Sex-specific association between prenatal androgenization (second-to-fourth digit length ratio) and frontal brain volumes in adolescents.

Prenatal androgenization associates sex-dependently with behavior and mental health in adolescence and adulthood, including risk-taking, emotionality, substance use, and depression. However, still little is known on how it affects underlying neural correlates, like frontal brain control regions. Thus, we tested whether prenatal androgen load is sex-dependently related to frontal cortex volumes in a sex-balanced adolescent sample. In a cross-sectional magnetic resonance imaging study, we examined 61 adolescents (28 males, 33 females; aged 14 or 16 years) and analyzed associations of frontal brain region volumes with the second-to-fourth digit length ratio (2D:4D), an established marker for prenatal androgenization, using voxel-based morphometry in a region-of-interest approach. Lower 2D:4D (indicative of higher prenatal androgen load) correlated significantly with smaller volumes of the right anterior cingulate cortex (r-ACC; ß = 0.45) in male adolescents and with larger volumes of the left inferior frontal gyrus orbital part (l-IFGorb; ß = - 0.38) in female adolescents. The regression slopes of 2D:4D on the r-ACC also differed significantly between males and females. The study provides novel evidence that prenatal androgenization may influence the development of the frontal brain in a sex- and frontal brain region-specific manner. These effects might contribute to the well-known sex differences in risk-taking, emotionality, substance use, and depression. Future research is needed to elucidate the role of prenatal androgenization within the biopsychosocial model.

Brain structural correlates of upward social mobility in ethnic minority individuals.

PURPOSE: Perigenual anterior cingulate cortex (pACC) is a neural convergence site for social stress-related risk factors for mental health, including ethnic minority status. Current social status, a strong predictor of mental and somatic health, has been related to gray matter volume in this region, but the effects of social mobility over the lifespan are unknown and may differ in minorities. Recent studies suggest a diminished health return of upward social mobility for ethnic minority individuals, potentially due to sustained stress-associated experiences and subsequent activation of the neural stress response system. METHODS: To address this issue, we studied an ethnic minority sample with strong upward social mobility. In a cross-sectional design, we examined 64 young adult native German and 76 ethnic minority individuals with comparable sociodemographic attributes using whole-brain structural magnetic resonance imaging. RESULTS: Results showed a significant group-dependent interaction between perceived upward social mobility and pACC gray matter volume, with a significant negative association in the ethnic minority individuals. Post-hoc analysis showed a significant mediation of the relationship between perceived upward social mobility and pACC volume by perceived chronic stress, a variable that was significantly correlated with perceived discrimination in our ethnic minority group. CONCLUSION: Our findings extend prior work by pointing to a biological signature of the "allostatic costs" of socioeconomic attainment in socially disadvantaged upwardly mobile individuals in a key neural node implicated in the regulation of stress and negative affect.

Anterior paracingulate and cingulate cortex mediates the effects of cognitive load on speech sound discrimination.

Perceiving speech while performing another task is a common challenge in everyday life. How the brain controls resource allocation during speech perception remains poorly understood. Using functional magnetic resonance imaging (fMRI), we investigated the effect of cognitive load on speech perception by examining brain responses of participants performing a phoneme discrimination task and a visual working memory task simultaneously. The visual task involved holding either a single meaningless image in working memory (low cognitive load) or four different images (high cognitive load). Performing the speech task under high load, compared to low load, resulted in decreased activity in pSTG/pMTG and increased activity in visual occipital cortex and two regions known to contribute to visual attention regulation-the superior parietal lobule (SPL) and the paracingulate and anterior cingulate gyrus (PaCG, ACG). Critically, activity in PaCG/ACG was correlated with performance in the visual task and with activity in pSTG/pMTG: Increased activity in PaCG/ACG was observed for individuals with poorer visual performance and with decreased activity in pSTG/pMTG. Moreover, activity in a pSTG/pMTG seed region showed psychophysiological interactions with areas of the PaCG/ACG, with stronger interaction in the high-load than the low-load condition. These findings show that the acoustic analysis of speech is affected by the demands of a concurrent visual task and that the PaCG/ACG plays a role in allocating cognitive resources to concurrent auditory and visual information.

