This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early -life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early -life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early -life prediction and intervention in neurodevelopment.

ADHD profoundly impacts educational attainment, quality of life, and health in young adults. However, certain subgroups of ADHD patients seem to do quite well, potentially due to differences in intelligence and socioeconomic status. Here we used paternal intelligence from the Swedish Defence Conscription and Assessment register, to investigate the role of genetic propensity for intelligence, on school performance in a large cohort of ADHD patients and matched controls. Patients treated for ADHD in Linköping, Sweden between 1995 and 2020 (n = 3262), sex- and age-matched controls (n = 9591) as well as their parents and siblings were identified using regional and national registers. Socioeconomic and demographic data, ADHD diagnosis and treatment and school grades at age 16 for the study population were extracted from Swedish National registers. We explored the associations between paternal intelligence and child school performance using linear mixed models and mediation analyses, taking a wide range of potential covariates into account. Results indicate that paternal intelligence was positively associated with standardized school grades in their offspring (Zadjusted=0.09, 95%CI 0.07, 0.10). This effect was present in both ADHD patients and controls, but ADHD patients had significantly lower standardized grades (Zadjusted=-1.03, 95%CI -1.08, -0.98). Child ADHD did not serve as a mediator for how paternal intelligence affected school grades. Our findings indicate that ADHD prevents children from reaching their academic potential at all levels of paternal intelligence. Increased understanding of the contributions of ADHD, intelligence, and SES to functional outcomes can help clinicians to better personalize interventions to the unique preconditions in each patient.

Background: Decreased sound tolerance (DST) is a disabling transdiagnostic phenomenon with high clinical relevance in autism. Neurodevelopmental DST is often studied as part of a general multisensory construct that includes both hyper- and hyposensitivity. Therefore, knowledge about the potential relevance of individual differences in the auditory modality is lacking. The purpose of the study was to begin to differentiate between commonly pooled auditory functions, by incorporating psychometric tools from the field of audiology.Methods: In a pilot sample (N = 520 adults, 23% autistic), we used Bayesian correlations to quantify the contribution of individual auditory items from the Glasgow Sensory Questionnaire to the degree of social, communicative, and rigid autistic traits measured with the Broad Autism Phenotype Questionnaire (BAPQ) subscales. Then, we recruited an independent sample (N = 175 adults, 18% autistic) to measure, more specifically, (1) emotional reactions to sounds (affective DST), (2) speech understanding difficulties, and (3) nonsocial auditory processing (spatial perception and stream segregation), using self-report questionnaires. We used multiple regression to test for associations with the autistic trait domains.Results: We found that all autistic traits measured by the BAPQ (social, communicative, and rigid) linearly predicted affective DST, and these associations remained when autistic participants were excluded. Difficulties with speech perception, as well as spatial perception and auditory stream segregation, were most strongly predicted by communication differences.Conclusion: The robust relationship between autistic traits and emotional sound reactivity suggests that affective DST falls on a spectrum just like autism. This argues against strict dichotomization and encourages the use of continuous measures. The results support a dominant role for emotional and stress systems in autism-related DST and may suggest that detailed audiological tests are clinically useful, in particular, in the context of pragmatic language difficulties. Community Brief Why is this an important issue? Differences in sensory perception go hand in hand with an autistic neurotype. Many individuals find everyday noises intolerable or difficult to understand, but there is little knowledge of how these experiences vary among individuals. What was the purpose of this study? To understand which aspects of auditory processing are related to autistic characteristics, using assessment tools from the audiology field. What did the researchers do? They studied 175 adults with different levels of autistic-like social function, communication style, and rigid thinking (18% with an autism diagnosis). They used clinical questionnaires to measure emotional reactions to sounds, speech understanding, auditory space perception, and the ability to distinguish overlapping sounds. What were the results of the study? All autistic characteristics were linked to strong emotional reactions to sounds. Those with an autistic communication style also reported difficulties with speech perception, auditory space perception, and separating overlapping sounds. What do these findings add to what was already known? The results highlight a role of emotional and stress responses in autistic sound sensitivity. In addition, they point to the existence of broader auditory difficulties in adults with an autistic communication style. What are potential weaknesses in the study? It did not include laboratory measurements of auditory function. How will these findings help autistic adults now or in the future? This study helps by breaking down specific hearing challenges in autism, such as trouble understanding speech or reacting strongly to everyday sounds, rather than looking at sensory issues as a whole. This can lead to better support and solutions for these specific difficulties.

