The association between early regulatory problems and adult peer relationship quality is mediated by the brain's allostatic-interoceptive system.

BACKGROUND: Early regulatory problems (RPs), i.e., problems with crying, sleeping, and/or feeding during the first years, increase the risk for avoidant personality traits in adulthood, associated with social withdrawal and anxiety. Even more, RPs are linked with functional alterations in the adult default mode and salience networks, comprising the brain's allostatic-interoceptive system (AIS) and playing a role in social interactions. We investigated whether RPs assessed in infancy are associated with difficulties in adult peer relationships mediated by functional alterations of the AIS. METHODS: As part of a large case-controlled prospective study, 42 adults with previous RPs and 70 matched controls (mean age = 28.48, SD = 2.65, 51% male) underwent fMRI during rest. The analysis focused on the intrinsic functional connectivity (iFC) of key nodes of the AIS. Peer relationship quality was assessed via a semi-structured Life Course Interview and the YASR scale. In these same individuals, RPs were assessed at ages 5, 20 and 56 months. RESULTS: RPs in infancy were associated with lower-quality peer relationships and enhanced functional connectivity of the AIS nodes in adulthood, with a stronger effect for multiple and persistent RPs compared with transient-multiple or single-persistent RPs. Importantly, iFC changes of the dorsal mid insula, a primary interoceptive cortex with frontal and temporal regions, mediated the relationship between early RPs and adult peer relationship quality. CONCLUSIONS: Results indicate long-lasting social and neural changes associated with early RPs. Our findings further implicate the AIS in both interoceptive and social processes, while indicating the need for early screening of early RPs.

Negative symptoms, striatal dopamine and model-free reward decision-making in schizophrenia.

Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free reward predictions on decision-making ('reward prediction influence', RPI) underlie negative symptoms. We focused on psychotic remission, because psychotic symptoms might confound reward-based decision-making. Moreover, we hypothesized that impaired model-based/model-free RPIs depend on alterations of both associative striatum dopamine synthesis and storage (DSS) and executive functioning. Both factors influence RPI in healthy subjects and are typically impaired in schizophrenia. Twenty-five patients with schizophrenia with pronounced negative symptoms during psychotic remission and 24 healthy controls were included in the study. Negative symptom severity was measured by the Positive and Negative Syndrome Scale negative subscale, model-based/model-free RPI by the two-stage decision task, associative striatum DSS by 18F-DOPA positron emission tomography and executive functioning by the symbol coding task. Model-free RPI was selectively reduced in patients and associated with negative symptom severity as well as with reduced associative striatum DSS (in patients only) and executive functions (both in patients and controls). In contrast, model-based RPI was not altered in patients. Results provide evidence for impaired model-free reward prediction influence as a mechanism for negative symptoms in schizophrenia as well as for reduced associative striatum dopamine and executive dysfunction as relevant factors. Data suggest potential treatment targets for patients with schizophrenia and pronounced negative symptoms.

Targeted rhythmic visual stimulation at individual participants' intrinsic alpha frequency causes selective increase of occipitoparietal BOLD-fMRI and EEG functional connectivity.

Neural oscillations in distinct frequency bands are ubiquitous in the brain and play a role in many cognitive processes. The "communication by coherence" hypothesis, poses that the synchronization through phase coupling of frequency-specific neural oscillations regulate information flow across distribute brain regions. Specifically, the posterior alpha frequency band (7-12 Hz) is thought to gate bottom-up visual information flow by inhibition during visual processing. Evidence shows that increased alpha phase coherency positively correlates with functional connectivity in resting state connectivity networks, supporting alpha mediates neural communication through coherency. However, these findings have mainly been derived from spontaneous changes in the ongoing alpha rhythm. In this study, we experimentally modulate the alpha rhythm by targeting individuals' intrinsic alpha frequency with sustained rhythmic light to investigate alpha-mediated synchronous cortical activity in both EEG and fMRI. We hypothesize increased alpha coherency and fMRI connectivity should arise from modulation of the intrinsic alpha frequency (IAF) as opposed to control frequencies in the alpha range. Sustained rhythmic and arrhythmic stimulation at the IAF and at neighboring frequencies within the alpha band range (7-12 Hz) was implemented and assessed in a separate EEG and fMRI study. We observed increased cortical alpha phase coherency in the visual cortex during rhythmic stimulation at the IAF as in comparison to rhythmic stimulation of control frequencies. In the fMRI, we found increased functional connectivity for stimulation at the IAF in visual and parietal areas as compared to other rhythmic control frequencies by correlating time courses from a set of regions of interest for the different stimulation conditions and applying network-based statistics. This suggests that rhythmic stimulation at the IAF frequency induces a higher degree of synchronicity of neural activity across the occipital and parietal cortex, which supports the role of the alpha oscillation in gating information flow during visual processing.

