Using a quantitative meta-analysis of 41 functional neuroimaging studies of executive functioning in schizophrenia, we found evidence of a superordinate, general-purpose cognitive control network that is associated with executive dysfunction in schizophrenia. Within-group analysis of all of the 41 studies indicated that healthy controls and schizophrenic patients activated a similarly distributed cortical-subcortical network while performing executive tasks, including the DLPFC, ACC, VLPFC, pre-motor cortex, lateral temporal cortical areas, parietal areas, cerebellum, and thalamus. Nevertheless, in direct between-group comparisons, schizophrenic patients exhibited reduced activation in several key nodes of this network, including the bilateral DLPFC, right VLPFC, right dorsal ACC, pre-SMA, left ventral premotor cortex, posterior areas in the temporal and parietal cortex, and sub-cortical areas, such as the mediodorsal thalamus and putamen. These results did not appear to reflect the inordinate influence of N-back studies. Of these regions, the DLPFC, ACC, and mediodorsal thalamus showed significant co-occurrence in between-group comparisons.
Increased activation in a frontocingulate network has been widely reported during normal executive functions60
and is consistent with models of cognitive control,7,8
which propose that the lateral PFC provides top-down control to establish an optimal pattern of processing across the brain to support task-appropriate responding. Consistent with this view, individual differences in DLPFC activation often correlate with superior task performance among the healthy subjects in these studies.61-63
Within this model, the ACC monitors performance, is sensitive to levels of conflict present during information processing, and serves to modulate the level of DLPFC task–related engagement in a dynamic manner.8,9
The consistent reduction of DLPFC and ACC activity observed in this meta-analysis is consistent with impairment in this dynamic cognitive control-related circuitry in schizophrenia. As noted, a broad network of frontal, subcortical, and posterior brain regions that support task performance were reduced in schizophrenic disrupted frontal-based top-down control functions (elaborated on in the Miller and Cohen “guided activation” model7
) that lead to a disruption of processing across the distributed brain network supporting task performance.
In contrast, patients with schizophrenia showed relatively greater activity in a region in the VLPFC; a midline cortical region located in the ACC extending into the SMA, which was dorsal and posterior to the ACC area showing reduced activity; posterior and inferior cortical areas (in the temporal and parietal cortex); the insula; and the amygdala. It is possible that these regions are associated with a compensatory response and/or are recruited to support alternate strategies to support task performance. With impaired DLPFC regulation of the distributed network engaged by task demands, patients may increase engagement of other processes to maintain task performance, such as attentional, mnemonic, and performance monitoring functions. These would be expected to manifest as relative hyperactivations in the ventral, medial, or posterior cortical regions. In addition, amygdala and insula activation clusters could reflect a differing emotional reactivity to task demands. This account could be compatible with a popular inefficiency hypothesis, as the compensatory hyperactivations could reasonably be viewed as reflecting an excessive distribution of cortical activity that is more restricted to the DLPFC and its tight control of these areas under normal (ie, healthy) conditions. A second possibility is that this profile of activity increases and decreases constitutes a disease-specific variation in the topographic basis for cognitive control and related executive functions. In this scenario, the topography of activity engaged during performance of these tasks is displaced for patients, giving rise to areas of relative hypoactivity adjacent to those with relative hyperactivity. This pattern of results does suggest a few adjacent regions with this pattern, notably in the medial wall of the PFC; however, this is not a comprehensive pattern in the present results, which suggests that other factors are at work. In any event, the present results taken together strongly argue against asimplehypofrontalityvshyperfrontalityaccountofthe altered function of the frontal cortex in schizophrenia.
Within the healthy control group, the distributed cognitive control network was engaged comparably across various executive function tasks, including the lateral PFC; premotor cortex; posterior neocortical areas, such as the parietal cortex and precuneus; and the thalamus. There were nonetheless some interesting task-specific areas of activation, which may be related to particular demands on certain component cognitive processes in these tasks. These include medial PFC (ACC and SMA/pre-SMA) activation in the Stroop and N-back tasks, potentially a function of conflict-processing demands; lateral (neocortical) temporal lobe and supramarginal gyrus activation in the Stroop task, both likely a function of linguistic processing involved in this task; and cerebellar activation in the N-back task, which may be related to the degree of temporal sequencing in processing of stimuli in this task. Notably, delayed match-to-sample performance was unassociated with above-threshold DLPFC activation (though significant VLPFC activity was evident), suggesting that these tasks were effectively performed by controls using simple maintenance strategies, obviating the need for higher-order dorsal PFC–mediated control.
The degree of task-specific variation appeared roughly comparable in the schizophrenia group, with lateral PFC activation in each task and similar variation in the observation of activation in midline PFC areas; in posterior cortical areas, such as the parietal cortex and cuneus; and in other elements of this distributed circuit, such as the cerebellum and thalamus. Inferences regarding which task-related areas of activation are significantly different between the 2 subject groups are best appreciated in the direct between-group comparisons described above.
A few limitations in this study are apparent. Activation likelihood estimation requires that source reports present data in 3-dimensional coordinates in a standard brain space and excludes studies that report only region-of-interest findings. However, the vast majority of published neuroimaging studies, including those focused on schizophrenia, report voxel-wise analyses in standard brain space.12,64
As a result, we included the largest set of studies of this kind to date in a quantitative meta-analysis. A further limitation is the relatively small set sizes for individual task types (other than the N-back). Therefore, results of the other major task types should be interpreted with caution. The future expansion of this primary source literature should enhance the reliability of meta-analytic approaches to these studies. Finally, in this type of meta-analysis, it would be generally desirable to have the capability to evaluate a range of study-wise factors that may be associated with variation in reported effects. These factors may include subject-specific factors, such as clinical or demographic factors or variation in sample size, and variation in data acquisition and analysis, which may affect both effect sizes and the brain topography of these effects. The considerable variation in study design and analysis and clinical measures used among the source studies () unfortunately precludes a quantitative assessment of these factors. Given this variation, it is remarkable that a number of reasonably predictable and coherent results were found. This suggests a degree of robustness in the present results and that we have achieved a fair view of the landscape of this literature, which is a distinct advantage of meta-analysis in general.10