Country-level gender inequality is associated with structural differences in the brains of women and men.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Intensity of repetitive negative thinking in depression is associated with greater functional connectivity between semantic processing and emotion regulation areas.

BACKGROUND: Repetitive negative thinking (RNT), a cognitive process that encompasses past (rumination) and future (worry) directed thoughts focusing on negative experiences and the self, is a transdiagnostic construct that is especially relevant for major depressive disorder (MDD). Severe RNT often occurs in individuals with severe levels of MDD, which makes it challenging to disambiguate the neural circuitry underlying RNT from depression severity. METHODS: We used a propensity score, i.e., a conditional probability of having high RNT given observed covariates to match high and low RNT individuals who are similar in the severity of depression, anxiety, and demographic characteristics. Of 148 MDD individuals, we matched high and low RNT groups (n = 50/group) and used a data-driven whole-brain voxel-to-voxel connectivity pattern analysis to investigate the resting-state functional connectivity differences between the groups. RESULTS: There was an association between RNT and connectivity in the bilateral superior temporal sulcus (STS), an important region for speech processing including inner speech. High relative to low RNT individuals showed greater connectivity between right STS and bilateral anterior insular cortex (AI), and between bilateral STS and left dorsolateral prefrontal cortex (DLPFC). Greater connectivity in those regions was specifically related to RNT but not to depression severity. CONCLUSIONS: RNT intensity is directly related to connectivity between STS and AI/DLPFC. This might be a mechanism underlying the role of RNT in perceptive, cognitive, speech, and emotional processing. Future investigations will need to determine whether modifying these connectivities could be a treatment target to reduce RNT.

Real-Time fMRI Functional Connectivity Neurofeedback Reducing Repetitive Negative Thinking in Depression: A Double-Blind, Randomized, Sham-Controlled Proof-of-Concept Trial.

INTRODUCTION: Repetitive negative thinking (RNT) is a cognitive process focusing on self-relevant and negative experiences, leading to a poor prognosis of major depressive disorder (MDD). We previously identified that connectivity between the precuneus/posterior cingulate cortex (PCC) and right temporoparietal junction (rTPJ) was positively correlated with levels of RNT. OBJECTIVE: In this double-blind, randomized, sham-controlled, proof-of-concept trial, we employed real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) to delineate the neural processes that may be causally linked to RNT and could potentially become treatment targets for MDD. METHODS: MDD-affected individuals were assigned to either active (n = 20) or sham feedback group (n = 19). RNT was measured by the Ruminative Response Scale-brooding subscale (RRS-B) before and 1 week after the intervention. RESULTS: Individuals in the active but not in the sham group showed a significant reduction in the RRS-B; however, a greater reduction in the PCC-rTPJ connectivity was unrelated to a greater reduction in the RRS-B. Exploratory analyses revealed that a greater reduction in the retrosplenial cortex (RSC)-rTPJ connectivity yielded a more pronounced reduction in the RRS-B in the active but not in the sham group. CONCLUSIONS: RtfMRI-nf was effective in reducing RNT. Considering the underlying mechanism of rtfMIR-nf, the RSC and rTPJ could be part of a network (i.e., default mode network) that might collectively affect the intensity of RNT. Understanding the relationship between the functional organization of targeted neural changes and clinical metrics, such as RNT, has the potential to guide the development of mechanism-based treatment of MDD.

Neuroethics and cultural context: The case of electroconvulsive therapy in Argentina.

As neuroethics continues to grow as an established discipline, it has been charged with not being sufficiently sensitive to the way in which the identification, conceptualization, and management of the ethical issues raised by neuroscience and its applications are shaped by local systems of knowledge and structures. Recently there have been calls for explicit recognition of the role played by local cultural contexts and for the development of cross-cultural methodologies that can facilitate meaningful cultural engagement. In this article, we attempt to fill this perceived gap by providing a culturally situated analysis of the practice of electroconvulsive therapy (ECT) in Argentina. ECT was introduced as a psychiatric treatment in Argentina in the 1930s but it is largely underutilized. While the use of ECT remains low in several countries, what makes the Argentinian case interesting is that the executive branch of government has taken a stance regarding both the scientific and moral appropriateness of ECT, recommending its prohibition. Here, we begin with a recent controversy over the use of ECT in Argentina and explain the legal recommendation to ban its application. Next, we offer an overview of some of the salient aspect of the international and local discussions on ECT. We argue that the governmental recommendation to ban the procedure should be rethought. While acknowledging the role that contexts and local conditions play in shaping the identification and assessment of the relevant ethical issues, we caution against using contextual and cultural considerations to avoid a necessary ethical debate on controversial issues.

