This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page Free parking in Lisbon is becoming increasingly difficult But we've discovered some places where you can still leave your car without paying a penny before going to work Lisbon is a city known for its heavy traffic but we can’t even say that there are so few places to park… for a fee because there are fewer and fewer free ones the city does offer some free parking options both in specific areas and in dedicated parks At Lisboa Secreta we know that the places where you usually park are either always full or are about to become yet another paid parking lot when we can’t park for free in Lisbon we’ve discovered some secret spots where you can still park for free before going to work But if you live in areas closer to Lisbon and don’t need four wheels to get to work because you even have to take the kids to nursery or school you can also use these tips to park for free in the city From what we’ve consulted on the planning maps of the company that manages parking in Lisbon some of these places can become outdated from one day to the next To give you a better idea of the free parking spots we’ve found in Lisbon we’ ve divided the city into five zones: namely their proximity to Lisbon’s most used public transport: metro some of these areas may require you to walk for a few minutes to find a metro station or bus stop But this can also be solved by opting for one of the mobility solutions scattered throughout the city, from scooters, bicycles or car and motorcycle sharing services the main parking lot manager in Lisbon already occupies a large part of the central area of the city leaving a few free parking spaces for areas further away from the center But let’s leave these discussions for other pages and get down to business Let’s start with the easternmost part of Lisbon and one of the city’s newest areas Although it ‘s very difficult to find free parking in the center of Parque das Nações there are some very interesting alternatives very close to public transport in this case the Sacavém train station and bus stops Near Sacavém train station there are a few parking lots where you can leave your car and then take the train or bus to the city center Here you can leave your car near the Parque do Rio urbanization The park is at the end of Via do Oriente and Passeio dos Heróis do Mar 📍Coordinates On your way to Parque das Nações from the south to the north if you go along the waterfront you’ll come across the Santa Apolóniatrain station and finding a parking space can be a challenge If you’re not one of the first to arrive So our suggestion is that you arrive at one of these places between 07h45 and 08h15 you’ll probably be scrambling around until you find a seat 📍Coordinates Rua Luís de Camões is one of the few streets where you can still see cars parked on the sidewalk In the parallel streets you’ll be able to find free parking without too much trouble If you can’t find a space as soon as you arrive in this well-known neighborhood we guarantee that you’ll have a parking space within 5-10 minutes But for that you’ll have to be in the area between 8.45 and 9.15am when the locals also drive to work in their cars and leave the spaces vacant 📍Coordinates you’re sure to find your parking space in the sun The area is very well served by public transport with trains and buses to almost every part of Lisbon you may have to park a little away from these stops otherwise take the opportunity to rent a scooter or bicycle along the way 📍Coordinates The Benfica area is the furthest away from the city center But that doesn’t mean you can’t find your free parking space in Lisbon there’s plenty of public transport you can take from here You’ll find free parking in all areas of Benfica but with the train station right next door it’s very difficult to get a parking space 📍Coordinates But the truth is that public transport is still not the ideal solution for those who want to get from place A to place B as comfortably and quickly as possible Lisbon can be a more pleasant place for people to move around We always believe that the solution will be better without cars but we also know that until these conditions are met finding free parking in Lisbon will always be a problem for those who want to move around the city At the general conference leadership session on Thursday 61 new Area Seventies from 28 countries were announced and presented for a sustaining vote Another 50 Area Seventies will be released on or before August 1 See the lists below of the new Area Seventies and those who will be released this year Africa Central Area; currently serving as stake Young Men counselor of the Nairobi Kenya West Stake; former bishop and stake president; wife: Josephine; four children Nigeria; currently serving as president of the Nigeria Port Harcourt Mission; former bishop branch president and stake president; wife: Nicoline; two children Democratic Republic of the Congo; coordinator Seminaries and Institutes of Religion; currently serving as stake president of the Ruashi Democratic Republic of the Congo Stake; former bishop and stake presidency counselor; wife: Mufuka Lyliane; five children Seminaries and Institutes of Religion; currently serving as high councilor of the Roodepoort South Africa Stake; former bishop stake president and mission president; wife: Andronica; four children Shepstone & Wylie Attorneys; currently serving as a branch presidency counselor and as counselor of the South Africa Durban Mission; former bishopric counselor branch president and stake presidency counselor; wife: Tumeka; three children Self-Reliance Services; currently serving as stake president of the Freetown Sierra Leone Stake; former bishopric counselor high councilor and stake presidency counselor; wife: Susan; five children Town and Country Planning; currently serving as president of the Kumasi Ghana Suame Stake; former bishop stake presidency counselor and stake president; wife: Linda; seven children MyVitalz Telehealth; currently serving as elders quorum president of the New Haven Ward; former bishopric counselor high councilor and stake president; wife: Stella Ebele; four children real estate; currently serving as stake president of the Phnom Penh Cambodia North Stake; former branch president district president and mission presidency counselor; wife: Dany; five children Japan; currently serving as president of the Japan Kobe Mission; former branch presidency counselor high councilor and stake presidency counselor; wife: Tomomi; six children Valcom IT Services Private Ltd.; currently serving as president of the Bengaluru India Stake; former branch president and district president; wife: Stella Christina; three children Seminaries and Institutes of Religion; currently serving as counselor of the Brazil Fortaleza Mission; former bishop stake presidency counselor and stake president; wife: Ana Rosa; three children Brazil; currently serving as president of the Brazil Maceio Mission; former bishop stake presidency counselor and stake president; wife: Daniela; three children doTerra Brazil; currently serving as Sunday School teacher of the Aldeia da Serra branch; former bishop high councilor and mission president; wife: Lilian; four children Dominican Republic; administrative director Orlando Industries; currently serving as Young Men ward adviser of the Herrera 1st ward; former bishop stake presidency counselor and stake president; wife: Dareidi; three children Mexico; currently serving as president of the México Tijuana Mission; former bishopric counselor high councilor and stake presidency counselor; wife: Julia; two children Cartonera Hued SAS; currently serving as president of the Santo Domingo Dominican Republic Las Americas Stake; former bishop branch presidency counselor and high councilor; wife: Niurka Atavelis; one child Mexico; construction manager; currently serving as a temple ordinance worker of the Monterrey México Temple; former bishop high councilor and stake president; wife: Myriam Elizabeth; four children Comisión Nacional de Áreas Naturales Protegidas; currently serving as elders quorum president of the Belenes Ward; former bishop stake presidency counselor and stake president; wife: Holly; two children Seminaries and Institutes of Religion; former president of the Nicaragua Managua South Mission high councilor and stake presidency counselor; wife: Zeidy; three children Argentina; currently serving as president of the Argentina Salta Mission; former bishopric counselor stake presidency counselor and stake president; wife: Gabriela; four children Central America Area; currently serving as president of the San Salvador El Salvador Stake; former bishop stake presidency counselor and stake president; wife: Claudia; three children KADRI Servicios S.a de C.V.; currently serving as elders quorum president of the Contry Ward; former bishop high councilor and mission president; wife: Elisa; five children Infonavit; currently serving as president of the México City Ermita Stake; former bishopric counselor high councilor and stake presidency counselor; wife: Nadia; four children Europe East and Middle East/Africa North Areas) Baringa Partners; currently serving as a Sunday School teacher in the Watford Ward; former bishop high councilor and stake president; wife: Jennifer L.; four children Finland; currently serving as president of the Bulgaria/Central Eurasian Mission; former stake president; wife: Anna-Maria; three children Europe Central Area; currently serving as emergency preparedness specialist of the Frankfurt 2nd Ward; former bishop and high councilor; wife: Elodie; three children self-employed; currently serving as president of the Prague Czech Republic Stake; former branch president district president and mission presidency counselor; wife: Alena; four children Pestana Tennis Academy; currently serving as an institute teacher of the Oeiras Stake; former bishop stake presidency counselor and stake president; wife: Zélia Lina Valente; four children England; managing director UK; Tyrus Capital Alternatives LLP; currently serving as president of the Ipswich England Stake; former bishop bishopric counselor and high councilor; wife: Amy; four children Eighth Quorum (Pacific and Philippines Areas) Philippines Area; currently serving as Sunday School president of the Cainta 2nd Ward; former mission presidency counselor stake presidency counselor and mission president; wife: Angie; three children Australia; recently released as president of the Philippines Missionary Training Center; former bishopric counselor stake presidency counselor and mission president; wife: Tracy; four children self-employed; currently serving as stake young single adult adviser of the Christchurch New Zealand Stake; former high councilor mission presidency counselor and stake president; wife: Stephanie; three children self-employed; currently serving as president of the Paco Roman Branch; former bishopric counselor stake president and mission president; wife: Marivic; five children Ninth Quorum (South America Northwest and South America South Areas) self-employed; currently serving as president of the Oruro Bolivia Stake; former bishopric counselor and high councilor; wife: Pamela Anabel; three children FamilySearch; recently released as stake president of the Santa Fe Argentina North Stake; former bishop branch president and high councilor; wife: Romina; five children Peru; recently released as president of the Perú Cusco Mission; former bishop mission presidency counselor and stake president; wife: Carol G.; three children Seminaries and Institutes of Religion; currently serving as Assistant Area Auditor of the Arequipa Hunter Stake; former bishop stake president and mission president; wife: Alicia; two children Peru; Welfare and Self-Reliance manager; currently serving as an area temple and family history advisor of the Peru Lima East Area; former bishop stake president and mission president; wife: Betsy; two children Ecuador; ICS Technical Support Representative The Church of Jesus Christ of Latter-day Saints; currently serving as counselor in the mission presidency of the Ecuador Quito Mission; former bishop stake presidency counselor and stake president; wife: Sandra; three children North America Northeast and North America Southeast Areas) currently serving as president of the Louisiana Baton Rouge Mission; former bishop bishopric counselor and stake presidency counselor; wife: Michelle; three children United Bilt Homes; recently released as stake president of the Springdale Arkansas Stake; former bishop high councilor and stake presidency counselor; wife: Deri Lyn; five children Grow Rasmussen LLP; currently serving as ward Young Men advisor; former bishop stake presidency counselor and mission president; wife: Becky; four children Canada; currently serving as president of the Edmonton Alberta Temple; former bishop high councilor and stake president; wife: Dixie; five children Pickett Ranch; currently serving as Sunday School teacher of the Oakley 3rd Ward; former bishop stake president and mission president; wife: Kristin; five children Missoula Bone & Joint; recently released as stake president of the Missoula Montana stake; former bishopric counselor stake presidency counselor and stake president; wife: Shalayne; five children White & Case LLP; currently serving as Sunday School teacher of the Palm Springs Ward; former bishop and stake president; wife: LaTeshia; two children Brock & Scott; currently serving as president of the Winston-Salem North Carolina Stake; former bishop high councilor and stake presidency counselor; wife: Ginger; seven children Canada; director of planning and forecasting Hydro-Québec; currently serving as president of the Montréal Québec stake; former bishop bishopric counselor and high councilor; wife: Marie-Lyne; five children University of Michigan; currently serving as president of the Ann Arbor Michigan Stake; former bishop stake presidency counselor and stake president; wife: Jana Lynn; six children Eleventh Quorum (North America Southwest and North America West Areas) Demolition/Deconstruction - EZ Services; currently serving as high councilor of the Vista California Stake; former bishop high councilor and mission president; wife: Linda; five children Alaska Dental Care; currently serving as stake president of the Eagle River Alaska Stake; former bishop bishopric counselor and high councilor; wife: Tiffany; four children Thomas and Mack Company; currently serving as president of the Las Vegas Nevada Redrock Stake; former bishop and stake president; wife: Leslie; five children Sunwarrior; currently serving as stake president of the Washington Utah Stake; former bishop; wife: Jennae; three children Burdsal & Fale; currently serving as president of the Provo Utah Wasatch Stake (Tongan); former bishop and high councilor; wife: Gaylene; five children Missionary Department; currently serving as stake presidency counselor of the Huntsville Utah stake; former bishop high councilor and mission president; wife: Kim; four children Space Dynamics Laboratory; currently serving as president of the Wellsville Utah Stake; former bishop and high councilor; wife: Natalie; six children Intermountain Healthcare; recently released as stake president of the Orem Utah Hillcrest Stake; former bishop stake presidency counselor and stake president; wife: Mary; five children Zions Bank; currently serving as an Area Seventy Executive Secretary; former bishop high councilor and stake 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Download a photo or video by clicking or tapping on it. To download all photos or videos related to this article, select the links at the bottom of each section. Detecting invalid cognitive performance is an important clinical challenge in neuropsychological assessment. The aim of this study was to explore behavior and eye-fixations responses during the performance of a computerized version of the Test of Memory Malingering (TOMM-C) under standard vs. feigning conditions. TOMM-C with eye-tracking recording was performed by 60 healthy individuals (31 with standard instruction – SI; and 29 were instructed to feign memory impairment: 21 Naïve Simulators – NS and 8 Coached Simulators – CS) and 14 patients with Multiple Sclerosis (MS) and memory complaints performed. Number of correct responses, response time, number of fixations, and fixation time in old vs. new stimuli were recorded. Nonparametric tests were applied for group comparison. Healthy simulators have a distinct behavioral and eye-fixation response pattern, reflecting a novelty preference. Oculomotor measures may be useful to detect exaggeration or fabrication of cognitive dysfunction. Though, its application in clinical populations may be limited. Volume 15 - 2024 | https://doi.org/10.3389/fpsyg.2024.1395434 This article is part of the Research TopicNeuropsychological Testing: From Psychometrics to Clinical NeuropsychologyView all 12 articles Background: Detecting invalid cognitive performance is an important clinical challenge in neuropsychological assessment The aim of this study was to explore behavior and eye-fixations responses during the performance of a computerized version of the Test of Memory Malingering (TOMM-C) under standard vs Participants and methods: TOMM-C with eye-tracking recording was performed by 60 healthy individuals (31 with standard instruction – SI; and 29 were instructed to feign memory impairment: 21 Naïve Simulators – NS and 8 Coached Simulators – CS) and 14 patients with Multiple Sclerosis (MS) and memory complaints performed Nonparametric tests were applied for group comparison Results: NS produced fewer correct responses and had longer response times in comparison to SI on all three trials SI showed more fixations and longer fixation time on