Physical And Mental Fatigue in Parkinson’s Disease Epidemiology, Pathophysiology And Treatment

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Jau-Shin Lou

Oregon Health & Science University, Portland, Oregon, USA

Abstract

Fatigue is one of the most common non-motor complaints of Parkinson’s disease (PD) patients and is associated with reduced activity and poorer quality of life. Fatigue can be experienced as a state of being tired or weary (subjective fatigue) or as a process of becoming tired or fatigued (fatigability). Subjective mental and physical fatigue are evaluated using self-report questionnaires such as the Multidimensional Fatigue Inventory. Physical fatigability is studied in a laboratory setting using physical exercise protocols and transcranial magnetic stimulation. Mental fatigability is evaluated by measuring attention over time using a reaction-time paradigm called the Attention Network Test (ANT). PD patients report more subjective physical and mental fatigue than controls on a variety of fatigue questionnaires. PD patients have increased physical fatigability in force generation and finger tapping. Levodopa and modafinil improve physical fatigability in PD subjects. Methylphenidate is useful for treating subjective physical fatigue. PD subjects have greater mental fatigability than control subjects and display abnormal performance in all three attention networks in the ANT. Therapies targeting Fatigue is a major problem in Parkinson’s disease (PD) and represent one of the most common non-motor complaints of PD patients.[1] It is also common in conditions such as multiple sclerosis, depression, neuromuscular diseases, renal failure, pulmonary disease, cardiovascular disease, and cancer. Fatigue is also common in healthy older people; up to 18% of normal healthy controls in one study complained of fatigue.[1] Physicians often fail to identify fatigue as a symptom in PD subjects. Shulman et al.[2] prospectively evaluated the diagnostic accuracy in terms of recognizing fatigue, depression, anxiety, and sleep disturbance for neurologists treating 101 PD patients. Their results showed that during routine office visits, neurologists failed to identify the presence of fatigue, depression, and anxiety more than half of the time. Because fatigue can impact on quality of life, it is important for physicians to be more aware of these non-motor symptoms in PD patients.

anti-fatigue and Parkinson’s disease herb: cistanche

1. Defining Fatigue

One of the major challenges in studying fatigue is the lack of a commonly accepted definition of fatigue. Physicians and patients often use the term ‘fatigue’ without defining it. In fact, there is no textbook definition of fatigue. Harrison’s textbook of internal medicine describes chronic fatigue syndrome as ‘‘a disorder characterized by debilitating fatigue and several associated physicals, constitutional, and neuropsychological complaints’’ without defining fatigue.[3] In practice, there are no medical criteria for fatigue. ‘Fatigue’ can have meanings ranging from mental depression to neuromuscular weakness. Defining fatigue has not been satisfactorily attempted in the literature. Establishing a working definition of fatigue is the first important step in researching fatigue. One obstacle in defining fatigue is that the word ‘fatigue’ is used to describe either a trait or a condition that is more or less chronic, whereas a state is a relatively temporary condition. In the body of fatigue research, the term ‘subjective fatigue’ usually refers to the general sensation of tiredness or of difficulty in initiating physical or mental activity experienced by a subject over several days to weeks. This is often assessed by questionnaires completed by the subject. The term ‘fatigability’ refers to difficulty in maintaining the physical or mental activity at the desired level. Physicians are familiar with the fatigability test used to examine a patient who is suspected to have myasthenia gravis. In the fatigability test, the examiner asks the patient to contract a muscle (for example, the deltoid muscle) repetitively and evaluates whether or not the force generated declines after a few repetitions. The muscle test is judged to be ‘fatigable’ if the examiner detects a decline in the force generated. Fatigability occurs in a short period of time; therefore, it can be measured quantitatively in a laboratory setting. It is important to note that subjective fatigue and fatigability are not necessarily correlated. In other words, even if a patient complains that they are ‘tired all the time’, they may perform well on measures of fatigability. Researchers need to be careful to correctly define and interpret findings of subjective fatigue and fatigability.

A second important differentiation is ‘physical’ versus ‘mental’ subjective fatigue and fatigability. Subjective physical fatigue refers to the amount of effort a subject feels he or she needs to complete certain activities, such as performing manual labor, walking, jogging, running, or lifting weights, which require skeletal muscles to generate force. Physical fatigability is the type of fatigability that is caused by motor tasks such as force generation. Subjective mental fatigue refers to the effort a subject feels he or she must put forth to pay attention to tasks. Mental fatigability is the degree of attention a subject can maintain when required to sustain attention or concentration for a certain period of time. Subjective mental and physical fatigue are not always correlated with each other.[4] To the best of the author’s knowledge, no studies have examined the correlation between mental and physical fatigability.

