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1.
Dev Cogn Neurosci ; 69: 101439, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39182418

RESUMO

Youth diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) often show deficits in various measures of higher-level cognition, such as, executive functioning. Poorer cognitive functioning in children with ADHD has been associated with differences in functional connectivity across the brain. However, little is known about the developmental changes to the brain's functional properties linked to different cognitive abilities in this cohort. To characterize these changes, we analyzed fMRI data (ADHD = 373, NT = 106) collected while youth between the ages of 6 and 16 watched a short movie-clip. We applied machine learning models to identify patterns of network connectivity in response to movie-watching that differentially predict cognitive abilities in our cohort. Using out-of-sample cross validation, our models successfully predicted IQ, visual spatial, verbal comprehension, and fluid reasoning in children (ages 6 - 11), but not in adolescents with ADHD (ages 12-16). Connections with the default mode, memory retrieval, and dorsal attention were driving prediction during early and middle childhood, but connections with the somatomotor, cingulo-opercular, and frontoparietal networks were more important in middle childhood. This work demonstrated that machine learning approaches can identify distinct functional connectivity profiles associated with cognitive abilities at different developmental stages in children and adolescents with ADHD.

2.
Cognition ; 251: 105845, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39047584

RESUMO

The structure of event knowledge plays a critical role in prediction, reconstruction of memory for personal events, construction of possible future events, action, language usage, and social interactions. Despite numerous theoretical proposals such as scripts, schemas, and stories, the highly variable and rich nature of events and event knowledge have been formidable barriers to characterizing the structure of event knowledge in memory. We used network science to provide insights into the temporal structure of common events. Based on participants' production and ordering of the activities that make up events, we established empirical profiles for 80 common events to characterize the temporal structure of activities. We used the event networks to investigate multiple issues regarding the variability in the richness and complexity of people's knowledge of common events, including: the temporal structure of events; event prototypes that might emerge from learning across many experiential instances and be expressed by people; the degree to which scenes (communities) are present in various events; the degree to which people believe certain activities are central to an event; how centrality might be distributed across an event's activities; and similarities among events in terms of their content and their temporal structure. Thus, we provide novel insights into human event knowledge, and describe 18 predictions for future human studies.


Assuntos
Conhecimento , Humanos , Adulto , Adulto Jovem , Masculino , Feminino , Memória Episódica
3.
Br J Clin Psychol ; 2024 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-38923582

RESUMO

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental condition and is characterized by inattention, hyperactivity, and impulsivity. Research suggests that some populations, such as females and individuals with high intelligence quotients may be a risk for late ADHD diagnosis and subsequent treatment. Our goal is to advance our understanding of ADHD diagnosis, by examining (1) how child sex and cognitive abilities together are related to the age of diagnosis and (2) whether symptom presentation, current internalizing and externalizing symptoms, and demographic factors are related to age of diagnosis. METHODS: Our analyses contained children who completed the required tests (N = 568) from a pre-existing dataset of 1380 children with ADHD from the Province of Ontario Neurodevelopmental Disorders (POND) Network (pond-network.ca). First, we conducted a moderation analysis with sex as the predictor, cognitive abilities as the moderator, and age of diagnosis as the outcome. Second, we conducted correlation analyses examining how symptom presentation, current internalizing and externalizing symptoms, and demographic factors are related to age of diagnosis. RESULTS: Higher IQ was related to a later age of diagnosis. Higher hyperactive-impulsive symptoms and externalizing symptoms were related to an earlier age of diagnosis. Internalizing symptoms were trend associated with a later age of diagnosis in girls. Higher socioeconomic status and non-White maternal ethnicity were related to later age of diagnosis. CONCLUSIONS: IQ, sex, ADHD symptomology, internalizing symptoms, externalizing symptoms, and socio-demographic factors affect the age of diagnosis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-38000717

