In the current study, we used a robust interference task in order to investigate the spatial distribution of individual activations in medial frontal cortex during interference and error processing. Our study employed an event-related design that permitted separation of neural activity related to errors from that associated with cognitive interference, extending previous work examining individual activation in schizophrenia using a blocked design (Heckers et al., 2004
). Topographic analysis of the location of individual activations provided a sensitive measure of group differences, revealing a significantly different anterior-posterior distribution of error-related individual activations in schizophrenics, whereas group-averaged data had inadequate power to detect this difference. These results not only speak to the nature of monitoring deficits in schizophrenia, but also provide important methodological implications for analyzing group data in neuroimaging experiments.
When making an error, the healthy control group showed a pattern of individual activations distributed throughout the entire medial frontal wall, with foci located in pre-SMA, ACC, and anterior medial prefrontal cortex including subgenual cingulate, while fewer individual activations were located in anterior regions of MFC/ACC among patients with schizophrenia. For interference contrasts, individual activations in both groups spanned a smaller area of MFC that was largely restricted to (dorsal and ventral) posterior regions. Such findings are consistent with previous studies examining error and interference processing in healthy controls, additionally providing insight into how psychotic patients differ in error monitoring. Errors and interference have both been found to elicit activity in pMFC (Botvinick et al., 2001
; Ridderinkhof et al., 2004
), possibly reflecting the detection of cognitive conflict associated with both conditions. However, error monitoring has been shown to additionally recruit activity in aMFC (Garavan et al., 2003
; Kiehl et al., 2000
; Taylor et al., 2006
), which may be related to emotional processing of an error (Gehring and Knight, 2000
; Luu et al., 2000
; Bush et al., 2000
; Simmons et al., 2006
; Steele and Lawrie, 2004
). The altered spatial distribution of individual activations in patients was not related to their decreased overall accuracy, and may reflect an impaired emotional response to errors related to reduced motivation (Liddle et al., 2006
A definitive explanation for altered anterior activity during errors in the patients will require more study, but it is unlikely to reflect a general failure to engage in the task. Error rates were relatively low for both groups, and while the patients were slower to respond, this fits the expected pattern of schizophrenic performance (Nuechterlein, 1977
). Further, during interference, the patient group actually showed a slightly larger BOLD signal in pMFC, a finding that is unlikely to be related to spatial variability considering that the groups did not show differing distributions of individual activations for interference contrasts. This increased pMFC signal for patients was somewhat unexpected given reports of reduced activation in this area in schizophrenia (Kerns et al., 2005
; Morey et al., 2005
; Snitz et al., 2005
; Yucel et al., 2007). However, a recent meta-analysis identified MFC hyperactivity in schizophrenia during working memory tasks (Glahn et al., 2005
), which may represent a compensatory mechanism resulting from reduced efficiency of cortical processing among patients at relatively low levels of demand. A similar explanation has been put forth to describe DLPFC activation in schizophrenia, where patients show increased activity relative to controls at lower levels of demand but decreased activity at higher levels of demand (Callicott et al., 2003
; Manoach, 2003
Given the degree of dispersion among individual activation foci, especially among healthy controls, the failure to find error-related group differences in MFC between patients and controls using spatial averaging is not surprising. Both groups exhibited considerable scatter of individual activations in MFC/ACC during errors, perhaps leading to the conclusion that no “true” signal occurs in anterior MFC during error processing. However, as discussed above, studies using group-averaged data have found an anterior focus for error processing, and reduced error-related anterior MFC/ACC activity has been identified in schizophrenia (Laurens et al., 2003
). In light of this topographic analysis, we suggest that the lack of MFC/ACC group differences in the spatially-averaged data reported here and by others (e.g., Carter et al., 2001
; Kerns et al., 2005
) may be due to the spatial dispersion of individual activations, especially among healthy control subjects, and consequent reduction in experimental power to detect differences.
A similar analysis of individual activations in schizophrenia performed by Heckers and colleagues (2004)
found that patients tended to activate locations dorsal to controls in pMFC during interference. Although we did not also find this effect in our radial measurement, these authors employed a blocked version of the MSIT that did not exclude errors from analysis of interference effects. As incongruent blocks had more errors than congruent blocks, it is possible that an anterior/ventral error signal was present in incongruent blocks for healthy controls. Consistent with the current data, patients with schizophrenia may not have exhibited such an anterior/ventral error signal in incongruent blocks, making them appear to activate dorsally relative to controls for interference contrasts. Thus, even at the level of individual activations, spatially distinct processes that are experimentally confounded may cause apparent shifts in an activation focus.
So why exactly is there so much dispersion among individual activations in MFC during error processing? There are several possibilities to consider. We believe that it is implausible that the scatter found among individual activations is a methodological artifact arising from differences in head movement or preprocessing parameters between subjects, as realignment of no more than a few millimeters (see Methods) is not likely to give rise to a difference of several centimeters in the location of activation foci. However, individual differences in the anatomical structure of multiple cortical regions, including MFC, have been noted (Devlin and Poldrack, 2007
; Paus et al., 1996
; Uylings et al., 2005
; Yucel et al., 2001), and interindividual variability in MFC folding patterns are related to differences in the location of functional activations (Crosson et al., 1999
). Although our current study was not able to assess the contribution of morphological or cytoarchitechtonic variability to functional activations, VBM analysis indicated that density of gray matter in anterior regions of MFC was not different between healthy controls and patients, either in variability of individual GM density values or group-averaged data. Even assuming similar anatomical structure, is it possible that dispersion of activations could be due to individual differences in the distribution of functional networks, with the same cognitive or emotional processes accomplished by different regions of cortex across subjects. Alternatively, variability in the location of activations may have a more functional significance, such that the processing elicited by a given task varies between subjects due to differences in individual strategies or personality characteristics (e.g., subjects who feel greater negative affect when making a mistake may show individual activations that are located anterior to those exhibited by subjects unconcerned about errors). Although the current study was not able to directly address the causes of individual activation variability, we probed for correlations between location of activations and number of errors, and, in the patient group, between location of activations and positive and negative symptomotogy, but did not find any significant relationships. However, more comprehensive personality measures were not examined, and may indeed be related to individual differences in the neural response to errors.
Several caveats should be noted for these data. All patient subjects were taking antipsychotics (the majority of which were atypical) and adjunctive psychotropic medications, making it difficult to disentangle the effects of the disorder from those of chronic medication. However, the fact that we found slightly increased activation for the interference condition in the schizophrenic subjects suggests that a general impairment of activation due to medication is not likely. Moreover, antipsychotics tend to normalize activity in MFC/ACC (Honey et al., 1999
; Lahti et al., 2004
; Ngan et al., 2002
; Snitz et al., 2005
), and it is possible that our findings represent an underestimation of the true impact of the disorder on neural activity in MFC/ACC. Clearly, however, future research would benefit from obtaining data from patients before and after antipsychotic treatment.
It is also important to note that the current methodology employing a non-parametric analysis of the distribution of clusters in a group allowed for variability in an individual’s contribution within each group (i.e., not all subjects contributed an equal amount of activations). However, this within-group variability was the same for both patients and controls, as evidenced by very similar standard deviation values (reported in results), and the groups were equated on total number of clusters contributed to the analysis. Furthermore, a larger sample size would have increased statistical power, possibly revealing differences in our group-averaged data. Nevertheless, the fact remains that, for the majority of researchers, the time and expense of neuroimaging experiments limit the ability to test the large number of subjects that would needed in order to eliminate this problem.