Evaluation of the structural integrity of different spinal cord tracts with magnetization transfer ratio in degenerative cervical myelopathy.

PURPOSE: Degenerative cervical myelopathy (DCM) is a common cause of spinal cord dysfunction. In this study, we explored the potential of magnetization transfer ratio (MTR) for evaluating the structural integrity of spinal cord tracts in patients with clinically significant DCM. METHODS: Fifty-three patients with DCM and 41 patients with cervical radiculopathy were evaluated using high-resolution cervical spinal cord magnetic resonance imaging (MRI), which included the magnetization transfer technique. MRI data were analyzed with the Spinal Cord Toolbox (v5.5); MTR values in each spinal tract were calculated and compared between groups after correction for patient age and sex. Correlations between MTR values and patients' clinical disability rate were also evaluated. RESULTS: A statistically significant reduction in the average MTR of the spinal cord white matter, as well as the MTR of the ventral columns and lateral funiculi, was revealed in the DCM group (adjusted p < 0.01 for all comparisons). Furthermore, reductions in MTR values in the fasciculus cuneatus, spinocerebellar, rubrospinal, and reticulospinal tracts were found in patients with DCM (adjusted p < 0.01 for all comparisons). Positive correlations between the JOA score and the MTR within the ventral columns of the spinal cord (R = 0.38, adjusted p < 0.05) and the ventral spinocerebellar tract (R = 0.41, adjusted p < 0.05) were revealed. CONCLUSION: The findings of our study indicate that demyelination in patients with DCM primarily affects the spinal tracts of the extrapyramidal system, and the extent of these changes is related to the severity of the condition.

Utilizing the amide proton transfer technique to characterize diffuse gliomas based on the WHO 2021 classification of CNS tumors.

PURPOSE: Diffuse gliomas present a significant challenge for healthcare systems globally. While brain MRI plays a vital role in diagnosis, prognosis, and treatment monitoring, accurately characterizing gliomas using conventional MRI techniques alone is challenging. In this study, we explored the potential of utilizing the amide proton transfer (APT) technique to predict tumor grade and type based on the WHO 2021 Classification of CNS Tumors. METHODS: Forty-two adult patients with histopathologically confirmed brain gliomas were included in the study. They underwent 3T MRI imaging, which involved APT sequence. Multinomial and binary logistic regression models were employed to classify patients into clinically relevant groups based on MRI findings and demographic variables. RESULTS: We found that the best model for tumor grade classification included patient age along with APT values. The highest sensitivity (88%) was observed for Grade 4 tumors, while Grade 3 tumors showed the highest specificity (79%). For tumor type classification, our model incorporated four predictors: APT values, patient's age, necrosis, and the presence of hemorrhage. The glioblastoma group had the highest sensitivity and specificity (87%), whereas balanced accuracy was the lowest for astrocytomas (0.73). CONCLUSION: The APT technique shows great potential for noninvasive evaluation of diffuse gliomas. The changes in the classification of gliomas as per the WHO 2021 version of the CNS Tumor Classification did not affect its usefulness in predicting tumor grade or type.

Application of the T1w/T2w mapping technique for spinal cord assessment in patients with degenerative cervical myelopathy.

STUDY DESIGN: Retrospective case-control study. OBJECTIVES: To investigate signal changes on T1w/T2w signal intensity ratio maps within cervical cord in patients with degenerative cervical myelopathy (DCM). SETTING: Novosibirsk Neurosurgery Center, Russia. METHODS: A total of 261 patients with DCM and 42 age- and sex-matched healthy controls were evaluated using the T1w/T2w mapping method and spinal cord automatic morphometry. The T1w/T2w signal intensity ratio, which reflects white matter integrity, and the spinal cord cross-sectional area (CSA) were calculated and compared between the patients and the controls. In patients with DCM, the correlations between these parameters and neurological scores were also evaluated. RESULTS: The regional T1w/T2w ratio values from the cervical spinal cord at the level of maximal compression in patients with DCM were significantly lower than those in healthy controls (p < 0.001), as were the regional CSA values (p < 0.001). There was a positive correlation between the regional values of the T1w/T2w ratio and the values of the CSA at the level of maximal spinal cord compression. CONCLUSIONS: T1w/T2w mapping revealed that spinal cord tissue damage exists at the level of maximal compression in patients with DCM in association with spinal cord atrophy according to automatic morphometry. These changes were correlated with each other.

