Edwin van Dellen

Direction of information flow in large-scale resting-state networks is frequency-dependent

Significance A description of the structural and functional connections in the human brain is necessary for the understanding of both normal and abnormal brain functioning. Although it has become clear in recent years that stable patterns of functional connectivity can be observed during the resting state, to date, it remains unclear what the dominant patterns of information flow are in this functional connectome and how these relate to the integration of brain function. Our results are the first to describe the large-scale frequency-specific patterns of information flow in the human brain, showing that different subsystems form a loop through which information “reverberates” or “circulates.” These results could be extended to give insights into how such flow optimizes integrative cognitive processing. Normal brain function requires interactions between spatially separated, and functionally specialized, macroscopic regions, yet the directionality of these interactions in large-scale functional networks is unknown. Magnetoencephalography was used to determine the directionality of these interactions, where directionality was inferred from time series of beamformer-reconstructed estimates of neuronal activation, using a recently proposed measure of phase transfer entropy. We observed well-organized posterior-to-anterior patterns of information flow in the higher-frequency bands (alpha1, alpha2, and beta band), dominated by regions in the visual cortex and posterior default mode network. Opposite patterns of anterior-to-posterior flow were found in the theta band, involving mainly regions in the frontal lobe that were sending information to a more distributed network. Many strong information senders in the theta band were also frequent receivers in the alpha2 band, and vice versa. Our results provide evidence that large-scale resting-state patterns of information flow in the human brain form frequency-dependent reentry loops that are dominated by flow from parieto-occipital cortex to integrative frontal areas in the higher-frequency bands, which is mirrored by a theta band anterior-to-posterior flow.

Early interventions in risk groups for schizophrenia: what are we waiting for?

Intervention strategies in adolescents at ultra high-risk (UHR) for psychosis are promising for reducing conversion to overt illness, but have only limited impact on functional outcome. Recent studies suggest that cognition does not further decline during the UHR stage. As social and cognitive impairments typically develop before the first psychotic episode and even years before the UHR stage, prevention should also start much earlier in the groups at risk for schizophrenia and other psychiatric disorders. Early intervention strategies could aim to improve stress resilience, optimize brain maturation, and prevent or alleviate adverse environmental circumstances. These strategies should urgently be tested for efficacy: the prevalence of ~1% implies that yearly ~22 in every 100,000 people develop overt symptoms of this illness, despite the fact that for many of them—e.g., children with an affected first-degree family member or carriers of specific genetic variants—increased risk was already identifiable early in life. Our current ability to recognize several risk groups at an early age not only provides an opportunity, but also implies a clinical imperative to act. Time is pressing to investigate preventive interventions in high-risk children to mitigate or prevent the development of schizophrenia and related psychiatric disorders.

EEG-directed connectivity from posterior brain regions is decreased in dementia with Lewy bodies: a comparison with Alzheimer's disease and controls.

Directed information flow between brain regions might be disrupted in dementia with Lewy bodies (DLB) and relate to the clinical syndrome of DLB. To investigate this hypothesis, resting-state electroencephalography recordings were obtained in patients with probable DLB and Alzheimers disease (AD), and controls (Nxa0= 66 per group, matched for age and gender). Phase transfer entropy was used to measure directed connectivity in the groups for the theta, alpha, and beta frequency band. A posterior-to-anterior phase transfer entropy gradient, with occipital channels driving the frontal channels, was found in controls in all frequency bands. This posterior-to-anterior gradient was largely lost in DLB in the alpha band (p < 0.05). In the beta band, posterior brain regions were less driving in information flow in AD than in DLB and controls. In conclusion, the common posterior-to-anterior pattern of directed connectivity in controls is disturbed in DLB patients in the alpha band, and in AD patients in the beta band. Disrupted alpha band-directed connectivity may underlie the clinical syndrome of DLB and differentiate between DLB and AD.

Theta Burst Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations: Negative Findings From a Double-Blind-Randomized Trial

