The main finding of this study is that patients with very mild bvFTD who performed within normal limits on clinical tests of executive functioning demonstrated selective impairment in conflict monitoring. On a flanker task, we found that while bvFTD-high and controls responded with comparable accuracy and speed on congruent trials, reaction time data showed an interaction between diagnosis and condition, whereby bvFTD-high patients showed a larger congruency effect (i.e., disproportionate slowing on incongruent trials) than normal controls. These results demonstrate that bvFTD is associated with deficits in executive cognitive control, even very early in the disease when standard clinical neuropsychological test scores are within normal limits. bvFTD-low patients also displayed a larger congruency effect than normal controls, suggesting that selective impairment in conflict monitoring continues as functional impairments progress. Although the flanker test yielded group-wise differences, it does not seem that this test can be used for diagnosis in individual patients.
Research has proposed that the medial frontal lobes detect and signal the occurrence of conflicts in information processing.32
A study examining the flanker interference effect as a function of the entire reaction time distribution in patients with mild cognitive impairment (MCI) as compared with normal controls found evidence that inefficient inhibition, rather than greater activation of the response induced by incongruent flankers, accounted for the enhanced interference effect in MCI patients.33
Accordingly, the greater interference effect found in patients with bvFTD as compared with normal controls is likely a function of inefficient response inhibition. Patients with early bvFTD may have subtle impairments in inhibiting their attention or response to irrelevant stimuli.
Functional imaging studies have demonstrated the role of the medial frontal circuits in response inhibition during the flanker task.11–13,17
Patients with diseases associated with impairment in these brain regions (e.g., Parkinson disease, MCI, attention-deficit hyperactivity disorder) show larger flanker interference effects as compared with healthy controls.33–37
The strong activation of medial frontal lobes, and specifically the rostral anterior cingulate, during response conflict trials of the flanker task in neurologic healthy controls suggests that the observed findings of impairment in conflict monitoring in patients with bvFTD as compared with normal controls in the current study are a result of dysfunction in this brain area and related anterior cingulate circuit. Research has illustrated the intrinsic corticocortical connections within the orbital and medial prefrontal cortex.38
Imaging results in the current study revealed significant orbitofrontal cortex atrophy in bvFTD-high patients as compared with controls. More lateral areas of the frontal lobes (middle frontal gyrus) were not as profoundly affected. The orbitofrontal cortex and associated network is likely the neuroanatomical substrate for the observed suppression difficulties evidenced in patients with bvFTD.39
Patients with bvFTD and normal controls differed on an experimental cognitive measure of executive control but did not deviate on widely used clinical measures of executive functioning. These results highlight the issue of task sensitivity in detecting executive cognitive control deficits in patients with bvFTD. Reaction time tasks may be more sensitive to these deficits than standard clinical measures. Current models of prefrontal function posit a dissociation between ventromedial or orbitofrontal areas that mediate behavioral control, and dorsolateral structures that are more heavily involved in cognition. Clinical neuropsychological tests of executive functioning sensitive to lateral prefrontal function may fail to test the distinct and separate functions of the areas of the prefrontal cortex that are predominantly affected in bvFTD.
One limitation to this study is the relatively small sample size; however, the sample size was comparable to other studies of this type, and statistically significant differences were found indicating fairly large effect sizes. In addition, although not a significant difference, controls were slightly older than subjects with bvFTD. Nevertheless, one might expect that the increased age in the controls would be associated with greater likelihood of neuropsychological deficits, if it had any effect at all.
Despite being a fairly common presenile neurodegenerative disease, bvFTD continues to be underdiagnosed and misdiagnosed.40
Early and accurate diagnosis remains essential to treat symptoms correctly and to help patients and families plan for the future. Identifying patients in the earliest stages of the disease not only allows for effective patient management, but also may be beneficial in the assessment of efficacious therapeutic interventions. Measures of neuropsychological functioning sensitive to the ventromedial prefrontal cortex may be useful in early diagnosis of patients with bvFTD. Future research examining the efficiency of selective inhibition, a fundamental component of executive cognitive control, may increase our understanding of this syndrome.