Noradrenaline causes a spread of association in the hippocampal cognitive map Renée S. Koolschijn, Prakriti Parthasarathy, Michael Browning, Xenia Przygodda, Liliana P. Capitão, William T. Clarke, Tim P. Vogels, Jill X. O’Reilly, Helen C. Barron Nature Communications, 2026 The mammalian brain organises knowledge about entities in the world and relationships between them using cognitive maps. When forming a cognitive map, there is a necessary trade-off between extending the map to make novel inferences, and storing a veridical copy of past experience. However, the neural mechanisms that control this trade-off remain unknown. Using a cross-scale approach that combines a pharmacological intervention in humans with neural network modelling, we show that the neuromodulator noradrenaline elicits a significant ‘spread of association’ across hippocampal cognitive maps. This neural spread of association can be explained by changes in synaptic plasticity that predict overgeneralisation in behaviour. Thus, elevated noradrenaline during learning increases the ‘smoothing kernel’ for plasticity across the cognitive map, allowing disparate memories to become linked and distorted.
Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group Chaira Serrarens, Yara J. Toenders, Elena Pozzi, André Aleman, Nina Alexander, Zeynep Başgöze, Vladimir Belov, Klaus Berger, Katharina Brosch, Robin Bülow, Geraldo Filho Busatto, Liliana P. Capitão, Colm G. Connolly, Baptiste Couvy-Duchesne, Kathryn R. Cullen, Udo Dannlowski, Christopher G. Davey, Greig I. de Zubicaray, Danai Dima, Katharina Dohm, Verena Enneking, Tracy Erwin-Grabner, Ulrika Evermann, Cynthia H. Y. Fu, Paola Fuentes-Claramonte, Beata R. Godlewska, Ali Saffet Gonul, Ian H. Gotlib, Roberto Goya-Maldonado, Hans J. Grabe, Nynke A. Groenewold, Dominik Grotegerd, Oliver Gruber, Tim Hahn, Geoffrey Hall, Ben J. Harrison, Walter Heindel, Marco Hermesdorf, Tiffany C. Ho, Naho Ichikawa, Eri Itai, Neda Jahanshad, Hamidreza Jamalabadi, Alec J. Jamieson, Andreas Jansen, Tilo Kircher, Bonnie Klimes-Dougan, Bernd Krämer, Axel Krug, Thomas M. Lancaster, Elisabeth J. Leehr, Meng Li, David E. J. Linden, Frank MacMaster, Katie L. McMahon, Sarah E. Medland, David M. A. Mehler, Susanne Meinert, Benson Mwangi, Igor Nenadić, Go Okada, Yasumasa Okamoto, Nils Opel, Julia-Katharina Pfarr, Edith Pomarol-Clotet, Maria J. Portella, Ronny Redlich, Liesbeth Reneman, Jonathan Repple, Kai Ringwald, Elena Rodriguez-Cano, Pedro G. P. Rosa, Matthew D. Sacchet, Philipp G. Sämann, Raymond Salvador, Anouk Schrantee, Hotaka Shinzato, Kang Sim, Egle Simulionyte, Jair C. Soares, Dan J. Stein, Frederike Stein, Benjamin Straube, Lachlan T. Strike, Florian Thomas-Odenthal, Sophia I. Thomopoulos, Paul M. Thompson, Marie-Jose van Tol, Paula Usemann, Aslihan Uyar, Nic van der Wee, Steven van der Werff, Yolanda Vives-Gilabert, Henry Völzke, Martin Walter, Sarah Whittle, Katharina Wittfeld, Adrian Wroblewski, Mon-Ju Wu, Tony T. Yang, Giovana B. Zunta-Soares, Dick J. Veltman, Lianne Schmaal, Laura S. van Velzen Molecular Psychiatry, 2025 The understanding of how antidepressant (AD) use is associated with brain structure in individuals with major depressive disorder (MDD) remains incomplete. We aimed to examine the association between AD medication use and brain morphology in relation to age and sex by pooling structural neuroimaging and clinical data from 32 cohorts within the ENIGMA-MDD working group. Interaction effects of group (2076 cases with current AD use (AD), 1495 cases not currently taking AD (nAD) and 5125 healthy controls (HC)) with age and sex, and main effects of group on regional brain structure (cortical surface area and thickness, and subcortical volume) were examined. Additionally, we examined the effect of AD type (SSRI, SNRI or mirtazapine) and duration of use on brain morphology. Younger individuals in the AD group showed lower bilateral middle temporal gyrus thickness compared to nAD and HC, but this was not seen in older individuals (crossover around 50 years). Lower hippocampal volume and thinner inferior temporal gyrus were shown in AD compared to nAD. These effects were independent of group differences in disease-course-related measures, but were driven by depressive symptom severity. Greater bilateral rostral anterior cingulate thickness was found in individuals older than approximately 40 years taking mirtazapine compared to individuals taking SSRIs or SNRIs. Evidence for subtle structural brain differences in temporal and limbic regions in individuals with MDD who currently use AD medication were found compared to those not currently taking AD medication. Future longitudinal studies are needed to determine the causality of these associations.
