Obsessive-compulsive disorder (OCD) affects approximately 2–3% of people at some point of their life (1). In the Diagnostic and Statistical Manual of Mental Disorders— Fifth Edition (2), OCD was moved from the group of anxiety disorders to a new category, named Obsessive-Compulsive and Related Disorders (1). Obsessive-compulsive disorder usually first appears during adolescence or in early adults, although treatment may not be sought until the middle age. The two sexes are equally affected. The onset of OCD is typically gradual and cannot be accurately dated, although, in some cases, it is triggered by a particular event in the patient's life. In most instances, OCD is engrafted into a personality in which rigidity and lack of adaptability are prominent. These traits are manifest in the individual's punctuality and in his/her dependability in the activities of everyday life. Additionally, there is always a prevailing undercurrent sense of insecurity (3–6). Clinically, the main symptoms of OCD are intrusive thoughts or images (obsessions), which increase anxiety, and repetitive and ritualistic actions (compulsions), which typically decrease anxiety (7, 8). In all of these obsessions and compulsions, patients suffer from a feeling of insufficiency in being unable to reject their troublesome thoughts (7, 8). This insight into the psychopathological experience and the struggle against it distinguish obsessions from delusions. Therefore, the majority of OCD patients are tense, irritable, and apprehensive. They may complain of anxiety attacks and become depressed with fatigue and lack of interest (7, 8). Education and pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) are first-line treatments, along with behavior therapy (7).

Neuropsychological studies indicate that patients with OCD may present some cognitive changes mainly involving executive functioning, information coding, organization strategy, set-shifting, motor and cognitive inhibition, visual-constructive and controlled fluency, verbal memory, and processing speed (9–11). Because of its neurobiological features, OCD may be included within the wide spectrum of dysfunctions of the frontal lobes and their connections with the limbic system, the associative cortex, and the basal ganglia which, in turn, influence the ability of abstract decisions needed to create more efficient and controlled behavioral judgment or action (12). In a previous study of patients who developed elements of obsessiveness and compulsive behavior after focal brain lesions, the authors found changes in the cingulate, frontal, and temporal cortices, as well as in the basal ganglia (13). On the other hand, the surgical disconnection of the orbito-frontal regions from limbic, thalamic, and striatal structures in severely affected patients improves symptoms of OCD (14). Moreover, neuroimaging studies in OCD demonstrate the involvement of the cortico-striato-thalamo-cortical loop, anterior cingulate cortex, prefrontal cortex, cerebellum, and hippocampus (15–18).

Based on this theoretical background, in this review we aimed to assess the utility of the P300 in the identification of any central nervous system (CNS) alteration, possibly correlated with cognitive dysfunction, in OCD patients. In particular, we focused on the electrophysiological correlates of some behaviors of individuals with OCD, such as the tendency of these patients to become aroused and exhibit strong defensive reactions to minimal stimulation (19, 20). Another aim was to assess the possible contribution of the P300 to the characterization of different OCD expressions, e.g., structural vs. functional brain abnormalities, within the clinical spectrum of a disease with a likely multifactorial basis.

As known, P300 is a positive component of the human event-related potential (ERP). It is associated with processes of encoding, identification, and categorization, that constitute, as a whole, the superior cortical function of information processing, and it is influenced by the effects of natural (i.e., circadian, ultradian, seasonal) and environmental state variables, such as fatigue (21–25). P300 is generated along a widely distributed network, rather than by a specific region, including the hippocampus and the medial temporal lobe, the temporo-parietal junction, and parietal areas, although the inferior and middle frontal, the orbito-frontal, and the cingulate cortices also contribute to it (26). For this reason, P300 involves several areas that seem to be implicated in the OCD pathophysiology (12–18).

