Professor Michael Breakspear

Healthy brain function depends on balancing stable integration between brain areas for effective coordinated functioning, with coexisting segregation that allows subsystems to express their functional specialization. Metastability, a concept from the dynamical systems literature, has been proposed as a key signature that characterizes this balance. Building on this principle, the neuroscience literature has leveraged the phenomenon of metastability to investigate various aspects of brain function in health and disease. However, this body of work often uses the notion of metastability heuristically, and sometimes inaccurately, making it difficult to navigate the vast literature, interpret findings and foster further development of theoretical and experimental methodologies. Here, we provide a comprehensive review of metastability and its applications in neuroscience, covering its scientific and historical foundations and the practical measures used to assess it in empirical data. We also provide a critical analysis of recent theoretical developments, clarifying common misconceptions and paving the road for future developments.

Cognition and behavior are emergent properties of brain systems that seek to maximize complex and adaptive behaviors while minimizing energy utilization. Different species reconcile this trade-off in different ways, but in humans the outcome is biased towards complex behaviors and hence relatively high energy use. However, even in energy-intensive brains, numerous parsimonious processes operate to optimize energy use. We review how this balance manifests in both homeostatic processes and task-associated cognition. We also consider the perturbations and disruptions of metabolism in neurocognitive diseases.

Background and aims: Adults with severe mental illness (SMI) have lower physical activity (PA) than the general population. Supervised exercise interventions provide high support but may not effectively promote motivation, which is important for behaviour change. Motivational strategies such as PA counselling may target motivation more directly; however, the effectiveness in people with SMI is unclear. Methods: This was a randomised controlled trial of interventions designed to promote PA in adults with SMI. Participants were randomised to either: (1) supervised exercise (GYM), or (2) motivational counselling and self-monitoring using fitness trackers (MOT). Group sessions were once/week over 8-weeks. The primary outcome was time spent in moderate-to-vigorous PA (MVPA) assessed using GENEActiv accelerometers worn continuously. Change in MVPA was assessed using the cumulative change from baseline, and as a composition of light activity, sedentary behaviour, and sleep. Results: Sixty-four participants were allocated (63% male, 82% overweight/obese, 59% psychotic disorder). Accelerometer-derived MVPA increased for the MOT group between baseline and post-intervention, and the cumulative sum of change in MVPA from baseline in the MOT group was higher than the GYM group. Compositional analyses showed stable weekly activity profiles, with no significant changes attributable to group allocation. Conclusions: The cumulative change in MVPA was higher for MOT than GYM; however, compositional analyses that considers MVPA as a composition of other daily behaviours showed no change in composition over the intervention period. Exercise interventions should incorporate motivational strategies and supervised exercise; future research should investigate behaviour change interventions with longer durations and more frequent sessions. Registration details: The trial is registered under the Australian and New Zealand Clinical Trial Registry (ACTRN12617001017314).

Background: Increasing physical activity (PA) is an effective strategy to slow reductions in cortical volume and maintain cognitive function in older adulthood. However, PA does not exist in isolation, but coexists with sleep and sedentary behaviour to make up the 24-hour day. We investigated how the balance of all three behaviours (24-hour time-use composition) is associated with grey matter volume in healthy older adults, and whether grey matter volume influences the relationship between 24-hour time-use composition and cognitive function. Methods: This cross-sectional study included 378 older adults (65.6 ± 3.0 years old, 123 male) from the ACTIVate study across two Australian sites (Adelaide and Newcastle). Time-use composition was captured using 7-day accelerometry, and T1-weighted magnetic resonance imaging was used to measure grey matter volume both globally and across regions of interest (ROI: frontal lobe, temporal lobe, hippocampi, and lateral ventricles). Pairwise correlations were used to explore univariate associations between time-use variables, grey matter volumes and cognitive outcomes. Compositional data analysis linear regression models were used to quantify associations between ROI volumes and time-use composition, and explore potential associations between the interaction between ROI volumes and time-use composition with cognitive outcomes. Results: After adjusting for covariates (age, sex, education), there were no significant associations between time-use composition and any volumetric outcomes. There were significant interactions between time-use composition and frontal lobe volume for long-term memory (p = 0.018) and executive function (p = 0.018), and between time-use composition and total grey matter volume for executive function (p = 0.028). Spending more time in moderate-vigorous PA was associated with better long-term memory scores, but only for those with smaller frontal lobe volume (below the sample mean). Conversely, spending more time in sleep and less time in sedentary behaviour was associated with better executive function in those with smaller total grey matter volume. Conclusions: Although 24-hour time use was not associated with total or regional grey matter independently, total grey matter and frontal lobe grey matter volume moderated the relationship between time-use composition and several cognitive outcomes. Future studies should investigate these relationships longitudinally to assess whether changes in time-use composition correspond to changes in grey matter volume and cognition.

Walking is a complex motor activity that requires coordinated interactions between the sensory and motor systems. We used mobile EEG and EMG to investigate the brain-muscle networks involved in gait control during overground walking in young people, older people, and individuals with Parkinson's disease. Dynamic interactions between the sensorimotor cortices and eight leg muscles within a gait cycle were assessed using multivariate analysis. We identified three distinct brain-muscle networks during a gait cycle. These networks include a bilateral network, a left-lateralized network activated during the left swing phase, and a right-lateralized network active during the right swing. The trajectories of these networks are contracted in older adults, indicating a reduction in neuromuscular connectivity with age. Individuals with the impaired tactile sensitivity of the foot showed a selective enhancement of the bilateral network, possibly reflecting a compensation strategy to maintain gait stability. These findings provide a parsimonious description of interindividual differences in neuromuscular connectivity during gait.

Voxel-based morphometry (VBM) and surface-based morphometry (SBM) are two widely used neuroimaging techniques for investigating brain anatomy. These techniques rely on statistical inferences at individual points (voxels or vertices), clusters of points, or a priori regions-of-interest. They are powerful tools for describing brain anatomy, but offer little insights into the generative processes that shape a particular set of findings. Moreover, they are restricted to a single spatial resolution scale, precluding the opportunity to distinguish anatomical variations that are expressed across multiple scales. Drawing on concepts from classical physics, here we develop an approach, called mode-based morphometry (MBM), that can describe any empirical map of anatomical variations in terms of the fundamental, resonant modes¿eigenmodes¿of brain anatomy, each tied to a specific spatial scale. Hence, MBM naturally yields a multiscale characterization of the empirical map, affording new opportunities for investigating the spatial frequency content of neuroanatomical variability. Using simulated and empirical data, we show that the validity and reliability of MBM are either comparable or superior to classical vertex-based SBM for capturing differences in cortical thickness maps between two experimental groups. Our approach thus offers a robust, accurate, and informative method for characterizing empirical maps of neuroanatomical variability that can be directly linked to a generative physical process.

Brain recordings collected at different resolutions support distinct signatures of neural coding, leading to scale-dependent theories of brain function. Here, we show that these disparate signatures emerge from a heavy-tailed, multiscale functional organization of neuronal activity observed across calcium-imaging recordings collected from the whole brains of zebrafish and nematodes as well as from sensory regions in flies, mice, and macaques. Network simulations demonstrate that this conserved hierarchical structure enhances information processing. Finally, we find that this organization is maintained despite significant cross-scale reconfiguration of cellular coordination during behavior. Our findings suggest that this nonlinear organization of neuronal activity is a universal principle conserved for its ability to adaptively link behavior to neural dynamics across multiple spatiotemporal scales while balancing functional resiliency and information processing efficiency.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

