Faculty Bibliography

A growing body of evidence shows that olfactory information is processed within a thalamic nucleus in both rodents and humans. The mediodorsal thalamic nucleus (MDT) receives projections from olfactory cortical areas including the piriform cortex (PCX) and is interconnected with the orbitofrontal cortex (OFC). Using electrophysiology in freely moving rats, we recently demonstrated the representation of olfactory information in the MDT and the dynamics of functional connectivity between the PCX, MDT and OFC. Notably, PCX-MDT coupling is specifically increased during odor sampling of an odor discrimination task. However, whether this increase of coupling is functionally relevant is unknown. To decipher the importance of PCX-MDT coupling during the sampling period, we used optogenetics to specifically inactivate the PCX inputs to MDT during an odor discrimination task and its reversal in rats. We demonstrate that inactivating the PCX inputs to MDT does not affect the performance accuracy of an odor discrimination task and its reversal, however, it does impact the rats' sampling duration. Indeed, rats in which PCX inputs to MDT were inactivated during the sampling period display longer sampling duration during the odor reversal learning compared to controls-an effect not observed when inactivating OFC inputs to MDT. We demonstrate a causal link between the PCX inputs to MDT and the odor sampling performance, highlighting the importance of this specific cortico-thalamic pathway in olfaction.

BACKGROUND:Restricted and repetitive behaviors (RRBs), detectable by 12 months in many infants in whom autism spectrum disorder (ASD) is later diagnosed, may represent some of the earliest behavioral markers of ASD. However, brain function underlying the emergence of these key behaviors remains unknown. METHODS:Behavioral and resting-state functional connectivity (fc) magnetic resonance imaging data were collected from 167 children at high and low familial risk for ASD at 12 and 24 months (n = 38 at both time points). Twenty infants met criteria for ASD at 24 months. We divided RRBs into four subcategories (restricted, stereotyped, ritualistic/sameness, self-injurious) and used a data-driven approach to identify functional brain networks associated with the development of each RRB subcategory. RESULTS:Higher scores for ritualistic/sameness behavior were associated with less positive fc between visual and control networks at 12 and 24 months. Ritualistic/sameness and stereotyped behaviors were associated with less positive fc between visual and default mode networks at 12 months. At 24 months, stereotyped and restricted behaviors were associated with more positive fc between default mode and control networks. Additionally, at 24 months, stereotyped behavior was associated with more positive fc between dorsal attention and subcortical networks, whereas restricted behavior was associated with more positive fc between default mode and dorsal attention networks. No significant network-level associations were observed for self-injurious behavior. CONCLUSIONS:These observations mark the earliest known description of functional brain systems underlying RRBs, reinforce the construct validity of RRB subcategories in infants, and implicate specific neural substrates for future interventions targeting RRBs.

Accumulating evidence suggests brain network dysfunction in attention-deficit/hyperactivity disorder (ADHD). Whether large-scale brain network connectivity patterns reflect clinical heterogeneity in ADHD remains to be fully understood. This study aimed to characterize the differential within- and between-network functional connectivity (FC) changes in children with ADHD combined (ADHD-C) or inattentive (ADHD-I) subtypes and their associations with ADHD symptoms. We studied the task-free functional magnetic resonance imaging (fMRI) data of 58 boys with ADHD and 28 demographically matched healthy controls. We measured within- and between-network connectivity of both low-level (sensorimotor) and high-level (cognitive) large-scale intrinsic connectivity networks and network modularity. We found that children with ADHD-C but not those with ADHD-I exhibited hyper-connectivity within the anterior default mode network (DMN) compared with controls. Additionally, children with ADHD-C had higher inter-network FC between the left executive control (ECN) and the salience (SN) networks, between subcortical and visual networks, and between the DMN and left auditory networks than controls, while children with ADHD-I did not show differences compared with controls. Similarly, children with ADHD-C but not ADHD-I showed lower network modularity compared with controls. Importantly, these observed abnormal inter-network connectivity and network modularity metrics were associated with Child Behavioral Checklist (CBCL) attention-deficit/hyperactivity problems and internalizing problems in children with ADHD. This study revealed relatively greater loss of brain functional network segregation in childhood ADHD combined subtype compared to the inattentive subtype, suggesting differential large-scale functional brain network topology phenotype underlying childhood ADHD heterogeneity.

What happens to early acquired but later abandoned motor skills? To investigate effects of disuse on early-developing motor skills, we examined crawling in two groups of habitual crawlers (34 6-12-month-old infants and five adults with Uner Tan Syndrome) and two groups of rusty crawlers (27 11-12-year-old children and 13 college-aged adults). Habitual crawlers showed striking similarities in gait patterns, limbs supporting the body, and crawling speed, despite dramatic differences in crawling practice, posture, and body size. Habitual crawlers trotted predominantly, whereas rusty crawlers showed a variety of gait patterns. Within sequences, habitual crawlers and children showed more switches in gait patterns than young adults. Children crawled faster and kept fewer limbs on the grounds than the other groups. Old crawling patterns were retained despite disuse, but new ones were also added. Surprisingly, results indicate that nothing was lost with disuse, but some features of crawling were gained or altered.