Negative priming: a meta-analysis of fMRI studies.

A phenomenon termed negative priming is defined as an increase in reaction time and/or decrease in performance during instances in which current target stimuli are employed as distractor stimuli in the previous trial. A recent qualitative review on negative priming reported neural regions of interest underlined by activity within the right middle frontal gyrus and left middle temporal gyrus; however, these areas of interest have not been tested and supported by using coordinate-based, quantitative meta-analysis. We compiled functional magnetic resonance imaging studies that examined neural correlates of priming tasks using perceptual, conceptual and lexical primes. Effect-size signed differential mapping was used to perform a neuroimaging meta-analysis on the negative priming effect. Results from fourteen studies (245 participants; 85 foci) show concordance across studies in the right middle frontal gyrus and the left superior temporal gyrus, as suggested by the previous review; however, results also yielded concordance within the anterior cingulate cortex. Our data support the extant hypothesis and offer new insights into the neural mechanisms of the negative priming effect.

Docosahexaenoic acid biostatus is associated with event-related functional connectivity in cortical attention networks of typically developing children.

OBJECTIVE: Although extant preclinical evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is important for neurodevelopment, little is known about its role in human cortical structural and functional maturation. In the present cross-sectional study, we investigated the relationship between DHA biostatus and functional connectivity in cortical attention networks of typically developing children. METHODS: Male children (aged 8-10 years, n = 36) were divided into 'low-DHA' (n = 18) and 'high-DHA' (n = 18) biostatus groups by a median split of erythrocyte DHA levels. Event-related functional connectivity during the performance of a sustained attention task (identical pairs continuous performance task (CPT-IP)) was conducted using functional magnetic resonance imaging. A voxelwise approach used the anterior cingulate cortex (ACC) as the seed-region. RESULTS: Erythrocyte DHA composition in the low-DHA group (2.6 ± 0.9%) was significantly lower than the high-DHA group (4.1 ± 1.1%, P ≤ 0.0001). Fish intake frequency was greater in the high-DHA group (P = 0.003) and was positively correlated with DHA levels among all subjects. The low-DHA group exhibited reduced functional connectivity between the ACC and the ventrolateral prefrontal cortex, insula, precuneus, superior parietal lobule, middle occipital gyrus, inferior temporal gyrus, and lingual gyrus compared with the high-DHA group (P < 0.05; corrected). The low-DHA group did not exhibit greater ACC functional connectivity with any region compared with the high-DHA group. On the CPT-IP task, the low-DHA group had slower reaction time (P = 0.03) which was inversely correlated with erythrocyte DHA among all subjects. DISCUSSION: These data suggest that low-DHA biostatus is associated with reduced event-related functional connectivity in cortical attention networks of typically developing children.

Pica in a Child with Anterior Cingulate Gyrus Oligodendroglioma: Case Report.

The anterior cingulate gyrus (ACG) is a continued focus of research as its exact role in brain function and vast connections with other anatomical locations is not fully understood. A review of the literature illustrates the role the ACG likely plays in cognitive and emotional processing, as well as a modulating role in motor function and goal-oriented behaviors. While lesions of the cingulate gyrus are rare, each new case broadens our understanding of its role in cognitive neuroscience and higher order processing. The authors present the case of an 8-year-old boy with a 1-month history of staring spells, agitated personality, and hyperphagia notable for the consumption of paper, who was found to have a 3-cm tumor in the left ACG. Following surgical resection of the tumor, his aggressive behavior and pica were ameliorated and the patient made an uneventful recovery, with no evidence of recurrence over the last 6 years since surgical resection. Here we discuss a unique behavioral presentation of pica, along with a review of the current literature, to illustrate functions of the ACG relevant to the location of the lesion.

Anatomical correlates of quality of life: evidence from voxel-based morphometry.

