Resting state functional magnetic resonance imaging (rs-fMRI) is increasingly applied for the development of functional biomarkers in brain disorders. Recent studies have revealed spontaneous ...vigilance drifts during the resting state, involving changes in brain activity and connectivity that challenge the validity of uncontrolled rs-fMRI findings. In a combined rs-fMRI/eye tracking study, the pupil size of 32 healthy subjects after 2h of sleep restriction was recorded as an indirect index for activity of the locus coeruleus, the brainstem's noradrenergic arousal center. The spontaneous occurrence of pupil dilations, but not pupil size per se, was associated with increased activity of the salience network, thalamus and frontoparietal regions. In turn, spontaneous constrictions of the pupil were associated with increased activity in visual and sensorimotor regions. These results were largely replicated in a sample of 36 healthy subjects who did not undergo sleep restriction, although in this sample the correlation between thalamus and pupil dilation fell below whole-brain significance. Our data show that spontaneous pupil fluctuations during rest are indeed associated with brain circuitry involved in tonic alertness and vigilance. Pupillometry is an effective method to control for changes in tonic alertness during rs-fMRI.
•Pupil size is not associated with robust brain network activity.•Spontaneous pupil dilations are associated with salience network activation.•Pupil constrictions involve activation of visual and sensorimotor areas.•Pupillometry provides a marker for alertness/vigilance during resting state fMRI.
Falling asleep is paralleled by a loss of conscious awareness and reduced capacity to process external stimuli. Little is known on sleep-associated changes of spontaneously synchronized anatomical ...networks as detected by resting-state functional magnetic resonance imaging (rs-fMRI). We employed functional connectivity analysis of rs-fMRI series obtained from 25 healthy participants, covering all non-rapid eye movement (NREM) sleep stages. We focused on the default mode network (DMN) and its anticorrelated network (ACN) that are involved in internal and external awareness during wakefulness. Using independent component analysis, cross-correlation analysis (CCA), and intraindividual dynamic network tracking, we found significant changes in DMN/ACN integrity throughout the NREM sleep. With increasing sleep depth, contributions of the posterior cingulate cortex (PCC)/retrosplenial cortex (RspC), parahippocampal gyrus, and medial prefrontal cortex to the DMN decreased. CCA revealed a breakdown of corticocortical functional connectivity, particularly between the posterior and anterior midline node of the DMN and the DMN and the ACN. Dynamic tracking of the DMN from wakefulness into slow wave sleep in a single subject added insights into intraindividual network fluctuations. Results resonate with a role of the PCC/RspC for the regulation of consciousness. We further submit that preserved corticocortical synchronization could represent a prerequisite for maintaining internal and external awareness.
Since the discovery of the close association between rapid eye movement (REM) sleep and dreaming, much effort has been devoted to link physiological signatures of REM sleep to the contents of ...associated dreams 1–4. Due to the impossibility of experimentally controlling spontaneous dream activity, however, a direct demonstration of dream contents by neuroimaging methods is lacking. By combining brain imaging with polysomnography and exploiting the state of “lucid dreaming,” we show here that a predefined motor task performed during dreaming elicits neuronal activation in the sensorimotor cortex. In lucid dreams, the subject is aware of the dreaming state and capable of performing predefined actions while all standard polysomnographic criteria of REM sleep are fulfilled 5, 6. Using eye signals as temporal markers, neural activity measured by functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) was related to dreamed hand movements during lucid REM sleep. Though preliminary, we provide first evidence that specific contents of REM-associated dreaming can be visualized by neuroimaging.
► Eye signals can be used to access dream content with concurrent EEG and neuroimaging ► Dreamed hand movements correspond to activity in the contralateral sensorimotor cortex
Graph theoretical analysis of functional magnetic resonance imaging (fMRI) time series has revealed a small-world organization of slow-frequency blood oxygen level-dependent (BOLD) signal ...fluctuations during wakeful resting. In this study, we used graph theoretical measures to explore how physiological changes during sleep are reflected in functional connectivity and small-world network properties of a large-scale, low-frequency functional brain network. Twenty-five young and healthy participants fell asleep during a 26.7 min fMRI scan with simultaneous polysomnography. A maximum overlap discrete wavelet transformation was applied to fMRI time series extracted from 90 cortical and subcortical regions in normalized space after residualization of the raw signal against unspecific sources of signal fluctuations; functional connectivity analysis focused on the slow-frequency BOLD signal fluctuations between 0.03 and 0.06 Hz. We observed that in the transition from wakefulness to light sleep, thalamocortical connectivity was sharply reduced, whereas corticocortical connectivity increased; corticocortical connectivity subsequently broke down in slow-wave sleep. Local clustering values were closest to random values in light sleep, whereas slow-wave sleep was characterized by the highest clustering ratio (gamma). Our findings support the hypothesis that changes in consciousness in the descent to sleep are subserved by reduced thalamocortical connectivity at sleep onset and a breakdown of general connectivity in slow-wave sleep, with both processes limiting the capacity of the brain to integrate information across functional modules.