2. Use of Questionnaires to Assess Physical and Mental Fatigue

Subjective fatigue is most often assessed using questionnaires. Both one-dimensional and multi-dimensional questionnaires have been used to assess the presence and prevalence of subjective fatigue in patients with PD. One-dimensional instruments give a single score to indicate the severity of subjective fatigue. Multidimensional fatigue instruments contain several subscales that are usually based on factor analysis.[5] The questionnaires discussed in the following sections are frequently used to assess subjective fatigue in PD.

2.1 One-Dimensional Questionnaires

The Parkinson Fatigue Scale (PFS)[6] is the only scale developed specifically for PD and validated in the PD population in the UK. The 16-item PFS (PFS-16) had its origin in statements made by PD patients who experienced fatigue. It is designed to assess physical fatigue and the impact of such fatigue on patients’ daily function. The scale does not assess aspects of fatigue that are related to cognitive or emotional features. The PFS-16 has good intrinsic properties, test-retest reliability, specificity, and sensitivity. A study to validate the PFS-16 in the US PD patient population has been completed and the manuscript is in preparation (Marsh L, personal communication). The Fatigue Severity Scale (FSS)[7] is a one-dimensional, nine-item fatigue inventory selected from a 28-item questionnaire. Its internal consistency, sensitivity, and test-retest reliability have been validated in patients with multiple sclerosis. The FSS is the most commonly used fatigue questionnaire in medicine. The visual analog scale (VAS)[8] is a simple 10-cm long horizontal line representing the severity of fatigue ranging from 0% to 100%.

2.2 Multidimensional Questionnaires

The Multidimensional Fatigue Inventory (MFI)[5] has 20 items that are divided into five dimensions of subjective fatigue: (i) general fatigue, such as ‘‘I feel fit’’; (ii) physical fatigue, such as ‘‘Physically, I feel only able to do a little’’; (iii) mental fatigue, such as ‘‘It takes a lot of effort to concentrate on things’’; (iv) reduced motivation, such as ‘‘I have a lot of plans’’; and (v) reduced activity, such as ‘‘I feel very active’’. The MFI has good internal consistency, inter-rater reliability, and intra-rater reliability. Several studies of fatigue in PD have used the MFI. The Piper Fatigue Scale[9] consists of 41 VAS representing the temporal, intensity, affective, and sensory dimensions of subjective fatigue. It includes 22 characteristics of fatigue in four different dimensions: (i) behavioural/severity; (ii) effective meaning; (iii) sensory; and (iv) cognitive/mood.[10] The validity and reliability of the Piper Fatigue Scale have been well established in cancer subjects,[9,11] as well as in subjects with myocardial infarction[12] and HIV infection.[13] The author prefers to use the MFI when assessing subjective fatigue in PD subjects because it is a multidimensional questionnaire that therefore allows researchers to examine if subjective physical or mental fatigue plays a more important role in subjects’ fatigue reporting. In addition to the author’s work, the MFI has been used in several recent studies of subjective fatigue in PD.[14-22] Because of its increasing prominence in fatigue research, the MFI should be validated in PD in the near future. Using the MFI allows researchers to parse out differences in the way fatigue is experienced by different patients. It is a powerful tool for quantifying subjective physical and mental fatigue, allowing researchers to examine the mechanisms and potential treatments for subjective physical and mental fatigue independently.

