Neural correlates of the revised reinforcement sensitivity theory: A cross-sectional structural neuroimaging study in middle-aged adults.

The revised reinforcement sensitivity theory (RST) proposes that neurobiological systems control behavior: the fight-flight-freeze (FFFS) for avoidance of threat; behavioral approach/activation (BAS) for approach to rewards; and behavioral inhibition (BIS) for conflict resolution when avoidance and approach are possible. Neuroimaging studies have confirmed some theoretical associations between brain structures and the BAS and BIS; however, little representative population data are available for the FFFS. We investigated the neural correlates of the revised RST in a sample of 404 middle-aged adults (Mage = 47.18 (SD = 1.38); 54.5% female). Participants underwent structural magnetic resonance imaging and completed health questionnaires and the BIS/BAS/FFFS scales. We used multiple regression analyses to investigate the association between scale scores and volumes of a priori theoretically linked regions of interest while controlling for sex, age, intracranial volume, and cardio-metabolic variables; and conducted exploratory analyses on cortical thickness. The BIS was negatively associated with hippocampus laterality. At standard significance levels, the fear component of the FFFS was positively associated with anterior cingulate cortex; the BAS was positively associated with bilateral caudate; and the BIS was positively associated with posterior cingulate cortex volume. Furthermore, these neurobiological systems showed distinct patterns of association with cortical thickness though future work is needed. Our results showed that the neurobiological systems of the revised RST characterized in rodents can also be identified in the human brain.

A role for retro-splenial cortex in the task-related P3 network.

OBJECTIVE: The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified. METHODS: We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm. RESULTS: Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses. CONCLUSIONS: The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG. SIGNIFICANCE: These results provide a new perspective for the interpretation of the extensive research based on the P3 response.

A role for retro-splenial cortex in the task-related P3 network.

Objective: The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified. Methods: We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm. Results: Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses. Conclusion: The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG. Significance: These results provide a new perspective for the interpretation of the extensive research based on the P3 response.

Association between Type 2 Diabetes Mellitus and Brain Atrophy: A Meta-Analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is known to be associated with cognitive decline and brain structural changes. This study systematically reviews and estimates human brain volumetric differences and atrophy associated with T2DM. METHODS: PubMed, PsycInfo and Cochrane Library were searched for brain imaging studies reporting on brain volume differences between individuals with T2DM and healthy controls. Data were examined using meta-analysis, and association between age, sex, diabetes characteristics and brain volumes were tested using meta-regression. RESULTS: A total of 14,605 entries were identified; after title, abstract and full-text screening applying inclusion and exclusion criteria, 64 studies were included and 42 studies with compatible data contributed to the meta-analysis (n=31,630; mean age 71.0 years; 44.4% male; 26,942 control; 4,688 diabetes). Individuals with T2DM had significantly smaller total brain volume, total grey matter volume, total white matter volume and hippocampal volume (approximately 1% to 4%); meta-analyses of smaller samples focusing on other brain regions and brain atrophy rate in longitudinal investigations also indicated smaller brain volumes and greater brain atrophy associated with T2DM. Meta-regression suggests that diabetes-related brain volume differences start occurring in early adulthood, decreases with age and increases with diabetes duration. CONCLUSION: T2DM is associated with smaller total and regional brain volume and greater atrophy over time. These effects are substantial and highlight an urgent need to develop interventions to reduce the risk of T2DM for brain health.

Midsagittal corpus callosal thickness and cognitive impairment in Parkinson's disease.

People diagnosed with Parkinson's disease (PD) can experience significant neuropsychiatric symptoms, including cognitive impairment and dementia, the neuroanatomical substrates of which are not fully characterised. Symptoms associated with cognitive impairment and dementia in PD may relate to direct structural changes to the corpus callosum via primary white matter pathology or as a secondary outcome due to the degeneration of cortical regions. Using magnetic resonance imaging, the corpus callosum can be investigated at the midsagittal plane, where it converges to a contiguous mass and is not intertwined with other tracts. The objective of this project was thus twofold: First, we investigated possible changes in the thickness of the midsagittal callosum and cortex in patients with PD with varying levels of cognitive impairment; and secondly, we investigated the relationship between the thickness of the midsagittal corpus callosum and the thickness of the cortex. Study participants included cognitively unimpaired PD participants (n = 35), PD participants with mild cognitive impairment (n = 22), PD participants with dementia (n = 17) and healthy controls (n = 27). We found thinning of the callosum in PD-related dementia compared with PD-related mild cognitive impairment and cognitively unimpaired PD participants. Regression analyses found thickness of the left medial orbitofrontal cortex to be positively correlated with thickness of the anterior callosum in PD-related mild cognitive impairment. This study suggests that a midsagittal thickness model can uncover changes to the corpus callosum in PD-related dementia, which occur in line with changes to the cortex in this advanced disease stage.

