Right frontal cingulate cortex mediates the effect of prenatal complications on youth internalizing behaviors.

Prenatal and perinatal complications represent well-known risk factors for the future development of psychiatric disorders. Such influence might become manifested during childhood and adolescence, as key periods for brain and behavioral changes. Internalizing and externalizing behaviors in adolescence have been associated with the risk of psychiatric onset later in life. Both brain morphology and behavior seem to be affected by obstetric complications, but a clear link among these three aspects is missing. Here, we aimed at analyzing the association between prenatal and perinatal complications, behavioral issues, and brain volumes in a group of children and adolescents. Eighty-two children and adolescents with emotional-behavioral problems underwent clinical and 3 T brain magnetic resonance imaging (MRI) assessments. The former included information on behavior, through the Child Behavior Checklist/6-18 (CBCL/6-18), and on the occurrence of obstetric complications. The relationships between clinical and gray matter volume (GMV) measures were investigated through multiple generalized linear models and mediation models. We found a mutual link between prenatal complications, GMV alterations in the frontal gyrus, and withdrawn problems. Specifically, complications during pregnancy were associated with higher CBCL/6-18 withdrawn scores and GMV reductions in the right superior frontal gyrus and anterior cingulate cortex. Finally, a mediation effect of these GMV measures on the association between prenatal complications and the withdrawn dimension was identified. Our findings suggest a key role of obstetric complications in affecting brain structure and behavior. For the first time, a mediator role of frontal GMV in the relationship between prenatal complications and internalizing symptoms was suggested. Once replicated on independent cohorts, this evidence will have relevant implications for planning preventive interventions.

Neurocognitive skills and vulnerability for psychosis in depression and across the psychotic spectrum: findings from the PRONIA Consortium.

BACKGROUND: Neurocognitive deficits are a core feature of psychosis and depression. Despite commonalities in cognitive alterations, it remains unclear if and how the cognitive deficits in patients at clinical high risk for psychosis (CHR) and those with recent-onset psychosis (ROP) are distinct from those seen in recent-onset depression (ROD). AIMS: This study was carried out within the European project 'Personalized Prognostic Tools for Early Psychosis Management', and aimed to characterise the cognitive profiles of patients with psychosis or depression. METHOD: We examined cognitive profiles for patients with ROP (n = 105), patients with ROD (n = 123), patients at CHR (n = 116) and healthy controls (n = 372) across seven sites in five European countries. Confirmatory factor analysis identified four cognitive factors independent of gender, education and site: speed of processing, attention and working memory, verbal learning and spatial learning. RESULTS: Patients with ROP performed worse than healthy controls in all four domains (P < 0.001), whereas performance of patients with ROD was not affected (P > 0.05). Patients at CHR performed worse than healthy controls in speed of processing (P = 0.001) and spatial learning (P = 0.003), but better than patients with ROP across all cognitive domains (all P ≤ 0.01). CHR and ROD groups did not significantly differ in any cognitive domain. These findings were independent of comorbid depressive symptoms, substance consumption and illness duration. CONCLUSIONS: These results show that neurocognitive abilities are affected in CHR and ROP, whereas ROD seems spared. Although our findings may support the notion that those at CHR have a specific vulnerability to psychosis, future studies investigating broader transdiagnostic risk cohorts in longitudinal designs are needed.

Brain volumes in alcohol use disorder: Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis.

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxel-based, multi-tissue mega-analytic approach, thereby extending our recent surface-based region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller group-by-sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD.

Prevalence of cognitive impairments and strengths in the early course of psychosis and depression.

BACKGROUND: Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. METHODS: A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. RESULTS: Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. CONCLUSIONS: These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets.

A review of resting-state fMRI correlations with executive functions and social cognition in bipolar disorder.