Background. Decreased sound intolerance (DST) is a disabling transdiagnostic phenomenon with high clinical relevance in autism. Neurodevelopmental DST is often studied as part of a general multisensory construct that includes both hyper- and hyposensitivity. Therefore, knowledge about the potential relevance of individual differences in the auditory modality is lacking. The purpose of the study was to begin to differentiate between commonly pooled auditory functions, by incorporating psychometric tools from the field of audiology. 

Methods. In a pilot sample (N = 520 adults, 23% autistic), we used Bayesian correlations to quantify the contribution of individual auditory items from the Glasgow Sensory Questionnaire to the degree of social, communicative and rigid autistic traits measured with the Broad Autism Phenotype Questionnaire (BAPQ) subscales. Then, we recruited an independent sample (N = 175 adults, 18% autistic) to measure, more specifically, 1) emotional reactions to sounds (affective DST), 2) speech understanding difficulties, and 3) non-social auditory processing (spatial perception and stream segregation), using self-report questionnaires. We used multiple regressions to test for associations with the autistic trait domains. 

Results. We found that all autistic traits measured by the BAPQ (social, communicative and rigid) linearly predicted affective DST, and these associations remained when autistic participants were excluded. Difficulties with speech perception, as well as spatial perception and auditory stream segregation, were most strongly predicted by communication differences. 

Conclusion. The robust relationship between autistic traits and emotional sound reactivity suggest that affective DST falls on a spectrum just like autism. This argues against strict dichotomization and encourages the use of continuous measures. The results support a dominant role for emotional and stress systems in autism-related DST, and may suggest that detailed audiological tests are clinically useful, in particular in the context of pragmatic language difficulties. 

BackgroundAutism spectrum conditions (ASC) and quantitative autistic traits (QATs) are associated with sensory symptoms, which may contribute to anxiety and adversely affect social and cognitive development. Although sensory symptoms can occur across all senses, the relative roles of specific sensory modalities as contributors to the autistic phenotype and to anxiety are not well understood. The objective of this study was to examine which sensory symptoms were most predictive of high anxiety.MethodsWe recruited 257 female primary caregivers of children aged 6 to 11 years (49% girls) to a questionnaire study comprising parent-report measures for classical QATs (social, communicative, and rigid), autism-related sensorimotor symptoms (visual, auditory, tactile, olfactory, gustatory, vestibular, proprioceptive, and motor), and anxiety symptoms. First, Bayesian stochastic search variable selection (SSVS) was used to identify the most probable sensorimotor predictors of specific QATs as well as diagnosed ASC. Then, the selected predictors were used in another SSVS, using anxiety symptoms as a dependent variable, to identify which of the autism-relevant sensorimotor symptoms were most robustly predictive of anxiety. Finally, the effect sizes of anxiety-related sensory symptoms were estimated with linear regressions.ResultsWe found that auditory symptoms and motor difficulties were most predictive of ASC diagnosis. Developmental motor difficulties were also strongly related to all individual QATs, whereas auditory symptoms were more selectively predictive of rigid traits. Tactile symptoms robustly predicted social interaction QATs, and proprioceptive symptoms predicted communicative QATs. Anxiety outcomes were most strongly predicted by difficulties with auditory and olfactory processing.ConclusionsThe results support the clinical importance of being alert to complaints about sounds and hearing in neurodevelopmental populations, and that auditory processing difficulties may be evaluated as an early marker of poor mental health in children with and without diagnosed autism. Olfactory processing differences appeared to be an anxiety marker less strongly associated with ASC or QATs, while motor difficulties were highly autism-relevant but not equally strongly associated with anxiety outcomes. We suggest that future studies may focus on the mechanisms and consequences of neurodevelopmental central auditory processing dysfunction and its potential relationship to anxiety disorders.

Background

Adults with attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) face multiple challenges in obtaining and maintaining employment.

Aims

To identify and describe how adults with ADHD or ASD experienced their ability to work and what factors affected their ability to find a sustainable work situation over time.

Methods

Individual in-depth interviews were performed with 20 purposively sampled participants with ADHD/ASD. Data were analysed inductively using reflexive thematic analysis.ResultsThree themes were identified, describing (1) one’s own cognitive abilities and challenges, (2) enablement by flexibility and acceptance in the work environment, and (3) accumulated stress that makes the work situation unsustainable over time.

Conclusions

Over time, a lack of continuity and predictability of support measures caused great stress and exhaustion, with severe consequences for working life and in life in general. Adaptations needed to be individually tailored and include nonoccupational factors.

Significance

The study shows that adults with ADHD/ASD need long-term interventions that flexibly adapt to individual needs, as they vary over time. The findings suggest that occupational therapists and other health care providers, employers, employment services and other involved agencies should pay a greater deal of attention to stability and predictability over time.