3. Subjective Fatigue in Parkinson’s Disease (PD)

Friedman and Friedman[23] used questionnaires to examine subjective fatigue in PD. They administered four different questionnaires to 58 consecutive PD patients from their movement disorders clinic and to 58 age- and sex-matched control subjects: (i) a 30-item questionnaire modified slightly from that used by Krupp et al.[7] in multiple sclerosis; (ii) the Geriatric Depression Scale; (iii) a VAS for fatigue; and (iv) a VAS for depression. These investigators found that PD patients were more fatigued and depressed than age-matched controls and that 67% of PD patients reported that their fatigue was ‘‘different in quality or severity than the fatigue experienced before’’ PD. Most interestingly, these investigators showed that although subjective fatigue correlated with depression, it did not correlate with disease severity as measured on the Hoehn and Yahr scale. Furthermore, many non-depressed patients had significant complaints about fatigue. Although the 30-item questionnaire contained items on general fatigue, physical fatigue, and mental fatigue, the investigators did not analyze the data categorically. Therefore, they did not demonstrate if PD patients had more subjective mental or physical fatigue. About 44% of 233 patients with PD and 18% of 100 healthy elderly control subjects reported fatigue in a questionnaire survey of a community-based PD population in Norway.[1] The mean (–SD) Mini-Mental State Examination score was 24.4 – 6.9 for the whole group and the mean Hoehn and Yahr staging was 2.9 – 1 for those with fatigue and 2.5 – 0.9 for those without fatigue. The study obtained the scores for subjective fatigue by combining the results from the rating scale for low energy in the Nottingham Health Profile (NHP)[24] with the results obtained from a 7-point scale devised to evaluate fatigue. The investigators found that subjective fatigue was significantly associated with depression, but not with PD severity, use of sleeping pills or dementia. Like Friedman and Friedman,[23] these investigators did not attempt to categorize fatigue. In a questionnaire study using the MFI to examine if PD subjects experience more subjective physical or mental fatigue together with the Center for Epidemiological Studies-Depression Scale (CES-D) to examine the correlation between subjective fatigue and depression, Lou et al.[4] showed that PD patients (mean Hoehn and Yahr score = 2.1) reported more fatigue than normal controls on all of the five dimensions of fatigue in the MFI (figure 1). Twenty-three of 32 PD patients (71.9%) had abnormal subjective physical or mental fatigue.

The severity of physical fatigue did not correlate with the severity of mental fatigue. Depression correlated with all dimensions of fatigue except physical fatigue in the MFI. Disease severity, as measured by modified Hoehn and Yahr staging, did not correlate with any of the measures. The investigators concluded that subjective physical fatigue and mental fatigue are independent symptoms in PD that need to be assessed and treated separately. Subjective fatigue in PD subjects is commonly accompanied by other non-motor symptoms such as depression, anxiety, and sleep disturbance.[4,25] Shulman et al.[25] evaluated 99 nondemented PD patients (mean Hoehn and Yahr score = 2.3 – 0.8 SD) using the Beck Anxiety Inventory, the Beck Depression Inventory, the FSS, and the Pittsburgh Sleep Quality Index (PSQI). These investigators found that 88% of the subjects had at least one non-motor symptom: 40% had fatigue, 36% had depression, 33% had anxiety, and 47% had sleep disturbance (PSQI >5). Fifty-nine percent of the patients had two or more non-motor symptoms and nearly 25% had four or more. Two studies examining the natural history of subjective fatigue in PD have shown conflicting results. In an American study, Friedman and Friedman mailed fatigue questionnaires to 26 non-demented patients from their original cohort 9 years later.[26] They found that subjective fatigue became more severe over time. In addition, those patients who reported fatigue at baseline remained fatigued, whereas those who did not report fatigue at baseline rarely developed fatigue. In contrast, a Norwegian study[27] reported that the incidence of subjective fatigue in PD increased over time. The study followed 233 PD patients for 8 years. Fatigue was measured on a combination of a seven-point scale and parts of the Nottingham Health Profile (NHP) at baseline and after 4 and 8 years. The mean (–SD) Hoehn and Yahr score were 3.1 – 1.1 for patients with fatigue and 2.6 – 1.0 for patients without fatigue.

In patients who were followed throughout the 8-year study period, subjective fatigue increased from 35.7% at baseline to 42.9% after 4 years and to 55.7% after 8 years. Correlation analysis showed that subjective fatigue was related to disease progression, depression, and excessive daytime sleepiness (EDS). About one-third of the patients in this study who reported fatigue had no depression. More than half (56%) of the patients who reported subjective fatigue at baseline had persistent fatigue throughout the study period. However, the investigators concluded that co-morbid factors such as depression and excessive daytime sleepiness are not sufficient to explain subjective fatigue in PD. PD patients with greater subjective fatigue have reduced physical activity, worse physical function[28], and lower quality of life.[29] With the increasing awareness that fatigue is a common and disabling symptom in PD patients, an item in fatigue has been added to the recently finalized Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (UPDRS).[30] The scale will be validated in the near future. In summary, patients with PD report more subjective physical and mental fatigue than normal controls. They also report that their fatigue is different from the fatigue they experienced before they had PD and is usually persistent throughout the disease progression. Subjective fatigue is correlated with depression, anxiety, and sleep disturbance and affects the quality of life. More studies of the natural history of subjective fatigue will be important to determine whether it is dependent on disease progression, symptoms experienced, and other co-morbidity factors such as sleep disturbance and depression.

