The following text is excerpted verbatim from the 2009 National Research Council report, Opportunities in Neuroscience for Future Army Applications (pp. 93–95, 98) and is offered to the reader as further explanation of the linkages between biomarkers and soldier performance.
TREND 1: DISCOVERING AND VALIDATING BIOMARKERS OF NEURAL STATES LINKED TO SOLDIERS’ PERFORMANCE OUTCOMES
As discussed in Chapters 3 through 6, the cognitive and behavioral performance of soldiers in many areas—training and learning, decision making, and responding to a variety of environmental stressors—has substantial neurological components. How the brain functions, even how it is functioning at a particular time, makes a difference in these and other types of performance essential to the Army’s missions. The techniques used to study and understand brain functioning at all levels—from the molecular and cellular biology of the brain to observable behavior and soldier interactions with other systems—are providing an ever-increasing number of potential indicators of neural status relevant to Army tasks. The Army will need to monitor these techniques and technologies for their potential to serve as biomarkers of differences in neural state that reliably correlate with changes in performance status. To illustrate this tendency for performance biomarkers to emerge from the methods of studying the brain, three broad kinds of such methods are discussed here: genomic and proteomic
markers, neuroimaging techniques, and physiological indicators of neural state or behavioral outcome.
Genetic Proteomic and Small-Molecule Markers
The development and functioning of the central and peripheral nervous systems of all animals, including humans, are regulated by genomic and proteomic factors. The genomic factors are associated with the nucleic acids of every cell. From embryonic development through senescence, the inherited genome and epigenetic1 modifications of it regulate the expression of proteins critical for neural cell functions. This regulated gene expression produces signaling elements (transmitters), signal receivers (receptors), guidance of communication processes (axons and dendrites), and cell–cell recognition materials.
Known genetic markers may, for example, allow identification of individuals at greater risk of damage from exposure to chemical agents or more likely to succumb to post-traumatic stress disorder. The cost of genetic tests is likely to decrease substantially in the next decade, while their effectiveness will increase markedly. Of the 20,000-25,000 genes in the human genome, more than 100 are involved in axonal guidance alone (Sepp et al., 2008). At least 89 genes have been shown to be involved in the faulty formations of axon’s myelin sheath (dysmyelination), associated with the development of schizophrenia (Hakak et al., 2001). Understanding the human genes associated with developments of the brain and peripheral nervous system can shed light on differential human susceptibilities to brain injury and may aid in predicting which pharmacological agents will be useful for sustaining performance. The Army should position itself to take advantage of the continuing scientific progress in this area.
A proteomic marker (a type of biomarker) is a protein (generally an enzyme) whose concentration, either systemically or in specific tissues, can serve as a reliable and readily measurable indicator of a condition or state that is difficult or even impossible to assay directly. Small variations in gene structure (polymorphisms) are often associated with differences in concentration of a particular individual, so there are important linkages between genetic factors and proteomic markers. However, specific enzyme concentrations (including tissue-specific concentration) can also be influenced (upregulated or downregulated) in response to environmental factors that vary on timescales of hours, or roughly the timescale of preparation for and conduct of an Army operation. Thus, proteomic markers can vary with
1 An epigenetic modification refers to changes in gene expression from mechanisms other than alteration of the underlying DNA sequence.
recent or current conditions (environmental stressors, for example) and can also reflect the genetic traits of an individual soldier.
Proteomic markers known to signal a change in vigilance or cognitive behavior include salivary amylase, blood homovanillic acid (which correlates with dopamine metabolism), and lactic acid (a metabolic product of glucose metabolism that increases as a result of intense muscle exercise). Proteomic factors associated with fatigue resistance include microtubule-associated protein 2 and the muscarinic acetylcholine receptor. Comparison of an individual’s current concentration (titer) of one of these proteomic markers with his or her baseline titer could quantify one or more neural (cognitive/behavioral) states relevant to the status of the individual’s current abilities.