Baclofen, a GABAb receptor agonist, impairs motor learning in healthy people and changes inhibitory dynamics in motor areas Ioana-Florentina Grigoras, Elias Geist, Ainslie Johnstone, William T. Clarke, Uzay Emir, Caroline Nettekoven, Jacob M. Levenstein, Liliana Capitao, Charlotte J. Stagg Imaging Neuroscience, 2025 Inhibition mediated by γ-aminobutyric acid (GABA) is implicated in motor plasticity and learning, with [GABA] in the motor cortex decreasing during motor learning. However, the causal relationship between [GABA] and learning has yet to be determined. Here, we conducted a within-subject, double-blind, placebo-controlled, crossover study to investigate the effect of increased GABAergic inhibition via GABAB-receptor agonist baclofen on motor learning and Magnetic Resonance Spectroscopic Imaging (MRSI) metrics. Increasing GABA-mediated inhibition with baclofen did not change response times, but significantly impaired motor sequence learning. In parallel, we demonstrated a blunting of the expected decrease in [GABA] during motor learning. These results highlight a causal role for GABAergic inhibition in motor learning and may have clinical implications: baclofen is commonly used to treat post brain-injury spasticity, but may impair motor learning during rehabilitation.
Angiotensin receptor blockade modulates resting state functional connectivity in the memory network rather than fear network – implications for posttraumatic stress disorder Lorika Shkreli, Caroline Nettekoven, Sirius Boessenkool, Marieke Martens, Nicola Filippini, Liliana Capitão, Phil Cowen, Andrea Reinecke Psychiatry Research, 2025 • Angiotensin-II receptor blockers (ARBs) are linked to reduced PTSD symptoms in population studies. • PTSD is marked by altered brain connectivity in networks for fear processing and memory formation. • The ARB losartan altered functional connectivity in the memory network, but not the fear network. • Losartan decreased functional connectivity between the hippocampus and the inferior frontal gyrus, and between the parahippocampal gyrus and the dorsolateral prefrontal cortex. Population-based studies have shown that the intake of Angiotensin-II receptor blockers (ARBs), commonly used to treat high blood pressure, is associated with reduced post-traumatic stress disorder (PTSD) symptoms. However, the underlying neural mechanisms remain unclear. While PTSD development is characterized by maladaptive processing within brain networks associated with fear processing and memory formation during trauma exposure, there is increasing evidence that such aberrations manifest in altered resting state functional connectivity (rsFC) of brain regions in these networks. In this double-blind placebo-controlled study in 45 healthy volunteers with high trait-anxiety, we investigated whether the ARB losartan would affect rsFC in prominent seeds of the fear and memory network, counteracting effects seen in PTSD. Seed selection was informed by established rsFC aberrations seen in PTSD and consisted of the hippocampus and the parahippocampal gyrus (memory network), as well the amygdala and insula (fear network). Our results showed that a single dose of the ARB losartan decreased rsFC in the memory network from modulatory structures in the frontal cortex: losartan decreased rsFC (i) between the hippocampus and the inferior frontal gyrus involved in threat processing and memory intrusion development, and (ii) between the parahippocampal gyrus and the dorsolateral prefrontal cortex involved in top-down control. There were no drug effects on the fear network seeds. These findings may imply that ARB preserves adaptive memory function during trauma.
A single dose of lamotrigine induces a positive memory bias in healthy volunteers Tarek Zghoul, Pilar Artiach Hortelano, Alexander Kaltenboeck, Lucy Wright, Guy M. Goodwin, Liliana P. Capitão, Catherine J. Harmer Psychological Medicine, 2025 Background Lamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks in healthy volunteers, previously shown to be sensitive to antidepressant drug action in similar experimental designs. Methods Healthy volunteers (n = 36) were randomized in a double-blind design to receive a single dose of placebo or 300 mg lamotrigine. Mood and subjective effects were monitored throughout the study period, and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post-administration. Results Participants receiving lamotrigine showed increased accurate recall of positive versus negative self-descriptors, compared to those in the placebo group. There were no other significant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience. Conclusions Lamotrigine did not induce widespread changes in emotional processing. However, there was increased positive bias in emotional memory, similar to the effects of antidepressants reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.
