**1. Introduction**

228 Neuroimaging – Cognitive and Clinical Neuroscience

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> The aging human brain undergoes a variety of structural and metabolic changes, often coinciding with, or leading to, cognitive decline (Bullitt et al., 2009). Over the past decade, investigators have been searching for better methods to detect, treat, and prevent cognitive decline. This has lead to the development of a plethora of pharmaceutical approaches with limited success. Identifying non-pharmaceutical approaches for the prevention/treatment of cognitive decline is paramount. Because of its non-invasiveness, neuroimaging is fast becoming a preferred technology for evaluating brain structure and function. In addition, exercise is being recognized as a potential adjunct modality for preventing or reducing structural decline in the brain and perhaps attenuating corresponding cognitive decline. These two methodologies can work in tandem: first, for identification of subtle changes in the brain not detectable via standard cognitive testing and second, for application of appropriate exercise regimes shown to be associated with healthy brain aging. Taken together, disruptions in cognitive function may be delayed, or even halted, but only if intervention occurs "soon enough". The obvious questions to answer are: 1) What is "soon enough"? 2) What type of neuroimaging might be "best"? and, 3) What kind of exercise? Simple questions with no simple answers. This chapter will begin with common, often overlooked issues regarding the use of exercise as a research modality and then progress to incorporating exercise into neuroimaging studies.

#### **1.1 Sedentary and unhealthy**

A sedentary lifestyle, low aerobic fitness and obesity are associated with both cardiovascular and cerebrovascular diseases (Burns et al. 2008). Research over the last decade has shown that 6 months of aerobic exercise may reduce or prevent brain volume atrophy in the prefrontal brain region related to executive function and memory in the aged (Burns et al., 2008; Colcombe et al., 2006; Erickson et al.,2009). It has also been suggested that aerobic fitness and obesity may selectively impact brain regions as well as different hemispheres (Cronk et al., 2009; Gustafson et al., 2004, 2008; Marks et al., 2007, 2010; Raji et al., 2009; Soreca et al., 2009; Ward et al., 2005). For instance, greater aerobic fitness has been moderately associated with greater cerebral white matter integrity in the anterior and middle cingulum regions on the left side of the brain whereas a higher body mass index and higher abdominal girth have been significantly associated with lower cerebral white matter integrity in the posterior cingulum region on the right side of the brain (Marks et al., 2010).

MRI Techniques to Evaluate Exercise Impact on the Aging Human Brain 231

weight lifting. Thus, physical activity or exercise could mean participating in a marathon or dance class, lifting a 10 kg medicine ball, raking leaves, meditating while performing yoga,

Exercise scientists and physical educators continually find themselves clarifying the words that describe their work and this debate has raged for decades. For instance, the term *physical activity* is classically defined as any bodily movement that results in muscular contractions and increases energy expenditure above that which is used during rest (USDHHS/NHLBI, 2008). In contrast, the term *exercise* is defined as "*the regular or repeated use of a faculty or bodily orga*n" (Meriam Webster Free Dictionary, 2011). Thus, the term physical activity is often used due to its broader utility, but the term exercise should be used whenever the researcher's intent is to demonstrate the impact of *repeated exposure* to a *specific type* of physical activity. Therefore, exercise can be considered a structured sub-category of physical activity, with specific dosing parameters that result in health maintenance and/or improvement (Caspersen et al., 1985). The term *fitness,* in biological terms, simply means the ability of an organism to survive and reproduce. This generic term is most often used to connote one's health status and is expanded as needed (i.e., health fitness, physical fitness, aerobic fitness, brain fitness). The American College of Sports Medicine (1990) suggested the following definition be used for *physical fitness*: "fitness is the ability to perform moderate to vigorous levels of physical activity without undue fatigue and the capability of maintaining such ability throughout life." Obviously, this exercise science-based definition can be applied to the neurological system as well, suggesting that *brain fitness* can be defined as *the ability to perform daily cognitive tasks without undue mental fatigue or memory impairment and the* 

Distinctions need to be made between the *acute* versus *chronic* impact of exercise on a physiological system, in this case, the brain. While it is important to know the short-term impact exercise has on physiological systems from a biological or safe participation standpoint, the establishment of long-term health benefits attributed to exercise exposures must account for the chronic adaptations due to historical (i.e., long-term) participation in an exercise regime. It is well-established that exercise is an acute stressor, thereby resulting in (relatively) immediate elevations in blood flow, heart rate, oxygen uptake, respiration, and increased circulation/uptake of most hormones and many metabolic substrates. However, the question remains, do any of these acute exercise responses, when experienced multiple times throughout the week, over several months to many years (i.e., chronic exposure), impact the brain in such a way as to become neuro-protective and prevent or attenuate neurological degeneration and cognitive decline commonly attributed to

Evaluating the brain at one point in time with a selection of a population is a cross-sectional study. One is able to infer relationships between brain structure/function and a host of variables, ranging from cognitive test scores to health fitness ratings. This is an excellent starting point and is where most of the exercise neurobiology literature is currently focused,

or simply walking around a shopping mall.

*capability to maintain cognitive abilities throughout life.* 

**3. Acute versus chronic exercise participation** 

**2.2 Working definitions** 

unsuccessful brain aging?

**3.1 Cross-sectional or outcome study?** 

This of course has implications beyond executive dysfunction; disruption of cerebral white matter integrity in the middle-posterior cingulum regions could impact motor movement, learning, and reading comprehension. Early transcranial doppler studies concluded that aerobic exercise may be beneficial for maintenance of cerebral blood flow (Marks et al., 2000; Orlandi and Murri, 1996). A decade later, cerebral blood vessel morphology studies suggested physically active older adults have younger-looking cerebral vasculature (Bullitt et al., 2009, 2010).

However, the retention and improvement of human brain plasticity via exercise is still not well understood. Despite animal studies demonstrating that exercise may promote neurogenesis, and human studies demonstrating a maintenance/increase in brain volume with exercise (Cotman et al., 2007; Ferris et al., 2007; van Praag et al., 1999), there is little information demonstrating the mechanism(s) for such changes. Furthermore, much of the evidence is equivocal as to whether these brain adaptations, presumably due to physical exercise, equates to improved cognitive function (Colcombe et al., 2003; Etnier and Nowell, 2006; Heyn et al., 2004; Kharti et al., 2001).

These aforementioned discrepancies may be due, at least in part, to the state of flux with research in this area. Numerous neuroimaging techniques are being used and the technology itself is rapidly changing. Cognitive tests commonly used for those with known cognitive deficits may not be sensitive enough to detect subtle cognitive changes in presumed healthy community dwelling elderly. Furthermore, researchers are using a variety of exercise paradigms, some of which are not reproducible due to lack of reporting standard exercise prescription procedures. Other factors such as age, gender, training status, and diet, known to be potential confounders in exercise and aging studies, are often overlooked. Finally, there is confusion in which term to use to simply identify the exercise paradigm itself. All of these factors make comparisons across studies difficult and the ability to draw definitive conclusions impossible (American College of Sports Medicine, 2010; Leasure and Jones, 2008; Lommatzsch et al., 2005).

Therefore, the aims of this chapter are threefold: 1) Clarify the use of exercise, physical activity and related terms as profiling variables versus intervention modalities, 2) Review neuroimaging techniques currently being used to study the impact of exercise and physical activity on the aging human brain structure, and 3) Highlight the pros and cons for use of such methods with exercise paradigms.
