Exercise

Pathophysiology of ADHD

ADHD is the most common neurobehavioral disorder in children and presents a challenging public health concern. Its impact is believed to be underestimated by public health as well as school officials. Genetic analyses, brain neuroimaging, and psychopharmacology have documented a host of neurobiological abnormalities associated with ADHD with no single identifiable etiology. The prefrontal cortex (PFC) is a region of central importance for attentional and inhibitory control and for working memory (Arnsten, 2009; Cohen, Braver, & Brown, 2002). Numerous studies have demonstrated neurochemical and neuroanatomical abnormalities in the PFC in brains of individuals with ADHD (Arnsten, 2009; Berridge & Devilbiss, 2011; Durston & Konrad, 2007).

Effects of Exercise on Neuroendocrine Responses

Exercise results in complex, integrated neuroendocrine adaptive responses with parallel activation of a number of separate responses, including metabolic mediators (regulating carbohydrate and lipid availability and utilization; Comacho, Galassetti, Davis, & Wasserman, 2005; Riddell, 2008), pro- and anti-inflammatory cytokines/chemokines, growth factors, and so on (Meckel et al., 2011). Several of these responses are interrelated, reciprocally enhancing or reducing respective effects. Epinephrine, for instance, is secreted during exercise in a dose-dependent manner relative to the intensity of the exercise challenge (Nemet, Oh, Kim, Hill, & Cooper, 2002), contributing to the activation of cardiovascular adaptation to increased physical work. Metabolically, epinephrine also acutely stimulates endogenous glucose production by the liver and release of nonesterified fatty acids from adipose tissue to match increased metabolic needs. At very high work intensities, however, catecholamine activation becomes disproportionate to exercise level, and excess glucose is mobilized, triggering an insulin reaction possibly resulting, paradoxically, in hypoglycemia at exercise cessation. Recent reports also indicate that epinephrine has a reciprocal stimulatory effect on the secretion of the proinflammatory cytokine interleukin-6 (IL-6; Sondegaard, Ostrowski, Ullum, & Pedersen, 2000; Steensberg, Toft, Schjerling, Halkjaer-Kristensen, & Pedersen, 2001).

Effects of Exercise on Neurotransmitters and Neurotrophins

The benefits of exercise on physical, cognitive, and emotional outcomes are well documented in research on adults (Barbour, Edenfield, & Blumenthal, 2007; Hillman, Erickson, & Kramer, 2008), and evidence of gains associated with exercise is accumulating with similar outcomes in research on youth (e.g., C. L. Davis et al., 2011; Hillman et al., 2009). One respected neurophysiological hypothesis proposed to help understand these benefits is that physical exercise induces increased levels of norepinephrine, dopamine, and serotonin in the PFC, hippocampus, and striatum (Ma, 2008; Meeusen & De Meirleir, 1995; Paluska & Schwenk, 2000) to affect cognitive functioning and mood. It is posited that, as a result of exercise, increased levels of dopamine enhance attention, focus, and acquisition to facilitate learning, whereas increases in norepinephrine improve executive operations, reduce distractibility, modulate arousal, and enhance memory to assist in learning (Wilens & Dodson, 2004; Winter et al., 2007). Thus, similar to stimulant medication, the physiological effects of exercise seem to increase levels of dopamine and norepinephrine, the catecholamines believed to influence information processing in the brain with potential impacts on cognitive functioning and mood (Ma, 2008; Rethorst, Wipfli, & Landers, 2009). Exercise-induced increases in serotonin and endogenous opioids (i.e., endorphins) may further facilitate improvements in affect and attention (Hillman et al., 2008; Paluska & Schwenk, 2000). Serotonin has been shown to modulate aggressive and hyperactive behavior (Pliszka, 2005), induce sleep, and influence mood states (Meeusen & De Meirleir, 1995). Endorphin release in frontolimbic brain areas measured using positron emission tomography has been implicated in the increased euphoria and sense of well-being following sustained aerobic exercise like running (Boecker et al., 2008). Yet, it is still unclear whether such endurance exercise changes mood state by the action of endogenous opioids specifically or in association with the catecholamines. Alternatively, it could be directly related to the exercise or to the act of completing a challenge.

