On the Role of Bilateral Brain Hypofunction and Abnormal Lateralization of Cortical Information Flow as Neural Underpinnings of Conventional Metaphor Processing Impairment in Schizophrenia: An fMRI and EEG Study.

Figurative language processing (e.g. metaphors) is commonly impaired in schizophrenia. In the present study, we investigated the neural activity and propagation of information within neural circuits related to the figurative speech, as a neural substrate of impaired conventional metaphor processing in schizophrenia. The study included 30 schizophrenia outpatients and 30 healthy controls, all of whom were assessed with a functional Magnetic Resonance Imaging (fMRI) and electroencephalography (EEG) punchline-based metaphor comprehension task including literal (neutral), figurative (metaphorical) and nonsense (absurd) endings. The blood oxygenation level-dependent signal was recorded with 3T MRI scanner and direction and strength of cortical information flow in the time course of task processing was estimated with a 64-channel EEG input for directed transfer function. The presented results revealed that the behavioral manifestation of impaired figurative language in schizophrenia is related to the hypofunction in the bilateral fronto-temporo-parietal brain regions (fMRI) and various differences in effective connectivity in the fronto-temporo-parietal circuit (EEG). Schizophrenia outpatients showed an abnormal pattern of connectivity during metaphor processing which was related to bilateral (but more pronounced at the left hemisphere) hypoactivation of the brain. Moreover, we found reversed lateralization patterns, i.e. a rightward-shifted pattern during metaphor processing in schizophrenia compared to the control group. In conclusion, the presented findings revealed that the impairment of the conventional metaphor processing in schizophrenia is related to the bilateral brain hypofunction, which supports the evidence on reversed lateralization of the language neural network and the existence of compensatory recruitment of alternative neural circuits in schizophrenia.

Prenatal exposure to air pollution and maternal depression: Combined effects on brain aging and mental health in young adulthood.

INTRODUCTION: Both maternal depression problems during pregnancy and prenatal exposure to air pollution have been associated with changes in the brain as well as worse mood and anxiety in the offspring in adulthood. However, it is not clear whether these effects are independent or whether and how they might interact and impact the brain age and mental health of the young adult offspring. METHODS: A total of 202 mother-child dyads from a prenatal birth cohort were assessed for maternal depression during pregnancy through self-report questionnaires administered in the early 90s, exposure to air pollutants (Sulfur dioxide [SO2], nitrogen oxides [NOx], and suspended particle matter [SPM]) during each trimester based on maternal address and air quality data, mental health of the young adult offspring (28-30 years of age; 52% men, all of European ancestry) using self-report questionnaires for depression (Beck Depression Inventory), mood dysregulation (Profile of Mood States), anxiety (State-Trait Anxiety Inventory), and psychotic symptoms (Schizotypal Personality Questionnaire), and brain age, estimated from structural magnetic resonance imaging (MRI) and previously published neuroanatomical age prediction model using cortical thickness maps. The brain age gap estimate (BrainAGE) was computed by subtracting structural brain age from chronological age. Trajectories of exposure to air pollution during pregnancy were assessed using Growth Mixture Modeling. The interactions of prenatal depression and prenatal exposure to air pollutants on adult mental health and BrainAGE were assessed using hierarchical linear regression. RESULTS: We revealed two distinct trajectories of exposure to air pollution during pregnancy: "early exposure," characterized by high exposure during the first trimester, followed by a steady decrease, and "late exposure," characterized by low exposure during the first trimester, followed by a steady increase in the exposure during the subsequent trimesters. Maternal depression during the first half of pregnancy interacted with NOX exposure trajectory, predicting mood dysregulation and schizotypal symptoms in young adults. In addition, maternal depression during the second half of pregnancy interacted with both NOx and SO2 exposure trajectories, respectively, and predicted BrainAGE in young adults. In those with early exposure to NOx, maternal depression during pregnancy was associated with worse mental health and accelerated brain aging in young adulthood. In contrast, in those with early exposure to SO2, maternal depression during pregnancy was associated with slower brain aging in young adulthood. CONCLUSIONS: Our findings provide the first evidence of the combined effects of prenatal exposure to air pollution and maternal depression on mental health outcomes and brain age in young adult offspring. Moreover, they point out the importance of the timing and trajectory of the exposure during prenatal development.

