Changes in perfusion, and structure of hippocampal subfields related to cognitive impairment after ECT: A pilot study using ultra high field MRI.

BACKGROUND: Electroconvulsive therapy (ECT) in patients with major depression is associated with volume changes and markers of neuroplasticity in the hippocampus, in particular in the dentate gyrus. It is unclear if these changes are associated with cognitive side effects. OBJECTIVES: We investigated whether changes in cognitive functioning after ECT were associated with hippocampal structural changes. It was hypothesized that 1) volume increase of hippocampal subfields and 2) changes in perfusion and diffusion of the hippocampus correlated with cognitive decline. METHODS: Using ultra high field (7 T) MRI, intravoxel incoherent motion and volumetric data were acquired and neurocognitive functioning was assessed before and after ECT in 23 patients with major depression. Repeated measures correlation analysis was used to examine the relation between cognitive functioning and structural characteristics of the hippocampus. RESULTS: Left hippocampal volume, left and right dentate gyrus and right CA1 volume increase correlated with decreases in verbal memory functioning. In addition, a decrease of mean diffusivity in the left hippocampus correlated with a decrease in letter fluency. LIMITATIONS: Due to methodological restrictions direct study of neuroplasticity is not possible. MRI is used as an indirect measure. CONCLUSION: As both volume increase in the hippocampus and MD decrease can be interpreted as indirect markers for neuroplasticity that co-occur with a decrease in cognitive functioning, our results may indicate that neuroplastic processes are affecting cognitive processes after ECT.

Childhood trauma is associated with reduced frontal gray matter volume: a large transdiagnostic structural MRI study.

BACKGROUND: Childhood trauma increases risk for psychopathology and cognitive impairment. Prior research mainly focused on the hippocampus and amygdala in single diagnostic categories. However, other brain regions may be impacted by trauma as well, and effects may be independent of diagnosis. This cross-sectional study investigated cortical and subcortical gray matter volume in relation to childhood trauma severity. METHODS: We included 554 participants: 250 bipolar-I patients, 84 schizophrenia-spectrum patients and 220 healthy individuals without a psychiatric history. Participants filled in the Childhood Trauma Questionnaire. Anatomical T1 MRI scans were acquired at 3T, regional brain morphology was assessed using Freesurfer. RESULTS: In the total sample, trauma-related gray matter reductions were found in the frontal lobe (ß = -0.049, p = 0.008; q = 0.048), this effect was driven by the right medial orbitofrontal, paracentral, superior frontal regions and the left precentral region. No trauma-related volume reductions were observed in any other (sub)cortical lobes nor the hippocampus or amygdala, trauma-by-group (i.e. both patient groups and healthy subjects) interaction effects were absent. A categorical approach confirmed a pattern of more pronounced frontal gray matter reductions in individuals reporting multiple forms of trauma and across quartiles of cumulative trauma scores. Similar dose-response patterns were revealed within the bipolar and healthy subgroups, but did not reach significance in schizophrenia-spectrum patients. CONCLUSIONS: Findings show that childhood trauma is linked to frontal gray matter reductions, independent of psychiatric morbidity. Our results indicate that childhood trauma importantly contributes to the neurobiological changes commonly observed across psychiatric disorders. Frontal volume alterations may underpin affective and cognitive disturbances observed in trauma-exposed individuals.

Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders.

Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free-water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations - a presumed proxy for neuro-inflammation - between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL-6, IL-8, IL-10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, nonFA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD.

Adverse childhood experiences and fronto-subcortical structures in the developing brain.