Longitudinal Effects of Physical Activity Change on Hippocampal Volumes over up to 12 Years in Middle and Older Age Community-Dwelling Individuals.

The objectives of this study were to investigate the long-term associations between changes in physical activity levels and hippocampal volumes over time, while considering the influence of age, sex, and APOE-ε4 genotype. We investigated the effects of change in physical activity on hippocampal volumes in 411 middle age (mean age = 47.2 years) and 375 older age (mean age = 63.1 years) adults followed up to 12 years. An annual volume decrease was observed in the left (middle age: 0.46%; older age: 0.51%) but not in the right hippocampus. Each additional 10 metabolic equivalents (METs, ~2 h of moderate exercise) increase in weekly physical activity was associated with 0.33% larger hippocampal volume in middle age (equivalent to ~1 year of typical aging). In older age, each additional MET was associated with 0.05% larger hippocampal volume; however, the effects declined with time by 0.005% per year. For older age APOE-ε4 carriers, each additional MET was associated with a 0.10% increase in hippocampal volume. No sex effects of physical activity change were found. Increasing physical activity has long-term positive effects on hippocampal volumes and appears especially beneficial for older APOE-ε4 carriers. To optimize healthy brain aging, physical activity programs should focus on creating long-term exercise habits.

Optimal Blood Pressure Keeps Our Brains Younger.

Background: Elevated blood pressure (BP) is a major health risk factor and the leading global cause of premature death. Hypertension is also a risk factor for cognitive decline and dementia. However, when elevated blood pressure starts impacting cerebral health is less clear. We addressed this gap by estimating how a validated measure of brain health relates to changes in BP over a period of 12 years. Methods: Middle-age (44-46 years at baseline, n = 335, 52% female) and older-age (60-64 years, n = 351, 46% female) cognitively intact individuals underwent up to four brain scans. Brain health was assessed using a machine learning approach to produce an estimate of "observed" age (BrainAGE), which can be contrasted with chronological age. Longitudinal associations between blood pressures and BrainAGE were assessed with linear mixed-effects models. Results: A progressive increase in BP was observed over the follow up (MAP = 0.8 mmHg/year, SD = 0.92; SBP = 1.41 mmHg/year, SD = 1.49; DBP = 0.61 mmHg/year, SD = 0.78). In fully adjusted models, every additional 10 mmHg increase in blood pressure (above 90 for mean, 114 for systolic, and 74 for diastolic blood pressure) was associated with a higher BrainAGE by 65.7 days for mean, and 51.1 days for systolic/diastolic blood pressure. These effects occurred across the blood pressure range and were not exclusively driven by hypertension. Conclusion: Increasing blood pressure is associated with poorer brain health. Compared to a person becoming hypertensive, somebody with an ideal BP is predicted to have a brain that appears more than 6 months younger at midlife.

Structural and functional neuroimaging changes associated with cognitive impairment and dementia in Parkinson's disease.

This study seeks a better understanding of possible pathophysiological mechanisms associated with cognitive impairment and dementia in Parkinson's disease using structural and functional MRI. We investigated resting-state functional connectivity of important subdivisions of the caudate nucleus, putamen and thalamus, and also how the morphology of these structures are impacted in the disorder. We found cognitively unimpaired Parkinson's disease subjects (n = 33), compared to controls (n = 26), display increased functional connectivity of the dorsal caudate, anterior putamen and mediodorsal thalamic subdivisions with areas across the frontal lobe, as well as reduced functional connectivity of the dorsal caudate with posterior cortical and cerebellar regions. Compared to cognitively unimpaired subjects, those with mild cognitive impairment (n = 22) demonstrated reduced functional connectivity of the mediodorsal thalamus with the paracingulate cortex, while also demonstrating increased functional connectivity of the mediodorsal thalamus with the posterior cingulate cortex, compared to subjects with dementia (n = 17). Extensive volumetric and surface-based deflation was found in subjects with dementia compared to cognitively unimpaired Parkinson's disease participants and controls. Our research suggests that structures within basal ganglia-thalamocortical circuits are implicated in cognitive impairment and dementia in Parkinson's disease, with cognitive impairment and dementia associated with a breakdown in functional connectivity of the mediodorsal thalamus with para- and posterior cingulate regions of the brain respectively.