Quality of life (QOL) has been defined in many ways, and these definitions usually emphasize happiness and satisfaction with life. Health-related problems are known to cause lower QOL. However, the neural mechanisms underlying individual differences in QOL measured by questionnaire (QOLMQ) in young healthy subjects are unknown. QOL is essential to our well-being, and investigation of the neural mechanisms underlying QOL in uncompromised subjects is obviously of great scientific and social interest. We used voxel-based morphometry to investigate the association between regional gray matter volume (rGMV) and QOLMQ across the brain in healthy young adults (age, 21.4 ± 1.8 years) men (n = 88) and women (n = 68) in humans. We found significant negative relationships between QOLMQ and rGMV in a region in the left rostrolateral prefrontal cortex and regions in the dorsal part of the anterior cingulate gyrus and contingent cingulate regions. These findings show that structural variations in regions associated with processing of negative emotions such as fear and anger as well as those associated with evaluation of internally generated information are associated with QOLMQ. These findings suggest that these processes might be related to QOLMQ in healthy young adults.

Clavulanic Acid Decreases Cocaine Cue Reactivity in Addiction-Related Brain Areas, a Randomized fMRI Pilot Study.

Background: Preclinical studies show that clavulanic acid (CLAV) inhibits cocaine self-administration. This study investigates the effect of CLAV on regions of brain activation in response to cocaine cues during functional magnetic resonance imaging (fMRI) in participants with cocaine use disorder (CUD). Methods: A double-masked, placebo-controlled clinical trial with thirteen individuals with severe CUD who were randomized to treatment with CLAV (N = 10, 9 completers) 500 mg/day or matched placebo (PBO) (N = 3) for 3 days. fMRI was used to assess brain reactivity to 18 alternating six-second video clips of cocaine or neutral scenes. In this paradigm, participants were exposed to three different stimulus conditions: NEUTRAL, WATCH (passive watching), and DOWN (actively inhibiting craving while watching). Results: Participants who received CLAV demonstrated a significant reduction in brain activity in the anterior cingulate gyrus (p = 0.009) and the caudate (p = 0.018) in response to DOWN cocaine cues. There was a trend toward lessened cue reactivity in other regions implicated in CUD. Conclusion: CLAV reduced the response of the brain regions associated with motivation and emotional response during the DOWN condition compared to PBO, suggesting CLAV may strengthen voluntary efforts to avoid cocaine use. This pilot data supports the use of CLAV for CUD. (Trial registered in ClinicalTrials.gov NCT04411914).

Aberrant functional connectivity in anterior cingulate gyrus subregions in migraine without aura patients.

Background: The anterior cingulate gyrus (ACG) is an important regulatory region for pain-related information. However, the ACG is composed of subregions with different functions. The mechanisms underlying the brain networks of different subregions of the ACG in patients with migraine without aura (MwoA) are currently unclear. Methods: In the current study, resting-state functional magnetic resonance imaging (rsfMRI) and functional connectivity (FC) were used to investigate the functional characteristics of ACG subregions in MwoA patients. The study included 17 healthy volunteers and 28 MwoA patients. The FC calculation was based on rsfMRI data from a 3 T MRI scanner. The brain networks of the ACG subregions were compared using a general linear model to see if there were any differences between the two groups. Spearman correlation analysis was used to examine the correlation between FC values in abnormal brain regions and clinical variables. Results: Compared with healthy subjects, MwoA patients showed decreased FC between left subgenual ACG and left middle cingulate gyrus and right middle temporal gyrus. Meanwhile, MwoA patients also showed increased FC between pregenual ACG and right angular gyrus and increased FC between right pregenual ACG and right superior occipital gyrus. The FC values between pregenual ACG and right superior occipital gyrus were significantly positively correlated with the visual analogue scale. Conclusion: Disturbances of FC between ACG subregions and default model network and visual cortex may play a key role in neuropathological features, perception and affection of MwoA. The current study provides further insights into the complex scenario of MwoA mechanisms.

Predictive factors of post-operative apathy in patients with diffuse frontal gliomas undergoing awake brain mapping.

