Todd L. Richards

Abnormal functional connectivity in autism spectrum disorders during face processing

Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning adults with ASD and 21 age-and IQ-matched control adults. Activation during identification of previously viewed faces and houses using a one-back paradigm was compared. The fusiform face area (FFA) was individually localized in each participant and used as the seed point for functional connectivity analyses. The degree of correlation between FFA and the extended neural circuitry involved in face identification was tested. A whole brain analysis was also conducted in order to determine whether connectivity from the FFA to aberrant brain locations was present in the ASD group. Measures of clinical severity (ADOS social score and ADI-R social score) were included as independent variables into the functional connectivity analyses. Significant FFA-amygdala and FFA-superior temporal sulcus functional connectivity was found in both the ASD and control participants. However, the control group had significantly increased connectivity to the left amygdala and the posterior cingulate compared to ASD. Post hoc analyses additionally found increased connectivity to the thalamus in the controls. A significant relationship between abnormal functional connectivity and clinical severity in the ASD group was observed. Specifically, greater social impairment was associated with reduced FFA-amygdala connectivity and increased FFA-right inferior frontal connectivity. These results suggest that abnormal neural connections within the limbic system may contribute to the social impairments observed in ASD.

Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives.

Achieving progress in understanding the cause, nature, and treatment of autism requires an integration of concepts, approaches, and empirical findings from genetic, cognitive neuroscience, animal, and clinical studies. The need for such integration has been a fundamental tenet of the discipline of developmental psychopathology from its inception. It is likely that the discovery of autism susceptibility genes will depend on the development of dimensional measures of broader phenotype autism traits. It is argued that knowledge of the cognitive neuroscience of social and language behavior will provide a useful framework for defining such measures. In this article, the current state of knowledge of the cognitive neuroscience of social and language impairments in autism is reviewed. Following from this, six candidate broader phenotype autism traits are proposed: (a) face processing, including structural encoding of facial features and face movements, such as eye gaze; (b) social affiliation or sensitivity to social reward, pertaining to the social motivational impairments found in autism; (c) motor imitation ability, particularly imitation of body actions; (d) memory, specifically those aspects of memory mediated by the medial temporal lobe-prefrontal circuits; (e) executive function, especially planning and flexibility; and (f) Language ability, particularly those aspects of language that overlap with specific language impairment, namely, phonological processing.

Writing and Reading Connections Between Language by Hand and Language by Eye

Four approaches to the investigation of connections between language by hand and language by eye are described and illustrated with studies from a decade-long research program. In the first approach, multigroup structural equation modeling is applied to reading and writing measures given to typically developing writers to examine unidirectional and bidirectional relationships between specific components of the reading and writing systems. In the second approach, structural equation modeling is applied to a multivariate set of language measures given to children and adults with reading and writing disabilities to examine how the same set of language processes is orchestrated differently to accomplish specific reading or writing goals, and correlations between factors are evaluated to examine the level at which the language-by-hand system and the language-by-eye system communicate most easily. In the third approach, mode of instruction and mode of response are systematically varied in evaluating effectiveness of treating reading disability with and without a writing component. In the fourth approach, functional brain imaging is used to investigate residual spelling problems in students whose problems with word decoding have been remediated. The four approaches support a model in which language by hand and language by eye are separate systems that interact in predictable ways.

Enhancement of BOLD-contrast sensitivity by single-shot multi-echo functional MR imaging.

Improved data acquisition and processing strategies for blood oxygenation level‐dependent (BOLD)‐contrast functional magnetic resonance imaging (fMRI), which enhance the functional contrast‐to‐noise ratio (CNR) by sampling multiple echo times in a single shot, are described. The dependence of the CNR on T2*, the image encoding time, and the number of sampled echo times are investigated for exponential fitting, echo summation, weighted echo summation, and averaging of correlation maps obtained at different echo times. The method is validated in vivo using visual stimulation and turbo proton echoplanar spectroscopic imaging (turbo‐PEPSI), a new single‐shot multi‐slice MR spectroscopic imaging technique, which acquires up to 12 consecutive echoplanar images with echo times ranging from 12 to 213 msec. Quantitative T2*‐mapping significantly increases the measured extent of activation and the mean correlation coefficient compared with conventional echoplanar imaging. The sensitivity gain with echo summation, which is computationally efficient provides similar sensitivity as fitting. For all data processing methods sensitivity is optimum when echo times up to 3.2 T2* are sampled. This methodology has implications for comparing functional sensitivity at different magnetic field strengths and between brain regions with different magnetic field inhomogeneities. Magn Reson Med 42:87–97, 1999.