The impact of adverse childhood experiences (ACEs) differs between individuals and depends on the type and timing of the ACE. The aim of this study was to assess the relation between various recently occurred ACEs and morphology in the developing brain of children between 8 and 11 years of age. We measured subcortical volumes, cortical thickness, cortical surface area and fractional anisotropy in regions of interest in brain scans acquired in 1,184 children from the YOUth cohort. ACEs were based on parent-reports of recent experiences and included: financial problems; parental mental health problems; physical health problems in the family; substance abuse in the family; trouble with police, justice or child protective services; change in household composition; change in housing; bereavement; divorce or conflict in the family; exposure to violence in the family and bullying victimization. We ran separate linear models for each ACE and each brain measure. Results were adjusted for the false discovery rate across regions of interest. ACEs were reported for 83% of children in the past year. Children were on average exposed to two ACEs. Substance abuse in the household was associated with larger cortical surface area in the left superior frontal gyrus, t(781) = 3.724, p FDR = 0.0077, right superior frontal gyrus, t(781) = 3.409, p FDR = 0.0110, left pars triangularis, t(781) = 3.614, p FDR = 0.0077, left rostral middle frontal gyrus, t(781) = 3.163, p FDR = 0.0195 and right caudal anterior cingulate gyrus, t(781) = 2.918, p FDR = 0.0348. Household exposure to violence (was associated with lower fractional anisotropy in the left and right cingulum bundle hippocampus region t(697) = -3.154, p FDR = 0.0101 and t(697) = -3.401, p FDR = 0.0085, respectively. Lower household incomes were more prevalent when parents reported exposure to violence and the mean parental education in years was lower when parents reported substance abuse in the family. No other significant associations with brain structures were found. Longer intervals between adversity and brain measurements and longitudinal measurements may reveal whether more evidence for the impact of ACEs on brain development will emerge later in life.

Modular-Level Functional Connectome Alterations in Individuals With Hallucinations Across the Psychosis Continuum.

Functional connectome alterations, including modular network organization, have been related to the experience of hallucinations. It remains to be determined whether individuals with hallucinations across the psychosis continuum exhibit similar alterations in modular brain network organization. This study assessed functional connectivity matrices of 465 individuals with and without hallucinations, including patients with schizophrenia and bipolar disorder, nonclinical individuals with hallucinations, and healthy controls. Modular brain network organization was examined at different scales of network resolution, including (1) global modularity measured as Qmax and Normalised Mutual Information (NMI) scores, and (2) within- and between-module connectivity. Global modular organization was not significantly altered across groups. However, alterations in within- and between-module connectivity were observed for higher-order cognitive (e.g., central-executive salience, memory, default mode), and sensory modules in patients with schizophrenia and nonclinical individuals with hallucinations relative to controls. Dissimilar patterns of altered within- and between-module connectivity were found bipolar disorder patients with hallucinations relative to controls, including the visual, default mode, and memory network, while connectivity patterns between visual, salience, and cognitive control modules were unaltered. Bipolar disorder patients without hallucinations did not show significant alterations relative to controls. This study provides evidence for alterations in the modular organization of the functional connectome in individuals prone to hallucinations, with schizophrenia patients and nonclinical individuals showing similar alterations in sensory and higher-order cognitive modules. Other higher-order cognitive modules were found to relate to hallucinations in bipolar disorder patients, suggesting differential neural mechanisms may underlie hallucinations across the psychosis continuum.

Shape and volume changes of the superior lateral ventricle after electroconvulsive therapy measured with ultra-high field MRI.

The subventricular zone (SVZ) of the lateral ventricles harbors neuronal stem cells in adult mammals. Rodent studies report neurogenic effects in the SVZ of electroconvulsive stimulation. We hypothesize that if this finding translates to depressed patients undergoing electroconvulsive therapy (ECT), this would be reflected in shape changes at the SVZ. Using T1-weighted MR images acquired at ultra-high field strength (7T), the shape and volume of the ventricles were compared from pre to post ECT after 10 ECT sessions (in patients twice weekly) or 5 weeks apart (controls) using linear mixed models with age and gender as covariates. Ventricle shape significantly changed and volume significantly decreased over time in patients for the left ventricle, but not in controls. The decrease in volume of the ventricles was associated to a decrease in depression scores, and an increase in the left dentate gyrus, However, the shape changes of the ventricles were not restricted to the neurogenic niche in the lateral walls of the ventricles, providing no clear evidence for neurogenesis as sole explanation of volume changes in the ventricles after ECT.

Changes in negative symptoms are linked to white matter changes in superior longitudinal fasciculus in individuals at ultra-high risk for psychosis.