The positive effects of exercise on specific cognitive processes may also be attributed to an upregulation of neurotrophins such as the brain-derived neurotrophic factor (BDNF; Ma, 2008; Seifert et al., 2010; Strohle et al., 2010). BDNF plays an integral role in hippocampal functioning, long-term potentiation for learning and memory, synaptic plasticity, neurogenesis, and neuroprotection (Cotman, Berchtold, & Christie, 2007; Hillman et al., 2008). Decreased central BDNF activity in the midbrain has been implicated in the pathogenesis of ADHD (Lee, Kim, Park, & Kim, 2007), with genetic research documenting increased hyperactivity and cognitive impairment in BDNF knockout mice (Tsai, 2007). Similar to the effects that psychostimulants exhibit, exercise has been found to increase the levels of hippocampal BDNF (Tsai, 2007), and some researchers theorize that exercise-induced increases in BDNF may subsequently facilitate improvements in attention, behavioral inhibition, learning, and affect (Cotman et al., 2007; Hillman et al., 2008; Ma, 2008). Interestingly, despite these benefits, surprisingly few studies have systematically examined exercise physiology in the context of ADHD.

Exercise Physiology and ADHD

In a review of the literature on ADHD and exercise, Tantillo, Kesick, Hynd, and Dishman (2002) integrated the catecholaminergic “bridge” between the physical exercise and ADHD areas of research. This review only included four published studies among which was the authors’ own report of the rate of spontaneous and acoustic startle response eye blinks (motor reflexes sensitive to dopaminergic agonists) and motor impersistence (i.e., the inability to sustain simple motor acts such as maintaining a conjugate gaze) in school-age children diagnosed with ADHD. Tantillo et al. found that a reduction in motor impersistence and increased spontaneous eye blinks were demonstrated among boys after short bouts of vigorous exercise, findings that were not found among girls.

Wigal et al. (2003) studied the physiological cardiorespiratory and hormonal responses during and after exercise tasks in children diagnosed with ADHD compared with control children who did not reach diagnostic criteria for ADHD. Prior to this study, such measurement in a controlled setting never had been made in children with ADHD, let alone those who were stimulant treatment naive. Each child (10 diagnosed with ADHD and 8 age-matched controls) performed a standardized exercise challenge on a cycle ergometer (10, 2-min bouts at 80% of their predetermined maximal capacity, separated by 1-min intervals). An indwelling intravenous catheter was placed in each child prior to exercise to measure physiological responses likely to influence attention and learning, namely, the catecholamines dopamine, norepinephrine, and epinephrine. These measurements were collected at baseline, during the last 2 min of the exercise challenge, and at 30 and 60 min post exercise and allowed for the comparison of relevant responses with moderate-to-vigorous intensity exercise across children with and without ADHD. Baseline levels of dopamine, norepinephrine, and epinephrine were within the normal range in both groups of children; however, resting norepinephrine levels were significantly lower among children with ADHD than among comparison children. Importantly, in children without ADHD, all three catecholamines displayed robust increases induced by exercise. However, in children with ADHD, the increase in circulating epinephrine and norepinephrine was severely blunted, and the increase in circulating dopamine was completely absent. Although this was the first study to systematically measure and compare physiological responses during and after an episode of physical exercise in children with and without ADHD, no cognitive or behavioral measures were included in this study. This clear discrepancy in the catecholamine response, dopamine in particular, may provide the conceptual basis for an exercise-related diagnostic test of ADHD. Thus, the peripherally blunted dopamine response may serve as a biomarker for ADHD. It should be noted that the development of such a biomarker should take into account other conditions in which catecholamine responses may be blunted such as in obesity as discussed in a later section of this article. The question remains unanswered whether greater intensity exercise or sustained exercise or a combination of the two would be necessary for an exercise regimen to increase baseline catecholamine levels as demonstrated in controls and whether such increases are necessary or sufficient to yield behavioral and/or cognitive improvements.