Facial emotion processing in patients with borderline personality disorder as compared with healthy controls: an fMRI and ECG study.

BACKGROUND: Maladaptive behaviors and interpersonal difficulties in patients with borderline personality disorder (BPD) seem connected to biased facial emotion processing. This bias is often accompanied by heightened amygdala activity in patients with BPD as compared to healthy controls. However, functional magnetic resonance imaging (fMRI) studies exploring differences between patients and healthy controls in facial emotion processing have produced divergent results. The current study explored fMRI and heart rate variability (HRV) correlates of negative facial emotion processing in patients with BPD and healthy controls. METHODS: The study included 30 patients with BPD (29 females; age: M = 24.22, SD = 5.22) and 30 healthy controls (29 females; M = 24.66, SD = 5.28). All participants underwent the "faces" task, an emotional face perception task, in an fMRI session simultaneously with ECG. In this task, participants are presented with emotional expressions of disgust, sadness, and fear (as a negative condition) and with the same pictures in a scrambled version (as a neutral condition). RESULTS: We found no differences in brain activity between patients with BPD and healthy controls when processing negative facial expressions as compared to neutral condition. We observed activation in large-scale brain areas in both groups when presented with negative facial expressions as compared to neutral condition. Patients with BPD displayed lower HRV than healthy controls in both conditions. However, there were no significant associations between HRV and amygdala activity and BPD symptoms. CONCLUSION: The results of this study indicate no abnormal brain activity during emotional facial processing in patients with BPD. This result contrasts with previous studies and more studies are needed to clarify the relationship between facial emotion processing and brain activity in patients with BPD. Possible reasons for the absence of brain activity differences are discussed in the study. Consistent with previous findings, patients showed lower HRV than healthy controls. However, HRV was not associated with amygdala activity and BPD symptoms.

Association of Maternal Depression During Pregnancy and Recent Stress With Brain Age Among Adult Offspring.

Importance: Maternal mental health problems during pregnancy are associated with altered neurodevelopment in offspring, but the long-term relationship between these prenatal risk factors and offspring brain structure in adulthood remains incompletely understood due to a paucity of longitudinal studies. Objective: To evaluate the association between exposure to maternal depression in utero and offspring brain age in the third decade of life, and to evaluate recent stressful life events as potential moderators of this association. Design, Setting, and Participants: This cohort study examined the 30-year follow-up of a Czech prenatal birth cohort with a within-participant design neuroimaging component in young adulthood conducted from 1991 to 2022. Participants from the European Longitudinal Study of Pregnancy and Childhood prenatal birth cohort were recruited for 2 magnetic resonance imaging (MRI) follow-ups, one between ages 23 and 24 years (early 20s) and another between ages 28 and 30 years (late 20s). Exposures: Maternal depression during pregnancy; stressful life events in the past year experienced by the young adult offspring. Main Outcomes and Measures: Gap between estimated neuroanatomical vs chronological age at MRI scan (brain age gap estimation [BrainAGE]) calculated once in participants' early 20s and once in their late 20s, and pace of aging calculated as the differences between BrainAGE at the 2 MRI sessions in young adulthood. Results: A total of 260 individuals participated in the second neuroimaging follow-up (mean [SD] age, 29.5 [0.6] years; 135 [52%] male); MRI data for both time points and a history of maternal depression were available for 110 participants (mean [SD] age, 29.3 [0.6] years; 56 [51%] male). BrainAGE in participants' early 20s was correlated with BrainAGE in their late 20s (r = 0.7, P < .001), and a previously observed association between maternal depression during pregnancy and BrainAGE in their early 20s persisted in their late 20s (adjusted R2 = 0.04; P = .04). However, no association emerged between maternal depression during pregnancy and the pace of aging between the 2 MRI sessions. The stability of the associations between maternal depression during pregnancy and BrainAGE was also supported by the lack of interactions with recent stress. In contrast, more recent stress was associated with greater pace of aging between the 2 MRI sessions, independent of maternal depression (adjusted R2 = 0.09; P = .01). Conclusions and Relevance: The findings of this cohort study suggest that maternal depression and recent stress may have independent associations with brain age and the pace of aging, respectively, in young adulthood. Prevention and treatment of depression in pregnant mothers may have long-term implications for offspring brain development.

