Últimos derrubios históricos del siglo XXI

Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstr. 1a, D-04103 Leipzig, Germany Received 23 February 2005; accepted 21 June 2005

Available online 8 November 2005

Abstract

Performance monitoring, an indispensable prerequisite of goal-directed, flexible behavior has attracted the interest of many researchers. Performance monitoring impairment may result in major daily-life problems in neurological and psychiatric patients. In this paper, I review the recent advances in clinical studies on performance monitoring in different populations of neurological and psychiatric patients. The findings are discussed with respect to current models of performance monitoring that have mostly arisen from correlational approaches. Moreover, perspectives for clinical use are given and methodological issues for patient studies of performance monitoring will be discussed. D 2005 Elsevier B.V. All rights reserved.

Keywords: Error processing; Conflict; Neuropsychology; ERP; fMRI

1. Introduction

The last decade has revealed a considerable body of new knowledge about functional and anatomical correlates and the underlying processes of goal-directed flexible behavior. Performance monitoring, i.e., continuous checking whether the action goals have been reached, is crucial for adjustments needed to optimize action outcome. Its impairment may result in major daily-life problems in neurological and psychiatric patients. However, until not long ago, patient studies had a more general view on flexible cognitive control (‘‘executive functions’’) rather than directly addressing performance monitoring. In this paper, I review the recent advances that have been made in clinical studies on performance monitor- ing. After a brief overview on the knowledge gathered in healthy participants and animal work, I will focus on the impairments that can be expected when performance moni- toring is dysfunctional. Further on, I will review the findings that have been observed in a number of neurological and psychiatric diseases. In the discussion I will summarize the currently investigated performance monitoring network and still open questions with respect to possible clinical use. Finally, important methodological issues for patient studies of performance monitoring will be discussed.

1.1. Correlates of performance monitoring

On the behavioral level, performance monitoring is reflected in the consequences resulting from errors, contextual feedback evaluation, and situations in which action outcome is at risk (e.g., decision uncertainty, response conflict). Performance- monitoring-induced behavioral adjustments are most obvious after error commission which is sometimes accompanied by verbal and emotional responses. In experimental situations, even if not instructed, participants often immediately correct errors by a second key press (Rabbitt, 1966). On subsequent trials, behavioral adjustments can occur, such as post-error slowing (Rabbitt, 1966) and post-error reduction of interfer- ence (Ridderinkhof et al., 2002; see below) which can result in lower error rates subsequent to an error. In some instances, e.g., with short inter-trial intervals, however, error detection can also interfere with performance on subsequent trials thus increasing error rates on subsequent trials (Rabbitt and Rodgers, 1977; Fiehler et al., 2005).

Since the early nineties error-related event-related brain potentials (ERPs) have been in the focus of performance monitoring research. The error-related negativity (ERN or Ne) is elicited by executing prepotent but incorrect responses in choice reaction time tasks, peaks about 50 to 100 ms after the erroneous response, and has a frontocentral scalp distribution (Falkenstein et al., 1990; Gehring et al., 1993). It is assumed to reflect the mismatch between representations of the executed

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International Journal of Psychophysiology 59 (2006) 59 – 69

response and the response tendency resulting from full stimulus evaluation (Falkenstein et al., 2000; Coles et al., 2001). Alternatively, the ERN has been suggested to reflect post- response conflict between executed and competing response tendencies (Yeung et al., 2004). A neurobiological hypothesis suggests that the ERN is elicited based on a dopaminergic reinforcement signal from the mesencephalon, when action outcome is worse than expected (Holroyd and Coles, 2002). A second error-related ERP, the error positivity (Pe) has a centroparietal distribution and occurs about 300 to 500 ms after the erroneous response (Falkenstein et al., 2000). Its functional significance is still unclear (Falkenstein, 2004); it may be related to the conscious awareness of errors (Nieu- wenhuis et al., 2001).

Recent observations of a negativity associated with correct responses that is similar to the ERN with respect to latency and scalp distribution but of smaller amplitude, sometimes called correct-related negativity (CRN;Ford, 1999), led to the notion of a permanently active response evaluation function of the brain structures generating the ERN (Vidal et al., 2000, 2003). This view was supported by recent findings that the CRN amplitude can predict performance on subsequent trials (Ridderinkhof et al., 2003; Allain et al., 2004). The CRN seems not directly to depend on response conflict but rather on the discrepancy between prepared and implemented strategy to solve the task (Bartholow et al., 2005). Finally, on immediate error corrections, a small frontocentral negativity time-locked to the corrective response, the correction-related negativity (CoRN) has been observed (Fiehler et al., 2005). It is also present on error-signaling responses (Ullsperger et al., 2005). Similarly to the CRN it appears to reflect a reevaluating function of the mesial cortical (pre)motor areas, although CRN and CoRN do not need to occur within the same task (Fiehler et al., 2005).