RESUMO

BACKGROUND: Impairing repetitive behaviors are one of the core diagnostic symptoms in autism spectrum disorder and obsessive-compulsive disorder, but they also manifest in attention-deficit/hyperactivity disorder. Although the dorsal striatal circuit has been implicated in repetitive behaviors, extensive heterogeneity in and cross-diagnostic manifestations of these behaviors have suggested phenotypic and likely neurobiological heterogeneity across neurodevelopmental disorders (NDDs). METHODS: Intrinsic dorsal striatal functional connectivity was examined in 3 NDDs (autism spectrum disorder, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder) and typically developing control participants in a large single-cohort sample (N = 412). To learn how diagnostic labels and overlapping behaviors manifest in dorsal striatal functional connectivity measured with functional magnetic resonance imaging, the main and interaction effects of diagnosis and behavior were examined in 8 models (2 seed functional connectivity [caudate and putamen] × 4 sub-behavioral domains [sameness/ritualistic, self-injury, stereotypy, and compulsions]). RESULTS: The obsessive-compulsive disorder group demonstrated distinctive patterns in visual and visuomotor coordination regions compared with the other diagnostic groups. Lower-order repetitive behaviors (self-injury and stereotypy) manifesting across all participants were implicated in regions involved in motor and cognitive control, although the findings did not survive effects of multiple comparisons, suggesting heterogeneity in these behavioral domains. An interaction between self-injurious behavior and an attention-deficit/hyperactivity disorder diagnosis were observed on caudate-cerebellum functional connectivity. CONCLUSIONS: These findings confirmed high heterogeneity and overlapping behavioral manifestations in NDDs and their complex underlying neural mechanisms. A call for diagnosis-free symptom measures that can capture not only observable symptoms and severity across NDDs but also the underlying functions and motivations of such behaviors across diagnoses is needed.


Assuntos
Transtorno do Espectro Autista , Transtornos do Neurodesenvolvimento , Transtorno Obsessivo-Compulsivo , Criança , Humanos , Adolescente , Mapeamento Encefálico , Cognição
6.
Trends Hear ; 27: 23312165221076681, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37377212

RESUMO

The reduction in spectral resolution by cochlear implants oftentimes requires complementary visual speech cues to facilitate understanding. Despite substantial clinical characterization of auditory-only speech measures, relatively little is known about the audiovisual (AV) integrative abilities that most cochlear implant (CI) users rely on for daily speech comprehension. In this study, we tested AV integration in 63 CI users and 69 normal-hearing (NH) controls using the McGurk and sound-induced flash illusions. To our knowledge, this study is the largest to-date measuring the McGurk effect in this population and the first that tests the sound-induced flash illusion (SIFI). When presented with conflicting AV speech stimuli (i.e., the phoneme "ba" dubbed onto the viseme "ga"), we found that 55 CI users (87%) reported a fused percept of "da" or "tha" on at least one trial. After applying an error correction based on unisensory responses, we found that among those susceptible to the illusion, CI users experienced lower fusion than controls-a result that was concordant with results from the SIFI where the pairing of a single circle flashing on the screen with multiple beeps resulted in fewer illusory flashes for CI users. While illusion perception in these two tasks appears to be uncorrelated among CI users, we identified a negative correlation in the NH group. Because neither illusion appears to provide further explanation of variability in CI outcome measures, further research is needed to determine how these findings relate to CI users' speech understanding, particularly in ecological listening conditions that are naturally multisensory.


Assuntos
Implantes Cocleares , Ilusões , Percepção da Fala , Humanos , Percepção da Fala/fisiologia , Ilusões/fisiologia , Percepção Visual/fisiologia , Percepção Auditiva/fisiologia , Estimulação Luminosa , Estimulação Acústica
7.
Res Child Adolesc Psychopathol ; 51(7): 1005-1019, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37014483