The human hippocampal formation can be divided into a set of cytoarchitecturally and functionally distinct subregions, involved in different aspects of memory formation. Neuroanatomical disruptions ...within these subregions are associated with several debilitating brain disorders including Alzheimer's disease, major depression, schizophrenia, and bipolar disorder. Multi-center brain imaging consortia, such as the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium, are interested in studying disease effects on these subregions, and in the genetic factors that affect them. For large-scale studies, automated extraction and subsequent genomic association studies of these hippocampal subregion measures may provide additional insight. Here, we evaluated the test–retest reliability and transplatform reliability (1.5T versus 3T) of the subregion segmentation module in the FreeSurfer software package using three independent cohorts of healthy adults, one young (Queensland Twins Imaging Study, N=39), another elderly (Alzheimer's Disease Neuroimaging Initiative, ADNI-2, N=163) and another mixed cohort of healthy and depressed participants (Max Planck Institute, MPIP, N=598). We also investigated agreement between the most recent version of this algorithm (v6.0) and an older version (v5.3), again using the ADNI-2 and MPIP cohorts in addition to a sample from the Netherlands Study for Depression and Anxiety (NESDA) (N=221). Finally, we estimated the heritability (h2) of the segmented subregion volumes using the full sample of young, healthy QTIM twins (N=728). Test–retest reliability was high for all twelve subregions in the 3T ADNI-2 sample (intraclass correlation coefficient (ICC)=0.70–0.97) and moderate-to-high in the 4T QTIM sample (ICC=0.5–0.89). Transplatform reliability was strong for eleven of the twelve subregions (ICC=0.66–0.96); however, the hippocampal fissure was not consistently reconstructed across 1.5T and 3T field strengths (ICC=0.47–0.57). Between-version agreement was moderate for the hippocampal tail, subiculum and presubiculum (ICC=0.78–0.84; Dice Similarity Coefficient (DSC)=0.55–0.70), and poor for all other subregions (ICC=0.34–0.81; DSC=0.28–0.51). All hippocampal subregion volumes were highly heritable (h2=0.67–0.91). Our findings indicate that eleven of the twelve human hippocampal subregions segmented using FreeSurfer version 6.0 may serve as reliable and informative quantitative phenotypes for future multi-site imaging genetics initiatives such as those of the ENIGMA consortium.
•FreeSurfer v6.0 produced reliable volume estimates for 11 hippocampal subregions.•Agreement between v5.3 and v6.0 was poor for small subregions (e.g. fimbria).•All hippocampal subregion volumes were highly heritable (h2=0.67–0.91).•Hippocampal subregions may be useful quantitative phenotypes for future GWA studies.
Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes ...to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.
► New genetic association for major depression (MD) found in 15,089 individuals ► Risk gene for MD: the neuron-specific amino acid transporter (SLC6A15) ► Human hippocampal gene expression and imaging studies support the genetic finding ► SLC6A15 expression moderated by environmental and genetic factors
Background
Smaller hippocampal volume in patients with posttraumatic stress disorder (PTSD) represents the most consistently reported structural alteration in the brain. Subfields of the hippocampus ...play distinct roles in encoding and processing of memories, which are disrupted in PTSD. We examined PTSD‐associated alterations in 12 hippocampal subfields in relation to global hippocampal shape, and clinical features.
Methods
Case‐control cross‐sectional studies of U.S. military veterans (n = 282) from the Iraq and Afghanistan era were grouped into PTSD (n = 142) and trauma‐exposed controls (n = 140). Participants underwent clinical evaluation for PTSD and associated clinical parameters followed by MRI at 3 T. Segmentation with FreeSurfer v6.0 produced hippocampal subfield volumes for the left and right CA1, CA3, CA4, DG, fimbria, fissure, hippocampus‐amygdala transition area, molecular layer, parasubiculum, presubiculum, subiculum, and tail, as well as hippocampal meshes. Covariates included age, gender, trauma exposure, alcohol use, depressive symptoms, antidepressant medication use, total hippocampal volume, and MRI scanner model.