Instructional treatment associated with changes in brain activation in children with dyslexia

Objective: To assess the effects of reading instruction on fMRI brain activation in children with dyslexia. Background: fMRI differences between dyslexic and control subjects have most often involved phonologic processing tasks. However, a growing body of research documents the role of morphologic awareness in reading and reading disability. Methods: The authors developed tasks to probe brain activation during phoneme mapping (assigning sounds to letters) and morpheme mapping (understanding the relationship of suffixed words to their roots). Ten children with dyslexia and 11 normal readers performed these tasks during fMRI scanning. Children with dyslexia then completed 28 hours of comprehensive reading instruction. Scans were repeated on both dyslexic and control subjects using the same tasks. Results: Before treatment, children with dyslexia showed less activation than controls in left middle and inferior frontal gyri, right superior frontal gyrus, left middle and inferior temporal gyri, and bilateral superior parietal regions for phoneme mapping. Activation was significantly reduced for children with dyslexia on the initial morpheme mapping scan in left middle frontal gyrus, right superior parietal, and fusiform/occipital region. Treatment was associated with improved reading scores and increased brain activation during both tasks, such that quantity and pattern of activation for children with dyslexia after treatment closely resembled that of controls. The elimination of group differences at follow-up was due to both increased activation for the children with dyslexia and decreased activation for controls, presumably reflecting practice effects. Conclusion: These results suggest that behavioral gains from comprehensive reading instruction are associated with changes in brain function during performance of language tasks. Furthermore, these brain changes are specific to different language processes and closely resemble patterns of neural processing characteristic of normal readers.

A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age.

OBJECTIVE Differences in diagnostic criteria and methods have led to mixed results regarding the metabolite pattern of HIV-associated brain injury in relation to neurocognitive impairment. Therefore, a multicenter MRS consortium was formed to evaluate the neurometabolites in HIV patients with or without cognitive impairment. METHODS Proton magnetic resonance spectroscopy (MRS) at short-echo time (30 ms) was assessed in the frontal white matter, basal ganglia, and parietal cortex of 100 HIV patients [61 with AIDS dementia complex (ADC) and 39 neuroasymptomatic (NAS)] and 37 seronegative (SN) controls. RESULTS Compared to SN, NAS had higher glial marker myoinositol-to-creatine ratio (MI/Cr) in the white matter (multivariate analyses, adjusted P=0.001), while ADC showed further increased MI/Cr in the white matter and basal ganglia (both P<0.001), and increased choline compounds (Cho)/Cr in white matter (P=0.04) and basal ganglia (P<0.001). Compared to NAS, ADC showed a reduction in the neuronal marker N-acetyl compound (NA)/Cr in the frontal white matter (P=0.007). CSF, but not plasma, viral load correlated with MI/Cr and Cho/Cr in white matter and NAA/Cr in parietal cortex. HIV infection and aging had additive effects on Cho/Cr and MI/Cr in the basal ganglia and white matter. CONCLUSIONS The results suggest that glial activation occurs during the NAS stages of HIV infection, whereas further inflammatory activity in the basal ganglia and neuronal injury in the white matter is associated with the development of cognitive impairment. Aging may further exacerbate brain metabolites associated with inflammation in HIV patient and thereby increase the risk for cognitive impairment.

Reduced Neural Habituation in the Amygdala and Social Impairments in Autism Spectrum Disorders

OBJECTIVE Amygdala dysfunction has been proposed as a critical component in social impairment in autism spectrum disorders. This study was designed to investigate whether abnormal habituation characterizes amygdala dysfunction in autism spectrum disorders and whether the rate of amygdala habituation is related to social impairment. METHOD Using functional MRI, the authors measured change over time in activation of the amygdala and fusiform gyrus to neutral facial stimuli in adults with autism spectrum disorders and healthy comparison adults. RESULTS The comparison group evidenced significantly greater amygdala habituation bilaterally than the autism spectrum group. There were no group differences in overall fusiform habituation. For the autism spectrum group, lower levels of habituation of the amygdala to the face stimuli were associated with more severe social impairment. CONCLUSIONS These results suggest amygdala hyperarousal in autism spectrum disorders in response to socially relevant stimuli. Further, sustained amygdala arousal may contribute to the social deficits observed in autism spectrum disorders.