Stronger influence of systemic than local hemodynamic-vascular factors on resting-state BOLD functional connectivity.

Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.

Indirect evidence for altered dopaminergic neurotransmission in very premature-born adults.

While animal models indicate altered brain dopaminergic neurotransmission after premature birth, corresponding evidence in humans is scarce due to missing molecular imaging studies. To overcome this limitation, we studied dopaminergic neurotransmission changes in human prematurity indirectly by evaluating the spatial co-localization of regional alterations in blood oxygenation fluctuations with the distribution of adult dopaminergic neurotransmission. The study cohort comprised 99 very premature-born (<32 weeks of gestation and/or birth weight below 1500 g) and 107 full-term born young adults, being assessed by resting-state functional MRI (rs-fMRI) and IQ testing. Normative molecular imaging dopamine neurotransmission maps were derived from independent healthy control groups. We computed the co-localization of local (rs-fMRI) activity alterations in premature-born adults with respect to term-born individuals to different measures of dopaminergic neurotransmission. We performed selectivity analyses regarding other neuromodulatory systems and MRI measures. In addition, we tested if the strength of the co-localization is related to perinatal measures and IQ. We found selectively altered co-localization of rs-fMRI activity in the premature-born cohort with dopamine-2/3-receptor availability in premature-born adults. Alterations were specific for the dopaminergic system but not for the used MRI measure. The strength of the co-localization was negatively correlated with IQ. In line with animal studies, our findings support the notion of altered dopaminergic neurotransmission in prematurity which is associated with cognitive performance.

The association of early regulatory problems with behavioral problems and cognitive functioning in adulthood: two cohorts in two countries.

BACKGROUND: Regulatory problems (RPs; excessive crying, sleeping, or feeding difficulties) that co-occur (i.e., multiple) or are persistent have been associated with cognitive and behavioral problems in childhood. However, it remains unknown if multiple or persistent RPs are associated with cognitive and behavioral problems in adulthood. METHODS: This large prospective longitudinal study (N = 759) was conducted in two cohorts in Germany (N = 342) and Finland (N = 417). RPs were assessed at 5, 20, and 56 months via the same standardized parental interviews and neurological examinations. In young adulthood, questionnaires were used to assess behavioral problems. Cognitive functioning was assessed with IQ tests. We examined the effects of multiple or persistent RPs on the outcomes via analysis of covariance tests and logistic regression controlled for the influence of cohort. RESULTS: Of 163 participants with RPs, 89 had multiple and 77 had persistent RPs. Adults who had early multiple or persistent RPs (N = 151) reported more internalizing (p = .001), externalizing (p = .020), and total behavioral problems (p = .001), and, specifically, more depressive (p = .012), somatic (p = .005), avoidant personality (p < .001), and antisocial personality problems (p = .006) than those who never had RPs (N = 596). Participants with multiple or persistent RPs were more likely to receive any ADHD diagnoses (p = .017), particularly of hyperactive/impulsive subtype (p = .032). In contrast, there were no associations between multiple or persistent RPs and IQ scores in young adulthood. CONCLUSIONS: The results indicate long-lasting associations between multiple or persistent RPs and behavioral problems. Thus, screening for early RPs could help to identify children who are at risk for later behavioral problems.

Associations of crying, sleeping, and feeding problems in early childhood and perceived social support with emotional disorders in adulthood.

BACKGROUND: Multiple or persistent crying, sleeping, or feeding problems in early childhood (regulatory problems) are associated with increased internalizing symptoms in adulthood. Unknown is whether early regulatory problems are associated with emotional disorders in adulthood, and what psychosocial factors may provide protection. We tested whether early childhood multiple or persistent regulatory problems are associated with a higher risk of (a) any mood and anxiety disorder in adulthood; (b) perceiving no social support in adulthood; and (c) whether social support provides protection from mood and anxiety disorders among participants who had multiple/persistent regulatory problems and those who never had regulatory problems. METHODS: Data from two prospective longitudinal studies in Germany (n = 297) and Finland (n = 342) was included (N = 639). Regulatory problems were assessed at 5, 20, and 56 months with the same standardized parental interviews and neurological examinations. In adulthood (24-30 years), emotional disorders were assessed with diagnostic interviews and social support with questionnaires. RESULTS: Children with multiple/persistent regulatory problems (n = 132) had a higher risk of any mood disorder (odds ratio (OR) = 1.81 [95% confidence interval = 1.01-3.23]) and of not having any social support from peers and friends (OR = 1.67 [1.07-2.58]) in adulthood than children who never had regulatory problems. Social support from peers and friends provided protection from mood disorders, but only among adults who never had regulatory problems (OR = 4.03 [2.16-7.94]; p = .039 for regulatory problems x social support interaction). CONCLUSIONS: Children with multiple/persistent regulatory problems are at increased risk of mood disorders in young adulthood. Social support from peers and friends may, however, only provide protection from mood disorders in individuals who never had regulatory problems.