BACKGROUNDnAuditory verbal hallucinations (AVH) in schizophrenia are resistant to antipsychotic medication in approximately 25% of patients. Treatment with repetitive transcranial magnetic stimulation (rTMS) for refractory AVH has shown varying results. A stimulation protocol using continuous theta burst rTMS (TB-rTMS) showed high efficacy in open label studies. We tested TB-rTMS as a treatment strategy for refractory AVH in a double-blind, placebo-controlled trial.nnnMETHODSnSeventy-one patients with AVH were randomly allocated to TB-rTMS or placebo treatment. They received 10 TB-rTMS or sham treatments over the left temporoparietal cortex in consecutive days. AVH severity was assessed at baseline, end of treatment and follow-up using the Psychotic Symptom Rating Scale (PSYRATS) and the Auditory Hallucinations Rating Scale (AHRS). Other schizophrenia-related symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS).nnnRESULTSnSeven patients dropped out before completing the study. In the remaining 64, AVH improved significantly after treatment in both groups as measured with both PSYRATS and AHRS. PANSS positive and general subscores also decreased, but the negative subscores did not. However, improvement did not differ significantly between the TB-rTMS and the placebo group on any outcome measure.nnnCONCLUSIONSnSymptom reduction could be achieved in patients with medication-resistant hallucinations, even within 1 week time. However, as both groups showed similar improvement, effects were general (ie, placebo-effects) rather than specific to treatment with continuous TB-rTMS. Our findings highlight the importance of double-blind trials including a sham-control condition to assess efficacy of new treatments such as TMS.

Random forest to differentiate dementia with Lewy bodies from Alzheimer's disease

The aim of this study was to build a random forest classifier to improve the diagnostic accuracy in differentiating dementia with Lewy bodies (DLB) from Alzheimers disease (AD) and to quantify the relevance of multimodal diagnostic measures, with a focus on electroencephalography (EEG).

Meditation is associated with increased brain network integration

INTRODUCTIONnThis study aims to identify novel quantitative EEG measures associated with mindfulness meditation. As there is some evidence that meditation is associated with higher integration of brain networks, we focused on EEG measures of network integration.nnnMETHODSnSixteen novice meditators and sixteen experienced meditators participated in the study. Novice meditators performed a basic meditation practice that supported effortless awareness, which is an important quality of experience related to mindfulness practices, while their EEG was recorded. Experienced meditators performed a self-selected meditation practice that supported effortless awareness. Network integration was analyzed with maximum betweenness centrality and leaf fraction (which both correlate positively with network integration) as well as with diameter and average eccentricity (which both correlate negatively with network integration), based on a phase-lag index (PLI) and minimum spanning tree (MST) approach. Differences between groups were assessed using repeated-measures ANOVA for the theta (4-8xa0Hz), alpha (8-13xa0Hz) and lower beta (13-20xa0Hz) frequency bands.nnnRESULTSnMaximum betweenness centrality was significantly higher in experienced meditators than in novices (Pxa0=xa00.012) in the alpha band. In the same frequency band, leaf fraction showed a trend toward being significantly higher in experienced meditators than in novices (Pxa0=xa00.056), while diameter and average eccentricity were significantly lower in experienced meditators than in novices (Pxa0=xa00.016 and Pxa0=xa00.028 respectively). No significant differences between groups were observed for the theta and beta frequency bands.nnnCONCLUSIONnThese results show that alpha band functional network topology is better integrated in experienced meditators than in novice meditators during meditation. This novel finding provides the rationale to investigate the temporal relation between measures of functional connectivity network integration and meditation quality, for example using neurophenomenology experiments.

Structural Brain Network Disturbances in the Psychosis Spectrum

BACKGROUNDnIndividuals with subclinical psychotic symptoms provide a unique window on the pathophysiology of psychotic experiences as these individuals are free of confounders such as hospitalization, negative and cognitive symptoms and medication use. Brain network disturbances of white matter connections are thought to play a central role in the pathophysiology of psychosis. Based on the structural network disconnection hypothesis in schizophrenia, we expect less and weaker connections, and altered brain network organization in individuals with clinical and those with subclinical psychotic symptoms.nnnMETHODSnWe used diffusion tensor imaging to study 35 patients with a psychotic disorder, 35 subjects with subclinical psychotic symptoms, and 36 healthy controls. The structural brain network was analyzed on 3 levels: connection density, white matter microstructure (fractional anisotropy, mean diffusivity, and magnetic transfer ratio), and network organization. Network organization was studied with minimum spanning tree analysis, a method to reconstruct a backbone of structural highways in the brain.nnnRESULTSnDecreased fractional anisotropy and increased mean diffusivity was found in both groups with psychotic symptoms, while their network topology showed decreased overlap with a healthy reference network. Decreased centrality was found in several brain regions, including parietal hubs and language areas, in both groups with psychotic symptoms. Deviation of network characteristics was more apparent in clinical subjects than in subclinical subjects.nnnDISCUSSIONnWeaker connections and decreased centrality of parietal hubs characterize the structural brain network in subjects with psychotic symptoms. These differences are more notable in clinical than in subclinical subjects with psychotic experiences.

