Case History StudyAnterior cingulate cortex and cognitive control: Neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex
Highlights
► A case study with two unilateral lesions including anterior cingulate cortex (ACC) is presented. ► Neuropsychologically, both patients had memory impairment while Stroop performance was normal. ► Both patients had a diminished Novelty P3 Event Related Potential (ERP) in a Novelty Oddball task. ► Both patients had an Error-Related Negativity (ERN) ERP-component in a Stop-Signal task. ► The study suggests ACC involvement in cognition that is not restricted to error monitoring.
Introduction
The role of the frontal lobes in top-down controlled information processing has been thoroughly documented (Duncan and Owen, 2000, Knight and Stuss, 2002, Stuss and Alexander, 2000) and there is increasing evidence that executive control is implemented by distributed networks of closely interacting, but anatomically dissociable areas (Stuss & Alexander, 2007). Major functional distinctions are commonly drawn between the dorsolateral, orbital and medial prefrontal cortex (MPFC). While the dorsolateral prefrontal cortex is associated with cognitive executive control and top-down processes (Miller and Desposito, 2005, Voytek and Knight, 2010a), the orbital division plays a major role in control of social and emotional behavior (Knight and Stuss, 2002, Stuss and Levine, 2002). Exploration of the role of MPFC in general, and the anterior cingulate cortex (ACC) in particular, has evoked great interest over the past decade.
The extensive connectivity of the MPFC and ACC with cortical and sub-cortical brain areas puts this region in a key position for top-down modulation of behavior (Devinsky, Morrell, & Vogt, 1995). A functional subdivision in a primarily rostral “affective” and a dorsal “cognitive” division of the ACC has been described (Bush et al., 2000, Mohanty et al., 2007), although such a dichotomy might represent an oversimplification (Etkin, Egner, & Kalisch, 2011). MPFC is proposed to play a critical role in the operations of the anterior attentional system responsible for the maintenance of an alert state (Posner & Petersen, 1990), and superior MPFC lesions have been shown to affect the capacity for task monitoring and maintenance of stable performance (Shallice, Stuss, Alexander, Picton, & Derkzen, 2008). A multitude of proposals regarding the specific role of ACC in executive control have emerged, typically converging on a key role in conflict detection, performance monitoring and response-selection (Alexander and Brown, 2010, Botvinick et al., 2001, Carter et al., 1998, Ridderinkhof et al., 2004). It has, however, been a challenge to provide a synthesized account of existing data and theoretical proposals (Ridderinkhof, Nieuwenhuis, & Braver, 2007).
Knowledge regarding the role of the ACC in cognitive control has derived largely from neuroimaging studies of healthy subjects (Cabeza and Nyberg, 2000, Carter et al., 1998). The Stroop color-word interference task is the neuropsychological test typically used to measure the ability to override a prepotent response in a cognitive conflict situation (Delis, Kaplan, & Kramer, 2001). ACC activation has been demonstrated during Stroop performance in both Positron Emission Tomography (PET) (Pardo, Pardo, Janer, & Raichle, 1990) and functional Magnetic Resonance Imaging (fMRI) studies (Matthews, Paulus, Simmons, Nelesen, & Dimsdale, 2004). Involvement of the ACC has also been suggested in long-term consolidation of memories, as it has been demonstrated that as memory traces are consolidated over time, reduced activity in the hippocampal formation is associated with an increased activity in MPFC in both rodents and humans (Frankland and Bontempi, 2005, Takashima et al., 2007). A role for ACC in attention and reward-based learning has also been suggested in both human and macaque studies (Hayden et al., 2011, Rushworth et al., 2011).
