Elevated emotion network connectivity is associated with fluctuations in depression.

Elevated emotion network connectivity is thought to leave people vulnerable to become and stay depressed. The mechanism through which this arises is however unclear. Here, we test the idea that the connectivity of emotion networks is associated with more extreme fluctuations in depression over time, rather than necessarily more severe depression. We gathered data from two independent samples of N = 155 paid students and N = 194 citizen scientists who rated their positive and negative emotions on a smartphone app twice a day and completed a weekly depression questionnaire for 8 wk. We constructed thousands of personalized emotion networks for each participant and tested whether connectivity was associated with severity of depression or its variance over 8 wk. Network connectivity was positively associated with baseline depression severity in citizen scientists, but not paid students. In contrast, 8-wk variance of depression was correlated with network connectivity in both samples. When controlling for depression variance, the association between connectivity and baseline depression severity in citizen scientists was no longer significant. We replicated these findings in an independent community sample (N = 519). We conclude that elevated network connectivity is associated with greater variability in depression symptoms. This variability only translates into increased severity in samples where depression is on average low and positively skewed, causing mean and variance to be more strongly correlated. These findings, although correlational, suggest that while emotional network connectivity could predispose individuals to severe depression, it could also be leveraged to bring about therapeutic improvements.

Connectome-based predictive modelling of cognitive reserve using task-based functional connectivity.

Cognitive reserve supports cognitive function in the presence of pathology or atrophy. Functional neuroimaging may enable direct and accurate measurement of cognitive reserve which could have considerable clinical potential. The present study aimed to develop and validate a measure of cognitive reserve using task-based fMRI data that could then be applied to independent resting-state data. Connectome-based predictive modelling with leave-one-out cross-validation was applied to predict a residual measure of cognitive reserve using task-based functional connectivity from the Cognitive Reserve/Reference Ability Neural Network studies (n = 220, mean age = 51.91 years, SD = 17.04 years). This model generated summary measures of connectivity strength that accurately predicted a residual measure of cognitive reserve in unseen participants. The theoretical validity of these measures was established via a positive correlation with a socio-behavioural proxy of cognitive reserve (verbal intelligence) and a positive correlation with global cognition, independent of brain structure. This fitted model was then applied to external test data: resting-state functional connectivity data from The Irish Longitudinal Study on Ageing (TILDA, n = 294, mean age = 68.3 years, SD = 7.18 years). The network-strength predicted measures were not positively associated with a residual measure of cognitive reserve nor with measures of verbal intelligence and global cognition. The present study demonstrated that task-based functional connectivity data can be used to generate theoretically valid measures of cognitive reserve. Further work is needed to establish if, and how, measures of cognitive reserve derived from task-based functional connectivity can be applied to independent resting-state data.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Impaired posterior cingulate cortex-parahippocampus connectivity is associated with episodic memory retrieval problems in amnestic mild cognitive impairment.

Episodic memory retention and retrieval decline are the most common impairments observed in amnestic mild cognitive impairment (aMCI) patients who progress to Alzheimer's disease (AD). Clinical electroencephalography research shows that patients with dementia due to AD exhibit a slowing of neural electrical activity in the parietal cortex. Memory research has further suggested that successful memory performance is associated with changes in a posterior cingulate-parahippocampal cortical network together with increased θ-γ oscillatory coupling, where θ oscillations act as carrier waves for γ oscillations, which contain the actual information. However, the neurophysiological link between the memory research and clinical studies investigating aMCI and AD is lacking. In this study, we look at brain activity in aMCI and how it relates to memory performance. We demonstrate decreased γ power in the posterior cingulate cortex and the left and right parahippocampus in aMCI patients in comparison to control participants. This goes together with reduced θ coherence between the posterior cingulate cortex and parahippocampus associated with altered memory performance aMCI patients in comparison to control participants. In addition, comparing patients with aMCI to control participants reveals an effect for θ-γ coupling for the posterior cingulate cortex, and the left and right parahippocampus. Taken together, our results show that parahippocampus and posterior cingulate cortex interact via θ-γ coupling, which is associated with memory recollection and is altered in aMCI patients, offering a potential candidate mechanism for memory decline in aMCI.

P3b amplitude as a signature of cognitive decline in the older population: An EEG study enhanced by Functional Source Separation.

