The Neural Mechanisms Supporting Structure and Inter-Brain Connectivity In Natural Conversation

Conversation is the height of human communication and social interaction, yet little is known about the neural mechanisms supporting it. To date, there have been no ecologically valid neuroimaging studies of conversation, and for good reason. Until recently, imaging techniques were hindered by artifact related to speech production. Now that we can circumvent this problem, I attempt to uncover the neural correlates of multiple aspects of conversation, including coordinating speaker change, the effect of conversation type (e.g. cooperative or argumentative) on inter-brain coupling, and the relationship between this coupling and social coherence. Pairs of individuals underwent simultaneous fMRI brain scans while they engaged in a series of unscripted conversations, for a total of 40 pairs (80 individuals). The first two studies in this dissertation lay a foundation by outlining brain regions supporting comprehension and production in both narrative and conversation - two aspects of discourse level communication. The subsequent studies focus on two unique features of conversation: alternating turns-at-talk and establishing inter-brain coherence through speech. The results show that at the moment of speaker change, both people are engaging attentional and mentalizing systems - which likely support orienting toward implicit cues signaling speaker change as well as anticipating the other person's intention to either begin or end his turn. Four networks were identified that are significantly predicted by a novel measure of social coherence; they include the posterior parietal cortex, medial prefrontal cortex, and right angular gyrus. Taken together, the findings reveal that natural conversation relies on multiple cognitive networks besides language to coordinate or enhance social interaction. &#8195

The Neural Correlates of Non-Spatial Working Memory in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)

Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant volumetric reductions in the parietal lobe of individuals with VCFS, but several studies have reported that the frontal lobe is relatively preserved. We used functional magnetic resonance imaging to investigate the neural correlates of non-spatial working memory in 17 youths with VCFS, 10 of their unaffected siblings, and 10 community controls (with the same proportion of learning disabilities as the VCFS youths). Task performance of siblings tended to be more accurate than children with VCFS, who did not differ from community controls. All three-study groups recruited parietal regions that were equivalent in location and magnitude. Whereas the sibling group also recruited the dorsolateral prefrontal cortex (DLPFC), Broca\u27s area, and anterior cingulate, DLPFC activation was absent in the whole brain analyses of children with VCFS and controls. Moreover, the magnitude of frontal activation in VCFS participants was restricted relative to both siblings and controls. These findings suggest that VCFS participants exhibit frontal hypoactivation that is not attributable to performance. In addition, VCFS children and controls (many with idiopathic learning disabilities) appear to rely on phonological rehearsal to hold information on line instead of the DLPFC. Despite previous anatomic MRI reports of preserved frontal lobe volumes in VCFS therefore, these fMRI findings suggest that the frontal component of the distributed network subserving executive function and working memory may be disrupted in youth with this disorder

Manic Symptoms and Behavioral Dysregulation in Youth with Velocardiofacial Syndrome (22q11.2 Deletion Syndrome).

Mania and bipolar disorder have been reported in adolescents and adults with velocardiofacial syndrome (VCFS; also known as 22q11.2 deletion syndrome). Children with VCFS have a high prevalence of attention-deficit/hyperactivity disorder (ADHD), which may constitute a risk factor for the eventual development of bipolar disorder in this population. Therefore, we sought to determine whether children with VCFS exhibit more manic symptoms than community controls that also may have learning disorders and ADHD. The study population consisted of 86 children with VCFS and 36 community controls from ages 9 to 15 years, using measures of Young Mania Rating Scale-Parent Version, Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), Child Behavior Checklist (CBCL), and Wechsler Intelligence Scale for Children-3rd edition (WISC-III). The results indicate that manic symptoms were not more prevalent in VCFS than in a community sample of children with learning disorders and ADHD. However, after accounting for symptoms of depression and ADHD, we found that manic symptoms in VCFS predicted uniquely to scores on four Child Behavior Checklist (CBCL) subscales, including anxiety, somatization, thought, and conduct problems. In contrast, manic symptoms in controls predicted uniquely to conduct problems only. Accordingly, our findings of severe behavioral impairment in youth with VCFS and manic symptoms suggest that these children may warrant more intensive monitoring and treatment relative to youth with VCFS and ADHD only

A Gender-Moderated Effect of a Functional COMT Polymorphism on Prefrontal Brain Morphology and Function in Velo-Cardio-Facial Syndrome (22q11.2 Deletion Syndrome)

Caused by a microdeletion at the q11.2 locus of chromosome 22, velo-cardio-facial syndrome (also known as VCFS, 22q11 deletion syndrome, DiGeorge sequence, and conotruncal anomalies face syndrome) is associated with a distinctive physical, neurocognitive, and psychiatric phenotype. Increasing interest has centered on identifying the candidate genes within the deleted region that may contribute to this phenotype. One attractive candidate gene is catechol-O-methyltransferase (COMT) because it encodes for a protein that degrades dopamine. Variability in COMT activity is related to a Val158Met polymorphism that has been implicated in prefrontal lobe cognitive and neuropsychiatric function. We examined the effect of this polymorphism on prefrontal anatomy and frontally-mediated neuropsychological function in 58 children with VCFS, 26 who were hemizygous for the Met allele and 32 for the Val allele. We found an allele by gender interaction effect on the volumes of the dorsal prefrontal and orbital prefrontal cortices. We did not find significant allele or gender by allele effects on neuropsychological tasks, although girls with the Met allele tended to perform better on the Wisconsin card sorting task. These data suggest that this functional COMT polymorphism may play a gender-moderated role in determining the neuroanatomic phenotype of individuals with VCFS. Longitudinal evaluation of these children is essential in order to identify potential clinical implications of this allele by gender interaction

