New Directions in Exercise Prescription: Is There a Role for Brain-Derived Parameters Obtained by Functional Near-Infrared Spectroscopy?

In the literature, it is well established that regular physical exercise is a powerful strategy to promote brain health and to improve cognitive performance. However, exact knowledge about which exercise prescription would be optimal in the setting of exercise–cognition science is lacking. While there is a strong theoretical rationale for using indicators of internal load (e.g., heart rate) in exercise prescription, the most suitable parameters have yet to be determined. In this perspective article, we discuss the role of brain-derived parameters (e.g., brain activity) as valuable indicators of internal load which can be beneficial for individualizing the exercise prescription in exercise–cognition research. Therefore, we focus on the application of functional near-infrared spectroscopy (fNIRS), since this neuroimaging modality provides specific advantages, making it well suited for monitoring cortical hemodynamics as a proxy of brain activity during physical exercise.


Introduction
There is a robust body of literature suggesting that regularly conducted physical activity (typically engendered through regular physical exercise) promotes brain health and cognitive performance regardless of age [1][2][3][4][5][6][7][8][9][10][11]. However, the multilevel mechanisms driving exercise-induced neurocognitive changes across different age groups are not well understood [7,12,13] and little is known about which exercise prescription (e.g., intensity, duration, type of exercise) might be optimal to promote neurocognitive changes [1,7,8,[14][15][16][17][18][19][20][21][22][23]]. An adequate exercise prescription is the key to appropriately (i) In CW-NIRS devices, the changes in light intensity (i.e., attenuation) are used to calculate the relative concentration changes in chromophores (e.g., oxyHb and deoxyHb) [98,171,174,180,181]. Light with a distinct intensity is emitted into the tissue (e.g., brain and scalp tissue) via an emitter (e.g., placed on the scalp) and the non-absorbed light components leaving the tissue at a distinct point are measured via a detector, from which the intensity of outgoing light is obtained. By using CW-NIRS, changes in the attenuation coefficient can be calculated and used to determine the relative concentration changes in the chromophores (e.g., relative to baseline) [171,182].
(ii) SRS-NIRS is a special type of CW-NIRS. In SRS-NIRS, at least two detectors (e.g., placed on the head surface) are used to measure the light which leaves the examined tissue after traveling through it (e.g., brain and scalp tissue) [183]. The information of the two detectors is used to determine the local gradients of light attenuation which, in turn, can be used to calculate the absolute concentration changes in chromophores (e.g., oxyHb and deoxyHb) and the tissue oxygenation index (TOI) [184,185]. TOI is the ratio of oxyHb to total hemoglobin (sum of oxy-and deoxyHb) and is also known as the tissue saturation index (TSI) and regional tissue oxygen saturation (StO2, and rSO2).
(iii) In FD-NIRS, the source(s) (e.g., placed on the scalp) continuously emit(s) light with a distinct intensity into the tissue, whose amplitude is modulated at a specific frequency in the MHz range. A detector (e.g., placed on the head's surface) measures the phase shift (delay) and light attenuation of the measured and non-absorbed light components, which, in turn, are With regard to the technical implementation of (functional) near-infrared spectroscopy ((f)NIRS), it is important to emphasize that the following four different methods exist. These different methods have unique advantages and disadvantages with respect to the usage in the field of exercise(-cognition) science: (i) continuous-wave NIRS (CW-NIRS), (ii) spatially resolved NIRS (SRS-NIRS), (iii) frequency domain NIRS (FD-NIRS) and (iv) time domain NIRS (TD-NIRS).
