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Objective Develop and validate models that predict mortality of patients diagnosed with COVID-19 admitted to the hospital.Design Retrospective cohort study.Setting A multicentre cohort across 10 Dutch hospitals including patients from 27 February to 8 June 2020.Participants SARS-CoV-2 positive patients (age ≥18) admitted to the hospital.Main outcome measures 21-day all-cause mortality evaluated by the area under the receiver operator curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value. The predictive value of age was explored by comparison with age-based rules used in practice and by excluding age from the analysis.Results 2273 patients were included, of whom 516 had died or discharged to palliative care within 21 days after admission. Five feature sets, including premorbid, clinical presentation and laboratory and radiology values, were derived from 80 features. Additionally, an Analysis of Variance (ANOVA)-based data-driven feature selection selected the 10 features with the highest F values: age, number of home medications, urea nitrogen, lactate dehydrogenase, albumin, oxygen saturation (%), oxygen saturation is measured on room air, oxygen saturation is measured on oxygen therapy, blood gas pH and history of chronic cardiac disease. A linear logistic regression and non-linear tree-based gradient boosting algorithm fitted the data with an AUC of 0.81 (95% CI 0.77 to 0.85) and 0.82 (0.79 to 0.85), respectively, using the 10 selected features. Both models outperformed age-based decision rules used in practice (AUC of 0.69, 0.65 to 0.74 for age >70). Furthermore, performance remained stable when excluding age as predictor (AUC of 0.78, 0.75 to 0.81).Conclusion Both models showed good performance and had better test characteristics than age-based decision rules, using 10 admission features readily available in Dutch hospitals. The models hold promise to aid decision-making during a hospital bed shortage.

Body Integrity Identity Disorder (BIID) is a condition in which individuals perceive a mismatch between their internal body scheme and physical body shape, resulting in an absolute desire to be either amputated or paralyzed. The condition is hypothesized to be of congenital nature, but evidence for a neuro-anatomical basis is sparse.We collected T1-weighted structural magnetic resonance imaging scans on a 3T scanner in eight individuals with BIID and 24 matched healthy controls, and analyzed the data using voxel-based morphometry.The results showed reduced grey matter volume in the left dorsal and ventral premotor cortices and larger grey matter volume in the cerebellum (lobule VIIa) in individuals with BIID compared to controls.The premotor cortex and cerebellum are thought to be crucial for the experience of body-ownership and the integration of multisensory information. Our results suggest that BIID is associated with structural brain anomalies and might result from a dysfunction in the integration of multisensory information, leading to the feeling of disunity between the mental and physical body shape.

Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3) receptor (D2/3R) binding has not been investigated in TRD subjects. We used [(123)I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p

Our body feels like it is ours. However, individuals with body integrity identity disorder (BIID) lack this feeling of ownership for distinct limbs and desire amputation of perfectly healthy body parts. This extremely rare condition provides us with an opportunity to study the neural basis underlying the feeling of limb ownership, since these individuals have a feeling of disownership for a limb in the absence of apparent brain damage. Here we directly compared brain activation between limbs that do and do not feel as part of the body using functional MRI during separate tactile stimulation and motor execution experiments. In comparison to matched controls, individuals with BIID showed heightened responsivity of a large somatosensory network including the parietal cortex and right insula during tactile stimulation, regardless of whether the stimulated leg felt owned or alienated. Importantly, activity in the ventral premotor cortex depended on the feeling of ownership and was reduced during stimulation of the alienated compared to the owned leg. In contrast, no significant differences between groups were observed during the performance of motor actions. These results suggest that altered somatosensory processing in the premotor cortex is associated with the feeling of disownership in BIID, which may be related to altered integration of somatosensory and proprioceptive information.

