Amygdala Activation Research Articles

Efficacy of MRI-guided rTMS for post-traumatic stress disorder by modulating amygdala activity: study protocol for a randomised controlled trial

IntroductionPost-traumatic stress disorder (PTSD) is a prevalent and severe psychiatric disorder. Repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex provides limited relief for symptoms of PTSD. This study...

Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

We describe the close correspondence between predatory imminence continuum theory (PICT) and the National Institute of Mental Health's Research Domain Criteria (RDoC) for negative valence. RDoC's negative valence constructs relate aversively motivated behavioral reactions to various levels of threat. PICT divides defensive responses into distinct modes that vary along a continuum of the psychological closeness of predatory threat. While there is a close correspondence between PICT modes and negative valence threat constructs, based on PICT, we describe some potential elaborations of RDoC constructs. Both have consonant views of fear and anxiety and provide explicit distinctions between these emotional states, relating them to specific defensive behaviors and functions. We describe recent data that causally implicate human subjective emotional states with amygdala activity, which is also critical for defensive behavior. We conclude that attention to neuroethological views of defense can advance our understanding of the etiology and treatment of anxiety and stress disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

S83 - Calcium Imaging of Central Amygdala Activity After Escalation of Fentanyl Self-Administration

S83 - Calcium Imaging of Central Amygdala Activity After Escalation of Fentanyl Self-Administration

Anxiety and curiosity in hierarchical models of neural emotion processing-A mini review.

Traditionally, two fundamentally different theoretical approaches have been used in emotion research to model (human) emotions: discrete emotion theories and dimensional approaches. More recent neurophysiological models like the hierarchical emotion theory suggest that both should be integrated. The aim of this review is to provide neurocognitive evidence for this perspective with a particular focus on experimental studies manipulating anxiety and/or curiosity. We searched for evidence that the neuronal correlates of discrete and dimensional emotional systems are tightly connected. Our review suggests that the ACC (anterior cingulate cortex) responds to both, anxiety, and curiosity. While amygdala activation has been primarily observed for anxiety, at least the NAcc (nucleus accumbens) responds to both, anxiety and curiosity. When these two areas closely collaborate, as indicated by strong connectivity, this may indicate emotion regulation, particularly when the situation is not predictable.

Dysfunction of Small-Conductance Ca2+-Activated Potassium (SK) Channels Drives Amygdala Hyperexcitability and Neuropathic Pain Behaviors: Involvement of Epigenetic Mechanisms.

Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we addressed the role of small-conductance Ca2+-activated potassium (SK) channels in pain-related amygdala plasticity. The facilitatory effects of the intra-CeA application of an SK channel blocker (apamin) on the pain behaviors of control rats were lost in a neuropathic pain model, whereas an SK channel activator (NS309) inhibited pain behaviors in neuropathic rats but not in sham controls, suggesting the loss of the inhibitory behavioral effects of amygdala SK channels. Brain slice electrophysiology found hyperexcitability of CeA neurons in the neuropathic pain condition due to the loss of SK channel-mediated medium afterhyperpolarization (mAHP), which was accompanied by decreased SK2 channel protein and mRNA expression, consistent with a pretranscriptional mechanisms. The underlying mechanisms involved the epigenetic silencing of the SK2 gene due to the increased DNA methylation of the CpG island of the SK2 promoter region and the change in methylated CpG sites in the CeA in neuropathic pain. This study identified the epigenetic dysregulation of SK channels in the amygdala (CeA) as a novel mechanism of neuropathic pain-related plasticity and behavior that could be targeted to control abnormally enhanced amygdala activity and chronic neuropathic pain.

