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The more physical inactivity, the more agitation in dementia

Published online by Cambridge University Press:  03 September 2010

Erik J.A. Scherder ,
Thorsten Bogen ,
Laura H.P. Eggermont ,
Jan P.H. Hamers  and
Dick F. Swaab
Erik J.A. Scherder*
Affiliation:
Department of Clinical Neuropsychology, VU University, Amsterdam, The Netherlands
Thorsten Bogen
Affiliation:
Department of Clinical Neuropsychology, VU University, Amsterdam, The Netherlands
Laura H.P. Eggermont
Affiliation:
Department of Clinical Neuropsychology, VU University, Amsterdam, The Netherlands
Jan P.H. Hamers
Affiliation:
Maastricht University, School for Public Health and Primary Care, Department of Health Care and Nursing Science, Maastricht, The Netherlands
Dick F. Swaab
Affiliation:
Netherlands Institute for Neurosciences, Amsterdam, The Netherlands
*
Correspondence should be addressed to: Professor Erik J.A. Scherder, PhD, Head of the Department of Clinical Neuropsychology, VU University, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands. Phone: +31-20-5988761; Fax: +31-20-5988971. Email: eja.scherder@psy.vu.nl.

Abstract

Epidemiological studies show a close relationship between physical activity and cognition. A causal relationship between physical activity and cognition has been observed in children, adolescents, older people without dementia, and in older people in a very early stage of dementia. Considering these positive effects, we argue that a decline in physical activity has a detrimental effect on cognition and behavior in patients with dementia. Merely living in a nursing home reduces the level of physical activity. The level of physical activity may even be reduced to a minimum when physical restraints are applied. The use of physical restraints coincides with stress, further aggravating the already existing neuropathology, which may increase stress and agitation even more. Exercise may reduce stress and agitation.

Keywords

physical activityagitationdementiacognitionbehaviorstress

Information

Type
Focus on prevention in psychogeriatrics
Information
International Psychogeriatrics , Volume 22 , Special Issue 8: Focus on prevention in psychogeriatrics , December 2010 , pp. 1203 - 1208
Copyright
Copyright © International Psychogeriatric Association 2010

Introduction

A close relationship between physical activities such as walking and cognitive functioning has been demonstrated in epidemiological studies (Rosano et al., Reference Rosano2005; Verghese et al., Reference Verghese, Wang, Lipton, Holtzer and Xue2007). A physically active lifestyle may protect against dementia (Fratiglioni et al., Reference Fratiglioni, Paillard–Borg and Winblad2004; Rovio et al., Reference Rovio2005). Similarly, a decrease in the level of physical activity, such as walking, coincides with a decline in cognitive functioning (Rosano et al., Reference Rosano2005). Epidemiological studies do not show a causal relationship. A causal relationship between physical activity – e.g. exercise improves cognitive functioning – has, however, been demonstrated in children (Tomporowski et al., Reference Tomporowski, Davis, Miller and Naglieri2008), adolescents (Budde et al., Reference Budde, Voelcker–Rehage, Pietrabyk–Kendziorra, Ribeiro and Tidow2008), and older people without dementia (Kramer et al., Reference Kramer1999). The authors indicate that the improvement in cognitive function (e.g. executive functions such as task switching and attention), reflect a positive response of, among others, the prefrontal cortex (PFC). An area that is functionally related to the PFC is the hippocampus, situated in the medial temporal lobe, and crucial for episodic memory (Dickerson and Eichenbaum, Reference Dickerson and Eichenbaum2010). In older persons without dementia, a high fitness level is associated with a larger volume of the hippocampus (Erickson et al., Reference Erickson2009). It is these areas, in particular, that are affected in the most prevalent subtypes of dementia, i.e. Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) (see next section for more details). This might explain why exercise has a beneficial influence on cognitive functioning in older persons at risk for dementia (Lautenschlager et al., Reference Lautenschlager2008) but not in persons at a more advanced stage of dementia (Eggermont et al., Reference Eggermont, Swaab, Hol and Scherder2009). One explanation for these negative findings might be that in a more advanced stage, ischemic lesions in the brain are more frequent, attenuating positive effects of (high) intensity on brain functioning (Eggermont et al., Reference Eggermont, Swaab, Luiten and Scherder2006). Indeed, a (too) high intensity of physical activity might be stressful, increasing the cortisol level (Kudielka et al., Reference Kudielka, Hellhammer and Wüst2009), which subsequently, affects brain regions such as the PFC and hippocampus (see section below on “Physical restraint, stress, and the HPA-axis” for more details).