RESUMO

This review aimed to explore the current understanding of sensory gating in neurodevelopmental disorders as a possible transdiagnostic mechanism. We applied methods according to the Joanna Briggs Institute Manual for Evidence Synthesis, following the population, concept, and context scoping review eligibility criteria. Using a comprehensive search strategy in five relevant research databases (Medline, EMBASE, CINAHL, PsychInfo, and Scopus), we searched for relevant peer-reviewed, primary research articles and unpublished data. Two independent reviewers screened the titles and abstracts, full-texts, and completed data extraction. We identified a total of 81 relevant articles and used descriptive analyses to summarize the characteristics and outcomes of all identified studies. Literature regarding sensory gating was most common in autistic populations with relatively fewer studies examining attention-deficit/hyperactivity disorder, tic disorders, and childhood-onset fluency disorder (COFD). The methods to assess sensory gating varied widely both within and between groups and included measures such as habituation, prepulse inhibition, affect-modulated inhibition, medication and other intervention trials. Most consistently, when participants complete questionnaires about their sensory experiences, those who have neurodevelopmental disorders report differences in their sensory gating. Affect-modulated inhibition appears to be discrepant between samples with and without neurodevelopmental disorder diagnoses. Habituation was the most commonly reported phenomenon and many differences in habituation have been found in autistic individuals and individuals with tic disorders whereas concerns with inhibition seemed more common in COFD. Overall, the evidence is inconsistent within and between disorders suggesting there is still much to learn about sensory gating in neurodevelopmental disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Autístico , Transtornos do Neurodesenvolvimento , Transtornos de Tique , Humanos , Criança , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtornos de Tique/tratamento farmacológico , Filtro Sensorial
8.
Acta Psychol (Amst) ; 231: 103779, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36327668

RESUMO

Event knowledge, a person's understanding of patterns of activities in the world, is crucial for everyday social interactions. Social communication differences are prominent in autism, which may be related to atypical event knowledge, such as atypical knowledge of the sequences of activities that comprise the temporal structure of events. Previous research has found that autistic individuals have atypical event knowledge, but research in this area is minimal, particularly regarding autistic individuals' knowledge of the temporal structure of events. Furthermore, no studies have investigated the link between event knowledge and autistic traits in a non-clinical sample. We investigated relationships between event knowledge and autistic traits in individuals from the general population with varying degrees of autistic traits. We predicted that atypical ordering of event activities is related to autistic traits, particularly social communication abilities, but not other clinical traits. In Study 1, atypical ordering of event activities correlated with social ability, but not with most measures of repetitive behaviours and restricted interests. In Study 2, the typicality of activity ordering varied by participants' social ability and the social nature of the events. Relationships were not found between event activity ordering and other clinical traits. These findings suggest a relationship between autistic traits, specifically social abilities, and knowledge of the temporal structure of events in a general population sample.


Assuntos
Transtorno Autístico , Habilidades Sociais , Humanos , Comunicação
9.
J Autism Dev Disord ; 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36306002

RESUMO

Sensory processing abilities are highly variable within and across people diagnosed with autism and attention-deficit/hyperactivity disorder (ADHD). This study examined the transdiagnostic nature of sensory processing abilities, and their association with features of autism and ADHD, in a large sample of autistic people (n = 495) and people with ADHD (n = 461). Five similar data-driven sensory phenotypes characterized sensory processing abilities, and showed similar patterns of association with features of autism and ADHD, across both diagnostic groups. These results demonstrate the transdiagnostic nature of sensory processing abilities, while contributing to a growing body of literature that suggests the autism and ADHD diagnostic labels have poor explanatory power.

10.
Neuropsychologia ; 174: 108336, 2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-35872233

RESUMO

Integrating sensory information from multiple modalities leads to more precise and efficient perception and behaviour. The process of determining which sensory information should be perceptually bound is reliant on both low-level stimulus features, as well as multisensory associations learned throughout development based on the statistics of our environment. Here, we explored the relationship between multisensory associative learning and multisensory integration using encephalography (EEG) and behavioural measures. Sixty-one participants completed a three-phase study. First, participants were exposed to novel audiovisual shape-tone pairings with frequent and infrequent stimulus pairings and completed a target detection task. EEG recordings of the mismatch negativity (MMN) and P3 were calculated as neural indices of multisensory associative learning. Next, the same learned stimulus pairs were presented in audiovisual as well as unisensory auditory and visual modalities while both early (<100 ms) and late neural indices of multisensory integration were recorded. Finally, participants completed an analogous behavioural speeded-response task, with behavioural indices of multisensory gain calculated using the Race Model. Significant relationships were found in fronto-central and occipital areas between neural measures of associative learning and both early and late indices of multisensory integration in frontal and centro-parietal areas, respectively. Participants who showed stronger indices of associative learning also exhibited stronger indices of multisensory integration of the stimuli they learned to associate. Furthermore, a significant relationship was found between neural index of early multisensory integration and behavioural indices of multisensory gain. These results provide insight into the neural underpinnings of how higher-order processes such as associative learning guide multisensory integration.


