Using one of the largest available datasets (> 40,000 participants), this study dissected the complex interplay between grip strength, behavioral outcomes, and brain structure. We replicated and extended established relationships between stronger handgrip strength and better mental health, both cross-sectionally and longitudinally. Furthermore, we identified novel associations between grip strength and greater GMV across basal ganglia and limbic regions, and we characterized how patterns of regional GMV associated with grip strength were related to various mental health outcomes. Moreover, we demonstrated that mean regional GMV considerably mediates the association between grip strength and several measures of cognition and mental health.
The reported link between grip strength and cognition aligns with previous studies [13, 15, 45], which suggests that grip strength may serve as a complementary measure of cognitive ability in aging adults. Going beyond limited domains or insensitive cognitive measures, we investigated a broader constellation of cognitive metrics spanning domains of memory, executive function, reasoning, and processing speed that are sensitive to subtle, early changes related to aging. In addition, we investigated several behavioral measures that are closely related to health status but have never been directly related to grip strength [12]. Of the 30 behavioral outcomes examined here, reaction time, which reflects cognitive domains of processing speed [37], demonstrated the most robust association with grip strength. As suggested by Joesh et al. [8], the strong association may be partially explained by the high dependence of the reaction time task on motor speed and dexterity, which are closely related to muscular function of hands. Further, in contrast to other behavioral outcomes that were based on self-report, the cognitive task-measured reaction time scores may be more informative in capturing inter-individual variability. Moreover, according to the general slowing theory, the decline in reaction time is a leading and sensitive indicator of cognitive aging and can lead to decrements in other domains like executive functions and working memory [46]. Deficits in processing speed have been observed across many psychiatric disorders, including schizophrenia and other neurodevelopmental disorders [47, 48], and recent work in the UK Biobank suggests that the association between grip strength and reaction time is weaker in individuals with schizophrenia, depression, and bipolar disorder relative to the general population [8, 9]. In addition, we found that the associations between grip strength and mental health outcomes were stronger in females than in males, implying distinct mechanisms between them. Consistently, a recent study [49] based on Mendelian randomization analysis also identified shared pathways between grip strength and depression in females but not in males. In light of this, it is of interest for future investigations to ascertain any gender specificity of the beneficial effects stemming from physical exercise aiming at enhancing muscular fitness.
These findings increased current understanding on the use of grip strength not only as a proxy of physical fitness but also as a malleable indicator for health status in detecting early impairment of specific domains. Unsurprisingly, some of the associations were small and likely due in part to the fact that we controlled for numerous demographic, socioeconomic, and anthropometric measures that are expected to co-occur with health status [50, 51] and muscular strength [27]. Consequently, the association effects should be interpreted as the relevance of grip strength to these mental health outcomes beyond the contribution of covariates [28]. Moreover, this result also implies the power of large samples in identifying subtle effects that may not be detectable in smaller samples.
Our study also provides evidence for the directionality of the connection between grip strength and mental health. Specifically, the longitudinal analyses showed that baseline grip strength was related to cognitive performance at ~9 years follow-up, while the reverse effect was much weaker, and a significant bi-directional relationship was only found for reaction time. This is consistent with most longitudinal findings that implicate stronger grip strength as a protective factor against cognitive decline and dementia [13, 14, 52, 53] but also supports the notion that changes in these two constructs parallel each other over time [19, 54]. This finding supports the utility of grip strength as a potential treatment target for improved cognitive outcomes in older adults. Indeed, a recent intervention study found that 6 months of resistance training, but not computerized cognitive training, can significantly improve global cognition in older patients with dementia [55]. The bi-directional relationship was also encouraging as they implied that interventions that enhance either muscular fitness or cognitive capabilities may generate beneficial effects on the other [3, 19]. Furthermore, we demonstrated significant paths from baseline neuroticism, health and financial satisfaction to subsequent grip strength. As these measures were pertinent to mental health and life satisfaction, it may suggest that people with greater resilience and satisfaction were more likely to engage in physical activities [19]. Together, the behavioral analyses emphasized the need for increased awareness in clinical practice to incorporate muscular strength into routine assessment and provided insights into possible interventions to prevent cognitive decline during aging.