Event-Related Potential (ERP) studies have demonstrated an error-related negativity that peaks over fronto-central electroencephalographic (EEG) recording sites 60–80 ms after an erroneous response (Danielmeier and Ullsperger, 2011, Danielmeier et al., 2009, Edwards et al., 2012). The error-related negativity is typically followed by a positive component, the “error-positivity” (Falkenstein et al., 1991, Simons, 2010). EEG source analysis (van Veen & Carter, 2002), magnetoencephalography (Miltner et al., 2003), fMRI (Nieuwenhuis, Schweizer, Mars, Botvinick, & Hajcak, 2007), as well as animal studies (Emeric et al., 2008, Gemba et al., 1986) have suggested that the error-related negativity is generated in the ACC.
A dynamic relationship between ACC and dorsolateral prefrontal cortex has been proposed in which the main role of the ACC is detection and evaluation of conflict, thus providing input to the top-down attentional dorsolateral system, where the actual stimulus manipulation and attentional maintenance and control is performed (MacDonald et al., 2000, Walsh et al., 2011). The error-related negativity of patients with lateral prefrontal lesions does not differ between erroneous and correct responses as in healthy subjects (Gehring & Knight, 2000), demonstrating a dynamic interaction between the two frontal subregions.
Lesion studies have not uniformly confirmed predictions derived from imaging studies of healthy subjects (Nachev, 2006, Ridderinkhof et al., 2007). One study with a fairly large sample (N = 8) demonstrated that patients with rostral ACC lesions failed to modulate performance depending on the level of conflict in a Simon task, and that they did not display the expected slowing of reaction times following errors (post-error slowing) (di Pellegrino, Ciaramelli, & Ladavas, 2007). In five patients with MPFC lesions resulting from aneurysms of the anterior communicating artery, the error-related negativity was absent in most, but not all patients (Stemmer, Segalowitz, Witzke, & Schonle, 2004). In one patient with a left rostral to mid-ACC lesion, a reduced midline error-related negativity was demonstrated, whereas stimulus-locked ERPs in successful inhibition trials were normal (Swick & Turken, 2002).
Studies of Stroop performance after ACC damage have also produced mixed results. One patient with a right dorsal ACC lesion displayed normal results for vocal response delivery, whereas manual response delivery was impaired (Turken & Swick, 1999). A later study adding a second person with a left rostral – to mid-ACC lesion (Swick & Jovanovic, 2002) showed reduced accuracy in incongruent trials for the patient with left – but not the one with right-ACC lesion. Stuss, Floden, Alexander, Levine, and Katz (2001) demonstrated an association between bilateral superior MPFC injury and increased error rate as well as reaction times in the incongruent Stroop-condition, whereas Vendrell and colleagues (Vendrell et al., 1995) found that right LPFC but not ACC injury was associated with an increased error rate.
In summary, controversy remains on the exact role of the ACC in cognition. One hypothesis that is largely based on case-studies of patients with ACC lesions is that the ACC is not involved in cognitive processing per se, but rather plays a role in linking cognitive control processes subserved by other prefrontal regions to autonomic arousal. Fellows and Farah (2005) described 4 patients with dorsal ACC lesions resulting from strokes who displayed normal Stroop and Go/NoGo performance, as well as a normal post-error slowing and performance adjustment after changing task instructions. A patient with a large left frontal lesion that included the ACC had largely normal behavioral performance on a task demanding executive control, but decreased skin conductance response (Naccache et al., 2005). Moreover, Critchley et al. (2003) demonstrated an association between ACC activation and modulation of heart-rate during cognitive and motor-tasks in healthy subjects. In the same paper, three patients with rostral and dorsal ACC-lesions demonstrated blunted autonomic reactions during working-memory performance. Of particular relevance to the current paper is a later publication of neurocognitive functioning in two of the three patients from the Critchley et al. study (Baird et al., 2006). One presented with a unilateral right ACC lesion, with additional right hemisphere frontal involvement, whereas the second patient had bilateral ACC-affection with widespread additional frontal damage. Only minor cognitive impairment was found in a few of the tests of executive functions employed, and prolonged reaction times were seen in attention tasks, although not on the same measures. The findings were taken to support the hypothesis that the ACC does not have a primary role in cognitive control.