Assuntos
Percepção Auditiva , Percepção Visual , Estimulação Acústica , Percepção Auditiva/fisiologia , Condicionamento Clássico , Humanos , Estimulação Luminosa , Percepção Visual/fisiologia
11.
Front Integr Neurosci ; 15: 760116, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790102

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects one in 66 children in Canada. The contributions of changes in the cortex and cerebellum to autism have been studied for decades. However, our understanding of brainstem contributions has only started to emerge more recently. Disruptions of sensory processing, startle response, sensory filtering, sensorimotor gating, multisensory integration and sleep are all features of ASD and are processes in which the brainstem is involved. In addition, preliminary research into brainstem contribution emphasizes the importance of the developmental timeline rather than just the mature brainstem. Therefore, the purpose of this systematic review is to compile histological, behavioral, neuroimaging, and electrophysiological evidence from human and animal studies about brainstem contributions and their functional implications in autism. Moreover, due to the developmental nature of autism, the review pays attention to the atypical brainstem development and compares findings based on age. Overall, there is evidence of an important role of brainstem disruptions in ASD, but there is still the need to examine the brainstem across the life span, from infancy to adulthood which could lead the way for early diagnosis and possibly treatment of ASD.

12.
Mol Autism ; 12(1): 67, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641960

RESUMO

BACKGROUND: Atypical reactions to the sensory environment are often reported in autistic individuals, with a high degree of variability across the sensory modalities. These sensory differences have been shown to promote challenging behaviours and distress in autistic individuals and are predictive of other functions including motor, social, and cognitive abilities. Preliminary research suggests that specific sensory differences may cluster together within individuals creating discrete sensory phenotypes. However, the manner in which these sensory differences cluster, and whether the resulting phenotypes are associated with specific cognitive and social challenges is unclear. METHODS: Short sensory profile data from 599 autistic children and adults between the ages of 1 and 21 years were subjected to a K-means cluster analysis. Analysis of variances compared age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder across the resultant clusters. RESULTS: A five-cluster model was found to minimize error variance and produce five sensory phenotypes: (1) sensory adaptive, (2) generalized sensory differences, (3) taste and smell sensitivity, (4) under-responsive and sensation seeking, and (5) movement difficulties with low energy. Age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder were found to differ significantly across the five phenotypes. LIMITATIONS: The results were based on parent-report measures of sensory processing, adaptive behaviour, traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder, which may limit the generalizability of the findings. Further, not all measures are standardized, or psychometrically validated with an autism population. Autistic individuals with an intellectual disability were underrepresented in this sample. Further, as these data were obtained from established records from a large provincial database, not all measures were completed for all individuals. CONCLUSIONS: These findings suggest that sensory difficulties in autistic individuals can be clustered into sensory phenotypes, and that these phenotypes are associated with behavioural differences. Given the large degree of heterogeneity in sensory difficulties seen in the autistic population, these sensory phenotypes represent an effective way to parse that heterogeneity and create phenotypes that may aid in the development of effective treatments and interventions for sensory difficulties.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/psicologia , Humanos , Fenótipo , Sensação
13.
Acta Psychol (Amst) ; 218: 103354, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34174491