At the brain level, grip strength revealed mostly significant positive correlations with brain volume, which aligns with previous evidence at the global level [23]. As the global GMV is a general reflection of health status and GM atrophy is a signature of neurodegeneration [27, 28], the identified association pattern may suggest that having stronger muscular strength also relates to better overall brain health [22]. Furthermore, given that many regional GM associations reach a significant effect after controlling for the total ICV, it implies that grip strength may exert a region-specific beneficial effect on brain structure. Specifically, prominent among these select regions were the ventral striatum, hippocampus, thalamus, temporal pole, parahippocampal gyrus, pallidum, and putamen, evidencing the possibility that GMV underlies individual differences in muscular strength. These findings accord with previous evidence suggesting the crucial role these subcortical, limbic (especially the hippocampus), and temporal cortices play in muscular fitness [23, 56, 57].
In addition, we showed that the brain association map of grip strength was highly similar to that of the behavioral phenotypes and that the GMV significantly and partially mediated their associations. These findings raised the possibility that common neurobiological pathways underlie individual differences in grip strength and these behavioral outcomes [58]. Indeed, this hypothesis has gained support from neuroimaging studies linking higher grip strength and better cognitive performance to greater brain volume. For instance, a cross-sectional study in 835 older adults observed that weakness in strength was associated with reduced GMV in the hippocampus and fusiform cortex, which were implicated in high-order cognitive processing and social functioning [57]. Similarly, subcortical nuclei degeneration may underlie the pathogenesis of “cognitive frailty,” which was defined as the simultaneous presence of cognitive decline and physical frailty [56]. Also supportive is the finding showing the enhancement of brain plasticity in older adults following physical training [55, 59,60,61]. Specifically, Suo et al. showed that 6-month resistance training improved not only overall cognitive performance but also elicited GM expansion for participants at risk for dementia [55]. This study, together with ours, suggests that the relationship between muscular fitness and mental health may be mediated by increased GMV in regions having high plasticity like the hippocampus.
The present findings are consistent with existing evidence of how musculoskeletal strength relates to brain health. Skeletal muscle plays a crucial role in the production and secretion of many cytokines such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 [14], which are involved in neuronal survival, synaptic development, angiogenesis, learning, and neural plasticity [62]. Higher levels of these peptides have been correlated with greater physical fitness and increased GMV [58], and more importantly, studies showed that resistance activities could stimulate the release of BDNF and evoke neuroplastic changes in frontal and hippocampal regions, which may further translate into cognitive improvements [63,64,65]. Therefore, cytokine-induced alterations in GMV may represent a mechanism through which muscular fitness influences cognition and mental status, yet further research is needed [66].
The results from both cross-sectional and longitudinal analyses indicated a significant association between grip strength and cognitive functioning and mental status. This implies that grip strength can be used as a complementary measure of mental health in aging adults and the routine assessment should be recommended in clinical practice. The large sample size (N > 40,000), sufficient control of confounders (including demographic, anthropometric, and socioeconomic covariates), use of multiple-comparisons correction, subgroup sensitivity analyses, and the longitudinal design ensure our current results are reliable and less likely to suffer from replication failure [67]. Moreover, our results regarding the association between grip strength, mental health, and brain structure are mostly consistent with existing small-sampled studies. There are some limitations to be acknowledged. First, we report statistical mediation effects that are strictly measures of association [39, 68], and causal inferences cannot be drawn from these models without further validation using randomized controlled trials. Nevertheless, these analyses represent a critical first step in characterizing associations between grip strength, brain structure, and mental health that can be further explored in longitudinal studies. To facilitate the use of grip strength in clinical settings, examining how interventions to enhance muscular strength would influence cognition capacities and brain health, especially in people with psychiatric disorders, is necessary. Second, as even small effects can reach statistical significance in a large sample, the magnitude of association may not be directly translated into clinical utility [69]. Third, as noted by Genon et al. [70], brain structure-behavior association studies are suffering from a replication crisis, where a poor replicability has been shown in both behavioral measurements and brain structure estimates. As such, reliability and replicability of the current findings merits further examination in external cohorts with great diversity in geographic, demographic, and sociocultural aspects. Further, going beyond statistical univariate approaches, further studies can take into account the multivariate nature of structural and behavioral measurements by leveraging machine learning techniques within cross-validated frameworks [71,72,73]. For in-depth discussion of this topic, we point the interested reader to [70]. Forth, some of the behavioral outcomes were assessed by ordinal measures, which represent different levels of fidelity [28]. It is possible that assessing these ordinal outcomes using continuous measures would prove more informative. Finally, there may be some other behavioral phenotypes that are related to health outcomes in the UK Biobank but not examined here. Future studies can examine the associations of grip strength with these less-commonly used outcomes.