BACKGROUND: Deficits in executive functions (EF) and social cognition (SC) are often observed in bipolar disorder (BD), leading to a severe impairment in engaging a functional interaction with the others and the surrounding environment. Therefore, in recent years, resting-state functional magnetic resonance imaging (rs-fMRI) studies on BD tried to identify the neural underpinnings of these cognitive domains by exploring the association between the intrinsic functional connectivity (FC) and the scores in clinical scales evaluating these domains. METHODS: A bibliographic search on PubMed and Scopus of studies evaluating the correlations between rs-fMRI findings and EF and/or SC in BD was conducted until March 2022. Ten studies met the inclusion criteria. RESULTS: Overall, the results of the reviewed studies showed that BD patients had FC deficits compared to healthy controls (HC) in selective resting-state networks involved in EF and SC, which include the default mode network, especially the link between medial prefrontal cortex and posterior cingulate cortex, and the sensory-motor network. Finally, it also emerged the predominant role of alterations in prefrontal connections in explaining the cognitive deficits in BD patients. LIMITATIONS: The heterogeneity of the reviewed studies, in terms of the cognitive domains explored and the neuroimaging acquisitions employed, limited the comparability of the findings. CONCLUSIONS: rs-fMRI studies could help deepen the brain network alterations underlying EF and SC deficits in BD, pointing the attention on the neuronal underpinning of cognition, whose knowledge may lead to the development of new neurobiological-based approaches to improve the quality of life of these patients.

Machine learning methods to predict outcomes of pharmacological treatment in psychosis.

In recent years, machine learning (ML) has been a promising approach in the research of treatment outcome prediction in psychosis. In this study, we reviewed ML studies using different neuroimaging, neurophysiological, genetic, and clinical features to predict antipsychotic treatment outcomes in patients at different stages of schizophrenia. Literature available on PubMed until March 2022 was reviewed. Overall, 28 studies were included, among them 23 using a single-modality approach and 5 combining data from multiple modalities. The majority of included studies considered structural and functional neuroimaging biomarkers as predictive features used in ML models. Specifically, functional magnetic resonance imaging (fMRI) features contributed to antipsychotic treatment response prediction of psychosis with good accuracies. Additionally, several studies found that ML models based on clinical features might present adequate predictive ability. Importantly, by examining the additive effects of combining features, the predictive value might be improved by applying multimodal ML approaches. However, most of the included studies presented several limitations, such as small sample sizes and a lack of replication tests. Moreover, considerable clinical and analytical heterogeneity among included studies posed a challenge in synthesizing findings and generating robust overall conclusions. Despite the complexity and heterogeneity of methodology, prognostic features, clinical presentation, and treatment approaches, studies included in this review suggest that ML tools may have the potential to predict treatment outcomes of psychosis accurately. Future studies need to focus on refining feature characterization, validating prediction models, and evaluate their translation in real-world clinical practice.

Environmental effects on brain functional networks in a juvenile twin population.

The brain's intrinsic organization into large-scale functional networks, the resting state networks (RSN), shows complex inter-individual variability, consolidated during development. Nevertheless, the role of gene and environment on developmental brain functional connectivity (FC) remains largely unknown. Twin design represents an optimal platform to shed light on these effects acting on RSN characteristics. In this study, we applied statistical twin methods to resting-state functional magnetic resonance imaging (rs-fMRI) scans from 50 young twin pairs (aged 10-30 years) to preliminarily explore developmental determinants of brain FC. Multi-scale FC features were extracted and tested for applicability of classical ACE and ADE twin designs. Epistatic genetic effects were also assessed. In our sample, genetic and environmental effects on the brain functional connections largely varied between brain regions and FC features, showing good consistency at multiple spatial scales. Although we found selective contributions of common environment on temporo-occipital connections and of genetics on frontotemporal connections, the unique environment showed a predominant effect on FC link- and node-level features. Despite the lack of accurate genetic modeling, our preliminary results showed complex relationships between genes, environment, and functional brain connections during development. A predominant role of the unique environment on multi-scale RSN characteristics was suggested, which needs replications on independent samples. Future investigations should especially focus on nonadditive genetic effects, which remain largely unexplored.

A systematic review on the potential use of machine learning to classify major depressive disorder from healthy controls using resting state fMRI measures.