RESUMO

Multisensory integration, the process by which sensory information from different sensory modalities are bound together, is hypothesized to contribute to perceptual symptomatology in schizophrenia, in whom multisensory integration differences have been consistently found. Evidence is emerging that these differences extend across the schizophrenia spectrum, including individuals in the general population with higher levels of schizotypal traits. In the current study, we used the McGurk task as a measure of multisensory integration. We measured schizotypal traits using the Schizotypal Personality Questionnaire (SPQ), hypothesizing that higher levels of schizotypal traits, specifically Unusual Perceptual Experiences and Odd Speech subscales, would be associated with decreased multisensory integration of speech. Surprisingly, Unusual Perceptual Experiences were not associated with multisensory integration. However, Odd Speech was associated with multisensory integration, and this association extended more broadly across the Disorganized factor of the SPQ, including Odd or Eccentric Behaviour. Individuals with higher levels of Odd or Eccentric Behaviour scores also demonstrated poorer lip-reading abilities, which partially explained performance in the McGurk task. This suggests that aberrant perceptual processes affecting individuals across the schizophrenia spectrum may relate to disorganized symptomatology.


Assuntos
Esquizofrenia , Transtorno da Personalidade Esquizotípica , Humanos , Personalidade , Transtorno da Personalidade Esquizotípica/diagnóstico , Inquéritos e Questionários
14.
Autism Res ; 14(7): 1322-1331, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34003584

RESUMO

The study of sensory phenotypes has great potential for increasing research translation between species, a necessity to decipher the neural mechanisms that contribute to higher-order differences in neurological conditions such as autism spectrum disorder (ASD). Over the past decade, despite separate advances in our understanding of the structural and functional differences within the brain of autistic and non-autistic individuals and in rodent models for ASD, researchers have had difficulty translating the findings in murine species to humans, mostly due to incompatibility in experimental methodologies used to screen for ASD phenotypes. Focusing on sensory phenotypes offers an avenue to close the species gap because sensory pathways are highly conserved across species and are affected by the same risk-factors as the higher-order brain areas mostly responsible for the diagnostic criteria for ASD. By first reviewing how sensory processing has been studied to date, we direct our focus to electrophysiological and behavioral techniques that can be used to study sensory phenotypes consistently across species. Using auditory sensory phenotypes as a template, we seek to improve the accessibility of translational methods by providing a framework for collecting cohesive data in both rodents and humans. Specifically, evoked-potentials, acoustic startle paradigms, and psychophysical detection/discrimination paradigms can be created and implemented in a coordinated and systematic fashion across species. Through careful protocol design and collaboration, sensory processing phenotypes can be harnessed to bridge the gap that exists between preclinical animal studies and human testing, so that mutually held questions in autism research can be answered. LAY SUMMARY: It has always been difficult to relate results from animal research to humans. We try to close this gap by studying changes in sensory processing using careful protocol design and collaboration between clinicians and researchers. Sensory pathways are comparable between animals and humans, and are affected in the same way as the rest of the brain in ASD. Using changes in hearing as a template, we point the field in an innovative direction by providing a framework for collecting cohesive data in rodents and humans.


Assuntos
Transtorno do Espectro Autista , Animais , Cognição , Potenciais Evocados , Humanos , Camundongos , Percepção , Sensação
15.
Multisens Res ; : 1-19, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33706260

RESUMO

Recent literature has suggested that deficits in sensory processing are associated with schizophrenia (SCZ), and more specifically hallucination severity. The DSM-5's shift towards a dimensional approach to diagnostic criteria has led to SCZ and schizotypal personality disorder (SPD) being classified as schizophrenia spectrum disorders. With SCZ and SPD overlapping in aetiology and symptomatology, such as sensory abnormalities, it is important to investigate whether these deficits commonly reported in SCZ extend to non-clinical expressions of SPD. In this study, we investigated whether levels of SPD traits were related to audiovisual multisensory temporal processing in a non-clinical sample, revealing two novel findings. First, less precise multisensory temporal processing was related to higher overall levels of SPD symptomatology. Second, this relationship was specific to the cognitive-perceptual domain of SPD symptomatology, and more specifically, the Unusual Perceptual Experiences and Odd Beliefs or Magical Thinking symptomatology. The current study provides an initial look at the relationship between multisensory temporal processing and schizotypal traits. Additionally, it builds on the previous literature by suggesting that less precise multisensory temporal processing is not exclusive to SCZ but may also be related to non-clinical expressions of schizotypal traits in the general population.

