Beyond the motor account of amyotrophic lateral sclerosis: Verbal humour and its relationship with the cognitive and pragmatic profile.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) was traditionally described as a disease restricted to the motor system. However, recent findings suggested that it also affects cognition, especially executive functions, social cognition, language and pragmatics. A relevant issue in current research is thus the description of the cognitive phenotype of ALS and the identification of the most vulnerable aspects. AIMS: The focus was on a communicative phenomenon placed at the crossroads of pragmatic and other cognitive domains, namely humour, which till now has been poorly explored in ALS. The first aim was to investigate whether ALS is associated with impairments in understanding and appreciating jokes. The second aim was to explore the predictors of humour comprehension and appreciation in patients, to confirm the involvement of pragmatic skills and to explore the role of other cognitive and clinical aspects. METHODS & PROCEDURES: A total of 30 non-demented patients with ALS and 27 controls were assessed with a task of verbal humour comprehension and appreciation, including two types of jokes: phonological and mental. We also administered a battery of pragmatic and other language tasks, and cognitive and socio-cognitive tasks. Mixed-effects models were used to test differences in the humour task between the two groups. Multiple regressions determined the best predictors of humour comprehension and appreciation in patients. OUTCOMES & RESULTS: Patients obtained lower comprehension accuracy scores than controls in the humour task, independently of the type of joke. Conversely, patients and controls did not differ in joke appreciation and both rated mental jokes as funnier than the phonological ones. Patients' comprehension accuracy was predicted by pragmatic skills and ALS severity, whereas appreciation was predicted by several clinical variables and, to a smaller extent, by language skills. CONCLUSIONS & IMPLICATIONS: The findings suggest that humour is a very vulnerable aspect in ALS, and that impairment in humour comprehension might be part of the larger cognitive impairment, being linked to pragmatic impairment. Clinical variables were also important, especially in relation to humour appreciation. More generally, these data speak in favour of pragmatics as a relevant aspect to sketch the cognitive phenotype of ALS. On the practical level, these findings point to the need of supporting communication at large, not only motor-related aspects such as dysarthria but also social-pragmatic aspects such as understanding jokes, to increase well-being in ALS. What this paper adds What is already known on this subject The literature of the last decades has shown that ALS comes with impairment in several cognitive domains, affecting especially executive functions as well as language. There is also initial evidence that the pragmatics of communication and humour comprehension are impaired, although non-serious talk has been documented in conversational interaction among people with ALS. What this paper adds to existing knowledge This study offers compelling evidence of an impairment in the comprehension of jokes in ALS, whereas the appreciation of joke funniness seems to be spared. The study also highlights the interplay of cognitive factors (especially pragmatics) and clinical factors (related to disease severity) in predicting the patients' performance in the humour task. What are the potential or actual clinical implications of this work? The study's findings call for the need of increased awareness among scholars as well as practitioners and caregivers of the profile of humour comprehension and appreciation in ALS. On a practical level, we highlight the need of assessing humour comprehension and adapting the communicative style accordingly. Second, we recommend that intervention programmes targeting communication in ALS go beyond speech-related difficulties and include pragmatic aspects such as humour. Considering the important communicative and social function of humour, as well as its use as a coping strategy, humour interventions are key to improve the quality of life of individuals with ALS.

Psychiatric Assessment of Social Impairment Across the Lifespan.

Although autism spectrum disorder (ASD) is the prototypical psychiatric disorder of social impairment, several if not most psychiatric disorders are characterized by prominent impairments in social functioning. A challenge in clinically assessing and describing social impairment is that it has been variably defined and can be difficult to measure. In this article we consider the psychiatric differential diagnosis of social impairment within the DSM-5 framework. We describe the features of social impairment in 13 DSM-5 disorders from a developmental perspective and highlight diagnostic factors that differentiate among the disorders, including the main features of social impairment, verbal communication, nonverbal communication, course of social impairment, social cognition, and key features of accompanying neuropsychiatric symptoms. We conclude by describing an approach for assessing social impairment across the lifespan.

Improved Conversation Outcomes After Social Communication Skills Training for People With Traumatic Brain Injury and Their Communication Partners: A Clinical Trial Investigating In-Person and Telehealth Delivery.