With the greying population, it is increasingly necessary to establish robust and individualized markers of cognitive decline. This requires the combination of well-established neural mechanisms, and the development of increasingly sensitive methodologies. The P300 event-related potential (ERP) has been one of the most heavily investigated neural markers of attention and cognition, and studies have reliably shown that changes in the amplitude and latency of the P300 ERP index the process of aging. However, it is still not clear whether either the P3a or P3b sub-components additionally index levels of cognitive impairment. Here, we used a traditional visual three-stimulus oddball paradigm to investigate both the P3a and P3b ERP components in sixteen young and thirty-four healthy elderly individuals with varying degrees of cognitive ability. EEG data extraction was enhanced through the use of a novel signal processing method called Functional Source Separation (FSS) that increases signal-to-noise ratio by using a weighted sum of all electrodes rather than relying on a single, or a small sub-set, of EEG channels. Whilst clear differences in both the P3a and P3b ERPs were seen between young and elderly groups, only P3b amplitude differentiated older people with low memory performance relative to IQ from those with consistent memory and IQ. A machine learning analysis showed that P3b amplitude (derived from FSS analysis) could accurately categorise high and low performing elderly individuals (78% accuracy). A comparison of Bayes Factors found that differences in cognitive decline within the elderly group were 87 times more likely to be detected using FSS compared to the best performing single electrode (Cz). In conclusion, we propose that P3b amplitude could be a sensitive marker of early, age-independent, episodic memory dysfunction within a healthy older population. In addition, we advocate for the use of more advanced signal processing methods, such as FSS, for detecting subtle neural changes in clinical populations.

Plasticity of the Right-Lateralized Cognitive Reserve Network in Ageing.

Cognitive reserve (CR) is the phenomenon where older adults with more cognitively stimulating environments show less age-related cognitive decline. The right-lateralized fronto-parietal network has been proposed to significantly contribute to CR and visual attention in ageing. In this study we tested whether plasticity of this network may be harnessed in ageing.We assessed CR and parameters of visual attention capacity in older adults. Transcranial direct current stimulation (tDCS) was employed to increase right fronto-parietal activity during a lateralized whole-report task. At baseline, older adults with greater CR showed a stronger hemifield asymmetry in processing speed towards the left visual-field, indicative of stronger involvement of the right hemisphere in these individuals. Correspondingly, processing speed improved during right prefrontal tDCS. Older adults with lower levels of CR showed tDCS-related improvements in processing speed in the left but not right hemifield: thus tDCS temporarily altered their processing speed asymmetry to resemble that of their high reserve peers.The finding that stronger right hemisphere involvement is related to CR supports Robertson's theory. Furthermore, preserved plasticity within the right prefrontal cortex in older adults suggests this is a viable target area to improve visual processing speed, a hallmark of age-related decline.

Cognitive functioning among cognitively intact dementia caregivers compared to matched self-selected and population controls.

PURPOSE OF THE STUDY: Caregiving for a person with dementia is frequently used to model the impact of chronic stress on health, including cognitive functioning. However, the prevalence of typically healthier, self-selecting non-caregiving control groups could contribute to a picture of poorer caregiver performance and overstate the negative effects of stress. We investigated differences in cognitive performance between dementia caregivers and two groups of non-caregivers recruited using different sampling methods. DESIGN AND METHODS: We compared cognitive function and psychological wellbeing among 252 spousal dementia caregivers with demographically matched non-caregiving control groups drawn from (1) a population study and (2) a self-selecting sample. Comparable cognitive measures included immediate and delayed recall, processing speed reaction time and verbal fluency. RESULTS: Caregiver and non-caregiver performance was comparable on most cognitive domains. However, caregivers outperformed both control groups on processing speed (p ≤ .05) and reaction time (p ≤ .05), despite having higher levels of stress and depression (ps < .001). Furthermore, caregivers had significantly better free recall than self-selecting controls (p < .001). IMPLICATIONS: Our results, overall, do not support the idea that caregiving is associated with stress-induced cognitive deficits. Rather, the trend toward better caregiver performance is consistent with the healthy caregiver hypothesis.

Prefrontal Modulation of Visual Processing and Sustained Attention in Aging, a tDCS-EEG Coregistration Approach.

The ability to sustain attention is integral to healthy cognition in aging. The right PFC (rPFC) is critical for maintaining high levels of attentional focus. Whether plasticity of this region can be harnessed to support sustained attention in older adults is unknown. We used transcranial direct current stimulation to increase cortical excitability of the rPFC, while monitoring behavioral and electrophysiological markers of sustained attention in older adults with suboptimal sustained attention capacity. During rPFC transcranial direct current stimulation, fewer lapses of attention occurred and electroencephalography signals of frontal engagement and early visual attention were enhanced. To further verify these results, we repeated the experiment in an independent cohort of cognitively typical older adults using a different sustained attention paradigm. Again, prefrontal stimulation was associated with fewer attentional lapses. These experiments suggest the rPFC can be manipulated in later years to increase top-down modulation over early sensory processing and improve sustained attention performance. This holds valuable information for the development of neurorehabilitation protocols to ameliorate age-related deficits in this capacity.