P300 is most commonly elicited with an oddball paradigm in which a subject detects an occasional target stimulus within a regular train of standard stimuli (23, 25). Another paradigm to elicit P300 is the so-called “Go/No-Go” task, in which subjects are required to respond to one of the choices but must withhold a response to the other alternative (27). The test is passed only when the “Go” condition is met and the “No-Go” condition fails (25, 27). In psychophysiology, Go/No-Go tests are used to measure the participant's capacity to sustain attention and to control responses during the electroencephalographic (EEG) recording and the acquisition of ERP waves for each answer (25, 27, 28). For instance, a “Go/No-Go” test can require a participant to perform an action given certain stimuli (e.g., press a button: “Go”) and to inhibit the same action under a different set of stimuli (e.g., not press the same button: “No-Go”) (25, 27).

P300, also referred to as P3b, is better recorded with a maximum peak over the Pz scalp location (according to the EEG international 10–20 system) if the subject is actively engaged in the task of detecting the target (25, 29). Otherwise, a distractor tone (novelty) usually elicits a P3a wave, that has a frontal/central maximum amplitude distribution and frontal sources (30, 31). The P3b amplitude is a function of some psychological variables, such as attention, expectation of the event, and attribution to the event of a significance and complexity of the task (22, 23). Wave latency provides an indirect measure of the duration of the processes involved in stimulus discrimination, and ranges approximately from 300 ms (for simple dual tone discrimination tasks) to 750 ms (for much more complex processes) (22).

The P300 has already been applied in depicting, better than neuropsychological tests, even subtle cognitive deficits in some neuropsychiatric diseases, both in adults and children, such as sporadic amyotrophic lateral sclerosis without dementia, narcolepsy, obstructive sleep apnoea syndrome, and migraine (32–36). Evoked potentials occurring after stimulus presentation and preceding (e.g., P100, N100, P200, N200) or following (slow wave) the P300 wave are all components reflecting the time course of task-related neural information-processing (25, 37–40). In detail, N200 is elicited by both expected and ignored rare stimuli; it is followed by P300 when the subject is engaged in a particular stimulus of recognition (40). N200 seems to be an automatic process independent of control; it is similar to P300 in terms of sensitivity to attention and stimulus infrequency, and its latency correlates with reaction time (37). Finally, it is worth reminding that P300 is not seen in the raw EEG recording and can only be detected by averaging (41).

In summary, P300 seems to be a tool to investigate possible and different information processing changes in patients with OCD. The number of studies published on this topic deserves a timely re-examination of the available literature. The conclusion arising from this review may lead to further insights into the research agenda of OCD and, translationally, into clinical applications in other psychiatric and neuropsychiatric disorders, in terms of diagnostic work-up, follow-up assessment, and pharmacological and/or behavioral treatment index of response.

This review included all relevant original articles published in peer-reviewed journals, indexed in the National Institutes of Health—National Library of Medicine (PubMed) literature search system, from database inception to July 2021. Search terms were “obsessive-compulsive disorder” and “P300.” The main inclusion criterion required that all the original research articles measured the P300 wave in humans; conversely, all the studies that did not explicitly report data concerning the evaluation of P300 in OCD were excluded. Non-English written articles, book chapters, monographs, commentaries, reviews, case studies, dissertations, abstracts, and letters to editor were also excluded, as well as any other article that did not fit the primary goal of the present review. Titles and abstracts of the retrieved studies were independently reviewed by two authors (G.L. and R.F.) based on the inclusion and exclusion criteria. Additional articles in the reference list of the papers identified by the search were also evaluated for inclusion in the review.

The PubMed-based search originally produced a group of 34 studies. Three of them were excluded because they were not written in English; another article was excluded because it was a review. Five additional papers were retrieved from the reference list of the selected articles. Therefore, a final group of 35 studies (summarized in Table 1) investigating P300 in patients with OCD was included in this review (19, 20, 28, 42–73). Figure 1 shows the flow of information through the different phases of the review process.

Since the studies eventually included in this review deal with different aspects and methods, we will analyze their content in the following separate paragraphs.

This review included 35 studies with different paradigms (e.g., classical visual or auditory oddball, novelty, Go/No-Go), which have different recording modes (from only a few to 256 electrodes) and several objectives (e.g., localization of dysfunctional brain areas and treatment response) in adults, adolescents, and children. This heterogeneity did not allow us to perform any meta-analytic calculation, although the most relevant findings about P300 in OCD have been addressed in this review and summarized in Table 2.

