Social Skills Intervention Participation and Associated Improvements in Executive Function Performance.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication. It has been postulated that such difficulties are related to disruptions in underlying cognitive processes such as executive function. The present study examined potential changes in executive function performance associated with participation in the Social Competence Intervention (SCI) program, a short-term intervention designed to improve social competence in adolescents with ASD. Laboratory behavioral performance measures were used to separately evaluate potential intervention-related changes in individual executive function component processes (i.e., working memory, inhibitory control, and cognitive flexibility) in a sample of 22 adolescents with ASD both before and after intervention. For comparison purposes, a demographically matched sample of 14 individuals without ASD was assessed at identical time intervals. Intervention-related improvements were observed on the working memory task, with gains evident in spatial working memory and, to a slightly lesser degree, verbal working memory. Significant improvements were also found for a working memory-related aspect of the task switching test (i.e., mixing costs). Taken together, these findings provide preliminary support for the hypothesis that participation in the SCI program is accompanied by changes in underlying neurocognitive processes such as working memory.

Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria.

The most widely-reported neurologic finding in individuals with early-treated phenylketonuria (PKU) is abnormality in the white matter of the brain. In contrast, much less is known regarding the impact of PKU on cortical gray matter (GM) structures. Presently, we applied advanced morphometric methods to the analysis of high-resolution structural MRI images from a sample of 19 individuals with early-treated PKU and an age- and gender-matched comparison group of 22 healthy individuals without PKU. Data analysis revealed decreased GM volume in parietal cortex for the PKU group compared with the non-PKU group. A similar trend was observed for occipital GM volume. There was no evidence of group-related differences in frontal or temporal GM volume. Within the PKU group, we also found a significant relationship between blood phenylalanine levels and GM volume for select posterior cortical sub-regions. Taken together with previous research on white matter and gray matter abnormalities in PKU, the present findings point to the posterior cortices as the primary site of neurostructural changes related to early-treated PKU.

Effect of propranolol on facial scanning in autism spectrum disorder: a preliminary investigation.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and restricted, repetitive behaviors. Whereas current pharmacological interventions for ASD focus primarily on psychiatric symptoms, including agitation and obsessive behaviors, few agents target core symptomatology. It has been previously hypothesized that abnormalities in facial scanning, such as reduced eye contact or increased mouth fixation, contribute to social communication deficits in ASD. In addition, previous reports have suggested elevated stress and anxiety in ASD, symptoms that are believed to impact facial scanning patterns. OBJECTIVES: The present pilot study sought to explore the effects of pharmacological intervention via propranolol, a nonselective ß-adrenergic antagonist and known anxiolytic, on facial scanning in ASD. Specifically, we wished to determine whether there is an increase in eye contact and a decrease in mouth fixation with administration of propranolol. METHOD: A sample of 14 participants with ASD and 14 matched controls participated in two study sessions in which propranolol and placebo were administered in a counterbalanced, double-blinded manner. At each session, ocular fixation data were collected during presentation of video stimuli of 16 human faces. Fixation time on the eye, nose, and mouth regions of the face stimuli was analyzed. RESULTS: The baseline fixation patterns for the ASD and control groups did not significantly differ; however, administration of propranolol was associated with a significant reduction in mouth fixation for the ASD group. Additionally, mouth fixation was positively related to nonverbal communication impairment in the ASD group. CONCLUSIONS: Although eye fixation in ASD appears typical in the present study, the effect of propranolol in reducing mouth fixation suggests an important focus for further research. Future studies are needed to better characterize the relationship between stress and anxiety and facial scanning in ASD, as well as the effects of pharmacological intervention.

The effects of tetrahydrobiopterin (BH4) treatment on brain function in individuals with phenylketonuria.

Phenylketonuria (PKU) is a rare genetic condition characterized by an absence or mutation of the PAH enzyme, which is necessary for the metabolism of the amino acid phenylalanine into tyrosine. Recently, sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), has been introduced as a supplemental treatment to dietary phe control for PKU. Very little is known regarding BH4 treatment and its effect on brain and cognition. The present study represents the first examination of potential changes in neural activation in patients with PKU during BH4 treatment. To this end, we utilized an n-back working memory task in conjunction with functional magnetic resonance imaging (fMRI) to evaluate functional brain integrity in a sample of individuals with PKU at three timepoints: Just prior to BH4 treatment, after 4 weeks of treatment, and after 6 months of treatment. Neural activation patterns observed for the PKU treatment group were compared with those of a demographically-matched sample of healthy non-PKU individuals who were assessed at identical time intervals. Consistent with past research, baseline evaluation revealed impaired working memory and atypical brain activation in the PKU group as compared to the non-PKU group. Most importantly, BH4 treatment was associated with improvements in both working memory and brain activation, with neural changes evident earlier (4-week timepoint) than changes in working memory performance (6-month timepoint).