Autistic Spectrum Disorders in Velo-cardio Facial Syndrome (22q11.2 Deletion)

The extent to which the phenotype of children comorbid for velocardiofacial syndrome (VCFS) and autism spectrum disorders (ASD) differs from that of VCFS-only has not been studied. The sample consisted of 41 children (20 females) with VCFS, ranging in age from 6.5 years to 15.8 years. Eight children with VCFS met formal DSM-IV diagnostic criteria for autism based upon the ADI-R. These eight plus an additional nine participants met diagnostic criteria for an autistic spectrum disorder (VCFS + ASD). Ninety-four percent of the children with VCFS + ASD had a co-occurring psychiatric disorder while 60% of children with VCFS had a psychiatric disorder. Children with VCFS + ASD had larger right amygdala volumes. All other neuroanatomic regions of interest were statistically similar between the two groups

22q11.2DS Deletion Syndrome: Developmental Milestones in Infants and Toddlers

The majority of children with 22q11.2DS deletion syndrome (22q11.2DS) have learning disabilities, and a substantial number have mental retardation. Although cognitive data have been reported on several samples of children with 22q11.2DS, data on their early developmental milestones are limited. Methods: The present study used a retrospective design and asked parents to recall developmental milestones. The participants were 88 children with 22q11.2DS, 47 community controls, and 29 sibling controls. Results: Although very early gross motor and expressive language milestones did not differ significantly from comparison groups, subsequent gross motor and expressive language milestones did, suggesting that children with 22q11.2DS may begin to lag behind their peers sometime after the first year of life in these two domains. These patterns were also apparent when a subset of intellectually comparable children (22q11.2DS, n = 40 vs community controls, n = 24) was analyzed. We further found that receptive language and social adaptive milestones did not differ from comparison samples in either the early or later period. Receptive language delays were predictive of later Wechsler Intelligence Scale for Children-Third Edition Perceptual Organization Index scores, particularly in girls with 22q11.2DS. Conclusions: This suggests that although receptive language may be an area of relative strength in the developmental profile of young children with 22q11.2DS, even mild receptive delays should not be overlooked in early interventions with children with this disorder

Temperament in Velocardiofacial Syndrome

Background Velocardiofacial syndrome (VCFS) is a microdeletion syndrome caused by a 22q11.2 chromosomal deletion. Methods In this study, parents reported on their own temperament as well as the temperament of their child. Sixty-seven children with VCFS (mean age = 10.8, SD = 2.8; range 6–15), and age-, race- and gender-ratio matched samples of 47 community control participants (mean age = 10.4, SD = 2.6; range 6–15), and 18 sibling control participants (mean age = 12.1, SD = 1.9; range 9–15) took part in the current project. Results Children with VCFS have a temperament that may best be described as modestly difficult; while participants with VCFS were not more difficult across all temperamental domains, children with VCFS were rated by their parents as being: (1) less regular in their daily habits (e.g. eating at the same time each day, etc.); (2) less able to focus/sustain attention; (3) less cheerful/pleasant; (4) less likely to stay with an activity for a long time; and (5) less able to respond flexibly to changes in the environment. Conclusions The best predictors of parent report of behavioural symptoms in children with VCFS were poor concordance between parent and child temperament across general activity level and mood domains

Associations Between Performance on the Rey-Osterrieth Complex Figure and Regional Brain Volumes in Children with and without Velocardiofacial Syndrome

Ninety-two children with velocardiofacial syndrome (VCFS), a genetic disorder caused by a microdeletion of chromosome 22q11.2 and an age, race, and gender-ratio comparable sample of 59 control participants were included in the project. Participants received an MRI as well as a comprehensive neuropsychological battery; the primary outcome measure in the current report is the Rey-Osterrieth Complex Figure (ROCF). Children with VCFS performed less well on the ROCF and have lower whole brain volume compared to controls. After controlling for whole brain volume differences, children with VCFS have bilaterally less parietal lobe gray and white matter yet more frontal lobe white matter. Brain-behavior relationships include: (a) for both groups, parietal volumes (both gray and white matter) predicted ROCF Copy Organization performance and frontal volumes (both gray and white matter) predicted ROCF Copy Accuracy performance; (b) for controls, frontal white matter also predicted ROCF Copy Organization performance; (c) ROCF Recall Organization performance was best predicted by frontal gray matter volume only in our controls; ROCF Recall Accuracy performance was best predicted by frontal gray matter volume in both groups; and (d) in children with VCFS, performance on the ROCF-Copy Structural Elements Accuracy scale was predicted by right hemisphere white matter volume. Our hypotheses were also retested using IQ-matched and whole brain volume-matched subsamples. Identical results were obtained in these analyses. Assumptions about the organization of and the localization of the brain structures that subserve specific cognitive functions in the typically developing brain may not apply in the abnormally developing brain