Neurohormones and neuropeptides—biologically active molecules much smaller than proteins or the nucleic acids of the genome—are another emerging class of markers of neurological and cognitive state and of psychophysiological response to stress. A study of candidates for the U.S. Navy Sea, Air, and Land Forces (SEALs) found that candidates with strong stress-hormone reactions to behavioral challenges like abrupt changes or interruptions are less likely to complete training successfully than those with weak reactions (Taylor et al., 2006, 2007). Another example is the work discussed in Chapter 3 on oxytocin, a neuropeptide signal, which is released when an individual experiences a sense of trust (Kosfeld et al., 2005; Zak et al., 2005). Hormonal markers are easily gathered with simple blood draws. The level in the bloodstream of a neural signaling molecule such as oxytocin has at best a very indirect relationship to its level in the brain; it may be necessary to figure out how to monitor its release in the hypothalamus. The monitoring of neurohormones and neuropeptides is likely to be a powerful means of identifying individuals who are well suited to particular tasks and may lend itself to assessing candidates for Special Operations training in particular.
Neuroimaging technologies available in the 2008-2010 time frame allow visualization of brain regions that are activated during action-guiding cognitive processes such as decision making. These activation patterns enable brain activity to be correlated with behavior. These imaging technologies and techniques include structural magnetic resonance imaging for volumetric analysis of brain regions, functional magnetic resonance imaging (fMRI) for cognitive control networks, diffusion tensor imaging for transcranial fibers, and hyperspectral electroencephalography (EEG).
Applications to Soldier Training
As an example relevant to evaluation of training, fMRI scans before and after training sessions can be compared to examine changes in the brain’s response to novel training-related stimuli. Novel visual and auditory inputs activate the brain in specific regions. An analysis of event-related potentials combined with fMRI before and after novel auditory cues revealed that a particular event-related potential (a P300-like potential, which is to say a positive potential occurring approximately 300 msec after a triggering stimulus) is associated with fMRI patterns of activity in the bilateral foci of the middle part of the superior temporal gyrus (Opitz et al., 1999). Only novel sounds evoke a contrasting event-related potential (an N400-like negative potential). Individuals with a strong response of the second type also have fMRI scans showing activation in the right prefrontal cortex. These observations suggest that an indicator based on combining fMRI and event-related potential could be used to assess training to criterion. At criterion—for example, when 90 percent of the appropriate responses are exhibited in response to a cue—effective training will no longer elicit a “novel-type” brain functional response or event-related potential response (Opitz et al., 1999).
Fear is a critical response to threat that can compromise appropriate action of an individual soldier or an entire Army unit. To incorporate desensitization to fear-invoking situations in soldier training, fMRI scans could be compared before and after training to determine which environments elicit fear-correlated neural activity patterns. A prime example is the response of soldiers in Operation Desert Shield and Operation Desert Storm when sensors for chemical warfare agents indicated that the environment might contain an active agent. These fear-invoking events led to significant disorganization of military units, even when the sensor warnings were false positives.
Tracking Change in the Visual Field
The ability to track dynamic changes in objects present in a soldier’s visual field is of great benefit to Army personnel. Examples include the sudden appearance of a potential threat on a Force XII Battle Command Brigade and Below display and the apparent change of terrain indicating recent placement of an improvised explosive device (IED). Jeremy Wolfe of Harvard has demonstrated that the visual system must focus on only a very limited region within the visual field to detect change (Angier, 2008). To accommodate human limitations, fMRI neurotechnology could be used to detect minor changes in the visual field and correlate them with activation events in the hippocampus (Bakker et al., 2008). Related research
has shown that shifts in visual attention to objects in a field of view tend to occur either as a series of microsaccades (rapid naturally occurring eye movements) or in response to cueing signals in the field of view. Recent studies suggest that the latter is more important (Horowitz et al., 2007).
Leveraging Opportunities for Neuroimaging Techniques
EEG and EEG image processing will continue to advance, and EEG will be incorporated in multimodal imaging equipment with magnetic resonance imaging and magnetic encephalography. The high-payoff opportunity here is to leverage this work to develop a sensor array that can be used on a free-moving subject. A good initial goal for proof-of-concept would be the collection of stable trace data from a treadmill runner.