Fig. 1. Patients with Parkinson’s disease report more fatigue than normal control subjects on the Multidimensional Fatigue Inventory (MFI). (a) Comparison of total MFI scores for patients and control subjects. Patients scored higher than controls, indicating more fatigue. (b) Comparisons of subscores for the five dimensions of the MFI (general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue) for patients and control subjects. Patients were more fatigued on every dimension (reproduced from Lou et al.,[4] with permission). SE = standard error; * p < 0.001, ** p < 0.01.

4. Measuring Physical Fatigability: Finger Tapping and Force Generation

The first step in understanding the pathophysiology of physical fatigability is to measure the fatigability associated with physical activity (such as force generation or a motor task). Researchers have defined physical fatigability as ‘‘the inability to maintain motor performance at the desired level.’’[31] Fatigability can be assessed in a laboratory setting using a motor task or force generation.

4.1 Finger Tapping: a Motor Task to Measure Physical Fatigability

Finger tapping is a motor task commonly used to evaluate the severity of PD and the effects of therapy. Clinically, the subject is asked to use the index finger to tap the thumb and the tapping speed is evaluated as a measure of bradykinesia. Tapping speed may decrease over seconds, a sign of fatigability. In therapeutic trials, finger tapping is evaluated using a mechanical tapper that has two keys 20 cm apart attached to a counter. Tapping speed is obtained by adding the numbers of the two counters together. This method is useful for clinical trials but is limited because it does not measure the change in tapping speed over time. An electronic keyboard equipped with musical instrument digital interface technology is a more powerful tool for studying finger tapping. The author’s laboratory has used this technique to measure physical fatigability objectively in PD.[32] In this task, the subject is asked to press two keys 20 cm apart as fast as possible for 30 seconds. The computer records the time and duration of each keypress. Using these data, we are able to measure instantaneous tapping frequency, dwell time (the duration that a finger is pressing a key), and movement time (the time from releasing a key to the beginning of the next keypress) in order to examine how fatigue develops over a 30-second period.

4.2 Force Generation to Measure Physical Fatigability

Two force-generation protocols are commonly used in the laboratory to assess physical fatigability: the continuous maximum force exercise protocol and the intermittent submaximal force exercise protocol.[33] In the continuous maximum force exercise protocol, the subject generates a sustained maximal voluntary contraction (MVC) of a muscle (for example, the extensor carpi radialis) for a period of time (for example, 30 seconds) and force level is recorded continuously. During a sustained MVC, force declines and fatigue develops over short periods of time (<60 seconds). The maximal force protocol mimics activities such as lifting heavy objects. The area under the force-time curve (AUC) is calculated by a computer. Fatigability is measured by the decay of the maximal force during continuous exercise. Fatigue or fatigability index, a quantitative measure of fatigability, is calculated as the difference between the measured AUC and the hypothetical AUC (i.e. what would have been measured if maximal force was maintained without fatigue throughout muscle activation).[33] In the intermittent submaximal force protocol, subjects generate submaximal contractions intermittently (usually 50% of MVC with three to five repetitions every minute). Performance can be maintained at the target intensity for long periods (10–30 minutes).[33] The submaximal force protocol mimics activities such as walking or cycling. In an intermittent submaximal exercise protocol, we first measure the baseline MVC (BMVC) in the muscles of interest, such as wrist extensors. BMVC is the contraction of the greatest force out of three trials in which a subject performs MVC. Once the BMVC is determined, the subject sustains a contraction of 50% MVC for 7 seconds and rests for 3 seconds repeatedly (i.e. the duty cycle is 70%). The subject attempts to perform an interval MVC (IMVC) every three cycles. This series is repeated until the subject is unable to generate an IMVC above 60% of the BMVC. We use the slope of the IMVCs to measure the fatigability associated with intermittent submaximal force generation.[32,33]

