Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia

Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4minutes in length), and a dynamic sense, computed using sliding windows (44s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical–subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.Highlights•Studied both static and dynamic connectivity changes in schizophrenia during rest•Small but significant connectivity differences might be obscured in static analysis.•Patients show significant differences in dwell times in multiple states.•Disrupted thalamo-cortical connectivity in schizophrenia in a state-specific manne

Digital health technologies in the accelerating medicines Partnership® Schizophrenia Program.

Although meta-analytic studies have shown that 25-33% of those at Clinical High Risk (CHR) for psychosis transition to a first episode of psychosis within three years, less is known about estimating the risk of transition at an individual level. Digital phenotyping offers a novel approach to explore the nature of CHR and may help to improve personalized risk prediction. Specifically, digital data enable detailed mapping of experiences, moods and behaviors during longer periods of time (e.g., weeks, months) and offer more insight into patterns over time at the individual level across their routine daily life. However, while novel digital health technologies open up many new avenues of research, they also come with specific challenges, including replicability of results and the adherence of participants. This paper outlines the design of the digital component of the Accelerating Medicines Partnership® Schizophrenia Program (AMP SCZ) project, a large international collaborative project that follows individuals at CHR for psychosis over a period of two years. The digital component comprises one-year smartphone-based digital phenotyping and actigraphy. Smartphone-based digital phenotyping includes 30-item short daily self-report surveys and voice diaries as well as passive data capture (geolocation, on/off screen state, and accelerometer). Actigraphy data are collected via an Axivity wristwatch. The aim of this paper is to describe the design and the three goals of the digital measures used in AMP SCZ to: (i) better understand the symptoms, real-life experiences, and behaviors of those at CHR for psychosis, (ii) improve the prediction of transition to psychosis and other health outcomes in this population based on digital phenotyping and, (iii) serve as an example for replicable and ethical research across geographically diverse regions and cultures. Accordingly, we describe the rationale, protocol and implementation of these digital components of the AMP SCZ project. **Link to video interview: https://vimeo.com/1060935583 *

Counterpoint. Early intervention for psychosis risk syndromes: Minimizing risk and maximizing benefit

Background: Malhi et al. in this issue critique the clinical high risk (CHR) syndrome for psychosis. Method: Response to points of critique. Results: We agree that inconsistency in CHR nomenclature should be minimized. We respectfully disagree on other points. In our view: a) individuals with CHR and their families need help, using existing interventions, even though we do not yet fully understand disease mechanisms; b) substantial progress has been made in identification of biomarkers; c) symptoms used to identify CHR are specific to psychotic illnesses; d) CHR diagnosis is not “extremely difficult”; e) the pattern of progression, although heterogenous, is discernible; f) “psychosis-like symptoms” are common but are not used to identify CHR; and g) on the point described as ‘the real risk,’ CHR diagnosis does not frequently cause harmful stigma. Discussion: Malhi et al.'s arguments do not fairly characterize progress in the CHR field nor efforts to minimize stigma. That said, much work remains in areas of consistent nomenclature, mechanisms of disease, dissecting heterogeneity, and biomarkers. With regard to what the authors term the “real risk” of stigma associated with a CHR “label,” however, our view is that avoiding words like “risk” and “psychosis” reinforces the stigma that both they and we mean to oppose. Moreover, patients and their families benefit from being given a term that describes what is happening to them

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Application of principal component analysis to distinguish patients with schizophrenia from healthy controls based on fractional anisotropy measurements

Principal component analysis (PCA) is often used to reduce the dimension of data before applying more sophisticated data analysis methods such as non-linear classification algorithms or independent component analysis. This practice is based on selecting components corresponding to the largest eigenvalues. If the ultimate goal is separation of data in two groups, then these set of components need not have the most discriminatory power. We measured the distance between two such populations using Mahalanobis distance and chose the eigenvectors to maximize it, a modified PCA method, which we call the discriminant PCA (DPCA). DPCA was applied to diffusion tensor based fractional anisotropy images to distinguish age-matched schizophrenia subjects from healthy controls. The performance of the proposed method was evaluated by the one-leave-out method. We show that for this fractional anisotropy data-set, the classification error with 60 components was close to the minimum error and that the Mahalanobis distance was twice as large with DPCA, than with PCA. Finally, by masking the discriminant function with the white matter tracts of the John Hopkins University atlas, we identified left superior longitudinal fasciculus as the tract which gave the least classification error. In addition, with six optimally chosen tracts the classification error was zero