Importance: Physical health and chronic medical comorbidities are underestimated, inadequately treated, and often overlooked in psychiatry. A multiorgan, systemwide characterization of brain and body health in neuropsychiatric disorders may enable systematic evaluation of brain-body health status in patients and potentially identify new therapeutic targets. Objective: To evaluate the health status of the brain and 7 body systems across common neuropsychiatric disorders. Design, Setting, and Participants: Brain imaging phenotypes, physiological measures, and blood- and urine-based markers were harmonized across multiple population-based neuroimaging biobanks in the US, UK, and Australia, including UK Biobank; Australian Schizophrenia Research Bank; Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing; Alzheimer's Disease Neuroimaging Initiative; Prospective Imaging Study of Ageing; Human Connectome Project-Young Adult; and Human Connectome Project-Aging. Cross-sectional data acquired between March 2006 and December 2020 were used to study organ health. Data were analyzed from October 18, 2021, to July 21, 2022. Adults aged 18 to 95 years with a lifetime diagnosis of 1 or more common neuropsychiatric disorders, including schizophrenia, bipolar disorder, depression, generalized anxiety disorder, and a healthy comparison group were included. Main Outcomes and Measures: Deviations from normative reference ranges for composite health scores indexing the health and function of the brain and 7 body systems. Secondary outcomes included accuracy of classifying diagnoses (disease vs control) and differentiating between diagnoses (disease vs disease), measured using the area under the receiver operating characteristic curve (AUC). Results: There were 85748 participants with preselected neuropsychiatric disorders (36324 male) and 87420 healthy control individuals (40560 male) included in this study. Body health, especially scores indexing metabolic, hepatic, and immune health, deviated from normative reference ranges for all 4 neuropsychiatric disorders studied. Poor body health was a more pronounced illness manifestation compared to brain changes in schizophrenia (AUC for body = 0.81 [95% CI, 0.79-0.82]; AUC for brain = 0.79 [95% CI, 0.79-0.79]), bipolar disorder (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.57-0.58]), depression (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.58-0.58]), and anxiety (AUC for body = 0.63 [95% CI, 0.63-0.63]; AUC for brain = 0.57 [95% CI, 0.57-0.58]). However, brain health enabled more accurate differentiation between distinct neuropsychiatric diagnoses than body health (schizophrenia-other: mean AUC for body = 0.70 [95% CI, 0.70-0.71] and mean AUC for brain = 0.79 [95% CI, 0.79-0.80]; bipolar disorder-other: mean AUC for body = 0.60 [95% CI, 0.59-0.60] and mean AUC for brain = 0.65 [95% CI, 0.65-0.65]; depression-other: mean AUC for body = 0.61 [95% CI, 0.60-0.63] and mean AUC for brain = 0.65 [95% CI, 0.65-0.66]; anxiety-other: mean AUC for body = 0.63 [95% CI, 0.62-0.63] and mean AUC for brain = 0.66 [95% CI, 0.65-0.66). Conclusions and Relevance: In this cross-sectional study, neuropsychiatric disorders shared a substantial and largely overlapping imprint of poor body health. Routinely monitoring body health and integrated physical and mental health care may help reduce the adverse effect of physical comorbidity in people with mental illness.

Cortical activity depends upon a continuous supply of oxygen and other metabolic resources. Perinatal disruption of oxygen availability is a common clinical scenario in neonatal intensive care units, and a leading cause of lifelong disability. Pathological patterns of brain activity including burst suppression and seizures are a hallmark of the recovery period, yet the mechanisms by which these patterns arise remain poorly understood. Here, we use computational modeling of coupled metabolic-neuronal activity to explore the mechanisms by which oxygen depletion generates pathological brain activity. We find that restricting oxygen supply drives transitions from normal activity to several pathological activity patterns (isoelectric, burst suppression, and seizures), depending on the potassium supply. Trajectories through parameter space track key features of clinical electrophysiology recordings and reveal how infants with good recovery outcomes track toward normal parameter values, whereas the parameter values for infants with poor outcomes dwell around the pathological values. These findings open avenues for studying and monitoring the metabolically challenged infant brain, and deepen our understanding of the link between neuronal and metabolic activity.

The dynamic integration of sensory and bodily signals is central to adaptive behaviour. Although the anterior cingulate cortex (ACC) and the anterior insular cortex (AIC) play key roles in this process, their context-dependent dynamic interactions remain unclear. Here, we studied the spectral features and interplay of these two brain regions using high-fidelity intracranial-EEG recordings fromfive patients (ACC: 13 contacts, AIC: 14 contacts) acquired duringmovie viewing with validation analyses performed on an independent resting intracranial-EEG dataset. ACC and AIC both showed a power peak and positive functional connectivity in the gamma (30-35 Hz) frequencywhile this power peakwas absent in the resting data.We then used a neurobiologically informed computational model investigating dynamic effective connectivity asking how it linked to the movie's perceptual (visual, audio) features and the viewer's heart rate variability (HRV). Exteroceptive features related to effective connectivity of ACC highlighting its crucial role in processing ongoing sensory information. AIC connectivity was related to HRV and audio emphasising its core role in dynamically linking sensory and bodily signals. Our findings provide new evidence for complementary, yet dissociable, roles of neural dynamics between the ACC and the AIC in supporting brain-body interactions during an emotional experience.

In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia's leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics, and Screening for Trials. Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now has a national Registry for Mild Cognitive Impairment and dementia with 55 participating clinical sites, an extensive map of memory clinic services, national Memory and Cognition Clinic Guidelines and specialized screening for trials sites in five states. This paper provides an overview of ADNeT's achievements to date and future directions. With the increase in dementia cases expected over coming decades, and with recent advances in plasma biomarkers and amyloid lowering therapies, the nationally coordinated initiatives and partnerships ADNeT has established are critical for increased national prevention efforts, co-ordinated implementation of emerging treatments for Alzheimer's disease, innovation of early and accurate diagnosis, driving continuous improvements in clinical care and patient outcome and access to post-diagnostic support and clinical trials. For a heterogenous disorder such as dementia, which is now the second leading cause of death in Australia following cardiovascular disease, the case for adequate investment into research and development has grown even more compelling.

Background and Hypothesis: Impairments in the expression, experience, and recognition of emotion are common in early psychosis (EP). Computational accounts of psychosis suggest disrupted top-down modulation by the cognitive control system (CCS) on perceptual circuits underlies psychotic experiences, but their role in emotional deficits in EP is unknown. Study Design: The affective go/no-go task was used to probe inhibitory control during the presentation of calm or fearful faces in young persons with EP and matched controls. Computational modeling of functional magnetic resonance imaging (fMRI) data were performed using dynamic causal modeling (DCM). The influence of the CCS on perceptual and emotional systems was examined using parametric empirical bayes. Study Results: When inhibiting motor response to fearful faces, EP participants showed higher brain activity in the right posterior insula (PI). To explain this, we used DCM to model effective connectivity between the PI, regions from the CCS activated during inhibition (dorsolateral prefrontal cortex [DLPFC] and anterior insula [AI]), and a visual input region, the lateral occipital cortex (LOC). EP participants exerted a stronger top-down inhibition from the DLPFC to the LOC than controls. Within the EP cohort, increased top-down connectivity between the LOC and AI was associated with a higher burden of negative symptoms. Conclusions: Young persons with a recent onset of psychosis show a disturbance in the cognitive control of emotionally salient stimuli and the suppression of irrelevant distractors. These changes are associated with negative symptoms, suggesting new targets for the remediation of emotional deficits in young persons with EP.

Biological aging of human organ systems reflects the interplay of age, chronic disease, lifestyle and genetic risk. Using longitudinal brain imaging and physiological phenotypes from the UK Biobank, we establish normative models of biological age for three brain and seven body systems. Here we find that an organ's biological age selectively influences the aging of other organ systems, revealing a multiorgan aging network. We report organ age profiles for 16 chronic diseases, where advanced biological aging extends from the organ of primary disease to multiple systems. Advanced body age associates with several lifestyle and environmental factors, leukocyte telomere lengths and mortality risk, and predicts survival time (area under the curve of 0.77) and premature death (area under the curve of 0.86). Our work reveals the multisystem nature of human aging in health and chronic disease. It may enable early identification of individuals at increased risk of aging-related morbidity and inform new strategies to potentially limit organ-specific aging in such individuals.

The diagnosis of obsessive-compulsive disorder (OCD) has been linked with changes in frontostriatal resting-state connectivity. However, replication of prior findings is lacking, and the mechanistic understanding of these effects is incomplete. To confirm and advance knowledge on changes in frontostriatal functional connectivity in OCD, participants with OCD and matched healthy controls underwent resting-state functional, structural and diffusion neuroimaging. Functional connectivity changes in frontostriatal systems were here replicated in individuals with OCD (n = 52) compared with controls (n = 45). OCD participants showed greater functional connectivity (t = 4.3, PFWE = 0.01) between the nucleus accumbens (NAcc) and the orbitofrontal cortex (OFC) but lower functional connectivity between the dorsal putamen and lateral prefrontal cortex (t = 3.8, PFWE = 0.04) relative to controls. Computational modelling suggests that NAcc-OFC connectivity changes reflect an increased influence of NAcc over OFC activity and reduced OFC influence over NAcc activity (posterior probability, Pp > 0.66). Conversely, dorsal putamen showed reduced modulation over lateral prefrontal cortex activity (Pp > 0.90). These functional deregulations emerged on top of a generally intact anatomical substrate. We provide out-of-sample replication of opposite changes in ventro-anterior and dorso-posterior frontostriatal connectivity in OCD and advance the understanding of the neural underpinnings of these functional perturbations. These findings inform the development of targeted therapies normalizing frontostriatal dynamics in OCD.

