"Actor-critic" dichotomous hyperactivation and hypoconnectivity in obsessive-compulsive disorder

Abstract

Dysfunctional response inhibition, mediated by the striatum and its connections, is thought to underly the clinical manifestations of obsessive-compulsive disorder (OCD). However, the exact neural mechanisms remain controversial. In this study, we undertook a novel approach by positing that a) inhibition is a dynamic construct inherently susceptible to numerous failures, which require error-processing, and b) the actor-critic framework of reinforcement learning can integrate neural patterns of inhibition and error-processing in OCD with their behavioural correlates. We invited nineteen adults with OCD and 21 age-matched healthy controls to perform an fMRI-adjusted stop-signal task. Then, we extracted brain activation and connectivity values regarding distinct task phases in the "actor" and "critic" regions, here corresponding to the caudate's head and dorsal putamen, and midbrain's nuclei (ventral tegmental area and substantia nigra). During response preparation phases of the inhibitory process, individuals with OCD exhibited decreased functional connectivity between the "critic" structures and frontal regions involved in cognitive and executive control. Activity analysis revealed task-related hyperactivation in the midbrain alongside error-processing-specific hyperactivation in the striatum, which was correlated with excessive behavioural slowness, also found in the clinical group. Finally, we identified a remarkable opponency between activity in the ventral tegmental area and caudate leading to direct increases and indirect decreases in symptom severity. We propose a unique "actor-critic"-based domain- and timing-dependent neural profile in OCD, reflecting "harm-avoidant" styles for response suppression, and influencing symptom severity. The dichotomy of hypoconnectivity and hyperactivation in the "critic" along with the opponent relationship between the "actor" and the "critic" in determining symptom severity suggests the implication of neural adaptation mechanisms in OCD with potential relevance for neurobiologically-driven therapies.

Keywords: Actor-critic; Caudate; Error monitoring; Inhibition; Obsessive–compulsive disorder; Putamen; Ventral tegmental area.

Graphical abstract

Fig. 1

Schematic of the stop-signal task. The task included 3 runs of 120 trials (a total of 360 trials). Within each run, the trials were presented in blocks of 20 repetitions (60 s) interleaved with a baseline/response preparation period of 25 s. Go-trials (75 %) began with a fixation dot (250 ms) followed by a go-signal, which was a white arrow either pointing to the right or left side on the screen, instructing participants to press the left or right button of the response box. Stop-trials (25 %) began with a fixation dot (250 ms) followed by the white arrow, which turned red (stop-signal) after a variable period of time (stop-signal delay), instructing the subject to withhold the response. Approximately half of the stop-trials could not be stopped, as a result of the staircase implementation. The inter-trial interval (time between the end of the previous trial and the start of the current one) was jittered between 750 and 2750 ms. ITI: inter-trial interval; jit: jittered; SSD: stop-signal delay. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Regions of interest based on the actor-critic model. Regions of interest to investigate inhibitory processes in OCD were defined in the striatum and midbrain using the intersection between our whole-brain activations related to the stop signal task and anatomical boundaries (Araújo et al., 2024, Ballard et al., 2011, Evans et al., 1992, Murty et al., 2014) of the caudate’s head (blue) and dorsal putamen (yellow) (RFX, t(39) = 7.21, P-Bonferroni = 0.003) (2A), ventral tegmental area (pink), substantia nigra (green) (RFX, t(39) = 4.22, P-FDR = 0.001) (2B). Bonferroni correction was set to the minimum threshold that allowed us to isolate these regions of interest from the larger clusters. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Mean brain activations (beta-values) in the striatum (3A) and midbrain (3B) during inhibition phases. Error bars represent the standard error of the mean. GLM analysis in the striatum revealed a group x phase interaction (Z(2,37) = 4.106, P = 0.024), which was driven by error-processing-related OCD hyperactivation in the caudate (t(38) = −3.201, P-FDR = 0.018) and putamen (t(38) = −2.928, P-FDR = 0.018) (see * symbol). In the midbrain, there was a significant group effect (Z(1,38) = 4.376, P = 0.043), resulting from the overall contribution of the ventral tegmental area and substantia nigra activations during all task phases (see * symbol). HC: healthy control group; OCD: obsessive–compulsive disorder group.

Fig. 4

Effect of the relationship between midbrain and striatal error-processing activity on OCD symptom severity. Serial multiple mediation model showing significant direct positive and indirect negative effects of the ventral tegmental area on OCD symptoms severity mediated by the caudate. Numbers represent unstandardized coefficients. Y-BOCS-2: Yale-Brown Obsessive-Compulsive Scale – Second Edition; X: predictor variable; M: mediator; Y: outcome variable; a: effect of X on Y; b: effect of M on Y; ab: indirect effect of X on Y; c’ direct effect of X on Y; CI: confidence interval.

Fig. 5

Whole-brain functional connectivity analysis when contrasting the OCD and control group and looking for differences either during response preparation or inhibition and considering the VTA as seed region. Individuals with OCD exhibited reduced connectivity between the VTA and a cluster centered in the prefrontal cortex (coordinates: x, y, z = 13, 40, 42; F(2,37) = 10.69, P-FDR = 0.0002; A), specifically during response preparation periods (t(38) = 4.542, P < 0.001; B). The colour bar represents the strength of the F-statistic when evaluating how much connectivity differs between OCD and healthy subjects either during response preparation or response inhibition periods. The differences in functional connectivity between the seed region and the rest of the brain are displayed at a voxel-level threshold of P = 0.001 and a cluster-size threshold of P-FDR = 0.05.