Purpose The aim of the study was to investigate the effectiveness of social communication skills training (TBIconneCT) for people with traumatic brain injury (TBI) and their communication partners, delivered in-person or via telehealth, on quality of conversations. Method This study is a clinical trial, including an in-person intervention group (n = 17), a telehealth intervention group (n = 19), and a historical control group (n = 15). Participants were adults at least 6 months post moderate-to-severe TBI with social communication skills deficits and their usual communication partners. Participants completed a casual and purposeful conversation task at pre-intervention, postintervention, and a follow-up assessment. A blinded assessor evaluated conversations using the Adapted Measure of Participation in Conversation and the Adapted Measure of Support in Conversation. Treatment effects were examined by comparing groups on change in ratings between pre- and posttraining. Maintenance of effects was examined using change between posttraining and follow-up assessment. The trial protocol was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615001024538). Results Trained participants with TBI had significant improvements in participation in casual conversation compared to controls. Trained communication partners also had significant improvements compared to controls on ratings of support in casual conversations. However, treatment effects were not maintained at follow-up for two of eight measures. Comparisons between outcomes of in-person and telehealth groups found negligible to small effect sizes for six of eight measures. Conclusions The findings reinforce previous studies demonstrating the efficacy of communication partner training after TBI. Telehealth delivery produced similar outcomes to in-person delivery.

Pragmatic language dysfunction in systemic lupus erythematosus patients: Results from a single center Italian study.

BACKGROUND: Cognitive impairment (CI) in systemic lupus erythematosus (SLE) is a frequent neuropsychiatric manifestation affecting several domains, even in apparently asymptomatic patients. Current research revealed that the typical CI pattern affects frontal-subcortical circuit and thus executive functions. The impairment of non-literal language or pragmatic language (PL), including metaphors, idioms, inferences or irony has been well described in several conditions such as autism disorders, Parkinson's disease, brain injury and even in earlier phases of neurodegenerative processes. Even if PL neuro-anatomy remains controversial, correlation between executive dysfunctions and non-literal language involvement has been reported both in traumatic injury and mild cognitive impairment patients. Nonetheless, no specific study has been performed to evaluate PL impairment in SLE patients so far. OBJECTIVES: We aimed at assessing the PL domain in a Italian monocentric SLE cohort in comparison to healthy controls, matched to age and education, through a specific battery, the batteria sul linguaggio dell'emisfero destro (BLED). Secondly, we focused attention on possible correlations between CI and clinical and laboratory SLE-related features. METHODS: Forty adult patients affected by SLE, according to the American College of Rheumatology (ACR) criteria, and thirty healthy subjects were enrolled consecutively in this cross-sectional study. The protocol included complete physical examination, extensive clinical and laboratory data collection (comprehensive of demographics, past medical history, co-morbidities, disease activity, chronic damage evaluation, previous and concomitant treatments) and cognitive assessment for five different domains: memory, attention, pragmatic language, executive and visuospatial functions. Self-reported scale for anxiety and depression were performed to exclude the influence of mood disorders on cognitive dysfunction. RESULTS: We studied 40 Caucasian SLE patients [male (M)/ female (F) 3/37; mean±standard deviation (SD) age 45.9±10.1 years, mean±SD disease duration 120.8±81.2 months] and 30 healthy subjects (M/F 9/21; mean±SD age 41.3±13 years). According to the low level of disease activity and damage (mean±SD Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 1.3±2.3, mean±SD Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) of 0.2±0.5), only 30% of patients was on glucocorticoid treatment at the study entry. PL was the most compromised domain in terms of Mean Domain Z scores. As for the Domain Cognitive Dysfunction score, a deficit of PL was observed in 45% of patients and was significantly more prevalent than memory, executive and visuospatial functions impairment (P = 0.0002, P = 0.0002 and P<0.000001, respectively). According to Global Cognitive Dysfunction score, 25% of patients experienced a mild impairment and 7.5% a moderate one. Anti-phospholipid antibodies positivity was significantly associated with memory impairment (P<0.0005), whereas the presence of other neuropsychiatric events was associated with executive dysfunctions (P<0.05); no further significant association nor correlation were identified. CONCLUSION: In this study we evaluated for the first time PL in SLE patients finding a dysfunction in almost half of patients. The dysfunction of PL was significantly more frequent than the other domains assessed.

