These results support a specific association between orbitofrontal areas and socioemotional disinhibition as compared to dorsolateral prefrontal areas and classical executive functions. OFC predicted disinhibition, but not executive functioning; whereas MFG predicted executive functioning, but not disinhibition. Disinhibition was strongly associated with tissue loss in the right hemisphere and with the OFC in particular, while differential contributions of left vs. right MFG in predicting EF could not be identified. Results were replicated using cortical surface area measurements, but mean cortical thickness measurements did not predict behavior similarly to volume.
Findings correspond with previous research linking the dorsolateral prefrontal cortex (DLPFC) to EF. Focal lesions in the DLPFC result in decreased performance on tasks of abstraction, set shifting, and error monitoring (Moore, Schettler, Killiany, Rosene, & Moss, 2009
; B. Yochim et al., 2007
; B. P. Yochim et al., 2008
). In neurodegenerative disease, decreases in lateral prefrontal cortex volume are associated with an increased tendency toward rule violation errors during EF tasks (Possin et al., 2009
), and left DLPFC disease has been associated with EF as measured by a sorting task specifically in patients with FTD (Huey et al., 2009
). Patients with subcortical dementias, such as Huntington's disease and Parkinson's disease, who have dysfunction in dorsolateral prefrontal circuits at the level of basal ganglia, also show executive dysfunction (Tekin & Cummings, 2002
). These findings, and similar ones in the literature on neurodegenerative disease, were generated using techniques such as voxel-based morphometry (VBM), which is typically used to identify brain behavior relationships at every location in the brain independently, based on statistical relationships exceeding a particular threshold (usually p<0.05 corrected for multiple comparisons). None of these studies used methodology that would establish whether the brain regions identified relate to the behavior of interest independent from other brain regions that may relate to the behavior but fall below the statistical threshold used for the analysis. There are several approaches that can be used to deal with this issue. The approach taken here of entering volumes for several frontal ROIs previously identified as having roles in EF and socioemotional behavior incorporates a-priori knowledge to test the specificity of the brain-behavior relationships and was able to establish a specific relationship between MFG volume and EF, independent of brain volumes in other regions. This finding reinforces previous studies linking dorsolateral frontal regions with classical EF, including inhibitory processes that are considered integral to control of cognitive performance. Despite the association between OFC and behavior described as disinhibited, our data indicate that OFC does not contribute significantly to classical EF.
The neural mechanisms underlying EF is a topic of ongoing debate; however, Miller and Cohen (2001)
argue that cognitive control is the primary function of the prefrontal cortex (PFC). They propose a model by which cognitive control is accomplished by increasing the gain of sensory or motor neurons that are engaged by task or goal relevant elements of the external environment (Miller & Cohen, 2001
). The cognitive control construct that they describe is mediated by neural connections between the PFC and sensory and motor cortices, and is crucial in selective attention, error monitoring, and other aspects of EF.
Findings are also consistent with previous research examining neural correlates of socioemotional disinhibition. Patients with neurodegenerative disease or lesions involving the right frontal lobe are more disinhibited and show decreased ability to behave in a socially appropriate manner as compared to patients with left frontal lobe damage (Mychack, Kramer, Boone, & Miller, 2001
; Tranel, Bechara, & Denburg, 2002
). Mychack and colleagues (2001)
found that eleven out of twelve patients with predominantly right-sided FTD displayed socially undesirable behavior as an early symptom whereas only two of nineteen patients with left-sided FTD exhibited these behaviors. Several studies have linked disinhibition as measured by the NPI with tissue loss (Rosen et al., 2005
; Massimo et al., 2009
) and hypometabolism (Peters et al., 2006
) in the ventromedial portion of the OFC. The current study extends these prior findings by establishing the specificity of the relationship between OFC and socioemotional disinhibition, and supporting the idea that these behavioral deficits are due to mechanisms that are at least partially independent of those supporting EF.
The underlying mechanisms linking OFC and behavioral disinhibition are poorly understood, although impaired processing of reinforcers may be central to this process (Rolls & Grabenhorst, 2008
). OFC projects to the amygdala, cingulate cortex, ventral striatum and head of the caudate nucleus (Rolls & Grabenhorst, 2008
), brain regions that are involved with the processing and response to the reward value of stimuli. Similarly, it projects to entorhinal and perirhinal cortex, providing a route for reward information to reach the hippocampus for remembering (Rolls & Xiang, 2005
). It also connects to the preoptic region and lateral hypothalamus, where neurons alter their firing rates in response to food and show sensory-specific satiety (Rolls, Burton, & Mora, 1976
). These connections provide several routes via which the OFC can influence behavior (Rolls, 2005
). The OFC reacts to the reward and punishment values of stimuli in the environment and guides adaptation of behaviors based upon the changing nature of these reinforcers (Kringelbach & Rolls, 2004
). For example, OFC activity increases when smelling a desirable food, but with satiety the activation found with the same food dampens (O'Doherty et al., 2000
). Similarly, the current pleasantness or reward value of odiferous somatosensory, and visual inputs are determined within the OFC (Rolls & Grabenhorst, 2008
). These patterns of activity are linked to emotions, because emotions can be viewed as states elicited by instrumental reinforcers (Rolls, 2005
). The firing patterns in the OFC can be seen as providing specific contexts for potential rewards and punishments so that their current value can be calculated based on the specific context and bodily state. It is easy to understand how failure to update reward and punishment values to the current context can lead to socially inappropriate behaviors. For instance, flirtatious comments might be appropriate for a college student at a fraternity party, but not for a married man visiting the mall with his family.