Longitudinal trajectories of hippocampal volume in middle to older age community dwelling individuals.

Understanding heterogeneity in brain aging trajectories is important to estimate the extent to which aging outcomes can be optimized. Although brain changes in late life are well-characterized, brain changes in middle age are not well understood. In this study, we investigated hippocampal change in a generally healthy community-living population of middle (n = 421, mean age 47.2 years) and older age (n = 411, mean age 63.0 years) individuals, over a follow-up of up to 12 years. Manually traced hippocampal volumes were analyzed using multilevel models and latent class analysis to investigate longitudinal aging trajectories and laterality and sex effects, and to identify subgroups that follow different aging trajectories. Hippocampal volumes decreased on average by 0.18%/year in middle age and 0.3%/year in older age. Men tended to experience steeper declines than women in middle age only. Three subgroups of individuals following different trajectories were identified in middle age and 2 in older age. Contrary to expectations, the subgroup containing two-thirds of older age participants maintained stable hippocampal volumes across the follow-up.

IMPARO: inferring microbial interactions through parameter optimisation.

BACKGROUND: Microbial Interaction Networks (MINs) provide important information for understanding bacterial communities. MINs can be inferred by examining microbial abundance profiles. Abundance profiles are often interpreted with the Lotka Volterra model in research. However existing research fails to consider a biologically meaningful underlying mathematical model for MINs or to address the possibility of multiple solutions. RESULTS: In this paper we present IMPARO, a method for inferring microbial interactions through parameter optimisation. We use biologically meaningful models for both the abundance profile, as well as the MIN. We show how multiple MINs could be inferred with similar reconstructed abundance profile accuracy, and argue that a unique solution is not always satisfactory. Using our method, we successfully inferred clear interactions in the gut microbiome which have been previously observed in in-vitro experiments. CONCLUSIONS: IMPARO was used to successfully infer microbial interactions in human microbiome samples as well as in a varied set of simulated data. The work also highlights the importance of considering multiple solutions for MINs.

Volumetric brain differences in clinical depression in association with anxiety: a systematic review with meta-analysis.

Background: Structural differences associated with depression have not been confirmed in brain regions apart from the hippocampus. Comorbid anxiety has been inconsistently assessed, and may explain discrepancies in previous findings. We investigated the link between depression, comorbid anxiety and brain structure. Methods: We followed Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42018089286). We searched the Cochrane Library, MEDLINE, PsycInfo, PubMed and Scopus, from database inception to Sept. 13, 2018, for MRI case-control studies that reported brain volumes in healthy adults and adults with clinical depression. We summarized mean volumetric differences using meta-analyses, and we assessed demographics, depression factors and segmentation procedure as moderators using meta-regressions. Results: We included 112 studies in the meta-analyses, assessing 4911 healthy participants and 5934 participants with depression (mean age 49.8 yr, 68.2% female). Volume effects were greater in late-onset depression and in multiple episodes of depression. Adults with depression and no comorbidity showed significantly lower volumes in the putamen, pallidum and thalamus, as well as significantly lower grey matter volume and intracranial volume; the largest effects were in the hippocampus (6.8%, p < 0.001). Adults with depression and comorbid anxiety showed significantly higher volumes in the amygdala (3.6%, p < 0.001). Comorbid anxiety lowered depression effects by 3% on average. Sex moderated reductions in intracranial volume. Limitations: High heterogeneity in hippocampus effects could not be accounted for by any moderator. Data on symptom severity and medication were sparse, but other factors likely made significant contributions. Conclusion: Depression-related differences in brain structure were modulated by comorbid anxiety, chronicity of symptoms and onset of illness. Early diagnosis of anxiety symptomatology will prove crucial to ensuring effective, tailored treatments for improving long-term mental health and mitigating cognitive problems, given the effects in the hippocampus.

Objectively measured physical activity is associated with dorsolateral prefrontal cortex volume in older adults.