Intensive and standard group-based treatment for persons with social communication difficulties after an acquired brain injury: study protocol for a randomised controlled trial.

INTRODUCTION: Social communication difficulties (SCDs) occur frequently after an acquired brain injury (ABI) and have disabling consequences, but effective interventions are scant. Group Interactive Structured Treatment (GIST) is a holistic group treatment targeting SCD that has received empirical support. OBJECTIVE: To determine the efficacy of two GIST protocols, standard GIST and a newly developed intensive GIST, comparing standard GIST results to a wait-list control group (WL), as well as to intensive GIST received by participants following WL. The within subject results for WL and intensive GIST will also be examined. METHODS AND ANALYSIS: Sixty adults (18-75 years) with SCD after ABI will be recruited for this randomised controlled trial. Standard GIST (n=30) will be delivered via outpatient sessions for 2.5 hours once per week for 12 weeks, plus one initial orientation session. Participants will be assessed at preintervention and postintervention and at 3-month and 6-month follow-ups (T1-T4). Intensive GIST (n=30) participants will be admitted to an inpatient rehabilitation unit for 4 weeks (two times 3 days/week, two times 4 days/week) and receive full-day sessions each week. Those participants will complete four assessments (T1-T4) in 12-week intervals as part of WL, assessments preintensive and postintensive GIST and at 3-month and 6-month follow-ups (T4-T7). The primary outcome measure is the La Trobe Questionnaire (self-report). Secondary outcome measures include the Profile of Pragmatic Impairment in Communication, a test of emotion recognition, the Goal Attainment Scale and questionnaires addressing social, emotional and cognitive functions, self-efficacy and quality of life. ETHICS AND DISSEMINATION: Results will be communicated through international, peer-reviewed and popular science journals and presentations at scientific conferences. The study is approved by the Regional Committees for Medical and Health Research Ethics Norway (2017/1360). The trial will be conducted in accordance with the Declaration of Helsinki and reported in accordance with the Consolidated Standards of Reporting Trials 2010 statement and Standard Protocol Items: Recommendations for Interventional Trials recommendations. TRIAL REGISTRATION NUMBER: NCT03636399.

Pragmatic Language Performance of Children Adopted Internationally.

Purpose Pragmatic language is important for social communication across all settings. Children adopted internationally (CAI) may be at risk of poorer pragmatic language because of adverse early care, delayed adopted language development, and less ability to inhibit. The purpose of this study was to compare pragmatic language performance of CAI from Asian and Eastern European countries with a nonadopted group of children who were of the same age and from similar socioeconomic backgrounds as well as explore the relationship among emotion identification, false belief understanding, and inhibition variables with pragmatic language performance. Method Using a quasi-experimental design, 35 four-year-old CAI (20 Asian, 15 Eastern European) and 33 children who were not adopted were included in this study. The children's pragmatic language, general language, and social communication (emotion identification of facial expressions, false belief understanding, inhibition) were measured. Comparisons by region of origin and adoption experience were completed. We conducted split-half correlation analyses and entered significant correlation variables into simple and backward regression models. Results Pragmatic language performance differed by adoption experience. The adopted and nonadopted groups demonstrated different correlation patterns. Language performance explained most of the pragmatic language variance. Discussion Because CAI perform less well than their nonadopted peers on pragmatic communication measures and different variables are related to their pragmatic performance, speech-language pathologists may need to adapt assessment and intervention practices for this population.

Adaptation to different communicative contexts: an eye tracking study of autistic adults.