BACKGROUND: Major Depressive Disorder (MDD) is a psychiatric disorder characterized by functional brain deficits, as documented by resting-state functional magnetic resonance imaging (rs-fMRI) studies. AIMS: In recent years, some studies used machine learning (ML) approaches, based on rs-fMRI features, for classifying MDD from healthy controls (HC). In this context, this review aims to provide a comprehensive overview of the results of these studies. DESIGN: The studies research was performed on 3 online databases, examining English-written articles published before August 5, 2022, that performed a two-class ML classification using rs-fMRI features. The search resulted in 20 eligible studies. RESULTS: The reviewed studies showed good performance metrics, with better performance achieved when the dataset was restricted to a more homogeneous group in terms of disease severity. Regions within the default mode network, salience network, and central executive network were reported as the most important features in the classification algorithms. LIMITATIONS: The small sample size together with the methodological and clinical heterogeneity limited the generalizability of the findings. CONCLUSIONS: In conclusion, ML applied to rs-fMRI features can be a valid approach to classify MDD and HC subjects and to discover features that can be used for additional investigation of the pathophysiology of the disease.

Resting-state functional connectivity and spontaneous brain activity in early-onset bipolar disorder: A review of functional Magnetic Resonance Imaging studies.

BACKGROUND: Early-onset bipolar disorder (BD) is a complex psychiatric illness characterized by mood swings, irritability and functional impairments. To improve our understanding of the pathophysiology of the disorder, we collected the existing resting-state functional Magnetic Resonance Imaging (rs-fMRI) studies exploring resting-state functional connectivity (rs-FC) and spontaneous activity alterations in children and adolescents with BD. METHODS: A search on PubMed, Web of Science and Scopus was conducted to identify all the relevant rs-fMRI investigations conducted in early-onset BD. A total of 14 studies employing different methodological approaches to explore rs-FC and spontaneous activity in early-onset BD were included (independent component analysis, n = 1; seed-based analysis, n = 7; amplitude of low frequency fluctuations analysis, n = 2; regional homogeneity analysis, n = 4). RESULTS: Overall, the studies showed abnormalities within the Default Mode Network (DMN) and between the DMN and the Salience Network (SN). Moreover, widespread alterations in rs-FC and spontaneous brain activity within and between cortico-limbic structures, involving primarily the occipital and frontal lobes, amygdala, hippocampus, insula, thalamus and striatum were also reported. LIMITATIONS: The small sample sizes, the use of medications, the presence of comorbidities and the heterogeneity in methods hamper the integration of the study findings. CONCLUSIONS: Early-onset BD seems to be characterized by selective rs-FC and spontaneous activity dysfunctions in DMN and SN as well as in the cortico-limbic and cortico-striatal circuits, which could explain the emotive and cognitive deficits observed in this disabling psychiatric illness.

Effects of age and gender on neural correlates of emotion imagery.

Mental imagery is part of people's own internal processing and plays an important role in everyday life, cognition and pathology. The neural network supporting mental imagery is bottom-up modulated by the imagery content. Here, we examined the complex associations of gender and age with the neural mechanisms underlying emotion imagery. We assessed the brain circuits involved in emotion mental imagery (vs. action imagery), controlled by a letter detection task on the same stimuli, chosen to ensure attention to the stimuli and to discourage imagery, in 91 men and women aged 14-65 years using fMRI. In women, compared with men, emotion imagery significantly increased activation within the right putamen, which is involved in emotional processing. Increasing age, significantly decreased mental imagery-related activation in the left insula and cingulate cortex, areas involved in awareness of ones' internal states, and it significantly decreased emotion verbs-related activation in the left putamen, which is part of the limbic system. This finding suggests a top-down mechanism by which gender and age, in interaction with bottom-up effect of type of stimulus, or directly, can modulate the brain mechanisms underlying mental imagery.

Can neuroimaging-based biomarkers predict response to cognitive remediation in patients with psychosis? A state-of-the-art review.

