Anterior cingulate activity during error and autonomic response
Introduction
Anterior cingulate cortex (ACC) is a large medial cerebral structure surrounding the anterior third of the corpus callosum. Despite remarkable homology in macroscopic and cellular ACC structure across species, its functional role is poorly understood. Influential models associate regions of human ACC with attentional and cognitive processes, in addition to emotional and visceral functions ascribed to ACC in other species.
Attempts have therefore been made on the basis of neuroimaging evidence to parse ACC into distinct (cognitive, emotional and visceral) functional components. However, anatomically, ACC presents a distinct and chiefly homogeneous structure rather than a set of cytoarchitectonically defined ‘modules’. Brodmann (1909) recognized only three subregions: subgenual area 25 and two areas that together stretch around the callosal genu to a transition zone with posterior cingulate at level of the central sulcus, labeled area 24 (area cingularis anterior ventralis, on the inside of the cingulate sulcus) and area 32 (area cingularis anterior dorsalis, on the outer rim of the cingulate sulcus). Recent histological studies extend this parcellation of human ACC to subgenual components of area 24 and 32 and a ‘vertical’ stratification of area 24 (Vogt et al., 1995, Öngür et al., 2003). Furthermore, a caudal ACC transition zone is now viewed as a distinct subregion (Vogt et al., 2003).
From a connectional perspective, ACC subregions are intrinsically interconnected (Morecraft and Van Hoesen, 1998). There are broad differences in the relative connectivity between inner area 24 (with other limbic structures and basal ganglia) compared to outer area 32 (with motor regions), however, areas 24 and 32 have close reciprocal connections (Barbas et al., 2003, Öngür and Price, 2000). Subgenual, genual and supragenual subregions of rostral ACC (rACC) interconnect closely with each other (Öngür and Price, 2000), with adjacent medial orbitofrontal cortex and with nearby regions implicated in autonomic control, emotional and appetitive behaviors, including hypothalamus, brainstem and nucleus accumbens (Öngür and Price, 2000, Barbas et al., 2003). The supragenual ACC merges caudally into a dorsal ACC (dACC) region that also interconnects with neighboring lateral prefrontal and premotor cortices and supplementary motor area (SMA) (Paus et al., 2001, Luppino et al., 2003, Takada et al., 2004). Caudally, ACC ‘motor’ cingulate areas interconnect with motor cortices, lateral basal ganglia and spinal motor units (Tachibana et al., 2004). However, these broad differences in external connectivity of rACC, dACC and caudal ACC regions do not convincingly indicate functional heterogeneity. In primates, afferents from all ACC regions probably converge on motor cingulate cortex (Morecraft and Van Hoesen, 1998), although evidence for a direct projection from cingulate gyrus (area 24) to motor cingulate areas is equivocal (Dum and Strick, 1993). However, rostral, dorsal and even motor ACC regions project to brainstem autonomic centers particularly (Vilensky and van Hoesen, 1981, An et al., 1998), and both rACC and dACC project to hippocampus via a posterior cingulate pathway (Morris et al., 1999).
While neuroanatomical studies suggest homogeneity within areas 24 and 32, neuroimaging studies suggest rostrocaudal functional parcellation of ACC. Supragenual rACC and dACC regions show enhanced activity in many effortful or attention-demanding tasks (Paus et al., 1998, Duncan and Owen, 2000), whereas subgenual ACC regions generally show decreased activity (Raichle et al., 2001, Gusnard et al., 2001, Simpson et al., 2001). Such activity decreases are negatively correlated with sympathetic autonomic arousal (Matthews et al., 2004, Nagai et al., 2004a). A further distinction is also proposed between “cognitive” dACC and “emotional” rACC (including all regions surrounding the genu) (Bush et al., 2000). This distinction seems critically dependent on task and response. For example, emotional experiences engendered by anticipatory anxiety or pain activate the “cognitive” dACC region rather than the predicted genual “emotional” rostral ACC (Büchel et al., 1998, Rainville, 2002, Ploghaus et al., 1999, Ploghaus et al., 2003).