In addition to an intensity level of physical activity that could be too high for a specific population (e.g. older persons at an advanced stage of dementia), we suggest in the present paper that a decline in physical activity or, even worse, passivity, is detrimental for the already vulnerable brain. This suggestion is supported by animal and human experimental studies. In animal experimental studies, the experimental condition concerns an impoverished environment, characterized by a loss of sensory information and a low level of physical activity. Sensory deprivation, characteristic for a passive apathetic life, reduces information processing in the hippocampus (Bartesaghi et al., Reference Bartesaghi, Raffi and Ciani2006), the PFC (Melendez et al., Reference Melendez, Gregory, Bardo and Kalivas2004), and the amygdala (Nikolaev et al., Reference Nikolaev, Kaczmarek, Zhu, Winblad and Mohammed2002). The latter structure is a medial temporal lobe area, important for the processing of emotional stimuli (Nikolaev et al., Reference Nikolaev, Kaczmarek, Zhu, Winblad and Mohammed2002). Degeneration of the amygdala, but also of the PFC, may contribute to agitation in dementia (Wright et al., Reference Wright, Feczko, Dickerson and Williams2007; Tsoi et al., Reference Tsoi, Baillon and Lindesay2008). In other words, agitation in dementia might be caused by a low level of physical activity.

An explanation for a relationship between agitation and a low level of physical activity might be that, in humans, those with a low level of physical activity show much higher cortisol responses to stress than those who are physically trained (Rimmele et al., Reference Rimmele, Seller, Marti, Wirtz, Ehlert and Heinrichs2009). This means that a sedentary person should preferably live in an environment as stress-free as possible to reduce the negative effects of low physical activity on brain functions. A stress-free environment has been applied in (long-term) space flight studies, examining the effect of bed rest on cognitive functioning (Lipnicki and Gunga, Reference Lipnicki and Gunga2009; Lipnicki et al., Reference Lipnicki, Gunga, Belavý and Felsenberg2009). The results of these studies are inconsistent, i.e. cognition improved, declined or did not change. A striking feature of these studies is heterogeneity in design, data analyses, and participants. In addition, the important issue of practice effects as a result of repeated administration of neuropsychological tests, particularly with respect to tests of executive functions, has not consistently been addressed in these studies. It is important to note that all subjects in the bed rest studies volunteered to participate. They knew in advance about the time they would have to spend in the experimental situation of inactivity; they knew when the state of physical inactivity would end. In other words, these subjects are likely to have an intrinsic motivation different from individuals that do not voluntarily choose an inactive life.

Indeed, an inactive life can also be something one has to accept, because there is no alternative, for example when entering a nursing home. The goal of the present paper is to address the negative effect of living in a nursing home on the level of physical activity and hence on the cognitive and behavioral functions related to the PFC, hippocampus and amygdala; these areas are particularly vulnerable in the most prevalent subtypes of dementia. A dysfunction of these areas, for example by a reduction in physical activity when entering the nursing home, may lead to executive dysfunction, apathy, and agitation. We discuss this issue first; next, we highlight that within the nursing home setting, an almost complete reduction in physical activity is achieved when physical restraints are used. Subsequently, not having the freedom to move often coincides with an increase in stress; stress may further aggravate the already existing neuropathology in dementia and related behavioral disturbances such as agitation. Therefore the relationship between physical restraint, stress and the hypothalamic-pituitary-adrenal (HPA) axis will be briefly addressed. Finally, we suggest ways of treating agitation in dementia.

Institutionalization: its effect on physical activity, cognition, and behavior

We argue that nursing home residents who are left on their own are, to some extent, forced to be physically inactive, even without the explicit use of physical restraint measures (see next section). Without being motivated to participate in activities and, more importantly, continuously being prompted to remain engaged with activities, nursing home residents are very likely to remain inactive and spend most of the their time with no external stimulation. Activity measurements of aged care residents have confirmed this (Egerton and Brauer, Reference Egerton and Brauer2009). Furthermore, a qualitative evaluation of health care facilities has revealed that nursing home residents spend more than 17 hours per day in bed (Bates-Jensen et al., Reference Bates-Jensen2004).