Sex differences in basal motivated behavior, chronic ethanol drinking, and amygdala activity in female and male mice

Alcohol use disorder (AUD) is a major public health concern that despite its prevalence, lacks a widely-effective treatment due to the complexity of AUD pathology. AUD is highly comorbid with other psychiatric conditions including anxiety and mood disorders, however it is unclear how these disorders influence each other. The underlying etiology of these comorbidities is difficult to decipher and factors including sex, stress, and the environment further complicate both diagnosis and treatment strategies. To understand more about this bidirectional relationship between AUD and comorbid psychiatric disorders, we ran male and female C57Bl/6j mice through baseline behavioral testing followed by intermittent access-two bottle choice (IA-2BC) drinking. We found no sex differences in basal anxiety-like or depressive-like behavior, however females displayed enhanced motivated feeding behavior. Females consumed more ethanol than males, at both 1hr and 24hr timepoints. Basal affective state did not predict subsequent ethanol intake in either sex, however exploratory behavior was positively correlated with drinking in males but not females. We then re-assessed negative affect behavior following chronic ethanol drinking to determine if drinking impacted subsequent affective behavior and found no relationship between ethanol intake and affective state in males or females. We also examined how chronic ethanol drinking affected central amygdala (CeA) and basolateral amygdala (BLA) neuronal activity in males and females. Ethanol-drinking females had a decrease in CeA neuronal activity, driven by reduced activity in the lateral (CeAl) sub-region, while in males there was no significant difference in CeA activity compared to water controls. Neither males or females had a significant change in BLA neuronal activity following chronic ethanol drinking. Collectively, these results demonstrate sex differences in basal motivated behavior, drinking behavior, and subregion-specific amygdala neuronal activity following chronic ethanol drinking which may inform the sex differences seen in patients diagnosed with AUD and comorbid conditions.

Racial Discrimination and Risk for Internalizing and Externalizing Symptoms Among Black Youths

Racial discrimination is a psychosocial stressor associated with youths' risk for psychiatric symptoms. Scarce data exist on the moderating role of amygdalar activation patterns among Black youths in the US. To investigate the association between racial discrimination and risk for psychopathology moderated by neuroaffective processing. This cohort study used longitudinal self-report and functional magnetic resonance imaging (fMRI) data from Black youth participants in the US from the Adolescent Brain Cognitive Development (ABCD) study. Data were analyzed from January 2023 to May 2024. At time 1 of the current study (12 months after baseline), youths self-reported on their experiences of interpersonal racial discrimination and their feelings of marginalization. Amygdalar response was measured during an emotionally valenced task that included blocks of faces expressing either neutral or negative emotion. At 24 and 36 months after baseline, youths reported their internalizing (anxiety and depressive symptoms) and externalizing symptoms (aggression and rule-breaking symptoms). A total of 1596 youths were a mean (SD) age of 10.92 (0.63) years, and 803 were female (50.3%). Families in the study had a mean annual income range of $25 000 to $34 999. Two factors were derived from factor analysis: interpersonal racial discrimination and feelings of marginalization (FoM). Using structural equation modeling in a linear regression, standardized β coefficients were obtained. Neural response to faces expressing negative emotion within the right amygdala significantly moderated the association between FoM and changes in internalizing symptoms (β = -0.20; 95% CI, -0.32 to -0.07; P < .001). The response to negative facial emotion within the right amygdala significantly moderated the association between FoM and changes in externalizing symptoms (β = 0.24; 95% CI, 0.04 to 0.43; P = .02). Left amygdala response to negative emotion significantly moderated the association between FoM and changes in externalizing symptoms (β = -0.16; 95% CI, -0.32 to -0.01; P = .04). In this cohort study of Black adolescents in the US, findings suggest that amygdala function in response to emotional stimuli can both protect and intensify the affective outcomes of feeling marginalized on risk for psychopathology, informing preventive interventions aimed at reducing the adverse effects of racism on internalizing and externalizing symptoms among Black youths.

Deterioration in cognitive control related mPFC function underlying development of treatment resistance in early psychosis

One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.

How movies move us - movie preferences are linked to differences in neuronal emotion processing of fear and anger: an fMRI study.

