Background:Ageing is associated with increased cardiovascular health risks and disproportionate atrophy in frontotemporal brain. Regional cerebral arterial elasticity correlates with regional grey matter volume, with stronger associations frontally and in older adults. Cardiorespiratory fitness (CRF) is linked to preserved brain structure and greater arterial elasticity, while sex differences exist in the timing of vascular versus structural changes. This study examines whether regional cerebral arterial elasticity in frontotemporal cortex mediates the association between age and corresponding grey matter volume decline, and whether sex and/or CRF moderate this relationship. Methods:We analysed data from 162 healthy adults (60-70 years) with structural MRI and diffuse optical tomography of the cerebral arterial pulse (Pulse-DOT) from the ACTIVate cohort. CRF was estimated from demographic and physiological measures. Pulse Relaxation Function (PReFx), an optical index of regional arterial elasticity, was measured across 28 frontal, temporal, and parietal regions of interest (ROI). Grey matter (GM) volume was quantified for corresponding ROIs. Mediation and moderated mediation models tested whether PReFx mediated the relationship between age and GM volume at bilateral frontal and temporal ROIs, and whether biological sex or CRF moderated this relationship. Results:Regional bivariate correlations identified associations between age, PReFx and GM volume across multiple ROIs, which PReFx and GM volume being associated primarily in left frontal and temporal areas. PReFx partially mediated the effect of age on GM volume in a left mid-inferior frontal ROI, accounting for approximately 16% of the total age effect and this relationship was only evident in females. Although higher CRF was associated with greater PReFx, it did not moderate the relationship between age, PReFx and GM volume. Conclusions:Consistent with cascade models of neurovascular aging, cerebral arterial stiffening was found to partially explain the effect of increasing age on frontal GM volume, even in this highly age-restricted and high functioning cohort. This effect was only significant over the left prefrontal cortex, consistent with greater vulnerability of frontal brain and associated cognitive functions. It was also exclusively present in females, who had better cardiovascular health, larger grey matter volume and greater arterial elasticity than males. These findings are consistent with pulse-DOT measures of cerebral arterial elasticity being more sensitive to subclinical brain structural variability.

When we smile, we expect that others will smile back. When one's smile is not reciprocated, these expectations are violated, producing prediction error signals in the brain. Prediction error signals may be experienced as aversive, disincentivizing smiling. Social smiling is impaired in psychotic disorders suggesting increased sensitivity to unreciprocated smiles. We developed the Incongruent Facial Emotion task to probe responses to unreciprocated smiles. Healthy controls and persons with schizophrenia or schizoaffective disorder voluntarily smiled, after which they viewed a stimulus face with a happy or angry expression. Brain activations were quantified with functional magnetic resonance imaging. Greater illness severity was associated with reduced smile amplitude. Across both groups, viewing an incongruent stimulus after initiating a smile activated the bilateral anterior insulae and right supplementary motor cortex. Brain activations in the left middle occipital and left superior frontal gyri were greater in the clinical group. The anterior insula response to incongruent facial reactions was significantly greater in more severely ill clinical participants. Dynamic causal modelling suggests that incongruent stimuli reduce tonic self-inhibition in the anterior insula, and that this disinhibition is enhanced by illness severity. The results suggest that the anterior insula processes affective prediction errors and sends feedback to supplementary motor areas to alter behavioural responses. The underlying brain circuits are enhanced in clinical participants with severe illness, suggesting new avenues to understand affective blunting in psychotic disorders.

The brain expresses activity in complex spatiotemporal patterns, reflecting the influence of spatially distributed cytoarchitectural, biochemical, and genetic properties. The correspondence between these different "brain maps" is a topic of substantial interest. However, these maps possess intrinsic smoothness (spatial autocorrelation, SA) which can inflate spurious cross-correlations, leading to false positive associations. Identifying true associations requires knowledge about the distribution of correlations that arise by chance in the presence of SA. This null distribution can be generated from an ensemble of surrogate brain maps that preserve the intrinsic SA but break the correlations between maps. The present work introduces the "eigenstrapping" method, which performs a spectral decomposition of brain maps, such as fMRI activation patterns, expressed on cortical and subcortical surfaces, using geometric eigenmodes, and then randomly rotating these modes to produce SA-preserving surrogate brain maps. It is shown that these surrogates appropriately represent the null distribution of chance pairwise correlations, with expected false positive control superior to current state-of-the-art procedures. Eigenstrapping is fast, eschews the need for parametric assumptions about the nature of a map's SA, and works with maps defined on smooth surfaces with a boundary, such as a single cortical hemisphere when the medial wall has been removed. Moreover, eigenstrapping generalizes to broader classes of null models than existing techniques, offering a unified approach for inference on cortical and subcortical maps, spatiotemporal processes, and complex patterns possessing higher-order correlations.