Exercise as a Potential Treatment for ADHD

Physical exercise may be used in multiple ways to complement current therapeutic approaches in the treatment of ADHD by increasing the availability of the monoaminergic catecholamines in the brain. This premise is based on previous research indicating that exercise naturally stimulates adrenoneurogenic mediators that are similar to the pharmacological agents commonly used in ADHD therapy. Children who have ADHD often experience impairments in executive functioning (e.g., working memory), behavioral inhibition, goal-oriented activity, and emotional regulation. These are problem areas that have been found to improve with acute physical exercise (see Davis et al., 2007; C. L. Davis et al., 2011, for such effects in overweight children). Exercise may be advantageous in managing the symptoms of ADHD because the physiological effects of physical activity influence the same catecholaminergic systems that stimulant medications for ADHD target (Tomporowski, Davis, Miller, & Naglieri, 2008).

Although the objective measurement of improved catecholamine secretion with exercise has not been performed in parallel with functional assessments of ADHD in children, several studies have demonstrated a positive association between exercise and a number of outcome measures in children with ADHD. A recent study (Verret, Guay, Berthiaume, Gardiner, & Beliveau, 2012) using a 10-week physical activity program, including 45-min periods of moderate-to-vigorous exercise 3 times per week, led to improved attention, thought problems, and social behavior in children with ADHD. This physical activity program also improved locomotor skills, which may be impaired in children with ADHD. Daily moderate-to-vigorous physical activity has also been associated with better performance in children with ADHD on the Tower of London planning task, which assesses executive function deficits specific to planning abilities (Gapin & Etnier, 2010). Taken together, this sampling of studies on exercise in children with ADHD provides potential outcome measures in the various domains affected by ADHD (e.g., attention, behavior, social skills, academics, and clinical severity of ADHD symptoms).

Findings from empirical cross-sectional studies of typically developing children without a history of ADHD offer support for short physical activity breaks before/during class as helping improve children’s ability to focus and stay on task. Mahar and colleagues (2006) assessed classroom behaviors in elementary school children 30 min immediately before and 30 min immediately after 10 min of a daily classroom-based physical activity break. They found that the children who engaged in the daily in-class “Energizers” activities (i.e., physical exercise integrated with grade-appropriate academic instruction) showed an increase in subsequent on-task classroom behaviors and were significantly more active across each school day (assessed with pedometers) than were children who did not participate in these daily physical activities. Interestingly, the students who were the least on task before the classroom intervention showed the greatest behavioral improvements. In a 2-week intervention among children ages 8 to 11 years, Hill et al. (2010) demonstrated pre- to postdaily improvements in cognitive tasks selected to specifically assess children’s attention and executive function (e.g., paced serial addition, backward digit-span) after 15 min of classroom-based physical activity (e.g., running in place, hopping sequences to music). Given the heightened disruptive behavioral problems as well as cognitive and academic difficulties that many children with ADHD tend to experience, links between exercise and improved problematic behaviors, and cognitive functioning may have particularly meaningful implications for this population of children. Surprisingly, limited studies have examined the theoretical and clinical assertion that exercise could potentially help manage symptoms of ADHD.

Benefits for children who have ADHD could derive from the acute effects of single exercise bouts as well as the prolonged effects of structured exercise training regimens with additive effects of acute “doses” of exercise. Lambourne and Tomporowski’s (2010) recent meta-regression analysis demonstrated that, regardless of the type of physical activity, individuals’ cognitive performance is improved beyond preexercise levels when tested after 20 min of exercise. Increased arousal and blood flow in the PFC during exercise are thought to augment cognitive processes to facilitate performance on tasks assessing executive functioning (i.e., information processing, response speed, and decision making). Similar to stimulants, cognitive processes and behaviors return to preexercise levels once the exercise-induced effects on the central nervous system are no longer sustained; however, cognitive performance, and memory storage and retrieval may be enhanced during the postexercise period until the effects of the exercise-induced arousal dissipate (Lambourne & Tomporowski, 2010). It is during this period of arousal that memory processes may be altered by exercise to facilitate the retention of information and acquisition to learn in response to novel stimuli. Theoretically, the cumulative effects of learning acquired across repeated, single bouts of exercise may, over time, influence more stable changes in cognitive processes (Pesce, 2009). Although this speculation appears promising, careful, systematic studies must be designed and implemented to identify the specific exercise parameters (e.g., type, duration, intensity, frequency) that yield the best outcomes; to better define the postexercise time window of improved functioning; and to identify the biochemical mechanisms underlying specific functional improvements, including the actual role of altered catecholamine metabolism. One might speculate that the catecholamine activity underlying these changes may accumulate over time in response to alteration across repeated acute bouts of exercise or with sustained exercise either in parallel or antecedent to cognitive and behavioral changes. It should be noted that most studies of naturalistic or laboratory-based short-term exercise do not report children’s everyday level of habitual physical activity such as sports participation. Individual differences in regular physical activity, sedentary behavior, and overall conditioning and physical fitness may be key mediators to explore in the relationship between acute exercise and positive outcomes in youth.