Diffusion tensor imaging reveals distributed white matter abnormalities in primary trigeminal neuralgia: Tract-based spatial statistics study.

BACKGROUND: Primary trigeminal neuralgia (PTN) is a prevalent chronic pain disorder whose pathogenesis is not limited to the trigeminal system. Despite the significant advances in uncovering underlying mechanisms, there is a paucity of comprehensive and consistent data regarding the role of white matter throughout the entire brain in PTN. METHODS: We performed a prospective case-control study. Sixty patients with PTN and 28 age- and sex-matched healthy controls were evaluated using diffusion tensor imaging (DTI). A tract-based spatial statistical approach was performed to investigate white matter impairment in patients with PTN with several metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). Additionally, ROI-based analysis was performed for each white matter tract to compare FA values between groups with correction for patient age and sex. Correlations between DTI data and nerve root compression severity, as well as pain severity, were also evaluated in patients with PTN. RESULTS: Our analysis demonstrated a widespread and symmetrical reduction in FA values among TN patients when compared to the control group (p < 0.05). Specifically, this FA decrease was predominantly observed in regions such as the corona radiata, internal capsule, optic radiation, and thalami, as well as structures within the posterior fossa, notably the cerebellar peduncles. No statistically significant differences were found between patients and the control group during the MD, AD and RD map analyses. ROI-based analysis did not reveal statistically significant changes in FA values in white matter tracts (p > 0.05 in all comparisons, FDR-corrected); however, there were trends towards FA value decreases in the internal capsule (p = 0.08, FDR-corrected) and inferior fronto-occipital fasciculus (p = 0.09, FDR-corrected). CONCLUSIONS: Our findings indicate the presence of microstructural abnormalities in white matter among individuals with primary trigeminal neuralgia, which may potentially play a role in the development and progression of the condition.

Brainstem and subcortical regions volume loss in patients with degenerative cervical myelopathy and its association with spinal cord compression severity.

BACKGROUND: In recent years, structural and functional reorganization of the brain and changes in brainstem structural connectivity have been shown in patients with degenerative cervical myelopathy (DCM). We hypothesized that volume loss in the basal ganglia, thalami, and brainstem structures exists and is associated with spinal cord compression severity in patients with DCM. METHODS: Forty-seven patients with DCM and 25 patients with cervical radiculopathy were evaluated using cervical spinal cord and brain magnetic resonance imaging (MRI). Brainstem structures, basal ganglia, and thalami volumes were evaluated with FreeSurfer and compared between groups with correction for individual intracranial volume, as well as patient age and sex. Additionally, spinal cord MRI data were analysed with the Spinal Cord Toolbox, and cross-sectional area (CSA) and fractional anisotropy (FA) values were calculated. Correlations between MR-morphometry data and spinal cord structural changes, as well as disease duration, were also evaluated in patients with DCM. RESULTS: A statistically significant reduction in the volume of the whole brainstem was revealed in the DCM group compared to the radiculopathy group (p < 0.01, FDR-corrected). Additionally, reductions in medulla oblongata, pons and midbrain volumes were found in patients with DCM (p < 0.01, p < 0.01 and p < 0.05, respectively, FDR-corrected). Additionally, a trend in the loss of volume of the left putamen was found (p = 0.087, FDR-corrected). Furthermore, medulla oblongata volume was correlated with spinal cord compression severity (R = 0.54, adjusted p < 0.001) and white matter damage (R = 0.46, adjusted p < 0.05) in patients with DCM. Negative correlations between the duration of the disease and the severity of spinal cord compression (R = -0.42, adjusted p < 0.05) and white matter damage (R = -0.49, adjusted p < 0.05) were also revealed, as well as a trend toward a negative association between the duration of the disease and the volume of the medulla oblongata (R = -0.35; adjusted p < 0.1). CONCLUSIONS: We revealed a reduction in the volume of brainstem structures in patients with DCM compared to patients with radiculopathy. Moreover, we found that these changes are associated with cord compression severity.