“Invisible Dangers”: Unconscious processing of angry vs fearful faces and its relationship to subjective anger Anna Pelliet, Marlene Nogueira, Catarina Fagundes, Susana Capela, Fátima Saraiva, Erdem Pulcu, Catherine J. Harmer, Susannah E. Murphy, Liliana P. Capitão Consciousness and Cognition, 2025 • Suppression times for angry faces were compared to those for fearful and happy faces using CFS. • Anger broke suppression more slowly than fear but did not significantly differ from happiness. • Differences in suppression times between anger and fear correlated with higher state anger post-induction. • This study provides new insights into unconscious mechanisms underlying subjective anger. Traditional paradigms for studying the unconscious processing of threatening facial expressions face methodological limitations and have predominantly focused on fear, leaving gaps in our understanding of anger. Additionally, it is unclear how the unconscious perception of anger influences subjective anger experiences. To address this, the current study employed Continuous Flash Suppression (CFS), a robust method for studying unconscious processing, to assess suppression times for angry, fearful and happy facial expressions. Following the administration of CFS, participants underwent an anger induction paradigm, and state anger symptoms were assessed at multiple timepoints. Suppression times for angry faces were compared to those for happy and fearful faces, and their relationship with state anger symptoms post-induction was examined. Results revealed that fearful faces broke suppression significantly faster than happy faces. Anger was slower to break suppression compared to fear, but no significant differences emerged between anger and happiness. In addition, the faster emergence into awareness of fear compared to anger was linked to an increased state anger after the induction, indicating that differences in the unconscious processing of these two emotions can potentially influence symptoms of subjective anger. These findings provide new insights into how angry and fearful faces are processed unconsciously, with implications for understanding the cognitive mechanisms underlying subjective anger.
Acute neural effects of the mood stabiliser lamotrigine on emotional processing in healthy volunteers: a randomised control trial Marieke A. G. Martens, Tarek Zghoul, Evelyn Watson, Sebastian W. Rieger, Liliana P. Capitão, Catherine J. Harmer Translational Psychiatry, 2024 Lamotrigine is an effective mood stabiliser, largely used for the management and prevention of depression in bipolar disorder. The neuropsychological mechanisms by which lamotrigine acts to relieve symptoms as well as its neural effects on emotional processing remain unclear. The primary objective of this current study was to investigate the impact of an acute dose of lamotrigine on the neural response to a well-characterised fMRI task probing implicit emotional processing relevant to negative bias. 31 healthy participants were administered either a single dose of lamotrigine (300 mg, n = 14) or placebo (n = 17) in a randomized, double-blind design. Inside the 3 T MRI scanner, participants completed a covert emotional faces gender discrimination task. Brain activations showing significant group differences were identified using voxel-wise general linear model (GLM) nonparametric permutation testing, with threshold free cluster enhancement (TFCE) and a family wise error (FWE)-corrected cluster significance threshold of p < 0.05. Participants receiving lamotrigine were more accurate at identifying the gender of fearful (but not happy or angry) faces. A network of regions associated with emotional processing, including amygdala, insula, and the anterior cingulate cortex (ACC), was significantly less activated in the lamotrigine group compared to the placebo group across emotional facial expressions. A single dose of lamotrigine reduced activation in limbic areas in response to faces with both positive and negative expressions, suggesting a valence-independent effect. However, at a behavioural level lamotrigine appeared to reduce the distracting effect of fear on face discrimination. Such effects may be relevant to the mood stabilisation effects of lamotrigine.
Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy Francesca Perini, Jadwiga Maria Nazimek, Shane Mckie, Liliana P. Capitão, Jessica Scaife, Deepa Pal, Michael Browning, Gerard R. Dawson, Hiroyuki Nishikawa, Una Campbell, Seth C. Hopkins, Antony Loebel, Rebecca Elliott, Catherine J. Harmer, Bill Deakin, Kenneth S. Koblan Schizophrenia, 2023 Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist without antagonist activity at dopamine D2 or the serotonin 5-HT2A receptors, has demonstrated efficacy in the treatment of schizophrenia. Here we report the phase 1 translational studies that profiled the effect of ulotaront on brain responses to reward, working memory, and resting state connectivity (RSC) in individuals with low or high schizotypy (LS or HS). Participants were randomized to placebo (n = 32), ulotaront (50 mg; n = 30), or the D2 receptor antagonist amisulpride (400 mg; n = 34) 2 h prior to functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent (BOLD) responses to task performance. Ulotaront increased subjective drowsiness, but reaction times were impaired by less than 10% and did not correlate with BOLD responses. In the Monetary Incentive Delay task (reward processing), ulotaront significantly modulated striatal responses to incentive cues, induced medial orbitofrontal responses, and prevented insula activation seen in HS subjects. In the N-Back working memory task, ulotaront modulated BOLD signals in brain regions associated with cognitive impairment in schizophrenia. Ulotaront did not show antidepressant-like biases in an emotion processing task. HS had significantly reduced connectivity in default, salience, and executive networks compared to LS participants and both drugs reduced this difference. Although performance impairment may have weakened or contributed to the fMRI findings, the profile of ulotaront on BOLD activations elicited by reward, memory, and resting state is compatible with an indirect modulation of dopaminergic function as indicated by preclinical studies. This phase 1 study supported the subsequent clinical proof of concept trial in people with schizophrenia.Clinical trial registration: Registry# and URL: ClinicalTrials.gov NCT01972711, https://clinicaltrials.gov/ct2/show/NCT01972711
Acute neural effects of fluoxetine on emotional regulation in depressed adolescents Liliana P. Capitão, Robert Chapman, Nicola Filippini, Lucy Wright, Susannah E. Murphy, Anthony James, Philip J. Cowen, Catherine J. Harmer Psychological Medicine, 2023 BackgroundAdolescent major depressive disorder (MDD) is associated with disrupted processing of emotional stimuli and difficulties in cognitive reappraisal. Little is known however about how current pharmacotherapies act to modulate the neural mechanisms underlying these key processes. The current study therefore investigated the neural effects of fluoxetine on emotional reactivity and cognitive reappraisal in adolescent depression.MethodsThirty-one adolescents with MDD were randomised to acute fluoxetine (10 mg) or placebo. Seventeen healthy adolescents were also recruited but did not receive any treatment for ethical reasons. During functional magnetic resonance imaging (fMRI), participants viewed aversive images and were asked to either experience naturally the emotional state elicited (‘Maintain’) or to reinterpret the content of the pictures to reduce negative affect (‘Reappraise’). Significant activations were identified using whole-brain analysis.ResultsNo significant group differences were seen when comparing Reappraise and Maintain conditions. However, when compared to healthy controls, depressed adolescents on placebo showed reduced visual activation to aversive pictures irrespective of the condition. The depressed adolescent group on fluoxetine showed the opposite pattern, i.e. increased visuo-cerebellar activity in response to aversive pictures, when compared to depressed adolescents on placebo.ConclusionsThese data suggest that depression in adolescence may be associated with reduced visual processing of aversive imagery and that fluoxetine may act to reduce avoidance of such cues. This could reflect a key mechanism whereby depressed adolescents engage with negative cues previously avoided. Future research combining fMRI with eye-tracking is nonetheless needed to further clarify these effects.
Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: A randomised, double-blind, placebo-controlled study Rita Baião, Liliana P. Capitão, Cameron Higgins, Michael Browning, Catherine J. Harmer, Philip W. J. Burnet Psychological Medicine, 2023 Background The potential antidepressant properties of probiotics have been suggested, but their influence on the emotional processes that may underlie this effect is unclear. Methods Depressed volunteers (n = 71) were recruited into a randomised double-blind, placebo-controlled study to explore the effects of a daily, 4-week intake of a multispecies probiotic or placebo on emotional processing and cognition. Mood, anxiety, positive and negative affect, sleep, salivary cortisol and serum C-reactive peptide (CRP) were assessed before and after supplementation. Results Compared with placebo, probiotic intake increased accuracy at identifying faces expressing all emotions (+12%, p < 0.05, total n = 51) and vigilance to neutral faces (mean difference between groups = 12.28 ms ± 6.1, p < 0.05, total n = 51). Probiotic supplementation also reduced reward learning (−9%, p < 0.05, total n = 51), and interference word recall on the auditory verbal learning task (−18%, p < 0.05, total n = 50), but did not affect other aspects of cognitive performance. Although actigraphy revealed a significant group × night-time activity interaction, follow up analysis was not significant (p = 0.094). Supplementation did not alter salivary cortisol or circulating CRP concentrations. Probiotic intake significantly reduced (−50% from baseline, p < 0.05, n = 35) depression scores on the Patient Health Questionnaire-9, but these did not correlate with the changes in emotional processing. Conclusions The impartiality to positive and negative emotional stimuli or reward after probiotic supplementation have not been observed with conventional antidepressant therapies. Further studies are required to elucidate the significance of these changes with regard to the mood-improving action of the current probiotic.
ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing Lianne Schmaal, Elena Pozzi, Tiffany C. Ho, Laura S. van Velzen, Ilya M. Veer, Nils Opel, Eus J. W. Van Someren, Laura K. M. Han, Lybomir Aftanas, André Aleman, Bernhard T. Baune, Klaus Berger, Tessa F. Blanken, Liliana Capitão, Baptiste Couvy-Duchesne, Kathryn R. Cullen, Udo Dannlowski, Christopher Davey, Tracy Erwin-Grabner, Jennifer Evans, Thomas Frodl, Cynthia H. Y. Fu, Beata Godlewska, Ian H. Gotlib, Roberto Goya-Maldonado, Hans J. Grabe, Nynke A. Groenewold, Dominik Grotegerd, Oliver Gruber, Boris A. Gutman, Geoffrey B. Hall, Ben J. Harrison, Sean N. Hatton, Marco Hermesdorf, Ian B. Hickie, Eva Hilland, Benson Irungu, Rune Jonassen, Sinead Kelly, Tilo Kircher, Bonnie Klimes-Dougan, Axel Krug, Nils Inge Landrø, Jim Lagopoulos, Jeanne Leerssen, Meng Li, David E. J. Linden, Frank P. MacMaster, Andrew M. McIntosh, David M. A. Mehler, Igor Nenadić, Brenda W. J. H. Penninx, Maria J. Portella, Liesbeth Reneman, Miguel E. Rentería, Matthew D. Sacchet, Philipp G. Sämann, Anouk Schrantee, Kang Sim, Jair C. Soares, Dan J. Stein, Leonardo Tozzi, Nic J. A. van Der Wee, Marie-José van Tol, Robert Vermeiren, Yolanda Vives-Gilabert, Henrik Walter, Martin Walter, Heather C. Whalley, Katharina Wittfeld, Sarah Whittle, Margaret J. Wright, Tony T. Yang, Carlos Zarate, Sophia I. Thomopoulos, Neda Jahanshad, Paul M. Thompson, Dick J. Veltman Translational Psychiatry, 2020
MRI amygdala volume in Williams Syndrome Liliana Capitão, Adriana Sampaio, Cassandra Sampaio, Cristiana Vasconcelos, Montse Férnandez, Elena Garayzábal, Martha E. Shenton, Óscar F. Gonçalves Research in Developmental Disabilities, 2011
Beliefs and attitudes of profissionals about marital violence: Studies with health profissionals, policemen and teachers Acta Medica Portuguesa, 2009
RECENT SCHOLAR PUBLICATIONS
Noradrenaline causes a spread of association in the hippocampal cognitive map RS Koolschijn, P Parthasarathy, M Browning, X Przygodda, LP Capitão, ... Nature communications , 2026 2026
ARTICLE IN RS Koolschijn, P Parthasarathy, M Browning, X Przygodda, LP Capitão, ... 2026
Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group C Serrarens, YJ Toenders, E Pozzi, A Aleman, N Alexander, Z Başgöze, ... Molecular psychiatry, 1-12 , 2025 2025 Citations: 2
Baclofen, a GABAB receptor agonist, impairs motor learning in healthy people and changes inhibitory dynamics in motor areas IF Grigoras, E Geist, A Johnstone, WT Clarke, U Emir, C Nettekoven, ... Imaging Neuroscience 3, IMAG. a. 979 , 2025 2025 Citations: 1
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“Invisible Dangers”: Unconscious processing of angry vs fearful faces and its relationship to subjective anger A Pelliet, M Nogueira, C Fagundes, S Capela, F Saraiva, E Pulcu, ... Consciousness and Cognition 130, 103848 , 2025 2025 Citations: 4
Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group YJ Toenders, E Pozzi, A Aleman, Z Başgöze, K Berger, K Brosch, R Bülow, ... 2025
A single dose of lamotrigine induces a positive memory bias in healthy volunteers T Zghoul, PA Hortelano, A Kaltenboeck, L Wright, GM Goodwin, ... Psychological Medicine 55, e139 , 2025 2025
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“Invisible Dangers”: preconscious detection of fearful vs angry faces influences the subjective experience of anger A Pelliet, M Nogueira, C Fagundes, S Capela, F Saraiva, E Pulcu, ... 2024
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Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: a randomised, double-blind, placebo-controlled study R Baião, LP Capitão, C Higgins, M Browning, CJ Harmer, PWJ Burnet Psychological Medicine 53 (8), 3437-3447 , 2023 2023 Citations: 77
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ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing L Schmaal, E Pozzi, T C. Ho, LS Van Velzen, IM Veer, N Opel, ... Translational psychiatry 10 (1), 172 , 2020 2020 Citations: 264
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