Neuroimaging-based multimodal approaches have led to the conclusion that subtle brain structural changes and functional abnormality are present in OCD (15, 17, 18), with PET studies showing hypermetabolism in the orbital frontal cortex of these patients (85, 97). In the context of structural changes in OCD, the value of a decreased amplitude of P300 becomes evident, as reported by several studies (28, 45, 51, 54, 55, 64–68, 70, 72), similarly to those performed in schizophrenia (77). The finding of attenuated P300 amplitude has also been considered to be a pattern of genetic endophenotype in OCD (75, 76), which has also been confirmed in pediatric studies (64, 68, 70). Moreover, it was found to correlate with illness severity, suggesting that the reduction in P300 amplitude may be a sensitive tool for measuring some biological aspects of OCD severity (64, 68), also based on the evidence that P300 is generated along a widely distributed network that includes several brain areas implicated in the pathophysiology of OCD (12–18, 26). Of note, one study in schizo-OCD patients showed a pattern of alteration, i.e., a reduced P300 amplitude as in schizophrenia (60), which suggests the occurrence of brain structural abnormalities also in this peculiar clinical psychosis with relevant obsessional symptoms (88–90).

Nevertheless, there are also studies, depending on the type of paradigm used but suggesting the possible existence of different expressions of OCD within its clinical spectrum, reporting enhanced P300 amplitude in patients with OCD, compared to healthy controls (50, 52, 58, 61–63, 66, 69). Most of these studies considered this result as the electrophysiological correlate of an OCD trait consisting in a special tendency to get aroused (50, 77). Notably, only one of these studies (69) revealed that there was a weak relationship between ERP abnormalities and symptoms severity in OCD; more specifically, the authors reported only a weak correlation between compulsion estimation and the P300 valence effect (69). Based on the enhanced P300 amplitude, a pattern of cortical hyperarousal and over-focused attention in OCD has been hypothesized (19, 20, 42–44, 46–50), as also supported by the findings on processing negativity, which were interpreted as an indication of the existence of a hyperactivation of the frontal cortical mechanisms (12, 16, 19, 20, 85).

The decreased N200 latency in OCD (19, 42–44, 47, 48) and P300 (20, 42–44, 47–49, 52, 55) further emphasizes the concept of dysfunctional speed of information processing, possibly leading to some clinical features, such as intrusive thoughts that increase anxiety. The loss of normal inhibitory processes (28, 53, 57, 65, 73) would then serve as a basic source for the initiation of compulsion, with the to decrease anxiety.

The pattern of different amplitude seems to suggest the presence of different expressions (structural abnormalities vs. brain dysfunction) within the clinical spectrum of OCD. For instance, patients with a severe symptomatology can be seen (64, 68), including those with schizo-OCD (60), as belonging to the first group (structural abnormalities), whose abnormalities mainly concern the frontal brain areas (85, 97). The dysfunction of the frontal lobes has been implicated in OCD (12, 85). Flor-Henry suggested that OCD may be secondary to a prominent frontal lobe dysfunction, along with a loss of the physiological inhibitory processes (98). Other studies confirmed the involvement of the cortico-striato-thalamo-cortical loop, the anterior cingulate cortex, and the prefrontal cortex in OCD (9–18, 85, 97). However, frontal damage or dysfunction has been found in a number of psychiatric disorders in addition to OCD, and particularly schizophrenia. Some neuroimaging studies indicate that OCD symptoms are associated with altered activity in the orbito-frontal cortex (12, 99, 100), being this finding likely due to the dominant role of the frontal lobe in executive functioning and self-regulatory behaviors (12, 100, 101), which are both altered in several psychiatric illnesses. Therefore, the frontal abnormality may reflect a final common pathway for abnormal behavior (12, 28). Alternatively, different disorders may result from the dysfunction of different frontal subsystems (12, 28). For instance, the dorsolateral frontal region has been found to be impaired in schizophrenia, whereas the orbito-frontal areas have been implicated in OCD (12, 102).