Neural correlates of social exclusion and overinclusion in patients with borderline personality disorder: an fMRI study.

BACKGROUND: Interpersonal difficulties of patients with borderline personality disorder (BPD) are closely related to rejection sensitivity. The aim of the present study was to gain further insight into the experience and cerebral processing of social interactions in patients with BPD by using fMRI during experimentally induced experiences of social exclusion, inclusion, and overinclusion. METHODS: The study involved 30 participants diagnosed with BPD (29 female and 1 male; age: M = 24.22, SD = 5.22) and 30 healthy controls (29 female and 1 male; age: M = 24.66, SD = 5.28) with no current or lifetime psychiatric diagnoses. In the fMRI session, all participants were asked to complete a Cyberball task that consisted of an alternating sequence of inclusion, exclusion, and overinclusion conditions. RESULTS: Compared to healthy controls, participants with BPD reported higher levels of inner tension and more unpleasant emotions across all experimental conditions. At the neural level, the participants with BPD showed lower recruitment of the left hippocampus in response to social exclusion (relative to the inclusion condition) than the healthy controls did. Lower recruitment of the left hippocampus in this contrast was associated with childhood maltreatment in patients with BPD. However, this difference was no longer significant when we added the covariate of hippocampal volume to the analysis. During social overinclusion (relative to the inclusion condition), we observed no significant differences in a group comparison of neural activation. CONCLUSIONS: The results of our study suggest that patients with BPD experience more discomfort than do healthy controls during social interactions. Compared to healthy participants, patients with BPD reported more inner tension and unpleasant emotions, irrespective of the extent to which others included them in social interactions. At a neural level, the participants with BPD showed a lower recruitment of the left hippocampus in response to social exclusion than the healthy controls did. The reduced activation of this neural structure could be related to a history of childhood maltreatment and smaller hippocampal volume in patients with BPD.

Birth outcomes, puberty onset, and obesity as long-term predictors of biological aging in young adulthood.

Background: Biological aging and particularly the deviations between biological and chronological age are better predictors of health than chronological age alone. However, the predictors of accelerated biological aging are not very well understood. The aim was to determine the role of birth outcomes, time of puberty onset, body mass index (BMI), and body fat in accelerated biological aging in the third decade of life. Methods: We have conducted a second follow-up of the Czech part of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC-CZ) prenatal birth cohort in young adulthood (52% male; age 28-30; n = 262) to determine the role of birth outcomes, pubertal timing, BMI, and body fat on biological aging. Birth outcomes included birth weight, length, and gestational age at birth. Pubertal timing was determined by the presence of secondary sexual characteristics at the age of 11 and the age of first menarche in women. Biological age was estimated using the Klemera-Doubal Method (KDM), which applies 9-biomarker algorithm including forced expiratory volume in one second (FEV1), systolic blood pressure, glycated hemoglobin, total cholesterol, C-reactive protein, creatinine, urea nitrogen, albumin, and alkaline phosphatase. Accelerated/decelerated aging was determined as the difference between biological and chronological age (BioAGE). Results: The deviations between biological and chronological age in young adulthood ranged from -2.84 to 4.39 years. Accelerated biological aging was predicted by higher BMI [in both early (R2 adj = 0.05) and late 20s (R2 adj = 0.22)], subcutaneous (R2 adj = 0.21) and visceral fat (R2 adj = 0.25), puberty onset (η p 2 = 0.07), birth length (R2 adj = 0.03), and the increase of BMI over the 5-year period between the two follow-ups in young adulthood (R2 adj = 0.09). Single hierarchical model revealed that shorter birth length, early puberty onset, and greater levels of visceral fat were the main predictors, together explaining 21% of variance in accelerated biological aging. Conclusion: Our findings provide comprehensive support of the Life History Theory, suggesting that early life adversity might trigger accelerated aging, which leads to earlier onset of puberty but decreasing fitness in adulthood, reflected by more visceral fat and higher BMI. Our findings also suggest that reduction of BMI in young adulthood slows down biological aging.