Background: Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depressive disorders. A recent multi-center study found no consistent changes in correlation-based (undirected) resting-state connectivity after ECT. Effective (directed) connectivity may provide more insight into the working mechanism of ECT. Objective: We investigated whether there are consistent changes in effective resting-state connectivity. Methods: This multi-center study included data from 189 patients suffering from severe unipolar depression and 59 healthy control participants. Longitudinal data were available for 81 patients and 24 healthy controls. We used dynamic causal modeling for resting-state functional magnetic resonance imaging to determine effective connectivity in the default mode, salience and central executive networks before and after a course of ECT. Bayesian general linear models were used to examine differences in baseline and longitudinal effective connectivity effects associated with ECT and its effectiveness. Results: Compared to controls, depressed patients showed many differences in effective connectivity at baseline, which varied according to the presence of psychotic features and later treatment outcome. Additionally, effective connectivity changed after ECT, which was related to ECT effectiveness. Notably, treatment effectiveness was associated with decreasing and increasing effective connectivity from the posterior default mode network to the left and right insula, respectively. No effects were found using correlation-based (undirected) connectivity. Conclusions: A beneficial response to ECT may depend on how brain regions influence each other in networks important for emotion and cognition. These findings further elucidate the working mechanisms of ECT and may provide directions for future non-invasive brain stimulation research.

AbstractExecutive functioning (EF) is a higher order cognitive process that is thought to depend on a network organization facilitating integration across subnetworks, in the context of which the central role of the fronto-parietal network (FPN) has been described across imaging and neurophysiological modalities. However, the potentially complementary unimodal information on the relevance of the FPN for EF has not yet been integrated. We employ a multilayer framework to allow for integration of different modalities into one ‘network of networks.’ We used diffusion MRI, resting-state functional MRI, MEG, and neuropsychological data obtained from 33 healthy adults to construct modality-specific single-layer networks as well as a single multilayer network per participant. We computed single-layer and multilayer eigenvector centrality of the FPN as a measure of integration in this network and examined their associations with EF. We found that higher multilayer FPN centrality, but not single-layer FPN centrality, was related to better EF. We did not find a statistically significant change in explained variance in EF when using the multilayer approach as compared to the single-layer measures. Overall, our results show the importance of FPN integration for EF and underline the promise of the multilayer framework toward better understanding cognitive functioning.

Abstract Major depressive disorder (MDD) is associated with structural and functional brain abnormalities. MDD as well as brain anatomy and function are influenced by genetic factors, but the role of gene expression remains unclear. Here, this work investigates how cortical gene expression contributes to structural and functional brain abnormalities in MDD. This work compares the gray matter volume and resting‐state functional measures in a Chinese sample of 848 MDD patients and 749 healthy controls, and these case‐control differences are then associated with cortical variation of gene expression. While whole gene expression is positively associated with structural abnormalities, it is negatively associated with functional abnormalities. This work observes the relationships of expression levels with brain abnormalities for individual genes, and found that transcriptional correlates of brain structure and function show opposite relations with gene dysregulation in postmortem cortical tissue from MDD patients. This work further identifies genes that are positively or negatively related to structural abnormalities as well as functional abnormalities. The MDD‐related genes are enriched for brain tissue, cortical cells, and biological pathways. These findings suggest that distinct genetic mechanisms underlie structural and functional brain abnormalities in MDD, and highlight the importance of cortical gene expression for the development of cortical abnormalities.

BackgroundAdequate and timely identification of depression is essential to improve patient care. A potential method to achieve this is by using neuroimaging. Many neuroimaging studies have revealed widespread abnormalities in brain structure and function in patients with depression, but in most studies only single neuroimaging modalities were used. Links between abnormalities in brain structure and function need to be therefore further explored in order to define diagnostic and therapeutic applications.MethodsA systematic literature review according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines was conducted.ResultsOut of 2,516 articles, only 14 studies were eligible to be included. These studies combined structural and functional neuroimaging methods in depressed patients compared to controls. Four studies reported a negative relationship between brain structure and function within the default mode network: reduced gray or white matter integrity in depressed patients compared to healthy controls was associated with enhanced neural activity or connectivity. The other studies reported positive relationships (two studies), mixed relationships (two studies), or no link (six studies) between structural and functional brain abnormalities.ConclusionThis systematic literature review revealed no robust relationship between abnormalities in brain structure and function in patients with depression. Remarkably, only 14 studies could be included and four of these suggested enhanced default mode network connectivity associated with reduced structural brain integrity. In the ongoing development of the diagnostic and treatment applications of neuroimaging, large-scale studies that combine structural with functional neuroimaging are required to determine the relationship between structural and functional abnormalities in depression.