Computerised working memory-based cognitive remediation therapy does not affect Reading the Mind in The Eyes test performance or neural activity during a Facial Emotion Recognition test in psychosis.

Working memory-based cognitive remediation therapy (CT) for psychosis has recently been associated with broad improvements in performance on untrained tasks measuring working memory, episodic memory and IQ, and changes in associated brain regions. However, it is unclear whether these improvements transfer to the domain of social cognition and neural activity related to performance on social cognitive tasks. We examined performance on the Reading the Mind in the Eyes test (Eyes test) in a large sample of participants with psychosis who underwent working memory-based CT (N = 43) compared to a control group of participants with psychosis (N = 35). In a subset of this sample, we used functional magnetic resonance imaging (fMRI) to examine changes in neural activity during a facial emotion recognition task in participants who underwent CT (N = 15) compared to a control group (N = 15). No significant effects of CT were observed on Eyes test performance or on neural activity during facial emotion recognition, either at p < 0.05 family-wise error or at a p < 0.001 uncorrected threshold, within a priori social cognitive regions of interest. This study suggests that working memory-based CT does not significantly impact an aspect of social cognition which was measured behaviourally and neurally. It provides further evidence that deficits in the ability to decode mental state from facial expressions are dissociable from working memory deficits, and suggests that future CT programmes should target social cognition in addition to working memory for the purposes of further enhancing social function.

Parsing the neural signatures of reduced error detection in older age.

Recent work has demonstrated that explicit error detection relies on a neural evidence accumulation process that can be traced in the human electroencephalogram (EEG). Here, we sought to establish the impact of natural aging on this process by recording EEG from young (18-35 years) and older adults (65-88 years) during the performance of a Go/No-Go paradigm in which participants were required to overtly signal their errors. Despite performing the task with equivalent accuracy, older adults reported substantially fewer errors, and the timing of their reports were both slower and more variable. These behavioral differences were linked to three key neurophysiological changes reflecting distinct parameters of the error detection decision process: a reduction in medial frontal delta/theta (2-7 Hz) activity, indicating diminished top-down input to the decision process; a slower rate of evidence accumulation as indexed by the rate of rise of a centro-parietal signal, known as the error positivity; and a higher motor execution threshold as indexed by lateralized beta-band (16-30 Hz) activity. Our data provide novel insight into how the natural aging process affects the neural underpinnings of error detection.

Transcranial direct current stimulation over right dorsolateral prefrontal cortex enhances error awareness in older age.

The ability to detect errors during cognitive performance is compromised in older age and in a range of clinical populations. This study was designed to assess the effects of transcranial direct current stimulation (tDCS) on error awareness in healthy older human adults. tDCS was applied over DLPFC while subjects performed a computerized test of error awareness. The influence of current polarity (anodal vs cathodal) and electrode location (left vs right hemisphere) was tested in a series of separate single-blind, Sham-controlled crossover trials, each including 24 healthy older adults (age 65-86 years). Anodal tDCS over right DLPFC was associated with a significant increase in the proportion of performance errors that were consciously detected, and this result was recapitulated in a separate replication experiment. No such improvements were observed when the homologous contralateral area was stimulated. The present study provides novel evidence for a causal role of right DLPFC regions in subserving error awareness and marks an important step toward developing tDCS as a tool for remediating the performance-monitoring deficits that afflict a broad range of populations.

Risk of Cognitive and Functional Impairment in Spouses of People With Dementia: Evidence From the Health and Retirement Study.

Caring for a spouse with dementia is a chronic stressor that may compromise caregivers' own cognitive functioning and capacity to provide adequate care. We examined whether having (i) a spouse with dementia and (ii) a spouse who requires assistance with activities of daily living predicted cognitive and functional impairments in respondents to the Health and Retirement Study (n = 7965). Respondents who had a spouse who requires care had poorer cognitive functioning, whereby this relationship was significantly stronger for male respondents. Having a spouse with dementia moderated the relationship between income and cognition and predicted caregiver functional impairment, though not when depression was controlled. Although we found no significant differences on any individual cognitive domains between 179 dementia caregivers and sociodemographically matched noncaregivers, our findings suggest that caregivers, especially men, and low-income individuals who have a spouse with dementia are more vulnerable to adverse cognitive outcomes. Targeting depression in spouses of people with dementia may help to prevent functional impairments.