AIM: Growing evidence suggests that subtle white matter (WM) alterations are associated with psychopathology in individuals at ultra-high risk for psychosis (UHR). However, the longitudinal relationship between symptom progression and WM changes over time remains under-explored. Here, we examine associations between changes in clinical symptoms and changes in WM over six months in a large UHR-cohort. METHODS: 110 UHR-individuals and 59 healthy controls underwent diffusion weighted imaging at baseline and after six months. Group × time effects on fractional anisotropy (FA) were tested globally and in four predefined regions of interest (ROIs) bilaterally using linear modelling with repeated measures. Correlations between the changes in clinical symptoms and FA changes in the ROIs were examined with Pearson's correlation. A partial least squares correlation-technique (PLS-C) explored multivariate associations between patterns of changes in psychopathology, regional FA and additional WM indices. RESULTS: At baseline, UHR-individuals displayed significantly lower FA globally (p = 0.018; F = 12.274), in right superior longitudinal fasciculus (p = 0.02; Adj R2 = 0.07) and in left uncinate fasciculus (p = 0.048; Adj R2 = 0.058) compared to controls (corrected). We identified a group × time interaction in global FA and right superior longitudinal fasciculus, but the finding did not survive multiple comparisons. However, an increase of negative symptoms in UHR-individuals correlated with FA increase in right superior longitudinal fasciculus (p = 0.048, corrected, r = 0.357), and this finding was supported by the multivariate PLS-C. CONCLUSION: We found a positive correlation with a moderate effect between change in negative symptoms and FA change over 6 months in right superior longitudinal fasciculus. This link appeared mainly to reflect a subgroup of UHR-individuals, which already at baseline presented as vulnerable.

Associations between cognition and white matter microstructure in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls: A multivariate pattern analysis.

BACKGROUND: Cognitive functions have been associated with white matter (WM) microstructure in schizophrenia, but most studies are limited by examining only select cognitive measures and single WM tracts in chronic, medicated patients. It is unclear if the cognition-WM relationship differs between antipsychotic-naïve patients with schizophrenia and healthy controls, as differential associations have not been directly examined. Here we examine if there are differential patterns of associations between cognition and WM microstructure in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls, and we characterize reliable contributors to the pattern of associations across multiple cognitive domains and WM regions, in order to elucidate white matter contribution to the neural underpinnings of cognitive deficits. METHODS: Thirty-six first-episode antipsychotic-naïve patients with schizophrenia and 52 matched healthy controls underwent cognitive tests and diffusion-weighted imaging on a 3T Magnetic Resonance Imaging scanner. Using a multivariate partial least squares correlation analysis, we included 14 cognitive variables and mean fractional anisotropy values of 48 WM regions. RESULTS: Initial analyses showed significant group differences in both measures of WM and cognition. There was no group interaction effect in the pattern of associations between cognition and WM microstructure. The combined analysis of patients and controls lead to a significant pattern of associations (omnibus test p = .015). Thirty-four regions and seven cognitive functions contributed reliably to the associations. CONCLUSIONS: The lack of an interaction effect suggests similar associations in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls. This, together with the differences in both WM and cognitive measurements, supports the involvement of WM in cognitive deficits in schizophrenia. Our findings add to the field by showing a coherent picture of the overall pattern of association between cognition and WM. These findings increase our understanding of the impact of WM on cognition, contributing to the search for neuromarkers of cognitive deficits in schizophrenia.

Diffusion MRI derived free-water imaging measures in patients with schizophrenia and their non-psychotic siblings.

Free-water imaging is a diffusion MRI technique that separately models water diffusion hindered by fiber tissue and water that disperses freely in the extracellular space. Studies using this technique have shown that schizophrenia is characterized by a lower level of fractional anisotropy of the tissue compartment (FAt) and higher free-water fractional volume (FW). It is unknown, however, whether such abnormalities are an expression of pre-existing (genetic) risk for schizophrenia or a manifestation of the illness. To investigate the contribution of familial risk factors to white matter abnormalities, we used the free-water imaging technique to assess FAt and FW in a large cohort of 471 participants including 161 patients with schizophrenia, 182 non-psychotic siblings, and 128 healthy controls. In this sample, patients did not show significant differences in FAt as compared to controls, but did exhibit a higher level of FW relative to both controls and siblings in the left uncinate fasciculus, superior corona radiata and fornix / stria terminalis. This increase in FW was found to be related to, though not solely explained by, ventricular enlargement. Siblings did not show significant FW abnormalities. However, siblings did show a higher level of FAt as compared to controls and patients, in line with results of a previous study on the same data using conventional DTI. Taken together, our findings suggest that extracellular free-water accumulation in patients is likely a manifestation of established disease rather than an expression of familial risk for schizophrenia and that super-normal levels of FAt in unaffected siblings may reflect a compensatory process.

Functional connectome differences in individuals with hallucinations across the psychosis continuum.

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.

Multimodal assessment of white matter microstructure in antipsychotic-naïve schizophrenia patients and confounding effects of recreational drug use.

