Melisa Carrasco

Abnormalities of intrinsic functional connectivity in autism spectrum disorders.

Autism spectrum disorders (ASD) impact social functioning and communication, and individuals with these disorders often have restrictive and repetitive behaviors. Accumulating data indicate that ASD is associated with alterations of neural circuitry. Functional MRI (FMRI) studies have focused on connectivity in the context of psychological tasks. However, even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic or resting connectivity. Notably, the default network, which includes the posterior cingulate cortex, retro-splenial, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus, is strongly active when there is no task. Altered intrinsic connectivity within the default network may underlie offline processing that may actuate ASD impairments. Using FMRI, we sought to evaluate intrinsic connectivity within the default network in ASD. Relative to controls, the ASD group showed weaker connectivity between the posterior cingulate cortex and superior frontal gyrus and stronger connectivity between the posterior cingulate cortex and both the right temporal lobe and right parahippocampal gyrus. Moreover, poorer social functioning in the ASD group was correlated with weaker connectivity between the posterior cingulate cortex and the superior frontal gyrus. In addition, more severe restricted and repetitive behaviors in ASD were correlated with stronger connectivity between the posterior cingulate cortex and right parahippocampal gyrus. These findings indicate that ASD subjects show altered intrinsic connectivity within the default network, and connectivity between these structures is associated with specific ASD symptoms.

Neural activation to emotional faces in adolescents with autism spectrum disorders

BACKGROUND Autism spectrum disorders (ASD) involve a core deficit in social functioning and impairments in the ability to recognize face emotions. In an emotional faces task designed to constrain group differences in attention, the present study used functional MRI to characterize activation in the amygdala, ventral prefrontal cortex (vPFC), and striatum, three structures involved in socio-emotional processing in adolescents with ASD. METHODS Twenty-two adolescents with ASD and 20 healthy adolescents viewed facial expressions (happy, fearful, sad and neutral) that were briefly presented (250 ms) during functional MRI acquisition. To monitor attention, subjects pressed a button to identify the gender of each face. RESULTS The ASD group showed greater activation to the faces relative to the control group in the amygdala, vPFC and striatum. Follow-up analyses indicated that the ASD relative to control group showed greater activation in the amygdala, vPFC and striatum (p < .05 small volume corrected), particularly to sad faces. Moreover, in the ASD group, there was a negative correlation between developmental variables (age and pubertal status) and mean activation from the whole bilateral amygdala; younger adolescents showed greater activation than older adolescents. There were no group differences in accuracy or reaction time in the gender identification task. CONCLUSIONS When group differences in attention to facial expressions were limited, adolescents with ASD showed greater activation in structures involved in socio-emotional processing.

INCREASED ERROR-RELATED BRAIN ACTIVITY IN YOUTH WITH OBSESSIVE-COMPULSIVE DISORDER AND UNAFFECTED SIBLINGS

The pathophysiology of obsessive‐compulsive disorder (OCD) involves increased activity in cortico‐striatal circuits connecting the anterior cingulate cortex (ACC) with other brain regions. The error‐related negativity (ERN) is a negative deflection in the event‐related potential following an erroneous response and is thought to reflect ACC activity. This study was done to assess the ERN as a biomarker for OCD by comparing ERN amplitudes in pediatric OCD patients, unaffected siblings of pediatric OCD patients, and healthy controls.

Age-related changes in the structure and function of prefrontal cortex-amygdala circuitry in children and adolescents: A multi-modal imaging approach

The uncinate fasciculus is a major white matter tract that provides a crucial link between areas of the human brain that underlie emotion processing and regulation. Specifically, the uncinate fasciculus is the major direct fiber tract that connects the prefrontal cortex and the amygdala. The aim of the present study was to use a multi-modal imaging approach in order to simultaneously examine the relation between structural connectivity of the uncinate fasciculus and functional activation of the amygdala in a youth sample (children and adolescents). Participants were 9 to 19years old and underwent diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). Results indicate that greater structural connectivity of the uncinate fasciculus predicts reduced amygdala activation to sad and happy faces. This effect is moderated by age, with younger participants exhibiting a stronger relation. Further, decreased amygdala activation to sad faces predicts lower internalizing symptoms. These results provide important insights into brain structure-function relationships during adolescence, and suggest that greater structural connectivity of the uncinate fasciculus may facilitate regulation of the amygdala, particularly during early adolescence. These findings also have implications for understanding the relation between brain structure, function, and the development of emotion regulation difficulties, such as internalizing symptoms.

The impact of serotonin transporter (5-HTTLPR) genotype on the development of resting-state functional connectivity in children and adolescents: a preliminary report.

A fundamental component of brain development is the formation of large-scale networks across the cortex. One such network, the default network, undergoes a protracted development, displaying weak connectivity in childhood that strengthens in adolescence and becomes most robust in adulthood. Little is known about the genetic contributions to default network connectivity in adulthood or during development. Alterations in connectivity between posterior and frontal portions of the default network have been associated with several psychological disorders, including anxiety, autism spectrum disorders, schizophrenia, depression, and attention-deficit/hyperactivity disorder. These disorders have also been linked to variants of the serotonin transporter linked polymorphic region (5-HTTLPR). The LA allele of 5-HTTLPR results in higher serotonin transporter expression than the S allele or the rarer LG allele. 5-HTTLPR may influence default network connectivity, as the superior medial frontal region has been shown to be sensitive to changes in serotonin. Also, serotonin as a growth factor early in development may alter large-scale networks such as the default network. The present study examined the influence of 5-HTTLPR variants on connectivity between the posterior and frontal structures and its development in a cross-sectional study of 39 healthy children and adolescents. We found that children and adolescents homozygous for the S allele (S/S, n=10) showed weaker connectivity in the superior medial frontal cortex compared to those homozygous for the LA allele (LA/LA, n=13) or heterozygotes (S/LA, S/LG, n=16). Moreover, there was an age-by-genotype interaction, such that those with LA/LA genotype had the steepest age-related increase in connectivity between the posterior hub and superior medial frontal cortex, followed by heterozygotes. In contrast, individuals with the S/S genotype had the least age-related increase in connectivity strength. This preliminary report expands our understanding of the genetic influences on the development of large-scale brain connectivity and lays down the foundation for future research and replication of the results with a larger sample.

