Tracing the boundaries of executive function fractionation: evidence from lesion-symptom mapping in brain tumor patients

The purpose of the present research project was to investigate, by means of different lesion-symptom mapping techniques, the behavioral consequences of focal frontal lobe injuries in order to tackle the currently debated issues regarding the PFC organization. In particular, in the first two studies we aimed at delineating the observed impairments as possible disruptions of common and/or distinct processes in order to test the dissociability of putatively distinct cognitive control processes. We focused on switching and response inhibition abilities, which according to the literature rely on left and right prefrontal areas, and tested whether their impairments could be accounted for by more general task-setting and/or sustained attention impairments. In particular, we tested brain tumor patients with left and right prefrontal damage, and compared their performance with non-prefrontal patients and healthy controls. Critically, in order to exclude eventual lower-level processing difficulties known to emerge after lateralized brain lesions, verbal and spatial features of the employed tasks were mostly balanced. The results from both studies suggest that there is probably no specialized inhibitory or switching module hosted by a particular brain area; instead they show how performance on tasks requiring both inhibitory and switching abilities can be disrupted by a more general task-setting impairment supported by left prefrontal areas and their connections with posterior regions. Furthermore, inhibitory impairments, previously observed in patients with right prefrontal lesion, might alternatively be explained by sustained attention impairments. In the last study, instead, we focused on finding out whether lesions in specific prefrontal areas could account for a general cognitive decline, as supported by unitary models of the PFC organization. In particular, we applied a latent variable analysis on distinct neuropsychological test scores in order to minimize the influence of low-level processing requirements and thus obtain a more pure measure of general cognitive functioning. Additionally, we examined the impact of surgical tumor removal on general cognitive functioning across different tumor histological types. The results confirmed previous findings on the impact of surgery on low-grade glioma. However, they also extend them by showing that surgery in left dorsolateral frontal areas causes a more prominent cognitive decline, regardless of the tumor histology. Taken together, the findings across all the three studies have highlighted a critical involvement of left- lateralized prefrontal areas in most of the high-level cognitive tasks we employed, event though the precise localization was somewhat different. However, the involvement of right prefrontal areas seemed critical in more sustained type of processing required to maintain attention to task-relevant events. This observation is in line with a more integrative, albeit lateralized, view of the PFC organization according to which higher, associative types of processes rely on the interaction between frontal and posterior brain regions, but their left and right lateralizations reflect separate, specialized type of processing probably involved in more phasic type of processing, necessary to form and flexibly implement task-relevant associations, and sustained type of processing, needed to maintain the relevant features of the task in an active state.L’attuale progetto di ricerca è volto ad indagare le funzioni specifiche della corteccia prefrontale e la loro localizzazione mediante studi neuropsicologici su pazienti con tumore al cervello. Nei primi due studi ci siamo focalizzati sui processi di inibizione e di switching che, in base alla letteratura, vengono sostenuti da aree nella corteccia prefrontale a destra e sinistra, rispettivamente. In particolare, testando pazienti con lesioni in queste aree, assieme ad altri con lesioni non frontali e soggetti sani, abbiamo cercato di disambiguare se i deficit osservati in questi pazienti possono venir spiegati meglio da danni ad altri processi di controllo cognitivo più generali, come il monitoring e il task-setting, per i quali diversi studi nei sani hanno dimostrato la lateralizzazione opposta nella corteccia prefrontale. I risultati di questi primi due studi suggeriscono che sia il controllo inibitorio che di switching possono venir compromessi da un deficit più generale di task-setting dovuto a lesioni prefrontali a sinistra. Inoltre, difficoltà inibitorie precedentemente osservate nei pazienti con lesioni prefrontali a destra sembrano essere dovute a un deficit più generale di monitoring. Nell’ultimo studio invece abbiamo indagato se le lesioni in aree prefrontali possono sottostare a un declino cognitivo generale, come suggerito da modelli unitari dell’organizzazione della corteccia prefrontale. In particolare, per ottenere una misura più pulita dello status cognitivo generale, abbiamo estrapolato mediante la Principal Component Analysis una componente che spiega la varianza comune nei diversi test neuropsicologici e l’abbiamo confrontata tra i diversi gruppi di pazienti divisi per il tipo di tumore (alto grado, basso grado, meningioma, metastasi) e le diverse aree lesionate. I risultati hanno confermato studi precedenti che trovano un maggiore declino generale dopo la chirurgia nei pazienti con tumore a basso grado. Tuttavia, abbiamo osservato che il declino maggiore è dovuto inoltre a lesioni in aree dorsolaterali della corteccia prefrontale a sinistra, indipendentemente dal tipo di tumore. I risultati di questi tre studi supportano una visione più integrativa, sebbene lateralizzata dell’organizzazione funzionale della corteccia prefrontale