(i) In CW-NIRS devices, the changes in light intensity (i.e., attenuation) are used to calculate the relative concentration changes in chromophores (e.g., oxyHb and deoxyHb) [98,171,174,180,181]. Light with a distinct intensity is emitted into the tissue (e.g., brain and scalp tissue) via an emitter (e.g., placed on the scalp) and the non-absorbed light components leaving the tissue at a distinct point are measured via a detector, from which the intensity of outgoing light is obtained. By using CW-NIRS, changes in the attenuation coefficient can be calculated and used to determine the relative concentration changes in the chromophores (e.g., relative to baseline) [171,182]. (ii) SRS-NIRS is a special type of CW-NIRS. In SRS-NIRS, at least two detectors (e.g., placed on the head surface) are used to measure the light which leaves the examined tissue after traveling through it (e.g., brain and scalp tissue) [183]. The information of the two detectors is used to determine the local gradients of light attenuation which, in turn, can be used to calculate the absolute concentration changes in chromophores (e.g., oxyHb and deoxyHb) and the tissue oxygenation index (TOI) [184,185]. TOI is the ratio of oxyHb to total hemoglobin (sum of oxyand deoxyHb) and is also known as the tissue saturation index (TSI) and regional tissue oxygen saturation (StO 2 , and rSO 2 ). (iii) In FD-NIRS, the source(s) (e.g., placed on the scalp) continuously emit(s) light with a distinct intensity into the tissue, whose amplitude is modulated at a specific frequency in the MHz range. A detector (e.g., placed on the head's surface) measures the phase shift (delay) and light attenuation of the measured and non-absorbed light components, which, in turn, are used to determine the absorption and scattering properties of the specific tissue (e.g., brain tissue).
Using the individual-specific information about the scattering and absorption properties of the distinct tissue allows the quantification of absolute concentration changes in the chromophores (e.g., oxyHb and deoxyHb) [98,171,174,180,181,186,187]. (iv) In TD-NIRS, multiple sources emit extremely short light impulses into the tissue (e.g., brain and scalp tissue) and detectors, placed at a certain distance from the light emitting source, quantify the time of flight, the temporal distribution, and the shape of the temporal distribution of the non-absorbed photons, which leave the examined tissue (e.g., brain and scalp tissue). The information about the time of flight, temporal distribution, and shape of the temporal distribution of the non-absorbed photons are used to determine the scattering and absorption properties of the distinct tissue (e.g., brain tissue). In general, photons that travelled through the cerebral tissue are more delayed than photons that are only traveling through the scalp.
The obtained information about scattering and absorption enables the calculation of absolute concentrations changes in chromophores (e.g., oxyHb and deoxyHb) [98,171,174,180,181,186,187].
With regard to the application of fNIRS in the field of exercise science (in particular to prescribe exercise), SRS-NIRS is the most promising of the four NIRS methods. SRS-NIRS allows, compared to CW-NIRS, the quantification of absolute changes in the concentration of chromophores [184,185], and, compared to FD-NIRS and TD-NIRS, SRS-NIRS devices are less expensive, have a higher acquisition rate, and are less bulky [98,180,188]. Furthermore, TD-NIRS suffers from the drawback that it is not able to detect small functional activation changes due to its working principle, which is based on time of flight photon detection. The latter returns a noisier parameter compared to SRS-NIRS, which is based on light attenuation measurement [171,180,188]. Moreover, multi-distance configurations of NIRS channels, as used in SRS-NIRS, allow measurements that are more robust against motion artefacts, resulting in a more stable acquisition of the signals [184]. In addition, in the field of exercise science, NIRS systems with LED sources (e.g., SRS-NIRS) are more suitable because they allow smaller and portable instrumentation and are safer in their application, as compared to NIRS systems with laser sources (e.g., FD-NIRS and TD-NIRS) [171,189]. More detailed information about the differences between CW-NIRS, SRS-NIRS, FD-NIRS, and TD-NIRS can be found in the referenced literature [98,171,174,180,181,183,185,186,[190][191][192][193][194][195][196].