A volumetric study of basal ganglia structures in individuals with early-treated phenylketonuria.

Whereas the impact of early-treated phenylketonuria (ETPKU) on cortical white matter is well documented, relatively little is known regarding the potential impact of this metabolic disorder on deep gray matter structures such as the basal ganglia. The current study used high-resolution (1mm(3)) magnetic resonance imaging to investigate bilateral basal ganglia structures (i.e., putamen, caudate nucleus, and nucleus accumbens) in a sample of 13 individuals with ETPKU and a demographically-matched sample of 13 neurologically intact individuals without PKU. Consistent with previous research, we found smaller whole brain volumes in the ETPKU group compared with the non-PKU group. Individuals with ETPKU also had significantly larger putamen volumes than non-PKU individuals. In addition, the degree of putamen enlargement was correlated with blood phenylalanine levels and full scale IQ in the ETPKU group. These findings are consistent with the hypothesis that ETPKU-related increases in phenylalanine lead to decreased central dopamine levels thus impacting dopamine-dependent brain regions such as the putamen that play an important role in cognition.

A longitudinal analysis of regional brain volumes in macaques exposed to X-irradiation in early gestation.

BACKGROUND: Early gestation represents a period of vulnerability to environmental insult that has been associated with adult psychiatric disease. However, little is known about how prenatal perturbation translates into adult brain dysfunction. Here, we use a longitudinal study design to examine the effects of disruption of early gestational neurogenesis on brain volume in the non-human primate. METHODS AND PRINCIPAL FINDINGS: Five Rhesus macaques were exposed to x-irradiation in early gestation (E30-E41), and four control monkeys were sham-irradiated at comparable ages. Whole brain magnetic resonance imaging was performed at 6 months, 12 months, and 3 and 5 years of age. Volumes of whole cerebrum, cortical gray matter, caudate, putamen, and thalamus were estimated using semi-automated segmentation methods and high dimensional brain mapping. Volume reductions spanning all ages were observed in irradiated monkeys in the putamen (15-24%, p = 0.01) and in cortical gray matter (6-15%, p = 0.01). Upon covarying for whole cerebral volume, group differences were reduced to trend levels (putamen: p = 0.07; cortical gray matter: p = 0.08). No group-by-age effects were significant. CONCLUSIONS: Due to the small number of observations, the conclusions drawn from this study must be viewed as tentative. Early gestational irradiation may result in non-uniform reduction of gray matter, mainly affecting the putamen and cerebral cortex. This may be relevant to understanding how early prenatal environmental insult could lead to brain morphological differences in neurodevelopmental diseases.

Decreased functional brain connectivity in individuals with early-treated phenylketonuria: evidence from resting state fMRI.

Previous histological and neuroimaging studies have documented structural abnormalities in the white matter of the brain in individuals with early-treated phenylketonuria (ETPKU). It remains unclear, however, the extent to which the function of the brain's interconnections are impacted by this condition. Presently, we utilized functional magnetic resonance imaging (fMRI) to evaluate the synchronization of neural signals (i.e., functional connectivity) among brain regions comprising the default mode network (DMN) in a sample of 11 individuals with ETPKU and 11 age- and gender-matched neurologically intact controls. The DMN is a group of interconnected brain regions that are known to be generally more active during rest than during task performance. Data analysis revealed decreased functional connectivity among DMN regions for the ETPKU group compared with the control group. Within the PKU group, we also found a significant relationship between blood phenylalanine (phe) levels and the functional connectivity between select regions of the DMN. In conjunction with findings from another recent fMRI study (Christ, Moffitt et al. 2010), the present results suggest that ETPKU-related deficiencies in functional connectivity are pervasive. The current findings also provide initial evidence that the extent of such impairment may be moderated in part by blood phe levels.

Disruption of prefrontal function and connectivity in individuals with phenylketonuria.