The association of matrix metalloproteinase 9 (MMP9) with hippocampal volume in schizophrenia: a preliminary MRI study.

Matrix metalloproteinases 9 (MMP9) are enzymes involved in regulating neuroplasticity in the hippocampus. This, combined with evidence for disrupted hippocampal structure and function in schizophrenia, has prompted our current investigation into the relationship between MMP9 and hippocampal volumes in schizophrenia. 34 healthy individuals (mean age = 32.50, male = 21, female = 13) and 30 subjects with schizophrenia (mean age = 33.07, male = 19, female = 11) underwent a blood draw and T1-weighted magnetic resonance imaging. The hippocampus was automatically segmented utilizing FreeSurfer. MMP9 plasma levels were measured with ELISA. ANCOVAs were conducted to compare MMP9 plasma levels (corrected for age and sex) and hippocampal volumes between groups (corrected for age, sex, total intracranial volume). Spearman correlations were utilized to investigate the relationship between symptoms, medication, duration of illness, number of episodes, and MMP9 plasma levels in patients. Last, we explored the correlation between MMP9 levels and hippocampal volumes in patients and healthy individuals separately. Patients displayed higher MMP9 plasma levels than healthy individuals (F(1, 60) = 21.19, p < 0.0001). MMP9 levels correlated with negative symptoms in patients (R = 0.39, p = 0.035), but not with medication, duration of illness, or the number of episodes. Further, patients had smaller left (F(1,59) = 9.12, p = 0.0040) and right (F(1,59) = 6.49, p = 0.013) hippocampal volumes. Finally, left (R = -0.39, p = 0.034) and right (R = -0.37, p = 0.046) hippocampal volumes correlated negatively with MMP9 plasma levels in patients. We observe higher MMP9 plasma levels in SCZ, associated with lower hippocampal volumes, suggesting involvement of MMP9 in the pathology of SCZ. Future studies are needed to investigate how MMP9 influences the pathology of SCZ over the lifespan, whether the observed associations are specific for schizophrenia, and if a therapeutic modulation of MMP9 promotes neuroprotective effects in SCZ.

Cognitive impairment and depression: Meta-analysis of structural magnetic resonance imaging studies.

Longitudinal comorbidity of depression and cognitive impairment has been reported by number of epidemiological studies but the underlying mechanisms explaining the link between affective problems and cognitive decline are not very well understood. Imaging studies have typically investigated patients with major depressive disorder (MDD) and mild cognitive impairment (MCI) separately and thus have not identified a structural brain signature common to these conditions that may illuminate potentially targetable shared biological mechanisms. We performed a meta-analysis of. 48 voxel-based morphometry (VBM) studies of individuals with MDD, MCI, and age-matched controls and demonstrated that MDD and MCI patients had shared volumetric reductions in a number of regions including the insula, superior temporal gyrus (STG), inferior frontal gyrus, amygdala, hippocampus, and thalamus. We suggest that the shared volumetric reductions in the insula and STG might reflect communication deficits and infrequent participation in mentally or socially stimulating activities, which have been described as risk factors for both MCI and MDD. We also suggest that the disease-specific structural changes might reflect the disease-specific symptoms such as poor integration of emotional information, feelings of helplessness and worthlessness, and anhedonia in MDD. These findings could contribute to better understanding of the origins of MDD-MCI comorbidity and facilitate development of early interventions.