Patients with diffuse frontal gliomas often present with post-operative apathy after tumour removal. However, the association between apathy and tumour removal of gliomas from the frontal lobe remains unknown. This study aimed to investigate the factors influencing post-operative apathy after tumour removal in patients with diffuse frontal gliomas. We compared the demographics and clinical characteristics of patients with and without post-operative apathy in a cohort of 54 patients who underwent awake brain mapping for frontal gliomas. The frequency of clinical parameters such as left-sided involvement, high-grade tumour types (WHO grades III, IV), main tumour location in the anterior cingulate gyrus (ACC) and/or dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) was significantly greater in the apathetic group compared to the non-apathetic group. The apathetic group scored significantly lower on neuropsychological assessments such as the Letter Fluency Test among the Word Fluency Tests than the non-pathetic group (p = .000). Moreover, the scores of Parts 3, and 3-1 of the Stroop test were significantly lower in the apathetic group than those in the non-apathetic group (p = .023, .027, respectively). Multivariate model analysis revealed that the appearance of post-operative apathy was significantly related to side of the of lesion [left vs. right, hazard ratio (HR) = 8.00, 95% confidence interval (CI) = 1.36-46.96, p = .021], location of the main tumour in the frontal lobe (ACC/DLPFC/OFC vs. others, HR = 7.99, 95% CI = 2.16-29.59, p = .002), and the Letter Fluency Test (HR = .37, 95% CI = .15-.90, p = .028). Post-operative apathy is significantly associated with ACC and/or DLPFC and OFC in the left hemisphere of diffuse frontal gliomas. Apathy in frontal gliomas is correlated with a decline in the Letter Fluency Test scores. Therefore, this instrument is a potential predictor of post-operative apathy in patients with diffuse frontal gliomas undergoing awake brain mapping.

Principal components of functional connectivity: a new approach to study dynamic brain connectivity during rest.

Functional connectivity (FC) as measured by correlation between fMRI BOLD time courses of distinct brain regions has revealed meaningful organization of spontaneous fluctuations in the resting brain. However, an increasing amount of evidence points to non-stationarity of FC; i.e., FC dynamically changes over time reflecting additional and rich information about brain organization, but representing new challenges for analysis and interpretation. Here, we propose a data-driven approach based on principal component analysis (PCA) to reveal hidden patterns of coherent FC dynamics across multiple subjects. We demonstrate the feasibility and relevance of this new approach by examining the differences in dynamic FC between 13 healthy control subjects and 15 minimally disabled relapse-remitting multiple sclerosis patients. We estimated whole-brain dynamic FC of regionally-averaged BOLD activity using sliding time windows. We then used PCA to identify FC patterns, termed "eigenconnectivities", that reflect meaningful patterns in FC fluctuations. We then assessed the contributions of these patterns to the dynamic FC at any given time point and identified a network of connections centered on the default-mode network with altered contribution in patients. Our results complement traditional stationary analyses, and reveal novel insights into brain connectivity dynamics and their modulation in a neurodegenerative disease.

Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: a pilot study.

BACKGROUND & AIMS: The aim of the study was to evaluate early metabolic perfusion, and microstructural cerebral changes in patients with the hepatitis C virus (HCV) infection and normal appearing brain on plain MR using advanced MR techniques, as well as to assess correlations of MR measurements with the liver histology activity index (HAI). METHODS: Fifteen HCV-positive patients and 18 control subjects underwent single voxel MR spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI), using a 1.5T MR unit. MRS metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr) were calculated. PWI values of relative cerebral blood volume (rCBV) were assessed from 8 areas including several cortical locations, basal ganglia, and fronto-parietal white matter. DTI fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from 14 white matter tracts. RESULTS: Compared to controls, HCV-positive patients showed significantly (p < 0.05) lower NAA/Cr ratios within frontal and parietal white matters, lower rCBV values within frontal and temporo-parietal cortices, decreased FA values, as well as increased ADC values in several white matter tracts. We also found elevated rCBV values in basal ganglia regions. The increase in mI/Cr and Cho/Cr ratio was correlated with a higher HAI score. CONCLUSIONS: The results of advanced MR techniques indicate neurotoxicity of HCV reflected by neuronal impairment within white matter, cortical hypoperfusion, and disintegrity within several white matter tracts. Hyperperfusion in basal ganglia may be an indicator of brain inflammation in HCV patients. Our findings may suggest a biologic link between HCV-related liver disease and cerebral dysfunction.

Cortical thickness of the rostral anterior cingulate gyrus is associated with frailty in patients with end-stage renal disease undergoing hemodialysis in Korea: a cross-sectional study.