Nevertheless, the above-mentioned features may not fully explain the inconsistency between the enhanced and reduced P300 in OCD, thus making the interpretation of these results challenging. Furthrmore, the fact that several data have been published by the same research group needs be taken into account (64, 67, 68, 70). However, it should be noted that most OCD individuals show a peculiar propensity to get aroused and typically exhibit strong defensive reactions even to minimal stimulation (19, 20, 42–46, 48, 50, 55, 71, 72). Translationally, these are the patients who can benefit from a targeted cognitive-behavioral rehabilitation, associated with drug therapy. On the contrary, pediatric subjects, schizo-OCD patients, and severe OCD cases frequently show low-amplitude P300 (28, 45, 51, 54, 55, 64, 65, 67, 68, 70, 72), a finding in line with the brain imaging data reported by different authors (15–18). Based on the P300 parameters, follow-up studies after drug and rehabilitation therapy are warranted in order to gain further insights on the disease severity and the possibility of clinical and cognitive improvement (64, 103). In this scenario, it is worth to highlight that Morault et al. (49) have already suggested that some pre-treatment features of ERPs might be associated with a more favorable outcome after treatment.

The laterality pattern, i.e., left<right, proposed by Flor-Henry (85), was partially confirmed by some N200/P300 studies and topographic mapping in OCD (20, 42, 44, 47, 49, 62, 65), whereas the partial recovery of P300 changes, in parallel with the clinical improvement (47, 49, 51, 62, 67, 68), seems to be mainly attributable to the effect of serotonin on ERP amplitude (68).

Regarding the effect of treatment, only one study (67) used psychotherapy combined with drugs. In this context, two studies have provided useful psychophysiological profiles in individuals with OCD with clinical and pharmacological implications, thus suggesting that the outcome of cognitive-behavioral therapy (CBT) combined to SSRI should be studied along with ERPs (47, 49). In addition, there were also a few reports of P300 amplitude with partial recovery after adequate pharmacological treatment (51, 67, 68, 70).

Notwithstanding the limitations of the studies and their heterogeneous methodology, the findings reviewed here seem to support that the different P300 patterns observed might suggest the presence of different expressions (structural vs. functional brain abnormalities) within the clinical spectrum of OCD. Event-related potentials may also be used as a treatment monitoring marker at the individual level, especially for both pharmacological treatment and/or CBT (104). In particular, the development of novel P3a paradigms in combination with P3b tasks seems to be promising for a more extensive application and reliability of ERPs (103). Moreover, similarly to patients with migraine, who can be re-tested during treatment and follow-up in order to detect an improvement of P300 habituation (35), also OCD patients might be serially evaluated over time to identify any possible change in their neurophysiological correlates of cortical hyperarousal, over-focused attention, and response inhibition. The same holds true for children and adolescents with decreased P300 amplitude at baseline, who might be re-evaluated during or after treatment in order to assess whether P300 changes reflect pharmacological and/or psychotherapeutic effects (67, 68).

Nevertheless, the majority of the articles reviewed here included very small cohorts of patients, thus emphasizing again the importance of objective evaluations in neuropsychiatric and psychological disorders, as well as the need for a systematic examination and the application of standardized procedures to obtain more realiable guidelines in the near future. For instance, it would be intriguing to apply the three-oddball paradigm (31) to record N100, MMN, and P3a with the same conscruct. Their abnormality would suggest a frontal dysfunction and might help the differentiation between OCD individuals, severe cases, and schizo-OCD. Other studies may deal with the lack of P300 habituation by using two or three blocks of stimuli, as already done in patients with migraine (35, 105). Finally, further data using multidimensional measurement techniques (e.g., behavioral, electrophysiological, structural, metabolic) will be also necessary before the relationship between brain (mainly frontal) dysfunction and OCD psychopathology can be conclusively clarified.

AR, GL, and RF designed research, performed literature review, analyzed data, wrote the paper, and revised the text. All authors contributed to this manuscript and agree with its content.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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