Functional Magnetic Resonance Imaging Study of Inhibitory Control in Bipolar Disorder and Major Depressive Disorder

Neurofunctional Characterization of Inhibitory Control in Bipolar Disorder and Major Depressive Disorder

Bipolar disorder and unipolar depressive disorder are two chronic mood disorders associated with a significant social impact, even during euthymic phases. Their differential diagnosis remains complex, particularly when bipolar disorder begins with a depressive episode. Identifying distinctive markers between these pathologies therefore represents a major clinical and economic challenge, as appropriate mood-stabilizing treatment can reduce healthcare costs and improve patients' functional outcomes.

Among potential biomarkers, executive functions-and more specifically inhibition-have received particular attention. Inhibitory deficits are observed in both disorders, including during euthymic states, and also among first-degree relatives, suggesting their potential as cognitive and cerebral endophenotypes. These deficits may help explain the difficulties in emotion regulation and impulsivity frequently observed in mood disorders.

Two components of inhibition are distinguished:

1. Behavioral inhibition, which refers to the ability to stop an ongoing response.
2. Interference control, which refers to the ability to resist distraction. These processes rely on partially distinct neural networks and operate at different stages of information processing. The few studies comparing these two components in bipolar disorder have shown contradictory results, and neuroimaging investigations have only partially explored these mechanisms, particularly their emotional dimension. It is, however, well established that patients with bipolar or depressive disorders show greater difficulties in executive tasks involving emotional stimuli than in purely cognitive tasks.

The study is expected to reveal:

• Differences in brain activation between euthymic bipolar and unipolar depressive patients in regions involved in inhibitory control, modulated by the emotional content of the task.
• Distinct cognitive performance profiles according to pathology, reflecting specific alterations in inhibitory and interference processes.

These findings should provide a better understanding of the differential neurocognitive bases of mood disorders. Identifying specific cognitive and neural profiles could contribute to more accurate differential diagnosis and to the personalization of therapeutic interventions, particularly through cognitive remediation strategies targeting executive and emotional deficits.

Bipolar disorder (BD) and unipolar depressive disorder (UDD) are chronic mood disorders that cause significant functional and social impairment, even during euthymic phases. The differential diagnosis between these two conditions remains challenging, especially when bipolar disorder initially manifests with a depressive episode, the most frequent onset pattern. Identifying reliable biomarkers that distinguish BD from UDD is therefore a major clinical and scientific objective. Early and appropriate introduction of mood-stabilizing treatments is associated with improved long-term outcomes and reduced healthcare costs through fewer hospitalizations.

Scientific Background and Rationale:

Executive dysfunctions, particularly inhibitory control deficits, have been consistently observed in both BD and UDD, including during remission. Similar deficits in first-degree relatives suggest that these alterations could represent cognitive or neural endophenotypes. Inhibition, defined as the ability to suppress a dominant or prepotent response, plays a central role in emotion regulation.

Inhibitory control can be divided into two complementary components:

1. Behavioral inhibition, the ability to suppress or stop a prepotent motor response.
2. Interference control, the ability to resist irrelevant or distracting information that interferes with ongoing cognitive processing.

Neuroimaging studies in healthy populations have revealed distinct but overlapping neural networks underlying these two processes. However, data on BD and UDD remain limited and sometimes inconsistent, particularly regarding the differential involvement of these two components and their modulation by emotional context.

Objectives:

The primary objective of this study is to investigate, using functional magnetic resonance imaging (fMRI), the brain circuits underlying the two mechanisms of inhibitory control - behavioral inhibition and interference control - in both their cognitive and emotional components, among euthymic patients with BD or UDD, compared with matched healthy controls.

Secondary objectives include:

• Comparing cognitive performance between groups.
• Exploring associations between cognitive performance, clinical characteristics (e.g., age at onset, number of episodes, symptom severity), and brain activation profiles.