BACKGROUND: Learning through social observation (i.e., watching other people interact) lays the foundation for later social skills and social cognition. However, social situations are often complex, and humans are only capable of attending to one aspect of a scene at a time. How do people choose where to allocate their visual resources when viewing complex social scenarios? For typically developing (TD) individuals, faces are often given priority. Depending upon context, however, it may be more useful to attend to other aspects of the environment, such as hands, tools, or background objects. Previous studies reported reduced face looking in individuals with autism spectrum disorder (ASD), but modulation of visual attention in response to contextual differences (e.g., according to social richness, or the presence/absence of communicative behaviors between two people) has only briefly been explored. In this study, we used eye-tracking technology to test the extent to which ASD adults and TD adults use social context to guide their gaze behavior. METHODS: Fifty-five adults participated (28 with ASD). The location and duration of participants' gaze were recorded while they watched a series of naturalistic social videos. Half of the videos depicted two people engaging in non-verbal communication (rich social scenes) while playing with toys. The other half depicted two people playing with toys separately, not interacting with each other (lean social scenes). RESULTS: ASD and TD adults both increased their attention to faces in communicative contexts (rich social scenes) as compared to non-communicative contexts (lean social scenes). However, TD adults increased their attention to faces significantly more when watching two people communicate than did ASD adults, who increased their attention to a lesser degree. Further analysis revealed that ASD adults persisted in looking at hands and toys, even when observing two people communicate in a rich social scene. CONCLUSIONS: Diminished gaze to faces when observing two people communicating may lead to fewer opportunities for social learning and subsequent reductions in social knowledge. Naturalistic measures of contextual modulation could help identify areas of need for individuals learning about the social world and could become treatment targets to improve everyday social learning.

Structural neuroimaging correlates of social deficits are similar in autism spectrum disorder and attention-deficit/hyperactivity disorder: analysis from the POND Network.

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal-parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to <0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders.

Differentiating social preference and social anxiety phenotypes in fragile X syndrome using an eye gaze analysis: a pilot study.

BACKGROUND: Fragile X syndrome (FXS) is the leading inherited cause of autism spectrum disorder, but there remains debate regarding the clinical presentation of social deficits in FXS. The aim of this study was to compare individuals with FXS to typically developing controls (TDC) and individuals with idiopathic autism spectrum disorder (ASD) across two social eye tracking paradigms. METHODS: Individuals with FXS and age- and gender-matched TDC and individuals with idiopathic ASD completed emotional face and social preference eye tracking tasks to evaluate gaze aversion and social interest, respectively. Participants completed a battery of cognitive testing and caregiver-reported measures for neurobehavioral characterization. RESULTS: Individuals with FXS exhibited reduced eye and increased mouth gaze to emotional faces compared to TDC. Gaze aversive findings were found to correlate with measures of anxiety, social communication deficits, and behavioral problems. In the social interest task, while individuals with idiopathic ASD showed significantly less social preference, individuals with FXS displayed social preference similar to TDC. CONCLUSIONS: These findings suggest fragile X syndrome social deficits center on social anxiety without the prominent reduction in social interest associated with autism spectrum disorder. Specifically designed eye tracking techniques clarify the nature of social deficits in fragile X syndrome and may have applications to improve phenotyping and evaluate interventions targeting social functioning impairments.

Pragmatic competence of children with autism spectrum disorder. Impact of theory of mind, verbal working memory, ADHD symptoms, and structural language.

The primary aim of this study is to increase the existing knowledge about the pragmatic skills of children with autism spectrum disorders (ASD). Specifically, the study has two objectives. The first is to provide a profile of characteristics based on The Children's Communication Checklist (CCC-2) pragmatics scales (inappropriate initiation, stereotyped language, use of context, nonverbal communication, and general pragmatics) and narrative task indicators. To this end, children with ASD will be compared to children with typical development (TD), controlling the effects of sex and structural language (speech, syntax, semantics, coherence). The second objective is to analyze whether theory of mind (ToM), verbal working memory, ADHD symptoms, and structural language can predict pragmatic competence in children with ASD without intellectual disability (ID). The results showed worse performance in the group with ASD on the majority of the pragmatic aspects evaluated. In addition, the application of ToM skills and structural language were significant predictors of the pragmatic skills of the children with ASD. These findings reinforce the importance of focusing intervention programs on mentalist abilities through experiences in real social scenarios, along with strengthening structural language components.

