The potential utility of evoked potentials in the treatment of mental illnesses

The “Decade of the Brain” referred to the 1990s, as the emergence of various brain imaging techniques allowed the analysis of both normal and pathological behaviors with specific patterns of distributed neural activity (Insel and Quirion, 2005). Among these techniques, electroencephalography (EEG) indexed spontaneous brain electrical activity, and included event-related potentials (ERPs), referring to epochs of EEG activity that are time-locked to the processing of stimuli (Rugg and Coles, 1995). Once mental diseases were also envisaged as resulting from brain alterations (Price et al., 2000), a neurocognitive approach emerged, promoting that: (i) significant cognitive disturbances are observed in psychiatric diseases (Green, 2006); (ii) these cognitive disturbances, indexed by dysfunctional neural networks, may trigger/subtend the onset and/or maintenance of clinical symptoms, thereby defining valid therapeutic targets (Verdejo-Garcia et al., 2023); and (iii) rehabilitating these cognitive functions (through neuropsychological training programs and/or neuromodulation tools) disclosed encouraging results by promoting reduction of clinical symptoms as well as enhancement of patients’ quality of life (Lesniak et al., 2014). In this view, ERPs, considered a useful tool to probe the information processing stream in the brain, can help pinpoint the specific neurocognitive functions that should be targeted in each patient through specific and individualized cognitive remediation procedures (Campanella, 2016). Obviously, even if we choose to focus this perspective paper on cognitive ERPs, several other electrophysiological tools (such as transcranial magnetic stimulation or neural oscillations) have proved to be useful for studying neurophysiological biomarkers of psychiatric disorders (Cao et al., 2021; Ferrarelli and Phillips, 2021).

Focusing on cognitive ERPs was triggered by the current idea that it is important to evaluate which cognitive dysfunction(s) may subtend the onset and/or maintenance of a clinical symptom to be able to rehabilitate (them) and to reduce the severity of this clinical symptom. Indeed, empirical evidence indicates that (i) some cognitive ERP markers can predict the clinical trajectory of psychiatric patients (Dousset et al., 2022; Kim et al., 2023); and (ii) cognitive training programs combined with neuromodulation tools can induce specific neural changes (Campanella et al., 2017; Schroder et al., 2020; Dousset et al., 2021) and promote clinical symptom reduction (Monnart et al., 2019; Dubuson et al., 2021). The most interesting part of such findings was to suggest that cognitive disturbances are closely linked to the onset and maintenance of clinical symptoms (e.g. altered inhibitory skill can favor negative intrusive thoughts in depressive disorders as well as a relapse in alcohol dependence; Monnart et al., 2016; Petit et al., 2014), or that various ERP parameters, i.e. the oddball P300 and the No-Go P300 components (ERP waveforms classically recorded thanks to the oddball and the Go/No-go tasks), could predict abstinence vs. relapse at 3 months in recently detoxified alcoholic patients (Campanella et al., 2020).

Indexing cognitive alterations could of course be done through neuropsychological testing, but this is too time consuming in psychiatric settings. Cognitive ERPs may then be used to quickly target main cognitive restrictions. However, despite being non-invasive, globally available, and cost-effective, and showing decades of research with recent encouraging results, the clinical utility of ERPs in psychiatry is still poor. A theoretically grounded framework to concretely apply ERPs in psychiatric care units has been proposed (Campanella, 2021). Currently, clinical symptoms are at the first plan to drive psychiatric evaluations, and the clinical trajectory is monitored by clinical interviews. However, reaching a diagnostic does not usually include the use of biomarkers (Casey et al., 2013). Once the idea that disturbed brain networks also subtend psychiatric diseases was admitted, a further assumption was to acknowledge that these neural alterations should be reflected in long-lasting neural modifications to trigger enduring real-world behavioral changes (Vinogradov et al., 2012). Therefore, we promoted test–retest ERP sessions at the individual level to favor “individualized” or “personalized” medicine (Campanella et al., 2019). Indeed, ERP markers may help (i) to monitor the spontaneous and/or treatment-related evolution of the specific neurocognitive processes that triggered the onset and persistence of all clinical symptoms observed in singular patients; and (ii) to evaluate whether these brain modifications triggered by the treatment can predict the clinical evolution of the patient (Fig. 1). Two recent ERP case reports showed, for instance, a perfect congruency between the clinical and the neurophysiological evolution (indexed through the P300 component) of a psychotic patient (Kajosch et al., 2020), and that cognitive ERPs may be used as relevant indicators of cognitive vulnerabilities in individual patients (Ingels et al., 2022).

Figure 1:

Illustration of ERP screening on an individual patient through test–retest sessions to orient neurocognitive rehabilitation.

To reach this aim, three main directions have been proposed (Campanella, 2021): (i) the definition of clear and applicable multi-site guidelines to validate an unambiguous set of normative data; (ii) the promotion of a multi-component ERP approach; and (iii) the development of ERP serial recordings.

First, at the methodological level, the worldwide current ERP literature is represented by a huge number of ERP studies reporting several conflicting results, mainly due to technical variations (Hajcak et al., 2019). Such variability in reported data has of course generated a lot of scepticism among clinicians as it raises questions regarding reliability. At the clinical level, technical guidelines already exist for some main ERPs (e.g. the P300, Duncan et al., 2009); however, their use is still by no means widespread throughout the world, and this could sometimes lead to some misunderstanding of the data (Campanella and Colin, 2014). Developing such normative technical guides adopted by the whole field would clearly help with clinical implementation. In this way, we would guarantee access to normative data recorded from large samples using similar procedures so as to index the progression of patients’ scores as a function of the treatment, but also ensuring that the impact of some potential confounding variables (sex, age, drug, or comorbidity for instance) was controlled for.

Second, a main advantage of ERPs is to present a high degree of sensitivity combined with some predictive power. However, it suffers from poor specificity (Pogarell, 2007). Accordingly, it could be argued that a “multivariate endophenotype,” mainly based on a weighted mixture of various ERP components (P50, P300, and mismatch negativity), may help to furnish a reliable diagnostic more accurately than any single component (Price et al., 2006). Further ERP recordings should then use a multi-component approach to potentially increase the sensitivity and/or specificity of ERP studies by decreasing the impact of group heterogeneity. This could also allow a better specification of the individual cognitive process(es) that should be reeducated in a singular patient.

Third, ERPs represented a well-suited tool for using serial recordings in follow-up studies to index neural modifications induced by a specific treatment (Pogarell et al., 2007). Indeed, if there are differences in waveshape, size, and timing of ERPs between individuals, ERPs have disclosed high stability within an individual due to a high internal consistency and a high test–retest reliability (Kappenman et al., 2017). Consequently, as ERPs can be recorded many times from the same individual with high reliability, session-related changes reported in brain activity should result from treatment intervention or disease evolution in a singular patient (Kappenman and Luck, 2016). Overall, by fostering a multi-component follow-up approach, ERPs may be used to monitor and/or predict specific modifications in brain function in response to therapy (e.g. psycho-social support, medication) as well as to index specific remaining cognitive alterations. In this way, clinicians may promote adapted individual interventions that will be tailored to the specific needs of an individual patient, thus providing a “personalized” medicine.

Author contributions

Salvatore Campanella (Conceptualization, Writing – original draft, Writing – review & editing)

Conflicts of interest

None declared.