BACKGROUND: Epidemiological studies suggest physical activity (PA) can slow or prevent both cognitive decline and age-related atrophy in frontal and hippocampal gray matter volumes. However, much of this evidence is based on self-reported measures of PA. METHODS: PA was measured objectively with a SenseWear™ Armband to examine the cross-sectional associations between the duration of light, moderate and vigorous intensity PA with gray matter volume in the dorsolateral prefrontal cortex (DLPFC) and hippocampus in 167 (female: 43%) cognitively healthy older adults aged 73 to 78. RESULTS: The duration of objective moderate to vigorous intensity physical activity (MVPA) was associated with a greater volume of the right DLPFC (ߠ​= â€‹0.16; p â€‹= â€‹0.04). In addition, objective moderate-intensity PA alone was also associated with greater volume of the left (ߠ​= â€‹0.17; p â€‹= â€‹0.03) and right (ߠ​= â€‹0.19; p â€‹= â€‹0.01) DLPFC after controlling for covariates and adjustment for multiple comparisons. In contrast, there were no significant associations between light- or vigorous-intensity PA and gray matter volumes (all p â€‹> â€‹0.05). No associations between PA and cognitive performance were detected, and self-reported PA was not associated with any of the outcomes investigated. CONCLUSIONS: These findings suggest that an intensity-dependent relationship may exist, whereby a greater duration of MVPA, perhaps driven by moderate-intensity PA, is associated with preserved gray matter volume in frontal regions of the brain. Future research should investigate the mechanisms of this dose-effect and determine whether greater brain volumes associated with objective PA convey protective effects against cognitive decline.

Cognitive/Functional Measures Predict Alzheimer's Disease, Dependent on Hippocampal Volume.

OBJECTIVES: This study aimed to investigate the predictive value of cognitive/functional measures in combination with hippocampal volume (HCV) on the probability of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: The Rey Auditory Verbal Learning Test for immediate memory, Mini-Mental State Examination, a functional assessment for independent daily activities and Alzheimer's Disease Assessment Scale were used as cognitive/functional measures and HCV as neuroimaging measure. Logistic regression and Cox proportional hazard analyses were used to explore the measures' predictive values for AD conversion and time to conversion. RESULTS: The probability of conversion from MCI to AD was associated with cognitive function, but this was moderated by HCV: higher at lower HCV and lower at higher HCV. General cognitive/functional measures were less predictive than immediate memory in predicting time to conversion to AD at small HCVs. CONCLUSION: Effectiveness of cognitive measures and subtle functional abnormality in predicting conversion from MCI to AD is dependent on HCV, thus combined evaluation should be considered. A combination of HCV and immediate memory appear to perform best in predicting time to conversion.

Regional brain atrophy predicts time to conversion to Alzheimer's disease, dependent on baseline volume.

A key question for the design of clinical trials for Alzheimer's disease (AD) is whether the timing of conversion from mild cognitive impairment (MCI) to AD can be predicted. This is also an important question for the clinical management of MCI. This study aims to address this question by exploring the contribution of baseline brain volume and annual volume change, using Cox regression, in predicting the time to conversion. Individuals with MCI, who converted to AD (n = 198), reverted to normal (n = 38), or remained stable (n = 96) for at least five years, were included in this study. The results revealed that the volumes of all the brain areas considered were predictive of the time to conversion from MCI to AD. Annual change in volume was also predictive of the time to conversion but only when initial volumes were above a certain threshold. This is important because it suggests that reduction in atrophy rate, which is the outcome of some clinical trials, is not inevitably associated with delay in conversion from MCI to AD.

Increased functional connectivity of thalamic subdivisions in patients with Parkinson's disease.

Parkinson's disease (PD) affects 2-3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.

Validated Alzheimer's Disease Risk Index (ANU-ADRI) is associated with smaller volumes in the default mode network in the early 60s.

Strong evidence is available suggesting that effective reduction of exposure to demonstrated modifiable risk factors in mid-life or before could significantly decrease the incidence of Alzheimer's disease (AD) and delay its onset. A key ingredient to achieving this goal is the reliable identification of individuals at risk well before they develop clinical symptoms. The aim of this study was to provide further neuroimaging evidence of the effectiveness of a validated tool, the ANU Alzheimer's Disease Risk Index, for the assessment of future risk of cognitive decline. Participants were 461 (60-64 years, 48% female) community-living individuals free of dementia at baseline. Associations between risk estimates obtained with the ANU-ADRI, total and regional brain volumes including in the default mode network (DMN) measured at the same assessment and diagnosis of MCI/dementia over a 12-year follow-up were tested in a large sample of community-living individuals free of dementia at baseline. Higher risk estimates on the ANU-ADRI were associated with lower cortical gray matter and particularly in the DMN. Importantly, difference in participants with high and low risk scores explained 7-9% of the observed difference in gray matter volume. In this sample, every one additional risk point on the ANU-ADRI was associated with an 8% increased risk of developing MCI/dementia over a 12-year follow-up and this association was partly mediated by a sub-region of the DMN. Risk of cognitive decline assessed with a validated instrument is associated with gray matter volume, particularly in the DMN, a region known to be implicated in the pathological process of the disease.