Brain but not serum BDNF levels are associated with structural alterations in the hippocampal regions in patients with drug-resistant mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy is the most common type of focal epilepsy, imposing a significant burden on the health care system worldwide. Approximately one-third of patients with this disease who do not adequately respond to pharmacotherapy are considered drug-resistant subjects. Despite having some clues of how such epileptic activity and resistance to therapy emerge, coming mainly from preclinical models, we still witness a scarcity of human data. To narrow this gap, in this study, we aimed to estimate the relationship between hippocampal and serum levels of brain-derived neurotrophic factor (BDNF), one of the main and most widely studied neurotrophins, and hippocampal subfield volumes in patients with drug-resistant mesial temporal epilepsy undergoing neurosurgical treatment. We found that hippocampal (but not serum) BDNF levels were negatively correlated with the contralateral volumes of the CA1 and CA4 subfields, presubiculum, subiculum, dentate gyrus, and molecular layer of the hippocampus. Taken together, these findings are generally in accordance with existing data, arguing for a proepileptic nature of BDNF effects in the hippocampus and related brain structures.

White and Gray Matter Perfusion in Children with Moyamoya Angiopathy after Revascularization Surgery.

INTRODUCTION: Surgical revascularization is very effective in patients with moyamoya angiopathy (MMA) and leads to improvements in cortical perfusion parameters. However, changes in white matter hemodynamics are still underestimated. To date, only a few studies have examined brain perfusion changes within deep white matter after bypass surgery in patients with MMA. METHODS: Ten children with MMA were evaluated using the CT perfusion technique before and after revascularization surgery. Brain perfusion parameters within gray and white matter were compared before and after surgery. The correlations between the perfusion parameters before surgery and the Suzuki stage, as well as between the perfusion parameters and the cognitive scores, were also evaluated. RESULTS: Brain perfusion parameters improved significantly in both gray matter (predominantly due to cerebral blood flow within the anterior circulation, p < 0.01) and white matter (predominantly due to cerebral blood volume within the semiovale centrum, p < 0.001). We revealed that the pattern of improvement in perfusion in white matter differed from the pattern of improvement in perfusion in gray matter. Significant correlations were revealed between the Suzuki stage before surgery and the perfusion parameters within the posterior cerebral artery circulation (adjusted p < 0.05). There were also significant correlations between cognitive scores and brain perfusion parameters in gray matter and white matter (adjusted p < 0.05). CONCLUSIONS: The perfusion parameters of gray matter and white matter in the brain improve differently after bypass surgery in patients with MMA. Different hemodynamics within these compartments could explain this.

Assessment of normal myelination in infants and young children using the T1w/T2w mapping technique.

Background: White matter myelination is a crucial process of CNS maturation. The purpose of this study was to validate the T1w/T2w mapping technique for brain myelination assessment in infants and young children. Methods: Ninety-four patients (0-23 months of age) without structural abnormalities on brain MRI were evaluated by using the T1w/T2w mapping method. The T1w/T2w signal intensity ratio, which reflects white matter integrity and the degree of myelination, was calculated in various brain regions. We performed a Pearson correlation analysis, a LOESS regression analysis, and a 2nd order polynomial regression analysis to describe the relationships between the regional metrics and the age of the patients (in months). Results: T1w/T2w ratio values rapidly increased in the first 6-9 months of life and then slowed thereafter. The T1w/T2w mapping technique emphasized the contrast between myelinated and less myelinated structures in all age groups, which resulted in better visualization. There were strong positive correlations between the T1w/T2w ratio values from the majority of white matter ROIs and the subjects' age (R = 0.7-0.9, p < 0.001). Within all of the analyzed regions, there were non-linear relationships between age and T1/T2 ratio values that varied by anatomical and functional location. Regions such as the splenium and the genu of the corpus callosum showed the highest R2 values, thus indicating less scattering of data and a better fit to the model. Conclusion: The T1w/T2w mapping technique may enhance our diagnostic ability to assess myelination patterns in the brains of infants and young children.