The study of functional MRI (fMRI) data is increasingly performed after mapping from volumetric voxels to surface vertices. Processing pipelines commonly used to achieve this mapping produce meshes with uneven vertex spacing, with closer neighbours in sulci compared to gyri. Consequently, correlations between the fMRI time series of neighbouring sulcal vertices are stronger than expected. However, the causes, extent, and impacts of this "gyral bias" are not completely understood or widely appreciated. We explain the origins of this bias, and usingin-silicomodels of fMRI data, illustrate how it leads to spurious results and leakage of anatomical cortical folding information into fMRI time series. We show that many common analyses can be affected by this bias, including test-retest reliability, fingerprinting, functional parcellations, and regional homogeneity. The recently developed onavg template partly reduces the bias but has relatively high residual variability in vertex spacing when projected to participant-specific surfaces. Finally, we outline recommendations to avoid or remedy the gyral bias.

Study Objectives:Evidence suggests that poor sleep impacts cognition, brain health, and dementia risk but the nature of the association is poorly understood. This study examined how self-reported sleep duration, napping, and subjective depression symptoms are associated with the brain-cognition relationship in older adults, using sulcal width as a measure of relative brain health. Methods:A canonical partial least squares analysis was used to obtain two composite variables that relate cognition and sulcal width in a cross-sectional study of 137 adults aged 46-72. We used a combination of ANCOVA and path analyses to test the associations of self-reported sleep duration, napping, and subjective depression symptoms with the brain-cognition relationship. Results:We observed a significant main effect of sleep duration on sulcal width, with participants reporting 7 hours showing narrower sulci than other durations. This effect remained significant after including subjective depression as a covariate, which also had a significant main effect on sulcal width in the model. There was no significant effect of napping on sulcal width. In path analyses where the effects of age, self-reported sleep duration and depression symptoms were investigated together, sulcal width mediated the relationship between age and cognition. We also observed a significant indirect effect of sulci width in the subjective depression-cognition relationship. Conclusions:Findings suggest that self-reported sleep duration and subjective depression may each be independently associated with brain morphology, which is related to cognitive functions. Results could help inform clinical trials and related intervention studies that aim at delaying cognitive decline in adults at risk of developing dementia.

Aligning brain maps using functional features rather than anatomical landmarks potentially improves individual identifiability and increases power in group neuroimaging studies. However, alignment based purely on functional magnetic resonance imaging (fMRI) risks omitting useful anatomical constraints. An optimized combination of anatomical and functional feature alignment could balance the advantages of each approach. We used 3T fMRI data from 80 Human Connectome Project participants during seven tasks. The effectiveness of functional and anatomical alignment methods was evaluated using interparticipant decoding accuracy. Functional alignment mapped vertices from participants to a template, aligning their fMRI responses to shared responses during movie viewing. The template was derived from the combined fMRI responses of a set of participants. We benchmarked the results against existing functional alignment methods, including the Procrustes method and ridge regression. A common practice in the field is to use the same participants for the alignment cohort and for template generation. We found that this inflates decoding accuracies by mixing anatomical and functional alignment. Based on this, we recommend that a template’s generalizability should be evaluated against held-out participants. Building on these findings, we investigated whether inter-subject alignment could be improved by integrating anatomical and functional information. We studied a modified alignment method where a single parameter interpolates between pure functional alignment and anatomical alignment. Optimizing the parameter with nested cross-validation, we found that integrating anatomical and functional information robustly reduced noise and improved alignment across a variety of alignment methods. Combining anatomical and functional information accounts for individual heterogeneity in functional topographies while incorporating anatomical constraints. The integrated alignment described here improves inter-subject decoding using functional brain maps. These findings also demonstrate that brain anatomy provides a lens into the inherent variability of individual neural landscapes.