previously presented stimuli (i.e. familiarity preference) specially on Trial 1 whereas NS had more fixations and longer fixation time on new stimuli (i.e. novelty preference) specially in the Retention trial MS patients produced longer response time and had a different fixation pattern than SI subjects No behavioral or oculomotor difference was observed between NS and CS Conclusion: Healthy simulators have a distinct behavioral and eye-fixation response pattern Oculomotor measures may be useful to detect exaggeration or fabrication of cognitive dysfunction its application in clinical populations may be limited whereas less than one tenth of low-functioning Child Protection claimants who are motivated to do well failed on PVTs patients referred for routine clinical neuropsychological evaluation utilize the results of the examination for Social Security documentation PVTs are objective tests designed to detect invalid cognitive performance, i.e., feigned and/or exaggerated diminished capability (Sweet et al., 2021). PVTs usually require little effort or ability, as they typically are normally performed by a wide range of patients who have bona fide neurologic, psychiatric, or developmental problems (Heilbronner et al., 2009) The Test of Memory Malingering (TOMM; Tombaugh, 1996) is one of the most widely used PVTs in research and clinical practice. TOMM is a forced-choice visual memory recognition test and the number of correct responses is the standard measure to discriminate between true memory impairment from noncredible performance. Response times are also able to detect feigned memory impairment on TOMM (Bolan et al., 2002; Kanser et al., 2019) The oculomotor behavior during the performance of TOMM has yet to be investigated This study aimed to quantify the potential information gains provided by eye fixation data in addition to behavioral response (i.e. in the performance of a computerized version of TOMM (TOMM-C) to distinguish simulators from non-simulators The clinical applicability of these measures was also explored in a sample of patients with multiple sclerosis and memory complaints could be an informative complement to behavioral responses on TOMM-C and that oculomotor measures are less vulnerable to coaching than behavioral responses Flowchart of the study participants and of the TOMM experiment Two areas of interest were identified: the “old” (i.e. drawing previously seen on the learning phase) and the “new” (i.e. Three behavioural measures were recorded: Number of Correct Responses and Median Response Time on Correct Responses Three oculomotor measures were considered: % of Total Number of Fixation on “new” items % of Total Fixation Time on “new” items and % of Fixation Time on “new” items for correct responses (A) TOMM encoding phase at Trials 1 and 2; (B) TOMM two choice recognition phase at Trial 1 Eye-fixation data on Trial 2 and Retention Trial from two NS participants were discarded due to recording problems that resulted in extensive missing data however their behavioral responses on those trials were analyzed One NS participant did not produce correct responses on Trial 2 therefore the Median Response Time on Correct Responses and the % of Fixation Time on “New” for Correct Responses could not be calculated SI and MS participants were asked to perform the TOMM-C to the best of their ability. The MS group were also asked to perform the Nine Hole Peg Test, the Symbol Digit Modalities Test – SDMT and the Auditory Verbal Learning Test - AVLT. The SDMT (Sousa et al., 2021) and AVLT (Cavaco et al., 2015) were adjusted to the demographic characteristics of the subjects according to the available norms the CS participants additionally received a series of suggestions to produce the most severe memory problems without making it too obvious to the examiner Multiple logistic regression analyses were used to explore the association between abnormal TOMM score performance and group while taking into consideration demographic characteristics TOMM score (recoded according to the cut-off) was the dependent variable and years of education were the independent variables No variable selection was applied and basic assumptions were verified Simple logistic regression analyses were used to explore in MS group the association between performance on the SDMT and AVLT and some TOMM-C measures As presented in Table 1 the SI group (n = 31) and the NS group (n = 21) had similar demographic characteristics SI group was younger than the MS group (n = 14; p = 0.018) and had fewer years of education than the CS group (n = 8; p = 0.031) NS individuals were younger (p < 0.001) and had more years of education (p = 0.011) than MS patients; and were younger than CS (p = 0.029) participants No group differences were recorded regarding sex 75th percentiles) on the SDMT was 44.1 (31.0 75th percentiles) of the AVLT-Delayed Recall was −1.0 (−1.7 These adjusted scores correspond to the number of standard deviations below/above the mean of the participant’s normal peers with the same sex Three MS patients (21.4%) scored below the estimated 18th percentile on AVLT-Delayed Recognition for the demographic characteristics of each individual the NS group produced fewer correct responses (large effect sizes) had longer total response time and median response time on correct responses (small effect sizes) higher % of total number of fixations on “new” and % of total fixation time on “new” stimuli (medium effect sizes for Trials 1 and Retention and % of fixation time on “new” stimuli for correct responses (small effect sizes on all trials) in comparison to the SI group on all TOMM-C trials MS participants were slower to respond (i.e. total response time and median response time for correct responses) on all trials (p < 0.001) but had similar number of correct responses The effect sizes for the response time measures were relatively small On both Trial 1 (p < 0.06) and Retention Trial (p < 0.01) the % of total fixation time on “new,” and the % of fixation time on “new” for correct responses was higher for the MS group than the SI group The MS group only differed from the NS group on the number of correct responses (all p < 0.001 and with large effect sizes) Neither response time nor oculomotor measures differed between MS and NS participants NS and CS groups did not differ on any of TOMM-C behavioral and oculomotor measures. As shown in Table 1 the comparison between SI group and CS group revealed significant differences on all measures a medium effect size was observed for Trial 1 and large effect sizes were recorded for Trials 2 and Retention For both Total Response Time and Median Response Time for Correct Responses Medium effect sizes were observed for Trial 1 on the % of Total Number of Fixation on “New” and % of Total Fixation Time on “New.” Small effect sizes were also recorded on these measures at Retention Trial Table 2 shows the best cut-off scores to differentiate SI and NS participants while setting the specificity at >90% These cut-off scores were then used to identify the frequency of abnormal scores in the MS group and CS group Multiple logistic regression analyses revealed that MS patients had higher odds of abnormal score than SI participants on Total Response Time and Median Response Time for Correct Responses at Trial 1 (respectively adjusted odds = 6.441 p = 0.076 and adjusted odds = 25.027 p = 0.016) and Trial 2 (respectively adjusted odds = 11.001 p = 0.008 and adjusted odds = 4.476 MS patients also had higher odds of abnormal score at Trial 1 on the following oculomotor measures: % of Total Number of Fixation on “New” (adjusted odds = 44.085 % of Total Fixation Time on “New” (adjusted odds = 34.961 and % of Fixation Time on “New” for Correct Responses (adjusted odds = 40.412 No statistically significant difference (p > 0.05) on oculomotor measures was found between SI and MS participants on Trial 2 and Retention trial when demographic characteristics were considered Simple logistic regressions were used to explore in MS patients the association between standard neuropsychological measures (i.e. SDMT and AVLT) and the following TOMM-C measures: Total Response Time Median Response Time for Correct Responses and % of Total Fixation Time on “New.” No significant association was found (p > 0.05) Study results revealed that both behavioral responses (i.e. response accuracy and response time) and eye-fixation data can distinguish simulators from non-simulators in a computerized version of TOMM Healthy simulators were asked to imagine experiencing “real” memory problems and needing to exaggerate their cognitive difficulties to obtain disability benefits gaze aversion could not be documented in the present study because only two areas of interest - AOI (i.e. the screen was divided in two - “old”/ “new” drawings) were considered fixations in non-relevant spaces within each AOI were considered on target and fixations outside the two AOI were discarded Future studies ought to explore in greater detail the viewing pattern during the performance of TOMM Future studies ought to explore the preference for familiarity / novelty in bona fide MS patients and in other clinical populations and to investigate their associations with standard measures of memory (both visual and verbal) The number of Correct Responses was similar between MS patients and SI healthy individuals on all trials only the number of Correct Responses clearly differentiated MS patients from NS participants These results provide support to its use in clinical practice in the present study no clear association was found between response time on TOMM-C and a standard measure of visual working memory and psychomotor speed (i.e. No effect of coaching how to avoid detection of invalid performance was observed on any of the behavioural and eye-fixation measures of TOMM-C. In other words, the performance of NS and CS participants did not differ, which may reflect lack of statistical power or resistance of the test to coaching (Jelicic et al., 2011) Larger samples are necessary to confirm these negative findings the characteristics of the clinical group were not ideal because none of the MS participants with cognitive complaints had a diagnosis of dementia and not all had memory impairment Future studies ought to study other clinical aetiologies and suspected clinical malingers Recent studies with pupillometry have reported that pupil dilation can detect feigned cognitive impairment on TOMM (Heaver and Hutton, 2011; Patrick et al., 2021a,b) the present study focused only on eye-fixations Future studies should explore the possibility of combining pupil reactivity with eye-fixation pattern in the detection of deception The standardization of the viewing period (3 s) prior to the behavioral response facilitated the comparison between participants though it also limited the informative value of the response time healthy individuals feigning memory impairment showed a distinct behavioral (i.e. fewer correct responses and longer response times) and oculomotor (i.e. longer fixation time on “new” stimuli) response pattern on a computerized version of TOMM which may reflect an increased effort to inhibit a natural response Further investigation is necessary to understand the potential application of response time and eye-fixation measures in real-life clinical situations The raw data supporting the conclusions of this article will be made available by the authors The studies involving humans were approved by Comissão de Ética do Centro Hospitalar Universitário de Santo António The studies were conducted in accordance with the local legislation and institutional requirements The participants provided their written informed consent to participate in this study The author(s) declare that financial support was received for the research This work was supported by Bial Foundation Grant 430/14 UIDB/00215/2020; UIDP/00215/2020; LA/P/0064/2020 We would like to express our gratitude for Ana Filipa Gerós and Paulo de Castro Aguiar contribution to data processing The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyg.2024.1395434/full#supplementary-material Infant memory for object motion across a period of three months: implications for a four-phase attention function A comparison of three tests to detect feigned amnesia: the effects of feedback and the measurement of response latency When familiarity not novelty motivates information-seeking behaviour Auditory verbal learning test in a large nonclinical Portuguese population PubMed Abstract | Crossref Full Text | Google Scholar Visual experience in infants: decreased attention to familiar patterns relative to novel ones PubMed Abstract | Crossref Full Text | Google Scholar Multiple measures of malingering on a forced-choice test of cognitive ability Crossref Full Text | Google Scholar Pupil size changes associated with recognition memory American academy of clinical neuropsychology consensus conference statement on the neuropsychological assessment of effort Self-reported disability-seeking predicts PVT failure in veterans undergoing clinical neuropsychological evaluation Crossref Full Text | Google Scholar Detecting coached feigning using the test of memory malingering (TOMM) and the structured inventory of malingered symptomatology (SIMS) Dissimulation strategies on standard neuropsychological tests: a qualitative investigation Crossref Full Text | Google Scholar Detecting feigned traumatic brain injury with eye tracking during a test of performance validity Detecting malingering in traumatic brain injury: combining response time with performance validity test accuracy The visual paired-comparison task as a measure of declarative memory Defining the temporal threshold for ocular fixation in free-viewing visuocognitive tasks Crossref Full Text | Google Scholar A systematic review and meta-analysis of the test of memory malingering in adults: two decades of deception detection Martins Da Silva Cognitive reserve in multiple sclerosis: protective effects of education Neonatal aspiration lesions of the hippocampal formation impair visual recognition memory when assessed by paired-comparison task but not by delayed nonmatching-to-sample task doi: 10.1002/(SICI)1098-1063(1999)9:6<609::AID-HIPO1>3.0.CO;2-A Detecting simulated versus bona fide traumatic brain injury using pupillometry Performance validity assessment using response time on the Warrington recognition memory test Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria Impact of criterion measures on the classification accuracy of TOMM-1 Five validation experiments of the test of memory malingering (TOMM) Crossref Full Text | Google Scholar Interpreting visual preferences in the visual paired-comparison task Crossref Full Text | Google Scholar Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes Rüsseler The effect of coaching on the simulated malingering of memory impairment Base rates of invalidity when patients undergoing routine clinical evaluations have social security disability as an external incentive Multidimensional malingering criteria for neuropsychological assessment: a 20-year update of the malingered neuropsychological dysfunction criteria Diagnostic criteria for malingered neurocognitive dysfunction: proposed standards for clinical practice and research doi: 10.1076/1385-4046(199911)13:04;1-Y;FT545 J.Group for Validation of the BRBN-T in the Portuguese MS Population (2021) Assessment of cognitive functions in patients with multiple sclerosis applying the normative values of the Rao’s brief repeatable battery in the Portuguese population American Academy of clinical neuropsychology (AACN) 2021 consensus statement on validity assessment: update of the 2009 AACN consensus conference statement on neuropsychological assessment of effort education and race predict TOMM performance in a retired NFL cohort Crossref Full Text | Google Scholar Google Scholar Eye tracking as a mean to detect feigned cognitive impairment in the word memory test Martins da Silva A and Cavaco S (2024) Using behavior and eye-fixations to detect feigned memory impairment Received: 03 March 2024; Accepted: 25 July 2024; Published: 20 September 2024 Copyright © 2024 Gomes, Ferreira, Rosa, Martins da Silva and Cavaco. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Sara Cavaco, c2FyYS5jYXZhY29AY2hwb3J0by5taW4tc2F1ZGUucHQ= Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish A garda investigation is ongoing in Wexford after an incident which saw two men hospitalised after being struck by separate vehicles at a rural Wexford GAA club A search of the car park and surrounding areas also turned up weapons which were seized by gardaí were brought to hospital by ambulance following the incident which took place in the car park of St Martin’s GAA Club in Piercestown at around 2am on bank holiday Sunday morning Their injuries were described as being “non-life threatening.” Sources locally indicate that the incident may have been linked to a local feud between rival factions which boiled over in chaotic fashion on the night in question only the injured men were present and no statements have been taken Gardaí refused to comment on the types of weapons which were seized but it is understood they were “scattered” around the car park Wexford Gardaí have confirmed that a full investigation is still ongoing and inquiries are being carried out Today's News in 90 seconds - 1st November 2024 GAALaois inflict further misery as Wexford Under-20 hurlers exit championship raceHistory was repeated in Chadwicks Wexford Park on Monday as a well-drilled Laois team recorded a fully-merited six-point win over the underperforming hosts in the oneills.com Leinster Under-20 hurling championship quarter-final Metrics details Oxytocin has recently received remarkable attention for its role as a modulator of human behaviour we aimed to expand our knowledge of the neural circuits engaged by oxytocin by investigating the effects of intranasal and intravenous oxytocin on the functional connectome at rest in 16 healthy men Oxytocin modulates the functional connectome within discrete neural systems but does not affect the global capacity for information transfer These local effects encompass key hubs of the oxytocin system (e.g amygdala) but also regions overlooked in previous hypothesis-driven research (i.e Increases in levels of oxytocin in systemic circulation induce broad effects on the functional connectome yet we provide indirect evidence supporting the involvement of nose-to-brain pathways in at least some of the observed changes after intranasal oxytocin our results suggest that oxytocin effects on human behaviour entail modulation of multiple levels of brain processing distributed across different systems our knowledge about the neural mechanisms through which oxytocin affects human behaviour is still insufficient investigating the effects of oxytocin on the functional brain substrates engaged at rest may provide insights that help us understand its pharmacodynamics and its potential as an adjunctive treatment for several neuropsychiatric disorders the application of graph theory to the study of the pharmacodynamics of oxytocin in the human brain has the potential to unravel new mechanisms through which oxytocin might modulate human cognition and behaviour we are not aware of any study investigating the effects of exogenous oxytocin on the human functional connectome at rest through the lens of graph theory The inclusion of this second method of intranasal administration allowed us to inspect whether we can maximize the effects of intranasal oxytocin on brain connectivity by increasing its deposition in putative areas of transport to the brain in this study we sought to expand our previous perfusion findings and apply connectomic analyses to investigate how exogenous oxytocin when administered using different routes and methods for intranasal administration we conducted exploratory connectomic analyses at the whole-brain as an attempt to unravel new aspects of the effects of oxytocin on the brain that previous studies might have missed by simply focusing on key hubs of the brain oxytocin system we demonstrate that oxytocin modulates the local topography of the human functional connectome at rest within discrete neural systems but does not affect the global capacity for information transfer among nodes of the functional connectome We show that in addition to brain systems previously identified as key hubs of the brain oxytocin system (e.g oxytocin also modulates several brain systems that have not been thoroughly investigated in the field We also demonstrate that the presence of oxytocin in systemic circulation has broad effects on human brain regional connectivity Yet we also provide indirect evidence supporting the involvement of nose-to-brain pathways in at least some of changes in brain function observed after intranasal oxytocin We tested the effects of the four treatment conditions on global efficiency using repeated measures one-way analysis of variance we present box and violin plots depicting the distribution of the global efficiency measure for each treatment condition; middle horizontal lines represent the median; boxes indicate the 25th and 75th percentiles we present the descriptive statistics for each condition (n = 16 per treatment condition) The green and red colours depict increases and decreases in betweenness-centrality The size of each nodal sphere is proportional to the T-statistic of each comparison Cereb Cerebellum; PostCG Postcentral gyrus toMTG temporo-occipital area of the middle temporal gyrus The green and red colours depict increases and decreases in local efficiency The green and red colours depict increases and decreases in node degree We did not find any individual edge where the four treatment conditions differed in connectivity after applying the stringent FDR correction for the number of edges Repeating this analysis with NBS also did not identify any subnetwork where the four treatment conditions differed on connectivity after correcting for multiple testing irrespective of the primary threshold used The functional decoding of the pathways for which we identified significant modulatory effects of oxytocin revealed terms mostly associated with early visual processing, mentalizing and theory-of-mind, social and audiovisual processing, facial processing, expectancy, aversion, somatosensation (pressure and nociception) and heart physiology (Fig. 5). The word cloud presents the top terms derived from the NeuroSynth decoder for the neural pathways engaged by oxytocin using reverse inference after excluding terms for brain regions or imaging methods Font size is coded by the correlation strength between the pathway and term Overlap was quantified using the Dice coefficient which measures the percentage of voxels of each resting-state network overlapping with our treatment effect mask we provide an overview of all regions where we found treatment effects irrespective of route/method of administration we provide a heatmap summarizing the percentage of overlap (Dice coefficient) between the regions in A and each of the seven networks (each network rendered in a 3D surface model) We conducted a linear mixed model on plasmatic oxytocin concentrations measured in a blood sample collected immediately before the beginning of the resting-state acquisition Treatment and Time × Treatment as fixed factors and a random intercept for subject We followed up the significant interaction with further post-hoc tests to examine differences between each pair of treatment conditions between baseline and post-administration and between treatment conditions within each time level using Tukey’s correction for multiple testing we present box and violin plots depicting the distribution of plasmatic concentrations of oxytocin for each treatment condition and time point; middle horizontal lines represent the mean; boxes indicate the 25th and 75th percentiles (n = 16 per treatment condition and time point) we present the descriptive statistics for each level of the two factors *Intravenous condition compared to the other three (p < 0.01) at post-administration; # Spray and Nebuliser conditions compared to placebo (<0.001) at post-administration Motivated by the current lack of clarity regarding the central targets of exogenous oxytocin we conducted an exploratory data-driven examination of the effects of exogenous oxytocin on the human brain functional connectome at rest using different routes of administration By identifying the functional substrates that oxytocin engages at rest we expected to provide insights that help understand its effects on human brain and behaviour We discuss each of our main findings below while our data is broadly compatible with these two studies We show that most likely the effects of oxytocin on brain processing involve several brain networks and can hardly be attributed to a single neural pathway oxytocin most likely operates at multiple levels spanning basic sensory processing to salience detection and attention orientation emotional processing and high-order mental representations of the self and others Considering that our data was acquired about 17 min later it is conceivable that the effects of oxytocin on the functional connectivity of the basal ganglia happened at a post-dosing window that we did not sample the ability of intravenous oxytocin to target these areas but also show that the effects of oxytocin when administered intravenously may be broader and encompass other cortical areas We can therefore infer that the presence of oxytocin in systemic circulation can influence brain function in a wide range of circuits potentially related to the behavioural effects associated with intranasal oxytocin our data showed increases in the betweenness-centrality of the right occipital pole and increases in local efficiency in the right superior frontal gyrus both for the intranasal (by spray) and the intravenous administration of oxytocin when compared to placebo; direct comparisons between spray and intravenous administrations for these nodes did not yield any significant differences our findings call for caution in attributing all of the neural/behavioural effects of intranasal oxytocin to direct nose-to-brain pathways While we show that systemic oxytocin produces widespread changes in the functional connectome at rest and that at least some of these effects mirror the changes observed after the intranasal administration of exogenous oxytocin we also show that the presence of oxytocin in systemic circulation does not fully account for all the changes we identified following the intranasal administration of oxytocin increases in betweenness-centrality in the left lateral occipital cortex or the right posterior medial temporal gyrus observed after the administration by spray were not observed after intravenous administration compared to placebo the direct comparison of these two methods confirmed that these effects were specific for the intranasal spray route Other examples include the increases in betweenness-centrality in the left temporo-occipital middle temporal gyrus and in node degree in the left superior temporal gyrus after the administration of oxytocin with the nebuliser compared to placebo These effects were not observed after the intravenous oxytocin administration (compared to placebo) and remained significant when we directly compared these two methods of administration There were many other effects induced by the intranasal (either by spray or nebuliser) administration of oxytocin which were not seen following intravenous oxytocin administration in these cases the direct comparisons between the intranasal and intravenous routes yielded no differences for these effects we cannot be certain about the exact route they originated from resulting in increased amounts of oxytocin reaching the brain (compared to the standard nasal spray) Our hypothesis invites for future dose-response studies using the nebuliser to inspect whether lowering the dose administered with the nebuliser may approximate the effects on the functional connectome achieved after the administration of a high dose of oxytocin with the standard spray using an exploratory connectomics approach oxytocin modulation involves several brain systems that have not been thoroughly investigated in the field but might contribute to the broad modulatory role of oxytocin on social-emotional behaviour in humans We demonstrate that the presence of oxytocin in systemic circulation has broad effects on human brain regional connectivity and may account for at least some of the effects on brain function and behaviour typically ascribed to direct nose-to-brain transport after intranasal oxytocin we also provide indirect evidence supporting the involvement of nose-to-brain pathways in at least some of changes in brain function observed after intranasal oxytocin our results suggest that an overarching model for the role of oxytocin in human behaviour should consider modulation of multiple levels of the brain processing hierarchy relevant for socio-affective related behaviours from basic sensory processing to high-level theory-of-mind inference which could have affected our neuroimaging metrics in unpredictable ways Only three participants were regular smokers (2–3 cigarettes/day) and one participant used to smoke occasionally (around 5 cigarettes/month) at the time of the study Our sample size would allow us to detect a medium effect size f = 0.25 with 80% of statistical power in a repeated measures one-way ANOVA testing for differences across our four treatment conditions in this study Intranasal administrations lasted for about 6 min while the intravenous administration occurred at the highest rate of 1IU/min for 10 min We collected plasma samples at baseline and at five timepoints post-dosing to measure changes in the concentration of oxytocin The resting-state BOLD-fMRI scan used in this study was acquired between 57–65 min post last drug administration offset (the end of our second intranasal administration was considered time = 0) *Duration of treatment administration in minutes we used specially manufactured placebo that contained the same excipients as Syntocinon except for oxytocin Participants self-administered intranasal oxytocin or placebo with the nasal spray or nebuliser following under the supervision of the lead experimenter who ensured the correct application of the devices all participants had been trained during the screening visit in the correct administration procedures each containing 0.1 ml Syntocinon (4IU) or placebo alternating between nostrils (hence 40 IU OT in total) Participants blocked opposite nostril while administering each puff and each puff was followed by an immediate The resting state fMRI scan lasted 8 min 10 s with collection of a total of 192 volumes for each echo Magnetisation Prepared Rapid Acquisition (3D MPRAGE) T1-weighted scan was acquired (TR/TE/TI = 7328/3024/400 ms each participant’s cleaned datasets were co-registered to their corresponding structural scan normalized to the study-specific template before warping to standard MNI152 space The final normalised images were visually inspected to ensure the quality of the preprocessing and the absence of artefacts we normalized our correlation measures to z-scores using the Fisher’s r-z transform per subject/session All of our statistical analyses on graph metrics were therefore run on AUC parameters rather than the raw values the terms related to brain regions or imaging methods were excluded We present these decoding results as a word cloud where font size codes correlation strengths This atlas includes a coarse parcellation of seven canonical resting-state networks which estimates the percentage of voxels of each resting-state network that overlap with our treatment effect mask We did so by examining treatment-related changes in mean connectivity and global efficiency of the whole-brain network (macroscale) graph properties of regional connectivity at the node level (mesoscale) and individual connections between pairs of nodes (microscale) These analyses were performed using repeated measures one-way analysis of variance we followed up with post-hoc paired t-tests between each pair of the four treatment conditions Mean functional connectivity was calculated as the average of the elements in the lower triangular connectivity matrix for each participant and treatment condition we retrieved the global efficiency of the brain network for each participant and treatment condition we compared treatment groups using repeated measures one-way analysis of variance betweenness-centrality and local efficiency of each node of the connectome for each subject and treatment condition We first compared the four treatment conditions using repeated measures one-way analysis of variance controlling false positives with FDR correction for the number of nodes examined we tested a range of arbitrary primary thresholds varying from 1.5 to 4 We then used a two-tailed secondary threshold of 0.025 (0.05/2) Further information on research design is available in the Nature Research Reporting Summary linked to this article Data can be accessed from the corresponding author upon reasonable request A reporting summary for this Article is available as a Supplementary Information file and Supplementary Figures 1 and 3 are provided as a Source data file (Supplementary Data 2) The role of oxytocin in psychiatric disorders: a review of biological and therapeutic research findings From autism to eating disorders and more: the role of oxytocin in neuropsychiatric disorders Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth Potential of oxytocin in the treatment of schizophrenia Oxytocin and potential benefits for obesity treatment Oxytocin and eating disorders: a narrative review on emerging findings and perspectives Bakermans-Kranenburg, M. J. & van IJzendoorn, M. H. Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl. Psychiatry https://doi.org/10.1038/tp.2013.34 (2013) Oxytocin and brain activity in humans: A systematic review and coordinate-based meta-analysis of functional MRI studies Task-free MRI predicts individual differences in brain activity during task performance Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain Quantifying the attenuation of the ketamine pharmacological magnetic resonance imaging response in humans: a validation using antipsychotic and glutamatergic agents Quantifying the test-retest reliability of cerebral blood flow measurements in a clinical model of on-going post-surgical pain: A study using pseudo-continuous arterial spin labelling Complex network measures of brain connectivity: uses and interpretations Complex brain networks: graph theoretical analysis of structural and functional systems Exploring the brain network: a review on resting-state fMRI functional connectivity Xin, F. et al. Oxytocin modulates the intrinsic dynamics between attention-related large-scale networks. Cereb. Cortex https://doi.org/10.1093/cercor/bhy295 (2018) Intranasal oxytocin selectively modulates large-scale brain networks in humans Oxytocin differentially modulates specific dorsal and ventral striatal functional connections with frontal and cerebellar regions Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women Application of graph theory for identifying connectivity patterns in human brain networks: a systematic review Test-retest reliability of graph theory measures of structural brain connectivity The Parieto-Frontal Integration Theory (P-FIT) of intelligence: converging neuroimaging evidence Altered functional network connectivity in preterm infants: antecedents of cognitive and motor impairments Reorganization of brain networks in aging: a review of functional connectivity studies Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile Dopaminergic modulation of hemodynamic signal variability and the functional connectome during cognitive performance Efficiency and cost of economical brain functional networks Quante, L., Kluger, D. S., Burkner, P. C., Ekman, M. & Schubotz, R. I. Graph measures in task-based fMRI: Functional integration during read-out of visual and auditory information. PLoS ONE https://doi.org/10.1371/journal.pone.0207119 (2018) Accessing the brain: the nose may know the way Visualization and quantification of nasal and olfactory deposition in a sectional adult nasal airway cast Oxytocin pathway gene networks in the human brain Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects Neuromodulation by oxytocin and vasopressin The social salience hypothesis of oxytocin A general approach-avoidance hypothesis of oxytocin: accounting for social and non-social effects of oxytocin and the amygdala: a neurofunctional model of social cognitive deficits in schizophrenia Oxytocin signaling in basolateral and central amygdala nuclei differentially regulates the acquisition and extinction of context-conditioned fear in rats Oxytocin reduces amygdala responses during threat approach Oxytocin modulates neural circuitry for social cognition and fear in humans The action radius of oxytocin release in the mammalian CNS: from single vesicles to behavior the fount of maternity: adaptations in pregnancy Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice Evidence for intranasal oxytocin delivery to the brain: recent advances and future perspectives Intranasal delivery of biologics to the central nervous system Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin-horseradish peroxidase applied to the nasal epithelium Avenues for entry of peripherally administered protein to the central-nervous-system in mouse Delivery of I-125-NGF to the brain via the olfactory route Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration: Distribution 2nd Delivery of interferon-beta to the monkey nervous system following intranasal administration Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques Kinetics and dose dependency of intranasal oxytocin effects on amygdala reactivity Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: a peripheral effect-controlled within-subjects randomized dose-response fMRI trial Test-retest reliability of graph metrics of resting state MRI functional brain networks: a review Reproducibility of graph-theoretic brain network metrics: a systematic review Reliability of graph analysis of resting state fMRI using test-retest dataset from the Human Connectome Project Comparing resting state fMRI de-noising approaches using multi- and single-echo acquisitions Sexual dimorphism in oxytocin responses to health perception and disgust with implications for theories on pathogen detection Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces the peptide that bonds the sexes also divides them Cerebrovascular reactivity measured by functional magnetic resonance imaging during breath-hold challenge: a systematic review Menstrual cycle-related changes in plasma oxytocin are relevant to normal sexual function in healthy women Symptom Checklist 90-Revised in neurological outpatients Psychometric properties and validity of Beck Depression Inventory II in multiple sclerosis Urinary and plasma oxytocin changes in response to MDMA or intranasal oxytocin administration Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans Salivary oxytocin concentrations in response to running breastfeeding and the TSST: The Regensburg Oxytocin Challenge (ROC) study Endogenous oxytocin levels in relation to food intake The impacts of actual and perceived nicotine administration on insula functional connectivity with the anterior cingulate cortex and nucleus accumbens Short- and long-term consequences of nicotine exposure during adolescence for prefrontal cortex neuronal network function Beyond the low frequency fluctuations: morning and evening differences in human brain Absence of a diurnal rhythm of oxytocin and arginine-vasopressin in human cerebrospinal fluid side-effects and subjective reactions to intranasal oxytocin in human research Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research Intravenous oxytocin in patients undergoing elective cesarean section Haemodynamic effects of oxytocin given as i.v bolus or infusion on women undergoing Caesarean section Evaluation of enzyme immunoassay and radioimmunoassay methods for the measurement of plasma oxytocin Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid AFNI: software for analysis and visualization of functional magnetic resonance neuroimages Integrated strategy for improving functional connectivity mapping using multiecho fMRI Dipasquale, O. et al. Comparing resting state fMRI de-noising approaches using multi- and single-echo acquisitions. PLoS ONE https://doi.org/10.1371/journal.pone.0173289 (2017) Enhancement of BOLD-contrast sensitivity by single-shot multi-echo functional MR imaging Automatic 3-D model-based neuroanatomical segmentation Spontaneous low-frequency BOLD signal fluctuations: an fMRI investigation of the resting-state default mode of brain function hypothesis Improved optimization for the robust and accurate linear registration and motion correction of brain images A reproducible evaluation of ANTs similarity metric performance in brain image registration Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks A whole brain fMRI atlas generated via spatially constrained spectral clustering Performance of modularity maximization in practical contexts Network analysis of functional brain connectivity in borderline personality disorder using resting-state fMRI Disrupted brain connectivity networks in drug-naive Large-scale automated synthesis of human functional neuroimaging data Knowing what from where: Hippocampal connectivity with temporoparietal cortex at rest is linked to individual differences in semantic and topographic memory The organization of the human cerebral cortex estimated by intrinsic functional connectivity Network-based statistic: identifying differences in brain networks BrainNet Viewer: a network visualization tool for human brain connectomics Download references We would like to thank all participants that volunteered for this study We would also like to thank Sofia Vasilakopoulou Jack Loveridge and Ndaba Mazibuko for their assistance in data collection and Dr Fernando Zelaya for his comments on the first draft of the manuscript This study was part-funded by: an Economic and Social Research Council Grant (ES/K009400/1) to Y.P.; scanning time support by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London to Y.P.; an unrestricted research grant by PARI GmbH to Y.P is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London wrote the first draft of the paper and all co-authors provided critical revisions The authors declare no competing interests This manuscript represents independent research The views expressed are those of the authors and not necessarily those of the NHS Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s42003-020-01610-z Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 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Volume 7 - 2013 | https://doi.org/10.3389/fnbeh.2013.00126 This article is part of the Research TopicProgress in Episodic Memory ResearchView all 45 articles Episodic memory refers to the capacity to bind multimodal memories to constitute a unique personal event Most developmental studies on episodic memory focused on one specific component The present study examines the relevance of a novel episodic paradigm to assess its developmental trajectories in a more comprehensive way according to the type of association (item-feature and item-sequence associations) with measures of both objective and subjective recollection We conducted a behavioral study aimed at testing the effects of age in a large sample of 160 children We confronted the behavioral data to the neural correlates in a subgroup of 30 children using voxel-based morphometry Behavioral data outlined differential developmental trajectories according to the type of association with a continuous increase of factual associative memory efficiency until 10 years a linear increase of performance in spatial associative memory that pursues until early adulthood and an abrupt increase in temporal associative memory efficiency between 9 and 10 measures showed a more pronounced enhancement from 9 to 10 years behavioral data highlight a peculiar period in late childhood (8–10 years old) crucial for the developmental time course of episodic memory we found that the improvement of associative memory efficiency was related to a decrease in gray matter volume in a large cerebral network including the dorsolateral and ventrolateral prefrontal cortex (and superior and anterior temporal regions) These data suggest that multimodal integration would probably be related to the maturation of temporal regions and modulated by a fronto-parietal network our findings emphasize the relevance of the present paradigm to assess episodic memory especially in the clinical setting when assessed with an ordered repeated word list paradigm It is noteworthy that comparisons across developmental studies are challenging due to methodological issues with multiple paradigms and variables that may impact pediatrics behavioral data such as motivational are related to increasing memory efficiency in this developmental period Developmental trends of the hippocampus and their relations with associative memory still need to be clarified Because associative memory is a defining feature of episodic memory the understanding of associative memory development needs to take into consideration the type of associations in order to better describe children’s capacity to form and retrieve episodic memories no behavioral studies have explored the three associative domains (i.e. and temporal – WHEN) with a single protocol in the same sample the first goal of the present study is to describe the development of within-domain and inter-domain associative memory in a large sample of 160 healthy participants We further examined our protocol’s reliance by confronting these behavioral results to structural imaging data collected in a subgroup of 30 children and adolescents to identify the regions that subserve episodic memory efficiency from childhood to young adulthood to consider the possible influence of verbalization and retrieval processes on associative memory efficiency during development we conducted additional correlational analyses between the 30 participants’ performance in verbal fluency and (1) behavioral data (the WHAT-WHERE-WHEN paradigm) and (2) volume of cerebral regions related to associative memory One hundred children from 6 to 10 years (from childhood to adolescence; Mean = 100.7 ± 17.04 months 51 females) and 60 adolescents and young adults from 12 to 23 years (from adolescence to adulthood; Mean = 194.30 ± 49.90 months 29 females) were involved in the behavioral study The children sample had been equally divided among five age groups (each group n = 20): 6 years old group (Mean = 77.1 ± 4 months 7 years old group (Mean = 88.7 ± 3.54 months 8 years old group (Mean = 109.5 ± 3.65 months 9 years old group (Mean = 113.2 ± 3.05 months and 10 years old group (Mean = 123.55 ± 3.27 months the adolescent and adult sample had been equally divided among three age groups: 11–12 years old group (Mean = 142.55 ± 6.14 months 14–15 years old group (Mean = 180.58 ± 6.77 months and 20–23 years old group (Mean = 259.5 ± 12.86 months 30 right-handed children and adolescents underwent a morphological MRI [age range: 79–180 months (6.6–15 years) Mean = 135.77 ± 28.19 months (11.31 ± 2.35 years) They additionally participated in various standard neuropsychological tests among which a verbal fluency test (i.e. this French task requires the participants to generate as many words as possible firstly in a letter fluency condition and secondly in a category fluency condition – 60 s are provided for each condition) All 30 children and adolescents accurately performed both the behavioral and the morphological MRI investigations on the same day objective recollection was assessed by asking the children to retrieve the corresponding source in the shape of the person who performed the match (matched by the experimenter; matched by the child or matched prior to the presentation) The WHERE task relied on between-domain spatial associations and is similar to the sub-test “Memory for designs” from the standardized battery NEPSY II (Korkman et al., 2007) Children were tested on their encoding of the exact location of each animal in an array (3 × 4 grid for children aged 6–10 years; 4 × 4 grid for children aged 11–18 years) They encoded the animal-location association by matching the colored frame surrounding the photograph of the animal to a colored marker in the center of each box of the grid Animals were presented one at a time and the child was asked to place each animal into the correct location The order of animals presentation was randomized across participants Animals remained in view as the child proceeded through the task children were given 1 min to review the animal-location associations children were again provided with the animals one at a time and were asked to place them in the array In this condition there were no color cues The WHEN task investigated between-domain sequential associative memory Children were asked to encode the animal-sequence association by placing the animals into slots in a wooden wheel the animal-sequence association was determined by color cues that appeared in each slot Each color corresponded to a specific animal children were provided with the full set of animals and required to place them into the slots following the sequence determined by the color showing in the slot at each turn of the wheel the children were given one opportunity to review the overall sequence for a maximum of 1 min children were again provided with the complete set of animals and required to retrieve the exact encoded sequence there were no color cues in this condition The measures derived from the WHAT-WHERE-WHEN test were then as follows: (i) For the WHAT task: (1) total number of correct animal-feature associations (WHAT); (2) total number of sources that were correctly provided (Objective Recollection); (3) ratio of Remember judgments provided for every accurate association (Subjective Recollection, with Recollection = Remember responses/total number of associations); (4) familiarity is calculated in absence of recollection (as defined by Yonelinas and Jacoby, 1995) with Familiarity = K/1-R where K = Know responses/total number of associations This formula allows us to analyze separately Know from Recollection judgments (ii) For the WHERE task: total number of correct animal-location associations (WHERE) (iii) For the WHEN task, we have taken into account both the correct placement of the animals individually and pairs of animals in the correct temporal order (see Riggins et al., 2009 for a similar approach) Thus one point was credited for each animal that was assigned to its rightful place in the sequence and 1/2 point was credited for each animals that accurately followed the original order but were inaccurately placed in the sequence [example A: animal one in first position animal three in third position = (1 + 1 + 1) = 4 points; example B: animal seven in first position and animal nine in third position = (2 × 1/2) = 1 point] The WHEN hits thus corresponds to the sum of placement and order in the sequence We normalized all associative memory scores and Objective Recollection scores This transformation of these possible heterogeneous raw scores into a common domain is needed prior to combining them into an episodic score (see below) and conducting parametric statistical analysis on normal distributions In order to assess overall episodic memory development we computed a composite score obtained as follow: first so it has been finally divided by the square root of the sum of the variance of the three subtests (which equals 3 × 1 since we used z-score) plus twice the sum of the covariance of the three subtests their covariances equal their correlation coefficients see “Combining different scores from tests” in “Advanced Topics” section of the Psych Assessment website This score assesses more specifically episodic memory since it encompasses three primary components of associative memory in the Service Hospitalier Frédéric Joliot (CEA-I2BM with the following parameters: TR = 9.9 ms; TE = 2 ms; IR-Prep-time = 600 ms; flip angle = 10°; voxel size:0.9 mm × 9 mm × 1.2 mm MRI data were segmented, normalized to a pediatric sample of the NIH (N = 324, age range = 4.5–18.5 years, Fonov et al., 2011), and modulated using the VBM5.1 toolbox (Ashburner and Friston, 2005) implemented in the Statistical Parametric Mapping 5 (SPM) software (Wellcome Trust Centre for Neuroimaging UK) to obtain maps of local gray matter volume corrected for brain size each image was smoothed with a Gaussian kernel (FWHM = 12 mm) we used a gray matter explicit mask in the voxelwise analyses so as to restrain the analyses to the gray matter This mask was obtained by first averaging all segmented gray matter and white matter images then thresholding the gray matter average to include voxels with a probability higher than 0.4 and the white matter average to include voxels with a probability higher than 0.2 the final GM mask used in the