Such a passive environment is detrimental for the active functioning of any person, in particular the active functioning of a patient with dementia. As mentioned before, brain areas such as the PFC, hippocampus, and amygdala that respond positively to physical activity are affected in the three most prevalent subtypes of dementia. A dysfunction of these areas has serious consequences for cognition and behavior. In AD, atrophy of the hippocampus and surrounding areas is observed (Coleman and Flood, Reference Coleman and Flood1987; Braak and Braak, Reference Braak and Braak1991; Uylings and de Brabander, Reference Uylings and de Brabander2002). In mild to moderate AD, a reduction in the plasticity of the medial PFC has been observed (Battaglia et al., Reference Battaglia2007). The consequence is disrupted communication between the hippocampus and the PFC (Wang et al., Reference Wang2006), which affects executive functioning (Grady et al., Reference Grady, Furey, Pietrini, Horwitz and Rapoport2001; Diaz et al., Reference Diaz, Sailor, Cheung and Kuslansky2004; Marczinski and Kertesz, Reference Marczinski and Kertesz2005). The same holds for patients with VaD and FTD. Both subtypes of dementia are characterized by neuropathology in the PFC (Tatemichi et al., Reference Tatemichi, Desmond and Prohovnik1995; Varrone et al., Reference Varrone2002; Rabinovici et al., Reference Rabinovici2007). A deterioration of executive functions, such as taking initiative, results in apathy, a lack of motivation, and agitation (Hodges, Reference Hodges2001; Chan et al., Reference Chan2001; Pugh and Lipsitz, Reference Pugh and Lipsitz2002; Román et al., Reference Román, Erkinjuntti, Wallin, Pantoni and Chui2002; Davies et al., Reference Davies, Graham, Xuerub, Williams and Hodges2004; Tsoi et al., Reference Tsoi, Baillon and Lindesay2008). With respect to agitation, in mild AD agitation is related to hyper-responsiveness/hypersensitivity of the amygdala (Wright et al., Reference Wright, Feczko, Dickerson and Williams2007). The hyper-responsiveness/hypersensitivity of the amygdala might be due to alterations in regions that modulate its activity such as the PFC (Wright et al., Reference Wright, Feczko, Dickerson and Williams2007). Atrophy of the amygdala has also been observed in VaD and FTD (Rabinovici et al., Reference Rabinovici2007; Sachdev et al., Reference Sachdev, Chen, Joscelyne, Wen, Altendorf and Brodaty2007).

Of course, behavioral and psychological symptoms of dementia, such as agitation, are not only due to hyper-responsiveness/hypersensitivity of the amygdala, as mentioned above. Agitation might also result from untreated pain, a noisy overcrowded ward, too little privacy, too high or too low temperatures, sleep disturbances, delirium, depression, violation of personal space (e.g. when bathing, dressing), physical restraint, loneliness, and illness (Haskell et al., Reference Haskell, Frankel and Rotondo1997; Neugroschl, Reference Neugroschl2002; Zuidema et al., Reference Zuidema, Koopmans and Verhey2007; Lemay and Landreville, Reference Lemay and Landreville2010).

Physical restraints: their effect on physical activity, cognition and behavior

By convention, a physical restraint is defined as “a device that is attached . . . and cannot be easily removed by the resident, which restricts freedom of movement and/or normal access to his/her body” (cited in Castle, Reference Castle2006). Given this definition, it becomes obvious that people restrained in this way find that daily routines, such as self-hygiene, dressing, toileting, are no longer possible without the help of another person.

The most common justification for the use of a physical restraint is to prevent falls and reduce agitation, the latter particularly so in patients with dementia. It is still commonly argued that physical restraints protect patients and their environment from serious injury caused by aggressive behavior against others and auto-aggressive behavior (Strumpf and Tomes, Reference Strumpf and Tomes1993; Hamers et al., Reference Hamers, Gulpers and Strik2004; Testad et al., Reference Testad, Ballard, Brønnick and Aarsland2010). Although there is no evidence for the beneficial effects of restraint use, these opinions clearly hinder the reduction or prevention of restraint use in clinical practice (Hamers et al. Reference Hamers, Meyer, Kopke, Lindenmann, Groven and Huizing2009; Huizing et al., Reference Huizing, Hamers, Gulpers and Berger2009). However, evidence shows that when nursing home residents are being physically restrained, cognitive performance, mood and social engagement suffer (Castle, Reference Castle2006). Indeed, individuals who are physically restrained, have fewer opportunities to participate in social encounters (Castle, Reference Castle2006). These patients become increasingly dependent, and mood changes are likely to occur more often as a result of this dependency and their reduced social interaction with other nursing home residents (Depp et al., Reference Depp, Vahia and Jeste2010). Indeed, social activity has been linked to reduced risk for dementia in this context (Buchman et al., Reference Buchman, Boyle, Wilson, Fleischman, Leurgans and Bennett2009). Generally, social interactions are considered to be protective against emotional stress (Loucks et al., Reference Loucks, Berkman, Gruenewald and Seeman2006). However, social interaction has not always been observed to have a positive effect on agitation in dementia. In a study by Burgio et al. (Reference Burgio, Butler, Roth, Hardin, Hsu and Ung2000), agitation was aggravated during interaction with the nurses, and the authors concluded that contact with nurses may invite the patient to express complaints (e.g. about pain), more clearly, causing an increase in agitation. Support for the notion of mood problems has also been found in several observational studies. For example, the use of physical restraints is associated with increased agitation and symptoms that are also observable in post-traumatic stress disorder (PTSD), as well as in tortured persons (Werner et al., Reference Werner, Cohen–Mansfield, Braun and Marx1989; Moss and La Puma, Reference Moss and La Puma1991; Coleman, Reference Coleman1993; Palmer et al., Reference Palmer, Abrams, Carter and Schluter1999; Sullivan-Marx et al., Reference Sullivan–Marx, Strumpf, Evans, Baumgarten and Maislin1999).