5. Pathophysiology of Physical Fatigability in PD: Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) has been a very useful tool for researchers investigating the pathophysiology of fatigability in PD. TMS is a safe and well-established method for stimulating the motor cortex in awake human subjects.[34] During TMS, a coil is held on the top of the head and an electric pulse is discharged. This pulse flows through the coil and generates a time-varying magnetic field, which in turn induces a current in the brain and excites neurons.[34] Because TMS is noninvasive and painless, it has been used extensively to study corticomotoneuron excitability in humans.[35] In single-pulse TMS, a single stimulation is delivered through a coil over the motor cortex and the motor-evoked potentials (MEPs) are recorded from the muscles of interest. In a typical TMS study, the researchers first determine the threshold required to activate a muscle. The threshold is typically defined as the stimulation intensity (the percentage of the TMS machine’s maximal output) required to evoke an MEP of >50 mV recorded from the target muscle in five of the ten trials. An increase in cortico-motorneuron excitability is defined as a decrease in the threshold or an increase in MEP amplitude when the same stimulation intensity is applied. In normal subjects, intermittent submaximal exercise is accompanied by post-exercise facilitation during exercise[36] and post-exercise depression after fatigue has developed. Post-exercise facilitation refers to the increase in TMS-evoked MEP amplitude relative to baseline during exercise before fatigue develops, whereas post-exercise depression refers to the decrease in MEP amplitude relative to baseline after fatigue. Both post-exercise facilitation and post-exercise depression are most likely mediated by cortical mechanisms.[36,37] PD patients in the ‘off-state have more pronounced post-exercise facilitation and absent post-exercise depression compared with normal controls,[38] according to a TMS study conducted in nine PD subjects (mean Hoehn and Yahr score = 2.2 – 0.7 SD) and eight controls. The researchers used an intermittent submaximal exercise protocol with MEPs recorded from the resting extensor carpi radialis muscle before (baseline), during, and after fatiguing exercise.

The results showed that PD patients in the ‘off-state had increased absolute MEP amplitudes compared with controls. The effect was present in all three exercise periods. A small dose of levodopa/carbidopa (100/25 mg) reduced the MEP amplitudes in PD patients but not in controls (figure 2). Post-exercise facilitation was more pronounced in PD patients before levodopa than in controls, but post-exercise depression was not significantly different between patients and controls. Absolute MEP amplitude showed a negative correlation with physical fatigability (measured by the continuous exercise protocol) in PD patients before levodopa. The investigators concluded that dopamine may play a role in exacerbated physical fatigability in PD because levodopa normalized abnormal corticomotoneuronal excitability in these patients.[38] The underlying mechanisms for the increased MEP amplitude and more pronounced post-exercise facilitation in PD are not clear. One possible explanation is a cortical compensatory mechanism for the dopamine deficiency caused by substantia nigra degeneration. Studies have suggested that compensatory mechanisms for nigral degeneration may extend beyond the basal ganglia and involve the cerebral cortex.[27] Based on the current basal ganglia model,[28] dopamine deficiency in the substantia nigra leads to a decrease in the thalamocortical excitatory input to the premotor and supplementary motor areas, which in turn leads to decreased excitatory input to the primary motor cortex. The increased MEP amplitude and more pronounced post-exercise facilitation in PD patients, which are indicative of increased cortico-motoneuronal excitability, might represent a compensatory mechanism for the reduced excitatory inputs from the premotor and supplementary motor areas. This notion is supported by a functional magnetic resonance imaging study that showed that movement-related neuronal activity is increased in the dorsal premotor cortex.[29] A longitudinal study currently underway in the author’s laboratory is examining how disease progression affects cortico-motoneuronal excitability and physical fatigability. The author has hypothesized that as the disease progresses, the compensatory mechanisms may fail (less increase in MEP amplitude) and patients will have greater physical fatigability.

Fig. 2. Levodopa normalizes cortico-motor excitability in patients with Parkinson’s disease. The absolute motor-evoked potentials (MEP) amplitude before, during, and after exercise in (a) a patient with Parkinson’s disease and (b) a normal control subject before and after administration of levodopa. Note the difference in scales on the y-axis in figures (a) and (b) [reprinted from Lou et al.,[38] copyright 2003, with permission from Elsevier].