The neural substrates of diminished humor comprehension in schizophrenia and its relationship with psychopathology.

Patients with schizophrenia commonly revealed difficulties in understanding humor. Previous research suggested links between impaired humor comprehension, psychopathology symptoms and cognitive deficits. In this study, we investigated the associations between neural substrates of humor processing and psychopathology and cognition in schizophrenia. We assessed 25 schizophrenia outpatients in an functional magnetic resonance imaging (fMRI) procedure and 40 in an electroencephalography (EEG) procedure. A punchline­based humor comprehension task was used in which outpatients rated stories by their comprehensibility and funniness. The symptom severity and cognition were correlated with activation within the humor processing network using fMRI and effective connectivity using an EEG­based directed transfer function (DTF) method. More severe positive and disorganization symptoms were associated with impaired humor comprehension and with altered temporo­parietal effective connectivity during humor processing. More severe excitement and emotional reactivity symptoms were associated with increased activation in the bilateral frontal and temporo­parietal regions. Moreover, schizophrenia outpatients with better cognitive functioning were more accurate in humor comprehension that was associated with increased fronto­temporo­parietal activation and effective connectivity. We found the intensity of humor processing (fMRI) in schizophrenia is related to the level of cognitive abilities and the severity of schizophrenia psychopathology that is also reflected in altered effective connectivity (EEG­DTF) in the humor processing network.

On the relation of white matter brain abnormalities and the asociality symptoms in schizophrenia outpatients - a DTI study.

Recent MRI studies have shown that abnormal functional connections in schizophrenia coexist with subtle changes in the structure of axons in the brain. However, there is a discrepancy in the literature concerning the relationship between white matter abnormalities and the occurrence of negative psychopathological symptoms. In the present study, we investigate the relationship between the altered white matter structure and specific psychopathology symptoms, i.e., subscales of Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptoms Scale (BNSS) in a sample of schizophrenia outpatients. For investigation on white matter abnormalities in schizophrenia, the diffusion tensor imaging analysis of between-group differences in main diffusion parameters by tract-based spatial statistics was conducted on schizophrenia outpatients and healthy controls. Hence, the correlation of PANSS and BNSS psychopathology subscales in the clinical group with fractional anisotropy was analyzed in the 17 selected cortical regions of interest. Presented between-group results revealed widespread loss of white matter integrity located across the brain in schizophrenia outpatients. Results on the white matter relationship with psychopathology revealed the negative correlation between fractional anisotropy in the left orbital prefrontal cortex, right Heschl's gyrus, bilateral precuneus and posterior cingulate cortex and the severity of asociality, as assessed with the BNSS. In conclusion, the presented study confirms the previous evidence on the widespread white matter abnormalities in schizophrenia outpatients and indicates the existence of the subtle but specific association between fractional anisotropy in the fronto-temporo-parietal regions with the asociality.Recent MRI studies have shown that abnormal functional connections in schizophrenia coexist with subtle changes in the structure of axons in the brain. However, there is a discrepancy in the literature concerning the relationship between white matter abnormalities and the occurrence of negative psychopathological symptoms. In the present study, we investigate the relationship between the altered white matter structure and specific psychopathology symptoms, i.e., subscales of Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptoms Scale (BNSS) in a sample of schizophrenia outpatients. For investigation on white matter abnormalities in schizophrenia, the diffusion tensor imaging analysis of between-group differences in main diffusion parameters by tract-based spatial statistics was conducted on schizophrenia outpatients and healthy controls. Hence, the correlation of PANSS and BNSS psychopathology subscales in the clinical group with fractional anisotropy was analyzed in the 17 selected cortical regions of interest. Presented between-group results revealed widespread loss of white matter integrity located across the brain in schizophrenia outpatients. Results on the white matter relationship with psychopathology revealed the negative correlation between fractional anisotropy in the left orbital prefrontal cortex, right Heschl's gyrus, bilateral precuneus and posterior cingulate cortex and the severity of asociality, as assessed with the BNSS. In conclusion, the presented study confirms the previous evidence on the widespread white matter abnormalities in schizophrenia outpatients and indicates the existence of the subtle but specific association between fractional anisotropy in the fronto-temporo-parietal regions with the asociality.