Results
Significantly lower subfield volumes were associated with PTSD in left CA1 (P = 0.01; d = 0.21; uncorrected), CA3 (P = 0.04; d = 0.08; uncorrected), and right CA3 (P = 0.02; d = 0.07; uncorrected) only if ipsilateral whole hippocampal volume was included as a covariate. A trend level association of L‐CA1 with PTSD (F4, 221 = 3.32, P = 0.07) is present and the other subfield findings are nonsignificant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD‐associated differences in global hippocampal shape were nonsignificant.
Conclusions
The present finding of smaller hippocampal CA1 in PTSD is consistent with model systems in rodents that exhibit increased anxiety‐like behavior from repeated exposure to acute stress. Behavioral correlations with hippocampal subfield volume differences in PTSD will elucidate their relevance to PTSD, particularly behaviors of associative fear learning, extinction training, and formation of false memories.
Object
In humans, even a single night of partial sleep deprivation (PSD) can have a negative impact on cognition and affective processing, suggesting that sleep pressure represents a basic ...physiological constraint of brain function. Among the spontaneously fluctuating resting state networks, the default mode network (DMN) and its anticorrelated network (ACN) hold key functions in segregating internally and externally directed awareness. Task fMRI after sleep deprivation has revealed altered activation patterns in both networks. We hypothesized that effects of PSD in these intrinsically coupled networks can be detected by resting state fMRI.
Methods
We obtained 6-minute echoplanar imaging time series (1.5 Tesla) during eyes-closed, wakeful-resting experiments from 16 healthy volunteers after normal sleep and after PSD. We used independent component and cross-correlation analysis to study functional connectivity (fc), focusing on the DMN and ACN.
Results
After PSD, focal reductions of auto-correlation strength were detected in the posterior and anterior midline node of the DMN and in the lateral parietal and insular nodes of the ACN. Cross-correlation analysis confirmed reduced cortico-cortical connectivity within and between the DMN and ACN.
Conclusions
Increased sleep pressure is reflected in reduced fc of main DMN and ACN nodes during rest. Results have implications for understanding perceptual and cognitive changes after sleep deprivation and are relevant to clinical studies on conditions in which increased sleep propensity is present.
Major depressive disorder (MDD) has been related to abnormal amygdala activity during emotional face processing. However, a recent large-scale study (
n
= 28,638) found no such correlation, which is ...probably due to the low precision of fMRI measurements. To address this issue, we used simultaneous fMRI and eye-tracking measurements during a commonly employed emotional face recognition task. Eye-tracking provide high-precision data, which can be used to enrich and potentially stabilize fMRI readouts. With the behavioral response, we additionally divided the active task period into a task-related and a free-viewing phase to explore the gaze patterns of MDD patients and healthy controls (HC) and compare their respective neural correlates. Our analysis showed that a mood-congruency attentional bias could be detected in MDD compared to healthy controls during the free-viewing phase but without parallel amygdala disruption. Moreover, the neural correlates of gaze patterns reflected more prefrontal fMRI activity in the free-viewing than the task-related phase. Taken together, spontaneous emotional processing in free viewing might lead to a more pronounced mood-congruency bias in MDD, which indicates that combined fMRI with eye-tracking measurement could be beneficial for our understanding of the underlying psychopathology of MDD in different emotional processing phases.
Trial Registration
: The BeCOME study is registered on ClinicalTrials (gov: NCT03984084) by the Max Planck Institute of Psychiatry in Munich, Germany.
Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3β) in mood disorders. We recently reported associations between GSK3β polymorphisms and brain structural changes in patients ...with recurrent major depressive disorder (MDD). Here we provide supporting observations by showing that polymorphisms in additional genes encoding proteins directly related to GSK3β biological functions are associated with similar regional grey matter (GM) volume changes in MDD patients. We tested specifically for associations with genetic variation in canonical Wnt signaling pathway genes and in genes that encode substrate proteins of GSK3β. We applied a general linear model with non-stationary cluster-based inference to examine associations between polymorphisms and regional voxel-based morphometry GM volume differences in recurrent MDD patients (n=134) and in age-, gender-, and ethnicity-matched healthy controls (n=144) to test for genotype-by-MDD interactions. We observed associations for polymorphisms in 8/13 canonical Wnt pathway genes and 5/10 GSK3β substrate genes, predominantly in the temporolateral and medial prefrontal cortices. Similar associations were not found for 100 unrelated polymorphisms tested. This work suggests that identifying SNPs related to genes that encode functionally-interacting proteins that modulate common anatomical regions offers a useful approach to increasing confidence in outcomes from imaging genetics association studies. This is of particular interest when replication datasets are not available. Our observations lend support to the hypothesis that polymorphisms in GSK3β play a role in MDD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates.
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