6. Treating Physical Fatigue and Fatigability in PD

To examine the impact of levodopa on fatigability in PD subjects, the author and co-workers conducted a double-blind, placebo-controlled, crossover study in PD patients (mean Hoehn and Yahr score = 2.3 – 0.6 SD) who had not taken their regular PD medicines for at least 12 hours.[32] The study measured fatigability associated with finger tapping and intermittent force generation. Finger tapping and force generation were repeated 1 hour after administration of levodopa/carbidopa (100/25 mg) or placebo. Results showed that the slope of dwell time decreased with levodopa/carbidopa (p = 0.004) but not with placebo. The rate of IMVC force decline also decreased with levodopa (p = 0.01) but not with placebo. The author and co-workers concluded that levodopa/carbidopa reduced physical fatigability while the PD patients were in an ‘off’ state and that physical fatigability in PD is at least partially related to dopamine deficiency. A study conducted in the author’s laboratory has demonstrated that modafinil, a drug commonly used to treat narcolepsy, is effective in reducing subjective physical fatigue and fatigability in PD patients when they are taking their regular PD medicines.[39] We randomized 19 PD patients (mean UPDRS score = 34 – 13 SD) who reported significant fatigue on the MFI to modafinil or placebo in a double-blind fashion. Patients remained on their regular medications and took modafinil (100 mg twice daily) or a placebo for 2 months. We used finger tapping and intermittent force generation to evaluate physical fatigability and the MFI to measure subjective fatigue. Patients also completed the Epworth Sleepiness Scale (ESS), the CES-D, and the multi-dimensional McGill Quality of Life questionnaire. There were no significant differences at baseline and after 1 month in finger tapping, MFI score, and ESS score between the modafinil and placebo groups. At month 2, the modafinil group had a higher tapping frequency (p < 0.05), shorter dwell time (p < 0.05), and less fatigue in finger tapping, and tended to have lower ESS scores (p < 0.12), than the placebo group.

At month 2, the modafinil group also reported significantly less physical fatigue than the control group (p < 0.01). We concluded that modafinil reduces fatigability associated with finger tapping and force generation in PD when patients are on their regular PD regimen. Two other studies[40,41] have examined the effectiveness of modafinil in sleepiness in PD patients (mean motor UPDRS score = 26.7 – 9.8 SD;[41] mean Hoehn and Yahr score = 2.0 – 0.5 SD[40]). Both of these studies used the FSS as a secondary outcome measure and showed that modafinil is not effective in reducing subjective fatigue in PD. Neither of these studies examined the effect of modafinil on physical fatigability. A randomized controlled trial has demonstrated that methylphenidate improves subjective fatigue in PD.[14] Methylphenidate inhibits dopamine and norepinephrine reuptake at presynaptic terminals and increases the extracellular levels of both neurotransmitters.[42] In this study, 36 patients were randomized to either methylphenidate (10 mg three times a day for 6 weeks) or placebo.[14] The methylphenidate group (mean Hoehn and Yahr score = 2.38 – 0.3 SD), but not the placebo group (mean Hoehn and Yahr score = 2.58 – 0.5 SD), showed a significant improvement in FSS scores and in general fatigue subscores and total scores for the MFI. The study did not examine the effect of methylphenidate on physical fatigability. In summary, several studies have examined different drugs as treatments for fatigue and fatigability in PD. Levodopa improves physical fatigability in PD when patients are in the ‘off’ state. Modafinil may be effective in reducing physical fatigability when PD patients are taking their regular PD medications. Methylphenidate is also effective in reducing subjective fatigue.

7. Measuring Mental Fatigability: Assessing Fatigability in Mental (Cognitive) Function Using the Attention Network Test

No definition for mental fatigability is currently available. In parallel with the definition of physical fatigability, which is ‘‘deterioration of performance of motor task over an extended period of time’’,[30] the author proposes defining mental fatigability as ‘‘deterioration in the performance of attention tasks over an extended period of time’’. Attention refers to the focused activation of the cerebral cortex that enhances information processing.[43] Because attention is often examined using a reaction time (RT) paradigm,[43] mental fatigability can be quantitatively assessed by measuring RTs or error rates over an extended period of time in an RT paradigm. An increase in RT or error rates over time would indicate mental fatigability. Attention comprises three anatomically defined brain networks: the alerting network, the orienting network, and the executive network.[44] These three attention networks have been related to specific cortical sites and neurotransmitters. The alerting network involves the ability to maintain the alert state. It involves the cortical projection of the norepinephrine system from the locus coeruleus to the parietal and frontal cortex.[45] The orienting network involves the selection of information from sensory inputs. It involves the cortical projection of the cholinergic system from the nucleus basalis to the temporal-parietal junction, superior parietal lobe, and frontal eye fields.[46]

