Loss of age-related laminar differentiation of intracortical myelin in bipolar disorder.

Age-related changes of intracortical myelin in bipolar disorder (BD) have been observed to deviate from the quadratic age curve observed in healthy controls (HC), but it is unclear if this holds at varying cortical depths. From BD (n = 44; age range = 17.6-45.5 years) and HC (n = 60; age range = 17.1-45.8 years) participants, we collected 3T T1-weighted (T1w) images with strong intracortical contrast. Signal values were sampled from 3 equivolume cortical depths. Linear mixed models were used to compare age-related changes in the T1w signal between depths and between groups at each depth. In HC, the age-related changes were significantly different between the superficial one-fourth depth and the deeper depths in the right ventral somatosensory (t = -4.63; FDRp = 0.00025), left dorsomedial somatosensory (t = -3.16; FDRp = 0.028), left rostral ventral premotor (t = -3.16; FDRp = 0.028), and right ventral inferior parietal cortex (t = -3.29; FDRp = 0.028). BD participants exhibited no differences in the age-related T1w signal between depths. Illness duration was negatively correlated with the T1w signal at the one-fourth depth in the right anterior cingulate cortex (rACC; rho = -0.50; FDRp = 0.029). Physiological age-related and depth-specific variation in the T1w signal were not observed in BD. The T1w signal in the rACC may reflect lifetime disease burden in the disorder.

Network properties of intracortical myelin associated with psychosocial functioning in bipolar I disorder.

OBJECTIVE: Psychosocial functioning in bipolar disorder (BD) persists even during euthymia and has repeatedly been associated with illness progression and cognitive function. Its neurobiological correlates remain largely unexplored. Using a structural covariance approach, we explored whole cortex intracortical myelin (ICM) and psychosocial functioning in 39 BD type I and 58 matched controls. METHOD: T1 -weighted images (3T) optimized for ICM measurement were analyzed using a surface-based approach. The ICM signal was sampled at cortical mid-depth using the MarsAtlas parcellation, and psychosocial functioning was measured via the Functioning Assessment Short Test (FAST). Following construction of structural covariance matrices, graph theoretical measures were calculated for each subject. Within BD and HC groups separately, correlations between network measures and FAST were explored. After accounting for multiple comparisons, significant correlations were tested formally using rank-based regressions accounting for sex differences. RESULTS: In BD only, psychosocial functioning was associated with global efficiency (ß = -0.312, pcorr  = 0.03), local efficiency in the right rostral dorsolateral prefrontal cortex (ß = 0.545, pcorr  = 0.001) and clustering coefficient in this region (ß = 0.497, pcorr  = 0.0002) as well as in the right ventromedial prefrontal cortex (ß = 0.428, pcorr  = 0.002). All results excepting global efficiency remained significant after accounting for severity of depressive symptoms. In contrast, no significant associations between functioning and network measures were observed in the HC group. CONCLUSION: These results uncovered a novel brain-behaviour relationship between intracortical myelin signal changes and psychosocial functioning in BD.

The prevalence of borderline personality features and borderline personality disorder during the perinatal period: a systematic review and meta-analysis.

Borderline personality disorder (BPD) is a psychiatric disorder marked by severe affective instability and poor interpersonal functioning. Existing literature has highlighted that individuals with BPD are at greater risk for a wide range of adverse physiological and psychosocial outcomes in the perinatal period compared to perinatal individuals without BPD. However, to date, no systematic review has addressed the prevalence of BPD and borderline personality features (BPF) in pregnant and postpartum individuals. A systematic review and meta-analysis was conducted by searching three databases (PubMed, PsycINFO, and Embase) on April 6th, 2021. Research articles and conference abstracts that evaluated BPF or BPD in pregnant, postpartum, or mixed perinatal populations were included. Sixteen publications were included in the systematic review (n = 14 research articles, n = 2 conference abstracts), seven of which were included in the meta-analysis. Among non-clinical samples, prevalence rates of BPF during pregnancy ranged from 6.9 to 26.7%, while rates of BPD across the perinatal period ranged from 0.7 to 1.7%. Among clinical samples, rates of BPF and BPD across the perinatal period spanned 9.7-34% and 2.0-35.2%, respectively. Results from the meta-analysis revealed that the pooled prevalence rate of BPD in clinical samples during the perinatal period is 14.0% (95% CI [7.0, 22.0]). Among clinical perinatal samples, there is a high prevalence of borderline personality pathology. This review highlights the need for appropriate validated screening methods to identify and treat BPD in the perinatal population.

The Link between Estradiol and Neuroplasticity in Transgender Women after Gender-Affirming Surgery: A Bimodal Hypothesis.

