Our results highlight the increased specificity of cortical regions that correlate with set-shifting when controlling for the influence of fundamental processes, such as motor control and visual scanning. In addition, we identify the key gray matter regions of bilateral prefrontal cortex and posterior parietal lobe that correlate across three distinct set-shifting tasks. As a secondary finding, we report the high multicol-linearity between the component processes and set-shifting conditions on the Trail Making Test and Color Word Interference tests.
Our neuroimaging findings are consistent with the literature implicating prefrontal function in set-shifting tasks. Multiple patient studies have recognized the impact of frontal lobe lesions on set-shifting performance (McDonald, Delis, Norman, Tecoma, et al., 2005
; McDonald, Delis, Norman, Wetter, Tecoma, & Iragui, 2005
; Pantelis, Barber, Barnes, Nelson, Owen, & Robbins, 1999
; Stuss et al., 2001
; Yochim et al., 2007
). Disrupted prefrontal lobe function, as measured by increased, aberrant blood flow, has also been implicated in set-shifting impairment in schizophrenia and bipolar patients (Jazbec, Panatelis, Robbins, Weickert, Weinberger, & Goldberg, 2007
; McKirdy, Sussmann, Hall, Lawrie, Johnstone, & McIntosh, 2009
; Pantelis et al., 1999
). In addition, functional neuroimaging studies have identified focal blood oxygenated level dependent (BOLD) or metabolic activity in prefrontal cortex in set-shifting tasks (Horacek et al., 2006
; Moll et al., 2002
; Zakzanis et al., 2005
Less evidence has been shown relating posterior parietal cortex to set-shifting performance, as reported in the current study. Methodological differences may be one explanation. Our study is distinct from other structural MRI studies on set-shifting, because we used a voxel-by-voxel approach to identifying gray matter regions involved in set-shifting. Previous studies used lobar volume measurements or a priori
regions of interest in the frontal lobe when probing neural correlates of set-shifting (Kramer et al., 2007
; Zimmerman et al., 2006
). This is an important distinction because lobar volume measurements may be less sensitive to focal neural correlates (i.e., posterior parietal cortex) of set-shifting. Some functional MRI studies, which conduct statistical analyses on a voxel-by-voxel basis have, however suggested parietal involvement in set-shifting. In fact, one study used a modified verbal form of the Trail Making Test to investigate functional activation (Moll et al., 2002
). This study found a task-induced, increase in the BOLD response in left dorsolateral and dorsomedial prefrontal cortex and bilateral intra-parietal sulcus. These findings are highly consistent with our current study, and these authors recognize a frontoparietal network in regulating cognitive control and flexibility. Another study aimed at elucidating regions involved in cognitive control also found bilateral lateral posterior parietal cortex activation during a cognitive set-shifting task (Asari et al., 2005
). Overall, the findings in the current study are consistent with the role of the prefrontal and parietal cortices in cognitive control, mental flexibility, and task switching.
One recent study sought out the relationship between multiple D-KEFS measures and gray matter density in FTD and CBD patients (Huey et al., 2009
). Their study did not specifically investigate set-shifting ability, but rather a set of general higher-order executive functions, and there was only overlapping test with the current study (Trail Making Test). They did not control for the component processes in their study, but used the D-KEFS computed scaled scale, which takes education level into account. In a CBD patient population, it is important to control for component processes that may be compromised due to deficits in basic cognitive functions (e.g., visual scanning, motor control).
Another study sought to identify regions involved in a set of executive function tasks, including a version of the Trail Making Test (shifting condition B) (Newman, Trivedi, Bendlin, Ries, & Johnson, 2007
). Gray matter correlates of performance were identified in bilateral prefrontal cortex, among other regions. Importantly, this study was conducted in healthy controls, possibly restricting the generalizability of the findings to patient populations and limiting the amount of variance in the data, as recognized by Newman and colleagues. This study did not control for component processes (i.e., Trail Making Test condition A).
Other studies have highlighted the importance of controlling for component processes when investigating complex cognitive processes. For example, Kramer and colleagues (2007)
found that DF-Switch significantly correlated with six lobar volumes (bilateral frontal, parietal, and temporal lobes). However, after controlling for DF-Filled, working memory, and nuisance variables, DF-Switch significantly correlated with the left and right frontal lobes.
To better understand the interplay between cognitive processes, we examined the relationship between the component processes and set-shifting tasks. Although no brain regions were significantly correlated with the Trail Making Test and Color Word Interference analyses after controlling for both
component processes, this is an interesting result. The high degree of multicollinearity between these set-shifting tasks and their component parts may limit the ability to identify brain regions correlated with set-shifting. It is possible that a significant result would be found in a larger sample size. However, one could still account for fundamental skills (e.g., motor speed, visual scanning) when assessing performance in set-shifting by controlling for one component process (as in the modified version of the Trail Making Test proposed by Reitan and Wolfson (1985
Identifying a high degree of multicollinearity between component processes and set-shifting may have potential practical applicability for clinicians in assessing set-shifting function. To date, the majority of studies probing set-shifting function use the Trail Making Test as their measures; however, given our current findings, Design Fluency may be a better measure for assessing pure set-shifting ability when controlling for component processes.
Taken together, the results from our study are consistent with the literature suggesting that set-shifting involves a frontal–parietal brain network. One limitation of our study, however, is the lack of consideration for white matter structures involved in set-shifting. Numerous studies have identified the impact of white matter hyperintensities and compromised fiber tracts on impaired set-shifting performance, among other executive function abilities (Marshall, Hendrickson, Kaufer, Ivanco, & Bohnen, 2006
; Perry et al., 2009
). The role of white matter regions in set-shifting is an important research area and should be explored in future studies. Another limitation of the study is the applicability of these gray matter correlates on other types of set-shifting tasks. As mentioned previously, the three set-shifting tasks used in this study require subjects to switch stimuli on a trial-by-trial basis. However, other set-shifting tasks require subjects to maintain a rule for a set number of trials (e.g., WCST). Therefore, the brain regions correlated in different types of set-shifting tasks may vary. Lastly, we plan to explore the relationship between surface-based morphometry, cortical thickness, and set-shifting in future studies.