The executive network involves self-regulation of cognitions and conflict resolution. It involves the projection of the dopaminergic system from the substantia nigra to the anterior cingulate cortex and lateral prefrontal cortical regions.[47] The Attention Network Test (ANT) has been developed to provide a behavioral measure of the efficiency of the three attention networks within a single task (figure 3).[48] The ANT is designed to provide an overall evaluation of the attention network with a minimum number of trials. It measures RT in 12 different experimental conditions (three different target types times four different cue conditions). The ANT uses differences in RT derived from the different experimental conditions to measure the alerting, orienting, and executive networks. This test provides outcome measures that indicate the efficiency of the networks that perform the alerting, orienting, and executive (conflict resolution) functions of attention. The ANT has been used as a behavioral test to evaluate the performance of normal children,[49,50] children with chromosome 22q11.2 deletion syndrome,[51,52] adults with borderline personality disorder[53], and patients with schizophrenia.[53] Because PD patients have deficiencies in all three neurotransmitter systems (noradrenergic, cholinergic, and dopaminergic)[54,55] that play crucial roles in the attention networks, we used the ANT (figure 3) to examine the attention networks in PD and to investigate if the ANT is useful for measuring mental fatigability in PD.[56]

Fig. 3. Schematic of the Attention Network Test. In each trial, a fixation cross appears in the center of the screen all the time. Depending on the cue condition, no cue or a cue (center cue, double cue, or spatial cue) appears for 100 ms. After 400 ms, the target (the center arrow), flankers of dashes, or left and right double arrows (neutral, congruent, or incongruent flankers) are presented until the participant responds with a button press, but for no longer than 1700 ms. After the participant responds, the target and flankers disappear immediately and a post-target fixation period continues for a variable duration (total time = 3500 ms) [adapted from Fan et al.[48] with permission]. RT = reaction time.

We administered the ANT to 16 PD patients and nine controls. PD patients were evaluated at two separate visits with (PDmed) or without (PDnomed) their regular PD medications. The patients’ regular PD medicines included different combinations of levodopa/carbidopa, dopamine receptor agonists, and anticholinergics. We used a laptop personal computer with a 15-inch screen to administer the ANT. Our version of the ANT consists of a 24-trial practice block and nine 96-trial blocks (48 conditions: 4 cue types · 2 target locations · 2 target directions · 3 target types, with two repetitions in each block). The ANT used differences in the median RT derived from the different cue and target conditions to measure the alerting, orienting, and executive networks to calculate the following effects. Alerting effect = RTno cue – RTdouble cue (neither of these conditions provided information on the spatial location of the target; the subtraction gave a measure of alerting) Orienting effect = RTcentre cue – RTspatial cue (in both conditions the patient was alerted but only the spatial cue provided spatial information on where to orient) Executive effect = RTincongruent – RTcongruent (five arrows were displayed in both conditions; patients determined if the middle arrow pointed in the same or different direction as the other four).

Our results[56] showed that PD patients, both on and off medication, had longer mean RTs (p < 0.001) and higher error rates (p < 0.001) than control subjects. Both PDmed and PDnomed patients developed more mental fatigability than controls in the nine-block ANT test (p < 0.001). Our results also showed that the alerting, orienting, and executive effects are abnormal in PD. No studies have attempted to treat mental fatigability in PD. Because PD patients have deficiencies in all three neurotransmitters (noradrenaline, acetylcholine, and dopamine) that play critical roles in the attention networks and the ANT showed that PD patients have abnormal alerting, orienting, and executive effects, drugs that interact with these three neurotransmitters have the potential to improve mental fatigability in PD patients. In summary, mental fatigability is a new area of research in which there is much to be explored. The author has shown that the ANT test is a powerful tool for quantifying mental fatigability in PD. PD patients have greater mental fatigability than controls. PD patients also have abnormal ANT scores. It is unknown whether mental fatigability correlates with subjective mental or physical fatigue or physical fatigability. Therapies targeting improvement in individual attention networks may help to improve mental fatigability.