The neural basis of impaired self-awareness after traumatic brain injury.

Self-awareness is commonly impaired after traumatic brain injury. This is an important clinical issue as awareness affects long-term outcome and limits attempts at rehabilitation. It can be investigated by studying how patients respond to their errors and monitor their performance on tasks. As awareness is thought to be an emergent property of network activity, we tested the hypothesis that impaired self-awareness is associated with abnormal brain network function. We investigated a group of subjects with traumatic brain injury (n = 63) split into low and high performance-monitoring groups based on their ability to recognize and correct their own errors. Brain network function was assessed using resting-state and event-related functional magnetic resonance imaging. This allowed us to investigate baseline network function, as well as the evoked response of networks to specific events including errors. The low performance-monitoring group underestimated their disability and showed broad attentional deficits. Neural activity within what has been termed the fronto-parietal control network was abnormal in patients with impaired self-awareness. The dorsal anterior cingulate cortex is a key part of this network that is involved in performance-monitoring. This region showed reduced functional connectivity to the rest of the fronto-parietal control network at 'rest'. In addition, the anterior insulae, which are normally tightly linked to the dorsal anterior cingulate cortex, showed increased activity following errors in the impaired group. Interestingly, the traumatic brain injury patient group with normal performance-monitoring showed abnormally high activation of the right middle frontal gyrus, putamen and caudate in response to errors. The impairment of self-awareness was not explained either by the location of focal brain injury, or the amount of traumatic axonal injury as demonstrated by diffusion tensor imaging. The results suggest that impairments of self-awareness after traumatic brain injury result from breakdown of functional interactions between nodes within the fronto-parietal control network.

Characterising neural signatures of successful aging: Electrophysiological correlates of preserved episodic memory in older age.

While aging is associated with a gradual decline in memory, substantial preservation of function is observed in certain individuals and dissecting this heterogeneity is paramount to understanding successful aging. A cohort of elderly individuals were classified according to their level of memory preservation and administered a test of episodic memory in which participants were cued to learn or simply read each word and then to identify previously presented items in a delayed recognition phase. Mathematical modelling revealed that relatively preserved memory function was specifically linked to a faster rate of memorial evidence accumulation (drift rate). Analysis of event-related potentials at encoding revealed that high-performing elderly exhibited signals over parietal regions that discriminated between words to be learned vs. read for an additional 300-ms compared to young subjects suggesting a compensatory encoding mechanism that was absent in the low-performing group. At recognition, parietal signals associated with recollection processes discriminated previously learned words from read words in the young and high-performing old but not in low-performing old. These results reveal that successful aging is associated with specific adaptive neural markers during both encoding and retrieval.

Pupil diameter covaries with BOLD activity in human locus coeruleus.

The locus coeruleus-noradrenergic (LC-NA) neuromodulatory system has been implicated in a broad array of cognitive processes, yet scope for investigating this system's function in humans is currently limited by an absence of reliable non-invasive measures of LC activity. Although pupil diameter has been employed as a proxy measure of LC activity in numerous studies, empirical evidence for a relationship between the two is lacking. In the present study, we sought to rigorously probe the relationship between pupil diameter and BOLD activity localized to the human LC. Simultaneous pupillometry and fMRI revealed a relationship between continuous pupil diameter and BOLD activity in a dorsal pontine cluster overlapping with the LC, as localized via neuromelanin-sensitive structural imaging and an LC atlas. This relationship was present both at rest and during performance of a two-stimulus oddball task, with and without spatial smoothing of the fMRI data, and survived retrospective image correction for physiological noise. Furthermore, the spatial extent of this pupil/LC relationship guided a volume-of-interest analysis in which we provide the first demonstration in humans of a fundamental characteristic of animal LC activity: phasic modulation by oddball stimulus relevance. Taken together, these findings highlight the potential for utilizing pupil diameter to achieve a more comprehensive understanding of the role of the LC-NA system in human cognition.

The effects of immunologic brainstem encephalopathy on cognitive function following awakening from a progressive autoimmune coma.