Functional connectivity and network analysis during hypoactive delirium and recovery from anesthesia

OBJECTIVEnTo gain insight in the underlying mechanism of reduced levels of consciousness due to hypoactive delirium versus recovery from anesthesia, we studied functional connectivity and network topology using electroencephalography (EEG).nnnMETHODSnEEG recordings were performed in age and sex-matched patients with hypoactive delirium (n=18), patients recovering from anesthesia (n=20), and non-delirious control patients (n=20), all after cardiac surgery. Functional and directed connectivity were studied with phase lag index and directed phase transfer entropy. Network topology was characterized using the minimum spanning tree (MST). A random forest classifier was calculated based on all measures to obtain discriminative ability between the three groups.nnnRESULTSnNon-delirious control subjects showed a back-to-front information flow, which was lost during hypoactive delirium (p=0.01) and recovery from anesthesia (p<0.01). The recovery from anesthesia group had more integrated network in the delta band compared to non-delirious controls. In contrast, hypoactive delirium showed a less integrated network in the alpha band. High accuracy for discrimination between hypoactive delirious patients and controls (86%) and recovery from anesthesia and controls (95%) were found. Accuracy for discrimination between hypoactive delirium and recovery from anesthesia was 73%.nnnCONCLUSIONnLoss of functional and directed connectivity were observed in both hypoactive delirium and recovery from anesthesia, which might be related to the reduced level of consciousness in both states. These states could be distinguished in topology, which was a less integrated network during hypoactive delirium.nnnSIGNIFICANCEnFunctional and directed connectivity are similarly disturbed during a reduced level of consciousness due to hypoactive delirium and sedatives, however topology was differently affected.

Oscillatory brain activity associates with neuroligin-3 expression and predicts progression free survival in patients with diffuse glioma

IntroductionDiffuse gliomas have local and global effects on neurophysiological brain functioning, which are often seen as ‘passive’ consequences of the tumor. However, seminal preclinical work has shown a prominent role for neuronal activity in glioma growth: mediated by neuroligin-3 (NLGN3), increased neuronal activity causes faster glioma growth. It is unclear whether the same holds true in patients. Here, we investigate whether lower levels of oscillatory brain activity relate to lower NLGN3 expression and predict longer progression free survival (PFS) in diffuse glioma patients.MethodsTwenty-four newly diagnosed patients with diffuse glioma underwent magnetoencephalography and subsequent tumor resection. Oscillatory brain activity was approximated by calculating broadband power (0.5–48xa0Hz) of the magnetoencephalography. NLGN3 expression in glioma tissue was semi-quantitatively assessed by immunohistochemistry. Peritumor and global oscillatory brain activity was then compared between different levels of NLGN3 expression with Kruskal–Wallis tests. Cox proportional hazards analyses were performed to estimate the predictive value of oscillatory brain activity for PFS.ResultsPatients with low expression of NLGN3 had lower levels of global oscillatory brain activity than patients with higher NLGN3 expression (Pu2009<u20090.001). Moreover, lower peritumor (hazard ratio 2.17, Pu2009=u20090.008) and global oscillatory brain activity (hazard ratio 2.10, Pu2009=u20090.008) predicted longer PFS.ConclusionsLower levels of peritumor and global oscillatory brain activity are related to lower NLGN3 expression and longer PFS, corroborating preclinical research. This study highlights the important interplay between macroscopically measured brain activity and glioma progression, and may lead to new therapeutic interventions in diffuse glioma patients.

EEG DIRECTED CONNECTIVITY FROM POSTERIOR BRAIN REGIONS IS DECREASED IN DEMENTIA WITH LEWY BODIES: A COMPARISON WITH ALZHEIMER’S DISEASE AND CONTROLS

not available. SATURDAY, JULY 23, 2016 ALZHEIMER’S IMAGING CONSORTIUM (AIC) ICI-02 ALZHEIMER’S DISEASE IMAGING BIOMARKERS AND AGING ICI-02-01 ALZHEIMER’S DISEASE IMAGING BIOMARKERS AND AGING Clifford R. Jack Jr, Mayo Clinic, Rochester, MN, USA. Contact e-mail: jack.clifford@mayo.edu Abstract not available.not available. SATURDAY, JULY 23, 2016 ALZHEIMER’S IMAGING CONSORTIUM (AIC) ICI-03 CONTROVERSY DEBATE: ALZHEIMER’S DISEASE — SINGLE VERSUS MULTIPLE BRAIN NETWORK DISORDER ICI-03-01 CONTROVERSY DEBATE: SINGLE BRAIN NETWORK DISORDER Christian Sorg, University Hospital Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. Contact e-mail: c.sorg@lrz.