Emotional Awareness in Schizophrenia Is Associated With Gray Matter Volume of Right Precuneus.

Objectives: We assessed the relationship between emotional awareness (e.g., the ability to identify and differentiate our own feelings and feelings of others) and regional brain volumes in healthy and in schizophrenia groups. Methods: Magnetic resonance images of 29 subjects with schizophrenia and 33 matched healthy controls were acquired. Brain gray matter was parcellated using FreeSurfer and 28 regions of interest associated with emotional awareness were analyzed. All participants were assessed using the Levels of Emotional Awareness Scale (LEAS) of Self and of Other. LEAS scores were correlated with gray matter volume for each hemisphere on the 14 brain regions of the emotional awareness network. Results: Individuals with schizophrenia showed decreased emotional awareness on both LEAS Self and LEAS Other compared to healthy controls. There were no statistically significant between-group differences in gray matter volumes of the emotional awareness network. The performance on LEAS Other correlated negatively with right precuneus gray matter volume only in the schizophrenia group. Conclusion: Our findings suggest a relationship between gray matter volume of the right precuneus and deficits in understanding of emotional states of others in schizophrenia.

Emotion recognition and theory of mind in schizophrenia: A meta-analysis of neuroimaging studies.

OBJECTIVES: Patients with schizophrenia have difficulties processing the emotional and cognitive states of others. Neuroimaging studies show inconsistent findings. METHODS: We used a Seed-based d Mapping meta-analytic method to explore brain activation during facial emotion recognition and theory of mind tasks in schizophrenia patients. RESULTS: The patients showed lesser recruitment of the facial emotion processing network; behavioural performance was associated with the activation of the precentral gyrus. We found abnormal activation of the mentalising network in schizophrenia patients during reasoning about other people's mental states; patients with worse performances showed lesser activation in the right insula and superior temporal gyrus. Multimodal meta-analysis showed overlaps of brain-related abnormalities for both modalities in schizophrenia, with reduced recruitment of the right insula, anterior cingulate and medial prefrontal cortex and increased activation in the bilateral parietal cortex. Meta-regression results indicate that illness duration, medication and symptomatology might influence social-cognitive network disruptions in schizophrenia. CONCLUSIONS: These findings suggest the complex impairment of social cognition, as demonstrated by neural-related circuit disruptions during facial emotion processing and theory of mind tasks in schizophrenia.

Theory of Mind Skills Are Related to Resting-State Frontolimbic Connectivity in Schizophrenia.

Patients with schizophrenia (SCH) often demonstrate impairment in social-cognitive functions as well as disturbances in large-scale network connectivity. The ventromedial prefrontal cortex (vmPFC) is a core region of the default mode network, with projections to limbic structures. It plays an important role in social and emotional decision-making. We investigated whether resting-state functional connectivity (FC) relates to the cognitive and affective domains of theory of mind (ToM). Twenty-three SCH patients and 19 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging scanning. vmPFC seed connectivity was correlated with behavioral measures assessing ToM domains. SCH performed less well than HCs in both ToM task domains. An analysis of the resting-state FC revealed that SCH had reduced connectivity from the vmPFC to the subcallosal cortex, right amygdala, and right hippocampus as a function of behavioral scores in both ToM domains. Within-group analyses indicated that in HCs, the performance in ToM was positively associated with frontoamygdalar resting-state connectivity, whereas in SCH, the performance in ToM was negatively associated with the frontosubcallosal connectivity. Differences in the pattern of the resting-state frontolimbic connectivity and its associations with performance in ToM tasks between the two study groups might represent a different setup for processing social information in patients with SCH.