Cerebral white matter (WM) aberrations in schizophrenia have been linked to multiple neurobiological substrates but the underlying mechanisms remain unknown. Moreover, antipsychotic treatment and substance use constitute potential confounders. Multimodal studies using diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) may provide deeper insight into the whole brain WM pathophysiology in schizophrenia. We combined DTI and MTI to investigate WM integrity in 51 antipsychotic-naïve, first-episode schizophrenia patients and 55 matched healthy controls, using 3 T magnetic resonance imaging (MRI). Psychopathology was assessed with the positive and negative syndrome scale (PANSS). A whole brain partial least squares correlation (PLSC) method was used to conjointly analyze DTI-derived measures (fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), mode of anisotropy (MO)) and the magnetization transfer ratio (MTR) to identify group differences, and associations with psychopathology. In secondary analyses, we excluded recreational substance users from both groups resulting in 34 patients and 51 healthy controls. The primary PLSC group difference analysis identified a significant pattern of lower FA, AD, MO and higher RD in patients (p = 0.04). This pattern suggests disorganized WM microstructure in patients. The secondary PLSC group difference analysis without recreational substance users revealed a significant pattern of lower FA and higher AD, RD, MO, MTR in patients (p = 0.04). This pattern in the substance free patients is consistent with higher extracellular free-water concentrations, which may reflect neuroinflammation. No significant associations with psychopathology were observed. Recreational substance use appears to be a confounding issue, which calls for attention in future WM studies.

No Effects of Cognitive Remediation on Cerebral White Matter in Individuals at Ultra-High Risk for Psychosis-A Randomized Clinical Trial.

BACKGROUND: Individuals at ultra-high risk for psychosis (UHR) present with subtle alterations in cerebral white matter (WM), which appear to be associated with clinical and functional outcome. The effect of cognitive remediation on WM organization in UHR individuals has not been investigated previously. METHODS: In a randomized, clinical trial, UHR individuals aged 18 to 40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation for 20 weeks. Cognitive remediation comprised 20 x 2-h sessions of neurocognitive and social-cognitive training. Primary outcome was whole brain fractional anisotropy derived from diffusion weighted imaging, statistically tested as an interaction between timepoint and treatment group. Secondary outcomes were restricted to five predefined region of interest (ROI) analyses on fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. For significant timepoint and treatment group interactions within these five ROIs, we explored associations between longitudinal changes in WM and cognitive functions/clinical symptoms. Finally, we explored dose-response effects of cognitive remediation on WM. RESULTS: A total of 111 UHR individuals were included. Attrition-rate was 26%. The cognitive remediation group completed on average 12 h of neurocognitive training, which was considerably lower than per protocol. We found no effect of cognitive remediation on whole-brain FA when compared to treatment as usual. Secondary ROI analyses revealed a nominal significant interaction between timepoint*treatment of AD in left medial lemniscus (P=0.016) which did not survive control for multiple comparisons. The exploratory test showed that this change in AD correlated to improvements of mental flexibility in the cognitive remediation group (p=0.001). We found no dose-response effect of neurocognitive training on WM. CONCLUSIONS: Cognitive remediation comprising 12 h of neurocognitive training on average did not improve global or regional WM organization in UHR individuals. Further investigations of duration and intensity of cognitive training as necessary prerequisites of neuroplasticity-based changes are warranted. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT02098408.

The YOUth study: Rationale, design, and study procedures.

Behavioral development in children shows large inter-individual variation, and is driven by the interplay between biological, psychological, and environmental processes. However, there is still little insight into how these processes interact. The YOUth cohort specifically focuses on two core characteristics of behavioral development: social competence and self-regulation. Social competence refers to the ability to engage in meaningful interactions with others, whereas self-regulation is the ability to control one's emotions, behavior, and impulses, to balance between reactivity and control of the reaction, and to adjust to the prevailing environment. YOUth is an accelerated population-based longitudinal cohort study with repeated measurements, centering on two groups: YOUth Baby & Child and YOUth Child & Adolescent. YOUth Baby & Child aims to include 3,000 pregnant women, their partners and children, wheras YOUth Child & Adolescent aims to include 2,000 children aged between 8 and 10 years old and their parents. All participants will be followed for at least 6 years, and potentially longer. In this paper we describe in detail the design of this study, the population included, the determinants, intermediate neurocognitive measures and outcomes included in the study. Furthermore, we describe in detail the procedures of inclusion, informed consent, and study participation.