Study Design:

This is a monocentric, prospective, cross-sectional study including four participant groups: patients with BD, patients with UDD, and their respective matched control groups. Each participant will complete three study visits:

• Visit 1 (V1): Clinical assessment and inclusion. Participants will provide informed consent and undergo a standardized diagnostic evaluation (DSM-5 criteria), assessment of current mood symptoms, and collection of sociodemographic and clinical data.
• Visit 2 (V2): Neuropsychological testing. A standardized battery will assess executive functions, including inhibition, interference control, cognitive flexibility, working memory, and processing speed.
• Visit 3 (V3): MRI acquisition. Participants will undergo both structural (T1-weighted) and functional (BOLD) MRI scans while performing two experimental tasks targeting inhibitory control.

Experimental Paradigms and Imaging Procedures:

Two validated cognitive paradigms will be used:

• Behavioral inhibition task (Stop-Signal task): assesses the ability to inhibit prepotent motor responses. Emotional and neutral stimuli will be randomly presented to explore emotional modulation of inhibitory processes.
• Interference control task (Flanker task): assesses the ability to resist interference from cognitive or emotional distractors, isolating attentional control mechanisms.

MRI data will be acquired using a 3-Tesla scanner. Functional sequences will use gradient-echo echo-planar imaging optimized for BOLD contrast, with a temporal resolution of approximately 2 seconds and a spatial resolution of ~3 mm isotropic. High-resolution T1-weighted anatomical images (1 mm isotropic) will be acquired for normalization and morphometric analysis.

Data Analysis:

Preprocessing and statistical analyses will be performed using standard neuroimaging software. Data will undergo motion correction, spatial normalization to MNI space, and Gaussian smoothing.

First-level analyses will be conducted using a general linear model to model activation for cognitive and emotional conditions.

Second-level (group) analyses will use hierarchical mixed-effects models to identify between-group differences in neural activation patterns (BD vs. UDD vs. controls). Correlation analyses will explore relationships between brain activation, cognitive performance, and clinical variables.

Statistical significance will be set at p < 0.05 family-wise error corrected for multiple comparisons, and p < 0.001 uncorrected for exploratory analyses.

Innovation and Expected Outcomes:

This study is among the first to jointly investigate behavioral and interference components of inhibitory control in both cognitive and emotional domains in euthymic BD and UDD patients. The combination of neuropsychological and fMRI approaches will:

• Characterize specific activation patterns underlying inhibitory control deficits.
• Identify potential cognitive and neural endophenotypes distinguishing BD from UDD.
• Clarify the influence of emotional context on inhibitory processing.
• Explore correlations between clinical, cognitive, and neurofunctional data. These findings are expected to improve understanding of the differential pathophysiology of mood disorders, contribute to the development of objective diagnostic biomarkers, and guide targeted therapeutic interventions (e.g., cognitive remediation, emotion regulation strategies).

Group 1 and 2: Bipolar patients, Depressive patients

Inclusion criteria:

• Patients between 18 and 65 years old, men or women, right-handed
• Having a diagnosis of bipolar disorder or depressive disorder
• No substantial change in treatment for 2 weeks preceding study enrollment
• Being a native French speaker
• Patients enrolled in the national healthcare insurance program
• Consenting to participate to the study

Exclusion criteria:

• The presence of any alcohol use disorder or any other substance use disorder in the last six months, except for tobacco dependence
• A significant general medical illness, including neurological disorders or head trauma
• Contraindication to the use of MRI
• A sensorial impairment uncorrected (visual and/or hearing)

Group 3 and 4: Healthy control participants

Inclusion criteria:

• Participants between 18 and 65 years old, men or women, right-handed
• Being a native French speaker
• Patients enrolled in the national healthcare insurance program
• Consenting to participate to the study

Exclusion criteria:

• A diagnosis of schizophrenia or of bipolar disorder or of major depressive disorder according to DSM-5 criteria
• The presence of any alcohol use disorder or any other substance use disorder in the last six months, except for tobacco dependence
• Participants having one first-degree relative presenting an bipolar disorder or depressive disorder or schizophrenia according to DSM-5 criteria
• A significant general medical illness, including neurological disorders or head trauma
• Contraindication to the use of MRI
• A sensorial impairment uncorrected (visual and/or hearing)