The classic brain criticality hypothesis postulates that the brain benefits from operating near a continuous second-order phase transition. Slow feedback regulation of neuronal activity could, however, lead to a discontinuous first-order transition and thereby bistable activity. Observations of bistability in awake brain activity have nonetheless remained scarce and its functional significance unclear. Moreover, there is no empirical evidence to support the hypothesis that the human brain could flexibly operate near either a first- or second-order phase transition despite such a continuum being common in models. Here, using computational modelling, we found bistable synchronization dynamics to emerge through elevated positive feedback and occur exclusively in a regime of critical-like dynamics. We then assessed bistability in vivo with resting-state magnetoencephalography in healthy adults (7 females, 11 males) and stereo-electroencephalography in epilepsy patients (28 females, 36 males). This analysis revealed that a large fraction of the neocortices exhibited varying degrees of bistability in neuronal oscillations from 3 to 200 Hz. In line with our modelling results, the neuronal bistability was positively correlated with classic assessment of brain criticality across narrow-band frequencies. Excessive bistability was predictive of epileptic pathophysiology in the patients whereas moderate bistability was positively correlated with task performance in the healthy subjects. These empirical findings thus reveal the human brain as a one-of-a-kind complex system that exhibits critical-like dynamics in a continuum between continuous and discontinuous phase transitions.

Current behavioural treatment of obsessive-compulsive disorder (OCD) is informed by fear conditioning and involves iteratively re-evaluating previously threatening stimuli as safe. However, there is limited research investigating the neurobiological response to conditioning and reversal of threatening stimuli in individuals with OCD. A clinical sample of individuals with OCD (N = 45) and matched healthy controls (N = 45) underwent functional magnetic resonance imaging. While in the scanner, participants completed a well-validated fear reversal task and a resting-state scan. We found no evidence for group differences in task-evoked brain activation or functional connectivity in OCD. Multivariate analyses encompassing all participants in the clinical and control groups suggested that subjective appraisal of threatening and safe stimuli were associated with a larger difference in brain activity than the contribution of OCD symptoms. In particular, we observed a brain-behaviour continuum whereby heightened affective appraisal was related to increased bilateral insula activation during the task (r = 0.39, pFWE =.001). These findings suggest that changes in conditioned threat-related processes may not be a core neurobiological feature of OCD and encourage further research on the role of subjective experience in fear conditioning.

The anatomy of the brain necessarily¿constrains its function, but precisely how remains unclear. The classical and dominant paradigm in neuroscience is that neuronal dynamics are driven by interactions between discrete, functionally specialized cell populations connected by a complex array of axonal fibres1¿3. However, predictions from neural field theory, an established mathematical framework for modelling large-scale brain activity4¿6, suggest that the geometry of the brain may represent a more fundamental constraint on dynamics than complex interregional connectivity7,8. Here, we confirm these theoretical predictions by analysing human magnetic resonance imaging data acquired under spontaneous and diverse task-evoked conditions. Specifically, we show that cortical and subcortical activity can be parsimoniously understood as resulting from excitations of fundamental, resonant modes of the brain's geometry (that is, its shape) rather than from modes of complex interregional connectivity, as classically assumed. We then use these geometric modes to show that task-evoked activations across over 10,000 brain maps are not confined to focal areas, as widely believed, but instead excite brain-wide modes with wavelengths spanning over 60 mm. Finally, we confirm predictions that the close link between geometry and function is explained by a dominant role for wave-like activity, showing that wave dynamics can reproduce numerous canonical spatiotemporal properties of spontaneous and evoked recordings. Our findings challenge prevailing views and identify a previously underappreciated role of geometry in shaping function, as predicted by a unifying and physically principled model of brain-wide dynamics.

The recruitment of participants for research studies may be subject to bias. The Prospective Imaging Study of Ageing (PISA) aims to characterize the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). Participants approached to take part in PISA were selected from existing cohort studies with available genomewide genetic data for both successfully and unsuccessfully recruited participants, allowing us to investigate the genetic contribution to voluntary recruitment, including the genetic predisposition to AD. We use a polygenic risk score (PRS) approach to test to what extent the genetic risk for AD, and related risk factors predict participation in PISA. We did not identify a significant association of genetic risk for AD with study participation, but we did identify significant associations with PRS for key causal risk factors for AD, IQ, household income and years of education. We also found that older and female participants were more likely to take part in the study. Our findings highlight the importance of considering bias in key risk factors for AD in the recruitment of individuals for cohort studies.

INTRODUCTION: Although many cognitive measures have been developed to assess cognitive decline due to Alzheimer's disease (AD), there is little consensus on optimal measures, leading to varied assessments across research cohorts and clinical trials making it difficult to pool cognitive measures across studies. METHODS: We used a two-stage approach to harmonize cognitive data across cohorts and derive a cross-cohort score of cognitive impairment due to AD. First, we pool and harmonize cognitive data from international cohorts of varying size and ethnic diversity. Next, we derived cognitive composites that leverage maximal data from the harmonized dataset. RESULTS: We show that our cognitive composites are robust across cohorts and achieve greater or comparable sensitivity to AD-related cognitive decline compared to the Mini-Mental State Examination and Preclinical Alzheimer Cognitive Composite. Finally, we used an independent cohort validating both our harmonization approach and composite measures. DISCUSSION: Our easy to implement and readily available pipeline offers an approach for researchers to harmonize their cognitive data with large publicly available cohorts, providing a simple way to pool data for the development or validation of findings related to cognitive decline due to AD.

The neurobiological mechanisms of arousal and anesthesia remain poorly understood. Recent evidence highlights the key role of interactions between the cerebral cortex and the diffusely projecting matrix thalamic nuclei. Here, we interrogate these processes in a whole-brain corticothalamic neural mass model endowed with targeted and diffusely projecting thalamocortical nuclei inferred from empirical data. This model captures key features seen in propofol anesthesia, including diminished network integration, lowered state diversity, impaired susceptibility to perturbation, and decreased corticocortical coherence. Collectively, these signatures reflect a suppression of information transfer across the cerebral cortex. We recover these signatures of conscious arousal by selectively stimulating the matrix thalamus, recapitulating empirical results in macaque, as well as wake-like information processing states that reflect the thalamic modulation of large-scale cortical attractor dynamics. Our results highlight the role of matrix thalamocortical projections in shaping many features of complex cortical dynamics to facilitate the unique communication states supporting conscious awareness.

Much of systems neuroscience posits the functional importance of brain activity patterns that lack natural scales of sizes, durations, or frequencies. The field has developed prominent, and sometimes competing, explanations for the nature of this scale-free activity. Here, we reconcile these explanations across species and modalities. First, we link estimates of excitation-inhibition (E-I) balance with time-resolved correlation of distributed brain activity. Second, we develop an unbiased method for sampling time series constrained by this time-resolved correlation. Third, we use this method to show that estimates of E-I balance account for diverse scale-free phenomena without need to attribute additional function or importance to these phenomena. Collectively, our results simplify existing explanations of scale-free brain activity and provide stringent tests on future theories that seek to transcend these explanations.

The current paper proposes a method to estimate phase to phase cross-frequency coupling between brain areas, applied to broadband signals, without any a priori hypothesis about the frequency of the synchronized components. N:m synchronization is the only form of cross-frequency synchronization that allows the exchange of information at the time resolution of the faster signal, hence likely to play a fundamental role in large-scale coordination of brain activity. The proposed method, named cross-frequency phase linearity measurement (CF-PLM), builds and expands upon the phase linearity measurement, an iso-frequency connectivity metrics previously published by our group. The main idea lies in using the shape of the interferometric spectrum of the two analyzed signals in order to estimate the strength of cross-frequency coupling. We first provide a theoretical explanation of the metrics. Then, we test the proposed metric on simulated data from coupled oscillators synchronized in iso- and cross-frequency (using both Rössler and Kuramoto oscillator models), and subsequently apply it on real data from brain activity. Results show that the method is useful to estimate n:m synchronization, based solely on the phase of the signals (independently of the amplitude), and no a-priori hypothesis is available about the expected frequencies.

Perceiving, anticipating and responding to the actions of another person are fundamentally entwined processes such that seeing another's movement can prompt automatic imitation, as in social mimicry and contagious yawning. Yet the direct-matching of others' movements is not always appropriate, so this tendency must be controlled. This necessitates the hierarchical integration of the systems for action mirroring with domain-general control networks. Here we use functional magnetic resonance imaging (fMRI) and computational modelling to examine the top-down and context-dependent modulation of mirror representations and their influence on motor planning. Participants performed actions that either intentionally or incidentally imitated, or counter-imitated, an observed action. Analyses of these fMRI data revealed a region in the mid-occipital gyrus (MOG) where activity differed between imitation versus counter-imitation in a manner that depended on whether this was intentional or incidental. To identify broader cortical network mechanisms underlying this interaction between intention and imitativeness, we used dynamic causal modelling to pose specific hypotheses which embody assumptions about inter-areal interactions and contextual modulations. These models each incorporated four regions - medial temporal V5 (early motion perception), MOG (action-observation), supplementary motor area (action planning), and anterior insula (executive control) ¿ but differ in their interactions and hierarchical structure. The best model of our data afforded a crucial role for the anterior insula, gating the interaction of supplementary motor area and MOG activity. This provides a novel brain network-based account of task-dependent control over the integration of motor planning and mirror systems, with mirror responses suppressed for intentional counter-imitation.