Sensory processing differences measured by self- or parent-report co-segregate with quantitative autistic traits and have potential endophenotypic properties. It is not known to what extent this reflects generalized sensory dysfunction versus more specific associations involving individual senses or autistic trait domains. We combined Bayesian variable selection with dominance analysis to obtain a more nuanced understanding of modality-specific associations. We recruited two independent samples of adults to complete the Broad Autism Phenotype Questionnaire and the Glasgow Sensory Questionnaire. For each domain of autistic traits (social interaction, communication, cognitive rigidity), we performed stochastic search variable selection using Glasgow Sensory Questionnaire modality subscales as predictors while controlling for uncertainty in other variables. Dominance analysis was applied to the reduced models to evaluate the relative importance of predictors. Only auditory scores reliably predicted all three autistic traits when other modalities were accounted for. The proprioceptive scale, which included motor and interoceptive deficits, predicted communicative autistic traits more than other trait domains. The tactile scale appeared most specific for social autistic traits. Although the findings must be interpreted in light of the limitations of the questionnaires, the study suggests that auditory differences may be more likely than differences in other senses to be a robust sensory endophenotype relevant to autism. Lay abstract Sensory symptoms are a major source of distress for many autistic people, causing anxiety, stress, and avoidance. Sensory problems are thought to be passed on genetically together with other autistic characteristics, such as social preferences. This means that people who report cognitive rigidity and autistic-like social function are more likely to suffer from sensory issues. We do not know what role the individual senses, such as vision, hearing, smell, or touch, play in this relationship, because sensory processing is generally measured with questionnaires that target general, multisensory issues. This study aimed to investigate the individual importance of the different senses (vision, hearing, touch, smell, taste, balance, and proprioception) in the correlation with autistic traits. To ensure the results were replicable, we repeated the experiment in two large groups of adults. The first group contained 40% autistic participants, whereas the second group resembled the general population. We found that problems with auditory processing were more strongly predictive of general autistic characteristics than were problems with the other senses. Problems with touch were specifically related to differences in social interaction, such as avoiding social settings. We also found a specific relationship between proprioceptive differences and autistic-like communication preferences. The sensory questionnaire had limited reliability, so our results may underestimate the contribution of some senses. With that reservation in mind, we conclude that auditory differences are dominant over other modalities in predicting genetically based autistic traits and may therefore be of special interest for further genetic and neurobiological studies.

The broad autism phenotype (BAP) is a set of characteristics often observed in typically developing people with a genetic load for autism, such as parents of autistic children. The Broad Autism Phenotypic Questionnaire (BAPQ) is a 36-item questionnaire developed to identify the BAP in first-degree relatives of autistic people. We translated the BAPQ into Swedish and examined its psychometric properties in a Swedish sample consisting of 45 parents of children with ASC and 74 parents of non-autistic children. We found support for the original 3-factor structure (aloof, pragmatic language and rigid), good internal consistency and convergent validity with the Autism Quotient. Thus, the Swedish BAPQ exhibits acceptable psychometric properties and may be useful for assessing the BAP in non-clinical populations.

Quantitative autistic-like traits (QATs) are a constellation of traits that mirror those of clinical autism and are thought to share the same mechanisms as the condition. There is great interest in identifying the genetic and neurobiological basis of QATs, but progress is hindered by the composite nature of these clinically based constructs. Social QATs are defined according to the diagnostic criteria for autism, comprising multiple potential neural mechanisms that may contribute to varying degrees. The objective of this study was to decompose social QATs into more specific constructs, in line with the Research Domain Criteria (RDoC). We chose constructs with trait-like properties and known or suggested significance for autistic social function: 1) social anhedonia, 2) prosopagnosia (face blindness), and 3) mentalizing (attributing mental states to images of eyes). We hypothesized that these constructs may all contribute to observed variance in social QATs. We recruited 148 adults with a broad range of QATs (mean age 37.9 years, range 18–69; 50% female; 5.4% autistic) to an experimental behavioral study conducted online. We estimated social QATs using the social factor of the Comprehensive Autistic Traits Inventory. We used the Oxford Face Matching Task and the Reading the Mind in the Eyes Test to measure face matching ability and mentalizing, respectively. Social anhedonia traits were measured with the Anticipatory and Consummatory Interpersonal Pleasure Scale, and prosopagnosic traits with the 20-item Prosopagnosia Index. A combination of frequentist and Bayesian statistics was used to test the social constructs as predictors of social QATs. We found that social anhedonic traits, prosopagnosic traits, and face matching performance were likely predictors of social QATs, whereas mentalizing showed limited contribution. The findings support prosopagnosic and anhedonic traits, but not mentalizing deficits, as dimensional predictors of individual differences in social function across the autistic spectrum. Further, the study strongly suggest that social reward systems and face processing networks play significant and independent roles in autistic-like social function.