Decreased structural connectivity and resting-state brain activity in the lateral occipital cortex is associated with social communication deficits in boys with autism spectrum disorder.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by atypical social communication and repetitive behaviors. In this study, we applied a multimodal approach to investigate brain structural connectivity, resting state activity, and surface area, as well as their associations with the core symptoms of ASD. Data from forty boys with ASD (mean age, 11.5 years; age range, 5.5-19.5) and forty boys with typical development (TD) (mean age, 12.3; age range, 5.8-19.7) were extracted from the Autism Brain Imaging Data Exchange II (ABIDE II) for data analysis. We found significantly decreased structural connectivity, resting state brain activity, and surface area at the occipital cortex in boys with ASD compared to boys with TD. In addition, we found that resting state brain activity and surface area in the lateral occipital cortex was negatively correlated with communication scores in boys with ASD. Our results suggest that decreased structural connectivity and resting-state brain activity in the occipital cortex may impair the integration of verbal and non-verbal communication cues in boys with ASD, thereby impacting their social development.

Application of the Communication Complexity Scale in Peer and Adult Assessment Contexts for Preschoolers With Autism Spectrum Disorders.

Purpose The purpose of this study was to measure changes in communication of preschoolers with autism using the Communication Complexity Scale (CCS; Brady et al., 2012 ) and to examine the utility of the CCS in measuring pretreatment and posttreatment changes within peer and adult assessment contexts. Method The CCS was used to code preassessment and postassessment for 23 children with autism randomly assigned to a treatment that incorporated a peer-mediated approach and a speech-generating device and 22 assigned to a business-as-usual condition with untrained peers. Children were assessed in 2 structured 30-min contexts-1 with an adult examiner and 1 with a peer partner coached by an adult. Results Children in both groups showed significant changes in communication complexity CCS scores from pretreatment to posttreatment in the adult and peer contexts. At both occasions, CCS scores were higher with adult partners yet showed greater improvements over time with peer partners. Conclusions Results showed that the CCS was sensitive to change over time but did not discriminate changes in communication complexity associated with maturation versus treatment. It did show some differences based on interactions with peer versus adult partners. Outcomes provide preliminary support for using this scale to measure communication changes in different contexts. Supplemental Material https://doi.org/10.23641/asha.7408856.

Association between maternal Autism Spectrum Quotient scores and the tendency to see pragmatic impairments as a problem.

The aim of the present study was to test the hypothesis that individuals with higher Autism Spectrum Quotient (AQ) scores would be more permissive of pragmatic impairments than those with lower AQ scores. We investigated the presence of a correlation between the AQ scores of mothers with children in grades 1 to 6 and their evaluation of assumed pragmatic impairments in children using the Maternal Evaluation of Pragmatic Impairments in Children (MEPC) measure. Mothers were asked to rate how they would feel if their child showed the communication behaviors listed in scales D (coherence), E (inappropriate initiation), F (stereotyped language), G (use of context), and H (nonverbal communication) of the Children's Communication Checklist-2, which measures pragmatic impairments. All responses were given on a five-point Likert scale. The results indicated that the higher the maternal AQ score, the less the mother tended to evaluate pragmatic impairments as a problem. We also examined whether the age and gender of assumed children influenced the correlation between AQ and MEPC scores, but found no significant correlation. The partial correlation coefficients were calculated for each subscale, none of which was significant. A negative correlation was found between AQ and MEPC scores as a whole.

Concurrent Validity and Reliability for the Communication Complexity Scale.

Purpose: The Communication Complexity Scale (CCS; Brady et al., 2012) was created to fill a void in measures of expressive communication skills in individuals who communicate primarily with presymbolic or early symbolic means. CCS scores reflect expressive communication observed during interactive communication contexts. Method: Two studies were completed to examine the reliability and validity of the revised CCS scores. Participants in both studies had minimal verbal skills (i.e., produced less than 20 functional words). Study 1 examined interobserver agreement, test-retest reliability, and concurrent validity for 239 participants with intellectual disabilities between the ages of 3-66 years, assessed with the protocol developed at the University of Kansas (KU CCS). CCS scores were compared with scores from the Vineland Adaptive Behavior Scales-Second Edition (Sparrow, Cicchetti, & Balla, 2005) and the Communication Matrix (Rowland & Fried-Oken, 2010). Study 2 examined the reliability and concurrent validity for CCS scores derived from 110 children (chronological age = 3-9) with autism from diverse backgrounds. These children were assessed with the Early Social Communication Scale (Mundy et al., 2003). CCS scores were compared with rates of communication derived from the Early Social Communication Scale. Results: CCS scores were moderately correlated with scores from existing measures of early communication. In addition, CCS scores from different raters were reliable, and test-retest scores were highly similar. Conclusions: These findings support the validity and reliability of the CCS when used with individuals across a wide range of ages and with various types of disabilities. The CCS can be used in research and clinical practice to describe extant communication levels in individuals with minimal verbal skills.