16.
Sci Rep ; 11(1): 3648, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574399

RESUMO

While atypical sensory processing is one of the more ubiquitous symptoms in autism spectrum disorder, the exact nature of these sensory issues remains unclear, with different studies showing either enhanced or deficient sensory processing. Using a well-established continuous cued-recall task that assesses visual working memory, the current study provides novel evidence reconciling these apparently discrepant findings. Autistic children exhibited perceptual advantages in both likelihood of recall and recall precision relative to their typically-developed peers. When autistic children did make errors, however, they showed a higher probability of erroneously binding a given colour with the incorrect spatial location. These data align with neural-architecture models for feature binding in visual working memory, suggesting that atypical population-level neural noise in the report dimension (colour) and cue dimension (spatial location) may drive both the increase in probability of recall and precision of colour recall as well as the increase in proportion of binding errors when making an error, respectively. These changes are likely to impact core symptomatology associated with autism, as perceptual binding and working memory play significant roles in higher-order tasks, such as communication.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Cognição/fisiologia , Memória de Curto Prazo/fisiologia , Percepção Visual/fisiologia , Adolescente , Criança , Feminino , Humanos , Masculino , Rememoração Mental/fisiologia
17.
J Clin Child Adolesc Psychol ; 50(5): 645-655, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33136459

RESUMO

OBJECTIVE: Early identification of autism spectrum disorder (ASD) is an essential healthcare priority. Girls may be at risk for late diagnosis, although research is equivocal regarding how sex and other factors relate to ASD identification. The goals of the current investigation were to (1) identify how child sex, cognitive abilities, and demographic factors relate to age of first concern (AOC) and age of diagnosis (AOD), (2) evaluate trends in AOC/AOD over time, and (3) consider whether main effects of sex on AOC/AOD are moderated by cognitive abilities or time. METHOD: Children (N = 365; 20% female; 85.6% identified as White) with ASD participated through the Province of Ontario Neurodevelopmental Disorders (POND) Network. Study records included AOD, date/timing of diagnosis (between 1996 and 2017), age of first parent concern, demographics, and standardized cognitive testing results (24.7% of children had IQ scores below standard scores of 70). RESULTS: Average AOC occurred before 2 years of age whereas average AOD occurred after 5 years of age. Girls did not differ on AOC but had a later AOD than boys. Higher verbal IQ was associated with later AOD more strongly in girls than boys. Regarding time-related changes, average AOC and AOD increased across the study period, more strongly for girls. CONCLUSIONS: Results support that sex is a key factor underlying delays in ASD identification and highlight the urgent need to improve diagnostic practices among girls. Limitations and implications for improving the diagnostic process are discussed.Abbreviations: ASD=autism spectrum disorder; IQ=intelligence quotient; AOC=parental report of age of first concern; AOD=age of diagnosis.


Assuntos
Transtorno do Espectro Autista , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Família , Feminino , Humanos , Masculino , Pais , Prevalência , Caracteres Sexuais
18.
Arterioscler Thromb Vasc Biol ; 41(1): e33-e45, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33267659