PFC contributions to EF and disinhibition, while significant and unique, only explained small proportions of the variance in the two dependent variables. Of course, DLPFC is not exclusively responsible for executive functioning. Other brain regions, as well as demographic variables contribute to EF. A larger proportion of the variance in EF was explained by control demographic/clinical variables, TIV, and diagnosis in particular. Furthermore, research suggests that EF is not anatomically restricted to the frontal lobes, but also depends upon the integrity of subcortical white matter and the basal ganglia, and neural networks that rely on input from posterior structures (S. W. Anderson, Damasio, Jones, & Tranel, 1991
; Ravizza & Ciranni, 2002
). After controlling for global cognition, TIV, diagnosis, and education the MFG uniquely accounted for only 3.5% of the variance in EF in the current study, but this is to be expected given that EF is a complex and multifaceted function that utilizes regions extending throughout the brain. Deficits in EF may be mediated by dysfunction in bilateral frontostriatal and frontoparietal networks that involve the ACC, DLPFC, and parietal cortex in the region of the intraparietal sulcus (Wang et al., 2009
; Wolf et al., 2008
). Similarly, the OFC uniquely accounted for only 4.7% of the variance in disinhibition. As is the case with MFG and EF, OFC is likely part of a network of regions relevant to behavioral regulation. Disinhibition in patients with bvFTD is also correlated with atrophy in the right nucleus accumbens, right superior temporal sulcus, and right mediotemporal limbic structures, reflecting the connections of the temporal lobe with orbitofrontal regions (Zamboni, Huey, Krueger, Nichelli, & Grafman, 2008
). Future research should examine brain networks related to disinhibition and EF.
Our findings are also notable in light of evidence that the right hemisphere plays an important role in the processing of emotion (Anderson et al., 2000
; Rosen et al., 2006
; Tranel et al.). Hemispheric specialization appears to have led to asymmetric elaborations of neural pathways (Tucker, Luu, & Pribram, 1995
). Understanding the inherent asymmetries of these networks may be important in interpreting the growing evidence that the left and right frontal lobes contribute differently to normal and pathological forms of socioemotional behavior (Tucker et al., 1995
Although volume measurements are most commonly used, our data analysis procedure allowed us a unique opportunity to analyze area and thickness data separately. Cortical surface area predicted behavior similarly to volume, but that mean cortical thickness did not. This suggests that atrophy in neurodegenerative disease may reflect multiple processes that affect surface area and cortical thickness differently. Other studies have also found that these two parameters are differentially affected by the disease. Dickerson et. al. (2009)
showed differential effects on thickness and area in healthy elderly and Alzheimer patients. Panizzon et al. (2009)
showed that although both thickness and area are highly heritable, the overlap in the genetic contributions to them is very low, indicating that cortical volume measures combine at least two distinct sources of genetic influences. The factors influencing the relative effects on cortical thickness versus surface area of aging and neurodegenerative disease have not been explored in great detail, but our results suggest that the different effects on these two parameters, and how these separate effects relate to behavior, should be a subject for future studies.
Our approach, which was designed to test whether our regions of interest accounted for specific behaviors independent of other relevant brain regions in the frontal lobes, constitutes a relative strength of the study. The current study provided a unique perspective on brain-behavior relationships because most studies do not specifically examine independent contributions of brain regions in predicting behaviors. A specific association was found between orbitofrontal areas and socioemotional behavior as compared to dorsolateral areas and EF. In addition to enhancing our understanding of the relationships between brain regions and specific cognitive-behavioral functions, a better understanding of this division of labor within the frontal lobe is important for early diagnosis, differential diagnosis, and improved counseling of patients. Our findings differ from some prior findings, such as the association of disinhibition with lesions in the ventromedial prefrontal cortex, including the area above the medial OFC. Discordant findings may be a result of different measures of disinhibition or EF, MRI acquisition and analytic techniques, or other methodological differences. Although human lesion-mapping supports the localization of response inhibition to the right inferior frontal cortex (Aron, Robbins, & Poldrack, 2004
), this study examined cognitive inhibition as measured by Go/NoGo or Stop-signal tasks as opposed to socioemotional disinhibition. The difference in quantitative methods used to measure our constructs (neuropsychological tests assessing EF vs. questionnaire evaluating socioemotional disinhibition) is a limitation of the study and may have influenced results. Relative weaknesses of the current study also include a lack of autopsy confirmed diagnoses and only using one measure of socioemotional disinhibition. Although the NPI is a validated measure of disinhibition commonly used in research, future studies should consider including other measures as well to explore the possible independent contributions of brain regions within the PFC in predicting socioemotional disinhibition.