BACKGROUND: The apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). It has been shown that APOE e4 allele (e4) relates to early pathological accumulation of cerebral amyloid-ß (Aß), leading to decade earlier age-of-onset of AD. However vascular and anatomical brain changes in the presence of Aß and e4 gene have not yet been fully examined in middle age. We aim to investigate how e4 and Aß level influence MR neuroimaging biomarkers such as white-matter hyperintensities and hippocampus volume in mid-life (45-65 year old) cognitively unimpaired (CU) individuals. METHOD: 149 middle age (44 to 66 years of age) CU adults (age 58.2±5.4, 115 Females, years of education 13.5±2.8) underwent 3T MRI and amyloid PET scans using 18 F-Florbetaben as part of the PISA study. Of this e4 enriched cohort (N=78 e4 carriers), 12 were classified as Aß+ (Centiloid=20). 5 participants with e2e4 genotypes were excluded due to the protective effect of the e2 allele. Multivariable general linear models were implemented to study the association of e4 and Aß with structural neuroimaging markers including white-matter hyperintensity volume (WMHV) and Hippocampus volume (HV). Both volumes were normalised using total intracranial volume, and age, gender and years-of-education were used as independent covariates. RESULT: There was no age difference between e4+ and e4- groups (Kruskal-Wallis test, p-value=0.8), but Aß+ participants were older compared to Aß- (p-value=0.005). There was no HV differences between e4+ and e4- groups when controlling for Centiloid (p-value=0.55). When comparing HV differences between groups based on joint e4 and Aß, Aß+e4+ had significantly lower HV compared to Aß-e4+ (p-value=0.01) and Aß-e4- (p-value=0.021) as shown in Figure 1. For WMHV differences, a trend towards significance exists for Aß+e4+ when compared to and Aß+e4- and Aß-e4- (p-value=0.069) as shown in Figure 2. CONCLUSION: In this study, we found that early signs of hippocampus degeneration may occur in the middle age in the presence of both high Aß level and APOE e4 allele. Future studies will investigate the effective age spread for middle-aged preclinical AD population which will be beneficial for participant recruitment for new clinical trials.

BACKGROUND: The PISA study aims to characterise the natural history and symptom progression of Alzheimer's disease (AD) at its prodromal phase. Utilising genetic risk prediction we have identified middle-aged and older Australians at high risk of dementia. In addition to onsite phenotyping, online surveys and cognitive testing have been used to economically collect information from an Australia-wide sample. METHOD: We have utilised our population based sample recruitment pool (N=15,351) of previous research participants who have been genome wide genotyped. Participants are invited to complete a comprehensive online survey, then complete online cognitive assessments, including Cambridge Brain Sciences (CBS), Cogstate, and an emotion recognition task. RESULT: Thus far nearly 4,000 participants have taken part in our online survey, and of these 2055 participants have completed the CBS assessment consisting of twelve subtests assessing memory, reasoning, attention, and planning. Recruitment for CBS and the other platforms is ongoing and participants are being invited to complete follow-up assessments after two years. At baseline we find significant association of both APOE genotype and polygenetic risk scores (PRS) for AD (omitting the APOE region) in healthy middle aged and elderly individuals with cognitive domains tested using the CBS platform. CONCLUSION: The utility of online cognitive testing for large scale testing in cohort and epidemiological studies will be discussed. The identification of cognitive changes associated with AD risk and prodromal disease gives important insights into mechanisms of AD development throughout the life span and is an opportunity to investigate prodromal markers to allow selection of individuals for early treatment strategies.

Rapid reconfigurations of brain activity support efficient neuronal communication and flexible behaviour. Suboptimal brain dynamics is associated to impaired adaptability, possibly leading to functional deficiencies. We hypothesize that impaired flexibility in brain activity can lead to motor and cognitive symptoms of Parkinson's disease (PD). To test this hypothesis, we studied the 'functional repertoire'¿the number of distinct configurations of neural activity¿using source-reconstructed magnetoencephalography in PD patients and controls. We found stereotyped brain dynamics and reduced flexibility in PD. The intensity of this reduction was proportional to symptoms severity, which can be explained by beta-band hyper-synchronization. Moreover, the basal ganglia were prominently involved in the abnormal patterns of brain activity. Our findings support the hypotheses that: symptoms in PD relate to impaired brain flexibility, this impairment preferentially involves the basal ganglia, and beta-band hypersynchronization is associated with reduced brain flexibility. These findings highlight the importance of extensive functional repertoires for correct behaviour.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD) can lead to the development of neuropsychiatric symptoms. These can include harmful changes in mood and behaviour that alienate family members and raise ethical questions about personal responsibility for actions committed under stimulation-dependent mental states. Qualitative interviews were conducted with twenty participants (ten PD patient-caregiver dyads) following subthalamic DBS at a movement disorders centre, in order to explore the meaning and significance of stimulation-related neuropsychiatric symptoms amongst a purposive sample of persons with PD and their spousal caregivers. Interview transcripts underwent inductive thematic analysis. Clinical and experiential aspects of post-DBS neuropsychiatric symptoms were identified. Caregivers were highly burdened by these symptoms and both patients and caregivers felt unprepared for their consequences, despite having received information prior to DBS, desiring greater family and peer engagement prior to neurosurgery. Participants held conflicting opinions as to whether emergent symptoms were attributable to neurostimulation. Many felt that they reflected aspects of the person's "real" or "younger" personality. Those participants who perceived a close relationship between stimulation changes and changes in mental state were more likely to view these symptoms as inauthentic and uncontrollable. Unexpected and troublesome neuropsychiatric symptoms occurred despite a pre-operative education programme that was delivered to all participants. This suggests that such symptoms are difficult to predict and manage even if best practice guidelines are followed by experienced centres. Further research aimed at predicting these complications may improve the capacity of clinicians to tailor the consent process.

Predictive coding has played a transformative role in the study of psychosis, casting delusions and hallucinations as statistical inference in a system with abnormal precision. However, the negative symptoms of schizophrenia, such as affective blunting, avolition, and asociality, remain poorly understood. We propose a computational framework for emotional expression based on active inference¿namely that affective behaviours such as smiling are driven by predictions about the social consequences of smiling. Similarly to how delusions and hallucinations can be explained by predictive uncertainty in sensory circuits, negative symptoms naturally arise from uncertainty in social prediction circuits. This perspective draws on computational principles to explain blunted facial expressiveness and apathy¿anhedonia in schizophrenia. Its phenomenological consequences also shed light on the content of paranoid delusions and indistinctness of self¿other boundaries. Close links are highlighted between social prediction, facial affect mirroring, and the fledgling study of interoception. Advances in automated analysis of facial expressions and acoustic speech patterns will allow empirical testing of these computational models of the negative symptoms of schizophrenia.

Executive dysfunctions in early psychosis (EP) are subtle but persistent, hindering recovery. We asked whether changes in the cognitive control system (CCS) disrupt the response to increased cognitive load in persons with EP. In all, 30 EP and 30 control participants undertook multimodal MRI. Computational models of structural and effective connectivity amongst regions in the CCS were informed by cortical responses to the multi-source interference task, a paradigm that selectively introduces stimulus conflict. EP participants showed greater activation of CCS regions, including the superior parietal cortex, and were disproportionately slower at resolving stimulus conflict in the task. Computational models of the effective connectivity underlying this behavioral response suggest that the normative (control) group resolved stimulus conflict through an efficient and direct modulation of gain between the visual cortex and the anterior insula (AI). In contrast, the EP group utilized an indirect path, with parallel and multi-region hops to resolve stimulus conflict at the AI. Individual differences in task performance were dependent on initial linear gain modulations in the EP group versus a single nonlinear modulation in the control group. Effective connectivity in the EP group was associated with reduced structural integration amongst those connections critical for task execution. CCS engagement during stimulus conflict is hampered in EP owing to inefficient use of higher-order network interactions, with high tonic gain impeding task-relevant (phasic) signal amplification.

Facial infra-red imaging (IRI) is a contact-free technique complimenting the traditional psychophysiological measures to characterize physiological profile. However, its full potential in affective research is arguably unmet due to the analytical challenges it poses. Here we acquired facial IRI data, facial expressions and traditional physiological recordings (heart rate and skin conductance) from healthy human subjects whilst they viewed a 20-min-long unedited emotional movie. We present a novel application of motion correction and the results of spatial independent component analysis of the thermal data. Three distinct spatial components are recovered associated with the nose, the cheeks and respiration. We first benchmark this methodology against a traditional nose-tip region-of-interest based technique showing an expected similarity of signals extracted by these methods. We then show significant correlation of all the physiological responses across subjects, including the thermal signals, suggesting common dynamic shifts in emotional state induced by the movie. In sum, this study introduces an innovative approach to analyse facial IRI data and highlights the potential of thermal imaging to robustly capture emotion-related changes induced by ecological stimuli.