Thus, despite extensive interest in the function of the ACC over the past decade, controversy and diverging findings persist. It has both been suggested that the ACC plays a generally vital role in cognitive control (Botvinick et al., 2001, Ridderinkhof et al., 2004, Shallice et al., 2008), that it has a very distinct role in error monitoring (Fan et al., 2007, Pailing and Segalowitz, 2004, Swick and Turken, 2002), and finally that the ACC is actually not involved in cognitive operations (Baird et al., 2006, Critchley et al., 2003). The present study provides neuropsychological, behavioral and electrophysiological data from two patients with unilateral dorsomedial frontal lesions that included the ACC. The lesions were comparable to those presented by Critchley et al. (2003) and Baird et al. (2006) in anatomical location and extent. The main goal was to examine behavioral and electrophysiological indices of neurocognitive functioning following ACC injury. A specific aim was to investigate Baird et al.’s (2006) proposition that the ACC is not involved in cognitive processing. As a distinct role of ACC has been proposed in attentional shifting (Crottaz-Herbette & Menon, 2006), we used an auditory Novelty Oddball task to study novelty and target detection (Polich, 2007, Soltani and Knight, 2000). Additionally, a Stop-signal task allowed investigation of behavioral and neurophysiological correlates of inhibitory control and error monitoring (Aron et al., 2007, Schmajuk et al., 2006). In line with existing knowledge of neuropsychological tests´ limited sensitivity to the effect of frontal lobe lesions (Knight and Stuss, 2002, Løvstad et al., 2012), it was hypothesized that the neurophysiological measures might reveal signs of altered information processing not evident in neuropsychological test results. It was predicted that lesion-related alterations of motor-inhibition, error-monitoring and novelty processing would be observed. Of particular interest was whether patients with unilateral ACC lesions would exhibit the error-related negativity and the post-error slowing of reaction times.
Section snippets
Patients
The patients participated in a research program at Oslo University Hospital investigating the effects of focal frontal lobe lesions. See Fig. 1 for MRI scans depicting the lesions.
Patient 1 is a right-handed male in his mid thirties with 12 years of formal education. He was assessed 20 months after surgical removal of a right frontal low-grade glioma. The lesion included medial, dorsal and rostral ACC (BA 24 and 32), with marginal involvement of BA 25. In addition to involvement of posterior
Functional outcome
Patient 1 scored 7 (Lower Good Recovery) and patient 2 scored 8 (Upper Good Recovery) on the GOS-E. Both patients were in full-time paid work at the time of study inclusion. Neither of the patients had any total- or subscale T-scores above 55 on the Symptom Checklist 90-Revised, indicating that they did not display significant psychopathology at the time of assessment.
Neuropsychological performance
Neuropsychological data for the healthy control group and patients 1 and 2 are reported in Table 1a–e. Patient 1 displayed
Discussion
The contribution of dorsomedial PFC in distributed cognitive control networks remains poorly understood. This case study examined neuropsychological, behavioral, and electrophysiological indices of cognitive control following ACC injury, with a specific aim to investigate the claim set forth by Baird et al. (2006) that the ACC is not involved in cognitive processing.
In summary, performance on the Color-Word Interference Test, the D–KEFS version of the traditional Stroop task, was normal in both
Conclusions
Although the role of the MPFC, and specifically the ACC, in cognitive operations has attracted substantial interest over the past decade, consensus has not been established. In this study, neuropsychological, behavioral and electrophysiological functioning was explored in two patients with MPFC damage including the ACC. Learning and memory was affected in both patients, but the Stroop-task was insensitive to unilateral ACC damage. It was also demonstrated that whereas unilateral ACC damage
Acknowledgments
We would like to thank Maya Tomstad and Martin Seem Sundal for coding of data. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This research is supported by the South-Eastern Norway Regional Health Authority (Grants SUN-001-SS and 2008047) and the Research Council of Norway (Grant No. 186504/V50) as well as the National Institute of Neurological Disorders (NINDS; Grant NS21135 to author R.T.K.). Author U.M.K. was supported
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