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The ability to use predictive information to guide perception and action relies heavily on the prefrontal cortex (PFC), yet the involvement of its subregions in predictive processes remains unclear. Recent perspectives propose that the orbitofrontal cortex (OFC) generates predictions about perceptual events, actions, and their outcomes while the lateral prefrontal cortex (LPFC) is involved in prospective functions, which support predictive processes, such as selective attention, working memory, response preparation or inhibition. To further delineate the roles of these PFC areas in predictive processing, we investigated whether lesions would impair the ability to build predictions of future events and detect deviations from expected regularities. We used an auditory deviance detection task, in which the structural regularities of played tones were controlled at two hierarchical levels by rules defined at a local (i.e., between tones within sequences) and global (i.e., between sequences) level. We have recently shown that OFC lesions affect detecting prediction violations at two hierarchical levels of rule abstraction, i.e., altered MMN and P3a to local and simultaneous local + global prediction violations (https://doi.org/10.7554/eLife.86386). Now, we focus on the task's predictive aspect and present the latest results showing the involvement of PFC subregions in anticipation of deviances informed by implicit predictive information. Behavioral data shows that deviance expectancy induced faster deviance detection in healthy adults (n=22), suggesting that participants track a state space representation of the task and anticipate upcoming deviant sequences. The analysis of EEG data from patients with focal lesions to the OFC (n = 12) or LPFC (n = 10), and SEEG from the same areas in patients with epilepsy (n = 7), revealed interesting differences. Healthy adults (n = 15) showed modulations of the Contingent Negative Variation (CNV) – a marker of anticipatory activity - tracking the expectancy of deviant tone sequences. However, patients with OFC lesions lacked CNV sensitivity to the predictive context, while patients with LPFC lesions showed moderate sensitivity compared to healthy adults. These results were further supported by intracranial recordings, which revealed expectancy modulation of the high-frequency broadband signal from electrodes in OFC and LPFC, with an earlier latency of activity modulation for the OFC and a later one for the LPFC. Altogether, the complementary approach from behavioral, intracerebral EEG, scalp EEG, and causal lesion data provides compelling evidence for the distinct engagement of the two prefrontal areas in predicting future events and signaling deviations.

Current findings of orbitofrontal cortex (OFC) function suggest that this region might have a role in the generation of prediction error signals associated with top-down expectation of upcoming stimuli. We investigated the impact of lesions to the OFC on the Contingent Negative Variation (CNV), an electrophysiological marker of cognitive expectation and time perception. Twelve OFC patients and fifteen healthy controls performed an auditory local-global paradigm while brain electrical activity was recorded. The structural regularities of the tones were controlled at two hierarchical levels by rules defined at a local (i.e., between tones within sequences) level with a short timescale and at a global (i.e., between sequences) level with a longer timescale. At the global level, deviant tone sequences were interspersed among standard tone sequences in a pseudorandom order, rendering some deviant sequences more anticipated than others. We found that healthy controls exhibited CNV build-up before the occurrence of deviant sequences. The CNV drift rate was modulated by the expectancy of deviant sequences (i.e., the higher the expectancy, the higher the CNV drift rate), reflecting their ability to anticipate when a deviant tone sequence would occur. However, patients with OFC lesions did not show CNV drift modulations by the expectancy of the deviant tone sequences, indicating impaired anticipation of these upcoming events. These findings suggest involvement of the OFC in generating auditory expectations based on the contextual and temporal structure of the task.

In this study, we tested the causal involvement of the OFC in noticing breaches of predictions (i.e., PEs) at different hierarchical levels of task structural complexity. With this aim, we examined the event-related potentials (ERPs) of patients with focal OFC lesions and healthy adults while performing an auditory local-global oddball paradigm. Altogether, we found that after OFC damage, low-level PEs (i.e., processing of stimuli that are unpredicted at the local level) and combined low- and high-level PEs (i.e., processing of stimuli that are unpredicted at both the local and global level) were impacted. However, the processing of standard tones was not affected. We conclude that the OFC may contribute to a top-down process that modulates the deviance detection system in the primary auditory cortices, and may be involved in connecting PEs at lower hierarchical areas with predictions at higher areas. The study sheds new light on the poorly explored deficits of hierarchical auditory prediction in patients with damaged OFC.