Effects of socioeconomic status in cognition of people with schizophrenia: results from a Latin American collaboration network with 1175 subjects.

BACKGROUND: Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. METHODS: We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. RESULTS: Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. CONCLUSIONS: Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low- and middle-income countries.

Structural brain abnormalities in schizophrenia in adverse environments: examining the effect of poverty and violence in six Latin American cities.

BACKGROUND: Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear. AIMS: We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed. METHOD: This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model. RESULTS: A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure. CONCLUSIONS: Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.

Elevated peripheral inflammation is associated with attenuated striatal reward anticipation in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide, and up to 40% of individuals with MDD do not respond to current treatments. Studies suggest that peripheral inflammation plays an important role in the striatal mesolimbic dopamine pathway and corticostriatal reward circuitry in MDD. Although MDD patients show blunted striatal responses to reward, the link between degree of inflammation and attenuation of reward processing is unclear. We investigated whether MDD patients with elevated peripheral inflammation exhibit attenuated reward responses to enhance our understanding of MDD pathophysiology and develop more effective treatments for current non-responders. METHODS: MDD subjects varying on serum C-reactive protein (CRP) concentrations (MDD-High CRP, >3 mg/L, n = 44; MDD-Low CRP, <3 mg/L, n = 44) and healthy comparisons (HC, n = 44) completed a monetary incentive delay (MID) task and provided blood samples to measure inflammation-related markers. MDD-High and MDD-Low were propensity score-matched on age, sex, body mass index (BMI), smoking status, exercise and MID task head motion. Percent change in blood oxygen level-dependent (BOLD) signal during anticipation of wins and losses was extracted from bilateral nucleus accumbens, dorsal caudate and dorsolateral putamen regions of interest (ROIs). A linear mixed-effects model was used to test group (MDD-High, MDD-Low and HC), condition (large-win, small-win and no win), and their interaction for these ROIs as well as whole-brain voxelwise data. Analyses also tested group differences in inflammatory mediators. Correlations were used to explore the relationship between inflammatory mediators and brain regions showing differences between MDD-High and MDD-Low. RESULTS: MDD-High exhibited: (a) lower BOLD signal change in dorsal caudate, thalamus, left insula and left precuneus during anticipation of small wins than MDD-Low; and (b) higher serum soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 6 (IL-6) concentrations than MDD-Low and HC. MDD as a whole, regardless of CRP-based inflammation, exhibited: (a) lower precuneus BOLD signal change to large wins than HC; and (b) higher Interleukin 1 receptor antagonist (IL-1ra), macrophage-derived chemokine (MDC) and macrophage inflammatory protein-1 alpha (MIP-1α) concentrations than HC. Higher serum sICAM-1 concentrations were associated with lower caudate BOLD signal change to small wins only within the MDD-High group. CONCLUSION: Within MDD patients, high inflammation (CRP, sICAM-1) was linked to reduced striatal activation recruited to discriminate intermediate reward magnitudes. These findings support an association between levels of peripheral inflammation and the degree of reward-related activation in individuals with MDD. REGISTRATION OF CLINICAL TRIALS: The ClinicalTrials.gov identifier for the clinical protocol associated with data published in this current paper is NCT02450240, "Latent Structure of Multi-level Assessments and Predictors of Outcomes in Psychiatric Disorders."

Brain Structural and Amyloid Correlates of Recovery From Semantic Interference in Cognitively Normal Individuals With or Without Family History of Late-Onset Alzheimer's Disease.

Failure to recover from proactive semantic interference (frPSI) has been shown to be more sensitive than traditional cognitive measures in different populations with preclinical Alzheimer's disease. The authors sought to characterize the structural and amyloid in vivo correlates of frPSI in cognitively normal offspring of patients with late-onset Alzheimer's disease (O-LOAD), compared with individuals without a family history of neurodegenerative disorders (CS). The authors evaluated the LASSI-L, a test tapping frPSI and other types of semantic interference and delayed recall on the RAVLT, along with 3-T MRI volumetry and positron emission tomography Pittsburgh compound B, in 27 O-LOAD and 18 CS with equivalent age, sex, years of education, ethnicity, premorbid intelligence, and mood symptoms. Recovery from proactive semantic interference (frPSI) and RAVLT delayed recall were lower in O-LOAD cases. Structural correlates of both cognitive dimensions were different in CS and O-LOAD, involving brain regions concerned with autonomic, motor, and motivational control in the former, and regions traditionally implicated in Alzheimer's disease in the latter. Better recovery from retroactive semantic interference was associated with less amyloid load in the left temporal lobe in O-LOAD but not CS. In middle-aged cognitively normal individuals with one parent affected with LOAD, frPSI was impaired compared with persons without a family history of LOAD. The neuroimaging correlates of such cognitive measure in those with one parent with LOAD involve Alzheimer's-relevant brain regions even at a relatively young age.