Error-related negativity and tic history in pediatric obsessive-compulsive disorder

OBJECTIVE The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response, which is often increased in patients with obsessive-compulsive disorder (OCD). However, the relation of the ERN to comorbid tic disorders has not been examined in patients with OCD. This study compared ERN amplitudes in patients with tic-related OCD, patients with non-tic-related OCD, and healthy controls. METHOD The ERN, correct response negativity, and error number were measured during an Eriksen flanker task to assess performance monitoring in 44 youth with a lifetime diagnosis of OCD and 44 matched healthy controls ranging in age from 10 to 19 years. Nine youth with OCD had a lifetime history of tics. RESULTS ERN amplitude was significantly increased in patients with OCD compared with healthy controls. ERN amplitude was significantly larger in patients with non-tic-related OCD than in patients with tic-related OCD or controls. ERN amplitude had a significant negative correlation with age in healthy controls but not in patients with OCD. Instead, in patients with non-tic-related OCD, ERN amplitude had a significant positive correlation with age at onset of OCD symptoms. ERN amplitude in patients was unrelated to OCD symptom severity, current diagnostic status, or treatment effects. CONCLUSIONS The results provide further evidence of increased error-related brain activity in pediatric OCD. The difference in the ERN between patients with tic-related and those with non-tic-related OCD provides preliminary evidence of a neurobiological difference between these two OCD subtypes. The results indicate the ERN is a trait-like measurement that may serve as a biomarker for non-tic-related OCD.

Age-related changes in error processing in young children: A school-based investigation

Highlights • Correlates of childrens response inhibition were evaluated using a Go/No-Go task.• The ERN and Pe were present for children from 3 to 7.• Response inhibition, as evidenced by faster, more accurate responses, increased with age.• Age-related changes were identified in the Pe, but not in the ERN.• Girls were more accurate and showed elevated Pe amplitudes relative to boys.

Increased error-related brain activity in youth with obsessive-compulsive disorder and other anxiety disorders

The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response that is thought to reflect activity in the anterior cingulate cortex (ACC) and is often increased in patients with anxiety disorders. This study measured the ERN and correct response negativity (CRN) during an Eriksen flanker task to assess performance monitoring in 26 youth with obsessive-compulsive disorder (OCD), 13 youth with a non-OCD anxiety disorder consisting of either generalized anxiety disorder or separation anxiety disorder, and 27 age-matched healthy controls ranging in age from 8 to 16 years. Compared to healthy controls, ERN amplitude was significantly increased in patients with either OCD or a non-OCD anxiety disorder. There were no significant group differences in CRN amplitude. Treatment with a serotonergic antidepressant or cognitive-behavior therapy had no effect on the ERN in patients. Scores from the Child Behavior Checklist DSM-oriented anxiety problems scale had a significant correlation with ERN amplitude in all subjects. The results provide further evidence that the pathophysiology of OCD and some non-OCD anxiety disorders involves increased ACC activity and that the ERN may serve as a quantitative phenotype in genetic and longitudinal studies of these complex traits.

Age-related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence

The S and LG alleles of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) lower serotonin transporter expression. These low‐expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala–prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces depression that emerges in adolescence, whereas decreased serotonin transporter that occurs later in development ameliorates depression. However, no brain imaging research has yet investigated the moderating influence of human development on the link between 5‐HTTLPR and effect‐related brain function. We investigated the age‐related effect of 5‐HTTLPR on amygdala activation and amygdala–prefrontal cortex connectivity using a well‐replicated probe, an emotional face task, in children and adolescents aged 9–19 years. A significant genotype‐by‐age interaction predicted amygdala activation, such that the low‐expressing genotype (S/S and S/LG) group showed a greater increase in amygdala activation with age compared to the higher expressing (LA/LA and S/LA) group. Additionally, compared to the higher expressing group, the low‐expressing genotype group exhibited decreased connectivity between the right amygdala and ventromedial prefrontal cortex with age. Findings indicate that low‐expressing genotypes may not result in the corticolimbic profile associated with depression risk until later adolescence. Hum Brain Mapp 35:646–658, 2014.

Altered Relationship Between Electrophysiological Response to Errors and Gray Matter Volumes in an Extended Network for Error-Processing in Pediatric Obsessive-Compulsive Disorder

Pediatric patients with obsessive‐compulsive disorder (OCD) show an increased electrophysiological response to errors that is thought to be localized to the posterior medial prefrontal cortex (pMFC). However, the relation of this response, the error‐related negativity (ERN), to underlying brain structures remains unknown. In an examination of 20 pediatric OCD patients and 20 healthy youth, we found that more negative ERN amplitude was correlated with lower gray matter (GM) density in pMFC and orbital frontal cortex. The association of the ERN with pMFC gray matter volume was driven by the patient group. In addition, a group difference in the association of ERN with gray matter in right insula was observed, showing an association of these measures in healthy youth (more negative ERN amplitude was associated with lower GM density in insula), but not in patients. These findings provide preliminary evidence linking gray matter volumes in an extended network for error processing to the ERN, and suggest that structural alterations in this network may underlie exaggeration of the ERN in pediatric OCD. Hum Brain Mapp 35:1143–1153, 2014.