A growing body of research suggests that symptoms of autism spectrum disorder (ASD) may present differently in males and females. This study examined gender differences in ASD symptoms and developmental functioning, using the Baby and Infant Screen for Children with aUtism Traits, Part 1 (BISCUIT-Part 1) and the Battelle Developmental Inventory, 2nd Edition (BDI-2), amongst children aged 17-37 months meeting ASD diagnostic criteria (n = 1317). No gender differences were found in regards to overall symptom severity or symptom domains on the BISCUIT-Part 1 when gender groups were matched by cognitive ability. Females with ASD had greater motor deficits and less communication impairment compared to their male counterparts as measured by the BDI-2. Secondary analyses examining item endorsement patterns were also conducted. Implications of the findings are discussed.

Anatomical studies of SCI using Magnetic Resonance Imaging (MRI) report diverging observations, from 'no changes' to 'tissue atrophy in motor and non-motor regions.' These discrepancies among studies can be attributed to heterogeneity in extent, level and post-injury duration observed within the SCI population. But, no studies have investigated structural changes associated with different levels of injury (paraplegia vs. tetraplegia). High-resolution MRI images were processed using Voxel-Based Morphometry technique to compare regional GM volume (GMV) between 16 complete paraplegia and 7 complete tetraplegia SCI subjects scanned within two years of injury when compared to 22 age-matched healthy controls using one-way Analysis of Covariance (ANCOVA). A post-hoc analysis using region of interest based approach was employed to quantify GMV differences between healthy controls and subgroups of SCI. A voxel-wise one sample t-test was also performed to evaluate the mean effect of post-injury duration on GMV of SCI group. ANCOVA resulted in altered GMV in inferior frontal gyrus, bilateral mid orbital gyrus extending to rectal gyrus and anterior cingulate cortex. Post-hoc analysis, in general, indicated GM atrophy after SCI but tetraplegia showed a greater decrease in GMV when compared to paraplegia and healthy controls. Further, the GMV of the middle frontal gyrus, superior frontal gyrus, inferior frontal gyrus, insula, mid-orbital gyrus and middle temporal gyrus was positively correlated with post-injury duration in both paraplegia and tetraplegia groups. GM atrophy after SCI is affected by the level of cord injury, with higher levels of injury resulting in greater loss of GMV. The magnitude of GMV loss in the frontal cortex after SCI also appears to be dynamic within the first two years of injury. Understanding the effect of injury level and injury duration on structural changes following SCI can help better understand the mechanisms leading to positive and negative clinical outcome in SCI patients.

It is unclear if impairments in social functioning and peer relationships significantly differ across common developmental conditions such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD), and associated callous-unemotional traits (CU traits). The current study explored sex differences and symptoms of parent- and teacher-reported psychopathology on peer relationships and prosocial behaviour in a sample of 147 referred children and adolescents (aged 5-17 years; 120 m). The results showed that increases in parent-reported ADHD Inattentive symptoms and teacher-reported ADHD Hyperactive-Impulsive symptoms, CD, ODD, and CU traits were significantly associated with peer relationship problems across sex. At the same time, teacher-reported symptoms of ODD and both parent- and teacher-reported CU traits were related to difficulties with prosocial behaviour, for both boys and girls, with sex explaining additional variance. Overall, our findings show a differential association of the most common disruptive behaviours to deficits in peer relationships and prosocial behaviour. Moreover, they highlight that different perspectives of behaviour from parents and teachers should be taken into account when assessing social outcomes in disruptive behaviours. Given the questionable separation of conduct problem-related constructs, our findings not only point out the different contribution of those aspects in explaining peer relationships and prosocial behaviour, but furthermore the variance from different informants about those aspects of conduct problems.

Objective/UNASSIGNED:Traditional measures for assessing functioning with adult patients with schizophrenia have been shown to be insufficient for assessing the issues that occur in adolescents and young adults at clinical high risk (CHR) for psychosis. The current study provides an expanded validation of the Global Functioning: Social (GF:Social) and Role (GF:Role) scales developed specifically for use with CHR individuals and explores the reliability and accuracy of the ratings, the validity of the scores in comparison to other established clinical measures, stability of functioning over a 2-year period, and psychosis predictive ability. Methods/UNASSIGNED:Seven hundred fifty-five CHR individuals and 277 healthy control (HC) participants completed the GF:Social and Role scales at baseline as part of the North American Prodrome Longitudinal Study (NAPLS2). Results/UNASSIGNED:Inter-rater reliability and accuracy were high for both scales. Correlations between the GF scores and other established clinical measures demonstrated acceptable convergent and discriminant validity. In addition, GF:Social and Role scores were unrelated to positive symptoms. CHR participants showed large impairments in social and role functioning over 2-years, relative to the HCs, even after adjusting for age, IQ, and attenuated positive symptoms. Finally, social decline prior to baseline was more pronounced in CHR converters, relative to non-converters. Conclusions/UNASSIGNED:The GF scales can be administered in a large-scale multi-site study with excellent inter-rater reliability and accuracy. CHR individuals showed social and role functioning impairments over time that were not confounded by positive symptom severity levels. The results of this study demonstrate that social decline is a particularly effective predictor of conversion outcome.