Promoting neuroplasticity and neuropsychological functioning in frailty through an app-based sensorimotor training: study protocol for a randomized trial

The term “frailty” refers to a clinical condition which is characterized by an increased vulnerability to stressors and poor health outcomes resulting from a cumulative decline in multiple physiological systems, such as the musculoskeletal, endocrine, and cardiovascular system [1, 2]. While a continuous decrease in physiological capacity also occurs with normal aging, this decrease is accelerated and exacerbated in frailty [3]. Neuroscientific models of pathological aging suggest that the brain might play a major role in determining healthy or pathological aging [4, 5]. For instance, age-related gray matter reductions in the frontal [6, 7] and medial-temporal [8, 9] regions have been associated with reduced gait and memory performance, while white matter atrophy in the corpus callosum is suggested to affect bihemispheric communication [10, 11]. From a functional perspective, aging is related to reduced neural differentiation and selectivity of perceptual [12, 13] and motor [14] representations. These altered representations in turn are thought to be involved in an age-related decline in cognitive performance, such as memory [15, 16] and sensorimotor performance, including upper extremity function, gait and balance [17, 18]. In this context, an important determinant is “disuse” of the brain, characterized by a reduction of perceptual inputs, motor actions, and cognitive stimulation that are required to refine existing skills and acquire new skills [5]. When people age they tend to stereotype and simplify behaviors and the brain is likely to adapt to these less complex behaviors by simplifying the underlying neuronal representations such as cortical sensorimotor maps [4, 5]. On the neuronal level, “disuse” of the brain is thought to lead to negative changes in neuronal metabolism, such as neurotransmitter production and function [19] and neuronal architecture, including the elaboration of dendrites, spines, and synapses [20]. Therefore, the fidelity and reliability of cortical representations is thought to decline, resulting in noisy neuronal processing in sensory and motor systems, which in turn might promote maladaptive behaviors such as motor instability, coordination deficits, movement slowing, inactivity, and social isolation. Low activity levels lead to an increase in peripheral and bodily symptoms, such as a loss of muscle mass, which would increase the risk of fall and fracture [21]. Together, these interrelated factors create a self-reinforcing downward spiral of altered brain function, physical disability and age-related functional decline.

Therefore, we assume that the brain might be at the center of the vicious cycle of frailty, starting with an initial impairment and leading to an accelerated decline of physical function. As the brain is a highly plastic organ that shows adaptive as well as maladaptive plasticity [22], it might be an optimal target for innovative interventions that utilize principles of neuroplasticity to delay or even reverse cortical and behavioral age-related changes.

To date, the majority of interventional studies in older frail individuals examine physical exercise protocols including aerobic [23] and muscular strengthening exercises [24]. Physical exercise has been suggested to improve physical performance such as muscle strength, balance, and gait speed [25], but also to enhance brain health and plasticity [26]. Physical therapy in pre-frail individuals was found to increase reduced plasma levels of brain-derived neurotrophic factor (BDNF), a neuronal growth factor involved in neurogenesis and synaptogenesis [27], which suggests a key role of neuromodulatory factors in mediating the syndrome of frailty [28]. However, only few of these studies have directly evaluated the influence of physical exercise on frailty itself [29] and the optimal procedure of how to prevent or reverse the syndrome of frailty is still a matter of debate [30, 31]. Moreover, despite the evidence suggesting a close link between structural as well as functional brain changes and physical decline during aging [17, 18], interventional studies targeting the relationship between brain structure and function and frailty are surprisingly rare. In healthy adults, neuroplasticity-oriented programs, including intensive sensory, cognitive, or motor stimulation, were shown to have the potential to strengthen neuromodulatory systems, promote beneficial neuroplasticity in cortical representations, and improve neurocognitive skills that decline with aging [32‐34]. As motivational and affective processes seem to be less affected by maladaptive plasticity [35], these processes provide useful means to enhance training compliance and success. With respect to the multi-system decline observed in frail individuals, computerized neuroplasticity-oriented applications using virtual environments can be more useful because they can stimulate several systems at the same time, can give immediate feedback and permit the use of everyday activities including bodily activation that are relevant for the participant’s life [36]. Therefore, we describe a randomized trial in which we use an app-based multimodal sensorimotor training in frailty.