Prediction-error checking processes play a key role in predictive coding models of perception. However, neural indices of such processes have yet to be unambiguously demonstrated. To date, experimental paradigms aiming to study such phenomena have relied upon the relative frequency of stimulus repeats and/or 'unexpected' events that are physically different from 'expected' events. These features of experimental design leave open alternative explanations for the observed effects. A definitive demonstration requires that presumed prediction error-related responses should show contextual dependency (rather than simply effects of frequency or repetition) and should not be attributable to low-level stimulus differences. Most importantly, prediction-error signals should show dose dependency with respect to the degree to which expectations are violated. Here, we exploit a novel experimental paradigm specifically designed to address these issues, using it to interrogate early latency event-related potentials (ERPs) to contextually expected and unexpected visual stimuli. In two electroencephalography (EEG) experiments, we demonstrate that an N1/N170 evoked potential is robustly modulated by unexpected perceptual events ('perceptual surprise') and shows dose-dependent sensitivity with respect to both the influence of prior information and the extent to which expectations are violated. This advances our understanding of perceptual predictions in the visual domain by clearly identifying these evoked potentials as an index of visual surprise.

The temporal pole (TP) is an associative cortical region required for complex cognitive functions such as social and emotional cognition. However, mapping the TP with functional magnetic resonance imaging is technically challenging and thus understanding its interaction with other key emotional circuitry, such as the amygdala, remains elusive. We exploited the unique advantages of stereo-electroencephalography (sEEG) to assess the responses of the TP and the amygdala during the perception of emotionally salient stimuli of pictures, music and movies. These stimuli consistently elicited high gamma responses (70¿140 Hz) in both the TP and the amygdala, accompanied by functional connectivity in the low frequency range (2¿12 Hz). Computational analyses suggested that the TP drove this effect in the theta frequency range, modulated by the emotional valence of the stimuli. Notably, cross-frequency analysis indicated the phase of theta oscillations in the TP modulated the amplitude of high gamma activity in the amygdala. These results were reproducible across three types of sensory inputs including naturalistic stimuli. Our results suggest that multimodal emotional stimuli induce a hierarchical influence of the TP over the amygdala.

Objective: The current international trend is to create large datasets with existing data and/or deposit newly collected data into repositories accessible to the scientific community. These practices lead to more efficient data sharing, better detection of small effects, modelling of confounders, establishment of sample generalizability and identification of differences between any given disorders. In Australia, to facilitate such data-sharing and collaborative opportunities, the Neurobiology in Youth Mental Health Partnership was created. This initiative brings together specialised researchers from around Australia to work towards a better understanding of the cross-diagnostic neurobiology of youth mental health and the translation of this knowledge into clinical practice. One of the mandates of the partnership was to develop a protocol for harmonised prospective collection of data across research centres in the field of youth mental health in order to create large datasets. Methods: Four key research modalities were identified: clinical assessments, brain imaging, neurocognitive assessment and collection of blood samples. This paper presents the consensus set of assessments/data collection that has been selected by experts in each domain. Conclusion: The use of this core set of data will facilitate the pooling of psychopathological and neurobiological data into large datasets allowing researchers to tackle important questions requiring very large numbers. The aspiration of this transdiagnostic approach is a better understanding of the mechanisms underlying mental illnesses.

Background: Predicting aphasia recovery is difficult due to a high variability in treatment response. Detailed measures of treatment response are compounded by a dearth of information that examine brain connections that contribute to clinical improvement. In this study we measure alterations to cortical connectivity pathways during a therapy paradigm to detect whether key brain connections that contribute to language recovery can be detected prior to therapy. Methods: We conducted a case¿control trial with twenty-three adults including eight adults with chronic, post-stroke aphasia. Aphasia patients underwent 12 naming therapy sessions over 4 weeks, consisting of semantic and phonological treatment approaches. High-density electroencephalography (128 channel EEG) was measured prior to therapy and immediately following treatment in patients with aphasia. Analysis via a dynamic causal modelling (DCM) was used to assess which cortical connections significantly correlated with therapy response. Results: Altered cortical responses in aphasia patients measured bilaterally in a dual stream DCM connectivity model were predictive of treatment-induced improvement in naming. Pre-treatment DCM coupling (i.e., strength of cortical connections) significant correlated with naming improvement for items treated with semantic therapy, as indicated by increased connection strengths between left inferior parietal lobule (LIPL) and inferior frontal gyrus (LIFG, r = .63, pFDR = .016). In particular, the mediating role of contralateral regions significantly influences overall treatment improvement in the latter stages of stroke recovery. Conclusions: Our findings identify a potential means to stratify larger cohorts of patients in neurorehabilitation settings into distinct treatments that are tailored to their individual language deficit.

The human brain integrates diverse cognitive processes into a coherent whole, shifting fluidly as a function of changing environmental demands. Despite recent progress, the neurobiological mechanisms responsible for this dynamic system-level integration remain poorly understood. Here we investigated the spatial, dynamic, and molecular signatures of system-wide neural activity across a range of cognitive tasks. We found that neuronal activity converged onto a low-dimensional manifold that facilitates the execution of diverse task states. Flow within this attractor space was associated with dissociable cognitive functions, unique patterns of network-level topology, and individual differences in fluid intelligence. The axes of the low-dimensional neurocognitive architecture aligned with regional differences in the density of neuromodulatory receptors, which in turn relate to distinct signatures of network controllability estimated from the structural connectome. These results advance our understanding of functional brain organization by emphasizing the interface between neural activity, neuromodulatory systems, and cognitive function.

Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.

Cognitive neuroscience has traditionally focused on simple tasks, presented sparsely and using abstract stimuli. While this approach has yielded fundamental insights into functional specialisation in the brain, its ecological validity remains uncertain. Do these tasks capture how brains function 'in the wild', where stimuli are dynamic, multimodal, and crowded? Ecologically valid paradigms that approximate real life scenarios, using stimuli such as films, spoken narratives, music, and multiperson games emerged in response to these concerns over a decade ago. We critically appraise whether this approach has delivered on its promise to deliver new insights into brain function. We highlight the challenges, technological innovations, and clinical opportunities that are required should this field meet its full potential.

Impulsivity in Parkinson's disease may be mediated by faulty evaluation of rewards or the failure to inhibit inappropriate choices. Despite prior work suggesting that distinct neural networks underlie these cognitive operations, there has been little study of these networks in Parkinson's disease, and their relationship to inter-individual differences in impulsivity. High-resolution diffusion MRI data were acquired from 57 individuals with Parkinson's disease (19 females, mean age 62, mean Hoehn and Yahr stage 2.6) prior to surgery for deep brain stimulation. Reward evaluation and response inhibition networks were reconstructed with seed-based probabilistic tractography. Impulsivity was evaluated using two approaches: (i) neuropsychiatric instruments were used to assess latent constructs of impulsivity, including trait impulsiveness and compulsivity, disinhibition, and also impatience; and (ii) participants gambled in an ecologically-valid virtual casino to obtain a behavioural read-out of explorative, risk-taking, impulsive behaviour. Multivariate analyses revealed that different components of impulsivity were associated with distinct variations in structural connectivity, implicating both reward evaluation and response inhibition networks. Larger bet sizes in the virtual casino were associated with greater connectivity of the reward evaluation network, particularly bilateral fibre tracts between the ventral striatum and ventromedial prefrontal cortex. In contrast, weaker connectivity of the response inhibition network was associated with increased exploration of alternative slot machines in the virtual casino, with right-hemispheric tracts between the subthalamic nucleus and the pre-supplementary motor area contributing most strongly. Further, reduced connectivity of the reward evaluation network was associated with more 'double or nothing' gambles, weighted by connections between the subthalamic nucleus and ventromedial prefrontal cortex. Notably, the variance explained by structural connectivity was higher for behavioural indices of impulsivity, derived from clinician-administered tasks and the gambling paradigm, as compared to questionnaire data. Lastly, a clinically-meaningful distinction could be made amongst participants with a history of impulse control behaviours based on the interaction of their network connectivity with medication dosage and gambling behaviour. In summary, we report structural brain-behaviour covariation in Parkinson's disease with distinct reward evaluation and response inhibition networks that underlie dissociable aspects of impulsivity (cf. choosing and stopping). More broadly, our findings demonstrate the potential of using naturalistic paradigms and neuroimaging techniques in clinical settings to assist in the identification of those susceptible to harmful behaviours.