Enhanced activity in dACC is observed using fMRI during many cognitive challenges. One explanation is that dACC activity is important to attention. Electroencephalographic (EEG) evidence implicates dACC as a generator of ‘attentional’ event-elated potentials (ERPs) during orientation, anticipation and response suppression (Nagai et al., 2004b). Neuroimaging studies also implicate dACC in attention-demanding executive control processes, particularly where stimuli specify a response choice (Posner and Petersen, 1999, Frith, 2001). A powerful line of evidence suggests that dACC is specifically engaged in processing conflict between competing stimuli or responses, as typified in tasks such as the Stroop color-naming task (Carter et al., 1995, Carter et al., 1998). Detection of response conflict is important in monitoring performance (Botvinick et al., 2001), and it is noteworthy that neuroimaging and ERP data show dACC sensitivity to errors in performance (Kiehl et al., 2000, Menon et al., 2001, Dehaene et al., 1994). This error-related activity reflects the rate and predictability of both external and internal error signals (Paulus et al., 2002, Holroyd et al., 2004). The functional significance of error-related negative potentials (ERN) to error detection is called into question by the observation that ACC damage may attenuate ERNs while error detection remains intact (Stemmer et al., 2004). Conflict detection and error monitoring are related processes, with errors occurring more frequently on trials with high response conflict. However, the observation that left dACC damage attenuates error-related ERPs (and causes deficits in error correction) yet leaves conflict-related ERPs intact (Swick and Turken, 2002) suggests further neuroanatomical dissociation.
Many neuroimaging and electrophysiological studies report correlates within ACC of a number of cognitive processes. However, lesion data provide only equivocal data to suggest a primary function of ACC in attention, executive function or cognitive control (Turken and Swick, 1999, Stuss et al., 2001, Rushworth et al., 2004, Fellows and Farah, 2005). Executive or cognitive control functions may be entirely normal in the context of large lesions involving ACC (Critchley et al., 2003, Fellows and Farah, 2005). ACC is a major component of MacLean's visceral limbic system, connected throughout its extent with autonomic nuclei (Vilensky and van Hoesen, 1981, Morecraft and Van Hoesen, 1998, An et al., 1998, Öngür and Price, 2000, Barbas et al., 2003). Moreover, activity in rostral and dACC regions correlates with (and predicts) cardiovascular and electrodermal arousal evoked by a range of cognitive, emotional and motivational tasks (Fredrikson et al., 1998, Critchley et al., 2000, Critchley et al., 2001a, Critchley et al., 2001b, Critchley et al., 2003, Gianaros et al., 2004, Gianaros et al., 2005). Damage to rostral and dorsal ACC impairs efferent sympathetic drive (Zahn et al., 1999, Critchley et al., 2003), whereas activity in subgenual cingulate shows an inverse relationship with tonic measures of sympathetic arousal (Matthews et al., 2004, Nagai et al., 2004a).
The above observations, we suggest, provide for an alternative hypothesis of an autonomic contribution to ACC function. Specifically, we have proposed that ACC integrates somatosensory, interoceptive, cognitive and motivational states with states of bodily arousal (Critchley et al., 2003), an integrative process that may underpin autonomic psychophysiology. Thus, errors can trigger autonomic arousal responses associated with electrophysiological potential putatively originating in ACC (Hajcak et al., 2003). We undertook a functional neuroimaging experiment to explore further the function of anterior cingulate cortex and how this may be reflected in regional brain activity measured using fMRI. We predicted that during Stroop task performance ACC activity would reflect variance associated with task-induced changes in autonomic arousal rather than stimulus properties such as response conflict that might engender activity in regions such as the supplementary motor area (SMA). We therefore used functional magnetic resonance imaging (fMRI) to test the hypothesis that control of autonomic states of arousal provides a robust unitary account of ACC activity. We used a measure of pupillary response to provide a rapid index of changes in autonomic activity induced during cognitive processing. Correlates of central cognitive influences on pupillary response have been hitherto underexplored.
Section snippets
Subjects
Fifteen healthy right-handed subjects were recruited to take part in a study at the Wellcome Department of Imaging Neuroscience. These volunteers gave fully informed consent which was approved by the local ethics committee. Each participant was screened to exclude medication and conditions including psychological or physical illness or history of head injury. Mean age (±SD) of participants was 23 ± 3 years.
Experimental design and task
We used functional magnetic resonance brain imaging (fMRI) to examine regional brain
Results
We scanned the subjects as they performed two numerical versions of the Stroop task, while simultaneously monitoring autonomic arousal responses from changes in pupil size. The Stroop tasks were extensively behaviorally piloted and required subjects to choose between a pair of numbers on each trial (Fig. 1). In one session (the Numerical task), the subject was instructed to select the numerically higher number while ignoring differences in the physical size of the stimuli. In the other session
Discussion
Our findings implicate adjacent contiguous rostral and dorsal regions of ACC in the control of autonomic arousal states (here indexed by using pupillometry) and in error processing. These findings suggest that these ACC regions support an integration of error processing with generation of states of autonomic arousal. We note that the variance in the magnitude of evoked autonomic changes in pupil response was maximal in error trials.
The selective association between autonomic arousal responses
Acknowledgment
This research was supported by the Wellcome Trust via a program grant to RJD and a fellowship to HDC.
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