Background and aimsChildhood trauma is associated with increased levels of anxiety later in life, an increased risk for the development of substance use disorders, and neurodevelopmental abnormalities in the amygdala and frontostriatal circuitry. The aim of this study was to investigate the (neurobiological) link among childhood trauma, state anxiety, and amygdala-frontostriatal activity in response to cocaine cues in regular cocaine users.MethodsIn this study, we included 59 non-treatment seeking regular cocaine users and 58 non-drug using controls. Blood oxygenation level-dependent responses were measured using functional magnetic resonance imaging while subjects performed a cue reactivity paradigm with cocaine and neutral cues. Psychophysiological interaction analyses were applied to assess functional connectivity between the amygdala and other regions in the brain. Self-report questionnaires were used to measure childhood trauma, state anxiety, drug use, drug use severity, and craving.ResultsNeural activation was increased during the presentation of cocaine cues, in a widespread network including the frontostriatal circuit and amygdala in cocaine users but not in controls. Functional coupling between the amygdala and medial prefrontal cortex was reduced in response to cocaine cues, in both cocaine users and controls, which was further diminished with increasing state anxiety. Importantly, amygdala-striatal connectivity was positively associated with childhood trauma in regular cocaine users, while there was a negative association in controls. At the behavioral level, state anxiety was positively associated with cocaine use severity and craving related to negative reinforcement.ConclusionChildhood trauma is associated with enhanced amygdala-striatal connectivity during cocaine cue reactivity in regular cocaine users, which may contribute to increased habit behavior and poorer cognitive control. While we cannot draw conclusions on causality, this study provides novel information on how childhood trauma may contribute to the development and persistence of cocaine use disorder.

Abstract Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (

Abstract No tools are currently available to predict whether a patient suffering from major depressive disorder (MDD) will respond to a certain treatment. Machine learning analysis of magnetic resonance imaging (MRI) data has shown potential in predicting response for individual patients, which may enable personalized treatment decisions and increase treatment efficacy. Here, we evaluated the accuracy of MRI-guided response prediction in MDD. We conducted a systematic review and meta-analysis of all studies using MRI to predict single-subject response to antidepressant treatment in patients with MDD. Classification performance was calculated using a bivariate model and expressed as area under the curve, sensitivity, and specificity. In addition, we analyzed differences in classification performance between different interventions and MRI modalities. Meta-analysis of 22 samples including 957 patients showed an overall area under the bivariate summary receiver operating curve of 0.84 (95% CI 0.81–0.87), sensitivity of 77% (95% CI 71–82), and specificity of 79% (95% CI 73–84). Although classification performance was higher for electroconvulsive therapy outcome prediction (n = 285, 80% sensitivity, 83% specificity) than medication outcome prediction (n = 283, 75% sensitivity, 72% specificity), there was no significant difference in classification performance between treatments or MRI modalities. Prediction of treatment response using machine learning analysis of MRI data is promising but should not yet be implemented into clinical practice. Future studies with more generalizable samples and external validation are needed to establish the potential of MRI to realize individualized patient care in MDD.

The clinical effect of electroconvulsive therapy (ECT) is mediated by eliciting a generalized seizure, which is achieved by applying electrical current to the head via scalp electrodes. The anatomy of the head influences the distribution of current flow in each brain region. Here, we investigated whether individual differences in simulated local electrical field strength are associated with ECT efficacy. We modeled the electric field of 67 depressed patients receiving ECT. Patient’s T1 magnetic resonance images were segmented, conductivities were assigned to each tissue and the finite element method was used to solve for the electric field induced by the electrodes. We investigated the correlation between modelled electric field and ECT outcome using voxel-wise general linear models. The difference between bilateral (BL) and right unilateral (RUL) electrode placement was striking. Even within electrode configuration, there was substantial variability between patients. For the modeled BL placement, stronger electric field strengths appeared in the left hemisphere and part of the right temporal lobe. Importantly, a stronger electric field in the temporal lobes was associated with less optimal ECT response in patients treated with BL-ECT. No significant differences in electric field distributions were found between responders and non-responders to RUL-ECT. These results suggest that overstimulation of the temporal lobes during BL stimulation has negative consequences on treatment outcome. If replicated, individualized pre-ECT computer-modelled electric field distributions may inform the development of patient-specific ECT protocols.