Background: Autistic adults have an elevated risk of many health problems compared with the general population, making health care access extra critical. Unfortunately, autistic people often find health care settings quite aversive, and many medical providers report feeling unsure about how to interact with autistic patients. We aimed at characterizing specific challenges regarding sensory experiences and communicative barriers in health care settings.

Methods: We recruited adults to complete an anonymous online questionnaire on the topic of improving healthcare experiences for everyone. The questions covered demographics, sensory experiences in medical settings, and communication with health care providers. We quantified the associations between autism diagnosis and experiences of sensory discomfort and communication barriers in health care settings. We also did a qualitative analysis of text responses to questions on how to improve sensory environments and communication with providers.

Results: Swedish adults (62 autistic and 36 nonautistic) participated in the study. The cohort was well educated, and autistic participants received their autism diagnosis late in life (median age 36 years, range 13–57). Compared with nonautistic participants, autistic participants reported greater discomfort with background sound levels in health care settings and felt more misunderstood by health care providers. Thematic analyses showed that auditory stimuli and proximity to other people were particularly bothersome for autistic participants, causing stress or avoidance and affecting the ability to interact with providers. Providers contributed to communication barriers by failing to recognize the need for individualized information, especially when respondents’ difficulties were not visible or taken seriously. Participants requested greater clarity and supplementary written information. Providers also misunderstood autistic adults’ body language or eye contact patterns, as they interpreted their clients through the lens of neurotypical expectations.

Conclusions: Our results extend previous research by emphasizing sensory aspects of health care settings and suggesting specific and reasonable adaptations. The results also highlight how the provider’s implicit expectations of nonverbal communication caused misinterpretations of autistic people who were socially skilled but did not use typical body language. Based on the data, we suggest specific adaptations, many of which may also benefit nonautistic people.

An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affective touch is an important means of social interaction, and C-Tactile (CT) afferents are thought to play a key role in the peripheral detection and encoding of these stimuli. Exploring the neural and behavioral mechanisms for processing CT-optimal touch (similar to 3 cm/s) may therefore provide useful insights into the pathophysiology of ASD. We examined the relationship between touch hedonics (i.e. the subjective pleasantness with which affective touch stimuli are perceived) and neural processing in the posterior superior temporal sulcus (pSTS). This region is less activated to affective touch in individuals with ASD, and, in typically developing individuals (TD), is correlated positively with touch pleasantness. TD and ASD participants received brushing stimuli at CT-optimal, and CT-non-optimal speeds during fMRI. Touch pleasantness and intensity ratings were collected, and affective touch awareness, a measure of general touch hedonics was calculated. As expected, slow touch was perceived as more pleasant and less intense than fast touch in both groups, whereas affective touch awareness was moderately higher in TD compared to ASD. There was a strong, positive correlation between right pSTS activation and affective touch awareness in TD, but not in ASD. Our findings suggest that altered neural coupling between right pSTS and touch hedonics in ASD may be associated with social touch avoidance in ASD.

Childhood maltreatment is considered a risk factor for substance use disorders (SUD), but this is largely based on retrospective self-reports that are subject to recall bias, designs that do not control for familial confounding, or both. The specific contribution of childhood maltreatment to SUD risk thus remains unclear. Here, we evaluated this contribution in a prospective cohort with objectively recorded childhood maltreatment, using a design that allows controlling for familial confounding. We used medical records and registers to study 525 young adults (20-37 years) with prospectively and objectively documented severe maltreatment exposure, 1979 clinical controls (unexposed former child and adolescent psychiatry patients), 1388 matched healthy controls; and their siblings and cousins. We examined the association between maltreatment and SUD using Cox regression models in the population, as well as stratified within siblings in the same family. SUD risk was significantly increased with childhood maltreatment exposure (crude HR: 6.61, 95% CI: 5.81-7.53; HR adjusted for sex, birthyear, externalizing problems, parents SUD and socioeconomic factors: 3.50, 95% CI 2.95, 4.16). An approximately threefold elevated SUD risk remained when comparing exposed individuals with their unexposed siblings (adjusted HR: 3.12, 95% CI 2.21, 4.42). We provide estimates of the association between childhood maltreatment and SUD accounting for possible confounds of both recall bias and familial factors. When familial confounding is controlled for, SUD risk attributable to severe childhood maltreatment is decreased, but nevertheless considerable. These findings establish a specific contribution of childhood maltreatment to SUD, underscoring the need for SUD prevention in young people exposed to maltreatment.