Brain Activation during Face Perception: Evidence of a Developmental Change

Behavioral studies suggest that children under age 10 process faces using a piecemeal strategy based on individual distinctive facial features, whereas older children use a configural strategy based on the spatial relations among the faces features. The purpose of this study was to determine whether activation of the fusiform gyrus, which is involved in face processing in adults, is greater during face processing in older children (1214 years) than in younger children (8 10 years). Functional MRI scans were obtained while children viewed faces and houses. A developmental change was observed: Older children, but not younger children, showed significantly more activation in bilateral fusiform gyri for faces than for houses. Activation in the fusiform gyrus correlated significantly with age and with a behavioral measure of configural face processing. Regions believed to be involved in processing basic facial features were activated in both younger and older children. Some evidence was also observed for greater activation for houses versus faces for the older children than for the younger children, suggesting that processing of these two stimulus types becomes more differentiated as children age. The current results provide biological insight into changes in visual processing of faces that occur with normal development.

Socioeconomic status predicts hemispheric specialisation of the left inferior frontal gyrus in young children.

Reading is a complex skill that is not mastered by all children. At the age of 5, on the cusp of prereading development, many factors combine to influence a childs future reading success, including neural and behavioural factors such as phonological awareness and the auditory processing of phonetic input, and environmental factors, such as socioeconomic status (SES). We investigated the interactions between these factors in 5-year-old children by administering a battery of standardised cognitive and linguistic tests, measuring SES with a standardised scale, and using fMRI to record neural activity during a behavioral task, rhyming, that is predictive of reading skills. Correlation tests were performed, and then corrected for multiple comparisons using the false discovery rate (FDR) procedure. It emerged that only one relationship linking neural with behavioural or environmental factors survived as significant after FDR correction: a correlation between SES and the degree of hemispheric specialisation in the left inferior frontal gyrus (IFG), a region which includes Brocas area. This neural-environmental link remained significant even after controlling for the childrens scores on the standardised language and cognition tests. In order to investigate possible environmental influences on the left IFG further, grey and white matter volumes were calculated. Marginally significant correlations with SES were found, indicating that environmental effects may manifest themselves in the brain anatomically as well as functionally. Collectively, these findings suggest that the weaker language skills of low-SES children are related to reduced underlying neural specialisation, and that these neural problems go beyond what is revealed by behavioural tests alone.

Magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

BACKGROUND Magnetic resonance (MR) technology offers noninvasive methods for in vivo assessment of neuroabnormalities. METHODS A comprehensive neuropsychological/psychiatric battery, coupled with MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessments, were administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The 4 study groups included: (i) fetal alcohol syndrome (FAS)/partial FAS (PFAS); (ii) static encephalopathy/alcohol exposed (SE/AE); (iii) neurobehavioral disorder/alcohol exposed (ND/AE) as diagnosed with the FASD 4-Digit Code; and (iv) healthy peers with no prenatal alcohol exposure. Presented here are the MRI assessments that were used to compare the sizes of brain regions between the 4 groups. The neuropsychological/behavioral, MRS, and fMRI outcomes are reported separately. RESULTS Progressing across the 4 study groups from Controls to ND/AE to SE/AE to FAS/PFAS, the mean absolute size of the total brain, frontal lobe, caudate, putamen, hippocampus, cerebellar vermis, and corpus callosum length decreased incrementally and significantly. The FAS/PFAS group (the only group with the 4-Digit FAS facial phenotype) had disproportionately smaller frontal lobes relative to all other groups. The FAS/PFAS and SE/AE groups [the 2 groups with the most severe central nervous system (CNS) dysfunction] had disproportionately smaller caudate regions relative to the ND/AE and Control groups. The prevalence of subjects in the FAS/PFAS, SE/AE, and ND/AE groups that had 1 or more brain regions, 2 or more SDs below the mean size observed in the Control group was 78, 58, and 43%, respectively. Significant correlations were observed between size of brain regions and level of prenatal alcohol exposure, magnitude of FAS facial phenotype, and level of CNS dysfunction. CONCLUSIONS Magnetic resonance imaging provided further validation that ND/AE, SE/AE, and FAS/PFAS as defined by the FASD 4-Digit Code are 3 clinically distinct and increasingly more affected diagnostic subclassifications under the umbrella of FASD. Neurostructural abnormalities are present across the spectrum. MRI could importantly augment diagnosis of conditions under the umbrella of FASD, once population-based norms for structural development of the human brain are established.