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António Macedo

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3 papers

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YNICL Journal 2025 Journal Article

“Actor-critic” dichotomous hyperactivation and hypoconnectivity in obsessive–compulsive disorder

Ana Araújo
Isabel C. Duarte
Teresa Sousa
Sofia Meneses
Ana T. Pereira
Trevor Robbins
António Macedo
Miguel Castelo-Branco

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.

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YNICL Journal 2021 Journal Article

A fundamental distinction in early neural processing of implicit social interpretation in schizophrenia and bipolar disorder

Nuno Madeira
Ricardo Martins
João Valente Duarte
Gabriel Costa
António Macedo
Miguel Castelo-Branco

BACKGROUND: Social cognition impairment is a key phenomenon in serious mental disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). Although genetic and neurobiological studies have suggested common neural correlates, here we hypothesized that a fundamental dissociation of social processing occurs at an early level in these conditions. METHODS: Based on the hypothesis that key structures in the social brain, namely the temporoparietal junction, should present distinctive features in SCZ and BPD during low-level social judgment, we conducted a case-control study in SCZ (n = 20) and BPD (n = 20) patients and controls (n = 20), using task-based fMRI during a Theory of Mind (ToM) visual paradigm leading to interpretation of social meaning based on simple geometric figures. RESULTS: We found opposite neural responses in two core ToM regions: SCZ patients showed social content-related deactivation (relative to controls and BPD) of the right supramarginal gyrus, while the opposite pattern was found in BPD; reverse patterns, relative to controls and SCZ, were found in the left posterior superior temporal gyrus, a region involved in inferring other's intentions. Receiver-operating-characteristic curve analysis showed 88% accuracy in discriminating the two clinical groups based on these neural responses. CONCLUSIONS: These contrasting activation patterns of the temporoparietal junction in SCZ and BPD represent mechanistic differences of social cognitive dysfunction that may be explored as biomarkers or therapeutic targets.

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YNICL Journal 2020 Journal Article

Morphometry and gyrification in bipolar disorder and schizophrenia: A comparative MRI study

Nuno Madeira
João Valente Duarte
Ricardo Martins
Gabriel Nascimento Costa
António Macedo
Miguel Castelo-Branco

Schizophrenia is believed to be a neurodevelopmental disease with high heritability. Differential diagnosis is often challenging, especially in early phases, namely with other psychotic disorders or even mood disorders. such as bipolar disorder with psychotic symptoms. Key pathophysiological changes separating these two classical psychoses remain poorly understood, and current evidence favors a more dimensional than categorical differentiation between schizophrenia and bipolar disorder. While established biomarkers like cortical thickness and grey matter volume are heavily influenced by post-onset changes and thus provide limited possibility of accessing early pathologies, gyrification is assumed to be more specifically determined by genetic and early developmental factors. The aim of our study was to compare both classical and novel morphometric features in these two archetypal psychiatric disorders. We included 20 schizophrenia patients, 20 bipolar disorder patients and 20 age- and gender-matched healthy controls. Data analyses were performed with CAT12/SPM12 applying general linear models for four morphometric measures: gyrification and cortical thickness (surface-based morphometry), and whole-brain grey matter/grey matter volume (voxel-based morphometry - VBM). Group effects were tested using age and gender as covariates (and total intracranial volume for VBM). Voxel-based morphometry analysis revealed a schizophrenia vs. control group effect on regional grey matter volume (p < 0.05, familywise error correction) in the right globus pallidus. There was no group effect on white matter volume when correcting for multiple comparisons neither on cortical thickness. Gyrification changes in clinical samples were found in the left supramarginal gyrus (BA40) - increased and reduced gyrification, respectively, in BPD and SCZ patients - and in the right inferior frontal gyrus (BA47), with a reduction in gyrification of the SCZ group when compared with controls. The joint analysis of different morphometric features, namely measures such as gyrification, provides a promising strategy for the elucidation of distinct phenotypes in psychiatric disorders. Different morphological change patterns, highlighting specific disease trajectories, could potentially generate neuroimaging-derived biomarkers, helping to discriminate schizophrenia from bipolar disorder in early phases, such as first-episode psychosis patients.

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