As a source of audio-visual stimulation, movies expose people to various emotions. Interestingly, several genres are characterized by negative emotional content. Albeit theoretical approaches exist, little is known about preferences for specific movie genres and the neuronal processing of negative emotions. We investigated associations between movie genre preference and limbic and reward-related brain reactivity to close this gap by employing an fMRI paradigm with negative emotional faces in 257 healthy participants. We compared the functional activity of the amygdala and the nucleus accumbens (NAcc) between individuals with a preference for a particular movie genre and those without such preference. Amygdala activation was relatively higher in individuals with action movie preference (p TFCE-FWE = 0.013). Comedy genre preference was associated with increased amygdala (p TFCE-FWE = 0.038) and NAcc activity (p TFCE-FWE = 0.011). In contrast, crime/thriller preference (amygdala: p TFCE-FWE ≤ 0.010, NAcc: p TFCE-FWE = 0.036), as well as documentary preference, was linked to the decreased amygdala (p TFCE-FWE = 0.012) and NAcc activity (p TFCE-FWE = 0.015). The study revealed associations between participants' genre preferences and brain reactivity to negative affective stimuli. Interestingly, preferences for genres with similar emotion profiles (action, crime/thriller) were associated with oppositely directed neural activity. Potential links between brain reactivity and susceptibility to different movie-related gratifications are discussed.

Oral Oxytocin Blurs Sex Differences in Amygdala Responses to Emotional Scenes

BackgroundSex differences are shaped both by innate biological differences and the social environment and are frequently observed in human emotional neural responses. Oral administration of oxytocin (OXT), as an alternative and noninvasive intake method, has been shown to produce sex-dependent effects on emotional face processing. However, it is unclear whether oral OXT produces similar sex-dependent effects on processing continuous emotional scenes. MethodsThe current randomized, double-blind, placebo-controlled neuropsychopharmacological functional magnetic resonance imaging experiment was conducted in 147 healthy participants (OXT = 74, men/women = 37/37; placebo = 73, men/women = 36/37) to examine the oral OXT effect on plasma OXT concentrations and neural response to emotional scenes in both sexes. ResultsAt the neuroendocrine level, women showed lower endogenous OXT concentrations than men, but oral OXT increased OXT concentrations equally in both sexes. Regarding neural activity, emotional scenes evoked opposite valence-independent effects on right amygdala activation (women > men) and its functional connectivity with the insula (men > women) in men and women in the placebo group. This sex difference was either attenuated (amygdala response) or even completely eliminated (amygdala-insula functional connectivity) in the OXT group. Multivariate pattern analysis confirmed these findings by developing an accurate sex-predictive neural pattern that included the amygdala and the insula under the placebo but not the OXT condition. ConclusionsThe results of the current study suggest a pronounced sex difference in neural responses to emotional scenes that was eliminated by oral OXT, with OXT having opposite modulatory effects in men and women. This may reflect oral OXT enhancing emotional regulation to continuous emotional stimuli in both sexes by facilitating appropriate changes in sex-specific amygdala-insula circuitry.

Selective estrogen receptor activation prior to global cerebral ischemia in female rats impacts microglial activation and anxiety-like behaviors without effects on CA1 neuronal injury

Estrogen receptor (ER) activation by 17-ß estradiol (E2) can attenuate neuronal injury and behavioral impairments following global cerebral ischemia (GCI) in rodents. This study sought to further examine the discrete roles of ERs through characterization of the effects of selective ER activation on post-ischemic pro-inflammatory microglial activation, hippocampal neuronal injury, and anxiety-like behaviors. Forty-six ovariectomized (OVX) adult female Wistar rats received daily s.c injections (100 μg/kg/day) of propylpyrazole triol (PPT; ERα agonist), diarylpropionitrile (DPN; ERβ agonist), G-1 (G-protein coupled ER agonist; GPER), E2 (activating all receptors), or vehicle solution (VEH) for 21 days. After final injection, rats underwent GCI via 4-vessel occlusion (n=8 per group) or sham surgery (n=6, vehicle injections). The Open Field Test (OFT), Elevated Plus Maze (EPM), and Hole Board Test (HBT) assessed anxiety-like behaviors. Microglial activation (Iba1, CD68, CD86) in the basolateral amygdala (BLA), CA1 of the hippocampus, and paraventricular nucleus of the hypothalamus (PVN) was determined 8 days post-ischemia. Compared to sham rats, Iba1 activation and CA1 neuronal injury were increased in all ischemic groups except DPN-treated rats, with PPT-treated ischemic rats also showing increased PVN Iba1-ir expression. Behaviorally, VEH ischemic rats showed slightly elevated anxiety in the EPM compared to sham counterparts, with no significant effects of agonists. While no changes were observed in the OFT, emotion regulation via grooming in the HBT was increased in G-1 rats compared to E2 rats. Our findings support selective ER activation to regulate post-ischemic microglial activation and coping strategies in the HBT, despite minimal impact on hippocampal injury.

