The Measurement of Language Lateralization with Functional Transcranial Doppler and Functional MRI: A Critical Evaluation

Cerebral language lateralization can be assessed in several ways. In healthy subjects, functional MRI (fMRI) during performance of a language task has evolved to be the most frequently applied method. Functional transcranial Doppler (fTCD) may provide a valid alternative, but has been used rarely. Both techniques have their own strengths and weaknesses and as a result may be applied in different fields of research. Until now, only one relatively small study (n = 13) investigated the correlation between lateralization indices (LIs) measured by fTCD and fMRI and showed a remarkably high correlation. To further evaluate the correlation between LIs measured with fTCD and fMRI, we compared LIs of 22 healthy subjects (12 left- and 10 right-handed) using the same word generation paradigm for the fTCD as for the fMRI experiment. LIs measured with fTCD were highly but imperfectly correlated with LIs measured with fMRI (Spearman's rho = 0.75, p < 0.001). The imperfectness of the correlation can partially be explained by methodological restrictions of fMRI as well as fTCD. Our results suggest that fTCD can be a valid alternative for fMRI to measure lateralization, particularly when costs or mobility are important factors in the study design

Delayed school progression and mental health problems in adolescence:A population-based study in 10,803 adolescents

Background Accumulating evidence suggests that several adult mental disorders, particularly psychoses, are preceded by impairments in cognitive function, reflected in scholastic underachievement. This study investigates the association between scholastic underachievement and general mental health problems in adolescence, using delay in school progression as a marker of poor scholastic performance.MethodCross-sectional secondary school survey comprising 10,803 adolescents. Participants completed the Strengths and Difficulties Questionnaire (SDQ) to assess mental health problems. The association of delayed school progression with the SDQ was investigated using logistic regression with SDQ as outcome and delayed school progression as primary exposure of interest while adjusting for socio-demographic characteristics, adverse life events, school-related factors, risk taking behaviour, healthy lifestyle and physical health.ResultsUnadjusted analysis showed an association between delayed school progression and total mental health problems (OR 1.83, 95% CI 1.27 - 2.63) in adolescents. After adjusting for other risk factors (socio-demographic factors and life events) in a logistic regression model the association between delayed school progression en mental health problems was attenuated (OR 1.33, 95% CI 0.86 - 2.05).ConclusionDelayed school progression is associated with general mental health problems in adolescence, but this relationship is heavily confounded by other factors. A causal relationship between impaired cognitive function such as poor scholastic performance and general mental health at adolescence is less likely and delayed school progression may merely be considered an indicator of risk for mental health problems.</p

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

Accelerated brain aging as a biomarker for staging in bipolar disorder:An exploratory study

Background:Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging. Methods:In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored. Results:A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages. Conclusions:These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.</p

Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder

Several studies have reported an association between traumatic stress and telomere length suggesting that traumatic stress has an impact on ageing at the cellular level. A newly derived tool provides an additional means to investigate cellular ageing by estimating epigenetic age based on DNA methylation profiles. We therefore hypothesise that in a longitudinal study of traumatic stress both indicators of cellular ageing will show increased ageing. We expect that particularly in individuals that developed symptoms of post-traumatic stress disorder (PTSD) increases in these ageing parameters would stand out.From an existing longitudinal cohort study, ninety-six male soldiers were selected based on trauma exposure and the presence of symptoms of PTSD. All military personnel were deployed in a combat zone in Afghanistan and assessed before and 6 months after deployment. The Self-Rating Inventory for PTSD was used to measure the presence of PTSD symptoms, while exposure to combat trauma during deployment was measured with a 19-item deployment experiences checklist. These groups did not differ for age, gender, alcohol consumption, cigarette smoking, military rank, length, weight, or medication use. In DNA from whole blood telomere length was measured and DNA methylation levels were assessed using the Illumina 450K DNA methylation arrays. Epigenetic ageing was estimated using the DNAm age estimator procedure.The association of trauma with telomere length was in the expected direction but not significant (. B=. -10.2, p=. 0.52). However, contrary to our expectations, development of PTSD symptoms was associated with the reverse process, telomere lengthening (. B=. 1.91, p=. 0.018). In concordance, trauma significantly accelerated epigenetic ageing (. B=. 1.97, p=. 0.032) and similar to the findings in telomeres, development of PTSD symptoms was inversely associated with epigenetic ageing (. B=. -0.10, p=. 0.044). Blood cell count, medication and premorbid early life trauma exposure did not confound the results.Overall, in this longitudinal study of military personnel deployed to Afghanistan we show an acceleration of ageing by trauma. However, development of PTSD symptoms was associated with telomere lengthening and reversed epigenetic ageing. These findings warrant further study of a perhaps dysfunctional compensatory cellular ageing reversal in PTSD

