key: cord-0706639-h4d8nvxk authors: Spreng, R. Nathan; Bzdok, Danilo title: Loneliness and Neurocognitive Aging date: 2021-03-29 journal: Adv Geriatr Med Res DOI: 10.20900/agmr20210009 sha: 57a17dfbd1b020ee2c98ba0e89ae1c5a8fc428bd doc_id: 706639 cord_uid: h4d8nvxk Loneliness imposes significant risks to physical, mental and brain health in older adulthood. With the social distancing regimes implemented during the COVID-19 pandemic, there is even greater urgency to understand the human health costs of social isolation. In this viewpoint we describe how the experience of loneliness may alter the structure and function of the human brain, and how these discoveries may guide public health policy to reduce the burden of loneliness in later life. companionship, feel left out, or isolated from others [4] . This prevelance soars in older adults, with 30-40% of older individuals reporting the experience of loneliness [5, 6] . The health consequences of loneliness are pervasive, affecting not only the mind, but the entire human body. The experience of loneliness is associated with physical health morbidities including hypertension and immune system dysfunction [7] , as well as higher mortality through suicidality [4] . A sense of loneliness has been associated with greater health risks than obesity, or smoking 15 cigarettes daily [8] . Self-reported loneliness has also been related to susceptibility to major psychiatric disorders [4] , cognitive decline [9] and increased dementia risk in later life [10] [11] [12] . Controlling for demographic, somatic, and psychiatric risk factors, including anxiety and depression, lonely individuals have been found to be 1.64 times more likely to develop clinical dementia than persons who do not self-report as lonely [13] . Consistent with this finding, there is now substantial evidence that loneliness is associated with an acceleration in Alzheimer's disease (AD) neuropathology [14] [15] [16] . In short, loneliness in older adulthood imposes clear risks to physical, mental and brain health. Human and non-human animal studies have now begun to elucidate the impact of loneliness on brain structure and function [1] . Yet uncertainty surrounds the precise biological mechanisms which link loneliness in humans to normative brain aging and neurodegenerative disease. Recent work from our laboratories is beginning to shed light on this question. We have identified the default network as a core substrate of perceived social isolation and loneliness in the human brain [17, 18] . The default network is a collection of functionally connected regions located principally along the brain's midline as well as regions of the medial temporal lobes including the hippocampus [19] . These regions show close spatial overlap with the "social brain" [20, 21] and are known to be strongly implicated in social abilities [22, 23] . Importantly, the default network is selectively vulnerable to agerelated decline and AD pathology [24] . We argue that the default network provides a candidate neural substrate linking loneliness, aging, and brain health across the lifespan. To directly interrogate this hypothesis, we have begun to harness large cohort data resources to identify associations between the experience of loneliness and brain structure and function. In an earlier study, we reported, in a sample of younger adults, that increased loneliness was associated with a shift in the functional connectivity patterns of the default network, towards greater functional integration with networks implicated in externally directed perceptual, attentional and cognitive control functions [17] . We speculated that these findings speak to the evolutionary hypothesis [2] , suggesting that loneliness is an adaptive signal, prompting a shift away from internal mentation towards a more external focus promoting social re-engagement. We have recently built on these early hints with the largest-to-date study of loneliness and brain health [18] . Drawing from the UK Biobank, the most comprehensive biomedical dataset, we examined loneliness, brain volume, functional connectivity and structural connectivity in approximately 40,000 middle to older age adults. Using pattern-learning methods, we found that loneliness-linked neurobiological profiles converged once again on the default network. Patterns of regional grey matter volume in the default network were most robustly associated with loneliness. Positive loneliness associations were observed for functional connectivity within the default network. Further, lonely individuals had greater microstructural integrity of the fornix, a key fibre pathway that emerges from the hippocampal formation in the medial temporal lobe structures to send axons to directly connect to the ventromedial prefrontal cortex, a core default network region [25] . This striking convergence of loneliness associations with default network structure and function raises intriguing questions regarding the shifting impact of loneliness on the brain from young, through middle, and into older adulthood. While our interpretations remain preliminary, we hypothesize that prolonged experiences of loneliness into middle and late adulthood may result in the up-regulation of default network circuits that support mentalizing, reminiscence and imagination to fulfill desired but unmet needs for social interactions. Although speculative, this heightening of internally-directed cognitive processes may promote changes in vigilance and heightened emotional reactivity to external stimuli, also associated with the experience of loneliness [26] . We are now extending this work to explore longitudinal associations between loneliness and brain health in normative aging and individuals at elevated risk for AD. This will provide a broader lifespan perspective on the lifespan trajectory of 'the lonely brain'. While much work remains to be done, there is a growing urgency to understand links between age-related brain changes in the context of loneliness. According to a 2018 report from the American Association of Retired Persons, nearly one-third of individuals surveyed over age 45 reported feeling lonely. In just the last decade, the population of lonely people over age 45 has grown by more than 5 million, from 42.6 million to 47.8 million, and these data do not account for the global pandemic. Social distancing restrictions during the COVID-19 pandemic raise significant concerns about loneliness among older adults [27] and increases in loneliness have indeed been observed [28] , with uncertain long-term consequences post-pandemic. Yet the experience of loneliness has clear implications for physical and mental health. Additionally, these impacts appear more acutely with advancing age. Surprisingly little data are currently available in humans that would illuminate how experiences of social isolation interact with brain structure and function in aging or brain disease. Reducing loneliness among older adults is a tractable public health issue. As the global pandemic has laid bare, public infrastructure to support connectedness is urgently needed. This is all the more the case in vulnerable populations, such as those in assisted living or Indigenous communities. Research progress is imperative to advance our understanding of the neural underpinnings of loneliness so that this knowledge may, in turn, inform public health policy, towards combating the oncoming pandemic of loneliness in older adulthood. The Neurobiology of Social Distance The Phenotype of Loneliness Luxemburgh (Luxemburgh): World Health Organization Loneliness in the general population: prevalence, determinants and relations to mental health Loneliness in older persons: a predictor of functional decline and death Loneliness, isolation and the health of older adults: do we need a new research agenda? Loneliness and acute stress reactivity: A systematic review of psychophysiological studies Loneliness and social isolation as risk factors for mortality: a meta-analytic review Loneliness and cognitive function in the older adult: a systematic review Loneliness and risk of Alzheimer disease Social relationships and risk of dementia: A systematic review and meta-analysis of longitudinal cohort studies Does loneliness contribute to mild cognitive impairment and dementia? A systematic review and meta-analysis of longitudinal studies Feelings of loneliness, but not social isolation, predict dementia onset: results from the Amsterdam Study of the Elderly (AMSTEL) Social Engagement and Amyloid-beta-Related Cognitive Decline in Cognitively Normal Older Adults Regional tau pathology and loneliness in cognitively normal older adults Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults Loneliness and meaning in life are reflected in the intrinsic network architecture of the brain The default network of the human brain is associated with perceived social isolation The default network and self-generated thought: component processes, dynamic control, and clinical relevance Computing the Social Brain Connectome Across Systems and States manuscript; available in PMC On the relationship between the "default mode network" and the "social brain Social-cognitive deficits in normal aging The common neural basis of autobiographical memory, prospection, navigation, theory of mind, and the default mode: a quantitative meta-analysis Neurodegenerative diseases target large-scale human brain networks Subspecialization within default mode nodes characterized in 10,000 UK Biobank participants Older Adults and the Mental Health Effects of COVID-19 The Impact of Sheltering in Place During the COVID-19 Pandemic on Older Adults' Social and Mental Well-Being manuscript; available in PMC