analyses was obtained by subtracting the WM mask from the GM mask We analyzed age-related changes on brain morphometry using two statistical models entering either age (linear) or age and age2 (quadratic) as predictors using this fitting model: volume = a0 + a1score + a2score2 + ϵ where a0, a1, and a2 are polynomial parameters to be found, and error represents the residual error of the model (Büchel et al., 1998; Hu et al., 2013) we included sex as a regressor of non-interest and WHEN) and the composite score referring to episodic memory were related to brain morphometry These analyses were conducted first on the whole brain and second within the hippocampus only using a hippocampus delineated on a template We performed the same regression analyses as before replacing age by the episodic score Note that the predictor variables were first orthogonalized before being entered together in the quadratic models: age and age2 for age-related analyses episodic and episodic score2 for brain-behavior relationships analyses Because any relationship between brain volumes and memory could be driven by the common effect of age or sex regression analyses with episodic memory were conducted with two regressors of non-interest (age and sex) we conducted a last set of correlations between fluency z-score (which combines both letter and category fluency) and: (1) each z-score (WHAT and WHEN) and the composite score referring to episodic memory (2) mean of gray matter volumes in clusters previously identified in brain-memory relationships analyses We performed one-way ANOVA for each task with age groups as between factor and Tukey’s adjustment for multiple comparisons (HSD). Those revealed three different developmental patterns (Figure 2) Behavioral performances on the associative memory tasks (A) Mean performance of associative cued recall (hits) for each memory task as a function of age (D) Mean subjective recollection and familiarity index Tuckey post hoc tests revealed a slight increase from the age of 6 to 9 followed by a marked increase between 9- and 10-year-olds (6 < 7 9; 10 – 7 < 10 – 8 < 10 – 9 < 10) The one-way ANOVAs conducted on each of the associative score revealed a significant group effect only for WHERE’s performance [F(2 57) = 4.74; p = 0.01; 11 – 12 < 21–24 age group] No significant developmental difference was evident for neither the two other associative memory tasks nor the episodic score Analysis conducted on the oldest age groups revealed that only the familiarity index decreased significantly from 11–12- to 21–23-year-olds [F(2 57) = 3.56; p = 0.03; 11 – 12 > 21–24 age group] The regression analysis focused on the hippocampus with the volume as the dependent variable and age as the predictor variable while controlling for the effect of sex indicate a significant reduction in the volume of the hippocampal body bilaterally extending (A) Age-related changes concern fronto-temporal and posterior parietal regions bilaterally (uncorrected p < 0.001 (B) A significant reduction was found in the hippocampus bilaterally with a more extended region in the left hippocampus (uncorrected p < 0.01 including the posterior part of the medial frontal gyrus (ii) the superior temporal cortex encroaching both the transverse temporal gyrus around the lateral sulcus and the inferior parietal lobule (iv) the ventrolateral prefrontal cortex (VLPFC) and Analyses performed on the hippocampus gray matter volume revealed significant relationships between memory efficiency and the body of the hippocampus on the right side and the anterior part of the hippocampus on the left side Scatterplots of these effects showed that the enhancement of episodic performances was mainly associated with a decrease in mean volumes except for three participants with the highest scores (A) Significant positive correlation (quadratic U-shaped) with episodic score was found with the volume of gray matter in dorsolateral frontal regions bilaterally and the ventrolateral prefrontal cortex (upper figure (B) Scatterplots of episodic effects are shown for regions identified in whole brain analyses (C) Significant positive correlation (quadratic U-shaped) was observed between memory and right hippocampal body and the anterior part of the left hippocampus (uncorrected p < 0.01 Brain – associative memory relationships Correlational behavioral analyses revealed significant positive correlation between fluency z-score and each associative memory task (p = 0.004 WHAT; p = 0.026 WHERE; p = 0.003 WHEN) and the episodic composite score (p = 0.003) indicating that better efficiency in verbal fluency was associated with better performances in associative memory we observed a significant negative correlation between the fluency z-score and two clusters previously detected dorsolateral frontal regions bilaterally and the superior temporal cortex a decrease in volume in these three cortical regions was associated with increased efficiency in verbal fluency These analyses did not detect any statistical correlation with the hippocampus The first aim of the present study was to describe the developmental trajectories of associative memory distinguishing within-domain (factual) and between-domain (spatial and temporal) associations by means of an original single paradigm Results showed that these three types of associative memory follow distinct developmental trajectories: a slight but continuous increase of within-domain factual associative memory (WHAT) a linear increase of between-domain spatial associative memory (WHERE) and noticeable changes in between-domain temporal associative memory from 9 to 10 years (WHEN) the composite score that combines the three associative components of episodic memory (the “episodic score”) showed a slight but significant increase up to 9 years followed by a marked increase from 9 to 10 source memory) and subjective recollection improved with age with the most important effects from 8 to 10 years these findings highlight major changes from 8–9 to 10 years adolescence is characterized by slight changes including enhancement of spatial associative memory and noticeable decrease in familiarity Voxel-based morphometry suggests that episodic memory performance is related to gray matter volume changes (i.e. following an inverted U-curve) in temporal regions including medial structures Although these cortical regions and medial temporal structures have been previously described in functional studies no such morphological data have been reported in developmental studies in relation with participants’ overall associative memory efficiency our results point out the relevance of using a single paradigm to assess associative memory and recollection in order to get a more comprehensive picture of episodic memory development All these cognitive functions develop through childhood and adolescence and may contribute to the age-related effect on spatial processes observed in the present study from six to early adulthood though not significant increase of performance during adolescence Debriefing of the participants after the test allows us to hypothesize that this results from the particular design of the task itself many adolescents explained that they intentionally created a script on the bases of the animal orders (i.e. “when the urodel runs after the almiqui …”) the use of verbal strategies to encode the sequence in a chronological and meaningful order at this age may impact subsequent retrieval this is in accordance with our additional analyses showing a significant correlation between verbal fluency efficiency and the WHEN the above mentioned data suggest that associative episodic memory maturation depends on the type of information to be bound and that the overall processes may differentially contribute to episodic memory enhancement the evolution of the combining episodic score through childhood tends to be non-linear prompted by the time course of temporal memory the period of late childhood (9–10 years of age) is crucial in the developmental time course of episodic memory Objective and subjective recollection have been distinguished in functional (Spaniol et al., 2009 for review) and clinical studies (Duarte et al., 2008) in adults and have more recently encounter an increasing interest in the developmental literature (Ghetti and Angelini, 2008; Picard et al., 2009; Friedman et al., 2010) The authors notably pointed out the relationship between familiarity and mid-frontal regions recruitment restricted to adolescents these data argue for a comprehensive approach based on both neuroimaging and behavioral studies to understand age-related effects on episodic memory maturation The present study pointed out the relationship between an increase in associative memory efficiency and a decrease in gray matter volume in a large cerebral network (including the dorsolateral and VLPFC, superior and anterior temporal regions) and the hippocampus bilaterally. In our sample, only three participants displayed a different pattern. As Shaw et al. (2006) argued in their study on global intellectual efficiency and cortical thickness in which they reported different developmental trajectories of cortical thickness according to participants’ IQs the variability in our sample may reflect different trajectories depending on the individual level of memory performance increased performances were related with volume reduction in the dorsolateral and the VLPFC the reduction of DLPFC was also correlated with increased performances in verbal fluency in our sample thus suggesting a possible contribution of executive functions to memory efficiency as measured by the WHAT-WHERE-WHEN paradigm further investigations are needed to understand the contribution of the hippocampus along its longitudinal axis to the development of episodic memory we observed that the reduced volume in the superior temporal cortex extending to the inferior parietal lobule was related to episodic enhancement in children and adolescents This region was not reported in previous structural studies but could support the generation of verbal strategies in our three associative tasks The negative correlation between the volume reduction in the superior temporal cortex and the increase in verbal fluency performance would be consistent with this hypothesis is this cortical region involved in a larger fronto-parietal network including dorsolateral PFC that would implement cognitive control functions on memory functioning and would support the progressive development of top-down attention modulation Our findings bring interesting perspectives to assess episodic memory from childhood to adolescence in a more comprehensive way the present study is the first to address episodic memory maturational trajectories by investigating its main components within the same paradigm It thus provides a more accurate picture of how episodic memory processes (i.e. binding of within/between-domain information By confronting behavioral results to structural data we also describe the cortical regions that subserve episodic memory efficiency as a whole the present study failed to detect finer relationships between each component (factual Knowing the large inter-individual variability in both memory efficiency and cerebral maturation in children and adolescents we assume that the lack of sensitivity in morphometric analyses could be overcome in a larger cohort the behavioral and structural analyses questioned the implication of maturing executive processes that may explain the differential trajectories that we report according to the type of information to be encoded and recollected This hypothesis needs to be directly addressed in a future study by using more dedicated executive tasks Besides its relevance to provide additional data to the research literature, the present paradigm is considered to be a sensitive and valid tool to assess episodic memory in the clinical setting. The WHAT-WHERE-WHEN paradigm has been administered to children and adolescents suffering from temporal lobe epilepsy and has successfully detected differential profiles of deficits according to epilepsy lateralization (Guillery-Girard et al., 2010) It thus can be helpful to reveal possible memory dissociations in young patients Episodic memory refers to the capacity to bind different components into a single representation that will promote a vivid sense of re-experiencing at retrieval our findings show the differential developmental trajectories of episodic memory processes in relationship with both cortical changes and neuropsychological factors such as verbal strategies and executive functions the present study suggests that the multimodal integration would be related to the maturation of temporal regions and may be modulated by a fronto-parietal network Despite a limited sample for structural analyses this study confirms the need to combine neuroimaging and behavioral data in order to better understand the developmental trajectory of episodic memory in a research setting and to use a single paradigm to assess episodic memory as a whole in a clinical setting We would like to thank Valerie Gyselinck and Maud Markus for their contribution to the WHAT-WHERE-WHEN paradigm development and Lionel Allirol for their assistance with data collection We are grateful to Jane Holmes-Bernstein for her helpful comments on the manuscript We are also indebted to the participants and institutions that took part in our research Assessment and development of executive function (EF) during childhood Associations between performance on the Rey-Osterrieth Complex Figure and regional brain volumes in children with and without velocardiofacial syndrome Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of sex differences in spatial memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Developmental patterns in priming and familiarity in explicit recollection Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of the adolescent brain: implications for executive function and social cognition Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Using model-based functional MRI to locate working memory updates and declarative memory retrievals in the fronto-parietal network Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Behavioral measurement of remembering phenomenologies: so simple a child can do it Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Characterizing stimulus-response functions using nonlinear regressors in parametric fMRI experiments CrossRef Full Text Memory for items and associations: distinct representations and processes in associative recognition Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The role of local and distal landmarks in the development of object location memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The role of landmarks and boundaries in the development of spatial memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of face recognition: a maturational component CrossRef Full Text Developmental differences in hippocampal and cortical contributions to episodic retrieval Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The effects of aging on the neural correlates of subjective and objective recollection Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Spatial and temporal episodic memory retrieval recruit dissociable functional networks in the human brain Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Unbiased average age-appropriate atlases for pediatric studies Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Changes in familiarity and recollection across the lifespan: an ERP perspective Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of temporal-reconstructive abilities Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The development of recollection and familiarity in childhood and adolescence: evidence from the dual-process signal detection model Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Neural changes underlying the development of episodic memory during middle childhood Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Developmental differences in medial temporal lobe function during memory encoding Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of subjective recollection: understanding of and introspection on memory states Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Structural magnetic resonance imaging of the adolescent brain Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dynamic mapping of human cortical development during childhood through early adulthood Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dynamic mapping of normal human hippocampal development Pubmed Abstract | Pubmed Full Text | CrossRef Full Text “L’évaluation neuropsychologique de la mémoire chez l’enfant,” in Approche Neuropsychologique des Troubles des Apprentissages The development of explicit memory for basic perceptual features Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Volumetric analysis of medial temporal lobe structures in brain development from childhood to adolescence Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Age-related change in executive function: developmental trends and a latent variable analysis doi:10.1016/j.neuropsychologia.2006.01.010 Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Delay-induced bias in children’s memory for location Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Verbal and visual memory impairment in children with epilepsy Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Making the case that episodic recollection is attributable to operations occurring at retrieval rather than to content stored in a dedicated subsystem of long-term memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Memory binding in early childhood: evidence for a retrieval deficit Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Feature