The habenular volume and PDE7A allelic polymorphism in major depressive disorder: preliminary findings.

OBJECTIVES: The habenula is a brain structure implicated in depression, yet with unknown molecular mechanisms. Several phosphodiesterases (PDEs) have been associated with a risk of depression. Although the role of PDE7A in the brain is unknown, it has enriched expression in the medial habenula, suggesting that it may play a role in depression. METHODS: We analysed: (1) habenula volume assessed by 3-T magnetic resonance imaging (MRI) in 84 patients with major depressive disorder (MDD) and 41 healthy controls; (2) frequencies of 10 single nucleotide polymorphisms (SNPs) in PDE7A gene in 235 patients and 41 controls; and (3) both indices in 80 patients and 27 controls. The analyses considered gender, age, body mass index and season of the MRI examination. RESULTS: The analysis did not reveal habenula volumetric changes in MDD patients regardless of PDE7A SNPs. However, in the combined group, the carriers of one or more mutations among 10 SNPs in the PDE7A gene had a lower volume of the left habenula (driven mainly by rs972362 and rs138599850 mutations) and consequently had the reduced habenular laterality index in comparison with individuals without PDE7A mutations. CONCLUSIONS: Our findings suggest the implication of the PDE7A gene into mechanisms determining the habenula structure.

Correction of Anticoagulant Therapy in Patients with Severe COVID-19 Virus Infection Using a Thrombodynamics Coagulation Assay.

BACKGROUND: The average frequency of thrombosis in patients with COVID-19 is still high despite low molecular weight heparin (LMWH) prophylactic. Global hemostasis assays, particularly thrombodynamics (TD), known to be sensitive to both hypercoagulation and heparin effects, could potentially be useful for individual management of anticoagulant therapy. METHODS: A total of 74 patients with lung involvement >50% were randomized into two groups: Group A (44 patients) received weight-based dosing of LMWH, and Group B (30 patients) received the first LMWH dose by a weight-based dosing protocol and then received an adjusted dose based on TD daily results. The endpoints of the study were thrombosis and bleeding as well as discharge or death of the patient. RESULTS: The incidence of thrombosis was 3 times lower in Group B under TD control compared to Group A without TD control: 7% versus 23 respectively (p = .05). The relative risk of thrombosis if the average clot growth rate V in TD exceeded the threshold value of 25 µm/min was 14.3 (p = .0005, 95% confidence interval 3.2-63.7). There were no clinically significant bleeding episodes in Group B while there were 7% in unregulated Group A. Mortality in Group B under TD control was lower than that in Group A without control: 27% versus 36%, respectively (p = .13). CONCLUSIONS: The dosing LMWH under thrombodynamics control in severe patients with COVID-19 allows for a significant reduction in thrombotic complications. Long-term hypercoagulation revealed by thrombodynamics (3 and more days) is a strong predictor of thrombosis (AUC = 0.83).

Myelin damage and cortical atrophy in watershed regions in patients with moyamoya angiopathy.

Background: Despite it being known that chronic ischemia results in myelin damage and gray matter atrophy, data regarding patients with moyamoya angiopathy is limited. We hypothesized that chronic ischemia in moyamoya angiopathy leads to myelin damage, especially in anterior watershed regions, as well as cortical atrophy in these areas. Materials and methods: Twenty adult patients with moyamoya angiopathy and 17 age- and sex-matched healthy controls were evaluated using the T1w/T2w mapping method and surface-based MR-morphometry. The T1w/T2w signal intensity ratio, which reflects the white matter integrity, and the cortical thickness, were calculated in watershed regions and compared between the patients and controls. In the patients with moyamoya angiopathy, the correlations between these parameters and the Suzuki stage were also evaluated. Results: The regional T1w/T2w ratio values from centrum semiovale in patients with MMA were significantly lower than those in healthy controls (p < 0.05); there was also a downward trend in T1w/T2w ratio values from middle frontal gyrus white matter in patients compared with the controls (p < 0.1). The cortical thickness of the middle frontal gyrus was significantly lower in patients than in healthy controls (p < 0.05). There were negative correlations between the Suzuki stage and the T1w/T2w ratio values from the centrum semiovale and middle frontal white matter. Conclusion: T1w/T2w mapping revealed that myelin damage exists in watershed regions in patients with moyamoya angiopathy, in association with cortical atrophy according to MR-morphometry. These changes were correlated with the disease stage.