RESUMO

OBJECTIVE: 12-LOX (12-lipoxygenase) produces a number of bioactive lipids including 12(S)-HETE that are involved in inflammation and platelet reactivity. The GPR31 (G-protein-coupled receptor 31) is the proposed receptor of 12(S)-HETE; however, it is not known whether the 12(S)-HETE-GPR31 signaling axis serves to enhance or inhibit platelet activity. Approach and Results: Using pepducin technology and biochemical approaches, we provide evidence that 12(S)-HETE-GPR31 signals through Gi to enhance PAR (protease-activated receptor)-4-mediated platelet activation and arterial thrombosis using both human platelets and mouse carotid artery injury models. 12(S)-HETE suppressed AC (adenylyl cyclase) activity through GPR31 and resulted in Rap1 (Ras-related protein 1) and p38 activation and low but detectable calcium flux but did not induce platelet aggregation. A GPR31 third intracellular (i3) loop-derived pepducin, GPR310 (G-protein-coupled receptor 310), significantly inhibited platelet aggregation in response to thrombin, collagen, and PAR4 agonist, AYPGKF, in human and mouse platelets but relative sparing of PAR1 agonist SFLLRN in human platelets. GPR310 treatment gave a highly significant 80% protection (P=0.0018) against ferric chloride-induced carotid artery injury in mice by extending occlusion time, without any effect on tail bleeding. PAR4-mediated dense granule secretion and calcium flux were both attenuated by GPR310. Consistent with these results, GPR310 inhibited 12(S)-HETE-mediated and PAR4-mediated Rap1-GTP and RASA3 translocation to the plasma membrane and attenuated PAR4-Akt and ERK activation. GPR310 caused a right shift in thrombin-mediated human platelet aggregation, comparable to the effects of inhibition of the Gi-coupled P2Y12 receptor. Co-immunoprecipitation studies revealed that GPR31 and PAR4 form a heterodimeric complex in recombinant systems. CONCLUSIONS: The 12-LOX product 12(S)-HETE stimulates GPR31-Gi-signaling pathways, which enhance thrombin-PAR4 platelet activation and arterial thrombosis in human platelets and mouse models. Suppression of this bioactive lipid pathway, as exemplified by a GPR31 pepducin antagonist, may provide beneficial protective effects against platelet aggregation and arterial thrombosis with minimal effect on hemostasis.


Assuntos
Plaquetas/metabolismo , Trombose das Artérias Carótidas/sangue , Hemostasia , Agregação Plaquetária , Receptores Acoplados a Proteínas G/sangue , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/sangue , Animais , Células CHO , Trombose das Artérias Carótidas/prevenção & controle , Cricetulus , Modelos Animais de Doenças , Feminino , Fibrinolíticos/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/sangue , Humanos , Masculino , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Trombina/sangue , Transdução de Sinais , Trombina/metabolismo
19.
J Autism Dev Disord ; 51(10): 3391-3400, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33236274

RESUMO

Restricted interests and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD), and commonly occur in attention-deficit/hyperactivity disorder (ADHD). Little is known about how RRBs manifest in ADHD. We quantified and compared factor structures of RRBs in children with ASD (n = 634) or ADHD (n = 448), and related factors to sex and IQ. A four-factor solution emerged, including Stereotypy, Self-Injury, Compulsions, and Ritualistic/Sameness. Factor structures were equivalent across diagnoses, though symptoms were more severe in ASD. IQ negatively correlated with Stereotypy, Self-Injury, and Compulsions in ASD, and negatively correlated with Compulsions and Ritualistic/Sameness behaviors in ADHD. In ASD only, females exhibited higher Self-Injury. Thus, patterns of RRBs are preserved across ASD and ADHD, but severity and relationship with IQ differed.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/diagnóstico , Criança , Feminino , Humanos , Comportamento Estereotipado
20.
J Commun Disord ; 89: 106036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33249356

RESUMO

The current study parsed out the distinct components of attention-deficit/hyperactivity disorder (ADHD) symptomatology to examine differential relations with language and social ability. Using a research domain criteria (RDoC) framework, we administered standardized tests and previously developed and validated questionnaires to assess levels of inattention and/or hyperactivity/impulsivity symptomatology, language, social responsivity and social competency in 98 young adults. Those with higher inattention and/or hyperactivity/impulsivity symptomatology had reduced language comprehension, social responsivity, and social competency. Inattention and hyperactivity/impulsivity both predicted language comprehension, but not language production. Interestingly, inattention uniquely contributed to social responsiveness and social competency, but hyperactivity/impulsivity did not. Findings suggest that inattention and/or hyperactivity/impulsivity symptoms, inattention in particular, may be especially important for social skills programs geared towards individuals with attention limitations.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Idioma , Interação Social , Atenção , Humanos , Comportamento Impulsivo , Adulto Jovem
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