BACKGROUND: Frailty is defined as a condition of being weak and delicate, and it represents a state of high vulnerability to adverse health outcomes. Recent studies have suggested that the cingulate gyrus is associated with frailty in the elderly population. However, few imaging studies have explored the relationship between frailty and the cingulate gyrus in patients with end-stage renal disease (ESRD) undergoing hemodialysis. METHODS: Eighteen right-handed patients with ESRD undergoing hemodialysis were enrolled in the study. We used the FreeSurfer software package to estimate the cortical thickness of the regions of interest, including the rostral anterior, caudal anterior, isthmus, and posterior cingulate gyri. The Beck Depression Inventory, Beck Anxiety Inventory, and laboratory tests were also conducted. RESULTS: The cortical thickness of the right rostral anterior cingulate gyrus (ACG) was significantly correlated with the Fried frailty index, age, and creatinine level. Multiple regression analysis indicated that the cortical thickness of the right rostral ACG was associated with frailty after controlling for age and creatinine level. CONCLUSION: Our results indicate that the cortical thickness of the rostral ACG may be associated with frailty in patients with ESRD on hemodialysis and that the rostral ACG may play a role in the frailty mechanism of this population.

EEG source derived salience network coupling supports real-world attention switching.

While the brain mechanisms underlying selective attention have been studied in great detail in controlled laboratory settings, it is less clear how these processes function in the context of a real-world self-paced task. Here, we investigated engagement on a real-world computerized task equivalent to a standard academic test that consisted of solving high-school level problems in a self-paced manner. In this task, we used EEG-source derived estimates of effective coupling between brain sources to characterize the neural mechanisms underlying switches of sustained attention from the attentive on-task state to the distracted off-task state. Specifically, since the salience network has been implicated in sustained attention and attention switching, we conducted a hypothesis-driven analysis of effective coupling between the core nodes of the salience network, the anterior insula (AI) and the anterior cingulate cortex (ACC). As per our hypothesis, we found an increase in AI - > ACC effective coupling that occurs during the transitions of attention from on-task focused to off-task distracted state. This research may inform the development of future neural function-targeted brain-computer interfaces to enhance sustained attention.

Toward the unknown: consciousness and pain.

Studies of consciousness are hindered by the complexity of the brain, but it is possible to study the consciousness of a sensation, namely pain. Three systems are necessary to experience pain: the somatosensory system conveys information about an injury to the thalamus where an awareness of the injury but not the painfulness emerges. The thalamus distributes the information to the affective system, which modulates the intensity of the pain, and to the cognitive system that imparts attention to the pain. Imaging of patients in pain and those experiencing placebo and hypnosis-induced analgesia shows that two essential cortical circuits for pain and attention are located within the anterior cingulate cortex. The circuits are activated when a high-frequency input results in the development of a long-term potentiation (LTP) at synapses on the apical dendrites of pyramidal neurons. The LTP acts via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, and an anterior cingulate cortex-specific type-1 adenylate cyclase is necessary for both the LTP and the pain. The apical dendrites form an extensive network such that the input from serious injuries results in the emergence of a local field potential. Using mouse models, I propose experiments designed to test the hypothesis that the local field potential is necessary and sufficient for the consciousness of pain.

The dysregulation of top-down control in individuals with high test anxiety: A resting state fMRI study.

BACKGROUND: Individuals with high test anxiety (HTA) have deficits in attentional control and in stress responses when faced with tests. However, little is known about the underlying neural mechanism. Anterior cingulate cortex (ACC) is involved in both attention and emotion networks, therefore this study examined the neural functional dysregulation in test anxiety from the perspective of functional connectivity (FC) using bilateral ACC as the regions of interest. METHODS: Fifty-one participants were divided into HTA (n = 23) and low test anxiety (LTA, n = 28) group according to their Test Anxiety Scale (TAS) scores. Brain imaging data in resting, preparing, and recovering phases of a modified social evaluative threat task were collected, and emotional changes were assessed. RESULTS: Compared with the LTA group, the HTA group exhibited significantly lower FCs between the ACC and superior frontal gyrus (SFG) in all 3 phases, significantly lower FCs between the ACC and inferior parietal gyrus (IPG), and significantly higher FCs between the ACC superior temporal gyrus (STG) in the preparing phase. Moreover, in the HTA group, the resting state IPG-ACC FC was associated with their TAS score, the preparing state STG-ACC FC was associated with the increased anxiety. CONCLUSIONS: Individuals with HTA have general prefrontal control deficits. When facing a test, they tend to recruit more resources to deal with high emotional interference. The dysregulated control of the ACC by the frontal-parietal network may underlie the pathophysiology of test anxiety.