Transcranial Current Stimulation as a Tool of Neuromodulation of Cognitive Functions in Parkinson's Disease.

Decrease in cognitive function is one of the most common causes of poor life quality and early disability in patients with Parkinson's disease (PD). Existing methods of treatment are aimed at both correction of motor and non-motor symptoms. Methods of adjuvant therapy (or complementary therapy) for maintaining cognitive functions in patients with PD are of interest. A promising subject of research in this regard is the method of transcranial electric current stimulation (tES). Here we reviewed the current understanding of the pathogenesis of cognitive impairment in PD and of the effects of transcranial direct current stimulation and transcranial alternating current stimulation on the cognitive function of patients with PD-MCI (Parkinson's Disease-Mild Cognitive Impairment).

Interstitial inflammation and pulmonary fibrosis in COVID-19: The potential role of cytostatic therapy for severe lung injury.

The progression of secondary pulmonary damage in SARS-COV-2 infection, associated with interstitial damage, inflammation and alveolar consolidation and eventually resulted in the development of pulmonary fibrosis (PF), remains one of the key clinical dilemmas for the treatment of patients in intensive care units (ICU). Currently, there is no standardized algorithm for PF prevention and timely management, although few studies have discussed the use of antifibrotic agents in COVID-19 patients. One of the treatment options for patients with interstitial PF, when irresponsive to the given corticosteroid therapy, is the administration of cytostatic agents, in particular, cyclophosphamide. Cyclophosphamide is one of the well-studied drugs in the cytostatic group, which effectiveness in inhibiting systemic inflammation suggests its ability to reduce the progression of the secondary lung damage, interstitial abnormalities and PF caused by the so-called "cytokine storm". The presented case reports provide data on the use of cyclophosphamide (Сy) in the management of severe respiratory failure in COVID-19 patients stationed in ICU. We describe three clinical cases characterized by different types of respiratory support, including extracorporeal membrane oxygenation.

Longitudinal multiparametric characterization of platelet dysfunction in COVID-19: Effects of disease severity, anticoagulation therapy and inflammatory status.

INTRODUCTION: Defects of platelet functional responses in COVID-19 were reported, but their origin and pathophysiological significance are unclear. The objective of this study was to characterize the thrombocytopathy in COVID-19. MATERIALS AND METHODS: Analysis of platelet functional responses to activation by flow cytometry and aggregometry in 46 patients with confirmed COVID-19 of different severity (non-ICU, ICU, and ECMO) over the course of hospitalization alongside with plasma coagulation, inflammatory markers (CRP, fibrinogen, NETosis assays in smears) was performed. RESULTS AND CONCLUSIONS: All patients had increased baseline percentage of procoagulant platelets (healthy: 0.9 ± 0.5%; COVID-19: 1.7 ± 0.6%). Patients had decreased agonist-induced platelet GPIb shedding (1.8 ± 0.7 vs 1.25 ± 0.4), P-Selectin exposure (1.51 ± 0.21 vs 1.1 ± 0.3) and aggregation. The values of these parameters among the non-ICU and ICU cohorts differed modestly, while the ECMO cohort differed significantly. Only ECMO patients had pronounced thrombocytopenia. While inflammatory markers improved over time, the observed platelet functional responses changed only moderately. SARS-CoV-2 RNA was found in 8% of blood samples and it did not correlate with platelet counts or responses. All patients had increased NETosis that moderately correlated with platelet dysfunction. High cumulative dosages of LMWH (average > 12,000 IU/day over 5 days) resulted in an improvement in platelet parameters. The observed pattern of platelet refractoriness was reproduced by in vitro pre-treatment of washed platelets with subnanomolar thrombin or perfusion of blood through a collagen-covered flow chamber. We conclude that platelet dysfunction in COVID-19 is consistent with the intravascular-coagulation-induced refractoriness rather than with an inflammation-induced mechanism or a direct activation by the virus.