Repetitive movements (RMs), colloquially called “stimming” among adult autistic people and “motor stereotypies” among scientists, are common in autism. These behaviors fall under the domain of restricted and repetitive behaviors in the current edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). RMs can be socially disruptive or cause self-harm, but can also be experienced as cognitively or emotionally helpful and even enjoyable. Overt RMs are less common in females than in males, which could contribute to clinical difficulties in detecting their autism. In the social domain, autistic people with intact intelligence can often mask their social difficulties through various compensation strategies, and females appear especially skilled at it. Subjective report from verbally able adults may be useful as a first step in detecting potential camouflaging of RMs, and to provide a foundation for further studies. We founded an Internet-based outreach platform that became particularly successful in reaching female and transgender individuals. We recruited 342 individuals to an anonymous online questionnaire, collected data about self-reported RMs and probed for potential camouflaging. The cohort comprised 56% formally diagnosed participants and 44% who self-identified as autistic, and 17% of all participants reported non-cisgender identity. Thus, in addition to diagnosed women, we reached two populations that would normally be excluded from autism studies: transgender and undiagnosed participants. We found high rates of RMs in both diagnosed and self-identifying participants, and a striking prevalence of camouflaging. We suggest that camouflaging of RMs may contribute to underdiagnosis of autism, at least in females and transgender people, and that further studies on this topic are exceptionally important.

The neural basis of autism spectrum disorder (ASD) is not yet understood. ASD is marked by social deficits and is strongly associated with cerebellar abnormalities. We studied the organization and cerebellar connectivity of the temporoparietal junction (TPJ), an area that plays a crucial role in social cognition. We applied localized independent component analysis to resting-state fMRI data from autistic and neurotypical adolescents to yield an unbiased parcellation of the bilateral TPJ into 11 independent components (ICs). A comparison between neurotypical and autistic adolescents showed that the organization of the TPJ was not significantly altered in ASD. Second, we used the time courses of the TPJ ICs as spatially unbiased “seeds” for a functional connectivity analysis applied to voxels within the cerebellum. We found that the cerebellum contained a fine-grained, lateralized map of the TPJ. The connectivity of the TPJ subdivisions with cerebellar zones showed one striking difference in ASD. The right dorsal TPJ showed markedly less connectivity with the left Crus II. Disturbed cerebellar input to this key region for cognition and multimodal integration may contribute to social deficits in ASD. The findings might also suggest that the right TPJ and/or left Crus II are potential targets for noninvasive brain stimulation therapies.

Information processing in specialized, spatially distributed brain networks underlies the diversity and complexity of our cognitive and behavioral repertoire. Networks converge at a small number of hubs – highly connected regions that are central for multimodal integration and higher-order cognition. We review one major network hub of the human brain: the inferior parietal lobule and the overlapping temporoparietal junction (IPL/TPJ). The IPL is greatly expanded in humans compared to other primates and matures late in human development, consistent with its importance in higher-order functions. Evidence from neuroimaging studies suggests that the IPL/TPJ participates in a broad range of behaviors and functions, from bottom-up perception to cognitive capacities that are uniquely human. The organization of the IPL/TPJ is challenging to study due to the complex anatomy and high inter-individual variability of this cortical region. In this review we aimed to synthesize findings from anatomical and functional studies of the IPL/TPJ that used neuroimaging at rest and during a wide range of tasks. The first half of the review describes subdivisions of the IPL/TPJ identified using cytoarchitectonics, resting-state functional connectivity analysis and structural connectivity methods. The second half of the article reviews IPL/TPJ activations and network participation in bottom-up attention, lower-order self-perception, undirected thinking, episodic memory and social cognition. The central theme of this review is to discuss how network nodes within the IPL/TPJ are organized and how they participate in human perception and cognition.

It is now well established that visual attention, as measured with standard spatial attention tasks, and visual awareness, as measured by report, can be dissociated. It is possible to attend to a stimulus with no reported awareness of the stimulus. We used a behavioral paradigm in which people were aware of a stimulus in one condition and unaware of it in another condition, but the stimulus drew a similar amount of spatial attention in both conditions. The paradigm allowed us to test for brain regions active in association with awareness independent of level of attention. Participants performed the task in an MRI scanner. We looked for brain regions that were more active in the aware than the unaware trials. The largest cluster of activity was obtained in the temporoparietal junction (TPJ) bilaterally. Local independent component analysis (ICA) revealed that this activity contained three distinct, but overlapping, components: a bilateral, anterior component; a left dorsal component; and a right dorsal component. These components had brain-wide functional connectivity that partially overlapped the ventral attention network and the frontoparietal control network. In contrast, no significant activity in association with awareness was found in the banks of the intraparietal sulcus, a region connected to the dorsal attention network and traditionally associated with attention control. These results show the importance of separating awareness and attention when testing for cortical substrates. They are also consistent with a recent proposal that awareness is associated with ventral attention areas, especially in the TPJ.

The temporoparietal junction (TPJ) is activated in association with a large range of functions, including social cognition, episodic memory retrieval, and attentional reorienting. An ongoing debate is whether the TPJ performs an overarching, domain-general computation, or whether functions reside in domain-specific subdivisions. We scanned subjects with fMRI during five tasks known to activate the TPJ, probing social, attentional, and memory functions, and used data-driven parcellation (independent component analysis) to isolate task-related functional processes in the bilateral TPJ. We found that one dorsal component in the right TPJ, which was connected with the frontoparietal control network, was activated in all of the tasks. Other TPJ subregions were specific for attentional reorienting, oddball target detection, or social attribution of belief. The TPJ components that participated in attentional reorienting and oddball target detection appeared spatially separated, but both were connected with the ventral attention network. The TPJ component that participated in the theory-of-mind task was part of the default-mode network. Further, we found that the BOLD response in the domain-general dorsal component had a longer latency than responses in the domain-specific components, suggesting an involvement in distinct, perhaps postperceptual, computations. These findings suggest that the TPJ performs both domain-general and domain-specific computations that reside within spatially distinct functional components.

The human temporoparietal junction (TPJ) is a topic of intense research. Imaging studies have identified TPJ activation in association with many higher-order functions such as theory-of-mind, episodic memory, and attention, causing debate about the distribution of different processes. One major challenge is the lack of consensus about the anatomical location and extent of the TPJ. Here, we address this problem using data-driven analysis to test the hypothesis that the bilateral TPJ can be parcellated into subregions. We applied independent component analysis (ICA) to task-free fMRI data within a local region around the bilateral TPJ, iterating the ICA at multiple model orders and in several datasets. The localized analysis allowed finer separation of processes and the use of multiple dimensionalities provided qualitative information about lateralization. We identified four subdivisions that were bilaterally symmetrical and one that was right biased. To test whether the independent components (ICs) reflected true subdivisions, we performed functional connectivity analysis using the IC coordinates as seeds. This confirmed that the subdivisions belonged to distinct networks. The right-biased IC was connected with a network often associated with attentional processing. One bilateral subdivision was connected to sensorimotor regions and another was connected to auditory regions. One subdivision that presented as distinct left- and right-biased ICs was connected to frontoparietal regions. Another subdivision that also had left- and right-biased ICs was connected to social or default mode networks. Our results show that the TPJ in both hemispheres hosts multiple neural processes with connectivity patterns consistent with well developed specialization and lateralization.

The human temporoparietal junction (TPJ) is a topic of intense research. Imaging studies have identified TPJ activation in association with many higher-order functions such as theory-of-mind, episodic memory, and attention, causing debate about the distribution of different processes. One major challenge is the lack of consensus about the anatomical location and extent of the TPJ. Here, we address this problem using data-driven analysis to test the hypothesis that the bilateral TPJ can be parcellated into subregions. We applied independent component analysis (ICA) to task-free fMRI data within a local region around the bilateral TPJ, iterating the ICA at multiple model orders and in several datasets. The localized analysis allowed finer separation of processes and the use of multiple dimensionalities provided qualitative information about lateralization. We identified four subdivisions that were bilaterally symmetrical and one that was right biased. To test whether the independent components (ICs) reflected true subdivisions, we performed functional connectivity analysis using the IC coordinates as seeds. This confirmed that the subdivisions belonged to distinct networks. The right-biased IC was connected with a network often associated with attentional processing. One bilateral subdivision was connected to sensorimotor regions and another was connected to auditory regions. One subdivision that presented as distinct left- and right-biased ICs was connected to frontoparietal regions. Another subdivision that also had left- and right-biased ICs was connected to social or default mode networks. Our results show that the TPJ in both hemispheres hosts multiple neural processes with connectivity patterns consistent with well developed specialization and lateralization.

Understanding how epileptic seizures are initiated and propagated across large brain networks is difficult, but an even greater mystery is what makes them stop. Failure of spontaneous seizure termination leads to status epilepticus—a state of uninterrupted seizure activity that can cause death or permanent brain damage. Global factors, like changes in neuromodulators and ion concentrations, are likely to play major roles in spontaneous seizure cessation, but individual neurons also have intrinsic active ion currents that may contribute. The recently discovered gene Slack encodes a sodium-activated potassium channel that mediates a major proportion of the outward current in many neurons. Although given little attention, the current flowing through this channel may have properties consistent with a role in seizure termination.

Purpose: Preclinical data have suggested that selective serotonin reuptake inhibitors (SSRIs) may have anticonvulsant properties, and some SSRIs are known to modulate ion channels in vitro. We screened citalopram, fluoxetine, and sertraline for anticonvulsant actions in mouse hippocampal slices, and studied the effects of citalopram on active membrane properties and repetitive action potential firing.

Methods: To enable testing of antiepileptic effects and target modulation in a single experimental system, we used the simplistic low‐Ca2+ model, which is strongly dependent on the intrinsic excitability of CA1 pyramidal neurons. Field potentials and whole‐cell currents were recorded from brain slices, and SSRIs were bath‐applied.

Key Findings: We found that citalopram, fluoxetine, and sertraline inhibited epileptiform activity recorded from area CA1. The effect of citalopram was more potent and less variable than that of fluoxetine and sertraline. The anticonvulsant action of citalopram was accompanied by marked slowing of action potential rise and decay, and robust inhibition of repetitive firing. This depression of membrane excitability appeared to be mediated in part by inhibition of a sustained potassium current.

Significance: These findings confirm that SSRIs can have anticonvulsant effects in the hippocampus, and further suggest that citalopram may exert these effects at least in part by inhibition of voltage‐gated ion currents.

Selective serotonin reuptake inhibitors (SSRIs) can reduce seizure frequency in humans, but no large‐scale clinical trials have been done to test the utility of SSRIs as potential antiepileptic drugs. This may be caused in part by a small number of reports on seizures triggered by SSRI treatment. The preclinical literature on SSRIs is somewhat conflicting, which is likely to contribute to the hesitance in accepting SSRIs as possible anticonvulsant drug therapy. A careful review of preclinical studies reveals that SSRIs appear to have region‐specific and seizure subtype–specific effects, with models of chronic partial epilepsy being more likely to respond than models of acute generalized seizures. Moreover, this preclinical profile is similar to that of clinical antiepileptic drugs. These observations suggest that SSRIs are promising antiepileptic agents, and that clinical trials may benefit from defining patient groups according to the underlying pathology.

The antidepressant drug fluoxetine (FLX) has been shown to exert antiepileptic effects in several animal models, but mixed preclinical findings and occasional reports of proconvulsant effects have led to hesitation towards its use in epileptic people. Despite being developed as a selective serotonin reuptake inhibitor, FLX has numerous other targets in the brain. One of the proposed targets is the neuronal sodium channel, which is inhibited by many existing antiepileptic drugs. In this study, we used electrophysiological methods in a brain slice model of seizures to test for anticonvulsant and Na+ channel-blocking effects of FLX. This approach allowed us to use a single biological system to study the effects of FLX on (1) epileptiform activity, (2) Na+-dependent action potential generation, and (3) the persistent Na+ current (INaP). We found that FLX was anticonvulsant in a dose- and time-dependent manner, and that this action was accompanied by strong INaP inhibition and impairment of repetitive firing. These findings suggest that the effect of FLX on active membrane properties is similar to that of many antiepileptic drugs, and that this action may contribute to anticonvulsant effects.

Magnesium-free medium can be used in brain slice studies to enhance glutamate receptor function, but this manipulation causes seizure-like activity in many cortical areas. The rodent olfactory bulb (OB) slice is a popular preparation, and potentially ictogenic ionic conditions have often been used to study odor processing. We studied low Mg2+-induced epileptiform discharges in mouse OB slices using extracellular and whole cell electrophysiological recordings. Low-Mg2+ medium induced two distinct types of epileptiform activity: an intraglomerular delta-frequency oscillation resembling slow sniff-induced activity and minute-long seizure-like events (SLEs) consisting of large negative-going field potentials accompanied by sustained depolarization of output neurons. SLEs were dependent on N-methyl-d-aspartate receptors and sodium currents and were facilitated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors. The events were initiated in the glomerular layer and propagated laterally through the external plexiform layer at a slow time scale. Our findings confirm that low-Mg2+ medium should be used with caution in OB slices. Furthermore, the SLEs resembled the so-called slow direct current (DC) shift of clinical and experimental seizures, which has recently been recognized as being of great clinical importance. The OB slice may therefore provide a robust and unique in vitro model of acute seizures in which mechanisms of epileptiform DC shifts can be studied in isolation from fast oscillations.

