Salvador Martín Guinjoan

Background: Major depressive disorder (MDD) is a prevalent chronic mental illness often treated by serotonergic pharmacotherapy and complicated by sex differences and comorbid anxiety disorders (COMs). Deficits in inhibitory control are a transdiagnostic feature of MDD and COM, though the presentation of these deficits may be impacted by competing cognitive demands, symptoms severity, sexes, and medication status. Methods: This project includes 233 participants from the Tulsa 1000 study who completed concurrent electroencephalography (EEG) and magnetic functional resonance imaging (MRI) during a stop signal task (SST). We examined how serotonergic antidepressants, biological sex, and comorbidity with an anxiety disorder uniquely relate to neural indices of inhibitory control for healthy controls (HCs), MDD, and COM using linear mixed effect models, type III ANOVAs, and optimal full propensity matching. N200, P300, and correct-related negativity (CRN) components were extracted and analyzed to index conflict monitoring, conflict resolution, and performance monitoring, respectively, in response to stop signals and their absence. Results: Our results revealed that HCs exhibited larger stop-P300 amplitudes than MDD and COM ( η ² = 0.068); females had smaller stop-N200 amplitudes than males ( η ² = 0.027); MDD/COM participants taking a serotonergic antidepressant exhibited less negative N200 amplitudes than those who were not (LME, B = 1.95; η ² = 0.044; ATE, B = 2.47). Conclusions: Our findings suggest being treated with serotonergic antidepressants are associated with neural differences in the conflict monitoring of inhibitory control in pure and comorbid depression.

Current efforts to establish anatomically precise and causal deep brain circuit-symptom relationships to predict surgical responses require the insertion of intracranial electrodes. In the present study (ClinicalTrials.gov NCT05697172) we examined whether low-intensity focused ultrasound (LIFU; FDA Q220192) could modulate the white matter tracts in the anterior limb of the internal capsule (ALIC), a common surgical target for the treatment of refractory depression. We based our human study on the in vitro observation that ultrasound attenuates conduction in myelinated axons by operating mechanosensitive potassium channels in nodes of Ranvier. We employed a cross-over, randomized, sham-controlled, double-blind design to establish the ability of LIFU (80 s; 0.5 MHz; estimated peak tissue energy 2.26 Watt/cm²; 10% duty cycle) to engage a target in the ALIC in 21 patients with Major Depressive Disorder. Targets were defined as the area with highest density of thalamo-prefrontal probabilistic tractography streamlines. We measured changes in magnetic resonance functional connectivity, repetitive mentation, emotional state, and cardiac autonomic output. Compared with sham stimulation, active LIFU produced a functional disconnection of gray matter hubs connected by the sonicated tracts (d = −1.55; p < 0.001), an increase in positive emotion (d = 0.6; p = 0.04), and decreased cardiac sympathovagal balance (d = −0.57; p = 0.01). The observation that LIFU engages deep white matter tracts related to depression symptoms paves the way for rigorously investigating (1) mechanistic definitions of brain circuit-symptom relationships, (2) noninvasive, reversible, and anatomically precise probing of such circuits before surgery, and (3) potential use as a new therapy for depression.

Background: The macro-social and environmental conditions in which people live, such as the level of a country’s development or inequality, are associated with brain-related disorders. However, the relationship between these systemic environmental factors and the brain remains unclear. We aimed to determine the association between the level of development and inequality of a country and the brain structure of healthy adults. Methods: We conducted a cross-sectional study pooling brain imaging (T1-based) data from 145 magnetic resonance imaging (MRI) studies in 7,962 healthy adults (4,110 women) in 29 different countries. We used a meta-regression approach to relate the brain structure to the country’s level of development and inequality. Results: Higher human development was consistently associated with larger hippocampi and more expanded global cortical surface area, particularly in frontal areas. Increased inequality was most consistently associated with smaller hippocampal volume and thinner cortical thickness across the brain. Conclusions: Our results suggest that the macro-economic conditions of a country are reflected in its inhabitants’ brains and may explain the different incidence of brain disorders across the world. The observed variability of brain structure in health across countries should be considered when developing tools in the field of personalized or precision medicine that are intended to be used across the world.

This study investigated the relationship between gut microbiota and neuropsychiatric disorders (NPDs), specifically anxiety disorder (ANXD) and/or major depressive disorder (MDD), as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV or V criteria. The study also examined the influence of medication use, particularly antidepressants and/or anxiolytics, classified through the Anatomical Therapeutic Chemical (ATC) Classification System, on the gut microbiota. Both 16S rRNA gene amplicon sequencing (16S) and shallow shotgun sequencing (WGS) were performed on DNA extracted from 666 fecal samples from the Tulsa-1000 and Neurocomputational Mechanisms of Affiliation and Personality Study Center for Biomedical Research Excellence (NeuroMAP CoBRE) cohorts. The results highlight the significant influence of medication use; antidepressant use is associated with significant differences in gut microbiota beta diversity and has a larger effect size than NPD diagnosis. Next, specific microbes were associated with ANXD and MDD, highlighting their potential for non-pharmacological intervention. Finally, the study demonstrated the capability of Random Forest classifiers to predict diagnoses of NPD and medication use from microbial profiles, suggesting a promising direction for the use of gut microbiota as biomarkers for NPD. Though the effect sizes were larger in females than males, similar trends emerged for both sexes. These findings encourage future research on the gut microbiota’s role in NPD and its interactions with pharmacological treatments.

Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. Significant symptom reduction was observed in the active group (t = −4.404, d = −0.704, p < 0.001) but not in the control group (t = −1.609, d = −0.430, p = 0.111). However, left amygdala activation did not account for the variability in clinical efficacy. To elucidate the brain training process underlying the clinical effect, we examined whole-brain activation patterns during two critical phases of the neurofeedback procedure: activation during the self-regulation period, and transient responses to feedback signal presentations. Using a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified two subtypes of regulation activation and three subtypes of brain responses to feedback signals. These subtypes were significantly associated with the clinical effect (regulation subtype: F = 8.735, p = 0.005; feedback response subtype: F = 5.326, p = 0.008; subtypes’ interaction: F = 3.471, p = 0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity during training is more critical for clinical efficacy than the level of activation in the neurofeedback target region itself. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.

Emotional well-being improves with age, but how neural activity related to emotional brain states changes with aging remains unclear. This study examined individualized brain activation patterns for rumination, worry, and positive thinking to explore age-related variations in emotional state representation. Thirty-five participants (aged 18-64) recalled autobiographical events tied to these emotional states during fMRI scanning. Brain activity was analyzed using an individualized machine learning classifier. Results showed increased discriminability of rumination and worry with age, with older adults exhibiting heightened activation in cognitive control regions during rumination and reduced activation in the cingulate and temporoparietal junction during worry. No significant age-related changes were found for positive thinking, although increased discriminability between positive and negative states correlated with well- being (FDR < 0.05). These findings suggest that aging enhances cognitive control during rumination and reduces anxiety responses during worry, potentially contributing to improved emotional well-being in older adults.

Background Repetitive negative thinking (RNT) in major depressive disorder (MDD) involves persistent focus on negative self-related experiences. Resting-state fMRI shows that the functional connectivity (FC) between the insula and the superior temporal sulcus is critical to RNT intensity. This study examines how insular FC patterns differ between resting-state and RNT-induction in MDD and healthy participants (HC). Methods Forty-one individuals with MDD and twenty-eight HCs (total n=69) underwent resting-state and RNT-induction fMRI scans. Seed-to-whole brain analysis using insular subregions as seeds was performed. Results No diagnosis-by-run interaction effects were observed across insular subregions. MDD participants showed greater FC between bilateral anterior, middle, and posterior insular regions and the cerebellum (z = 4.31 to 6.15). During RNT-induction, both MDD and HC participants demonstrated increased FC between bilateral anterior and middle insula and key brain regions, including prefrontal cortices, parietal lobes, posterior cingulate cortex, and medial temporal gyrus, encompassing the STS (z = 4.47 to 8.31). Higher trait-RNT was associated with increased FC between the right dorsal anterior and middle insula and regions in the DMN and salience network in MDD participants (z = 4.31 to 6.15). Greater state-RNT scores were linked to increased FC in similar insular regions, the bilateral angular gyrus and right middle temporal gyrus (z = 4.47 to 8.31). Conclusions Hyperconnectivity in insula subregions during active rumination, especially involving the DMN and salience network, supports theories of heightened self-focused and negative emotional processing in depression. These findings emphasize the neural basis of RNT when actively elicited in MDD.

Major depressive disorder has a point prevalence of 5% of the world population and is the main cause of disability, with up to a third of patients not responding to first-line treatments. Surgical neuromodulation is offered to only an anecdotal proportion of these patients, because while these methods are curative in some individuals, the proportion of responders rarely exceeds 50%. Recent efforts to establish reliable brain circuit-symptom relationships and thus predict response have involved mapping with multiple intracranial electrodes, but the impracticality of this approach currently prevents its application at scale. In the present study ( ClinicalTrials.gov identifier NCT05697172 ; FDA Q220192) we begin to address this gap by leveraging low-intensity focused ultrasound (LIFU), a novel noninvasive technique, to modulate the anterior limb of the internal capsule, which is an established surgical deep white matter target for depression. We based our study on burgeoning in vitro evidence that LIFU attenuates axonal conduction by operating mechanosensitive channels in nodes of Ranvier. Compared with sham stimulus, active LIFU produced a functional disconnection of gray matter hubs reached by the sonicated axonal tracts, an increase in positive emotion, and top-down effects on the cardiovascular autonomic balance. Our results using LIFU of deep-brain white matter tracts in humans open three potential avenues to understand the mechanisms and improve the outcome of depression, namely attaining a personalized definition of brain circuit-symptom relationships, serving as a noninvasive probe for neuromodulation before irreversible procedures in a “try before you buy” approach, and ultimately emerging as a therapeutic intervention itself.