A neural measure of behavioral engagement: Task-residual low-frequency blood oxygenation level-dependent activity in the precuneus

Abstract

Brain imaging has provided a useful tool to examine the neural processes underlying human cognition. A critical question is whether and how task engagement influences the observed regional brain activations. Here we highlighted this issue and derived a neural measure of task engagement from the task-residual low-frequency blood oxygenation level-dependent (BOLD) activity in the precuneus. Using independent component analysis, we identified brain regions in the default circuit – including the precuneus and medial prefrontal cortex (mPFC) – showing greater activation during resting as compared to task residuals in 33 individuals. Time series correlations with the posterior cingulate cortex as the seed region showed that connectivity with the precuneus was significantly stronger during resting as compared to task residuals. We hypothesized that if the task-residual BOLD activity in the precuneus reflects engagement, it should account for a certain amount of variance in task-related regional brain activation. In an additional experiment of 59 individuals performing a stop signal task, we observed that the fractional amplitude of low-frequency fluctuation (fALFF) of the precuneus but not the mPFC accounted for approximately 10% of the variance in prefrontal activation related to attentional monitoring and response inhibition. Taken together, these results suggest that task-residual fALFF in the precuneus may be a potential indicator of task engagement. This measurement may serve as a useful covariate in identifying motivation-independent neural processes that underlie the pathogenesis of a psychiatric or neurological condition.

Introduction

Functional imaging is widely used to explore the neural processes of human cognition. An important question is whether motivation or behavioral engagement influences the degree brain regions activate during cognitive performance. For instance, this issue seems particularly critical in studies of patients with a neurological or psychiatric condition, who behaviorally were less engaged and frequently showed altered cerebral activation, as compared to healthy controls. Here we used imaging research of the endophenotypes of mental illnesses as an example to illustrate this issue.

In studies of the neural phenotypes of mental illnesses, a common approach is to compare regional brain activation in patients and healthy controls performing a behavioral task thought to be of pathogenetic importance, e.g., using working memory process to probe schizophrenia (Tan et al., 2006, Barch and Csernansky, 2007, Driesen et al., 2008, Koch et al., 2008, Lee et al., 2008, Schlosser et al., 2008). The results are typically described in two ways. In one scenario, patients showed less regional brain activation concomitant with altered behavioral performance, as compared to healthy controls (Barch and Csernansky, 2007, Lee et al., 2008, Schlosser et al., 2008). One criticism of this approach is that patients may not be as motivated or engaged during the task, hence their inferior performance and decreased cerebral activity (Fig. 1a). In a second approach, aimed to resolve this disparity, investigators compared patient and control subjects matched in task performance (Tan et al., 2006, Driesen et al., 2008, Koch et al., 2008). Thus, differences in regional brain activation cannot easily be attributed to discrepancy in task engagement (Fig. 1b). However, two arguments are often raised against this latter approach. First, some investigators suggest that patients simply employ different neural circuits and, as long as they do the task equally well, the differences in brain activation do not necessarily speak to underlying pathology. Second and perhaps more critically, indistinguishable behavioral performance could potentially result from a ceiling effect; namely, the task is not adequate to elicit veridical differences in performance as well as performance-related regional brain activation. On the other hand, once a task is used to “break” the ceiling, findings of between-group differences are subject to the issue of discrepancy in behavioral engagement. Here we proposed that a potential solution would be to obtain a neural measure of motivation or behavioral engagement, independent of task-related processes (Fig. 1c). The neural measure of behavioral engagement would facilitate the identification of motivation-independent differences in task-related process between patients and controls.

Brain regions in the “default” network are more active when individuals are in a resting state compared to when they respond to an external environment or engage in mental effort (Raichle et al., 2001, Fox and Raichle, 2007). For instance, McKiernan and colleagues (2003) showed that task-induced deactivations in several of the default mode regions varied parametrically as a function of task difficulty. We hypothesized that activity in these default brain regions, including the precuneus, posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC), may signal the extent to which individuals are engaged in a behavioral task, independent of task-related processes. Such a neural signal would be useful in indexing whether individuals are adequately motivated in a laboratory test and whether comparison of task-related brain activation between patients and healthy controls is “legitimate.” However, the idea of task-independent deactivation of the default brain circuit has been challenged on a number of grounds, including evidence suggesting that the default brain regions activate rather than deactivate in response to task-related events (Morcom and Fletcher, 2007). This latter issue confounds its potential use as a neural signature of task-independent behavioral engagement.

We sought to overcome this confound by removing task-related activities from the time series to derive “task-residual” low-frequency blood oxygenation level-dependent (BOLD) activity (Fair et al., 2007). It is known that low-frequency BOLD signal fluctuations that occur during rest reflect connectivity between functionally related brain regions (Biswal et al., 1995, Fair et al., 2007, Fox and Raichle, 2007). Recent studies of this “spontaneous” activity have provided insight into the intrinsic functional architecture of the brain, variability in behavior and potential physiological correlates of neurological and psychiatric disease (Fox and Raichle, 2007). Notably, it was suggested that the spontaneous activity continues during a behavioral task and task-related brain activations represent a combination of the spontaneous activity and responses to stimulus input, behavioral output or attention (Arfanakis et al., 2000, Fox et al., 2006a, Fair et al., 2007). In particular, Fair and colleagues (2007) reported that the functional connectivity of low-frequency task-residual is similar to resting state. Therefore, we hypothesized that, by deactivating to a behavioral task, the default brain regions would show greater activity during resting state as compared to task-residual data. In addition, we hypothesized that, as an indicator of motivation or task engagement, the activity of the default brain regions would explain a certain amount of variance in task-related regional brain activations during fMRI.