of use.

Methods: In 2,442 children aged 7 to 11 years, we investigated relationships between weekly video game use, selected cognitive abilities, and conduct-related problems. A large subgroup of these children (n = 260) was further examined with magnetic resonance imaging approximately 1 year later to assess the impact of video gaming on brain structure and function.

Results: Playing video games for 1 hour per week was associated with faster and more consistent psychomotor responses to visual stimulation. Remarkably, no further change in motor speed was identified in children playing >2 hours per week. By comparison, the weekly time spent gaming was steadily associated with conduct problems, peer conflicts, and reduced prosocial abilities. These negative implications were clearly visible only in children at the extreme of our game-playing distribution, with 9 hours or more of video gaming per week. At a neural level, changes associated with gaming were most evident in basal ganglia white matter and functional connectivity.

Interpretation: Significantly better visuomotor skills can be seen in school children playing video games, even with relatively small amounts of use. Frequent weekly use, by contrast, was associated with conduct problems. Further studies are needed to determine whether moderate video gaming causes improved visuomotor skills and whether excessive video gaming causes conduct problems, or whether children who already have these characteristics simply play more video games. Ann Neurol 2016;80:424-433.
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http://dx.doi.org/10.1002/ana.24745DOI Listing
September 2016

Airborne copper exposure in school environments associated with poorer motor performance and altered basal ganglia.

Brain Behav 2016 06 22;6(6):e00467. Epub 2016 Apr 22.

Centre for Research in Environmental Epidemiology (CREAL) Barcelona Catalonia Spain; Pompeu Fabra University Barcelona Catalonia Spain; Ciber on Epidemiology and Public Health (CIBERESP) Barcelona Spain; IMIM (Hospital del Mar Medical Research Institute) Barcelona Catalonia Spain.

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.
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http://dx.doi.org/10.1002/brb3.467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842931PMC
June 2016

Traffic pollution exposure is associated with altered brain connectivity in school children.

Neuroimage 2016 Apr 26;129:175-184. Epub 2016 Jan 26.

Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain; Pompeu Fabra University, Barcelona, Catalonia, Spain; Ciber on Epidemiology and Public Health (CIBERESP), Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain.

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 12 years, 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.
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http://dx.doi.org/10.1016/j.neuroimage.2016.01.036DOI Listing
April 2016

Anomalous brain functional connectivity contributing to poor adaptive behavior in Down syndrome.

Cortex 2015 Mar 28;64:148-56. Epub 2014 Oct 28.

Human Pharmacology and Clinical Neurosciences, Hospital del Mar Medical Research Institute, Barcelona, Spain; CIBER-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), S. de Compostela, Spain. Electronic address:

Research in Down syndrome has substantially progressed in the understanding of the effect of gene overexpression at the molecular level, but there is a paucity of information on the ultimate consequences on overall brain functional organization. We have assessed the brain functional status in Down syndrome using functional connectivity MRI. Resting-state whole-brain connectivity degree maps were generated in 20 Down syndrome individuals and 20 control subjects to identify sites showing anomalous synchrony with other areas. A subsequent region-of-interest mapping served to detail the anomalies and to assess their potential contribution to poor adaptive behavior. Down syndrome individuals showed higher regional connectivity in a ventral brain system involving the amygdala/anterior temporal region and the ventral aspect of both the anterior cingulate and frontal cortices. By contrast, lower functional connectivity was identified in dorsal executive networks involving dorsal prefrontal and anterior cingulate cortices and posterior insula. Both functional connectivity increases and decreases contributed to account for patient scoring on adaptive behavior related to communication skills. The data overall suggest a distinctive functional organization with system-specific anomalies associated with reduced adaptive efficiency. Opposite effects were identified on distinct frontal and anterior temporal structures and relative sparing of posterior brain areas, which is generally consistent with Down syndrome cognitive profile. Relevantly, measurable connectivity changes, as a marker of the brain functional anomaly, could have a role in the development of therapeutic strategies addressed to improve the quality of life in Down syndrome individuals.
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http://dx.doi.org/10.1016/j.cortex.2014.10.012DOI Listing
March 2015

Does motion-related brain functional connectivity reflect both artifacts and genuine neural activity?

Neuroimage 2014 Nov 3;101:87-95. Epub 2014 Jul 3.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Melbourne, Australia.

Imaging research on functional connectivity is uniquely contributing to characterize the functional organization of the human brain. Functional connectivity measurements, however, may be significantly influenced by head motion that occurs during image acquisition. The identification of how motion influences such measurements is therefore highly relevant to the interpretation of a study's results. We have mapped the effect of head motion on functional connectivity in six different populations representing a wide range of potential influences of motion on functional connectivity. Group-level voxel-wise maps of the correlation between a summary head motion measurement and functional connectivity degree were estimated in 80 young adults, 71 children, 53 older adults, 20 patients with Down syndrome, 24 with Prader-Willi syndrome and 20 with Williams syndrome. In highly compliant young adults, motion correlated with functional connectivity measurements showing a system-specific anatomy involving the sensorimotor cortex, visual areas and default mode network. Further characterization was strongly indicative of these changes expressing genuine neural activity related to motion, as opposed to pure motion artifact. In the populations with larger head motion, results were more indicative of widespread artifacts, but showing notably distinct spatial distribution patterns. Group-level regression of motion effects was efficient in removing both generalized changes and changes putatively related to neural activity. Overall, this study endorses a relatively simple approach for mapping distinct effects of head motion on functional connectivity. Importantly, our findings support the intriguing hypothesis that a component of motion-related changes may reflect system-specific neural activity.
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http://dx.doi.org/10.1016/j.neuroimage.2014.06.065DOI Listing
November 2014