Scopolamine infusion in the basolateral amygdala after saccharin intake induces conditioned taste avoidance in rats

RationaleMuscarinic receptor activity in the basolateral amygdala (BLA) is known to be involved in plasticity mechanisms that underlie emotional learning. The BLA is involved in the Attenuation of Neophobia, an incidental taste learning task in which a novel taste becomes familiar and recognized as safe.ObjectiveHere we assessed the role of muscarinic receptor activity in the BLA in incidental taste learning.MethodsYoung adult male Wistar rats were bilaterally implanted with cannulas aimed at BLA. After recovery, rats were randomly assigned to either vehicle or muscarinic antagonist group, for each experiment. We tested the effect of specific and non-specific muscarinic antagonists administered either 1) 20 min before novel taste presentation; 2) immediately after novel taste presentation; 3) immediately after retrieval (the second taste presentation on Day 5 -S2-) or immediately after the fifth taste presentation on Day 8 (S5).ResultsNon-specific muscarinic receptor antagonist scopolamine infused prior to novel taste, while not affecting novel taste preference, abolished AN, i.e., the increased preference observed in control animals on the second presentation. When administered after taste consumption, intra-BLA scopolamine not only prevented AN but caused a steep decrease in the taste preference on the second presentation. This scopolamine-induced taste avoidance was not dependent on taste novelty, nor did it generalize to another novel taste. Targeting putative postsynaptic muscarinic receptors with specific M1 or M3 antagonists appeared to produce a partial taste avoidance, while M2 antagonism had no effect.ConclusionThese data suggest that if a salient gustatory experience is followed by muscarinic receptors antagonism in the BLA, it will be strongly and persistently avoided in the future. The study also shows that scopolamine is not just an amnesic drug, and its cognitive effects may be highly dependent on the task and the structure involved.

Effects of early life adversity and adolescent basolateral amygdala activity on corticolimbic connectivity and anxiety behaviors.

Early postnatal development of corticolimbic circuitry is shaped by the environment and is vulnerable to early life challenges. Prior work has shown that early life adversity (ELA) leads to hyperinnervation of glutamatergic basolateral amygdala (BLA) projections to the prefrontal cortex (PFC) in adolescence. While hyperinnervation is associated with later-life anxiety behaviors, the physiological changes underpinning corticolimbic and behavioral impacts of ELA are not understood. We tested whether postsynaptic BLA-driven PFC activity is enhanced in ELA-exposed animals, using the maternal separation (MS) model of ELA. PFC local-field potential following BLA stimulation was facilitated in MS-exposed adolescents. Since ELA increases activity of the early-developing BLA, while the PFC exhibits protracted development, we further examined impacts of glutamatergic BLA activity during early adolescence on later-life PFC innervation and heightened anxiety. In early adolescence, MS-exposed animals exhibited decreased anxiety-like behavior, and acute adolescent BLA inhibition induced behaviors that resembled those of MS animals. To examine long-lasting impacts of adolescent BLA activity on innervation, BLA-originating axonal boutons in the PFC were quantified in late adolescence after early adolescent BLA inhibition. We further tested whether late adolescent BLA-PFC changes were associated with anxious reactivity expressed as heightened acoustic startle responses. MS rearing increased BLA-PFC innervation and threat reactivity in late adolescence, however early adolescent BLA inhibition was insufficient to prevent MS effects, suggesting that earlier BLA activity or post-synaptic receptor rearrangement in the PFC drives altered innervation. Taken together, these findings highlight both pre- and postsynaptic changes in the adolescent BLA-PFC circuit following ELA.