Source localization studies and functional neuroimaging suggest that the ERN is generated in the posterodorsal mesial frontal cortex (pMFC), specifically in the rostral cingulate zone (RCZ; note that this region is located in caudal and not rostral anterior cingulate cortex [ACC]) (Dehaene et al., 1994; Ullsperger and Von Cramon, 2001, 2004a,b). Functional magnetic resonance imaging suggests on a more general perspective that the pMFC is involved when the state of the individual or the outcome of an action are undesired (e.g., errors, pain, loss), or when the outcome is at risk (e.g., response conflict, decision uncertainty), thus signaling the need for behavioral adjustments (Ullsperger et al., 2004; Ridderinkhof et al., 2004). Subspecialization of areas in the pMFC and the models of performance monitoring are a matter of ongoing debate (Rush- worth et al., 2004; Botvinick et al., 2004). In any case, correlational studies (ERP, neuroimaging, single- and multiunit recordings) strongly suggest the RCZ, pre-SMA, and mesial cortical area 8 to play key roles in performance monitoring functions. Correlational studies, although commonly accepted as providing strong suggestive evidence, by themselves cannot prove the necessity of specific brain regions for specific cognitive functions. Therefore, loss-of-function studies, e.g., in patients are needed for confirmation and hypothesis testing.

1.2. Anatomical connectivity of the rostral cingulate zone A schematic overview of the connections of the RCZ is shown inFig. 1. Evidence from nonhuman primates suggests that the RCZ receives inputs from the adjacent pre-SMA and dorsal premotor cortex as well as the thalamic ventroanterior nucleus (pars caudalis) and the oral part of the ventrolateral nucleus (Hatanaka et al., 2003). These thalamic nuclei in turn are sites of termination of pallidal efferents (Dum and Strick, 1993). The RCZ projects to premotor and caudal motor areas as well as the striatum, particularly in the putamen and the striatal cell bridges (Haber, 2003; Takada et al., 2001). Furthermore, reciprocal connections of the RCZ and lateral prefrontal cortex (LPFC) have been described (Bates and Goldman-Rakic, 1993; Petrides and Pandya, 1999). Tachibana et al. (2004)recently suggested that most of these connections go via the dorsal premotor cortex. In humans, RCZ and pre-SMA are function- ally connected with LPFC (Koski and Paus, 2000; Paus et al., 2001; Derrfuss et al., 2004). The LPFC itself also projects to the BG, specifically to the rostral striatum. While original models suggested segregated parallel information processing in cortico-striato-thalamocortical circuits (Alexander et al., 1990), more recent views advocate an additional integrative function of the BG (Haber, 2003; Bar-Gad et al., 2003). In particular, the structure of the BG-thalamus-cortex connections appears to ‘‘mediate information flow from higher cortical Fassociation_ areas of the prefrontal cortex to rostral motor areas’’ (p.325;

Haber, 2003).

Furthermore, the striatal patch compartments project to the mesencephalic dopaminergic nuclei (substantia nigra pars

Fig. 1. Simplified schematic of the performance monitoring network connected to the rostral cingulate zone (RCZ). The RCZ and the lateral prefrontal cortex (LPFC) are each parts of segregated cortico-striato-thalamo-cortical loops, the (pre)motor (light grey arrows) and prefrontal loops (dark grey arrows), respectively. These loops interact at several stages, e.g., via non-reciprocal cortico-thalamic connections (hatched grey arrow). A connection between RCZ and LPFC (grey dotted arrow) is under debate, possibly going indirectly via dorsal premotor cortex and pre-supplementary motor area. Modulatory dopaminergic projections from the midbrain are shown as hatched dashed light grey arrows. Direct and indirect pathways of the basal ganglia are collapsed. Abbreviations: CCZ = caudal cingulate zone, DA = dopamine, M1 = primary motor cortex, SNr = substantia nigra pars reticularis, SNc = substantia nigra pars compacta, VLo = nucleus ventrolateralis pars oralis of the thalamus, VTA = ventral tegmental area.

M. Ullsperger / International Journal of Psychophysiology 59 (2006) 59 – 69 60

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compacta (SNc), ventral tegmental area (VTA), retrorubral area). Dopaminergic neurons project back to the striatum but also to the frontal cortex including the RCZ. These latter connections form the anatomical basis of reinforcement learning models explaining the function of the BG as well as the generation of the ERN (Barto, 1995; Holroyd and Coles, 2002).