Background: Deep brain stimulation (DBS) is a new treatment option for patients with therapy-resistant obsessive–compulsive disorder (OCD). Approximately 60% of patients benefit from DBS, which might be improved if a biomarker could identify patients who are likely to respond. Therefore, we evaluated the use of preoperative structural magnetic resonance imaging (MRI) in predicting treatment outcome for OCD patients on the group- and individual-level. Methods: In this retrospective study, we analyzed preoperative MRI data of a large cohort of patients who received DBS for OCD (n = 57). We used voxel-based morphometry to investigate whether grey matter (GM) or white matter (WM) volume surrounding the DBS electrode (nucleus accumbens (NAc), anterior thalamic radiation), and whole-brain GM/WM volume were associated with OCD severity and response status at 12-month follow-up. In addition, we performed machine learning analyses to predict treatment outcome at an individual-level and evaluated its performance using cross-validation. Results: Larger preoperative left NAc volume was associated with lower OCD severity at 12-month follow-up (pFWE

Randomized controlled trials have shown efficacy of trauma-focused psychotherapies in youth with posttraumatic stress disorder (PTSD). However, response varies considerably among individuals. Currently, no biomarkers are available to assist clinicians in identifying youth who are most likely to benefit from treatment. In this study, we investigated whether resting-state functional magnetic resonance imaging (rs-fMRI) could distinguish between responders and non-responders on the group- and individual patient level. Pre-treatment rs-fMRI was recorded in 40 youth (ages 8–17 years) with (partial) PTSD before trauma-focused psychotherapy. Change in symptom severity from pre- to post-treatment was assessed using the Clinician-Administered PTSD scale for Children and Adolescents to divide participants into responders (≥30% symptom reduction) and non-responders. Functional networks were identified using meta-independent component analysis. Group-differences within- and between-network connectivity between responders and non-responders were tested using permutation testing. Individual predictions were made using multivariate, cross-validated support vector machine classification. A network centered on the bilateral superior temporal gyrus predicted treatment response for individual patients with 76% accuracy (pFWE = 0.02, 87% sensitivity, 65% specificity, area-under-receiver-operator-curve of 0.82). Functional connectivity between the frontoparietal and sensorimotor network was significantly stronger in non-responders (t = 5.35, pFWE = 0.01) on the group-level. Within-network connectivity was not significantly different between groups. This study provides proof-of-concept evidence for the feasibility to predict trauma-focused psychotherapy response in youth with PTSD at an individual-level. Future studies are required to test if larger cohorts could increase accuracy and to test further generalizability of the prediction models.

Background: Deep brain stimulation (DBS) is an innovative treatment for treatment-refractory depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%). Objective/Hypothesis: Our aim was to associate distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response. Methods: We performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response. Results: Stimulation closer to both tracts was significantly correlated to a larger symptom decrease (r = 0.61, p = 0.02), suggesting that stimulation more proximal to the tracts was beneficial. Biophysical modelling indicated that 37.5% of tracts were even outside the volume of activated tissue. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy. Conclusions: Our results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.