We describe a unique patient who experienced a progressive autoimmune coma from age 14 to 17. The patient awoke after treatment with immunosuppressant medication. Although alertness, verbalization, and mobilization markedly improved, the patient reported persistent cognitive difficulties. Neuropsychological assessment from age 21 showed impairments in selective attention, distractibility, and memory. Conversely, higher-order executive functions were preserved. Electrophysiological analysis also identified abnormal neural signatures of selective attention. Eighteen months after the neuropsychological assessment, voxel-based morphometry revealed reduced white matter in the medulla compared to controls. The findings are discussed in terms of the impact of brainstem encephalopathy on cognitive mechanisms.

Cerebellum and cognition: evidence for the encoding of higher order rules.

Converging anatomical and functional evidence suggests that the cerebellum processes both motor and nonmotor information originating from the primary motor cortex and prefrontal cortex, respectively. However, it has not been established whether the cerebellum only processes prefrontal information where rules specify actions or whether the cerebellum processes any form of prefrontal information no matter how abstract. Using functional magnetic resonance imaging, we distinguish between two competing hypotheses: (1) activity within prefrontal-projecting cerebellar lobules (Crus I and II) will only be evoked by rules that specify action (i.e. first-order rules; arbitrary S-R mappings) and (2) activity will be evoked in these lobules by both first-order rules and second-order rules that govern the application of lower order rules. The results showed that prefrontal-projecting cerebellar lobules Crus I and II were commonly activated by processing both first- and second-order rules. We demonstrate for the first time that cerebellar circuits engage both first- and second-order rules and in doing so show that the cerebellum can contribute to cognitive control independent of motor control.

Greater physical fitness ( VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ ) in healthy older adults associated with increased integrity of the locus coeruleus-noradrenergic system.

AIM: Physical activity (PA) is a key component for brain health and Reserve, and it is among the main dementia protective factors. However, the neurobiological mechanisms underpinning Reserve are not fully understood. In this regard, a noradrenergic (NA) theory of cognitive reserve (Robertson, 2013) has proposed that the upregulation of NA system might be a key factor for building reserve and resilience to neurodegeneration because of the neuroprotective role of NA across the brain. PA elicits an enhanced catecholamine response, in particular for NA. By increasing physical commitment, a greater amount of NA is synthetised in response to higher oxygen demand. More physically trained individuals show greater capabilities to carry oxygen resulting in greater Vo 2 max $$ {\mathrm{Vo}}_{2_{\mathrm{max}}} $$ - a measure of oxygen uptake and physical fitness (PF). METHODS: We hypothesized that greater Vo 2 max $$ {\mathrm{Vo}}_{2_{\mathrm{max}}} $$ would be related to greater Locus Coeruleus (LC) MRI signal intensity. In a sample of 41 healthy subjects, we performed Voxel-Based Morphometry analyses, then repeated for the other neuromodulators as a control procedure (Serotonin, Dopamine and Acetylcholine). RESULTS: As hypothesized, greater Vo 2 max $$ {\mathrm{Vo}}_{2_{\mathrm{max}}} $$ related to greater LC signal intensity, and weaker associations emerged for the other neuromodulators. CONCLUSION: This newly established link between Vo 2 max $$ {\mathrm{Vo}}_{2_{\mathrm{max}}} $$ and LC-NA system offers further understanding of the neurobiology underpinning Reserve in relationship to PA. While this study supports Robertson's theory proposing the upregulation of the NA system as a possible key factor building Reserve, it also provides ground for increasing LC-NA system resilience to neurodegeneration via Vo 2 max $$ {\mathrm{Vo}}_{2_{\mathrm{max}}} $$ enhancement.

Cognitive function is preserved in older adults with a reported history of childhood sexual abuse.

Childhood sexual abuse (CSA) is associated with mood and cognitive deficits in children and young adults. Evidence suggests that the effects of early-life adversity persist throughout adulthood; however, the impact of CSA on cognition in older adults is largely unknown. This study investigated cognitive function in older adults with a reported history of CSA. Data are from a population-based study (The Irish Longitudinal Study on Ageing) of 6,912 adults aged 50 years and older. Participants answered questions about CSA as part of a stressful life events questionnaire. Global cognition, executive function, memory (both objective and self-rated), attention, and processing speed were measured via a comprehensive battery of tests. Anxiety and depression, other childhood adversity, health behaviours, chronic disease, and medication use were also assessed. Of the total sample, 6.5% reported CSA. These individuals were more likely to have experienced other forms of childhood adversity and to exhibit poor mental health compared to those who reported no history of CSA. Multivariate regression analyses revealed, however, that CSA was associated with better global cognition, memory, executive function, and processing speed, despite poorer psychological health in this group. Future studies should aim to investigate possible reasons for this finding.