Reward-mediated associative learning is important for recognizing the significance of environmental cues. Such learning involves convergence of multimodal sensory inputs with circuits involved in affective and memory processes. Dopamine-dependent plasticity in the striatum plays a pivotal role, but the wider circuits engaged in cue-reward association are poorly understood. To identify candidate structures that may be of particular interest for further detailed electrophysiological and functional analysis, we quantified c-Fos expression in a selection of brain structures. c-Fos is a well-known marker of cell activation with additional potential importance for synaptic plasticity. We compared c-Fos expression between animals exposed to 100 pairings of a novel conditioned stimulus with a subsequent reward, and control animals exposed to the same number of cues and rewards, but where the cues and rewards occurred at random with respect to each other. We found significant increases in c-Fos expression in the superior colliculus in the group exposed to cue-reward pairing. This is consistent with previous recordings in conscious animals, showing modulation of phasic visual responses of single collicular neurons depending on their association with reward. Further, the data also suggest the possibility that the thalamic paraventricular nucleus and septal nuclei may be selectively activated during cue-reward association learning. Little is known of the neurophysiological responses in these structures during such tasks, so the present results suggest they would be targets of interest for future single-neuron recording experiments, designed to confirm whether the neurons show learning-specific modulation.

Autism spectrum conditions (ASC) and quantitative autistic traits (QATs) are associated with sensory symptoms, which may contribute to anxiety and adversely affect social and cognitive development. Although sensory symptoms can occur across all senses, the relative roles of specific sensory modalities as contributors to the autistic phenotype and to anxiety are not well understood. The objective of this study was to examine which sensory symptoms were most predictive of high anxiety. We recruited 257 female primary caregivers of children aged 6 to 11 years (49 % girls) to a questionnaire study comprising parent-report measures for classical QATs (social, communicative, and rigid), autism-related sensorimotor symptoms (visual, auditory, tactile, olfactory, gustatory, vestibular, proprioceptive, and motor), and anxiety symptoms. First, Bayesian stochastic search variable selection (SSVS) was used to identify the most probable sensorimotor predictors of specific QATs as well as diagnosed ASC. Then, the selected predictors were used in another SSVS, using anxiety symptoms as a dependent variable, to identify which of the autism-relevant sensorimotor symptoms were most robustly predictive of anxiety. Finally, the effect sizes of anxiety-related sensory symptoms were estimated with linear regressions. We found that auditory symptoms and motor difficulties were most predictive of ASC diagnosis. Developmental motor difficulties were also strongly related to all individual QATs, whereas auditory symptoms were more selectively predictive of rigid traits. Tactile symptoms robustly predicted social interaction QATs, and proprioceptive symptoms predicted communicative QATs. Anxiety outcomes were most predicted by difficulties with auditory and olfactory processing. The results support the clinical importance of being alert to complaints about sounds and hearing in neurodevelopmental populations, and that auditory processing difficulties may be evaluated as an early marker of poor mental health in children with and without diagnosed autism. Olfactory processing differences appeared to be an anxiety marker less strongly associated with ASC or QATs, while motor difficulties were highly autism-relevant but not equally strongly associated with anxiety outcomes. We suggest that future studies may focus on the mechanisms and consequences of neurodevelopmental central auditory processing dysfunction and its potential relationship to anxiety disorders.

Early motor function is important for emerging social pragmatic communication (SPC) skills in both typical and atypical development. However, the nature of motor impairments relevant for higher-level communication is not well understood. Inefficient cerebellar error correction might directly cause both developmental coordination disorder (DCD) symptoms and SPC difficulties, through the extensive communication between cerebellar zones and brain-wide sensorimotor and higher-order networks. DCD symptoms related to cerebellar deficits could also impact SPC through affecting the developmental trajectory of social development, which requires motor skills. This study aimed to test the hypothesis that error correction deficits affect SPC outcomes through childhood DCD symptoms, by using contemporary causal inference methodology. We used a finger tapping task and computational modeling to measure cerebellar error correction in adult participants (n = 138), and quantified childhood DCD symptoms and SPC skills using psychometric measures. The results confirmed that error correction ability likely affects SPC skills, and indicated that childhood motor skills significantly mediated this. These results argue against a direct effect of domain-general error correction deficits on SPC, and instead suggest that cerebellum-related DCD symptoms affect sociocommunicative development more directly through motor deficits during development. Further research is required to test whether cerebellar error correction could be used as an early marker to identify children in need for early SPC interventions.