8. Searching for Gold Standards in Assessing Subjective Fatigue and Fatigability – a Major Challenge in Fatigue Research

Several confounding factors make it difficult to develop gold standards for assessing fatigue and fatigability. The first confounding factor is the different constructs of different questionnaires. Many different questionnaires have been developed to assess subjective fatigue. However, different questionnaires have different constructs. They measure different aspects of subjective fatigue with different phrasing, making comparisons between studies difficult. For example, the PFS-16 was designed to measure the physical aspects of subjective fatigue and its impact on daily activity exclusively.[6] The 29-item FSS contains items related to both subjective physicals (‘‘Fatigue interferes with my physical functioning’’) and mental fatigue (‘‘When I am fatigued, I have difficulty concentrating’’).[8] The Piper Fatigue Scale includes 22 characteristics of fatigue in four different dimensions: (i) behavioral/severity; (ii) effective meaning; (iii) sensory; and (iv) cognitive/mood.[10] Because each questionnaire is constructed differently, administering all three to a group of subjects may yield three different scores in fatigue severity. The second confounding factor is the inter-subject variability in assessing individuals’ fatigue. Because a fatigue questionnaire measures fatigue subjectively, the same scores given by two subjects using the same questionnaires may have very different meanings. For example, a marathon runner may give a score of ‘‘I am very tired’’ when she gets winded after running 2 miles compared with 5 miles 1 year previously. In contrast, a bed-ridden patient with congestive heart failure may give a score of ‘‘I am not tired at all’’ on a day when he can get up and walk around the room. Differences in physical fitness may be a reason fatigue questionnaires rarely correlate with measures of fatigability. Deconditioning as a result of disease progression may be another reason PD patients report more fatigue than controls. More in-depth studies of fatigue in PD should help to answer this question, but controlling for physical fitness remains a problem in fatigue research. The third confounding factor is response-shift bias.[57] A shift in response occurs when a subject redefines the sensation of fatigue over time based on a new experience.[58]

As symptoms of fatigue become more severe, a patient may abandon his/her previous experience of feeling ‘‘not at all tired’’, so that the previous response ‘‘a little tired’’ becomes the new ‘‘not at all tired’’. Similarly, a previous ‘‘I am very tired’’ can become the new ‘‘I am moderately tired’’. The fourth confounding factor is the lack of correlation between subjective fatigue and fatigability. The severity of subjective fatigue does not necessarily correlate with that of fatigability in a subject. A patient with more severe subjective fatigue might have less fatigability than another patient who reported less fatigue. Subjective fatigue is measured by questionnaires. Currently available questionnaires often assess the severity of fatigue over days or weeks. For example, the FSS asks patients to complete the questionnaire based on their experience over the past week. The MFI assesses the patient’s feelings about fatigue over the last 2 weeks. In contrast, physical and mental fatigability are measured in a laboratory using tasks that range in duration from <1 minute (such as finger tapping or maximal force generation) to tens of minutes (such as the ANT and intermittent submaximal force generation). Because fatigability is measured over minutes, it may fluctuate during the day. Furthermore, measurement of fatigability depends on patients’ determination to put out their maximal effort. Therefore, a patient who generates a higher maximal force with maximal effort may develop more fatigability than another patient who does not generate ‘real’ maximal force because of lack of effort. For these reasons, subjective evaluation of fatigue based on experience over days therefore may not correlate with fatigability measured over minutes. Developing gold standards to assess the severity of subjective fatigue and fatigability is one of the major challenges in fatigue research. Work to validate questionnaires and develop commonly accepted protocols for studying fatigability is the first step in developing gold standards. When doing this, researchers should be cognizant of the limiting factors outlined in this section.

9. Conclusion Patients with PD report more subjective physical and mental fatigue than normal controls.

Their fatigue is different from that experienced before they had PD, is usually persistent throughout disease progression, and is correlated with depression, anxiety, and sleep disturbance. TMS studies have shown that changes in cortical excitability during fatiguing exercises may be dopamine-mediated. Levodopa and modafinil are effective in reducing physical fatigability and methylphenidate reduces subjective physical fatigue. Mental fatigability is a new area of research and can be measured using the ANT. PD patients have greater mental fatigability and abnormal attention network scores compared with controls. Future research should focus on the natural history of, the pathophysiology of, and the relationship between subjective fatigue and fatigability in PD. A better understanding of these areas is needed to develop effective treatments. The flow chart in figure 4 summarizes how fatigue can be approached systematically. We need to investigate several questions in the future. What is the relationship between subjective fatigue and fatigability (measured by force generation tasks or attention tasks)? What factors predict the development of subjective fatigue and fatigability in PD? Is depression a factor? The author’s data have shown that depression correlates with the severity of subjective mental fatigue but not with the severity of physical fatigue. Can genetic factors play a role in fatigue or fatigability? Does physical deconditioning play a role in fatigue or fatigability in PD? What are the aetiologies of fatigue and fatigability in PD? The author’s data suggest that dopamine deficiency plays a partial role in physical fatigability. How can the adverse effects of dopaminergic agents on cognitive function and mental fatigability be minimized? Almost all dopaminergic agents that improve motor function (and hence reduce physical fatigability) worsen cognitive functions and have the potential to increase subjective mental fatigue or fatigability. Will treatment of depression improve subjective physical or mental fatigue or fatigability? Will exercise reduce subjective fatigue or fatigability?

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