Physical restraint, stress, and the HPA-axis

When one experiences stress, corticotrophin-releasing hormone (CRH) is released by neurons in the hypothalamic paraventricular nucleus (PVN), which subsequently causes the production of adrenocorticotropin hormone (ACTH) in the pituitary gland; ACTH induces in the adrenal cortex the release of cortisol into the blood (hypothalamic-pituitary-adrenal (HPA)-axis) (Pruessner et al., Reference Pruessner2010). It is beyond the scope of the present paper to describe this cascade of events in detail. Instead, we briefly present a simplistic model of inhibition and activation of the HPA-axis as a reaction to restraint stress, particularly in relation to the hippocampus, amygdala and medial PFC (mPFC); brain areas that respond positively to physical activity and are affected in dementia.

Several different (sub)cortical networks are involved in the regulation of cortisol in reaction to stress, depending, among others, on the nature of the stressor (Herman et al., Reference Herman, Ostrander, Mueller and Figueiredo2005). Physical restraint in dementia could be considered a type of anticipatory stressor that appeals to a limbic system network, including the hippocampus, amygdala and mPFC, with a physical component (more amygdala) and a psychological component (more hippocampus) (Dedovic et al., Reference Dedovic, Duchesne, Andrews, Engert and Pruessner2009). Particularly as a reaction to restraint stress, the cascade of events in which the hippocampus inhibits HPA-axis activity is as follows. After exposure to a stressor, activity of the HPA-axis in, for example, male mice increases with a subsequent increase in the levels of corticosterone (Furay et al., Reference Furay, Bruestle and Herman2008). Corticosterone subsequently occupies hippocampal glucocorticoids receptors (Furay et al., Reference Furay, Bruestle and Herman2008), initiating a negative feedback which inhibits HPA-axis activity (Dedovic et al., Reference Dedovic, Duchesne, Andrews, Engert and Pruessner2009). Support for a negative feedback from the hippocampus to the HPA-axis has also been found in humans (Tessner et al., Reference Tessner, Walker, Dhruv, Hochman and Hamann2007). In humans, the relationship between the activity of the medial amygdala and the activity of the HPA-axis has not been studied extensively, and seems to be dependent of the type of threat, i.e. psychosocial threat or fear (Dedovic et al., Reference Dedovic, Duchesne, Andrews, Engert and Pruessner2009). In the latter case, activation of the amygdala leads to an increase in HPA-axis activity (Dedovic et al., Reference Dedovic, Duchesne, Andrews, Engert and Pruessner2009). On the other hand, activation of the mPFC may inhibit medial amygdala output, decreasing HPA-axis activity, and consequently, suppressing fear (Akirav and Maroun, Reference Akirav and Maroun2007). Within the scope of the present paper, it is important to note that hippocampal and prefrontal dysfunction may increase HPA-axis activity (Swaab et al., Reference Swaab, Bao and Lucassen2005; Radley et al., Reference Radley, Arias and Sawchenko2006) and that subsequently, an increase in HPA-axis activity may further degenerate these areas (Leonard, Reference Leonard2006). We argue that exercise may reverse this process by stimulating hippocampal and prefrontal cortex functioning. Indeed, agitation has been shown to decrease after participation in an exercise program (Volicer et al., Reference Volicer, Simard, Heartquist, Medrek and Riordan2006).

Conclusions

  • • In children, adolescents, and older people without dementia, physical activity may improve cognitive functioning, in particular executive functions.

  • • Animal experimental studies show a detrimental effect of impoverished environment on the functioning of the PFC and hippocampus, and consequently on cognition and behavior.

  • • Institutionalization and the use of physical restraints reduces and minimizes the level of physical activity, respectively, and together aggravate behavioral disturbances such as agitation.

  • • The restriction of movement, particularly through the use of physical restraints, produces an increase in stress, damaging those regions of the brain that play a role in cognition and behavior, and which are already affected in the early stages of dementia. More stress then follows.

  • • Agitation should not be treated by immobilization but by an increase in physical activity, i.e. by participation in an exercise program.

Conflict of interest

None.

Description of authors' roles

E. Scherder devised the overall plan, wrote the introduction and conclusions, and combined the various sections of the review; T. Bogen wrote the section on physical inactivity in nursing homes; L. Eggermont addressed the effects of physical activity on cognition; J. Hamers wrote the section on physical restraints; and D. Swaab related physical restraints to stress and the HPA-axis.

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