Skin Wound Healing: Of Players, Patterns, and Processes.

BACKGROUND: Wound healing of the skin is a very complex biological activity. For a better understanding, an attempt is made to describe and subdivide the different players (cell types and signaling molecules), patterns (different regeneration or repair mechanisms), and processes (division of the overall process into categories, phases, and steps). However, this is always based on different points of view. On the one hand, the temporality of the phases and on the other hand, the dominant activity in each step can play a role. In addition, classifications according to wound theory and wound treatment are possible. SUMMARY: To gain an initial overview of (human) skin wound healing, simple classifications are advantageous for understanding and thus deserve to exist. The complexity of the underlying biology of skin wound healing takes on a multidimensional configuration upon closer examination, in which new actors are constantly being identified, making the events more precise and comprehensible but also significantly confusing when viewed as a whole. From this point of view, the healing process must be categorized so that the observer does not get lost in the multitude of interacting processes. In view of the steadily increasing knowledge, which includes in parallel the physiological as well as the pathophysiological processes of wound healing, the classification according to function in the sense of consecutive and overlapping phases seems the most convenient and considers the corresponding processes more precisely. Despite that many mechanisms and specific cellular functions in wound healing have been identified, many underlying (patho-)physiological processes still remain unknown. KEY MESSAGES: Currently, a substantial part of research activities in medicine is limited to molecular levels, while evidence for therapies currently in use is lacking or newly gained knowledge is quite far from clinical applicability and reality. This article aimed to shed more light on the various classifications of skin wound healing and presents the underlying paradigms starting from simple approaches and ending with more detailed concepts.

[Balancing Family and Career in Medicine: Greatly Desired but Given Little Consideration Results of the Study Arm VI of the KARiMED Study]. / Vereinbarkeit von Familie und Beruf in der Medizin: vom großen Wunsch und wenig Berücksichtigung.

AIM OF THE STUDY: Family life and professional practice are both highly important for young physicians. Accordingly, a good balancing of both areas of life is necessary. Despite political framework conditions and legal requirements that have been in place for years, implementation of measures to achieve this seems to be difficult, especially in medicine, and is associated with great reservations and problems on the part of those involved. METHODS: By means of an online survey, the medical mid-level staff from university and peripheral hospitals was questioned on topics related to family, children and professional biographical as well as career-relevant topics and subsequently analyzed on a gender-specific basis. RESULTS: Of the study participants, 65.1% were married and already had children or expressed a desire to have children (86.0%). Most were employed full-time (80.8%). The majority of part-time employees were female (87.4%). For 34.6%, there was a career break of 18.5±21.3 months, 87.8% of which were taken due to pregnancy or children. Female physicians generally took significantly more parental leave than male physicians (6-12 months: females 62.2%; males 22.4%; 12 months or more: females 25.2%; males 6.6%). Family planning received little support from superiors (21.2% much to very much support) and 45.6% reported having experienced problems with their return to work or career advancement. Almost 60% of the participants did not have any specific working time models in their own hospital for employees with children who need to be cared for. CONCLUSION: In order to implement a work-life balance for physicians, changes are first and foremost necessary on the part of the institutions. In addition, the respective superiors must rethink in order to enable a parallelization of these two areas of their employees' lives. However, young physicians must also rethink their view of this issue. Demanding changes in labor law while continuing traditional family constellations at home does not seem to do address this issue adequately.

[Academic Careers in Medicine: a Sex-Related Analysis of Career Goals]. / Akademische Karriere in der Medizin: eine geschlechterbezogene Analyse zu beruflichen Zielen.