Word processing during reading sentences in patients with schizophrenia: evidences from the eyetracking technique.

PURPOSE: The current study analyze the effect of word properties (i.e., word length, word frequency and word predictability) on the eye movement behavior of patients with schizophrenia (SZ) compared to age-matched controls. METHOD: 18 SZ patients and 40 age matched controls participated in the study. Eye movements were recorded during reading regular sentences by using the eyetracking technique. Eye movement analyses were performed using linear mixed models. FINDINGS: Analysis of eye movements revealed that patients with SZ decreased the amount of single fixations, increased their total number of second pass fixations compared with healthy individuals (Controls). In addition, SZ patients showed an increase in gaze duration, compared to Controls. Interestingly, the effects of current word frequency and current word length processing were similar in Controls and SZ patients. The high rate of second pass fixations and its low rate in single fixation might reveal impairments in working memory when integrating neighbor words. In contrast, word frequency and length processing might require less complex mechanisms, which were functioning in SZ patients. CONCLUSION: To the best of our knowledge, this is the first study measuring how patients with SZ process dynamically well-defined words embedded in regular sentences. The findings suggest that evaluation of the resulting changes in eye movement behavior may supplement current symptom-based diagnosis.

[Endophenotypes in Psychiatry]. / Endofenotipos en Psychiatría.

We review the concept of endophenotype, and its relationship with related terms in use in the scientific literature, including "biomarker" and "intermediate phenotype". We then explain the importance of the concept in current psychiatry research. Specifically, we focus in the potential importance of endophenotypes in both disentangling the genetic causes, and improving the dimensional and pathophysiologic definition, of psychiatric nosological categories. After delineating which types of variables could constitute valid endophenotypes, we describe efforts in defining neurobiological signatures of social cognitive deficits in schizophrenia as an example with potential heuristic value.

Olfactory Dysfunction Evaluation Is Not Affected by Comorbid Depression in Parkinson's Disease.

BACKGROUND: Olfactory function assessment is an important screening tool for Parkinson's disease (PD) diagnosis. It is debated whether olfaction is affected by comorbid depression. We assessed the relationship between depression and olfaction in PD and determined whether depression may limit the usefulness of olfactory testing for PD diagnosis. METHODS: Olfaction was evaluated using the Sniffin' Sticks test and the Hyposmia Rating Scale in four groups of subjects: PD patients without depression (n = 30); PD patients with major depression (PDD; n = 30); major depressive disorder (MDD) patients (n = 29); and healthy controls (HCs; n = 30). RESULTS: No differences were found between PD and PDD patients for total Sniffin' Sticks test, threshold, discrimination or identification scores, or in Hyposmia Rating Scale, although both groups differed from HCs and MDD patients (P < 0.05), which, in turn, showed similar olfactory scores. CONCLUSIONS: Lack of differences in olfactory impairment between PD and PDD suggest that depression may not contribute to olfactory dysfunction in PD.

From Semantic to Social Deficits: Dysfunction of the Nondominant Posterior Perisylvian Area in Schizophrenia.

Schizophrenia is characterized by profound deficits in social competence and functioning, independent from active psychotic symptoms at different stages of the disease. Social deficits in schizophrenia are clinically well characterized, but their neurobiological underpinnings are undetermined. This article reviews recent evidence supporting heritable deficits in a circuit necessary for appropriate naming of emotions and mental states in others, centered at the temporoparietal junction of the nondominant hemisphere. The clinical implications of this model are discussed, including the potential use of rehabilitation techniques oriented to recognition and naming of emotions and mental states as a necessary step for social rehabilitation.

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update.