binding in children and young adults Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Associative memory and the medial temporal lobes Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Memory and temporal perspective: the role of temporal frameworks in memory development CrossRef Full Text The relationship between theory of mind and episodic memory: evidence for the development of autonoetic consciousness Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Differential developmental trajectories for egocentric environmental and intrinsic frames of reference in spatial memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The development of spatial location coding: place learning and dead reckoning in the second and third years CrossRef Full Text General and specific brain regions involved in encoding and retrieval of events: what Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The development of brain systems associated with successful memory retrieval of scenes Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of the declarative memory system in the human brain Pubmed Abstract | Pubmed Full Text | CrossRef Full Text From perception to memory: changes in memory systems across the lifespan Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dissociating memory processes in the developing brain: the role of hippocampal volume and cortical thickness in recall after minutes versus days Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Age differences in source monitoring of performed and imagined actions on immediate and delayed tests CrossRef Full Text Young children’s memory for the times of personal past events CrossRef Full Text Strength of Coupling within a mnemonic control network differentiates those who can and cannot suppress memory retrieval Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Developmental differences in implicit and explicit memory performance Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Episodic memory and autonoetic consciousness: developmental evidence and a theory of childhood amnesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text How do the different components of episodic memory develop Role of executive functions and short-term feature-binding abilities Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of autonoetic autobiographical memory in school-age children: genuine age effect or development of basic cognitive abilities Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Do school-age children remember or know the personal past CrossRef Full Text Developmental differences in memory for cross-modal associations Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Developmental changes in the engagement of episodic retrieval processes and their relationship with working memory during the period of middle childhood Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of allocentric spatial memory abilities in children from 18 months to 5 years of age CrossRef Full Text Relational memory during infancy: evidence from eye tracking Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Electrophysiological indices of memory for temporal order in early childhood: implications for the development of recollection Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Sequential memory: a developmental perspective on its relation to frontal lobe functioning CrossRef Full Text Source monitoring and false memories in children: relation to certainty and executive functioning Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Memory development in the second year: for events or locations Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The two-component model of memory development and its potential implications for educational settings Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Intellectual ability and cortical development in children and adolescents Pubmed Abstract | Pubmed Full Text | CrossRef Full Text and recall of naturalistic events: a developmental perspective Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Improved memory functioning and frontal lobe maturation between childhood and adolescence: a structural MRI study Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Event-related fMRI studies of episodic encoding and retrieval: meta-analyses using activation likelihood estimation doi:10.1016/j.neuropsychologia.2009.02.028 Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Developmental aspects of working and associative memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text doi:10.1146/annurev.psych.53.100901.135114 CrossRef Full Text Rey AVLT: developmental norms for children and the sensitivity of different memory measures to age CrossRef Full Text Cortical correlates of self-generation in verbal paired associate learning Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The NIH MRI study of normal brain development: performance of a population based sample of healthy children aged 6 to 18 years on a neuropsychological battery Object location memory: the interplay of multiple representations Pubmed Abstract | Pubmed Full Text | CrossRef Full Text An integrative model of the development of autobiographical memory CrossRef Full Text Neural indices of improved attentional modulation over middle childhood Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dissociating automatic and controlled processes in a memory-search task: beyond implicit memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Separating the brain regions involved in recollection and familiarity in recognition memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Cognitive correlates of medial temporal lobe development across adolescence: a magnetic resonance imaging study Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish. Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases. Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training. Long-term spatial memory was assessed 28 days later. Ex-vivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume. Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later. Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition, sensory, and motor processing. Discussion: Our findings give the first whole brain overview of long-term anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease. Volume 17 - 2023 | https://doi.org/10.3389/fnsys.2023.1134594 Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training Long-term spatial memory was assessed 28 days later Ex-vivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition Discussion: Our findings give the first whole brain overview of long-term anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease there has not yet been investigation of the effect of 7,8-DHF on brain-wide changes in volume In the current study we assessed the effect of 7,8-DHF administration on long-term spatial memory in mice and evaluated effects on brain volume using post-mortem whole-brain anatomical T2-weighted (T2w) imaging. Superior resolution and contrast can be gained by using ex-vivo MRI (Lerch et al., 2012) although arguably less stress is caused compared to alternative tests that use prolonged dietary restriction Steps taken to limit stress in this study included using low level lighting and limiting the number of trials to three on the first day of exposure to the water Stress caused by the experimenter was also limited as outlined in the section above was filled with water to a depth of ~0.29 m the mice were required to find a hidden platform (diameter 21 cm) with fixed location and submerged approximately 1 cm below the water surface The swim paths of the mice were recorded and tracked using Watermaze software (Actimetrics During the training period the mice received four trials per day for a total of 7 days In each trial they were placed into the pool at one of eight different starting points in a randomly selected order The mice had a maximum of 90 s to find the platform and once found remained on the platform for 15 s the mice were guided gently to the platform’s location Twenty-eight days later the mice underwent a probe test During the probe test the platform was removed and the mice swam freely for 45 s The percentage of time they spent in the four quadrants of the maze along with their average speed were recorded Following the MWM probe test, 24 randomly selected mice (DHF n = 12; f = 9/m = 3, vehicle n = 12; f = 7/m = 5) were anaesthetized using pentobarbital and perfused with 30 ml of PBS containing Gadovist (2 mM, Bayer, Berlin, Germany), followed by 30 ml of 4% paraformaldehyde containing Gadovist (2 mM, Bayer) and Heparin (1 μl/ml, Wockhardt, Wrexham, UK) at a flow rate of 1 ml/min (Cahill et al., 2012) The skulls containing the brains were removed and postfixed in 4% PFA with 2 mM Gadovist for 36 h at 4°C They were then transferred into PBS with 0.02% sodium azide and Gadovist and stored at 4°C the skulls were transferred into a 15 ml falcon tube containing fluorinert (3M) and placed in a vacuum pump to remove any potential bubbles The MRI data was collected on a BioSpec 70/20 (7T field strength 20 cm bore diameter) small animal MR system with a Paravision 360 console (Bruker BioSpin MRI T2w anatomical MRI was acquired using TurboRARE 3D with the following parameters: TR = 350 ms field of view (FOV) 24 × 9.6 × 12 mm matrix size 400 × 160 × 200 resolution = 60 × 60 × 60 μm MWM behavioural data were assessed for normal distribution using the Shapiro-Wilk test and for homogeneity of variances using Levene’s test If the data was found to have normal distribution and homogeneity of variances then two-way mixed ANOVA independent student’s t-test or Pearson’s r test were used If the assumptions for parametric tests were not met then a Wilcoxon rank sum test was used Data were analysed with R studio (version 2021.09.2) Data are presented as mean ± standard deviation (SD) or standard error of the mean (SEM); graphs were generated in GraphPad Prism (version 9.3.0) A linear mixed effect model was then fit either at each voxel or at each ROI Two mice were excluded from the T2w analysis due to incomplete Jacobian outputs Voxelwise clusters showing significant drug-related effects were then used to extract average Jacobian values across voxels within the cluster for each mouse These Jacobian values were then correlated with the respective behavioural performance of each mouse (as measured by the percentage of time spent in the target quadrant) through a Pearson’s r two-tailed test Long-term memory performance in the Morris water maze (A) Both the mice that received 7,8-DHF and vehicle following each training session successfully learnt the location of the platform during the training period (B) The 7,8-DHF group spent a greater percentage of time in the target quadrant during the 28-day probe test (C,D) The 7,8-DHF group found the platform quicker and crossed it more often than the controls (E) Swim speed was equivalent between groups A voxelwise analysis tested for whole-brain volumetric bidirectional changes using Jacobian determinant images in mice that had received 7,8-DHF (n = 10; f = 8/m = 2) during the MWM training period compared with those that received vehicle (n = 12; f = 7/m = 5) Widespread volumetric changes were observed (tpeak = 4.21 the average Jacobian values across all significant voxelwise clusters for each subject in the 7,8-DHF group were not found to correlate with the percentage of time spent in the target quadrant of the MWM during the 1-month probe test (Pearson’s r = −0.1 p > 0.05) Other ROIs showed a smaller volume in the 7,8-DHF group including the right (q = 0.05) and left (q = 0.05) ventral tenia tecta and the left stratum lucidum hippocampus (SLu q = 0.05) and the cornu ammonis 1 (CA1) pyramidal layer (q = 0.05) Brain regions showing volume expansion and contraction following 7,8-DHF administration Brain structures showing an increase in volume following 7,8-DHF administration Brain structures showing a decrease in volume following 7,8-DHF administration We found that administering 7,8-DHF resulted in changes to brain volume in a wide range of brain areas including area 24 of the cingulate cortex and deep cerebellar nuclei including the fastigial nucleus 7,8-DHF was also found to decrease volume in other regions including the ventral tenia tecta and regions of the hippocampus find any significant correlation with the percentage of time spent in the target quadrant time to reach the target platform or number of platform crosses during the MWM probe test Given the broad range of diseases and behaviours that 7,8-DHF has been associated with it is perhaps not surprising that numerous brain areas were found to be altered by its administration Further research will be needed to determine the behaviours these brain volumes changes are associated with We have outlined below previous literature indicating potential roles of these brain regions in behaviour and disease to inspire future work using 7,8-DHF we found that 7,8-DHF when administered during MWM training enhances long-term spatial memory Changes in brain volume in a wide range of brain areas was observed but were not found to correlate with spatial memory enhancement Gaining an overview of the brain regions affected by 7,8-DHF administration is critical when assessing it for therapeutic use All animal experiments were approved under the UK Animals (Scientific Procedures) Act 1986 and JL contributed to the data analysis and revised the manuscript HJ-B contributed to interpretation of the data and revised the manuscript All authors gave final approval of the version to be published and agree to be accountable for all aspects of the work All authors contributed to the article and approved the submitted version This work was funded by a senior Wellcome Trust grant HMR01180 to HJ-B We thank Claire Bratley for initial MRI acquisition training Flavonoid derivative 7,8-DHF attenuates TBI pathology via TrkB activation Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice 7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer’s disease by reversing oxidative stress mitochondrial dysfunction and insulin resistance Optimized integration of fluoxetine and 7,8-dihydroxyflavone as an efficient therapy for reversing depressive-like behavior in mice during the perimenopausal period blocks long-term spatial memory impairment caused by immobilization stress in rats Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory Protective effects of 7,8-dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer’s disease Bermudez-Rattoni The forgotten insular cortex: its role on recognition memory formation PubMed Abstract | CrossRef Full Text | Google Scholar 7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice improves spatial memory and increases thin spine density in a mouse model of alzheimer disease-like neuronal loss Performing label-fusion-based segmentation using multiple automatically generated templates Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: a systematic review of symptom-general and -specific lesion patterns 7,8-dihydroxyflavone protects high glucose-damaged neuronal cells against oxidative stress A unified statistical approach to deformation-based morphometry PubMed Abstract | CrossRef Full Text | Google Scholar reverses memory deficits and BACE1 elevation in a mouse model of alzheimer’s disease High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice The organization of the primate insular cortex PubMed Abstract | CrossRef Full Text | Google Scholar Sex-specific stress and biobehavioral responses to human experimenters in rats Differential insular cortex sub-regional atrophy in neurodegenerative diseases: a systematic review and meta-analysis Afferents to anterior cingulate areas 24a and 24b and midcingulate areas 24a’ and 24b’ in the mouse Efferents of anterior cingulate areas 24a and 24b and midcingulate areas 24a’ and 24b’ in the mouse Pydpiper: a flexible toolkit for constructing novel registration pipelines TrkB activation by 7,8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer’s disease Thresholding of statistical maps in functional neuroimaging using the false discovery rate Timing of treatment with the flavonoid 7,8-DHF critically impacts on its effects on learning and memory in the Ts65Dn mouse Social interaction rescues memory deficit in an animal model of Alzheimer’s disease by increasing BDNF-dependent hippocampal neurogenesis A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone Small-molecule TrKB receptor agonists improve motor function and extend survival in a mouse model of huntington’s disease 7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis 7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: implications for early brain trauma recovery Posterior cingulate cortex network predicts Alzheimer’s disease progression The tradeoff between in-vivo versus ex-vivo MR brain imaging in the mouse is useful for treating various BDNF-implicated human disorders Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents Dietary strawberry improves cognition in a randomised Spatial localization does not require the presence of local cues CrossRef Full Text | Google Scholar 7,8-dihydroxyflavone protects nigrostriatal dopaminergic neurons from rotenone-induced neurotoxicity in rodents The mystery of claustral neural circuits and recent updates on its role in neurodegenerative pathology The insular cortex and the regulation of cardiac function PubMed Abstract | CrossRef Full Text | Google Scholar Do small molecules activate the TrkB receptor in the same manner as BDNF Limitations of published TrkB low molecular agonists and screening for novel TrkB orthosteric agonists Role of the anterior cingulate cortex in the retrieval of novel object recognition memory after a long delay Mouse MRI shows brain areas