Structural Sensitivity Analysis and Optimization 2

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However, little is known about structural cerebral correlates of loneliness in healthy older adults. We examined such correlates in a magnetic resonance imaging MRI subsample of older adults aged 61 to 82 years drawn from the Berlin Aging Study II. Using voxel-based morphometry VBM and structural equation modeling SEM , latent hierarchical regression analyses were performed to examine associations of i loneliness, ii a range of covariates, and iii loneliness by covariate interactions with latent brain volume estimates of brain structures known to be involved in processing, expressing, and regulating emotions.

Significant associations and interactions between loneliness and latent factors for the amygdala and the hippocampus were confirmed with a region-of-interest ROI -based approach.

These findings suggest that individual differences in loneliness among older adults are correlated with individual differences in the volumes of brain regions that are central to cognitive processing and emotional regulation, also after correcting for confounders such as social network size. We discuss possible mechanisms underlying these associations and their implications.

With increasing life expectancy 1 older adults are more likely to be confronted with changes in their social network structure 2.

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As a consequence, loneliness is on the rise with about 20 to 40 percent of older adults in Western countries reporting to feel lonely today 3. Interestingly, loneliness seems to be a stronger predictor of physical and mental health outcomes than quantitative objective measures of social integration e. In particular, having a large social network does not necessarily prevent the feeling of loneliness 9. Lifespan research has long demonstrated that loneliness is associated with key outcomes of aging, including increases in morbidity, overall mortality 3 , 7 , 10 , and poorer mental health 9 , 11 , 12 , Even though numerous studies have examined behavioral, physical and structural brain correlates of loneliness in relation to specific mental disorders such as anxiety, depression 14 , 15 astonishingly little is known about the neural structures and processes associated with feelings of loneliness among healthy older adults 16 , Conceptual models suggest that across adulthood and old age numerous social and health factors profoundly shape perceptions of loneliness 19 , Because these key sources of loneliness are often accumulating in old age 4 , one could expect that older adults have increasingly fewer opportunities to be socially embedded and integrated, thereby resulting in age-related increases of overall loneliness.

At the same time, it has long been argued that with decreases in remaining lifetime older adults aim to increase their well-being by focusing more on fewer but emotionally meaningful relationships and less on expanding their social networks As a consequence, loneliness would be expected to remain relatively stable across adulthood and old age. Empirical studies on age-related changes in loneliness have so far revealed an inconsistent pattern. In contrast, other studies did not find associations between loneliness and age, especially when accounting for well-known correlates of loneliness and age e.

These discrepant findings may be caused by study differences in the selection of the samples, its characteristics and size, or measurement and also highlight the need for more fine-grained exploration of the antecedents and consequences of loneliness in old age.

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Thus, individual differences in subjective perception of loneliness may in part reflect differences in brain regions that are functionally involved in processing, expressing, and regulating emotionally and socially relevant information 16 , Indeed, several findings from functional and structural neuroimaging studies have reported links between specific brain structures and loneliness. It can be assumed that age-related increases in loneliness might be linked to age-related structural changes in brain regions that are in turn related to cognitive processing of emotional and social stimuli and their regulation 16 , To shed light onto the current state of research in this field, we reviewed recent studies that aimed to examine neuronal correlates of perceived loneliness.

We provide a comprehensive overview of the measures used and reported relevant outcomes of these studies in the Supplementary Information. For example, in a recent VBM study Kanai and colleagues showed that individuals reporting higher loneliness showed less gray matter volume of left posterior superior temporal sulcus, a region that has been implicated in processing of social information.

Although this study showed that such brain correlates of loneliness may indeed exist, the sample consisted exclusively of younger and middle-aged adults and consequently does not allow to draw conclusions about how these associations evolve in older age. Additionally, the authors did not control for well-known covariates that have been linked to loneliness such as depressive affect, overall physical functioning and personality traits such as openness. In a different study Sato and colleagues showed that larger amygdala volume was associated with more perceived social support in a sample of younger adults However, the authors focused only on associations between perceived social support and amygdala volume, but did not examine the involvement of other covariates of loneliness as well as other brain regions that may be crucial for social and emotional processing.

Furthermore, another area of research on brain plasticity has pointed out that changes in environmental demands can shape brain structure, also in the aging brain 28 , 29 , In recent years, promising evidence from animal models and intervention studies in humans indicates that e. One can assume that brain regions that are sensitive to changes in environmental demands and social as well as cognitive stimulation are also more vulnerable to the negative consequences of prolonged loneliness, social disconnection and environmental deprivation 33 , 34 , 35 , These are e.

Also, the earlier studies noted have investigated associations between loneliness and brain structure using exploratory analyses such as VBM or only focused on one specific brain region such as the amygdala. In our study, we aim to obtain a broader view on the links and interactions between loneliness, the brain and its covariates by combining exploratory and confirmatory analyses instead. Moreover, relatively little is known about whether and how loneliness and its confounders are associated with the aforementioned brain structures in healthy aging.

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On the whole brain level we apply VBM in order to exploratory investigate direct association of gray matter volume and loneliness after taking into account important confounders of loneliness. Since this study is based on cross-sectional data a causal directionality of specific effect cannot be inferred. We hypothesized that higher perceived loneliness would be linked to smaller volumes in brain regions that have been implicated in prior studies in emotional and social cognition due to negative consequences of loneliness such as stress, reduced social and cognitive stimulation.

In a second set of analyses, we aim to validate in a confirmatory model a latent brain factor model including a priori defined brain regions to jointly observe how loneliness affects these regions.