With the number of older people strongly increasing in almost all countries, frailty prevalence is expected to rise dramatically [2], placing a heavy burden on health and aged care systems [88, 89]. As clinical studies in frail older patients are challenging and still rare, or yielded inconsistent results, procedures to reliably identify early onset stages of frailty as well as appropriate interventions to prevent disability and preserve physical functions are desperately needed.

The objective of our intervention is to increase relevant input into the sensorimotor system in order to engage competitive processes in the brain that refine the representations of sensory inputs and motor actions, thereby increasing the strength of cortical resources and reversing the maladaptive “disuse” of the brain [5]. Therefore, we expect our approach to promote sensorimotor and physical abilities, including motor stability, gait, and extremity function, and to reduce maladaptive behaviors, such as inactivity and social isolation, thereby leading to an improvement in frailty status.

Previous interventional studies in frailty included various types of intervention, such as physical exercise [24, 90, 91], nutritional intervention [92, 93], cognitive training [94], or geriatric assessment intervention [95, 96]. In particular physical exercise interventions demonstrated to be effective in reducing frailty and improving physical performance, while other interventions revealed only small or no training effects [25, 29]. This heterogeneity of study results might be due to differences in the study protocols with respect to training protocol, intensity, frequency, delivering method, and outcome measures. Thus, the reasons why some interventions are effective while others are not still remain unclear. This impedes interpretability and generalizability of the findings [29].

Despite the fact that frailty is associated with a decline in multiple physiological systems [1], the role of the central nervous system and in particular the brain in the pathogenesis of frailty has been addressed in only a small number of studies and still remains unclear. In fact, evidence suggested a link between frailty and brain physiology. For instance, the physical frailty phenotype has been related to reduced cerebellar gray matter volume [97], and some of the phenotype criteria, particularly walking speed, have been associated to regional brain volumes in the prefrontal cortex [6] and corpus callosum [98]. Moreover, evidence suggested a clear link between frailty and cognition, such that the presence of frailty can predict cognitive impairment and neurodegenerative diseases, such as dementia, within a few years [99, 100]. In this context, neurotrophic factors, including BDNF, may play an important role in survival, due to their role in promoting the differentiation of new neurons and synapses [101] and in preventing neuronal death during stress [102]. In fact, physical therapy intervention was found to increase plasma BDNF levels in pre-frail elderly women, suggesting that BDNF may be a key mediator in the pathophysiology of frailty [28]. However, interventional studies in frailty focusing on training effects in the brain are still lacking.

With the current trial, we will employ a multidimensional characterization of frailty, including neurophysiological, physical, sensorimotor, cognitive, and functional variables, which will enable us to investigate training effects on frailty status as well as on frailty-related outcomes. Through our intervention, we will target core central nervous processing in the sensorimotor system, by which we intend to create a link between structural, functional and biological markers of neuroplasticity and potential changes in frailty status. This approach aims at identifying the underlying pathogenic mechanisms of frailty and the results may add to previous interventional studies by offering new possible explanations for training effects found in frailty status and peripheral physical outcomes, such as muscle strength and muscle mass. Moreover, our study will provide new insights into how to prevent the continuous decline and avoid adverse outcomes in the development of frailty. This is important because frailty is a condition, which evolves from a subclinical state into a state of decompensation and ultimately overt frailty in the presence of stressors [103, 104]. Depending on one’s preceding frailty state, transitions between frailty states may occur frequently over time and may also be recurrent, suggesting that frailty is a dynamic process [41]. By including frail as well as pre-frail subjects, we will be able to relate the training effects to changes in frailty status across a broad range of severity levels of pathological aging. In this context, our study might contribute to identify useful strategies, such as the maintenance of sensorimotor stimulation and function, for slowing progression in an early state and preserving older people’s physical functions, autonomy, and quality of life that future studies can be based on.