Few studies have examined the physiological changes that accompany exercise among children with ADHD, particularly in relation to catecholamines. Although a growing body of research suggests a shared physiological mechanism underlying the cognitive improvements associated with acute exercise and psychostimulants, it is possible that cognitive improvements following exercise may not be dependent on increased catecholamine availability. A recent study found no group differences in the cognitive performance of (stimulant) medicated versus unmedicated children diagnosed with ADHD after 30 min of moderately vigorous exercise, yet improvements in sustained attention, impulsivity, and response speed were demonstrated across both groups of children regardless of stimulant treatment (Medina et al., 2010). In other words, children receiving pharmacological treatment known to elevate catecholaminergic activity still benefited from acute exercise similar to their unmedicated diagnosed peers; however, physiological measurement of catecholamines in response to exercise was not assessed in the Medina et al. (2010) study.

From this very succinct and incomplete overview, it is already apparent how an alteration in the magnitude and intensity of the catecholamine response to exercise may affect a number of related adaptive systems (see Figure 1 for a conceptual overview).

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Figure 1.

Overview of potential effects of exercise on PFC and behavior.

It is therefore logical to expect that in a condition such as ADHD, in which a catecholamine metabolism defect is presumed to be at the very base of the pathology, exercise-induced modulation of catecholamine release may play a role in pathogenesis and therapeutic strategies.

Insights on Applying Exercise Challenges to ADHD From Diabetes and Obesity Research

The findings highlighted in the prior section indicate the need for a better understanding of the role of catecholamines in response to physical activity among those with ADHD and, moreover, the extent to which other biochemical factors may influence cognitive, behavioral, and emotional outcomes. ADHD shares a number of features including the blunting of catecholamine responses and health risks related to abnormal physical activity levels with other common pediatric conditions that have been broadly studied. Therefore, additional indirect evidence for the potential effectiveness of exercise as a therapeutic tool for ADHD may be acquired from studies of other metabolic conditions in relation to exercise and underlying physiology.

Other than the initial findings from the Wigal et al. (2003) study mentioned earlier, however, very little is currently known on the extent and characteristics of catecholamine release during exercise among individuals with ADHD. A considerable amount of relevant information, however, that could help design further studies and hypothesize at least the basic components of therapeutic interventions in ADHD, can be inferred from studies on children with other conditions also resulting in altered catecholamine responses to exercise. For these inferences to be valid, it is important that the format of exercise testing is carefully standardized. In the study mentioned above, for instance, methodology was borrowed from basic exercise physiology, using a well-established exercise protocol, depicted in Figure 2, which has been documented to fully activate most key adaptive exercise responses (Rosa et al., 2011; Schwindt et al., 2010). An additional advantage of this format is that it is easily accepted by children and reproduces the basic stop-and-go pattern of “real-life,” aerobic physical activity achieved during organized sports or a dance class.

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Figure 2.

Schema for measuring circulating catecholamines and other potential physiological mediators following exercise.