Functional brain networks in the schizophrenia spectrum and bipolar disorder with psychosis

Psychotic experiences have been proposed to lie on a spectrum, ranging from subclinical experiences to treatment-resistant schizophrenia. We aimed to characterize functional connectivity and brain network characteristics in relation to the schizophrenia spectrum and bipolar disorder with psychosis to disentangle neural correlates to psychosis. Additionally, we studied antipsychotic medication and lithium effects on network characteristics. We analyzed functional connectivity strength and network topology in 487 resting-state functional MRI scans of individuals with schizophrenia spectrum disorder (SCZ), bipolar disorder with a history of psychotic experiences (BD), treatment-naïve subclinical psychosis (SCP), and healthy controls (HC). Since differences in connectivity strength may confound group comparisons of brain network topology, we analyzed characteristics of the minimum spanning tree (MST), a relatively unbiased backbone of the network. SCZ and SCP subjects had a lower connectivity strength than BD and HC individuals but showed no differences in network topology. In contrast, BD patients showed a less integrated network topology but no disturbances in connectivity strength. No differences in outcome measures were found between SCP and SCZ, or between BD patients that used antipsychotic medication or lithium and those that did not. We conclude that functional networks in patients prone to psychosis have different signatures for chronic SCZ patients and SCP compared to euthymic BD patients, with a limited role for medication. Connectivity strength effects may have confounded previous studies, as no functional network alterations were found in SCZ after strict correction for connectivity strength.</p

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.publishedVersio

Childhood Adversity Is Associated With Increased KITLG Methylation in Healthy Individuals but Not in Bipolar Disorder Patients

Background: Childhood adversity increases the risk of a range of mental disorders including bipolar disorder, but the underlying mechanisms are still unknown. Previous studies identified DNA methylation levels at the cg27512205 locus on the KIT Ligand (KITLG) gene as a mediator between childhood adversity and stress responsivity. This raises the question whether this locus also plays a role in stress related disorders such as bipolar disorder. Therefore, the current study aims to compare the level of KITLG (cg27512205) methylation between bipolar patients and healthy individuals and its relation to childhood adversity.Methods:KITLG (cg27512205) methylation was measured in 50 bipolar disorder patients and 91 healthy control participants using the HumanMethylation450K BeadChip platform. Childhood adversity in each individual was assessed using the Childhood Trauma Questionnaire. Analyses of the association of KITLG methylation with bipolar disorder, the association of childhood adversity with bipolar disorder as well as the association of KITLG methylation with childhood adversity in bipolar patients and controls were conducted using linear regression with age, gender, childhood adversity, smoking, and cell-type composition estimates as covariates.Results:KITLG (cg27512205) methylation level was significantly lower in bipolar disorder patients (β = −0.351, t = −6.316 p &lt; 0.001). Childhood adversity levels were significantly higher in the bipolar disorder group (β = 4.903, t = 2.99, p = 0.003). In the bipolar disorder patients KITLG methylation was not associated with childhood adversity (β = 0.004, t = 1.039, p = 0.304) in contrast to the healthy controls (β = 0.012, t = 3.15, p = 0.002).Conclusions:KITLG methylation was lower in bipolar disorder despite high levels of childhood adversity, whereas childhood adversity was associated with higher KITLG methylation in healthy controls. In addition to lower methylation at this locus there is an indication that failure to adjust KITLG methylation to high levels of childhood adversity is a risk factor for bipolar disorder