Event-related potentials (ERPs) acquired during task-free passive listening can be used to study how sensitivity to common pattern repetitions and rare deviations changes over time. These changes are purported to represent the formation and accumulation of precision in internal models that anticipate future states based on probabilistic and/or statistical learning. This study features an unexpected finding; a strong order-dependence in the speed with which deviant responses are elicited that anchors to first learning. Participants heard four repetitions of a sequence in which an equal number of short (30 ms) and long (60 ms) pure tones were arranged into four blocks in which one was common (the standard, p=0.875) and the other rare (the deviant, p=0.125) with probabilities alternating across blocks. Some participants always heard the sequences commencing with the 30 ms deviant block, and others always with the 60 ms deviant block first. A deviance-detection component known as mismatch negativity (MMN) was extracted from responses and the point in time at which MMN reached maximum amplitude was used as the dependent variable. The results show that if participants heard sequences commencing with the 60 ms deviant block first, the MMN to the 60 ms and 30 ms deviant peaked at an equivalent latency. However, if participants heard sequences commencing with the 30 ms deviant first, the MMN peaked earlier to the 60 ms deviant. Furthermore, while the 30 ms MMN latency did not differ as a function of sequence composition, the 60 ms MMN latency did and was earlier when the sequences began with a 30 ms deviant first. By examining MMN latency effects as a function of age and hearing level it was apparent that the differentiation in 30 ms and 60 ms MMN latency expands with older age and raised hearing threshold due to prolongation of the time taken for the 30 ms MMN to peak. The observations are discussed with reference to how the initial sound composition may tune the auditory system to be more sensitive to different cues (i.e., offset responses versus perceived loudness). The order-effect demonstrates a remarkably powerful anchoring to first learning that might reflect initial tuning to the most valuable discriminating feature within a given listening environment, an effect that defies explanation based on statistical information alone.

Background: Multiple sclerosis (MS) is a long-term autoimmune inflammatory disorder that affects the central nervous system leading to neurodegeneration, and can involve a variety of symptoms. These symptoms can include fatigue, anxiety, depression, and cognitive decline, which may be silent. The objective of this study was to explore changes in brain iron deposition in people with relapsing-remitting MS (pw-RRMS) compared to healthy controls (HCs), with a particular focus on regions of fear circuit. Additionally, the study aimed to evaluate relationship between iron deposition in these areas and clinical measurements. Methods: Pw-RRMS and HCs participants underwent brain MRI scans using quantitative susceptibility mapping (QSM) to assess iron deposition in the fear circuit between the two groups. The study analyzed correlations between brain susceptibility changes and clinical measurements. Results: We recruited 35 pw-RRMS (mean age = 46.7 +/- 11 years; median EDSS = 2.5) and 18 HCs (mean age = 40.6 +/- 17.8 years). Our research revealed significant increases in QSM signals relating to iron deposition in pw-RRMS compared to HCs, whole fear circuit (beta = 5.82, p < 0.001), caudate (beta = 21.48, p < 0.001), and putamen (beta = 17.53, p = 0.03), showing the greatest difference. The whole fear circuit and particularly the caudate are strongly associated with fatigue in pw-RRMS. QSM values in the anterior cingulate cortex significantly differed between pw-RRMS with normal and abnormal depression scores (p = 0.007). Conclusions: These results strengthen the relationship between increased iron deposition in fear circuit regions and specific silent symptoms in pw-RRMS. However, further studies are required to confirm these findings and clarify the implications of iron accumulation in MS pathophysiology.

Background Transcranial magnetic stimulation (TMS) (including the theta burst stimulation (TBS) form of TMS used in this study) is a non-invasive means to stimulate nerve cells in superficial areas of the brain. In recent years, there has been a growth in the application of TMS to investigate the modulation of neural networks involved in substance use disorders. This study examines the feasibility of novel TMS protocols for the treatment of methamphetamine (MA) use disorder in an ambulatory drug and alcohol treatment setting.Methods Thirty participants meeting the criteria for moderate to severe MA use disorder will be recruited in community drug and alcohol treatment settings and randomised to receive active TMS or sham (control) intervention. The treatment is intermittent TBS (iTBS) applied to the left dorsolateral prefrontal cortex (DLPFC), then continuous TBS (cTBS) to the left orbitofrontal cortex (OFC). Twelve sessions are administered over 4 weeks with opt-in weekly standardized cognitive behaviour therapy (CBT) counselling and a neuroimaging sub-study offered to participants. Primary outcomes are feasibility measures including recruitment, retention and acceptability of the intervention. Secondary outcomes include monitoring of safety and preliminary efficacy data including changes in substance use, cravings (cue reactivity) and cognition (response inhibition).Discussion This study examines shorter TBS protocols of TMS for MA use disorder in real-world drug and alcohol outpatient settings where withdrawal and abstinence from MA, or other substances, are not eligibility requirements. TMS is a relatively affordable treatment and staff of ambulatory health settings can be trained to administer TMS. It is a potentially scalable and translatable treatment for existing drug and alcohol clinical settings. TMS has the potential to provide a much-needed adjuvant treatment to existing psychosocial interventions for MA use disorder. A limitation of this protocol is that the feasibility of follow-up is only examined at the end of treatment (4 weeks).Trial registration Australia New Zealand Clinical Trial Registry ACTRN12622000762752. Registered on May 27, 2022, and retrospectively registered (first participant enrolled) on May 23, 2022, with protocol version 7 on February 24, 2023.