A key component of the flexibility and complexity of the brain is its ability to dynamically adapt its functional network structure between integrated and segregated brain states depending on the demands of different cognitive tasks. Integrated states are prevalent when performing tasks of high complexity, such as maintaining items in working memory, consistent with models of a global workspace architecture. Recent work has suggested that the balance between integration and segregation is under the control of ascending neuromodulatory systems, such as the noradrenergic system, via changes in neural gain (in terms of the amplification and non-linearity in stimulus-response transfer function of brain regions). In a previous large-scale nonlinear oscillator model of neuronal network dynamics, we showed that manipulating neural gain parameters led to a 'critical' transition in phase synchrony that was associated with a shift from segregated to integrated topology, thus confirming our original prediction. In this study, we advance these results by demonstrating that the gain-mediated phase transition is characterized by a shift in the underlying dynamics of neural information processing. Specifically, the dynamics of the subcritical (segregated) regime are dominated by information storage, whereas the supercritical (integrated) regime is associated with increased information transfer (measured via transfer entropy). Operating near to the critical regime with respect to modulating neural gain parameters would thus appear to provide computational advantages, offering flexibility in the information processing that can be performed with only subtle changes in gain control. Our results thus link studies of whole-brain network topology and the ascending arousal system with information processing dynamics, and suggest that the constraints imposed by the ascending arousal system constrain low-dimensional modes of information processing within the brain.

Subthalamic deep brain stimulation (DBS) for Parkinson's disease (PD) may modulate chronometric and instrumental aspects of choice behaviour, including motor inhibition, decisional slowing, and value sensitivity. However, it is not well known whether subthalamic DBS affects more complex aspects of decision-making, such as the influence of subjective estimates of uncertainty on choices. In this study, 38 participants with PD played a virtual casino prior to subthalamic DBS (whilst 'on' medication) and again, 3-months postoperatively (whilst 'on' stimulation). At the group level, there was a small but statistically significant decrease in impulsivity postoperatively, as quantified by the Barratt Impulsiveness Scale (BIS). The gambling behaviour of participants (bet increases, slot machine switches and double or nothing gambles) was associated with this self-reported measure of impulsivity. However, there was a large variance in outcome amongst participants, and we were interested in whether individual differences in subjective estimates of uncertainty (specifically, volatility) were related to differences in pre- and postoperative impulsivity. To examine these individual differences, we fit a computational model (the Hierarchical Gaussian Filter, HGF), to choices made during slot machine game play as well as a simpler reinforcement learning model based on the Rescorla-Wagner formalism. The HGF was superior in accounting for the behaviour of our participants, suggesting that participants incorporated beliefs about environmental uncertainty when updating their beliefs about gambling outcome and translating these beliefs into action. A specific aspect of subjective uncertainty, the participant's estimate of the tendency of the slot machine's winning probability to change (volatility), increased subsequent to DBS. Additionally, the decision temperature of the response model decreased post-operatively, implying greater stochasticity in the belief-to-choice mapping of participants. Model parameter estimates were significantly associated with impulsivity; specifically, increased uncertainty was related to increased postoperative impulsivity. Moreover, changes in these parameter estimates were significantly associated with the maximum post-operative change in impulsivity over a six month follow up period. Our findings suggest that impulsivity in PD patients may be influenced by subjective estimates of uncertainty (environmental volatility) and implicate a role for the subthalamic nucleus in the modulation of outcome certainty. Furthermore, our work outlines a possible approach to characterising those persons who become more impulsive after subthalamic DBS, an intervention in which non-motor outcomes can be highly variable.

Cognitive activity emerges from large-scale neuronal dynamics that are constrained to a low-dimensional manifold. How this low-dimensional manifold scales with cognitive complexity, and which brain regions regulate this process, are not well understood. We addressed this issue by analyzing sub-second high-field fMRI data acquired during performance of a task that systematically varied the complexity of cognitive reasoning. We show that task performance reconfigures the low-dimensional manifold and that deviations from these patterns relate to performance errors. We further demonstrate that individual differences in thalamic activity relate to reconfigurations of the low-dimensional architecture during task engagement. Shine et al. demonstrate that cognitive complexity reconfigures the low-dimensional state space of the human brain. The low-dimensional trajectories of whole-brain activity dissociate correct and error trials and relate to activity within the medial and posterior thalamic nuclei.

Subthalamic deep brain stimulation is an advanced therapy that typically improves quality of life for persons with Parkinson's disease (PD). However, the effect on caregiver burden is unclear. We recruited 64 persons with PD and their caregivers from a movement disorders clinic during the assessment of eligibility for subthalamic DBS. We used clinician-, patient- and caregiver-rated instruments to follow the patient¿caregiver dyad from pre- to postoperative status, sampling repeatedly in the postoperative period to ascertain fluctuations in phenotypic variables. We employed multivariate models to identify key drivers of burden. We clustered caregiver-rated variables into 'high' and 'low' symptom groups and examined whether postoperative cluster assignment could be predicted from baseline values. Psychiatric symptoms in the postoperative period made a substantial contribution to longitudinal caregiver burden. The development of stimulation-dependent mood changes was also associated with increased burden. However, caregiver burden and caregiver-rated psychiatric symptom clusters were temporally stable and thus predicted only by their baseline values. We confirmed this finding using frequentist and Bayesian statistics, concluding that in our sample, subthalamic DBS for PD did not significantly influence caregiver burden or caregiver-rated psychiatric symptoms. Specifically, patient¿caregiver dyads with high burden and high levels of psychiatric symptoms at baseline were likely to maintain this profile during follow-up. These findings support the importance of assessing caregiver burden prior to functional neurosurgery. Furthermore, they suggest that interventions addressing caregiver burden in this population should target those with greater symptomatology at baseline and may usefully prioritise psychiatric symptoms reported by the caregiver.

Biological phenomena arise through interactions between an organism's intrinsic dynamics and stochastic forces¿random fluctuations due to external inputs, thermal energy, or other exogenous influences. Dynamic processes in the brain derive from neurophysiology and anatomical connectivity; stochastic effects arise through sensory fluctuations, brainstem discharges, and random microscopic states such as thermal noise. The dynamic evolution of systems composed of both dynamic and random effects can be studied with stochastic dynamic models (SDMs). This article, Part I of a two-part series, offers a primer of SDMs and their application to large-scale neural systems in health and disease. The companion article, Part II, reviews the application of SDMs to brain disorders. SDMs generate a distribution of dynamic states, which (we argue) represent ideal candidates for modeling how the brain represents states of the world. When augmented with variational methods for model inversion, SDMs represent a powerful means of inferring neuronal dynamics from functional neuroimaging data in health and disease. Together with deeper theoretical considerations, this work suggests that SDMs will play a unique and influential role in computational psychiatry, unifying empirical observations with models of perception and behavior.

Brain activity derives from intrinsic dynamics (due to neurophysiology and anatomical connectivity) in concert with stochastic effects that arise from sensory fluctuations, brainstem discharges, and random microscopic states such as thermal noise. The dynamic evolution of systems composed of both dynamic and random fluctuations can be studied with stochastic dynamic models (SDMs). This article, Part II of a two-part series, reviews applications of SDMs to large-scale neural systems in health and disease. Stochastic models have already elucidated a number of pathophysiological phenomena, such as epilepsy and hypoxic ischemic encephalopathy, although their use in biological psychiatry remains rather nascent. Emerging research in this field includes phenomenological models of mood fluctuations in bipolar disorder and biophysical models of functional imaging data in psychotic and affective disorders. Together with deeper theoretical considerations, this work suggests that SDMs will play a unique and influential role in computational psychiatry, unifying empirical observations with models of perception and behavior.

Millions of people worldwide suffer from depression. Do commonalities exist in their nonverbal behavior that would enable cross-culturally viable screening and assessment of severity? We investigated the generalisability of an approach to detect depression severity cross-culturally using video-recorded clinical interviews from Australia, the USA and Germany. The material varied in type of interview, subtypes of depression and inclusion healthy control subjects, cultural background, and recording environment. The analysis focussed on temporal features of participants' eye gaze and head pose. Several approaches to training and testing within and between datasets were evaluated. The strongest results were found for training across all datasets and testing across datasets using leave-one-subject-out cross-validation. In contrast, generalisability was attenuated when training on only one or two of the three datasets and testing on subjects from the dataset(s) not used in training. These findings highlight the importance of using training data exhibiting the expected range of variability.

Criticality has emerged as a leading dynamical candidate for healthy and pathological neuronal activity. At the heart of criticality in neural systems is the need for parameters to be tuned to specific values or for the existence of self-organizing mechanisms. Existing models lack precise physiological descriptions for how the brain maintains its tuning near a critical point. In this paper we argue that a key ingredient missing from the field is a formulation of reciprocal coupling between neural activity and metabolic resources. We propose that the constraint of optimizing the balance between energy use and activity plays a major role in tuning brain states to lie near criticality. Important recent findings aligned with our viewpoint have emerged from analyses of disorders that involve severe metabolic disturbances and alter scale-free properties of brain dynamics, including burst suppression. Moreover, we argue that average shapes of neuronal avalanches are a signature of scale-free activity that offers sharper insights into underlying mechanisms than afforded by traditional analyses of avalanche statistics. © 2014 Roberts, Iyer, Vanhatalo and Breakspear.