AIM OF THE STUDY: For female and male physicians of the clinical-academic mid-level staff, working conditions as well as the attitude towards profession and career play a decisive role. For years, there has been an increasing proportion of women in medicine. Despite this increase, a significant sex incongruence is still evident, especially in academic medicine. The aim of this work was to analyze current opinions of female and male physicians on sex-related aspects for career. METHODS: By means of an online survey, medical mid-level staff from university and peripheral hospitals were asked about professional biographical as well as career-related topics and the data analyzed in terms of the sexes. RESULTS: Compared to their male counterparts, female physicians had lower career goals and mainly aimed to qualify as senior physicians. Women planned to have families and raise children earlier in their careers. Men were more likely to have their professional careers in mind during the same time period. Although only just under 47% of respondents considered an academic career to be worthwhile, 65% continued to rate the acquisition of an academic title highly. When evaluating equal treatment by superiors, female physicians tended to feel disadvantaged in their professional careers compared to male physicians. Thus, physicians rated the treatment by their respective superiors as characterized by the quality of the work (44% for both genders of superiors) or dependent on sympathy (female superiors 30%; male superiors 24%). Female physicians, however, saw a preference for male colleagues in 37% of male superiors. CONCLUSION: Despite a significantly larger proportion of women in medicine for decades, there is still an incongruence in sexes in favor of men in management positions. The professional and private goals of women and men differ significantly depending on their age decade. The academic career per se is increasingly losing importance, although the acquisition of academic degrees still seems to be desirable. Therefore, to improve the future of academic medicine, significant structural changes are needed to enable projectable career paths (e. g., tenure track, assistant professorship, young medical professionals model) for mid-level academic staff.

Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing.

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Comparing myelin-sensitive magnetic resonance imaging measures and resulting g-ratios in healthy and multiple sclerosis brains.

The myelin concentration and the degree of myelination of nerve fibers can provide valuable information on the integrity of human brain tissue. Magnetic resonance imaging (MRI) of myelin-sensitive parameters can help to non-invasively evaluate demyelinating diseases such as multiple sclerosis (MS). Several different myelin-sensitive MRI methods have been proposed to determine measures of the degree of myelination, in particular the g-ratio. However, variability in underlying physical principles and different biological models influence measured myelin concentrations, and consequently g-ratio values. We therefore investigated similarities and differences between five different myelin-sensitive MRI measures and their effects on g-ratio mapping in the brains of both MS patients and healthy volunteers. We compared two different estimates of the myelin water fraction (MWF) as well as the inhomogeneous magnetization transfer ratio (ihMTR), magnetization transfer saturation (MTsat), and macromolecular tissue volume (MTV) in 13 patients with MS and 14 healthy controls. In combination with diffusion-weighted imaging, we derived g-ratio parameter maps for each of the five different myelin measures. The g-ratio values calculated from different myelin measures varied strongly, especially in MS lesions. While, compared to normal-appearing white matter, MTsat and one estimate of the MWF resulted in higher g-ratio values within lesions, ihMTR, MTV, and the second MWF estimate resulted in lower lesion g-ratio values. As myelin-sensitive measures provide rough estimates of myelin content rather than absolute myelin concentrations, resulting g-ratio values strongly depend on the utilized myelin measure and model used for g-ratio mapping. When comparing g-ratio values, it is, thus, important to utilize the same MRI methods and models or to consider methodological differences. Particular caution is necessary in pathological tissue such as MS lesions.

In search of convergent regional brain abnormality in cognitive emotion regulation: A transdiagnostic neuroimaging meta-analysis.

Ineffective use of adaptive cognitive strategies (e.g., reappraisal) to regulate emotional states is often reported in a wide variety of psychiatric disorders, suggesting a common characteristic across different diagnostic categories. However, the extent of shared neurobiological impairments is incompletely understood. This study, therefore, aimed to identify the transdiagnostic neural signature of disturbed reappraisal using the coordinate-based meta-analysis (CBMA) approach. Following the best-practice guidelines for conducting neuroimaging meta-analyses, we systematically searched PubMed, ScienceDirect, and Web of Science databases and tracked the references. Out of 1,608 identified publications, 32 whole-brain neuroimaging studies were retrieved that compared brain activation in patients with psychiatric disorders and healthy controls during a reappraisal task. Then, the reported peak coordinates of group comparisons were extracted and several activation likelihood estimation (ALE) analyses were performed at three hierarchical levels to identify the potential spatial convergence: the global level (i.e., the pooled analysis and the analyses of increased/decreased activations), the experimental-contrast level (i.e., the analyses of grouped data based on the regulation goal, stimulus valence, and instruction rule) and the disorder-group level (i.e., the analyses across the experimental-contrast level focused on increasing homogeneity of disorders). Surprisingly, none of our analyses provided significant convergent findings. This CBMA indicates a lack of transdiagnostic convergent regional abnormality related to reappraisal task, probably due to the complex nature of cognitive emotion regulation, heterogeneity of clinical populations, and/or experimental and statistical flexibility of individual studies.