Advantages of Brain-Derived Indicators of Internal Load
In this section, we discuss the advantages of brain-derived indicators of internal load to prescribe physical exercise in exercise-cognition research. Therefore, we focus on the exercise variable exercise intensity because a full discussion of all exercise variables is beyond the scope of this perspective article. It is undoubted that the established approach prescribing the exercise intensity using specific indicators of internal load, such as percentages of maximal heart rate (HR max ) or maximal oxygen uptake (VO 2 max ), which were obtained during a preceding graded exercise test, has its merits. However, this established approach for the prescription of exercise intensity can cause a considerable amount of interindividual heterogeneity in neurocognitive outcomes [15]. Hence, we recommend alternative approaches to exercise prescription, which make use of specific indicators of internal load, and which are known to be causally related to the intended outcome [15]. In this respect, fNIRS-derived brain parameters (e.g., oxyHb, deoxyHb, totHb, or StO 2 ) can be a promising option for prescribing exercise intensity because they are more closely related to the organic system which is intended to be modulated (i.e., brain). This assumption is supported by the evidence outlined in the following: (a) cortical hemodynamics are sensitive to the level of physical load (e.g., exercise intensity) [125,126,128,139] and a decline in prefrontal oxygenation (i.e., oxyHb and StO 2 /TOI) at very high exercise intensities was observed [126,158,164,197,198]. The latter corroborates the notion of a "central governor" limiting maximal exercise performance [198][199][200][201][202][203][204][205], (b) cortical hemodynamics are sensitive to the influence of psychophysiological parameters (e.g., exercise tolerance) [129,206], Brain Sci. 2020, 10, 342 6 of 23 (c) cortical hemodynamics during physical exercise are indicators of responsiveness, as levels of oxyHb in the right ventrolateral prefrontal cortex (PFC) during exercise are higher in individuals who show superior performance in a spatial memory task (e.g., being responders) after an acute bout of physical exercise [207], (d) the level of cortical hemodynamics during physical exercise might act as an indicator of the optimal brain state since lower levels of oxygenated hemoglobin in the PFC during physical exercise were associated with slower reaction times in an executive function task (i.e., Stroop task [208]. Regarding (c) and (d), comparable findings have, to the best of our knowledge, not been reported for conventional parameters of exercise prescription (e.g., heart rate (HR)) when neurocognitive outcomes were considered. Hence, (c) and (d) of the above-mentioned points especially support the idea that brain-derived parameters may be superior when prescribing physical exercise (e.g., exercise intensity) in the setting of exercise-cognition research. Moreover, commonly used conventional parameters of exercise prescription, such as HR, also suffer from the drawback that they are not able to sufficiently reflect psychophysiological responses to non-cardiorespiratory demands (e.g., cognitive load), which are posed by non-endurance exercises, such as simultaneous motor-cognitive exercise (e.g., dancing [14]). However, these demands are mirrored in brain-derived measures. Regarding fNIRS-derived brain parameters, it was reported that they are sensitive to: (e) the level of cognitive load [209][210][211][212]], (f) the level of cognitive fatigue [213][214][215], (g) the influence of stress [216][217][218][219][220], (h) the influence of expertise level [104,122,212,221] or skill level [106,222], (i) training-related changes in motor-cognitive performance [105,117].
Accordingly, the provided evidence further buttresses the idea to use brain-derived parameters in exercise prescription. Brain-derived parameters, as compared to conventional parameters, have, at least theoretically, an added value in exercise prescription. Both the monitoring of brain parameters (e.g., during the course of a physical intervention) and the use of brain parameters to prescribe physical exercises (i.e., exercise intensity) are valuable options to gain more knowledge about the exercise-cognition interaction. The first approach (i.e., solely monitoring cerebral hemodynamics) can help us to answer specific research questions related to the effects of exercise on the brain which, in turn, can later be used to inform exercise prescription (e.g., To what extent does an exercise prescription based on conventional parameters cause interindividual heterogeneity concerning cerebral hemodynamics?). The second approach (i.e., brain-derived parameters to prescribe exercise) opens a new perspective, as it allows the study of the effects of an alternative exercise prescription on specific outcome measures (e.g., To what extent does an exercise prescription based on brain-derived parameters influence interindividual heterogeneity in cognitive performance changes in response to an acute bout of physical exercise?). Hence, both approaches should be seen as complementary options, which enable us to study the subject of exercise-cognition from two different perspectives.