Relationship Between Sulcal Characteristics and Brain Aging.

This study aimed to determine whether sulcal morphology differs between middle age (MA) and older healthy individuals. Furthermore, we sought to determine whether age-related differences in sulcal characteristics were more strongly associated with differences in local or global cortical volumes. Participants (age 44-50, N = 403; age 64-70, N = 390) from the Personality and Total Health Through Life (PATH) study were included. Sulci were 17.3% wider, on average, in old age (OA) compared to MA participants, with the largest difference in the left superior frontal sulcus. Differences in sulcal width were generally higher in males than females. Differences in the width of the superior frontal and central sulci were significantly associated with differences in the volume of adjacent local gyri, while age-related differences in the width of lateral and superior temporal sulci were associated with differences in whole brain cortical volume. These findings suggest that sulcal characteristics provide unique information about changes in local and global brain structure in aging.

Longitudinal Assessment of Hippocampal Atrophy in Midlife and Early Old Age: Contrasting Manual Tracing and Semi-automated Segmentation (FreeSurfer).

It is important to have accurate estimates of normal age-related brain structure changes and to understand how the choice of measurement technique may bias those estimates. We compared longitudinal change in hippocampal volume, laterality and atrophy measured by manual tracing and FreeSurfer (version 5.3) in middle age (n = 244, 47.2[1.4] years) and older age (n = 199, 67.0[1.4] years) individuals over 8 years. The proportion of overlap (Dice coefficient) between the segmented hippocampi was calculated and we hypothesised that the proportion of overlap would be higher for older individuals as a consequence of higher atrophy. Hippocampal volumes produced by FreeSurfer were larger than manually traced volumes. Both methods produced a left less than right volume laterality difference. Over time this laterality difference increased for manual tracing and decreased for FreeSurfer leading to laterality differences in left and right estimated atrophy rates. The overlap proportion between methods was not significantly different for older individuals, but was greater for the right hippocampus. Estimated middle age annualised atrophy rates were - 0.39(1.0) left, 0.07(1.01) right, - 0.17(0.88) total for manual tracing and - 0.15(0.69) left, - 0.20(0.63) right, - 0.18(0.57) total for FreeSurfer. Older age atrophy rates were - 0.43(1.32) left, - 0.15(1.41) right, - 0.30 (1.23) total for manual tracing and - 0.34(0.79) left, - 0.68(0.78) right, - 0.51(0.65) total for FreeSurfer. FreeSurfer reliably segments the hippocampus producing atrophy rates that are comparable to manual tracing with some biases that need to be considered in study design. FreeSurfer is suited for use in large longitudinal studies where it is not cost effective to use manual tracing.

Higher fasting plasma glucose is associated with smaller striatal volume and poorer fine motor skills in a longitudinal cohort.

Previous studies have demonstrated associations between higher blood glucose and brain atrophy and functional deficits, however, little is known about the association between blood glucose, striatal volume and striatal function despite sensori-motor deficits being reported in diabetes. This study investigated the relationship between blood glucose levels, striatal volume and fine motor skills in a longitudinal cohort of cognitively healthy individuals living in the community with normal or impaired fasting glucose or type 2 diabetes. Participants were 271 cognitively healthy individuals (mean age 63 years at inclusion) with normal fasting glucose levels (<5.6 mmol/L) (n=173), impaired fasting glucose (5.6-6.9 mmol/L) (n=57), or with type 2 diabetes (≥7.0 mmol/L) (n=41). Fasting glucose, Purdue Pegboard scores as measurement of fine motor skills, and brain scans were collected at wave 1, 2 and 4, over a total follow-up of twelve years. Striatal volumes were measured using FreeSurfer after controlling for age, sex and intracranial volume. Results showed that type 2 diabetes was associated with smaller right putamen volume and lower Purdue Pegboard scores after controlling for age, sex and intracranial volume. These findings add to the evidence suggesting that higher blood glucose levels, especially type 2 diabetes, may impair brain structure and function.