For transgender individuals, gender-affirming surgery (GAS) and cross-sex hormone therapy (CSHT) are part of the gender transition process. Scientific evidence supporting the maintenance of CSHT after GAS-related gonadectomy is accumulating. However, few data are available on the impact of CSHT on the brain structure following hypogonadism. Thus, we aimed to investigate links between estradiol and brain cortical thickness (CTh) and cognition in 18 post-gonadectomy transgender women using a longitudinal design. For this purpose, the participants underwent a voluntary period of CSHT washout of at least 30 days, followed by estradiol re-institution for 60 days. High-resolution T1-weighted brain images, hormonal measures, working and verbal memory were collected at 2 time points: on the last day of the washout (t1) and on the last day of the 2-month CSHT period (t2). Between these 2 time points, CTh increased within the left precentral gyrus and right precuneus but decreased within the right lateral occipital cortex. However, these findings did not survive corrections of multiple comparisons. Nevertheless, there was a significant negative correlation between changes in estradiol levels and changes in CTh. This effect was evident in the left superior frontal gyrus, the left middle temporal gyrus, the right precuneus, the right superior temporal gyrus, and the right pars opercularis. Although there was an improvement in verbal memory following hypogonadism correction, we did not observe a significant relationship between changes in memory scores and CTh. Altogether, these findings suggest that there is a link between estradiol and CTh.

Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis.

BACKGROUND: Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear. We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS. METHODS: We used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs. RESULTS: Mice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity-but did not significantly attenuate the loss of PNNs. CONCLUSIONS: These findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.

Gray matter volume drives the brain age gap in schizophrenia: a SHAP study.

Neuroimaging-based brain age is a biomarker that is generated by machine learning (ML) predictions. The brain age gap (BAG) is typically defined as the difference between the predicted brain age and chronological age. Studies have consistently reported a positive BAG in individuals with schizophrenia (SCZ). However, there is little understanding of which specific factors drive the ML-based brain age predictions, leading to limited biological interpretations of the BAG. We gathered data from three publicly available databases - COBRE, MCIC, and UCLA - and an additional dataset (TOPSY) of early-stage schizophrenia (82.5% untreated first-episode sample) and calculated brain age with pre-trained gradient-boosted trees. Then, we applied SHapley Additive Explanations (SHAP) to identify which brain features influence brain age predictions. We investigated the interaction between the SHAP score for each feature and group as a function of the BAG. These analyses identified total gray matter volume (group × SHAP interaction term ß = 1.71 [0.53; 3.23]; pcorr < 0.03) as the feature that influences the BAG observed in SCZ among the brain features that are most predictive of brain age. Other brain features also presented differences in SHAP values between SCZ and HC, but they were not significantly associated with the BAG. We compared the findings with a non-psychotic depression dataset (CAN-BIND), where the interaction was not significant. This study has important implications for the understanding of brain age prediction models and the BAG in SCZ and, potentially, in other psychiatric disorders.

A detailed manual segmentation procedure for the hypothalamus for 3T T1-weighted MRI.

The hypothalamus is a small grey matter structure which plays a crucial role in many physiological functions. Some studies have found an association between hypothalamic volume and psychopathology, which stresses the need for a standardized method to maximize segmentation accuracy. Here, we provide a detailed step-by-step method outlining the procedures to manually segment the hypothalamus using anatomical T1w images from 3T scanners, which many neuroimaging studies collect as a standard anatomical reference image. We compared volumes generated by manual segmentation and those generated by an automatic algorithm, observing a significant difference between automatically and manually segmented hypothalamus volumes on both sides (left: U = 222842, p-value < 2.2e-16; right: U = 218520, p- value < 2.2e-16).•Significant difference exists between existing automatic segmentation methods and the manual segmentation procedure.•We discuss potential drift effects, segmentation quality issues, and suggestions on how to mitigate them.•We demonstrate that the present manual segmentation procedure using standard T1-weighted MRI may be significantly more accurate than automatic segmentation outputs.

Structural and Functional Brain Correlates of Neuroprogression in Bipolar Disorder.

Neuroprogression is associated with structural and functional brain changes that occur in parallel with cognitive and functioning impairments. There is substantial evidence showing early white matter changes, as well as trajectory-related gray matter alterations. Several structures, including prefrontal, parietal, temporal cortex, and limbic structures, seem to be altered over the course of bipolar disorder, especially associated with the number of episodes and length of the disease. An important limitation is that most of the studies used either a cross-sectional design or a short follow-up period, which may be insufficient to identify all neuroprogressive changes over time. In addition, the heterogeneity of patients with bipolar disorder is another challenge to determine which subjects will have a more pernicious trajectory. Larger studies and the use of new techniques, such as machine learning, may help to enable more discoveries and evidence on the role of neuroprogression in BD.

Accelerated brain aging in major depressive disorder and antidepressant treatment response: A CAN-BIND report.