Practical Implementation of Brain-Derived Parameters to Prescribe Physical Exercise
In the previous section, we have outlined that there is a strong theoretical rationale to use brain-derived parameters to prescribe exercise variables (e.g., exercise intensity), but this approach is currently underutilized. As this approach will open a new perspective on exercise-cognition interaction, we highlight potential areas of application by answering the following questions, which seem relevant for the practical implementation: (i) How Can We Prescribe Exercise Intensity by Using fNIRS-Derived Brain Parameters?, (ii) Which Cortical Brain Area Should Be Targeted?, (iii) How Can We Minimize Confounders in Order to Successfully Apply fNIRS During Physical Exercise? and (iv) Which Additional Internal Load Indicators Should Be Recorded Alongside fNIRS?

How Can We Prescribe Exercise Intensity by Using fNIRS-Derived Brain Parameters?
In our opinion, a prescription of exercise intensity using fNIRS-derived brain parameters can be implemented in a manner comparable to routinely used conventional indicators of internal load (HR). To test the practicability of the novel approach to prescribe exercise intensity by using fNIRS-derived brain parameters, continuous endurance exercises (e.g., cycling) could be a good starting point. Similar to the conventional approach of exercise prescription, the individual firstly performs a graded exercise test in which brain-derived indicators of internal load (e.g., StO 2 ) can be measured alongside conventional ones (e.g., HR or VO 2 ). Based on this graded exercise test, the external load (e.g., workload) can be identified, which corresponds, for instance, to the highest StO 2 or to a specific percentage of a maximal StO 2 (see Figure 2). This external load (i.e., workload) can then, in turn, be used to set the initial exercise intensity in an exercise session. Importantly, as fNIRS allows a non-invasive online monitoring of brain parameters, such as StO 2 while exercising, the external load can be individually adjusted during the course of the exercise session, in order to ensure that the target StO 2 is achieved (e.g., comparable to HR monitoring). Hence, using brain parameters, such as StO 2 , allows one to account for daily variations in performance capacity in the same manner as the established conventional approaches (e.g., heart rate monitoring). However, before the application of fNIRS can be recommended unreservedly, further research is necessary. Such research should aim, for instance, at investigating the reproducibility of fNIRS-derived brain parameters in the exercise setting, at studying the relationship between fNIRS-derived brain parameters and conventional parameters of exercise prescription (e.g., HR, level of peripheral blood lactate, and relative perceived exertion (RPE)), and at examining whether this novel approach of exercise prescription may be superior in inducing neurocognitive changes (e.g., acute influence on cognitive performance or blood-based markers), as compared to conventional approaches of exercise prescription. In our opinion, a prescription of exercise intensity using fNIRS-derived brain parameters can be implemented in a manner comparable to routinely used conventional indicators of internal load (HR). To test the practicability of the novel approach to prescribe exercise intensity by using fNIRS-derived brain parameters, continuous endurance exercises (e.g., cycling) could be a good starting point. Similar to the conventional approach of exercise prescription, the individual firstly performs a graded exercise test in which brain-derived indicators of internal load (e.g., StO2) can be measured alongside conventional ones (e.g., HR or VO2). Based on this graded exercise test, the external load (e.g., workload) can be identified, which corresponds, for instance, to the highest StO2 or to a specific percentage of a maximal StO2 (see Figure 2). This external load (i.e., workload) can then, in turn, be used to set the initial exercise intensity in an exercise session. Importantly, as fNIRS allows a noninvasive online monitoring of brain parameters, such as StO2 while exercising, the external load can be individually adjusted during the course of the exercise session, in order to ensure that the target StO2 is achieved (e.g., comparable to HR monitoring). Hence, using brain parameters, such as StO2, allows one to account for daily variations in performance capacity in the same manner as the established conventional approaches (e.g., heart rate monitoring). However, before the application of fNIRS can be recommended unreservedly, further research is necessary. Such research should aim, for instance, at investigating the reproducibility of fNIRS-derived brain parameters in the exercise setting, at studying the relationship between fNIRS-derived brain parameters and conventional parameters of exercise prescription (e.g., HR, level of peripheral blood lactate, and relative perceived exertion (RPE)), and at examining whether this novel approach of exercise prescription may be superior in inducing neurocognitive changes (e.g., acute influence on cognitive performance or blood-based markers), as compared to conventional approaches of exercise prescription.

Which Cortical Brain Area Should Be Targeted?
The exact placement of fNIRS optodes is crucial to obtaining cerebral hemodynamic signals from a specific brain area. To test the practicability of an exercise prescription which is based on brain-derived measures, we propose that the PFC could be a promising initial target area. The PFC is a key structure for the performance of cognitive control/executive functions [223,224], which is the most investigated cognitive domain in acute exercise-cognition studies [225]. More specifically, and based on evidence that is outlined in more detail below, the ventrolateral PFC, dorsolateral PFC, and the frontopolar area (FPA) are promising brain areas for investigations: Brain Sci. 2020, 10, 342 8 of 23 (a) Regarding the ventrolateral PFC; it was observed that young adults with superior performance in a spatial memory tasks in response to an acute bout of endurance exercise (i.e., responders) exhibited higher levels of oxyHb in the right ventrolateral PFC during the exercise [207]. (b) Regarding the dorsolateral PFC; it was noticed that in young adults, higher levels of oxyHb in the left dorsolateral PFC (measured during a cognitive test after exercising) [226][227][228] were associated with exercise-induced behavioral changes in the performance of the Stroop test. (c) Regarding the FPA; it was observed that in young adults, higher levels of oxyHb in the left FPA (measured during a cognitive test after exercising) [227] were associated with exercise-induced behavioral changes in the performance of the Stroop test. Similar findings have been observed for older adults regarding the right FPA [229].
In addition, more detailed information regarding an accurate and standardized placement of fNIRS optodes can be found in the referenced literature [176].

