There is growing interest in the complex topology of human brain functional networks, often measured using resting-state functional MRI (fMRI). Here, we used a meta-analysis of the large primary ...literature that used fMRI or PET to measure task-related activation (>1,600 studies; 1985-2010). We estimated the similarity (Jaccard index) of the activation patterns across experimental tasks between each pair of 638 brain regions. This continuous coactivation matrix was used to build a weighted graph to characterize network topology. The coactivation network was modular, with occipital, central, and default-mode modules predominantly coactivated by specific cognitive domains (perception, action, and emotion, respectively). It also included a rich club of hub nodes, located in parietal and prefrontal cortex and often connected over long distances, which were coactivated by a diverse range of experimental tasks. Investigating the topological role of edges between a deactivated and an activated node, we found that such competitive interactions were most frequent between nodes in different modules or between an activated rich-club node and a deactivated peripheral node. Many aspects of the coactivation network were convergent with a connectivity network derived from resting state fMRI data (n = 27, healthy volunteers); although the connectivity network was more parsimoniously connected and differed in the anatomical locations of some hubs. We conclude that the community structure of human brain networks is relevant to cognitive function. Deactivations may play a role in flexible reconfiguration of the network according to cognitive demand, varying the integration between modules, and between the periphery and a central rich club.
A statistically principled way of conducting brain network analysis is still lacking. Comparison of different populations of brain networks is hard because topology is inherently dependent on wiring ...cost, where cost is defined as the number of edges in an unweighted graph. In this paper, we evaluate the benefits and limitations associated with using cost-integrated topological metrics. Our focus is on comparing populations of weighted undirected graphs that differ in mean association weight, using global efficiency. Our key result shows that integrating over cost is equivalent to controlling for any monotonic transformation of the weight set of a weighted graph. That is, when integrating over cost, we eliminate the differences in topology that may be due to a monotonic transformation of the weight set. Our result holds for any unweighted topological measure, and for any choice of distribution over cost levels. Cost-integration is therefore helpful in disentangling differences in cost from differences in topology. By contrast, we show that the use of the weighted version of a topological metric is generally not a valid approach to this problem. Indeed, we prove that, under weak conditions, the use of the weighted version of global efficiency is equivalent to simply comparing weighted costs. Thus, we recommend the reporting of (i) differences in weighted costs and (ii) differences in cost-integrated topological measures with respect to different distributions over the cost domain. We demonstrate the application of these techniques in a re-analysis of an fMRI working memory task. We also provide a Monte Carlo method for approximating cost-integrated topological measures. Finally, we discuss the limitations of integrating topology over cost, which may pose problems when some weights are zero, when multiplicities exist in the ranks of the weights, and when one expects subtle cost-dependent topological differences, which could be masked by cost-integration.
Approximately 188 million people use cannabis yearly worldwide, and it has recently been legalised in 11 US states, Canada, and Uruguay for recreational use. The potential for increased cannabis use ...highlights the need to better understand its risks, including the acute induction of psychotic and other psychiatric symptoms. We aimed to investigate the effect of the cannabis constituent Δ9-tetrahydrocannabinol (THC) alone and in combination with cannabidiol (CBD) compared with placebo on psychiatric symptoms in healthy people.
In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published in English between database inception and May 21, 2019, with a within-person, crossover design. Inclusion criteria were studies reporting symptoms using psychiatric scales (the Brief Psychiatric Rating Scale BPRS and the Positive and Negative Syndrome Scale PANSS) following the acute administration of intravenous, oral, or nasal THC, CBD, and placebo in healthy participants, and presenting data that allowed calculation of standardised mean change (SMC) scores for positive (including delusions and hallucinations), negative (such as blunted affect and amotivation), and general (including depression and anxiety) symptoms. We did a random-effects meta-analysis to assess the main outcomes of the effect sizes for total, positive, and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo. Because the number of studies to do a meta-analysis on CBD's moderating effects was insufficient, this outcome was only systematically reviewed. This study is registered with PROSPERO, CRD42019136674.
15 eligible studies involving the acute administration of THC and four studies on CBD plus THC administration were identified. Compared with placebo, THC significantly increased total symptom severity with a large effect size (assessed in nine studies, with ten independent samples, involving 196 participants: SMC 1·10 95% CI 0·92–1·28, p<0·0001); positive symptom severity (assessed in 14 studies, with 15 independent samples, involving 324 participants: SMC 0·91 95% CI 0·68–1·14, p<0·0001); and negative symptom severity with a large effect size (assessed in 12 studies, with 13 independent samples, involving 267 participants: SMC 0·78 95% CI 0·59–0·97, p<0·0001). In the systematic review, of the four studies evaluating CBD's effects on THC-induced symptoms, only one identified a significant reduction in symptoms.
A single THC administration induces psychotic, negative, and other psychiatric symptoms with large effect sizes. There is no consistent evidence that CBD induces symptoms or moderates the effects of THC. These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purposes.
UK Medical Research Council, Maudsley Charity, Brain and Behavior Research Foundation, Wellcome Trust, and the UK National Institute for Health Research.
Network analysis has become a tool of choice for the study of functional and structural Magnetic Resonance Imaging (MRI) data. Little research, however, has investigated connectivity dynamics in ...relation to varying cognitive load. In fMRI, correlations among slow (<0.1Hz) fluctuations of blood oxygen level dependent (BOLD) signal can be used to construct functional connectivity networks. Using an anatomical parcellation scheme, we produced undirected weighted graphs linking 90 regions of the brain representing major cortical gyri and subcortical nuclei, in a population of healthy adults (n=43). Topological changes in these networks were investigated under different conditions of a classical working memory task — the N-back paradigm. A mass-univariate approach was adopted to construct statistical parametric networks (SPNs) that reflect significant modifications in functional connectivity between N-back conditions. Our proposed method allowed the extraction of ‘lost’ and ‘gained’ functional networks, providing concise graphical summaries of whole-brain network topological changes. Robust estimates of functional networks are obtained by pooling information about edges and vertices over subjects. Graph thresholding is therefore here supplanted by inference. The analysis proceeds by firstly considering changes in weighted cost (i.e. mean between-region correlation) over the different N-back conditions and secondly comparing small-world topological measures integrated over network cost, thereby controlling for differences in mean correlation between conditions. The results are threefold: (i) functional networks in the four conditions were all found to satisfy the small-world property and cost-integrated global and local efficiency levels were approximately preserved across the different experimental conditions; (ii) weighted cost considerably decreased as working memory load increased; and (iii) subject-specific weighted costs significantly predicted behavioral performances on the N-back task (Wald F=13.39,df1=1,df2=83,p<0.001), and therefore conferred predictive validity to functional connectivity strength, as measured by weighted cost. The results were found to be highly sensitive to the frequency band used for the computation of the between-region correlations, with the relationship between weighted cost and behavioral performance being most salient at very low frequencies (0.01–0.03Hz). These findings are discussed in relation to the integration/specialization functional dichotomy. The pruning of functional networks under increasing cognitive load may permit greater modular specialization, thereby enhancing performance.
►fMRI functional networks dynamics investigated under N-back task; ►Cost-integrated global and local efficiencies are preserved under all levels of cognitive load; ►Weighted cost significantly decreased as working memory load increased; ►Subject-specific weighted costs predicted behavioral performances on N-back task.
Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to ...antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.
To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites.
The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.
In total, 45 1H-MRS studies contributed data.
Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor.
Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).
In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean SD age, 30.3 10.4 years) and 1197 healthy volunteers (mean SD age, 27.5 8.8 years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose.
Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.
Abnormalities of tau protein are central to the pathogenesis of progressive supranuclear palsy, whereas haplotype variation of the tau gene MAPT influences the risk of Parkinson disease and ...Parkinson's disease dementia. We assessed whether regional MAPT expression might be associated with selective vulnerability of global brain networks to neurodegenerative pathology. Using task-free functional magnetic resonance imaging in progressive supranuclear palsy, Parkinson disease, and healthy subjects (n = 128), we examined functional brain networks and measured the connection strength between 471 gray matter regions. We obtained MAPT and SNCA microarray expression data in healthy subjects from the Allen brain atlas. Regional connectivity varied according to the normal expression of MAPT. The regional expression of MAPT correlated with the proportionate loss of regional connectivity in Parkinson's disease. Executive cognition was impaired in proportion to the loss of hub connectivity. These effects were not seen with SNCA, suggesting that alpha-synuclein pathology is not mediated through global network properties. The results establish a link between regional MAPT expression and selective vulnerability of functional brain networks to neurodegeneration.
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