relatively larger in males emerge before those larger in females Segmentation of the mouse hippocampal formation in magnetic resonance images The cingulate cortex and limbic systems for emotion PubMed Abstract | CrossRef Full Text | Google Scholar The orbitofrontal cortex and emotion in health and disease doi: 10.1016/j.neuropsychologia.2017.09.021 PubMed Abstract | CrossRef Full Text | Google Scholar Functional connectivity of the anterior cingulate cortex in depression and in health The impact of handling technique and handling frequency on laboratory mouse welfare is sex-specific 7,8-DHF and their co-treatment prevents loss of vision and cognitive decline in a Wolfram syndrome rat model A role for the claustrum in salience processing causes stress and related analgesia in rodents The insular cortex and the neuroanatomy of major depression A flavonoid agonist of the TrkB receptor for BDNF improves hippocampal neurogenesis and hippocampus-dependent memory in the Ts65Dn mouse model of DS Genetic effects on cerebellar structure across mouse models of autism using a magnetic resonance imaging atlas 7,8-dihydroxyflavone ameliorates cognitive impairment by inhibiting expression of tau pathology in ApoE-knockout mice 7,8-Dihydroxyflavone leads to survival of cultured embryonic motoneurons by activating intracellular signaling pathways Structure and function of the human insula A segmentation protocol and MRI atlas of the C57BL/6J mouse neocortex Value of water mazes for assessing spatial and egocentric learning and memory in rodent basic research and regulatory studies Utility of 7,8-dihydroxyflavone in preventing astrocytic and synaptic deficits in the hippocampus elicited by PTSD 7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease 7,8-Dihydroxyflavone protects neurons against oxygen-glucose deprivation induced apoptosis and activates the TrkB/Akt pathway Connections of the mouse orbitofrontal cortex and regulation of goal-directed action selection by brain-derived neurotrophic factor Lerch JP and Johansen-Berg H (2023) 7,8-dihydroxyflavone enhances long-term spatial memory and alters brain volume in wildtype mice Received: 30 December 2022; Accepted: 21 February 2023; Published: 15 March 2023 Copyright © 2023 Rawlings-Mortimer, Lazari, Tisca, Tachrount, Martins-Bach, Miller, Lerch and Johansen-Berg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Florence Rawlings-Mortimer, ZmxvcmVuY2VyYXdsaW5nc21vcnRpbWVyQGdtYWlsLmNvbQ== Metrics details Preventing childhood obesity is a public health challenge of the twenty-first century and it must be a priority Governments play a major role in creating and supporting a healthy school environment and should prioritise actions to improve children’s health Sintra Grows Healthy aims to promote healthy lifestyles to prevent childhood obesity and improve children’s health-related quality of life and social and emotional skills through the development of a school evidence-based and sustainable model This protocol describes a quasi-experimental design and community-based participatory research The participants included in the study are the school community of Portuguese public primary schools from the municipality of Sintra Data will be collected on demographic and socio-economic characterization There is evidence to support interventions in school settings as strategies for obesity prevention Up-to-date homogeneous and community-based interventions for preventing childhood obesity are lacking therefore Sintra Grows Healthy intends to fill this gap Sintra Grows Healthy aims to contribute with relevant scientific findings that will allow the development of better strategies for policymakers and society to manage this major public health problem this study protocol aimed to describe the design and methodology of the Sintra Grows Healthy This protocol reports a community intervention with a quasi-experimental design and community-based participatory research The study was developed by the municipality of Sintra (the project owner) with a partnership between health and academic entities as stakeholders: Sintra Health Centres Group College of Communication and Media Studies (Polytechnic Institute of Lisbon) Lisbon School of Health Technology (Polytechnic Institute of Lisbon) Nutrition Laboratory of Faculty of Medicine (University of Lisbon) Faculty of Human Kinetics (University of Lisbon) SGH has the institutional support of organisations such as Ministry of Health Portuguese National Programme for the Promotion of Healthy Eating Portuguese National Programme for the Promotion of Physical Activity Food and Agriculture Organisation of the United Nations (FAO) – Portugal NOVA National School of Public Health (NOVA University Lisbon) and Food Farming & Forestry College (F3) (University of Lisbon) Sintra’s School Network includes 20 public school clusters with a total of 96 kindergartens and primary schools The study includes the respective subgroup of 83 primary schools from the municipality of Sintra (approximately 13,100 children) we are recruiting 16 schools and our goal is to reach within 5 years the entire population - the 83 primary schools from the municipality of Sintra The sample is selected by the schools’ convenience and split into an intervention group and a control group guaranteeing the sample size required to reach the minimum difference of proportions between groups of 3–5% with at least 80% statistical power Any children who meet the inclusion criteria (attend the primary schools belonging to the project and give written freely given informed consent for participation with children’s legal guardian approval and signature) and do not meet the exclusion criteria (to have a motor and/or intellectual disabilities and/or not present a valid consent for participation) are eligible (census procedure) As mentioned in the informed consent this study does not represent any risk SGH aims to develop a sustainable model of intervention to promote healthy lifestyles in a school environment and to evaluate its impact SGH community-based intervention focuses on community actors and prioritises three axes: 1) food and nutrition curricula named Health at the Table 2) school food environment and 3) physical activity a specialised team will design a set of communication tools to inform engage and motivate all the stakeholders involved in the process teachers and other actors who play an important role in the school environment The intervention follow-up will occur during each school year from the first to fourth grade SGH researchers will assure continuous monitoring and disclosure of a quarterly report for all intervention axes to the schools to communicate and verify the school community engagement This axis will be monitored through a weekly submission in an SGH platform for each food and nutrition education sessions applied by the teachers teachers will fill in a form regarding the application of each session and will answer several questions children’s competencies achieved and activity adequacy) The municipality of Sintra has already developed several policies to provide children with a healthier school food environment such as assuring the quality of school meals being all menus established by registered nutritionists/dietitians a salt control policy has been implemented at school lunches Sintra assures professional ongoing training of cooks and monthly healthy culinary workshops for families Snacks Diagnosis – Qualitative and quantitative evaluation of foods consumed by children in both morning and afternoon snacks Snacks Assembly – Within the scope of health at the table children will organise an assembly to discuss the quality of theirs snacks: what is a healthy snack which causes lead to the consumption of unhealthy snacks by the class and what they could implement to improve their snacks with the main conclusions of their debate to be discussed in an assembly with the school community the school community will afterwards construct a healthy snacks policy After construction and approval of the healthy snacks policy it will be incorporated into the school regulation Sintra Grows Healthy framework of action Questionnaires are important to assess physical activity because they help to understand the context in which it occurs the questionnaires do not allow to determine the intensity of the activity practised regularly children also have difficulty reporting the intensity of activities accurately accelerometers are important to understand the levels of intensity of physical activity practised To determine the physical activity intensity children will wear an accelerometer for at least two weekdays and one weekend SGH study data will be centralized by the project executive responsible who will hold the participant individuals’ coded key All individuals involved in the study will be assigned a single anonymised code that will be used to link the respective data across all the existing databases/tables Each of the performed surveys will have its own database/table with the participant individuals anonymised code Regular reporting will be performed using RStudio Notebooks that collect information from the several available databases/tables The iterative process of automatic generation of data reporting identifies errors originated by OCR transposition of paper questionnaires to digital databases/tables The SGH protocol promotes extensive data collection with baseline data points and follow-up points and with individuals entering and exiting the study during its expected implementation this represents a great challenge for the study data management and analysis statistical characterisation will be performed using descriptive statistics (absolute and relative frequencies for qualitative variables and mean and standard-deviations or median and IQRs for quantitative variables according to verification normality distribution assumption using the Shapiro-Wilk test) Bivariate relations with the main socioeconomic characteristics will be tested using chi-square tests or Fisher exact test (when both variables will be qualitative); Pearson or Spearman’s correlation coefficients (when both variables will be quantitative); and t- ANOVA or Mann-Whitney and Kruskal-Wallis tests (when one variable will be quantitative and the other qualitative whether parametric test use will be met or not and according to the discrepancy of sample size between groups) For the comparison of two moments of the same quantitative variable the paired-samples t-test or the Wilcoxon signed-rank test will be used the Generalized Linear Models family will be used (it includes Multiple Linear Regression and Negative Binomial regression among other models) SGH aims to contribute with relevant research to obtain evidence-based practices providing significant knowledge for policymakers and health and education professionals’ actions the sustainability and future reproduction of good practices through the empowerment of the school community preventing the increase of childhood obesity prevalence and improving children’s social and emotional skills and health-related quality of life SGH will innovate by its consistent monitoring and scientific evaluation to establish a sustainable and effective intervention model to prevent childhood obesity Quality control and assurance of procedures through training of researchers processes of internal data quality verification will be taken an annual report addressed to policymakers will be developed there will be strategic thinking about all the issues concerning the institutional communication of the intervention as well as social behaviour change communication SGH scientific dissemination of findings will be assured through a shared publication policy with SGH consortium It is crucial to reinforce public investment in health namely through the presence of more health professionals in local governments and schools prioritsing the measurement of the impact of their interventions through partnerships with academic researchers In addition to having evidence-based practices it is also essential to obtain more evidence based on practices Implementing this study protocol will bring relevant scientific findings regarding different factors related to childhood obesity allowing the development of better strategies to manage this major health problem Blundell JE, Baker JL, Boyland E, Blaak E, Charzewska J, de Henauw S, et al. Variations in the prevalence of obesity among European countries, and a consideration of possible causes. Obes Facts. 2017;10:25–37. https://doi.org/10.1159/000455952 World Health Organization. Adolescent obesity and related behaviours : trends and inequalities in the WHO region 2002-2014; 2017. https://doi.org/10.4103/0972-5229.178178 Development Initiatives. 2020 global nutrition report: action on equity to end malnutrition. Bristol, UK; 2020. https://doi.org/10.2499/9780896295841 Manios Y, Costarelli V, Ahrens W. Epidemiology of obesity in children and adolescents. New York, NY: Springer New York; 2011. https://doi.org/10.1007/978-1-4419-6039-9 Goisis A, Martinson M, Sigle W. When richer doesn’t mean thinner: Ethnicity, socioeconomic position, and the risk of child obesity in the United Kingdom. Demogr Res. 2019;41(September):649–78. https://www.demographic-research.org/volumes/vol41/23/ Litwin SE. Childhood obesity and adulthood cardiovascular disease. J Am Coll Cardiol. 2014;64:1588–90. https://doi.org/10.1016/j.jacc.2014.07.962 Reilly JJ, Kelly J. Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review. Int J Obes. 2011;35:891–8. https://doi.org/10.1038/ijo.2010.222 OECD. The heavy burden of obesity. In: OECD health policy studies, editor. Paris: OECD Publishing; 2019. https://doi.org/10.1787/b53ed5f9-fr Lopes C, Torres D, Oliveira A, Severo M, Alarcão V, Guiomar S, et al. Inquério Alimentar Nacional e de Atividade Física, IAN-AF 2015–2016: Relatório de resultados: Universidade do Porto; 2017. www.ian-af.up.pt Ferreira RJ, Marques-Vidal PM. Prevalence and determinants of obesity in children in public schools of Sintra. Portugal Obesity. 2008;16:497–500. https://doi.org/10.1038/oby.2007.74 UN General Assembly. Universal Declaration of Human Rights. 1948. https://www.refworld.org/docid/3ae6b3712c.html Food and Agriculture Organisation of the United Nations, World Health Organization. Conference Outcome Document: Rome Declaration on Nutrition. In: Second International Conference on Nutrition. 2014. p. 19–21. https://doi.org/10.1044/leader.PPL.19102014.18 Hawkes C, Smith TG, Jewell J, Wardle J, Hammond RA, Friel S, et al. Smart food policies for obesity prevention. Lancet. 2015;385:2410–21. https://doi.org/10.1016/S0140-6736(14)61745-1 Assembleia da República. Lei n.o 75/2013. Diário da República no 176. 2013;:5688–724. https://dre.pt/application/conteudo/500023 Assembleia da República. Lei n.o 50/2018. Diário da República no 157. 2018;:4102–8. https://dre.pt/application/conteudo/500023 Quality physical education: guidelines for policy-makers Scientific and Cultural Organization; 2015 World Health Organization Regional Office for Europe. Food and nutrition policy for schools: A Tool for the Development of School Nutrition Programmes in the European Region. WHO Regional Office for Europe. Copenhagen; 2006. http://www.euro.who.int/pubrequest Warburton DER, Bredin SSD. Health benefits of physical activity. Curr Opin Cardiol. 2017;32:541–56. https://doi.org/10.1097/HCO.0000000000000437 Global recommendations on physical activity for health Global trends in insufficient physical activity among adolescents: a pooled analysis of 298 population-based surveys with 1·6 million participants Correlates of gross motor competence in children and adolescents: a systematic review and meta-analysis World Health Organization. Ottawa Charter for Health Promotion: First International Conference on Health Promotion. Ottawa; 1986. https://www.healthpromotion.org.au/images/ottawa_charter_hp.pdf Food and Agriculture Organization of the United Nations. Nutrition education in primary schools. Food and Agriculture Organization of the United Nations; 2006. http://www.fao.org/3/a-a0333e.pdf Buijs GJ. Better schools through health: networking for health promoting schools in Europe. Eur J Educ. 2009;44:507–20. https://doi.org/10.1111/j.1465-3435.2009.01410.x Clift S, Jensen BB. The health promoting school : international advances in theory, evaluation and practice. 1st edition. Copenhagen: European Network of Health Promoting Schools by Danish University of Education Press The; 2005. www.dpu.dk/forlag Centers for Disease Control and Prevention. Comprehensive School Physical Activity Programs: A Guide for Schools. GA: U.S. Department of Health and Human Services; 2013. http://www.shapeamerica.org/cspap/index.cfm Brown T, Moore TH, Hooper L, Gao Y, Zayegh A, Ijaz S, et al. Interventions for preventing obesity in children. Cochrane Database Syst Rev. 2019. https://doi.org/10.1002/14651858.CD001871.pub4 World Health Organization. First Conference of the European Network of Health Promoting Schools “The Health Promoting School-an investment in education, health and democracy.” Thessaloniki-Halkidiki, Greece; 1997. https://apps.who.int/iris/handle/10665/107850 Physical activity and nutrition education at the school environment aimed at preventing childhood obesity: evidence from systematic reviews Population-based approaches to childhood obesity prevention Switzerland: World Health Organization; 2012 Skills for social Progress: the power of social and emotional skills Weihrauch-Blüher S, Kromeyer-Hauschild K, Graf C, Widhalm K, Korsten-Reck U, Jödicke B, et al. Current guidelines for obesity prevention in childhood and adolescence. Obes Facts. 