How Can We Minimize Confounders in Order to Successfully Apply fNIRS during Physical Exercise?
With respect to the practical application of fNIRS during physical exercising, it is mandatory to emphasize that movement artefacts or systemic physiological artefacts, which occur during physical exercising, influence the accuracy of the brain signal measurement of fNIRS significantly [99,101,149,151,[230][231][232][233][234][235]. To minimize the influence of such signal confounders, appropriate data processing techniques should be applied (e.g., short-separation channel regression (SSR) to account for superficial blood flow [99,111,176,235,236] or SSR in conjunction with accelerometer signals to account for superficial blood flow and motion artefacts in CW-NIRS [237]). Furthermore, the application of other NIRS methods, namely SRS-NIRS, should be considered in the context of physical exercise, since they are less influenced by systemic physiological interference [238] and motion-related artefacts [184].
In addition, it is strongly recommended to record multiple physiological signals along with fNIRS signals (e.g., HR and heart rate variability (HRV), electrodermal activity (skin conductance), mean arterial blood pressure, systolic and diastolic blood pressure, respiration rate, and partial pressure of exhaled CO 2 (P ET CO 2 )) to make valid assumptions about the physiological origin of the observed changes in fNIRS signals and, in turn, to improve the interpretation of fNIRS signals [99]. This approach has been recently termed systematic physiological augmented functional near-infrared spectroscopy (SPA-fNIRS) [239,240]. However, the study of Tempest et al. [108] supports the application of fNIRS, for instance, during motor-cognitive exercises, as robust cognitive task-evoked changes in cortical cerebral hemodynamics during cycling were measured by fNIRS, which are comparable to cortical hemodynamic changes observed without exercise [131]. Notwithstanding, it is important to emphasize that further efforts are necessary to improve the signal quality of fNIRS-based brain monitoring devices, which would allow for the more reliable conclusion of the origin of observed signal changes [99].

Which Additional Internal Load Indicators Should Be Recorded Alongside fNIRS?
In order to quantify the state of organic systems more comprehensively, it seems useful to complement the measures of the central nervous system (e.g., StO 2 in the PFC) with (easily quantifiable) measures of the autonomous nervous system. A promising indicator of the state of the autonomous nervous system is the HRV, which is operationalized by the beat-to-beat variations of the heart rate over a specific time period (e.g., during a resting state or during physical exercises) [45, [241][242][243][244][245]. HRV is considered to be a proxy of the actual health state [246][247][248][249] and stress level [247,250] of an individual. HRV also reflects, at least partly, the fitness level and daily readiness [243,244,[251][252][253][254][255] of an individual, as well as the organismic demands [256][257][258][259][260]. There are numerous non-linear analysis approaches to appraise HRV, which reflect the systemic character of the organism [245,248,249,[261][262][263]. Moreover, HRV is linked to cognitive performance in specific cognitive domains (e.g., during a resting state) [245,[264][265][266][267][268][269][270][271][272][273] and it is, as outlined in the neurovisceral integration model, associated with the integrity of specific subareas of the PFC (e.g., medial PFC) [247,[273][274][275][276][277][278][279][280]. In summary, this evidence suggests that HRV is a valuable parameter which should be recorded along with fNIRS in order to assess changes in the autonomic system more precisely. However, there is, to the best of our knowledge, no study available using HRV as an indicator of internal load to directly prescribe exercise intensity. Existing studies used resting-state HRV to guide the exercise prescription, but exercise intensity was prescribed with other parameters than HRV (e.g., HR or running velocity) [252,[281][282][283].
Another parameter of interest is the pulse-respiration quotient, which provides a unique measure of the physiological state and traits [284,285] and which, therefore, should be more often assessed in physical exercise studies.

Summary and Conclusion
The optimal exercise prescription in the field of exercise-cognition is a topic of emerging interest, and a lively discussion on the matter has started. However, the question about which indicators of internal load may be the most appropriate ones remains open [15]. In this perspective article, we discuss and advocate for the use of brain-derived parameters in the exercise prescription of exercise-cognition studies (e.g., to prescribe exercise intensity). Brain-derived parameters provide the advantages that they are more closely related to the organic system that is aimed to be influenced and that they are sensitive to demands (e.g., cognitive load), which are not sufficiently reflected in conventional measures (e.g., HR). In particular, we discuss the promising potential of fNIRS-derived brain parameters (e.g., oxyHB, deoxyHb, totHb, and StO 2 ) to prescribe physical exercise (e.g., exercise intensity) and we encourage the research community to test the practicability and effectiveness of this novel approach of exercise prescription.