Phenylketonuria (PKU) is a genetic disorder associated with disruption of prefrontal cortex (PFC) development and executive dysfunction. To date, however, there is little evidence directly linking these two sequelae of PKU. We utilized functional magnetic resonance imaging (fMRI) to evaluate prefrontal functioning in six individuals with early-treated PKU (ETPKU) during performance of an n-back working memory task and compared results with those of six age- and gender-matched neurologically intact individuals. In addition, we evaluated the possible presence of PKU-related disruptions in functional connectivity, as might be hypothesized based on prior reports of white matter injury in individuals with ETPKU. A number of brain regions, nearly half of which were located in the PFC, were found to show atypical neural activity in individuals with ETPKU during working memory performance. We also found decreased connectivity both within the PFC as well as between the PFC and other brain regions in individuals with ETPKU compared with controls. Results from this preliminary study suggest that both prefrontal dysfunction and disruptions in functional connectivity may contribute to PKU-related executive impairment. In addition to advancing our understanding of PKU, the current findings have a broader impact in that PKU is regularly used as a model of early prefrontal dysfunction in the study of other neurodevelopmental disorders (e.g., autism).

Structural abnormalities in gyri of the prefrontal cortex in individuals with schizophrenia and their unaffected siblings.

BACKGROUND: The relatives of individuals with schizophrenia exhibit deficits of overall frontal lobe volume, consistent with a genetic contribution to these deficits. AIMS: To quantify the structure of gyral-defined subregions of prefrontal cortex in individuals with schizophrenia and their siblings. METHOD: Grey matter volume, cortical thickness, and surface area of the superior, middle and inferior frontal gyri were measured in participants with schizophrenia and their unaffected (non-psychotic) siblings (n = 26 pairs), and controls and their siblings (n = 40 pairs). RESULTS: Grey matter volume was reduced in the middle and inferior frontal gyri of individuals with schizophrenia, relative to controls. However, only inferior frontal gyrus volume was also reduced in the unaffected siblings of those with schizophrenia, yielding a volume intermediate between their affected siblings and controls. CONCLUSIONS: The structure of subregions of the prefrontal cortex may be differentially influenced by genetic factors in schizophrenia, with inferior frontal gyrus volume being most related to familial risk.

Detecting 3D Corpus Callosum abnormalities in phenylketonuria.

Phenylketonuria (PKU) is a genetic disorder characterised by an inability to metabolise phenylalanine. Several studies have reported that the Corpus Callosum (CC) is one of the most severely affected structures with respect to volume loss in early treated PKU patients. In this work, we aim to detect the abnormalities of the CC in PKU from both global and local perspectives. 3D models of the CC are extracted from MRI data using a semiautomatic segmentation method. In the global analysis, raw and scaled volumes of the CC are compared between PKU patients and the controls. An oriented bounding box of the CC is constructed and its length, width and height are used as the MRI traits in our study. The raw and scaled values of these traits are compared between patients and controls. In the local analysis, shape differences at every surface point of the CC between PKU patients and the controls are computed using Hotelling T(2) two-sample metric followed by a permutation test. The height of the CC is found to be significantly shorter in the patients and significant shape abnormalities in the genu and splenium of the CC is also found in the patients.

Inter-rater reliability of manual segmentation of the superior, inferior and middle frontal gyri.

Precise rules for locating the anatomical boundaries of the dorsolateral prefrontal cortex (DLPFC) or its subdivisions, i.e., superior, inferior and middle frontal gyri (SFG, IFG and MFG) on magnetic resonance images (MRI), have not been defined. The present study describes the inter-rater reliability of manual segmentation of the SFG, IFG and MFG using guidelines based on sulcal-gyral anatomical boundaries as well as the cytoarchitectonic features of the sub-regions of the prefrontal cortex (PFC). Variations in the application of these guidelines in different subjects to account for normal sulcal variability were developed using the atlas of Ono et al. (Ono, M., Kubik, S., Abernathey, C.D., 1990. Atlas of the Cerebral Sulci. Georg Thieme Verlag, New York). Based on previous cytoarchitectonic studies, the coronal plane of the anterior termination of olfactory sulcus (ATOS) was used as a landmark for delimiting the boundary between the frontal pole (FP) and the frontal gyri. The left hemisphere gray-matter volumes of the SFG, IFG and MFG were determined using a set of 10 MRIs (5 normal and 5 schizophrenia subjects) by two trained raters independently. The intra-class correlation coefficients (ICC) for the SFG, IFG and MFG volumes by the two raters were 0.97, 0.94 and 0.93, respectively. Thus, we describe a reliable method of parcellating the SFG, IFG and MFG, which constitute the DLPFC, a brain region involved in a variety of neuropsychiatric conditions.