This work provides a new method for fast post-processing of MRI data acquired using the WASAB1 sequence for simultaneous B 0 and B 1 mapping, used in CEST imaging for field inhomogeneity corrections. We are proposing a new processing method with outstanding acceleration of the parameter estimation procedure, without compromising the stability of the estimation. The stability of the method is demonstrated on phantom data and in vivo 3 Tesla clinical data.

Predictive processing theories suggest that a principal function of the brain is to reduce the surprise of incoming sensory information by creating accurate and precise models of the environment. These models are commonly explored by looking at the prediction errors elicited when experience departs from predictions. One such prediction error is the mismatch negativity (MMN). Using this component, it is possible to examine the effect of external noise on the precision of the developed model. Recent studies have shown that the brain may not update its model every time there is a change in the environment, rather it will only update it when doing so will increase precision and or accuracy of the model. The current study examined this process using oddball sound sequences with high and low spatial variability and examining how this affected the elicited MMN to a duration deviant sound. The results showed a strong null effect of spatial variance both at a local and sequence levels. These results indicate that variability in the sound sequence will not invariably affect model precision estimates and thus the amplitude of the MMN component.

The functional organization of the hippocampus mirrors that of the cortex, changing smoothly along connectivity gradients and abruptly at inter-areal boundaries. Hippocampal-dependent cognitive processes require flexible integration of these hippocampal gradients into functionally related cortical networks. To understand the cognitive relevance of this functional embedding, we acquired fMRI data while participants viewed brief news clips, either containing or lacking recently familiarized cues. Participants were 188 healthy mid-life adults and 31 adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD). We employed a recently developed technique - connectivity gradientography - to study gradually changing patterns of voxel to whole brain functional connectivity and their sudden transitions. We observed that functional connectivity gradients of the anterior hippocampus map onto connectivity gradients across the default mode network during these naturalistic stimuli. The presence of familiar cues in the news clips accentuates a stepwise transition across the boundary from the anterior to the posterior hippocampus. This functional transition is shifted in the posterior direction in the left hippocampus of individuals with MCI or AD. These findings shed new light on the functional integration of hippocampal connectivity gradients into large-scale cortical networks, how these adapt with memory context and how these change in the presence of neurodegenerative disease.

Emerging evidence suggests that poor sleep is associated with worse cognitive and structural brain health, and an increased risk of developing dementia (Bubu et al., 2016; Fjell et al., 2022; Tai et al., 2022). The present study investigated the influence of sleep duration on the cognition-brain relationship in older adults using sulcal width (SW), a reliable measure of changes in the ageing brain (Bertoux et al., 2019). The influence of napping, depression likelihood, and genetic risk for dementia (APOE ε4 status) was also explored. Participants were 137 cognitively normal adults, aged 46-72 from the Prospective Imaging Study of Ageing (PISA). Demographic information, sleep duration, and depressive symptoms were collected via online questionnaires. Cognition was assessed using the Cambridge Brain Systems battery. APOE genotype was determined from blood-extracted DNA. Imaging data was acquired using a 3T Siemens PRISMA scanner. SW was extracted using the Morphologist pipeline (Borne et al., 2020). Canonical Partial Least Squares (PLS) were used to obtain latent variables of cognition and SW. ANCOVAs measured the effect of sleep duration categories (7-7.5 hours versus {<7 or ≥8 hours}) on the cognitive and SW components, with sex and age as covariates. Status of depression likelihood was added as a covariate of interest. The effect of napping, and APOE ɛ4 allele on these same components were measured by ANCOVAs, with sex and age as covariates. We observed a significant effect of sleep duration on SW (F(1, 133) = 4.17, p = 0.043, Fig. 1). This effect remained significant (F(1,132) = 4.89, p = 0.029) after including depression likelihood as a covariate, which was also significant in the model (F(1,132) = 4.62, p = 0.034). A significant interaction between APOE ε4 status and age (p = 0.050) on SW was also observed. Results add weight to studies suggesting that not too much or too little sleep is needed to maintain brain health in later life (Li et al., 2022; Liang et al., 2019). Depression, a risk factor for dementia (Livingston et al., 2020), was also associated with poorer brain health. Results suggest that at approximately 60 years of age, the influence of a positive APOE ε4 status is associated with increasing age-related brain atrophy.