A rare familial rearrangement of chromosomes 9 and 15 associated with intellectual disability: a clinical and molecular study.

BACKGROUND: There are many reports on rearrangements occurring separately in the regions of chromosomes 9p and 15q affected in the case under study. 15q duplication syndrome is caused by the presence of at least one extra maternally derived copy of the Prader-Willi/Angelman critical region. Trisomy 9p is the fourth most frequent chromosome anomaly with a clinically recognizable syndrome often accompanied by intellectual disability. Here we report a new case of a patient with maternally derived unique complex sSMC resulting in partial trisomy of both chromosomes 9 and 15 associated with intellectual disability. CASE PRESENTATION: We characterise a supernumerary derivative chromosome 15: 47,XY,+der(15)t(9;15)(p21.2;q13.2), likely resulting from 3:1 malsegregation during maternal gametogenesis. Chromosomal analysis showed that a phenotypically normal mother is a carrier of balanced translocation t(9;15)(p21.1;q13.2). Her 7-year-old son showed signs of intellectual disability and a number of physical abnormalities including bilateral cryptorchidism and congenital megaureter. The child's magnetic resonance imaging showed changes in brain volume and in structural and functional connectivity revealing phenotypic changes caused by the presence of the extra chromosome material, whereas the mother's brain MRI was normal. Sequence analyses of the microdissected der(15) chromosome detected two breakpoint regions: HSA9:25,928,021-26,157,441 (9p21.2 band) and HSA15:30,552,104-30,765,905 (15q13.2 band). The breakpoint region on chromosome HSA9 is poor in genetic features with several areas of high homology with the breakpoint region on chromosome 15. The breakpoint region on HSA15 is located in the area of a large segmental duplication. CONCLUSIONS: We discuss the case of these phenotypic and brain MRI features in light of reported signatures for 9p partial trisomy and 15 duplication syndromes and analyze how the genomic characteristics of the found breakpoint regions have contributed to the origin of the derivative chromosome. We recommend MRI for all patients with a developmental delay, especially in cases with identified rearrangements, to accumulate more information on brain phenotypes related to chromosomal syndromes.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders : Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = -0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

Brain structural correlates of insomnia severity in 1053 individuals with major depressive disorder: results from the ENIGMA MDD Working Group.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice.

Serotonin 5-HT2A receptors and the brain-derived neurotrophic factor (BDNF) are involved in the pathophysiology and treatment of many psychiatric diseases. However, the interaction between 5-HT2A and BDNF is still poorly understood. In the present paper, the effects of chronic treatment with mixed 5-HT2A/2C receptor agonist DOI, highly selective 5-HT2A agonists TCB-2 and 25CN-NBOH on behavior and the BDNF system have been investigated. Chronic treatment of males of C57Bl/6 mice with DOI, TCB-2 and 25CN-NBOH (1 mg/kg, i.p., 14 days) resulted in desensitization of 5-HT2A receptors. Treatment with 25CN-NBOH significantly increased startle amplitude. At the same time all used drugs failed to affect anxiety, exploratory and stereotyped behavior as well as spatial memory and learning. TCB-2 and 25CN-NBOH increased the BDNF mRNA level. All 5-HT2A agonists increased the proBDNF level but failed to alter the mature BDNF protein level. TrkB and p75NTR mRNA levels were affected by all utilized agonists. All drugs decreased the total level as well as membrane TrkB protein one indicating downregulation of TrkB receptors. All agonists decreased the membrane p75NTR protein level. Thus, we have shown for the first time that the chronic activation of the 5-HT2A receptor with agonists has affected the BDNF system almost on all levels-transcription, proBDNF production, TrkB and p75NTR receptors' level. The obtained data suggested possible suppression in BDNF-TrkB signaling under chronic treatment with 5-HT2A agonists.