Amanda J. Moffitt

A neural region of abstract working memory

Over 350 years ago, Descartes proposed that the neural basis of consciousness must be a brain region in which sensory inputs are combined. Using fMRI, we identified at least one such area for working memory, the limited information held in mind, described by William James as the trailing edge of consciousness. Specifically, a region in the left intraparietal sulcus was found to demonstrate load-dependent activity for either visual stimuli (colored squares) or a combination of visual and auditory stimuli (spoken letters). This result was replicated across two experiments with different participants and methods. The results suggest that this brain region, previously well known for working memory of visually presented materials, actually holds or refers to information from more than one modality.

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.

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.

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).

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).

Intracranial Volume and Whole Brain Volume in Infants With Unicoronal Craniosynostosis

Objective Craniosynostosis has been hypothesized to result in alterations of the brain and cerebral blood flow due to reduced intracranial volume, potentially leading to cognitive deficits. In this study we test the hypothesis that intracranial volume and whole brain volume in infants with unilateral coronal synostosis differs from those in unaffected infants. Design Our study sample consists of magnetic resonance images acquired from 7- to 72-week-old infants with right unilateral coronal synostosis prior to surgery (n = 10) and age-matched unaffected infants (n = 10). We used Analyze 9.0 software to collect three cranial volume measurements. We used nonparametric tests to determine whether the three measures differ between the two groups. Correlations were calculated between age and the three volume measures in each group to determine whether the growth trajectory of the measurements differ between children with right unicoronal synostosis and unaffected infants. Results Our results show that the three volume measurements are not reduced in infants with right unicoronal synostosis relative to unaffected children. Correlation analyses between age and various volume measures show similar correlations in infants with right unicoronal synostosis compared with unaffected children. Conclusions Our results show that the relationship between brain size and intracranial size in infants with right unicoronal synostosis is similar to that in unaffected children, suggesting that reduced intracranial volume is not responsible for alterations of the brain in craniosynostosis.

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.

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 β-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.

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.

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.