2018;11:263–76. https://doi.org/10.1159/000486512 Khambalia AZ, Dickinson S, Hardy LL, Gill T, Baur LA. A synthesis of existing systematic reviews and meta-analyses of school-based behavioural interventions for controlling and preventing obesity. Obes Rev. 2012;13:214–33. https://doi.org/10.1111/j.1467-789X.2011.00947.x Pearson M, Chilton R, Wyatt K, Abraham C, Ford T, Woods H, et al. Implementing health promotion programmes in schools: a realist systematic review of research and experience in the United Kingdom. Implement Sci. 2015;10:149. https://doi.org/10.1186/s13012-015-0338-6 Filipe J, Godinho CA, Graça P. Intervenções comportamentais de prevenção da obesidade infantil: Estado da arte em portugal. Psychol Community Heal. 2016;5:170–84. https://doi.org/10.5964/pch.v5i2.175 Borowy I. Sustainable health: the need for new developmental models. Bull World Health Organ. 2014;92:699. https://doi.org/10.2471/BLT.14.145219 Transforming Our World: The 2030 Agenda for Sustainable Development 2015 Assembleia da República. Lei n.o 55/2018. Diário da República no 129. 2018;:29228–2943. https://dre.pt/home/-/dre/115652962/details/maximized Perfil dos alunos à saída da Escolaridade Obrigatória A. Carvalho; C. Matos; C. Minderico C de A et. al. Referencial de Educação para a Saúde. 2017. http://www.dgidc.min-edu.pt/index.php?s=noticias&noticia=443 Direção - Geral da Educação. Bufetes Escolares Circular n.o 11/DG1DC/2007. 2007;:28. https://www.dge.mec.pt/sites/default/files/Esaude/orientacoes_bufetes_final.pdf Chen S, Kim Y, Gao Z. The contributing role of physical education in youth’s daily physical activity and sedentary behavior. BMC Public Health. 2014;14:110. https://doi.org/10.1186/1471-2458-14-110 Characteristics of teacher training in school-based physical education interventions to improve fundamental movement skills and/or physical activity: a systematic review Classroom teachers’ perceptions of the impact of barriers to teaching physical education on the quality of physical education programs Serra-Majem L, Ribas L, Ngo J, Ortega RM, García A, Pérez-Rodrigo C, et al. Food, youth and the Mediterranean diet in Spain. Development of KIDMED, Mediterranean diet quality index in children and adolescents. Public Health Nutr. 2004;7:931–5. https://doi.org/10.1079/PHN2004556 Martínez-González MA, García-Arellano A, Toledo E, Salas-Salvadó J, Buil-Cosiales P, Corella D, et al. A 14-item Mediterranean diet assessment tool and obesity indexes among high-risk subjects: the PREDIMED trial. PLoS One. 2012;7:e43134. https://doi.org/10.1371/journal.pone.0043134 Exploring the association between food insecurity and food skills among school-aged children Slater JJ, Mudryj AN. Self-Perceived Eating Habits and Food Skills of Canadians. J Nutr Educ Behav [Internet]. 2016;48(7):486–95.e1. https://linkinghub.elsevier.com/retrieve/pii/S1499404616305164 Slater J, Mudryj AN. Nurturing Future Generations: Household Food Practices of Canadian Children and Family Meal Participation. Can J Diet Pract Res [Internet]. 2016;77(3):113–8. https://dcjournal.ca/doi/10.3148/cjdpr-2015-050 A physical activity screening measure for use with adolescents in primary care Trends and age-related changes of physical activity among Portuguese adolescent girls from 2002-2014: highlights from the health behavior in school-aged children study Participation des jeunes Européens aux activités physiques et sportives Matos MG de, Equipa Aventura Social. A saúde dos adolescentes portugueses: Relatório do estudo HBSC 2010. 2012. www.researcherid.com/rid/H-3824-2012 Promoting Active and Healthy Lifestyles at School: Views of Students Clustering of sedentary behaviors and physical activity among youth: a cross-national study Inquérito Alimentar Nacional e de Atividade Física IAN-AF Ravens-Sieberer U, Herdman M, Devine J, Otto C, Bullinger M, Rose M, et al. The European KIDSCREEN approach to measure quality of life and well-being in children: development, current application, and future advances. Qual Life Res. 2014;23:791–803. https://doi.org/10.1007/s11136-013-0428-3 Gaspar T, Gaspar de Matos M. Qualidade de vida em crianças e adolescentes: versão portuguesa dos instrumentos kidscreen-52. 2008. www.aventurasocial.com Guia de Avaliação do Estado Nutricional Infantil e Juvenil Development and validation of a test instrument for the assessment of basic motor competencies in primary school MOBAK 1 assessment in primary physical education : exploring basic motor competences of Portuguese 6-year-olds; 2018 Phelan SM, Burgess DJ, Yeazel MW, Hellerstedt WL, Griffin JM, van Ryn M. Impact of weight bias and stigma on quality of care and outcomes for patients with obesity. Obes Rev. 2015;16:319–26. https://doi.org/10.1111/obr.12266 World Health Organization Regional Office for Europe. European Food and Nutrition Action Plan 2015-2020. 2015. http://www.euro.who.int/pubrequest European Union. EU action plan on childhood obesity 2014–2020. 2014. http://www.who.int/dietphysicalactivity/childhood_consequences/en Oetzel JG, Wallerstein N, Duran B, Sanchez-Youngman S, Nguyen T, Woo K, et al. Impact of participatory Health Research: a test of the community-based participatory research conceptual model. Biomed Res Int. 2018;2018:1–12. https://doi.org/10.1155/2018/7281405 Download references This research is funded by the Municipality of Sintra and co-funded by Gulbenkian Academies for Knowledge The Sintra Grows Healthy is promoted by the Municipality of Sintra supports the Municipality of Sintra assigning a subsidy in order to promote social and emotional skills but played no role in the study design The Municipality of Sintra provides financial support to Faculty of Medicine for this institution to undertake the technical and scientific leadership development and dissemination of Sintra Grows Healthy Ferreira and Telma Nogueira contributed equally to this work Escola Superior de Tecnologia da Saúde de Lisboa Paulo Jorge Nogueira & Adilson Marques Laboratório de Biomatemática Faculdade de Medicina Instituto de Medicina Preventiva e Saúde Pública Faculdade de Motricidade Humana & UIDEF AQ and AP contributed to the initial study design protocol and the final research protocol RJF and TN coordinate the study implementation data collection and methodological and operational adjustments PN and AMP coordinate statistical analyses plan and database management AR coordinates the institutional communication TN coordinates the impact evaluation of the study VDS and MP drafted and critically revised the manuscript All authors contributed to further discussion and critically revised the manuscript All authors read and approved the final manuscript This study is conducted according to the guidelines laid down in the Declaration of Helsinki and it is obtained written informed consent from the children’s legal guardian Lisbon Academic Medical Centre ethics committee (401/17) the National Data Protection Commission (11468/2017) and the Ethics Boards of each participating school approved the study Permission from the relevant rights holders of each questionnaire applied was obtained The authors declare that they have no competing interests Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations unless otherwise stated in a credit line to the data Download citation DOI: https://doi.org/10.1186/s12889-020-09715-0 a shareable link is not currently available for this article Chairman of the Board Ryan Cohen is an audacious young capitalist who promises to reinvent the video game retailer Armed with bold plans and an activist mindset the Chairman is seen as one key piece in the company’s turnaround efforts Wall Street Memes discusses the importance of Chairman Cohen to GME stock investors (Read more from WS Memes: 2 Reasons Why Buying CLOV Could Be A Good Idea) 36-year-old Ryan Cohen was the CEO of Chewy, the pet e-commerce company that he founded when he was only 25 years old. In 2017, he sold Chewy to PetSmart in a $3.3 billion deal for the purpose of pursuing other personal goals Then, the investor side of Ryan Cohen’s began to gain notoriety. After the sale of Chewy, he invested a large sum in Apple and became the company's largest individual investor holding around 6 million split-adjusted shares By the end of 2020, Cohen had also become the largest single shareholder in GameStop, having acquired 10% of GME's shares and subsequently increasing the ownership percentage to about 13% These investments were made before the short squeeze of GameStop stock the investor was appointed as Charmain of the Board Cohen’s revolutionUpon taking over as chairman in early 2021, Cohen had already seen his initial investment in GME rise by more than 2,500%. With a bold and defiant speech, he opposed the board members' idea to issue $100 million in equity due to concerns over the value of GME stock Mr. Cohen proposed a series of changes to the company's strategy He encouraged investments beyond brick-and-mortar stores and aiming for a high-quality customer service model the chairman helped to change the company's team of executives cutting a few loose and hiring former Chewy and Amazon employees for senior managerial positions (Read more from WS Memes: AMC Stock: 3 Reasons The Short Squeeze Could Be On Its Way) GameStop has been reporting annual losses for the last three consecutive years (see chart below) the company began to suffer from the secular trends that favor the digital channel over brick-and-mortar stores The COVID-19 crisis only served to worsen GameStop’s competitive position Figure 2: GameStop’s net income chart in the last 5 years. Ryan Cohen was one of the few billionaire investors who understood how Reddit forums worked even before the meme stock boom of January 2021. He saw in GME an investment opportunity that combined potential for future financial performance with the stock's popularity among individual investors. It did not take long for prominent and vocal retail investors to see “Papa Cohen” as one of their representatives and allies inside the company. One of the appeals of GameStop stock to retail investors is Ryan Cohen’s influence and unconventional vision as a chairman. In addition, Mr. Cohen has a proven track record in what GameStop probably needs the most right now: e.g. growth in e-commerce and startup-like momentum. GameStop’s fundamentals and growth prospects are far from being pristine at this moment. Yet, Ryan Cohen may very well be a bullish factor that keeps GME investors hopeful about another leg higher in the company’s share price. Twitter speaksGameStop’s Chairman Ryan Cohen is seen as one key piece in the company’s turnaround efforts. How do you believe that “the Ryan Cohen factor” will be reflected on the stock? (Disclaimers: this is not investment advice. The author may be long one or more stocks mentioned in this report. Also, the article may contain affiliate links. These partnerships do not influence editorial content. Thanks for supporting Wall Street Memes) By Bernard is the co-producer of The Street's financial channels and holds the researcher and operations manager position at DM Martins Research. Additionally, he contributes articles to Seeking Alpha. By Head researcher and portfolio strategist of independent firm DM Martins Research WEST PALM BEACH — About 9 a.m. on May 8, two maintenance workers at an apartment complex west of Boca Raton heard a sound coming from a dumpster That's how we found out," one of them told a 911 dispatcher Sergio Vega and Yusdani Gonzalez-Delgado had found the Palm Beach County Sheriff's Office presented the two men with its Samaritan Award as part of the agency's annual awards ceremony “She was dirty and bloody but she was alive and well," Vega said at the event with two felonies after they say she confessed to placing the baby in the trash bin "You cannot understand how someone can do something like that Both the father and daughter were at Thursday's ceremony pointed a loaded handgun at him and his son Khaled and would not let them leave their West Palm Beach-area business And also in July, deputy David German commented that he'd love to sit by his pool on his birthday A colleague contacted her pool service technician was able to spend his birthday and his last days enjoying his pool Life-saving medals were presented in three separate incidents and two others pulled a woman out of a burning car following a crash Responding to a report that a woman had shot her husband in their driveway roused its eight occupants and led them to safety as a large explosion rocked the garage Others recognized were agent Charles Booth named Investigator of the Year for helping bring down two gang members; Luis Pacheco was honored as Deputy of the Year for his work in catching a major drug operator; and Kimberly Wright was named Corrections Deputy of the Year for busting a homemade liquor operation inside the county satellite jail in Belle Glade PBSO also commended its communications training unit, jail emergency response team, District 3 North and District 5 West community policing, Greenacres district detective bureau, narcotics interdiction unit, airport drone unit and emergency field force. It also honored the Palm Beach County Sober Homes Task Force Staff photographer Lannis Waters contributed to this story MEO Kalorama Festival added another splash of colour to the landscape’s canvas It’s a big departure from the muddied fields and rowdy lads we’ve come accustomed to back in the UK but art and sustainability taking centre stage with its amphitheatre-like shape provided unobstructed views of the main stage – a welcome sight for anyone blocked by 6ft+ giants at previous festivals this summer The wide open space allowed for a crisp listening experience mustering up an energy that delighted both eyes and ears earth shattering bass could be felt in your chest throughout the festival grounds Karen O left it all on the stage as she ran through a cascade of hits including ‘Spitting off the Edge of the World’ and ‘Heads Will Roll’ Metronomy anthem ‘The Look,’ sent the crowd into a giddy frenzy the legendary Blur offered a welcome hit of nostalgia performing timeless classics like ‘Country House’ There’s something about Britpop abroad that feels like it shouldn’t work Saturday night was an emotional but uplifting experience with Florence + The Machine the star implored fans to savour the moment by putting away their phones as she serenaded with ‘You’ve Got the Love’ – making everyone there feel like she was singing to them alone with Pongo’s contagious energy almost hypnotising the crowd into replicating her dance moves (it’s safe to say all our dancing shoes must’ve been left back at home) anticipation filled the air for Pabllo Vittar’s performance – and she didn’t disappoint closing out the weekend with her infectious confidence But it wasn’t just about the music: the festival embraced the spirit of art, partnering with Lisbon-based arts and culture platform Underdogs While wandering through the festival grounds vibrant murals brought Lisbon’s rich artistic heritage to life crafted by local artists working with Underdogs transformed the venue into a contemporary art gallery a collective of artists from the Mem Martins region in Sintra The group draw inspiration from their life experiences of communities on the outskirts of Lisbon where social inequalities are still rife and their artwork pulsates with the raw essence of these often-overlooked suburbs a visionary Portuguese graphic artist and designer brought the Samsung stage to life with a display of his psychedelic designs featuring beloved characters and heroes from his childhood graced the main stage with artwork that paid homage to The Prodigy a band that held a special place in her heart during her formative years there was a chance for the general public to get their hands dirty festival attendees are too smashed to partake in anything other than terribly screaming lyrics needlessly close to your ear activities like stencil workshops added a wholesome and communal element with festival-goers coming together to contribute to a mural highlighting the sense of togetherness felt throughout the event’s duration MEO Kalorama stands as a love letter to Lisbon’s art and music scene and moment of unity resonates on a deep level rising talent and sense of community make for a uniquely pure festival experience We’d be lying if I said the sun didn’t help Read today's Portuguese stories delivered to your email The Cash & Carry chain of Amaral e Filhos will open the new Poupança de Leiria in May.  this will be the chain's largest store and the first to open its doors outside the Greater Lisbon area further expanding the offer to the central part of the country The new store will open in the Zicofa Industrial Zone (warehouse 3) and in addition to being the largest in the area the store will have a more diversified offer of products with emphasis on the new bakery and fresh vegetables sections provided by suppliers from the Western Region This space will have more than 12 thousand products available on the shelves In 2023, Grupo BEL acquired Amaral & Filhos reinforcing its presence in the Distribution and Logistics sector The entry of the BEL Group into the capital of the distribution and wholesale trade company allowed the opening of the Famões store in June last year and it is preparing to open another commercial space in the Central area For the opening of the new store in Leiria Amaral & Filhos Distribuição operates exclusively in Portugal and currently has a total of 11 stores in Almeirim We appreciate that not everyone can afford to pay for our services but if you are able to we ask you to support The Portugal News by making a contribution – no matter how small You can change how much you give or cancel your contributions at any time Send us your comments or opinion on this article Reaching over 400,000 people a week with news about Portugal Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page.