1.3. Signs and symptoms of impaired performance monitoring Impaired monitoring for situations in which action outcome is at risk or worse than expected and impaired signaling the need for behavioral adjustments can lead to a number of behavioral deficits. The function of the perfor- mance monitoring system can be tested by investigating behavioral consequences of errors. Impairments should result in decreased and delayed error correction. Post-error slowing (Rabbitt, 1966) is often interpreted as a measure of post-error adjustments as a consequence of error detection. This is probably true in a large number of studies; and it has been shown that it is modulated by error significance (Ullsperger and Szymanowski, 2004; Fiehler et al., 2005). However, it should be noted that a response on a trial after an error could be slow because of the persistence of the processing problem that caused the error (Gehring et al., 1993). In addition, when tasks are performed with high emphasis on response speed, post-error slowing can be absent. Thus, the function- ality of the performance monitoring cannot be assessed merely relying on post-error slowing. A more specific measure of behavioral adjustments subsequent to errors seems to be post-error reduction of interference effects (Ridderinkhof et al., 2002). Similarly, impaired conflict- adaptation effects subsequent to increased response conflict may reveal performance monitoring deficits (Ullsperger et al., in press). Furthermore, when errors and reduced rewards do not result in a signal to change behavior, impairments in the implementation of alternative actions may be expected, generally reflected in perseveration. In contrast, when the signaling system is dysfunctional, this could also lead to spontaneous switches from successful to less appropriate actions (e.g., decay of task contingencies and rule breaking as described, e.g., in Burgess et al., 2000). As the implementation of alternative actions requires updating of task representation and increases of top-down control, damage to the brain systems involved in these functions would result in similar impairments as would direct dysfunctions of the performance monitoring system. Finally, dysfunction of the performance monitoring system may be expected to result in lower performance in complex and new tasks. However, it should be pointed out that in well-learned tasks, problems with performance monitoring do not neces- sarily result in generally increased error rates.

With the increased use of ERP and fMRI investigations, additional dependent variables that can hint at impairments of the performance monitoring system have been identified. Particular attention has been paid to modulations of the ERN and of fMRI signals in the pMFC.

2. Studies in neurological patients

Studies on performance monitoring changes mostly focused to the influence of acquired focal lesions on electrophysiolog- ical measures of performance monitoring, particularly the ERN. In the following, studies are reviewed ordered by lesion topology.

2.1. The anterior cingulate cortex (mesial frontal cortex) Isolated, focal lesions in the ACC are very rare. Swick and colleagues reported extensive behavioral and ERP results on two patients with focal unilateral lesions of the RCZ (Turken and Swick, 1999; Swick and Jovanovic, 2002; Swick and Turken, 2002, 2004). One patient (D.L.) had a lesion in the right posterior RCZ reaching into the caudal cingulate zone, whereas the other patient (R.N.) had a lesion in the left anterior RCZ extending superiorly into the adjacent region where areas 32 and 8 adjoin. Patient D.L. with the posterior RCZ lesion showed normal levels of interference and accurate performance on incongruent trials in a Stroop task, but lower facilitation effects on congruent trials and no modulation of the interfer- ence effect by probability of incongruent trials (high vs. low conflict). It seems that this patient was incapable of modulating performance and ‘‘economizing’’ response selection by use of supportive stimulus features, as healthy subjects usually do on congruent trials. In other words, ‘‘patient D.L. adopted a conservative compensatory strategy [. . .] to reduce her susceptibility to [response] conflict’’ (p. 1251, Swick and Jovanovic, 2002). In contrast, patient R.N. with the anterior RCZ lesion showed consistently lower accuracy on incongru- ent trials and increased interference effects. Moreover, R.N.’s capability to modulate performance based on response conflict probability was reduced. Similarly, in a cued task-switching version of a word-arrow Stroop task R.N. showed increased interference in the mixed blocks requiring fast and flexible updating of task representations (Swick and Turken, 2004). The ERP findings were rather intriguing. R.N. showed a post- response negativity in the time range of the ERN on both errors and correct responses, but the ERN was attenuated and not different in amplitude from the CRN (Swick and Turken, 2002). Several interpretations are possible. First, the generator of the ERN was damaged by the unilateral lesion, but the contralateral side was still able to elicit a negativity, although not distinguishing between correct and incorrect anymore. Second, a number of studies suggest that ERN and CRN are related but not identical (Ford, 1999; Bartholow et al., 2005), i.e., the ERN may be superimposed on the CRN. Then, the generator of the CRN may still have been intact, while the generator of the ERN has been sufficiently damaged to prevent it from eliciting an error-related response. Regarding response conflict monitoring on correct trials, R.N. showed unimpaired congruency modulation of the stimulus-locked N2, which suggests that N2 and ERN have at least in part dissociable generators. The preserved N2, however, is difficult to reconcile with the obvious conflict-adaptation deficits found in the patient’s performance. It is necessary to investigate a larger

number of similar patients to make final conclusions about the functional relevance of the N2 modulation by response conflict.