BACKGROUND: Cognitive Remediation (CR) is designed to halt the pathological neural systems that characterize major psychotic disorders (MPD), and its main objective is to improve cognitive functioning. The magnitude of CR-induced cognitive gains greatly varies across patients with MPD, with up to 40% of patients not showing gains in global cognitive performance. This is likely due to the high degree of heterogeneity in neural activation patterns underlying cognitive endophenotypes, and to inter-individual differences in neuroplastic potential, cortical organization and interaction between brain systems in response to learning. Here, we review studies that used neuroimaging to investigate which biomarkers could potentially serve as predictors of treatment response to CR in MPD. METHODS: This systematic review followed the PRISMA guidelines. An electronic database search (Embase, Elsevier; Scopus, PsycINFO, APA; PubMed, APA) was conducted in March 2021. peer-reviewed, English-language studies were included if they reported data for adults aged 18+ with MPD, reported findings from randomized controlled trials or single-arm trials of CR; and presented neuroimaging data. RESULTS: Sixteen studies were included and eight neuroimaging-based biomarkers were identified. Auditory mismatch negativity (3 studies), auditory steady-state response (1), gray matter morphology (3), white matter microstructure (1), and task-based fMRI (7) can predict response to CR. Efference copy corollary/discharge, resting state, and thalamo-cortical connectivity (1) require further research prior to being implemented. CONCLUSIONS: Translational research on neuroimaging-based biomarkers can help elucidate the mechanisms by which CR influences the brain's functional architecture, better characterize psychotic subpopulations, and ultimately deliver CR that is optimized and personalized.

Sustained attention alterations in major depressive disorder: A review of fMRI studies employing Go/No-Go and CPT tasks.

BACKGROUND: Major depressive disorder (MDD) is a severe psychiatric condition characterized by selective cognitive dysfunctions. In this regard, functional Magnetic Resonance Imaging (fMRI) studies showed, both at resting state and during tasks, alterations in the brain functional networks involved in cognitive processes in MDD patients compared to controls. Among those, it seems that the attention network may have a role in the disease pathophysiology. Therefore, in this review we aim at summarizing the current fMRI evidence investigating sustained attention in MDD patients. METHODS: We conducted a search on PubMed on case-control studies on MDD employing fMRI acquisitions during Go/No-Go and continuous performance tasks. A total of 12 studies have been included in the review. RESULTS: Overall, the majority of fMRI studies reported quantitative alterations in the response to attentive tasks in selective brain regions, including the prefrontal cortex, the cingulate cortex, the temporal and parietal lobes, the insula and the precuneus, which are key nodes of the attention, the executive, and the default mode networks. LIMITATIONS: The heterogeneity in the study designs, fMRI acquisition techniques and processing methods have limited the generalizability of the results. CONCLUSIONS: The results from the included studies showed the presence of alterations in the activation patterns of regions involved in sustained attention in MDD, which are in line with current evidence and seemed to explain some of the key symptoms of depression. However, given the paucity and heterogeneity of studies available, it may be worthwhile to continue investigating the attentional domain in MDD with ad-hoc study designs to retrieve more robust evidence.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Case Report: Repeated Transcranial Magnetic Stimulation Improves Comorbid Binge Eating Disorder in Two Female Patients With Treatment-Resistant Bipolar Depression.

Introduction: Binge eating disorder (BED) is the most common eating disorder, affecting a large population worldwide. It is characterized by recurrent episodes of binge eating, with no compensatory behaviors. BED is often associated with psychiatric comorbidities, and still represents a challenge in terms of treatment strategies. In the last years, neuromodulation has represented a promising approach in the treatment of BED. We report the cases of two women, affected by Bipolar Disorder Type II (BD-II) and comorbid BED, whose BED symptoms improved after a course of accelerated intermittent Theta Burst Stimulation (iTBS). Methods: We carried out a clinical study, involving neurostimulation on six patients with a treatment-resistant depressive episode. The trial consisted of a 3-week accelerated iTBS treatment, delivered to the left dorsolateral pre-frontal cortex. Clinical evaluation scales (Hamilton Rating Scale for Depression, Montgomery-Åsberg Depression Rating Scale, and Young Mania Rating Scale) were administered at baseline, after 2 weeks, and at the end of the stimulation cycle. Pharmacotherapy was maintained unchanged during iTBS treatment. Patients gave their informed consent both for the protocol and for the publication. Results: The treatment was well-tolerated. Depressive symptoms only slightly improved; however, patients' binge episodes remitted completely, which was a serendipitous finding. BED symptomatology complete remission lasted up to 12 weeks follow-up. Discussion: This is the first study regarding iTBS use in BED in comorbidity with BD-II. Further research is still needed to assess the efficacy of this technique in BED treatment.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Brain Anatomical Mediators of GRIN2B Gene Association with Attention/Hyperactivity Problems: An Integrated Genetic-Neuroimaging Study.