Decoupling of regional neural activity and inter-regional functional connectivity in Alzheimer's disease: a simultaneous PET/MR study.

PURPOSE: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are characterized by both aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). However, the effect of AD/MCI on the coupling between regional neural activity (measured by regional fluorodeoxyglucose imaging (rFDG)) and inter-regional FC (measured by resting-state functional magnetic resonance imaging (rs-fMRI)) is poorly understood. METHODS: We scanned 19 patients with MCI, 33 patients with AD, and 26 healthy individuals by simultaneous FDG-PET/rs-fMRI and assessed rFDG and inter-regional FC metrics (i.e., clustering coefficient and degree centrality). Next, we examined the potential moderating effect of disease status (MCI or AD) on the link between rFDG and inter-regional FC metrics using hierarchical moderated multiple regression analysis. We also tested this effect by considering interaction between disease status and inter-regional FC metrics, as well as interaction between disease status and rFDG. RESULTS: Our findings revealed that both rFDG and inter-regional FC metrics were disrupted in MCI and AD. Moreover, AD altered the relationship between rFDG and inter-regional FC metrics. In particular, we found that AD moderated the effect of inter-regional FC metrics of the caudate, parahippocampal gyrus, angular gyrus, supramarginal gyrus, frontal pole, inferior temporal gyrus, middle frontal, lateral occipital, supramarginal gyrus, precuneus, and thalamus on predicting their rFDG. On the other hand, AD moderated the effect of rFDG of the parietal operculum on predicting its inter-regional FC metric. CONCLUSION: Our findings demonstrated that AD decoupled the link between regional neural activity and functional segregation and global connectivity across particular brain regions.

Aberrant Claustrum Microstructure in Humans after Premature Birth.

Several observations suggest an impact of prematurity on the claustrum. First, the claustrum's development appears to depend on transient subplate neurons of intra-uterine brain development, which are affected by prematurity. Second, the claustrum is the most densely connected region of the mammalian forebrain relative to its volume; due to its effect on pre-oligodendrocytes, prematurity impacts white matter connections and thereby the development of sources and targets of such connections, potentially including the claustrum. Third, due to its high connection degree, the claustrum contributes to general cognitive functioning (e.g., selective attention and task switching/maintaining); general cognitive functioning, however, is at risk in prematurity. Thus, we hypothesized altered claustrum structure after premature birth, with these alterations being associated with impaired general cognitive performance in premature born persons. Using T1-weighted and diffusion-weighted magnetic resonance imaging in 70 very preterm/very low-birth-weight (VP/VLBW) born adults and 87 term-born adults, we found specifically increased mean diffusivity in the claustrum of VP/VLBW adults, associated both with low birth weight and at-trend with reduced IQ. This result demonstrates altered claustrum microstructure after premature birth. Data suggest aberrant claustrum development, which is potentially related with aberrant subplate neuron and forebrain connection development of prematurity.

Visual processing speed is linked to functional connectivity between right frontoparietal and visual networks.

Visual information processing requires an efficient visual attention system. The neural theory of visual attention (TVA) proposes that visual processing speed depends on the coordinated activity between frontoparietal and occipital brain areas. Previous research has shown that the coordinated activity between (i.e., functional connectivity and "inter-FC") cingulo-opercular (COn) and right-frontoparietal (RFPn) networks is linked to visual processing speed. However, how inter-FC of COn and RFPn with visual networks links to visual processing speed has not been directly addressed yet. Forty-eight healthy adult participants (27 females) underwent resting-state (rs-)fMRI and performed a whole-report psychophysical task. To obtain inter-FC, we analyzed the entire frequency range available in our rs-fMRI data (i.e., 0.01-0.4 Hz) to avoid discarding neural information. Following previous approaches, we analyzed the data across frequency bins (Hz): Slow-5 (0.01-0.027), Slow-4 (0.027-0.073), Slow-3 (0.073-0.198), and Slow-2 (0.198-0.4). We used the mathematical TVA framework to estimate an individual, latent-level visual processing speed parameter. We found that visual processing speed was negatively associated with inter-FC between RFPn and visual networks in Slow-5 and Slow-2, with no corresponding significant association for inter-FC between COn and visual networks. These results provide the first empirical evidence that links inter-FC between RFPn and visual networks with the visual processing speed parameter. These findings suggest that direct connectivity between occipital and right frontoparietal, but not frontoinsular, regions support visual processing speed.