The role of the RCZ in reward-guided behavior and performance monitoring has found support in a number of intracranial recording studies in patients who underwent pre- operative diagnosis for epilepsy (Brazdil et al., 2002; Wang et al., 2005). These studies revealed error- and negative-feedback- related electrical activity in the RCZ. Moreover,Wang et al. (2005)demonstrated error-related theta-band phase-locking of RCZ activity and other cortical areas in the brain, supporting the notion of a signal indicating the need to adjust behavior. A recent reward-processing study in patients who underwent cingulotomy in the RCZ combined correlative single-cell recordings (during the pre-cingulotomy phase of surgery) with a post-surgery loss-of-function examination (Williams et al., 2004). Activity in RCZ neurons not only responded to reward reductions but also predicted subsequent response alternations. Specifically the latter performance adjustments were impaired after partial ablation of the rostral cingulate zone.

A recent study challenged the view that the pMFC is necessary to signal the need for cognitive control.Fellows and Farah (2005)investigated four patients with extensive lesions involving the majority of pMFC and RCZ. One of them had bilateral lesions to the RCZ and adjacent cortical areas. In both, Stroop and Go – NoGo tasks, all four patients showed normal performance adjustments to manipulations of response conflict. Post-error slowing as well as the ability to adjust performance to speed or accuracy instructions was not different from healthy controls. The authors therefore con- cluded that the pMFC may not be necessary for cognitive adjustments in response to errors or increased conflict. They argued that its activity found in neuroimaging studies may be rather epiphenomenal and more related to autonomic control (Fellows and Farah, 2005; Critchley et al., 2003). The findings of preserved flexible adjustments in behavior are intriguing, particularly given the large lesion size. However, as has been shown previously, impairments subsequent to ACC lesions are at least in part transient in nature and disappear in chronic stages (Cohen et al., 1999), thus suggesting a high plasticity of the performance monitoring system. It might be that the patients in the Fellows & Farah study have recovered from impairments that were larger in the acute postlesional phase. Second, as pointed out previously, post-error slowing alone may be an insufficient measure to assess adjustments resulting from error processing. In sum, although evidence from loss-of- function studies is scarce and not entirely unequivocal, they appear to provide initial support for the view (derived from correlative studies) that the pMFC is essential for cognitive control by monitoring for and signaling the need to adjust behavior.

Neuroimaging and ERP studies have also suggested involvement of more rostral regions of the ACC in perfor- mance monitoring, particularly in affective processing of errors (Kiehl et al., 2000a; Luu and Pederson, 2004).Stemmer et al. (2004)investigated five patients with bilateral lesions of the anterior mesial frontal cortex involving the pregenual and

subcallosal ACC. They found largely impaired or absent ERN and Pe responses on errors in all patients, except for one who had a more inferior lesion, which was less extensive on the left side. The reinforcement-learning theory (Holroyd and Coles, 2002) suggests that dopaminergic input to the RCZ is necessary to elicit the ERN, andPaus (2001)pointed out the importance of cholinergic inputs for ACC function. Both, the dopaminergic projections from the midbrain and the choliner- gic fibers from the septal region can be assumed to be largely impaired in the bilaterally lesioned patients. Thus, the absence of ERP responses to errors may result from the deprivation of the generator from modulating neurotransmitters. Interestingly, some of the patients seemed to show signs of error awareness (vocal responses, grimaces), suggesting that the activity of the ERN generator in the RCZ is not necessary to consciously detect errors. Taken together with the study byNieuwenhuis et al. (2001)it appears that the error signaling process involving the RCZ is completely dissociated from the processing route enabling conscious error awareness.

2.2. The lateral prefrontal cortex

The LPFC has been shown to be involved in maintenance and updating of task representations (MacDonald et al., 2000; Derrfuss et al., 2004; Brass and Von Cramon, 2004; Brass et al., 2005). Contextual information about the task is necessary to make outcome predictions for an action. In addition, the LPFC seems to be involved in the increase in cognitive control as a consequence of detected errors or response conflict on preceding trials (Kerns et al., 2004; Garavan et al., 2002). Thus, bidirectional information flow between LPFC and the