The YOUth cohort study: MRI protocol and test-retest reliability in adults.

The YOUth cohort study is a unique longitudinal study on brain development in the general population. As part of the YOUth study, 2000 children will be included at 8, 9 or 10 years of age and planned to return every three years during adolescence. Magnetic resonance imaging (MRI) brain scans are collected, including structural T1-weighted imaging, diffusion-weighted imaging (DWI), resting-state functional MRI and task-based functional MRI. Here, we provide a comprehensive report of the MR acquisition in YOUth Child & Adolescent including the test-retest reliability of brain measures derived from each type of scan. To measure test-retest reliability, 17 adults were scanned twice with a week between sessions using the full YOUth MRI protocol. Intraclass correlation coefficients were calculated to quantify reliability. Global brain measures derived from structural T1-weighted and DWI scans were reliable. Resting-state functional connectivity was moderately reliable, as well as functional brain measures for both the inhibition task (stop versus go) and the emotion task (face versus house). Our results complement previous studies by presenting reliability results of regional brain measures collected with different MRI modalities. YOUth facilitates data sharing and aims for reliable and high-quality data. Here we show that using the state-of-the art YOUth MRI protocol brain measures can be estimated reliably.

Vasogenic edema versus neuroplasticity as neural correlates of hippocampal volume increase following electroconvulsive therapy.

BACKGROUND: Volume increases of the hippocampus after electroconvulsive therapy (ECT) are a robust finding, pointing into the direction of neurogenesis. However, such volumetric increases could also be explained by edema and/or neuroplastic changes (such as angiogenesis). OBJECTIVES: If edema explains the volume increase of the hippocampus we hypothesize it would lead to increased mean diffusivity (MD). If neuroplastic would explain the volume increase, it would lead to decreased MD. To investigate angiogenesis as explanation we studied the perfusion fraction f and the pseudodiffusion component D∗ obtained from intravoxel incoherent motion (IVIM) data, and relative perfusion changes obtained from arterial spin labelling (ASL) data. METHODS: Using ultra-high field (7 tesla) MRI we acquired IVIM and ASL data. We compared MD, f, D∗ and ASL values for both hippocampi in 21 patients (before and after 10 ECT sessions) and 8 healthy controls (without ECT) in a linear mixed model adjusting for age and gender. RESULTS: We found a significant decrease in MD (which was absent in the healthy controls) in the left and right hippocampus (t = -3.98, p < 0.001). In addition, a decrease in f (t = -4.61, p < 0.001, but not in controls) and no differences in D∗ or ASL perfusion values (both p > 0.05) were found. CONCLUSIONS: The decrease in MD in perfusion fraction f suggest that formation of edema nor angiogenesis are responsible for the ECT-induced volume increases in the hippocampus. Also, it supports the hypothesis that hippocampal volume increases might be due to neuroplastic changes.

Volume increase in the dentate gyrus after electroconvulsive therapy in depressed patients as measured with 7T.

Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its working mechanism remains unclear. In the animal analog of ECT, neurogenesis in the dentate gyrus (DG) of the hippocampus is observed. In humans, volume increase of the hippocampus has been reported, but accurately measuring the volume of subfields is limited with common MRI protocols. If the volume increase of the hippocampus in humans is attributable to neurogenesis, it is expected to be exclusively present in the DG, whereas other processes (angiogenesis, synaptogenesis) also affect other subfields. Therefore, we acquired an optimized MRI scan at 7-tesla field strength allowing sensitive investigation of hippocampal subfields. A further increase in sensitivity of the within-subjects measurements is gained by automatic placement of the field of view. Patients receive two MRI scans: at baseline and after ten bilateral ECT sessions (corresponding to a 5-week interval). Matched controls are also scanned twice, with a similar 5-week interval. A total of 31 participants (23 patients, 8 controls) completed the study. A large and significant increase in DG volume was observed after ECT (M = 75.44 mm3, std error = 9.65, p < 0.001), while other hippocampal subfields were unaffected. We note that possible type II errors may be present due to the small sample size. In controls no changes in volume were found. Furthermore, an increase in DG volume was related to a decrease in depression scores, and baseline DG volume predicted clinical response. These findings suggest that the volume change of the DG is related to the antidepressant properties of ECT, and may reflect neurogenesis.