Aberrant functional connectivity in autism: Evidence from low-frequency BOLD signal fluctuations

Abstract

A number of recent studies have examined functional connectivity in individuals with Autism Spectrum Disorders (ASD), generally converging on the finding of reduced interregional coordination, or underconnectivity. Underconnectivity has been reported between many brain regions and across a range of cognitive tasks, and has been proposed to underlie behavioral and cognitive impairments associated with ASD. The current study employed functional connectivity MRI (fcMRI) to examine interregional correlations of low-frequency BOLD signal fluctuations in 10 high-functioning participants with ASD and 10 typically developing control participants. Whole-brain connectivity with three seed regions of interest (left middle frontal, left superior parietal, and left middle occipital cortex) was evaluated using fMRI datasets acquired during performance of a source recognition task. While fcMRI patterns were found to be largely similar across the two groups, including many common areas, effects for the ASD group were generally more extensive. These findings, although inconsistent with generalized underconnectivity in ASD, are compatible with a model of aberrant connectivity in which the nature of connectivity disturbance (i.e., increased or reduced) may vary by region. Taking into consideration methodological factors that might influence measured fcMRI effects, we suggest that ASD is associated with an inefficiency in optimizing network connections to achieve task performance.

Introduction

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders defined by impairments in social, behavioral, and communicative functioning (APA, 2000). The precise nature of the neuropathology in ASD is not fully understood. MRI and postmortem studies have identified cellular and volumetric abnormalities of numerous brain regions (Rapin and Katzman, 1998, Sokol and Edwards-Brown, 2004, Trottier et al., 1999), yet with the exception of the relatively consistent finding of early brain overgrowth (Courchesne et al., 2001, Hazlett et al., 2005, Sparks et al., 2002), there is little consensus regarding primary neuroanatomical disturbance. Functional neuroimaging investigations have been similarly inconsistent, with reports of atypical brain response in a variety of areas. Nonetheless, evidence of aberrant localization, intensity, and variability of neural activity in ASD suggests widely disrupted functional brain organization (Cody et al., 2002, Courchesne et al., 2004).

Inconsistent reports of regional brain abnormalities are not particularly surprising given the developmental nature of ASD. It is a strongly genetic disorder marked by atypical early brain growth (Courchesne et al., 2001, Courchesne et al., 2003), abnormal patterns of white matter development (Courchesne et al., 2001), and impairment in numerous cognitive domains by age three (APA, 2000). Such early disturbances undoubtedly alter developmental trajectories for afflicted individuals in diverse and complex ways, and would therefore not be predicted to have circumscribed neural effects. Rather, effects would be widespread, reflecting the ongoing interplay of pathology, normal maturational processes, and experience. Increasingly, research into the neural bases of ASD is moving away from explanations of isolated brain disturbances toward characterization of alterations in neural circuitry.

A number of recent studies have assessed anatomical connectivity in ASD through examination of white matter volume and integrity. On the whole, evidence from volumetric studies suggests atypical white matter growth patterns. That is, the relationship between age and white matter volume is abnormal, such that enlarged volume may be observed relative to typically developing individuals at one age, with relative reductions in volume or no group differences noted at other ages (Carper et al., 2002, Courchesne et al., 2001, Courchesne et al., 2003, Herbert et al., 2003, Herbert et al., 2004). One of the most commonly reported regions of white matter abnormality is the corpus callosum, which has been found to be smaller in ASD in several studies (Boger-Megiddo et al., 2006, Chung et al., 2004, Piven et al., 1997, Vidal et al., 2006, Waiter et al., 2005). Disturbance of this major pathway for interhemispheric information transfer provides compelling evidence of altered connectivity in ASD (Just et al., 2007, Kana et al., 2006). Additional evidence of aberrant anatomical connectivity has emerged from diffusion tensor imaging and transverse relaxation time imaging, which evaluate the integrity rather than volume of cerebral white matter. While the majority of studies employing these methodologies have demonstrated reduced white matter integrity in ASD (Alexander et al., 2007, Barnea-Goraly et al., 2004, Hendry et al., 2006), recent findings from Ben Bashat et al. (2007) suggest that very young children with autism (1.8–3.3 years of age) may show precocious axonal development and myelination.

In addition to investigations of anatomical connectivity, information about patterns of functional connectivity will likely be necessary to further understand the profile of cognitive and behavioral impairments associated with ASD. In particular, functional connectivity approaches can help characterize the neural basis of higher-order integrative processes, believed to be particularly impaired in this population (Hill and Frith, 2003, Minshew et al., 1997, Minshew et al., 2002). Functional connectivity MRI (fcMRI) assesses the correlation of BOLD signal fluctuations across brain regions and is based on the observation that interacting regions demonstrate similar BOLD signal profiles (Biswal et al., 1995, Hampson et al., 2002, Xiong et al., 1999). When measured during task performance, functional connectivity may reveal networks of regions coordinating to meet the particular cognitive demands of the task. Resting-state functional connectivity measures, on the other hand, are considered less context-dependent, and have the potential to reveal widespread neuroanatomical networks in the human brain (see Fox and Raichle, 2007 for review). Although several recent studies have investigated task-related functional connectivity in ASD (Just et al., 2004, Just et al., 2007, Kana et al., 2006, Kana et al., 2007, Kleinhans et al., 2008, Koshino et al., 2005, Koshino et al., 2008, Welchew et al., 2005), predominantly showing reduced functional connectivity, or “underconnectivity”, evidence of altered connectivity associated with task-free conditions remains limited (Cherkassky et al., 2006, Kennedy and Courchesne, 2008).

Some functional domains, such as theory of mind and face processing, have been extensively studied in ASD with neuroimaging techniques. Much less is known, however, about the functional organization of memory in this population. Within the behavioral literature, numerous studies have reported impairment of higher-order memory abilities. For example, across a series of studies, Minshew and colleagues have shown that while simple memory abilities are typically intact, memory for more complex material is often compromised (Minshew et al., 1997, Minshew and Goldstein, 1998, Minshew and Goldstein, 2001, Williams et al., 2006). Furthermore, episodic memory has been found to be impaired in ASD relative to control participants when task performance is aided by spontaneous use of organizational strategies (Bennetto et al., 1996, Minshew and Goldstein, 1993, Minshew and Goldstein, 2001, Tager-Flusberg, 1991). This finding likely reflects impaired higher-order integrative processes in ASD, on which spontaneous organization of items in memory relies. Source memory, a component of episodic memory referring to the ability to recall from which source and in which context an item was encoded into memory, has not been widely studied in ASD. Results from the few published studies have been mixed, providing inconsistent evidence of source memory deficits (Bennetto et al., 1996, Bowler et al., 2004, Hala et al., 2005, O'Shea et al., 2005).

The present study examined functional connectivity in ASD and control participants in the context of a source memory task. Source memory judgments required memory for single words and their encoding context (whether the word had been encountered in the auditory or visual modality). This task is well suited to detect regions involved in higher-order integrative functions, as performance relies on coordination between distributed brain regions to evaluate and integrate information presented across the two modalities. Three regions, identified on the basis of conventional activation analyses, were chosen as seed volumes for functional connectivity analyses. The three seed regions showed distinct profiles of source memory related activation across the two groups; one was engaged during task performance by control participants only (left middle frontal gyrus), one by ASD participants only (left middle occipital gyrus), and one by both groups (left superior parietal lobule).