This study aims to investigate the genetic and neural determinants of attention and hyperactivity problems. Using a proof-of-concept imaging genetics mediation design, we explore the relationship between the glutamatergic GRIN2B gene variants and inattention/hyperactivity with neuroanatomical measures as intermediates. Fifty-eight children and adolescents were evaluated for behavioral problems at three time points over approximately 7 years. The final assessment included blood drawing for genetic analyses and 3T magnetic resonance imaging. Attention/hyperactivity problems based on the Child Behavior Checklist/6-18, six GRIN2B polymorphisms and regional cortical thickness, and surface area and volume were estimated. Using general linear model (GLM) and mediation analyses, we tested whether GRIN2B exerted an influence on stable inattention/hyperactivity over development, and to what extent this effect was mediated by brain morphology. GLM results enlightened the relation between GRIN2B rs5796555-/A, volume in the left cingulate isthmus and inferior parietal cortices and inattention/hyperactivity. The mediation results showed that rs5796555-/A effect on inattention/hyperactivity was partially mediated by volume in the left isthmus of the cingulate cortex, suggesting a key role of this region in translating glutamatergic GRIN2B variations to attention/hyperactivity problems. This evidence can have important implications in the management of neurodevelopmental and psychiatric disorders.

Effective Connectivity During Rest and Music Listening: An EEG Study on Parkinson's Disease.

Music-based interventions seem to enhance motor, sensory and cognitive functions in Parkinson's disease (PD), but the underlying action mechanisms are still largely unknown. This electroencephalography (EEG) study aimed to investigate the effective connectivity patterns characterizing PD in the resting state and during music listening. EEG recordings were obtained from fourteen non-demented PD patients and 12 healthy controls, at rest and while listening to three music tracks. Theta- and alpha-band power spectral density and multivariate partial directed coherence were computed. Power and connectivity measures were compared between patients and controls in the four conditions and in music vs. rest. Compared to controls, patients showed enhanced theta-band power and slightly enhanced alpha-band power, but markedly reduced theta- and alpha-band interactions among EEG channels, especially concerning the information received by the right central channel. EEG power differences were partially reduced by music listening, which induced power increases in controls but not in patients. Connectivity differences were slightly compensated by music, whose effects largely depended on the track. In PD, music enhanced the frontotemporal inter-hemispheric communication. Our findings suggest that PD is characterized by enhanced activity but reduced information flow within the EEG network, being only partially normalized by music. Nevertheless, music capability to facilitate inter-hemispheric communication might underlie its beneficial effects on PD pathophysiology and should be further investigated.

Ultra-high field imaging in Major Depressive Disorder: a review of structural and functional studies.

BACKGROUND: Major depressive disorder (MDD) is a severe and pervasive psychiatric condition with a lifetime prevalence of 15-25%. Numerous Magnetic Resonance Imaging (MRI) studies employing scans at field strengths of 1.5T or 3T have been carried out in the last decades, providing an unprecedented insight into the neural correlates of MDD. However, in recent years, MRI technology has largely progressed and the use of scans at ultra-high field (≥ 7T) has improved the sensitivity and the resolution of MR images. In this context, with this review we aim to summarize evidence of structural and functional brain mechanisms underlying MDD obtained with ultra-high field MRI. METHODS: We conducted a search on PubMed, Scopus and Web of Science of neuroimaging studies on MDD patients, which employed ultra-high field MRI. We detected six structural MRI studies, two Diffusion Tensor Imaging (DTI) studies and five functional MRI (fMRI) studies. RESULTS: Overall, the MRI and DTI studies showed volumetric and structural connectivity alterations in the hippocampus and, to a lesser extent, in the amygdala. In contrast, more heterogeneous results were reported by fMRI studies, which, though, described functional abnormalities in the cingulate cortex, thalamus and several other brain areas. LIMITATIONS: The small sample size and the heterogeneity in patients' samples, processing and study design limit the conclusion of the present review. CONCLUSIONS: Studies employing scans at ultra-high magnetic field may provide a useful contribution to the mixed body of literature on MDD. This preliminary but promising evidence confirms the importance of performing ultra-high field MRI investigations in order to detect and better characterize subtle brain abnormalities in MDD.