Fatigue in Cirrhosis.

Fatigue is a common symptom in patients with liver disease and has a significant impact on the health-related quality of life (HR-QoL). Its pathogenesis is poorly understood and is considered multifactorial. The liver is central in the pathogenesis of fatigue because it uniquely regulates much of the production, storage, and release of substrate for energy generation. Also, the liver "cross-talks" with the key organs that are responsible for this symptom complex-gut, skeletal muscle, and brain. Fatigue can have both peripheral (i.e., neuromuscular) and central (i.e., resulting from changes in neurotransmission within the brain) components. The treatment strategies for the management of fatigue are behavioral changes and pharmacotherapy, along with dietetic intervention and exercise. However, there is no consensus on management strategies for fatigue in patients with liver disease. This article gives an overview of fatigue as a concept, its pathophysiology, measures to evaluate fatigue in patients with liver disease, the impact of fatigue on chronic liver disease, assessment of fatigue in an appropriate clinical setting, and various interventions to manage fatigue.

Determinants of Schizophrenia Endophenotypes Based on Neuroimaging and Biochemical Parameters.

Despite extensive research, there is no convincing evidence of a reliable diagnostic biomarker for schizophrenia beyond clinical observation. Disorders of glutamatergic neurotransmission associated with N-methyl-D-aspartate (NMDA) receptor insufficiency, neuroinflammation, and redox dysregulation are the principal common mechanism linking changes in the periphery with the brain, ultimately contributing to the emergence of negative symptoms of schizophrenia that underlie differential diagnosis. The aim of the study was to evaluate the influence of these systems via peripheral and cerebral biochemical indices in relation to the patient's clinical condition. Using neuroimaging diagnostics, we were able to define endophenotypes of schizophrenia based on objective laboratory data that form the basis of a personalized approach to diagnosis and treatment. The two distinguished endophenotypes differed in terms of the quality of life, specific schizophrenia symptoms, and glutamatergic neurotransmission metabolites in the anterior cingulate gyrus. Our results, as well as further studies of the excitatory or inhibitory balance of microcircuits, relating the redox systems on the periphery with the distant regions of the brain might allow for predicting potential biomarkers of neuropsychiatric diseases, including schizophrenia. To the best of our knowledge, our study is the first to identify an objective molecular biomarker of schizophrenia outcome.

Effects of transcutaneous auricular vagus nerve stimulation on brain functional connectivity of medial prefrontal cortex in patients with primary insomnia.

As a representative of acupuncture and nonpharmaceutical therapy, auricular acupuncture has been widely for the treatment of insomnia. Transcutaneous auricular vagus nerve stimulation (taVNS) is a combination of auricular point stimulation and vagus nerve stimulation. It can not only treat primary insomnia effectively, but also is noninvasive, painless, portable and economical. The medial prefrontal cortex (mPFC) is a core region of default mode network (DMN), which is important for maintenance of sleep. However, the mechanism of taVNS in alleviating primary insomnia (PI) remains to be clarified. In this study, we found that taVNS could not only effectively reduce the score of Pittsburgh Sleep Quality Index, but also decreased functional connection (FC) between the left mPFC and bilateral dorsal anterior cingulate gyrus as well as FC between the right mPFC and the occipital cortex in patients with PI. Furthermore, the decrease in FC was positively correlated with the decline of sleep index score. Therefore, we proposed that treatment with taVNS can improve sleep quality and prolong sleep duration in patients with PI by reducing FC within DMN, FC between DMN and salience network, as well as FC between DMN and the occipital cortex. This may be one of mechanisms of taVNS in treating PI.

Disrupted hemispheric connectivity specialization in patients with major depressive disorder: Evidence from the REST-meta-MDD Project.

BACKGROUND: Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied. METHODS: Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes). RESULTS: Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities. LIMITATIONS: Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results. CONCLUSIONS: Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective.