Our findings demonstrated that prefrontal cortex, medial temporal structures, and basal ganglia are differentially involved in determining the apathetic and disinhibited profiles of FTD.
In a previous study, a VBM correlation analysis was performed in patients with different diagnoses of dementia to correlate subscores of the NPI with atrophy.19
The NPI subscore for apathy correlated with volume loss in the medial superior frontal gyrus, and the NPI subscore of disinhibition correlated with atrophy in the subgenual cingulate cortex. Our study differs from that study in patient population, because we focused on a homogeneous group that included only FTD patients. In addition, the FrSBe Apathy and Disinhibition subscales are better suited to identify the neural correlates of complex behavioral profiles based on the co-occurrence of several specific behaviors, whereas in the NPI, the same terms refer to sub-items measuring single specific behaviors. Therefore, although the NPI might have provided more specificity in characterizing distinct behaviors, the FrSBe better suited the purpose of the present study, which was to identify the neural correlates of complex behavioral profiles based on the aggregation of a set of behaviors. An exploratory principal factor analysis of the FrSBe23
confirmed that the 46 items describing different behaviors consistently loaded together on each of the three subscales that were proposed on the basis of the anatomofunctional interpretation of prefrontal-subcortical circuits.5,6
Therefore, the FrSBe is more descriptive of disinhibited and apathetic types
, whereas the NPI more precisely refers to apathy and disinhibition as specific behaviors. This difference may have contributed to the dissimilarities of our results with previous findings.
Consistent with previous studies on FTD and brain-injured patients,26,27
our results demonstrated a predominant involvement of the right hemisphere in both behavioral abnormalities, supporting the notion that the right hemisphere has a critical role in complex social behaviors.
The severity of the score measuring apathy was associated with atrophy in different prefrontal regions—including DLPFC, OFC, and ACC—and in the putamen. The DLPFC has a role in executive functions such as planning, rule finding, and problem solving.28,29
The impairment of those functions results from difficulty in elaborating and executing goal-directed behaviors, a deficit that may also be reflected in a type of apathy that has been described as “cognitive inertia.”30
Interestingly, the FrSBe Apathy subscale score was significantly predicted by a model that included not only peak values of gray matter density in the DLPFC bilaterally, but also a measure of dementia severity (Mattis-DRS). According to the anatomic organization of frontal-subcortical circuits,6,31
the DLPFC projects to the putamen that was similarly associated with apathy in our study. In addition, our results showed the involvement of the ACC, which is part of a circuit important in the integration of emotional information with motivation32
and has been repeatedly associated with apathy and disorders characterized by decreased spontaneous goal directed behavior, including akinetic mutism.33
The severity of the score measuring disinhibition was associated with gray matter loss in right mediotemporal structures (amygdala and hippocampus) and right nucleus accumbens (ventral striatum). The multiple regression confirmed that peak values of atrophy in these regions significantly predict the variance of the FrSBe Disinhibition subscale. Those structures are densely interconnected and are part of the mesolimbic dopaminergic system, which plays a key role in motivated and emotional behavior.34
The amygdala has a demonstrated role in fear conditioning and, more generally, in the detection of environmental cues such as threat and danger.35
The accumbens (ventral striatum) plays a key role in the dopaminergic system responsible for reinforcement and reward, as well as for goal-directed behaviors such as compulsive drug seeking in addicts.34
In addition, functional neuroimaging studies have demonstrated its role in the expectation of the rewarding value of complex socially meaningful stimuli, such as commercial products.36
The association of mainly temporal structures with the FrSBe Disinhibition subscale seems consistent with the behavioral deficits shown by patients with focal temporal lesions or with temporal lobe epilepsy, in which an extensive range of behavioral symptoms, including mania, euphoria, and aggressive behaviors, have been described.37
These deficits are often interpreted as reflecting the connections of the temporal lobe with orbitofrontal regions and not as a consequence of the loss of specific functions represented in the temporal lobes.37
According to one functional interpretation of frontal-subcortical circuits,31
temporolimbic structures and nucleus accumbens are part of the orbitofrontal circuit, whose dysfunction is characterized by disinhibition syndromes including irritability, impulsivity, and undue familiarity. This has been interpreted as the consequence of loss of inhibition by the frontal monitoring system on the limbic system that is responsible for instinctual behaviors. But in our study, there were no frontal areas in which gray matter loss was specifically associated with the severity of disinhibition when controlling for apathy, dementia severity, and other demographic variables. Therefore, our results suggest an alternative interpretation: that disinhibited behaviors may result from impaired risk perception and reward/punishment attribution mechanisms and may occur independently from prefrontal dysfunction. This supports the view that the role of prefrontal structures important in executive functions and motivation and the role of temporolimbic structures involved in reward and emotional processing need to be integrated38
to properly perform complex social behaviors.