An important concept in the field of altered exercise responses is the dichotomy between permanent and reversible alterations. A good representative example is the catecholamine response to exercise in type 1 diabetes. Catecholamines are part of the neuroendocrine response to stress that is altered when diabetic autonomic neuropathy becomes established in patients who had poorly controlled diabetes for many years (Bottini et al., 1997). In these patients, therefore, when exercise is initiated, the expected, physiological rise in epinephrine and norepinephrine (and possibly dopamine) does not occur, or is severely blunted, causing insufficient availability of glucose to the exercising muscle, thereby favoring onset of hypoglycemia and often severely limiting exercise performance. As diabetic autonomic neuropathy is irreversible, this catecholamine response is permanently lost in these patients (Bottini et al., 1995).

Obese patients also display permanently reduced catecholamine responses (including dopamine) to exercise (see Figure 3; Eliakim et al., 2006). Obesity per se is not an irreversible condition; physiological catecholamine responses could be restored after weight loss; however, this has not been demonstrated experimentally to date. The parallels between obesity and ADHD are several. First, considering the exponential increase in the prevalence of pediatric obesity in Western societies, a growing share of ADHD children are likely to be overweight, with possible synergistic effects on catecholamine secretion. For instance, 38% of children in the state of California in more than 250 cities are overweight or obese as reported by the California Center for Public Health Advocacy and the UCLA Center for Health Policy Research (http://www.publichealthadvocacy.org/research_overweight2010.html, accessed on June 7, 2012). The percentage varies from county to county as well as in different areas of cities within the same county, in this study, funded by the Robert Woods Johnson Foundation of 5th, 7th, and 9th graders with rates ranging from 11% to 53%.

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Figure 3.

Reduced catecholamine responses (including dopamine) to exercise in patients with ADHD (left panels adapted from Wigal et al., 2003) and in obese patients (right panels adapted from Eliakim et al., 2006) compared with controls.

Furthermore, in obesity, growth factor responses to exercise are reduced in a parallel manner to catecholamine responses. In particular, the growth hormone (GH) response to exercise has been shown to be blunted in a dose-dependent manner with increasing severity of obesity (Oliver et al., 2010) and, even in healthy children, could be acutely blunted by the ingestion of a fat-rich meal before exercising (see Figure 4; Galassetti et al., 2006).

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Figure 4.

Dose-dependent blunting of GH response to exercise with increasing severity of obesity (top panel adapted from Oliver et al., 2010) and with ingestion of a fat-rich meal prior to exercising in healthy children (bottom panel adapted from Galassetti et al., 2006).

These specific GH effects on the insulinlike growth factor–1 (IGF-1) axis have not been tested in ADHD participants. Yet, it is intriguing that altered growth patterns, either related to baseline GH levels in stimulant naive children or especially relating to stimulant therapy in exposed children, are current major issues in ADHD management. These topics are reserved for a separate article to focus on the topic at hand.

Alterations in catecholamine responses to exercise can also be transient and fully reversible. Returning to our earlier example of impaired catecholamine secretion in diabetic autonomic neuropathy, fortunately many patients can now avoid this complication through aggressive glycemic control strategies. Even these patients, however, may experience transient reductions in catecholamine responses after specific blunting stimuli, of which the best described is hypoglycemia (Cryer, 2001). During a significant drop in blood glucose (down to ~50 mg/dl), the hypothalamic–pituitary–adrenal axis is strongly activated, resulting, among other effects, in binding of several subtypes of hypothalamic steroid receptors, through which the efferent hypothalamic impulses are regulated (Arbelaez, Powers, Videen, Price, & Cryer, 2007). Even after the hypoglycemic episode is resolved, this hypothalamic receptor binding will prevent full activation of hypothalamic-triggered responses over the following several hours, possibly days. Therefore, if during this time span patients engage in intense exercise activities, their catecholamine response will be significantly reduced (as well as other adaptive response, such as the glucagon, cortisol, and GH responses; S. N. Davis, Galassetti, Wasserman, & Tate, 2000; Galassetti et al., 2003). If sufficient time elapses after the prior hypoglycemic episodes, catecholamine responses return to normal. However, in many patients hypoglycemia occurs often, and the blunting of the catecholamine and other response render further hypoglycemia more likely to occur, de facto establishing a vicious cycle in which the physiological responses are continuously blunted. Although hypoglycemia is not an issue in the management of ADHD, some of the above concepts may be relevant to ADHD children, as the underlying mechanism triggered during hypoglycemia, such as activation of the hypothalamic–pituitary–adrenal axis (i.e., Volkow et al., 2011), is shared by other stimuli. It has in fact been clearly documented that a prior intense emotional experience (Seematter, Battilana, & Tappy, 2002), or a prior intense exercise challenge (Sandoval, Guy, Richardson, Ertl, & Davis, 2004), also result in significant blunting of catecholamine and other physiological responses to a stress occurring during the following hours to days. This “interchangeability” of the prior blunting stimulus may suggest that yet other factors may be at play (especially emotional/psychological elements), possibly further modulating the presence and the magnitude of alterations in catecholamine secretion in ADHD and other children, in basal conditions or in response to specific triggers. It must also be noted that both the absolute magnitude of catecholamine response to exercise (S. N. Davis et al., 2000) and the extent of their blunting after appropriate prior stimuli (Galassetti et al., 2001) are strongly influenced by gender in sexually mature individuals, with women displaying in general smaller responses and less blunting as compared with men. Although this may not concern prepubertal participants, it may add another layer of complexity in understanding adolescent patients with ADHD.