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The selection of the ROIs was based on findings from the current literature on brain structure and loneliness see Supplementary Information. Our goal was to explore possible moderation and interaction effects of a number of potential confounders that have been previously shown to be associated with loneliness and brain structure, namely age, gender, years of education, depressive affect, openness, morbidity, total intercranial volume TIV and number of confidants 3 , 15 , To our knowledge our study is the first to investigate in an exploratory and confirmatory fashion these associations in healthy older adults.

There were no significant associations found between depressive affect, openness, or morbidity and the latent brain factors. The VBM analysis revealed three significant clusters Fig. The right panel of Fig.

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A post-hoc VBM analyses we additionally investigated possible associations between social network size and brain structure that revealed no significant cluster when taking into account the same covariates. Upper right panel: Correlation between the individual GM volumes in the first cluster and loneliness score. Core results of the CFA for the intercorrelated seven latent brain factor model are shown in Fig. As a consequence, we used this latent brain factor model as baseline model to investigate brain-loneliness associations in more depth.

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A simplified illustration of the CFA of the latent brain factor model. Latent brain factors are drawn in circles. Squares represent observed variables. Single-headed arrows represent significant factor loadings, and double-headed arrows represent covariances. Double-headed arrows with both heads pointing on a manifest variable represent the variance of a variable.

Next, we set up a latent regression model to examine simultaneous associations of the individual loneliness scores and the latent brain factor model, whilst simultaneously investigating the main effects as well as the interactions with loneliness and its covariates. Loneliness, depressive affect, openness and educations are represented as mean scores squares.

Regression coefficients represent standardized estimates. Regarding the associations between loneliness and covariates not depicted in Fig. It can be obtained that older adults reporting a higher level of perceived loneliness show significantly lower volumes in specific brain regions such as the amygdala depicted in Fig. Exemplary plot of the interaction between loneliness, age, and left amygdala volume.

For illustration, the participants were divided into two age groups by applying a In the present study we applied multivariate methods to identify associations between individual differences in loneliness and regional brain volumes in a sample of healthy older adults. An additional aim of this study was to explore interactive effects of potential confounders of loneliness on these associations and to disentangle the effects of perceived loneliness and social network size regarding their specific associations with brain structure.

Another significant cluster evolved in the left posterior parahippocampal gyrus, and in the cerebellum, after taking a comprehensive set of confounders into account Fig. The VBM results show that higher levels of loneliness are associated with smaller volumes in these regions. These findings are consistent with previous studies in animals and human young adults showing that the amygdala plays an important role in emotion processing and social functioning e.

Interestingly, previous studies have shown that the GM volume of the amygdala among other structures is correlated with real-world social network size as well as online social network size For instance, individuals who have encountered more social stimulation and interactions throughout their life may have enlarged their amygdala volumes, or individuals with larger amygdala to begin with may be more socially inclined.

Moreover, our VBM results point towards a relation between loneliness, hippocampal and parahippocampal regions in healthy aging. First, higher levels of stress induced by prolonged loneliness could lead to hippocampal injury due to elevated levels of glucocorticoids, and blood pressure 39 , 40 , 41 , Second, loneliness is associated with deprivation of social interactions and then the associated impoverishment of hippocampal drive could lead to atrophy in these regions.

One may assume that individuals reporting higher loneliness show a reduced engagement in an active, socially and cognitively stimulating lifestyle which has been repeatedly shown to be crucial to successful cognitive and brain aging 43 , 44 , On the other side, it has been shown in lesion studies that damage in the amygdala impairs the ability to recognize emotional facial expressions 46 , Consistent with this lesion finding, a previous functional MRI fMRI study supports the association between amygdala activation and emotion processing because amygdala activity in response to negative emotional facial expressions and increased anxiety was associated with perceiving more social support Another fMRI study used a modified emotional Stroop task, in which lonely participants showed greater Stroop interference effects specifically for negative social as compared to negative nonsocial words and to the non-lonely participants These fMRI findings suggest that loneliness may increase attention to negative social stimuli and vice versa e.

Thus, the hypersensitivity to negative social information and the diminished pleasure derived from positive social stimuli found in the aforementioned studies might shape social expectations and motivations and contribute to higher perception of loneliness. This disposition, in turn, may increase age-related structural changes in the underlying neurobiological systems such as in the amygdala. Interestingly, VBM analysis additionally revealed a significant cluster in regions of the left cerebellum.


The cerebellum has previously been suggested to play a role not only in motor behavior but also in multiple domains of cognitive functioning and emotional control see 50 , In a next set of analyses, we applied a latent factor model of a priori selected brain regions in order to test their simultaneous association with loneliness and selected covariates using CFA. By establishing latent factors of brain regions the dimensionality of the data can be reduced and the shared variance can be captured while measurement error is taken care of. As a result we achieved a good model fit for the data thus, validating the latent brain factor model.

In line with our findings these regions have been shown to be involved in neural processes that are recruited when experiencing physical pain but also when experiencing social deprivation Whereas the ACC is more implicated in self reflectional processes 53 which acts as a neural conflict monitor, detecting conflicts with current goals.


In addition, large parts of the dlPFC comprise a brain region that is commonly described as ventromedial prefrontal cortex. This is a key region of central midline structures that have been consistently related to brain activation while participants process stimuli that are strongly related to themselves 54 , The frontoparietal executive networks have been implicated in conscious emotion regulation and reappraisal, whereas the ACC, I, and Amy are rather implicated in emotional reactivity. In general, studies have found that reappraisal of negative emotion activates dorsal ACC and PFC systems that support the selection and application of reappraisal strategies, and decreases, increases or maintains activity in appraisal systems such as the amygdala or insula in accordance with the goal of reappraisal In contrast, younger older adults reporting higher loneliness showed higher volumes within these brain regions.

This interaction suggest that the negative effect of loneliness is stronger with advanced age. The present study has a set of limitations.