Differentiating Autism from Typical Development: Preliminary Findings of Greek Versions of a Pragmatic Language and Social Communication Questionnaire.

OBJECTIVE: A social pragmatic communication disorder is one of the primary characteristics of children with autism. Although several measures of pragmatics and social communication exist, many are not comprehensive, do not examine the quality of interactions across contexts and interlocutors, and cannot be easily administered and interpreted. The aim of this article is to report on preliminary data collected using the Greek version of comprehensive social communication and pragmatic language questionnaires completed by parents and teachers interacting with young children in different contexts. METHODS: A Greek translation of the social communication and pragmatic language questionnaires was administered to parents and teachers of 31 children diagnosed with autism and of 51 typically developing children aged 3.0-6.0 years. Analysis and Results: The performance on the Greek versions of the social communication and pragmatic language questionnaires of typically developing children was compared with the performance of the children with autism using a series of independent t tests. Descriptive statistics were used to summarize participant characteristics and performances on the measure. Preliminary results showed that significant differences with moderate effect sizes were found between groups on 63% of the 30 test items. CONCLUSIONS: The performance of children on questionnaires may lead to the development of easily administered and interpretable assessments for differentiating children with pragmatics and social communication impairments, such as children with autism, from typically developing children.

Design of an Autonomous Social Orienting Training System (ASOTS) for Young Children With Autism.

Social communication is among the core areas of impairment for children with Autism Spectrum Disorders (ASD). The training of social orientation is important for improving social communication of children with ASD. In recent years, technology-assisted ASD intervention had gained momentum due to its potential advantages in terms of precision, sustainability, flexibility and cost. In this paper, we propose a closed-loop autonomous computer system, named ASOTS, for training social orientation skills to young children with ASD. This system is designed to detect and track a child's attention in response to social orientation bids and help the child towards appropriate social orientation when needed. Response to name, an important social orientation skill, was used to demonstrate the functionality of the proposed system. Ten toddlers with ASD participated in a pilot user study to show whether the system could be used on young children who have been diagnosed with ASD. Another pilot user study with 10 TD infants tested whether this system has a potential to be applied for early detection for infants who were younger than the age when ASD diagnoses can be done. This was done intentionally to separately demonstrate utility and functionality for the clinical population of interest and to demonstrate functionality beyond current clinical identification capacity (i.e., infants). The results showed that the proposed system and the protocol were well tolerated by both groups, successfully captured young children's attention, and elicited the desired behavior.

Cellular and Circuitry Bases of Autism: Lessons Learned from the Temporospatial Manipulation of Autism Genes in the Brain.

Transgenic mice carrying mutations that cause Autism Spectrum Disorders (ASDs) continue to be valuable for determining the molecular underpinnings of the disorders. Recently, researchers have taken advantage of such models combined with Cre-loxP and similar systems to manipulate gene expression over space and time. Thus, a clearer picture is starting to emerge of the cell types, circuits, brain regions, and developmental time periods underlying ASDs. ASD-causing mutations have been restricted to or rescued specifically in excitatory or inhibitory neurons, different neurotransmitter systems, and cells specific to the forebrain or cerebellum. In addition, mutations have been induced or corrected in adult mice, providing some evidence for the plasticity and reversibility of core ASD symptoms. The limited availability of Cre lines that are highly specific to certain cell types or time periods provides a challenge to determining the cellular and circuitry bases of autism, but other technological advances may eventually overcome this obstacle.

Downregulation of glutamatergic and GABAergic proteins in valproric acid associated social impairment during adolescence in mice.