A distinction must be made between the effects on catecholamine secretion of an acute exercise bout or a prolonged exercise regimen. Most of the considerations reported above about exercise responses concern acute catecholamine secretion after an isolated exercise challenge and its possible permanent or reversible alterations after prior acute blunting stimuli. Prolonged exercise programs, however, affect not only the acute catecholamine response to each new exercise bout but also the resting systemic rates of catecholamine secretion. Interestingly, these effects appear to develop in opposite directions: While training reduces the magnitude of the catecholamine response to a comparable exercise challenge, it also increases the basal resting catecholamine levels (an important concept for the use of training regimens in ADHD; Zouhal, Jacob, Delamarche, & Gratas-Delamarche, 2008). The reasons for this discrepancy are complex, but a similar dichotomy between acute and chronic effects of exercise has also been reported in a number of other exercise responses such as secretion of inflammatory and oxidative stress mediators (Cooper, Nemet, & Galassetti, 2004).

Concluding Remarks

A thorough understanding of possible mechanisms blunting the acute exercise response of catecholamines in children with ADHD, such as those in place in obese and diabetic patients, would also help optimize the magnitude and stability of intervention results. Physical activity is slowly being integrated in school curricula in only certain schools and school districts, in increasingly sophisticated ways, aimed at maximizing its beneficial effects in the general student population. For instance, students in Saskatoon, Saskatchewan, Canada, school systems have access to treadmills and stationary cardiovascular equipment during instructional classroom time (see this and other successful school fitness models at http://sparklinglife.org). Imple-mentation of specific exercise regimens tailored for ADHD children (in terms of format and timing with respect to other school activities as determined in laboratory school studies; Wigal et al., 2007; Wigal & Wigal, 2006) is not unrealistic even in large public schools.

Long-term exercise interventions, however, should be aimed at achieving sustained and constant improvements in ADHD symptoms through a stable increase in catecholamine levels, independent of individual exercise bouts. Although prior evidence suggests that this is a reasonable target, again characterizing the most effective exercise strategies (e.g., intensity, frequency, and duration) and promoting habitual physical activity through organized sports, for example, to help manage symptoms of ADHD will require a considerable amount of future work. Considerations include that different types/duration of exercise may be necessary at younger rather than older ages, possibly across genders, and in participants with different degrees of functional impairment. It is also conceivable that acute and long-term effects of an exercise regimen may be integrated in a synergistic manner, that is, using an exercise design aimed at long-term, stable improvements, but in which the individual exercise components are timed so that the immediate, short-term benefits of each bout are also enjoyed, and overlap with an improved, long-term basal status.

Finally, ADHD is now recognized as a lifelong disorder. Therefore, a wide-ranging patient base stands much to gain from an alternative and/or complementary treatment such as exercise with minimal risks imposed. The rigorous study of exercise training to understand its efficacy and utility as a model of underlying physiology in ADHD has yet to provide such answers sufficiently.