Frustrative nonreward: Detailed c-Fos expression patterns in the amygdala after consummatory successive negative contrast

The amygdala has been implicated in frustrative nonreward induced by unexpected reward downshifts, using paradigms like consummatory successive negative contrast (cSNC). However, existing evidence comes from experiments involving the central and basolateral nuclei on a broad level. Moreover, whether the amygdala’s involvement in reward downshift requires a cSNC effect (i.e., greater suppression in downshifted animals than in unshifted controls) or just consummatory suppression without a cSNC effect, remains unclear. Three groups were exposed to (1) a large reward disparity leading to a cSNC effect (32-to-2% sucrose), (2) a small reward disparity involving consummatory suppression in the absence of a cSNC effect (8-to-2% sucrose), and (3) an unshifted control (2% sucrose). Brains obtained after the first reward downshift session were processed for c-Fos expression, a protein often used as a marker for neural activation. c-Fos-positive cells were counted in the anterior, medial, and posterior portions (A/P axis) of ten regions of the rat basolateral, central, and medial amygdala. c-Fos expression was higher in 32-to-2% sucrose downshift animals than in the other two groups in four regions: the anterior and the medial lateral basal amygdala, the medial capsular central amygdala, and the anterior anterio-ventral medial amygdala. None of the areas exhibited differential c-Fos expression between the 8-to-2% sucrose downshift and the unshifted conditions. Thus, amygdala activation requires exposure to a substantial reward disparity. This approach has identified, for the first time, specific amygdala areas relevant to understand the cSNC effect, suggesting follow-up experiments aimed at testing the function of these regions in reward downshift.

Pathways to adolescent social anxiety: Testing interactions between neural social reward function and perceived social threat in daily life.

Recent theories suggest that for youth highly sensitive to incentives, perceiving more social threat may contribute to social anxiety (SA) symptoms. In 129 girls (ages 11-13) oversampled for shy/fearful temperament, we thus examined how interactions between neural responses to social reward (vs. neutral) cues (measured during anticipation of peer feedback) and perceived social threat in daily peer interactions (measured using ecological momentary assessment) predict SA symptoms two years later. No significant interactions emerged when neural reward function was modeled as a latent factor. Secondary analyses showed that higher perceived social threat was associated with more severe SA symptoms two years later only for girls with higher basolateral amygdala (BLA) activation to social reward cues at baseline. Interaction effects were specific to BLA activation to social reward (not threat) cues, though a main effect of BLA activation to social threat (vs. neutral) cues on SA emerged. Unexpectedly, interactions between social threat and BLA activation to social reward cues also predicted generalized anxiety and depression symptoms two years later, suggesting possible transdiagnostic risk pathways. Perceiving high social threat may be particularly detrimental for youth highly sensitive to reward incentives, potentially due to mediating reward learning processes, though this remains to be tested.

Neural mechanisms of costly helping in the general population and mirror-pain synesthetes

It has been argued that experiencing the pain of others motivates helping. Here, we investigate the contribution of somatic feelings while witnessing the pain of others onto costly helping decisions, by contrasting the choices and brain activity of participants that report feeling somatic feelings (self-reported mirror-pain synesthetes) against those that do not. Participants in fMRI witnessed a confederate receiving pain stimulations whose intensity they could reduce by donating money. The pain intensity could be inferred either from the facial expressions of the confederate in pain (Face condition) or from the kinematics of the pain-receiving hand (Hand condition). Our results show that self-reported mirror-pain synesthetes increase their donation more steeply, as the intensity of the observed pain increases, and their somatosensory brain activity (SII and the adjacent IPL) was more tightly associated with donation in the Hand condition. For all participants, activation in insula, SII, TPJ, pSTS, amygdala and MCC correlated with the trial by trial donation made in the Face condition, while SI and MTG activation was correlated with the donation in the Hand condition. These results further inform us about the role of somatic feelings while witnessing the pain of others in situations of costly helping.