Given the restricted total scanning time for clinical neuroimaging, it is unclear whether clinical diffusion MRI protocols would benefit more from higher spatial resolution or higher angular resolution. In this work, we investigated the relative benefit of improving spatial or angular resolution in diffusion MRI to separate two parallel running white matter tracts that are targets for deep brain stimulation: the anterior thalamic radiation and the supero-lateral branch of the medial forebrain bundle. Both these tracts are situated in the ventral anterior limb of the internal capsule, and recent studies suggest that targeting a specific tract could improve treatment efficacy. Therefore, we scanned 19 healthy volunteers at 3T and 7T according to three diffusion MRI protocols with respectively standard clinical settings, increased spatial resolution of 1.4 mm, and increased angular resolution (64 additional gradient directions at b = 2200s/mm2). We performed probabilistic tractography for all protocols and quantified the separability of both tracts. The higher spatial resolution protocol improved separability by 41% with respect to the clinical standard, presumably due to decreased partial voluming. The higher angular resolution protocol resulted in increased apparent tract volumes and overlap, which is disadvantageous for application in precise treatment planning. We thus recommend to increase the spatial resolution for deep brain stimulation planning to 1.4 mm while maintaining angular resolution. This recommendation complements the general advice to aim for high angular resolution to resolve crossing fibers, confirming that the specific application and anatomical considerations are leading in clinical diffusion MRI protocol optimization. Keywords: Diffusion MRI, Tractography, Deep brain stimulation, Internal capsule, Angular and spatial resolution

Background: Gamma-hydroxybutyric acid (GHB) is a recreational drug associated with increasing numbers of GHB-dependent patients and emergency attendances often related to GHB-induced comas. Working memory (WM) deficits have been reported in association with GHB use, and animal studies have shown that GHB induces oxidative stress in vulnerable WM-related brain areas such as the dorsolateral prefrontal cortex (DLPFC). However, the effects of chronic GHB use and multiple GHB-induced comas on WM-related brain function in humans remains unknown. Methods: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users who never experienced GHB-induced coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants performed an n-back WM task during functional magnetic resonance imaging (fMRI) to probe DLPFC functioning. Results: The GHB-Coma group had lower premorbid IQ (p = .006) than the GHB-NoComa group despite comparable age and education level. There were also group differences in the use of other drugs than GHB. Therefore, all group comparisons were adjusted for IQ and drug use other than GHB. Compared with the GHB-NoComa and the No-GHB groups, the GHB-Coma group showed increased activity in the right DLPFC (pSVC = 0.028) and increased functional connectivity of the right DLPFC with a cluster comprising the left anterior cingulate and medial frontal gyrus (pFWE = 0.003). No significant fMRI differences were observed between the GHB-NoComa and No-GHB groups. Due to technical problems, no behavioural data were collected. Discussion: These results suggest that multiple GHB-induced comas, but not GHB-use per se, are associated with alterations in WM-related brain function. Public awareness campaigns are required to minimize the potential adverse effects induced by GHB recreational use, and especially GHB-induced comas, even if no immediate side effects are experienced. Keywords: Functional magnetic resonance imaging (fMRI), Functional connectivity, Drug addiction, Gamma-Hydroxybutyric acid (GHB) abuse, GHB-induced coma, Working memory

Acute stress is known to induce a state of hypervigilance, allowing optimal detection of threats. Although one may benefit from sensitive sensory processing, it comes at the cost of unselective attention and increased distraction by irrelevant information. Corticosteroids have been shown to profoundly influence brain function in a time-dependent manner, causing rapid non-genomic and slow genomic effects. Here, we investigated how these time-dependent effects influence the neural mechanisms underlying selective attention and the inhibition of emotional distracters in humans. Implementing a randomized, double-blind, placebo-controlled design, 65 young healthy men received 10 mg hydrocortisone either 60 min (rapid effects) or 270 min (slow effects), or placebo prior to an emotional distraction task, consisting of color-naming of either neutral or aversive words. Overall, participants responded slower to aversive compared to neutral words, indicating emotional interference with selective attention. Importantly, the rapid effects of corticosteroids increased emotional interference, which was associated with reduced amygdala inhibition to aversive words. Moreover, they induced enhanced amygdala connectivity with frontoparietal brain regions, which may reflect increased influence of the amygdala on an executive network. The slow effects of corticosteroids acted on the neural correlates of sustained attention. They decreased overall activity in the cuneus, possibly indicating reduced bottom-up attentional processing, and disrupted amygdala connectivity to the insula, potentially reducing emotional interference. Altogether, these data suggest a time-specific corticosteroid modulation of attentive processing. Whereas high circulating corticosteroid levels acutely increase emotional interference, possibly facilitating the detection of threats, a history of elevation might promote sustained attention and thereby contribute to stress-recovery of cognitive function.