OBJECTIVES: Previous studies suggest that major depressive disorder (MDD) may be associated with volumetric indications of accelerated brain aging. This study investigated neuroanatomical signs of accelerated aging in MDD and evaluated whether a brain age gap is associated with antidepressant response. METHODS: Individuals in a major depressive episode received escitalopram treatment (10-20 mg/d) for 8 weeks. Depression severity was assessed at baseline and at weeks 8 and 16 using the Montgomery-Asberg Depression Rating Scale (MADRS). Response to treatment was characterized by a significant reduction in the MADRS (≥50%). Nonresponders received adjunctive aripiprazole treatment (2-10 mg/d) for a further 8 weeks. The brain-predicted age difference (brain-PAD) at baseline was determined using machine learning methods trained on 3377 healthy individuals from seven publicly available datasets. The model used features from all brain regions extracted from structural magnetic resonance imaging data. RESULTS: Brain-PAD was significantly higher in older MDD participants compared to younger MDD participants [t(147.35) = -2.35, p < 0.03]. BMI was significantly associated with brain-PAD in the MDD group [r(155) = 0.19, p < 0.03]. Response to treatment was not significantly associated with brain-PAD. CONCLUSION: We found an elevated brain age gap in older individuals with MDD. Brain-PAD was not associated with overall treatment response to escitalopram monotherapy or escitalopram plus adjunctive aripiprazole.

Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

An investigation of cortical thickness and antidepressant response in major depressive disorder: A CAN-BIND study report.

Major depressive disorder (MDD) is considered a highly heterogeneous clinical and neurobiological mental disorder. We employed a novel layered treatment design to investigate whether cortical thickness features at baseline differentiated treatment responders from non-responders after 8 and 16 weeks of a standardized sequential antidepressant treatment. Secondary analyses examined baseline differences between MDD and controls as a replication analysis and longitudinal changes in thickness after 8 weeks of escitalopram treatment. 181 MDD and 95 healthy comparison (HC) participants were studied. After 8 weeks of escitalopram treatment (10-20 mg/d, flexible dosage), responders (>50% decrease in Montgomery-Åsberg Depression Scale score) were continued on escitalopram; non-responders received adjunctive aripiprazole (2-10 mg/d, flexible dosage). MDD participants were classified into subgroups according to their response profiles at weeks 8 and 16. Baseline group differences in cortical thickness were analyzed with FreeSurfer between HC and MDD groups as well as between response groups. Two-stage longitudinal processing was used to investigate 8-week escitalopram treatment-related changes in cortical thickness. Compared to HC, the MDD group exhibited thinner cortex in the left rostral middle frontal cortex [MNI(X,Y,Z=-29,9,54.5,-7.7); CWP=0.0002]. No baseline differences in cortical thickness were observed between responders and non-responders based on week-8 or week-16 response profile. No changes in cortical thickness was observed after 8 weeks of escitalopram monotherapy. In a two-step 16-week sequential clinical trial we found that baseline cortical thickness does not appear to be associated to clinical response to pharmacotherapy at 8 or 16 weeks.

Cortical thickness in major depressive disorder: A systematic review and meta-analysis.

Neuroimaging studies assessing neurobiological differences between patients with major depressive disorder (MDD) and healthy controls (HC) are often hindered by small sample sizes and heterogeneity of the patient sample. We performed a comprehensive literature search for studies assessing cortical thickness between patient and control groups, including studies investigating treatment effects on cortical thickness. We identified 34 studies meeting criteria for the systematic review and used Seed-based d Mapping to meta-analyze 24 of those that met additional criteria. Analysis of the full sample of subjects (MDD = 1073; HC = 936) revealed significant thinning in the MDD group in the bilateral orbitofrontal gyrus (BA 11), left pars opercularis (BA 45) and left calcarine fissure/lingual gyrus (BA 17), as well as an area of significant thickening in the left supramarginal gyrus (BA 40). These results support other imaging modalities that report disruptions in various frontal and temporal areas in MDD and identify additional areas in all major cerebral lobes likely to be significant when parsing for biomarkers of treatment or relapse.

Cerebral cortical thickness after treatment with desvenlafaxine succinate in major depressive disorder.

Thickness of the cerebral cortex has been previously investigated for its potential as a biomarker in major depressive disorder (MDD). This is the first study to examine the longitudinal effects of a serotonin-norepinephrine reuptake inhibitor, desvenlafaxine succinate (DVS), on whole-brain cortical thickness (CT) in patients treated for MDD. We also aimed to replicate a previous finding of an association between improvement in clinical severity and CT in one of five predefined regions-of-interest (ROI). Twenty-five individuals with MDD received treatment with DVS (50 mg/day) for 8 weeks, with 19 completing the study. We used FreeSurfer 6.0 to compare group differences between MDD and controls (n=23) and between treatment responders, treatment nonresponders and controls. We tested correlations between 8-week change in depression severity and regional CT in five ROIs: the rostral and caudal anterior cingulate cortex, lateral and medial orbitofrontal cortex and inferior temporal gyrus. There were no differences in CT between MDD and controls or DVS responders and controls. There was greater CT in DVS nonresponders in the left pars orbitalis when compared to controls [MNI (X, Y, Z=-38.4, 37.6, -11.1); P=0.027]. There were no significant correlations between change in depression severity and CT in any of the five ROIs. Brain CT does not seem to be a sensitive marker of short-term antidepressant response in MDD, except increased CT in nonresponders. Duration of the intervention and interindividual heterogeneity may impede identification of discriminating features of treatment response as associated to CT.