Spontaneous brain activity, that is, activity in the absence of controlled stimulus input or an explicit active task, is topologically organized in multiple functional networks (FNs) maintaining a high degree of coherence. These "resting state networks" are constrained by the underlying anatomical connectivity between brain areas. They are also influenced by the history of task-related activation. The precise rules that link plastic changes and ongoing dynamics of resting-state functional connectivity (rs-FC) remain unclear. Using the framework of the open source neuroinformatics platform "The Virtual Brain," we identify potential computational mechanisms that alter the dynamical landscape, leading to reconfigurations of FNs. Using a spiking neuron model, we first demonstrate that network activity in the absence of plasticity is characterized by irregular oscillations between low-amplitude asynchronous states and high-amplitude synchronous states. We then demonstrate the capability of spike-timing-dependent plasticity (STDP) combined with intrinsic alpha (8-12 Hz) oscillations to efficiently influence learning. Further, we show how alpha-state-dependent STDP alters the local area dynamics from an irregular to a highly periodic alpha-like state. This is an important finding, as the cortical input from the thalamus is at the rate of alpha. We demonstrate how resulting rhythmic cortical output in this frequency range acts as a neuronal tuner and, hence, leads to synchronization or de-synchronization between brain areas. Finally, we demonstrate that locally restricted structural connectivity changes influence local as well as global dynamics and lead to altered rs-FC.

Intrinsic coupling of neuronal assemblies constitutes a key feature of ongoing brain activity, yielding the rich spatiotemporal patterns observed in neuroimaging data and putatively supporting cognitive processes. Intrinsic coupling has been investigated in electrophysiological recordings using two types of functional connectivity measures: amplitude and phase coupling. These two coupling modes differ in their likely causes and functions, and have been proposed to provide complementary insights into intrinsic neuronal interactions. Here, we investigate the relationship between amplitude and phase coupling in source-reconstructed electroencephalography (EEG). Volume conduction is a key obstacle for connectivity analysis in EEG-we therefore also test the envelope correlation of orthogonalized signals and the phase lag index. Functional connectivity between six seed source regions (bilateral visual, sensorimotor, and auditory cortices) and all other cortical voxels was computed. For all four measures, coupling between homologous sensory areas in both hemispheres was significantly higher than with other voxels at the same physical distance. The frequency of significant coupling differed between sensory areas: 10 Hz for visual, 30 Hz for auditory, and 40 Hz for sensorimotor cortices. By contrasting envelope correlations and phase locking values, we observed two distinct clusters of voxels showing a different relationship between amplitude and phase coupling. Large clusters contiguous to the seed regions showed an identity (1:1) relationship between amplitude and phase coupling, whereas a cluster located around the contralateral homologous regions showed higher phase than amplitude coupling. These results show a relationship between intrinsic coupling modes that is distinct from the effect of volume conduction.

Vibrotactile discrimination tasks involve perceptual judgements on stimulus pairs separated by a brief interstimulus interval (ISI). Despite their apparent simplicity, decision making during these tasks is biased by prior experience in a manner that is not well understood. A striking example is when participants perform well on trials where the first stimulus is closer to the mean of the stimulus-set than the second stimulus, and perform comparatively poorly when the first stimulus is further from the stimulus mean. This "time-order effect" suggests that participants implicitly encode the mean of the stimulus-set and use this internal standard to bias decisions on any given trial. For relatively short ISIs, the magnitude of the time-order effect typically increases with the distance of the first stimulus from the global mean. Working from the premise that the time-order effect reflects the loss of precision in working memory representations, we predicted that the influence of the time-order effect, and this superimposed "distance" effect, would monotonically increase for trials with longer ISIs. However, by varying the ISI across four intervals (300, 600, 1200, and 2400 ms) we instead found a complex, non-linear dependence of the time-order effect on both the ISI and the distance, with the time-order effect being paradoxically stronger at short ISIs. We also found that this relationship depended strongly on participants' prior experience of the ISI (from previous task titration). The time-order effect not only depends on participants' expectations concerning the distribution of stimuli, but also on the expected timing of the trials. © 2013 Karim, Harris, Langdon and Breakspear.

Psychiatric illnesses characterised by disorganized cognition, such as schizophrenia, have been described in terms of fragmentation and hence understood as reduction in functional brain connectivity, particularly in prefrontal and parietal areas. However, as graph-theory shows, relatively small numbers of nonlocal connections are sufficient to ensure global coherence in the modular small world network structure of the brain. We reconsider fragmentation in this perspective. Computational studies have shown that for a given level of connectivity in a model of coupled nonlinear oscillators, modular small-world networks evolve from an initially random organization. Here we demonstrate that with decreasing connectivity, the probability of evolving into a modular small-world network breaks down at a critical point, which scales to the percolation function of random networks with a universal exponent of a=1.17. Thus, according to the model, local modularity systematically breaks down before there is loss of global coherence in network connectivity. We therefore propose that fragmentation may involve, at least in its initial stages, the inability of a dynamically evolving network to sustain a modular small-world structure. The result is in a shift in the balance in schizophrenia from local to global functional connectivity. © 2012 Van den berg, Gong, Breakspear and Van leeuwen.

Adaptive changes in behavior require rapid changes in brain states yet the brain must also remain stable. We investigated two neural mechanisms for evoking rapid transitions between spatiotemporal synchronization patterns of beta oscillations (13-30 Hz) in motor cortex. Cortex was modeled as a sheet of neural oscillators that were spatially coupled using a center-surround connection topology. Manipulating the inhibitory surround was found to evoke reliable transitions between synchronous oscillation patterns and traveling waves. These transitions modulated the simulated local field potential in agreement with physiological observations in humans. Intermediate levels of surround inhibition were also found to produce bistable coupling topologies that supported both waves and synchrony. State-dependent perturbation between bistable states produced very rapid transitions but were less reliable. We surmise that motor cortex may thus employ state-dependent computation to achieve very rapid changes between bistable motor states when the demand for speed exceeds the demand for accuracy. © 2012 Heitmann, Gong and Breakspear.

Computational models of neuromotor control require forward models of limb movement that can replicate the natural relationships between muscle activation and joint dynamics without the burdens of excessive anatomical detail. We present a model of a three-link biomechanical limb that emphasizes the dynamics of limb movement within a simplified two-dimensional framework. Muscle co-contraction effects were incorporated into the model by flanking each joint with a pair of antagonist muscles that may be activated independently. Muscle co-contraction is known to alter the damping and stiffness of limb joints without altering net joint torque. Idealized muscle actuators were implemented using the Voigt muscle model which incorporates the parallel elasticity of muscle and tendon but omits series elasticity.The natural force-length-velocity relationships of contractile muscle tissue were incorporated into the actuators using ideal mathematical forms. Numerical stability analysis confirmed that co-contraction of these simplified actuators increased damping in the biomechanical limb consistent with observations of human motor control. Dynamic changes in joint stiffness were excluded by the omission of series elasticity. The analysis also revealed the unexpected finding that distinct stable (bistable) equilibrium positions can co-exist under identical levels of muscle co-contraction. We map the conditions under which bistability arises and prove analytically that monostability (equifinality) is guaranteed when the antagonist muscles are identical. Lastly we verify these analytic findings in the full biomechanical limb model.© 2012 Heitmann, Ferns and Breakspear.

Bipolar disorder is a common and highly disabling condition necessitating early and effective therapeutic intervention. This review focuses on recent progress in pharmacotherapies reported in the last few years. The recent literature suggests two distinct developmental themes. The first is the consolidation of knowledge concerning the role of the atypical antipsychotics and anticonvulsants in bipolar disorder, with increasing clarity regarding which actions are 'class effects' and which actions are, in contrast, specific to particular agents. The second theme is the first 'glimmerings' of the mood stabilizing efficacy of compounds with 'novel' actions, with tamoxifen being perhaps the agent of most interest. While demonstration of the efficacy of truly innovative compounds developed specifically for bipolar disorder has yet to occur, the gradual understanding of some of the critical pharmacological mechanisms of action of current agents suggests that this may not be too distant a reality. © 2009 Future Medicine Ltd.

The fluid nature of perceptual experience and the transient repetition of patterns in neurophysiological data attest to the dynamical character of neural activity. An approach to neuroscience that starts from this premise holds the potential to unite neuronal connectivity and brain activity by treating space and time in the same framework. That is the philosophy of this chapter. Our goals are threefold: Firstly, we discuss the formalism that is at the heart of all dynamical sciences, namely the evolution equation. Such an expression ties the temporal unfolding of a system to its physical properties and is typically a differential equation. The form of this equation depends on whether time and space are treated as continuous or discrete entities. Secondly, we aim to motivate, illustrate and provide definitions for the language of dynamical systems theory - that is, the theoretical framework that integrates analysis and geometry, hence permitting the qualitative understanding and quantitative analysis of evolution equations. To this end we provide a mini-encyclopedia of the basic terms of phase space analysis and a description of the basic bifurcations of dynamics systems. Our third aim is to provide a survey of single neuron and network models from a historical and pedagogical perspective. Here we first trace microscopic models from their birth in the 1950's showing how the neuronal firing properties can be understood as a bifurcation in the underlying phase space. Then we review the spatiotemporal network dynamics, which emerges as a function of the networks anatomical connectivity.