Associations between perceived parenting, brain activity and connectivity, and depression symptoms in Brazilian adolescents

ABSTRACT In adolescence, parental care is associated with lower depression symptoms whereas parental overprotection is associated with greater depression symptoms, effects which may be mediated by adolescent brain activity and connectivity. The present study examined associations between perceived parenting, brain activity and connectivity, and depression symptoms in adolescents from Brazil, a middle-income country (MIC). Analyses included 100 adolescents who underwent functional magnetic resonance imaging scanning while completing a face matching task. Parental care and overprotection were associated with adolescent depression symptoms in expected directions. We also found that parental care and overprotection were associated with amygdala connectivity with several brain regions; however, amygdala activity was not associated with parenting and neither activity or connectivity mediated the association between parenting and depression symptoms. Results identify how parenting influences brain function and depression symptoms in youth from a MIC.

Neural responses to facial emotions and subsequent clinical outcomes in difficult-to-treat depression.

Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD. Forty-five people with current MDD who had not responded to ⩾2 serotonergic antidepressants (n = 42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad v. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item). We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad v. happy faces predicted favorable clinical outcomes (rs[38] = 0.40, p = 0.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38] = 0.18, p = 0.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p < 0.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels. We confirmed the prediction that a lower amygdala response to negative v. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.

Acute stress during witnessing injustice shifts third-party interventions from punishing the perpetrator to helping the victim.

People tend to intervene in others' injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances. However, how acute stress affects a third party's intervention in injustice events remains open. Here, we show a stress-induced shift in third parties' willingness to engage in help instead of punishment by acting on emotional salience and central-executive and theory-of-mind networks. Acute stress decreased the third party's willingness to punish the violator and the severity of the punishment and increased their willingness to help the victim. Computational modeling revealed a shift in preference of justice recovery from punishment the offender toward help the victim under stress. This finding is consistent with the increased dorsolateral prefrontal engagement observed with higher amygdala activity and greater connectivity with the ventromedial prefrontal cortex in the stress group. A brain connectivity theory-of-mind network predicted stress-induced justice recovery in punishment. Our findings suggest a neurocomputational mechanism of how acute stress reshapes third parties' decisions by reallocating neural resources in emotional, executive, and mentalizing networks to inhibit punishment bias and decrease punishment severity.

Metabolome-associated psychological comorbidities improvement in irritable bowel syndrome patients receiving a probiotic

Our recent randomized, placebo-controlled study in Irritable Bowel Syndrome (IBS) patients with diarrhea or alternating bowel habits showed that the probiotic Bifidobacterium longum (BL) NCC3001 improves depression scores and decreases brain emotional reactivity. However, the involved metabolic pathways remain unclear. This analysis aimed to investigate the biochemical pathways underlying the beneficial effects of BL NCC3001 using metabolomic profiling. Patients received probiotic (1x 1010CFU, n=16) or placebo (n=19) daily for 6 weeks. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale. Brain activity in response to negative emotional stimuli was assessed by functional Magnetic Resonance Imaging. Probiotic fecal abundance was quantified by qPCR. Quantitative measurement of specific panels of plasma host-microbial metabolites was performed by mass spectrometry-based metabolomics. Probiotic abundance in feces was associated with improvements in anxiety and depression scores, and a decrease in amygdala activation. The probiotic treatment increased the levels of butyric acid, tryptophan, N-acetyl tryptophan, glycine-conjugated bile acids, and free fatty acids. Butyric acid concentration correlated with lower anxiety and depression scores, and decreased amygdala activation. Furthermore, butyric acid concentration correlated with the probiotic abundance in feces. In patients with non-constipation IBS, improvements in psychological comorbidities and brain emotional reactivity were associated with an increased abundance of BL NCC3001 in feces and specific plasma metabolites, mainly butyric acid. These findings suggest the importance of a probiotic to thrive in the gut and highlight butyric acid as a potential biochemical marker linking microbial metabolism with beneficial effects on the gut-brain axis.