Automated claustrum segmentation in human brain MRI using deep learning.

In the last two decades, neuroscience has produced intriguing evidence for a central role of the claustrum in mammalian forebrain structure and function. However, relatively few in vivo studies of the claustrum exist in humans. A reason for this may be the delicate and sheet-like structure of the claustrum lying between the insular cortex and the putamen, which makes it not amenable to conventional segmentation methods. Recently, Deep Learning (DL) based approaches have been successfully introduced for automated segmentation of complex, subcortical brain structures. In the following, we present a multi-view DL-based approach to segment the claustrum in T1-weighted MRI scans. We trained and evaluated the proposed method in 181 individuals, using bilateral manual claustrum annotations by an expert neuroradiologist as reference standard. Cross-validation experiments yielded median volumetric similarity, robust Hausdorff distance, and Dice score of 93.3%, 1.41 mm, and 71.8%, respectively, representing equal or superior segmentation performance compared to human intra-rater reliability. The leave-one-scanner-out evaluation showed good transferability of the algorithm to images from unseen scanners at slightly inferior performance. Furthermore, we found that DL-based claustrum segmentation benefits from multi-view information and requires a sample size of around 75 MRI scans in the training set. We conclude that the developed algorithm allows for robust automated claustrum segmentation and thus yields considerable potential for facilitating MRI-based research of the human claustrum. The software and models of our method are made publicly available.

Effective connectivity in the default mode network is distinctively disrupted in Alzheimer's disease-A simultaneous resting-state FDG-PET/fMRI study.

A prominent finding of postmortem and molecular imaging studies on Alzheimer's disease (AD) is the accumulation of neuropathological proteins in brain regions of the default mode network (DMN). Molecular models suggest that the progression of disease proteins depends on the directionality of signaling pathways. At network level, effective connectivity (EC) reflects directionality of signaling pathways. We hypothesized a specific pattern of EC in the DMN of patients with AD, related to cognitive impairment. Metabolic connectivity mapping is a novel measure of EC identifying regions of signaling input based on neuroenergetics. We simultaneously acquired resting-state functional MRI and FDG-PET data from patients with early AD (n = 35) and healthy subjects (n = 18) on an integrated PET/MR scanner. We identified two distinct subnetworks of EC in the DMN of healthy subjects: an anterior part with bidirectional EC between hippocampus and medial prefrontal cortex and a posterior part with predominant input into medial parietal cortex. Patients had reduced input into the medial parietal system and absent input from hippocampus into medial prefrontal cortex (p < 0.05, corrected). In a multiple linear regression with unimodal imaging and EC measures (F4,25 = 5.63, p = 0.002, r2 = 0.47), we found that EC (ß = 0.45, p = 0.012) was stronger associated with cognitive deficits in patients than any of the PET and fMRI measures alone. Our approach indicates specific disruptions of EC in the DMN of patients with AD and might be suitable to test molecular theories about downstream and upstream spreading of neuropathology in AD.

Alertness Training Increases Visual Processing Speed in Healthy Older Adults.

In this study, we investigated whether alertness training in healthy older adults increases visual processing speed (VPS) and whether functional connectivity in the cingulo-opercular network predicts training gain. Using the theory of visual attention, we derived quantitative estimates of VPS before and after training. In Study 1, 75 healthy older adults participated in alertness training, active-control training, or no training (n = 25 each). A significant Group × Session interaction indicated an increase in VPS in the alertness-training group but not in the control group, despite VPS not differing significantly between groups before training. In Study 2, 29 healthy older adults underwent resting-state functional MRI and then participated in alertness training. Pretraining functional connectivity in the cingulo-opercular network correlated with the individual training-induced change in VPS. In conclusion, results indicate that alertness training improves visual processing in older adults and that functional connectivity in the cingulo-opercular network provides a neural marker for predicting individual training gain.

Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia.

Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological link between these two alterations is suggested by theoretical models based on striatal dopamine's topographic modulation of cortico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the auditory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19 age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-l-alanine PET (18F-DOPA-PET) and resting state functional MRI (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure striatal dopamine synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis capacity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic circuits in schizophrenia.