For neuroimaging with near-infrared spectroscopy (NIRS), Defense Advanced Research Projects Agency (DARPA) has been active in research and development (R&D) on NIRS sensor arrays that can be worn in situ. This is an opportunity to advance a noninvasive cerebral blood monitoring tool. Expected improvements in the next 5 years include advanced designs for multichannel data collection from cortical sources. In the 10- to 20-year time frame, one R&D opportunity is to use NIRS for more accurate imagining of the deeper brain.
Physiological Indicators of Neural-Behavioral State
Physiological indicators include individual characteristics such as age, gender, muscle power, neuroendocrine effects, neuromuscular function, vascular tone, and circadian cycling. While neural information processing is primarily a result of brain functioning and can be revealed by brain imaging, the general wellness and physiological condition of the entire human organism can affect combat capability and response to threat. This is true in large part because the brain depends on nutrient input (e.g., glucose and oxygen) via the circulatory system and on neuroendocrine function involving other organ systems. (The complex interactions between the brain and other organ systems of the body were discussed in Chapters 2 and 5.)
For Army applications, physiological indicators of neural state are important because they are often more readily accessible and measurable in the field than more direct indicators of neural state derived from neuroimaging techniques. As discussed in Chapter 2 in the section on reliable biomarkers for neurophysiological states and behavioral outcomes and in Chapter 7 in the section on field-deployable biomarkers, the idea is to find a monitorable physiological condition that correlates to a neural state with sufficient accuracy and precision to be useful as a reliable sign of that state.
Often, the laboratory studies that define the neural state and establish the correlation will begin with neuroimaging techniques (such as fMRI).
Angier, N. (2008). Blind to change, even as it stares us in the face. New York Times, April 1, p. F2.
Bakker, A., C.B. Kirwan, M. Miller, and C.E.L. Stark. (2008). Pattern separation in the human hippocampal CA3 and dentate gyrus. Science, 319(5,870):1,640–1,642.
Horowitz, T.S., E.M. Fine, D.E. Fencsik, S. Yurgenson, and J.M. Wolfe. (2007). Fixational eye movements are not an index of covert attention. Psychological Science, 18(4):356–363.
Kosfeld, M., M. Heinrichs, P.J. Zak, U. Fischbacher, and E. Fehr. (2005). Oxytocin increases trust in humans. Nature, 435(7,042):673–676.
National Research Council. (2009). Opportunities in Neuroscience for Future Army Applications. Committee on Opportunities in Neuroscience for Future Army Applications, Board on Army Science and Technology, Division on Engineering and Physical Sciences. Washington, DC: The National Academies Press.
Opitz, B., A. Mecklinger, A.D. Friederici, and D.Y. von Cramon. (1999). The functional neuroanatomy of novelty processing: Integrating ERP and fMRI results. Cerebral Cortex, 9(4):379–391.
Sepp, K.J., P. Hong, S.B. Lizarraga, J.S. Liu, L.A. Mejia, C.A. Walsh, and N. Perrimon. (2008). Identification of neural outgrowth genes using genome-wide RNAi. Available: http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000111 [September 2014].
Taylor, M., A. Miller, L. Mills, E. Potterat, G. Padilla, and R. Hoffman. (2006). Predictors of Success in Basic Underwater Demolition/SEAL (BUD/S) Training. Part I: What Do We Know and Where Do We Go from Here? Naval Health Research Center Technical Document No. 06-37. San Diego, CA: Naval Health Research Center.
Taylor, M., G. Larson, A. Miller, L. Mills, E. Potterat, J. Reis, G. Padilla, and R. Hoffman. (2007). Predictors of Success in Basic Underwater Demolition/SEAL (BUD/S) Training. Part II: A Mixed Quantitative and Qualitative Study. Naval Health Research Center Technical Document No. 07-10. San Diego, CA: Naval Health Research Center.
Zak, P.J., R. Kurzban, and W.T. Matzner. (2005). Oxytocin is associated with human trustworthiness. Hormones and Behavior, 48(5):522–527.