Objective: Nonlinear properties exist within the brain across a hierarchy of scales and within a variety of critical neural processes. Only a few studies of brain activity in schizophrenia, however, have used nonlinear methods. This review paper evaluates the contribution of the nonlinear sciences towards understanding schizophrenia. Method: Applications of nonlinear methods to the study of schizophrenia symptoms and to healthy and schizophrenia functional neuroscience data are reviewed. The main flaws of nonlinear algorithms and recent methods to correct these are also appraised. Results: Initial research methods utilized in the study of nonlinearity in schizophrenia have fundamental methodological limitations. In the last decade, many of these problems have been addressed, facilitating future progress. Research incorporating these improvements has been applied to normal electroencephalogram (EEG) data and to the symptoms of schizophrenia, but not systematically to brain imaging data collected from patients with schizophrenia. Conclusion: There is strong statistical evidence for weak nonlinearity in normal EEG and in the fluctuations of the symptoms of schizophrenia. However, the contribution of nonlinear processes to brain dysfunction in schizophrenia is yet to be properly established or accurately quantified. Despite this, recent methodological advances suggest that a 'nonlinear theory' of schizophrenia may be helpful in understanding this disorder. © 2006 Royal Australian and New Zealand College of Psychiatrists.

Depression is one of the most common mental health disorders with strong adverse effects on personal and social functioning. The absence of any objective diagnostic aid for depression leads to a range of subjective biases in initial diagnosis and ongoing monitoring. Psychologists use various visual cues in their assessment to quantify depression such as facial expressions, eye contact and head movements. This paper studies the contribution of (upper) body expressions and gestures for automatic depression analysis. A framework based on space-time interest points and bag of words is proposed for the analysis of upper body and facial movements. Salient interest points are selected using clustering. The major contribution of this paper lies in the creation of a bag of body expressions and a bag of facial dynamics for assessing the contribution of different body parts for depression analysis. Head movement analysis is performed by selecting rigid facial fiducial points and a new histogram of head movements is proposed. The experiments are performed on real-world clinical data where video clips of patients and healthy controls are recorded during interactive interview sessions. The results show the effectiveness of the proposed system to evaluate the contribution of various body parts in depression analysis. © 2013 IEEE.

Accurate detection of depression from spontaneous speech could lead to an objective diagnostic aid to assist clinicians to better diagnose depression. Little thought has been given so far to which classifier performs best for this task. In this study, using a 60-subject real-world clinically validated dataset, we compare three popular classifiers from the affective computing literature - Gaussian Mixture Models (GMM), Support Vector Machines (SVM) and Multilayer Perceptron neural networks (MLP) - as well as the recently proposed Hierarchical Fuzzy Signature (HFS) classifier. Among these, a hybrid classifier using GMM models and SVM gave the best overall classification results. Comparing feature, score, and decision fusion, score fusion performed better for GMM, HFS and MLP, while decision fusion worked best for SVM (both for raw data and GMM models). Feature fusion performed worse than other fusion methods in this study. We found that loudness, root mean square, and intensity were the voice features that performed best to detect depression in this dataset. © 2013 IEEE.

Major depressive disorders are mental disorders of high prevalence, leading to a high impact on individuals, their families, society and the economy. In order to assist clinicians to better diagnose depression, we investigate an objective diagnostic aid using affective sensing technology with a focus on acoustic features. In this paper, we hypothesise that (1) classifying the general characteristics of clinical depression using spontaneous speech will give better results than using read speech, (2) that there are some acoustic features that are robust and would give good classification results in both spontaneous and read, and (3) that a 'thin-slicing' approach using smaller parts of the speech data will perform similarly if not better than using the whole speech data. By examining and comparing recognition results for acoustic features on a real-world clinical dataset of 30 depressed and 30 control subjects using SVM for classification and a leave-one-out cross-validation scheme, we found that spontaneous speech has more variability, which increases the recognition rate of depression. We also found that jitter, shimmer, energy and loudness feature groups are robust in characterising both read and spontaneous depressive speech. Remarkably, thin-slicing the read speech, using either the beginning of each sentence or the first few sentences performs better than using all reading task data. © 2013 IEEE.

Depression is a common and disabling mental health disorder, which impacts not only on the sufferer but also on their families, friends and the economy overall. Despite its high prevalence, current diagnosis relies almost exclusively on patient self-report and clinical opinion, leading to a number of subjective biases. Our aim is to develop an objective affective sensing system that supports clinicians in their diagnosis and monitoring of clinical depression. In this paper, we analyse the performance of eye movement features extracted from face videos using Active Appearance Models for a binary classification task (depressed vs. non-depressed). We find that eye movement low-level features gave 70% accuracy using a hybrid classifier of Gaussian Mixture Models and Support Vector Machines, and 75% accuracy when using statistical measures with SVM classifiers over the entire interview. We also investigate differences while expressing positive and negative emotions, as well as the classification performance in gender-dependent versus gender-independent modes. Interestingly, even though the blinking rate was not significantly different between depressed and healthy controls, we find that the average distance between the eyelids ('eye opening') was significantly smaller and the average duration of blinks significantly longer in depressed subjects, which might be an indication of fatigue or eye contact avoidance. © 2013 IEEE.

Depression is a serious psychiatric disorder that affects mood, thoughts, and the ability to function in everyday life. This paper investigates the characteristics of depressed speech for the purpose of automatic classification by analysing the effect of different speech features on the classification results. We analysed voiced, unvoiced and mixed speech in order to gain a better understanding of depressed speech and to bridge the gap between physiological and affective computing studies. This understanding may ultimately lead to an objective affective sensing system that supports clinicians in their diagnosis and monitoring of clinical depression. The characteristics of depressed speech were statistically analysed using ANOVA and linked to their classification results using GMM and SVM. Features were extracted and classified over speech utterances of 30 clinically depressed patients against 30 controls (both gender-matched) in a speaker-independent manner. Most feature classification results were consistent with their statistical characteristics, providing a link between physiological and affective computing studies. The classification results from low-level features were slightly better than the statistical functional features, which indicates a loss of information in the latter. We found that both mixed and unvoiced speech were as useful in detecting depression as voiced speech, if not better. Copyright © 2013 ISCA.

Depression and other mood disorders are common and disabling disorders. We present work towards an objective diagnostic aid supporting clinicians using affective sensing technology with a focus on acoustic and statistical features from spontaneous speech. This work investigates differences in expressing positive and negative emotions in depressed and healthy control subjects as well as whether initial gender classification increases the recognition rate. To this end, spontaneous speech from interviews of 30 subjects of each depressed and controls was analysed, with a focus on questions eliciting positive and negative emotions. Using HMMs with GMMs for classification with 30-fold cross-validation, we found that MFCC, energy and intensity features gave highest recognition rates when female and male subjects were analysed together. When the dataset was first split by gender, log energy and shimmer features, respectively, were found to give the highest recognition rates in females, while it was loudness for males. Overall, correct recognition rates from acoustic features for depressed female subjects were higher than for male subjects. Using temporal features, we found that the response time and average syllable duration were longer in depressed subjects, while the interaction involvement and articulation rate wesre higher in control subjects. Copyright © 2012, Association for the Advancement of Artificial Intelligence. All rights reserved.

In recent years, the problem of automatic detection of mental illness from the speech signal has gained some initial interest, however questions remaining include how speech segments should be selected, what features provide good discrimination, and what benefits feature normalization might bring given the speaker-specific nature of mental disorders. In this paper, these questions are addressed empirically using classifier configurations employed in emotion recognition from speech, evaluated on a 47-speaker depressed/neutral read sentence speech database. Results demonstrate that (1) detailed spectral features are well suited to the task, (2) speaker normalization provides benefits mainly for less detailed features, and (3) dynamic information appears to provide little benefit. Classification accuracy using a combination of MFCC and formant based features approached 80% for this database. Copyright © 2011 ISCA.

This paper is motivated by Ellgring's work in non-verbal communication in depression to measure and compare the levels of facial activity, before and after treatment, of endogenous and neurotic depressives. Similar to that work, we loosely associate the measurements with Action Units (AU) groups from the Facial Action Coding System (FACS). However, we use the neologism Region Units (RU) to describe regions of the face that encapsulate AUs. In contrast to Ellgring's approach, we automatically generate the measurements and provide both prototypical expression recognition and RU-specific activity measurements. Latency between expressions is also measured and the system is conducive to comparison across groups and individual subjects. By using Active Appearance Models (AAM) to locate the fiduciary facial points, and MultiBoost to classify prototypical expressions and the RUs, we can provide a simple, objective, flexible and cost-effective means of automatically measuring facial activity. ©2009 IEEE.