The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public-private partnership, the initiative has set a new standard for data sharing without embargo and for the use of biomarkers in dementia research. The ADNI effort in North America is not the only such effort in the world. The Alzheimer's Association recognized these global efforts and formed Worldwide ADNI (WW-ADNI). By creating a platform for international collaboration and cooperation, WW-ADNI's goals are to harmonize projects and results across geographical regions and to facilitate data management and availability to investigators around the world. WW-ADNI projects include those based in North America, Europe, Japan, Australia, Korea, and Argentina.

Creation of the Argentina-Alzheimer's Disease Neuroimaging Initiative.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite, longitudinal study that assesses clinical, imaging, genetic, and biospecimen biomarkers through the process of normal aging to mild cognitive impairment and dementia. We present the creation of the Argentina-ADNI - the first South American ADNI - and its effort to acquire data comparable with those gathered in other worldwide ADNI centers.

Rumination and Overrecruitment of Cognitive Control Circuits in Depression.

BACKGROUND: Rumination is associated with greater cognitive dysfunction and treatment resistance in major depressive disorder (MDD), but its underlying neural mechanisms are not well understood. Because rumination is characterized by difficulty in controlling negative thoughts, the current study investigated whether rumination was associated with aberrant cognitive control in the absence of negative emotional information. METHODS: Individuals with MDD (n = 176) and healthy control individuals (n = 52) completed the stop signal task with varied stop signal difficulty during functional magnetic resonance imaging. In the task, a longer stop signal asynchrony made stopping difficult (hard stop), whereas a shorter stop signal asynchrony allowed more time for stopping (easy stop). RESULTS: In participants with MDD, higher rumination intensity was associated with greater neural activity in response to difficult inhibitory control in the frontoparietal regions. Greater activation for difficult inhibitory control associated with rumination was also positively related to state fear. The imaging results provide compelling evidence for the neural basis of inhibitory control difficulties in individuals with MDD with high rumination. CONCLUSIONS: The association between higher rumination intensity and greater neural activity in regions involved in difficult inhibitory control tasks may provide treatment targets for interventions aimed at improving inhibitory control and reducing rumination in this population.

Clinical Response to Neurofeedback in Major Depression Relates to Subtypes of Whole-Brain Activation Patterns During Training.

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.

Childhood adversity modulates structural brain changes in borderline personality but not in major depression disorder.

Adverse childhood experiences (ACEs) negatively affect the function and structure of emotion brain circuits, increasing the risk of various psychiatric disorders. It is unclear if ACEs show disorder specificity with respect to their effects on brain structure. We aimed to investigate whether the structural brain effects of ACEs differ between patients with major depression (MDD) and borderline personality disorder (BPD). These disorders share many symptoms but likely have different etiologies. To achieve our goal, we obtained structural 3T-MRI images from 20 healthy controls (HC), 19 MDD patients, and 18 BPD patients, and measured cortical thickness and subcortical gray matter volumes. We utilized the Adverse Childhood Experiences (ACE) questionnaire to quantify self-reported exposure to childhood trauma. Our findings suggest that individuals with MDD exhibit a smaller cortical thickness when compared to those with BPD. However, ACEs showed a significantly affected relationship with cortical thickness in BPD but not in MDD. ACEs were found to be associated with thinning in cortical regions involved in emotional behavior in BPD, whereas HC showed an opposite association. Our results suggest a potential mechanism of ACE effects on psychopathology involving changes in brain structure. These findings highlight the importance of early detection and intervention strategies.

Medication Use is Associated with Distinct Microbial Features in Anxiety and Depression.

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 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 and shallow shotgun sequencing were performed on DNA extracted from 666 fecal samples from the Tulsa-1000 and 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. The findings suggest that future research on the gut microbiota's role in NPD and its interactions with pharmacological treatments are needed.

[DSM-5: a young Kraepelin and the "schizoaffective disorder" oxymoron]. / El nuevo DSM-V o Kraepelin antes de su madurez: el oxímoron del "Trastorno esquizoafectivo"

The last several years have witnessed the accumulation of evidence suggesting that the Kraepelinian binary system of classification of the psychoses does not capture their true nature, as Kraepelin himself had cautioned in his late years. The long-awaited new edition of the APA's Diagnostic and Statistical Manual will in all probability incorporate symptom dimensions and suppress schizophrenia subtypes. However, the initial Kraepelinian conceptualization of the psychoses is maintained, along with the diagnostic category that epitomizes its obsolescence: schizoaffective disorder. We hereby make a brief critical appraisal of this fact, pointing out how the current classification system might be an obstacle to much-needed advances in this knowledge field.