The etiology of Autism Spectrum Disorder (ASD) remains controversial. Deficits in social communication are one of the key criteria for ASD diagnosis. Valproic acid (VPA), which is an anti-epileptic and anti-depressive drug, is one of the teratogens to cause ASD onset. Moreover, synaptic dysfunction is suggested as one of the major causative factor in VPA-induced ASD in vitro and in vivo studies. Herein, this study aimed to determine the excitatory/inhibitory synaptic mRNA and protein expression in VPA-induced autistic mice. Pregnant BALB/c mice were injected peritoneally with a single dose of 600mg/kg VPA on embryonic day (E) 12.5. Social impairment was verified by three chamber sociability tests on postnatal days (PND) 28, 35, 42 and 49. Cortical synaptic mRNA and protein expressions were examined on PND 50. The excitatory synaptic proteins NR2A, NR2B, NR2C were significantly down-regulated by 80.0% (p<0.01), 51.5% (p<0.05) and 81.5% (p<0.05) respectively. Furthermore, the NMDAR expression regulatory protein BDNF was also found to be significantly downregulated by 76.8% (p<0.05). GAD65, GAD67, GABRA1, GABRA5, GABRB2 from the GABAergic inhibitory synaptic pathway were significantly downregulated by 21.3% (p<0.05), 77.0% (p<0.05), 53.9% (p<0.05), 56.9% (p<0.05) and 55.2% (p<0.01) respectively in the cortex of VPA-induced mice. Taken together, our results suggested that synaptic dysfunction might be involved in the social impairments in VPA-induced ASD.

Symptom profiles of autism spectrum disorder in tuberous sclerosis complex.

OBJECTIVE: To determine the extent to which deficits associated with autism spectrum disorder (ASD) in toddlers with tuberous sclerosis complex (TSC) overlap with those in toddlers with nonsyndromic ASD (nsASD) and to examine cognitive function and epilepsy severity in toddlers with TSC and comorbid ASD. This is the endpoint analysis from a longitudinal investigation of ASD risk factors in children with TSC. METHODS: Measures included the Autism Diagnostic Observation Schedule (ADOS), the Mullen Scales of Early Learning, and clinical epilepsy variables. A repeated-measures analysis of variance was performed with between-subjects factor of group (typically developing, TSC/no ASD, TSC/ASD, nsASD) and within-subjects factors of individual ADOS item scores in the social communication and repetitive behavior/restricted interest domains. Within the TSC group, comparisons of epilepsy characteristics and cognitive domains were performed using independent-samples t tests. RESULTS: Children with TSC/ASD demonstrated a profile of social communication impairment that had complete convergence with nsASD. Measured social communication impairments included gestures, pointing, eye contact, responsive social smile, and shared enjoyment. This convergence was observed despite the high comorbidity between ASD and cognitive impairment in TSC. CONCLUSIONS: This study supports the clinical diagnosis of ASD in young children with TSC and demonstrates remarkable convergence of autism symptoms between TSC/ASD and nsASD. Our results strongly suggest the need for early intervention in toddlers with TSC, with treatment strategies targeting social communication function as well as broader developmental domains, before the onset of autism symptoms.

Frontal and Temporal Structural Connectivity Is Associated with Social Communication Impairment Following Traumatic Brain Injury.

OBJECTIVES: Although it has been well documented that traumatic brain injury (TBI) can result in communication impairment, little work to date has examined the relationship between social communication skills and structural brain integrity in patients with TBI. The aim of the current study was to investigate the association between self- and other-perceived communication problems and white matter integrity in patients with mild to severe TBI. METHODS: Forty-four individuals (TBI=24) and people with whom they frequently communicate, as well as demographically matched normal healthy comparisons (NC) and their frequent communication partners, were administered, respectively, the La-Trobe Communication Questionnaire Self form (LCQ-SELF) and Other form (LCQ-OTHER). In addition, diffusion tensor imaging data were collected, and fractional anisotropy (FA) measures were extracted for each lobe in both hemispheres. RESULTS: Within the TBI group, but not within the NC group, participants who were perceived by their close others as having more communication problems had lower FA in the left frontal and temporal lobes (p<.01), but not in other brain regions. CONCLUSIONS: Frontotemporal white matter microstructural integrity is associated with social communication abilities in adults with TBI. This finding contributes to our understanding of the mechanisms leading to communication impairment following TBI and can inform the development of new neuromodulation therapies as well as diagnostic tools. (JINS, 2016, 22, 705-716).