OBJECTIVE:Borderline Personality Disorder (BPD) diagnosis comprises several constellations of trait, neurocognitive, and psychosocial alterations. Dimensional models of psychopathology provide new opportunities to parse heterogeneity and create a stronger interface between individual characterization and psychosocial outcomes. However, dimensional models have focused on either traits or neurocognitive features, lacking integration to capture the multifaceted nature of BPD.METHOD:We assessed 100 participants with BPD using a combination of tools stemming from trait (Alternative Model for Personality Disorders) and neurocognitive models (Research Domain Criteria; RDoC) to examine if trait-derived subgroups display distinctive social-processing and psychosocial profiles. We used two complementary analytical approaches: person-centered (k-means clustering) and construct-based (multiple factor analysis).RESULTS:Our person-centered approach identified four subgroups with separable internalizing, detached, externalizing, and low psychopathology trait profiles. These profiles revealed distinctive patterns of affiliation, emotion recognition and mentalization performance in RDoC tasks, and psychosocial measures of quality of life and social connectedness. RDoC-based measures showed close construct proximity with negative affectivity, disinhibition, and antagonism trait domains, relative to the detachment domain, which had close proximity with self-knowledge.CONCLUSIONS:Altogether, findings support consilience between trait-based and neurobiological frameworks and suggest that trait models are useful to parse BPD heterogeneity leading to unique social functioning profiles.

Many aspects of cognitive ability and brain function that change as we age look like deficits on account of measurable differences in comparison to younger adult groups. One such difference occurs in auditory sensory responses that index perceptual learning. Meta-analytic findings show reliable age-related differences in auditory responses to repetitive patterns of sound and to rare violations of those patterns, variously attributed to deficits in auditory sensory memory and inhibition. Here, we determine whether proposed deficits would render older adults less prone to primacy effects, robustly observed in young adults, which present as a tendency for first learning to have a disproportionate influence over later perceptual inference. The results confirm this reduced sensitivity to primacy effects but do not support impairment in auditory sensory memory as the origin of this difference. Instead, the aging brain produces data consistent with shorter timescales of contextual reference. In conclusion, age-related differences observed previously for perceptual inference appear highly context-specific necessitating reconsideration of whether and to what function the notion of deficit should be attributed, and even whether the notion of deficit is appropriate at all.

IntroductionApproximately 40% of late-life dementia may be prevented by addressing modifiable risk factors, including physical activity and diet. Yet, it is currently unknown how multiple lifestyle factors interact to influence cognition. The ACTIVate Study aims to (1) explore associations between 24-hour time-use and diet compositions with changes in cognition and brain function; and (2) identify duration of time-use behaviours and the dietary compositions to optimise cognition and brain function.Methods and analysisThis 3-year prospective longitudinal cohort study will recruit 448 adults aged 60–70 years across Adelaide and Newcastle, Australia. Time-use data will be collected through wrist-worn activity monitors and the Multimedia Activity Recall for Children and Adults. Dietary intake will be assessed using the Australian Eating Survey food frequency questionnaire. The primary outcome will be cognitive function, assessed using the Addenbrooke’s Cognitive Examination-III. Secondary outcomes include structural and functional brain measures using MRI, cerebral arterial pulse measured with diffuse optical tomography, neuroplasticity using simultaneous transcranial magnetic stimulation and electroencephalography, and electrophysiological markers of cognitive control using event-related potential and time frequency analyses. Compositional data analysis, testing for interactions between time point and compositions, will assess longitudinal associations between dependent (cognition, brain function) and independent (time-use and diet compositions) variables.ConclusionsThe ACTIVate Study will be the first to examine associations between time-use and diet compositions, cognition and brain function. Our findings will inform new avenues for multidomain interventions that may more effectively account for the co-dependence between activity and diet behaviours for dementia prevention.Ethics and disseminationEthics approval has been obtained from the University of South Australia’s Human Research Ethics committee (202639). Findings will be disseminated through peer-reviewed manuscripts, conference presentations, targeted media releases and community engagement events.Trial registration numberAustralia New Zealand Clinical Trials Registry (ACTRN12619001659190).