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Neuroscience and the Army

This chapter provides a brief overview of neuroscience and neuroscience technology, including the definition of neuroscience used by the committee for the study. It describes major applications areas that were considered by the study and provides rationale for not considering some applications.

HISTORY, SCOPE, AND DEFINITION OF NEUROSCIENCE

“Neuroscience” refers to the multiple disciplines that carry out scientific research on the nervous system to understand the biological basis for behavior. Modern studies of the nervous system have been ongoing since the middle of the nineteenth century. Neuroanatomists studied the brain’s shape, its cellular structure, and its circuitry; neurochemists studied the brain’s chemical composition, including its lipids and proteins; neurophysiologists studied the brain’s bioelectric properties; and psychologists and neuropsychologists investigated the organization and neural substrates of behavior and cognition.

The term “neuroscience” was introduced in the mid-1960s, signaling the start of an era when these disciplines would work together cooperatively, sharing a common language, common concepts, and a common goal: to understand the structure and function of the normal and abnormal brain. Neuroscience today spans a wide range of research endeavors, from the molecular biology of nerve cells, which contain the genes that command production of the proteins needed for nervous system function, to the biological bases of normal and disordered behavior, emotion, and cognition, including the mental properties of individuals as they interact with each other and with their environments.

Neuroscience is one of the fastest growing areas of science, and the brain is sometimes referred to as the last frontier of biology. In 1971, for example, the first meeting of the Society for Neuroscience was attended by only 1,100 scientists; in 2007, 26,000 scientists participated at the society’s 37th annual meeting and more than 15,000 research presentations were made. At this time, national societies of neuroscience exist throughout the world, and there exists a Federation of European Neuroscience Societies.

Neuroscience incorporates a number of interacting areas, including cognitive neuroscience, systems neuroscience, cellular and molecular neuroscience, developmental neuroscience, clinical neuroscience, theoretical neuroscience, and computational neuroscience. Operations involving neurons1 form the basis for all of these areas and take place on four fundamental hierarchical levels: molecular, cellular, systems, and behavioral. These levels rest on the principle that neurons communicate chemically by the activity-dependent secretion of “neurotransmitters” at specialized points of contact called “synapses.” In order for the brain to perform its multiple functions, the mental operations of the brain rely on a properly functioning and integrated system of autonomous bodily functions, monitored by the brain and modified by behavioral operations only when the autonomous regulatory systems—thermal control, control of blood nutrients, orientation of the body and limbs in space while moving, gesturing, and transporting, control of the salt and water balance, and so on—are compromised.

The autonomous peripheral systems monitored by the brain and over which it has ultimate control allow for an extreme but generally subconscious interaction between the body’s physical fitness and the brain’s emotional and cognitive powers to drive the body’s performance under demanding conditions. For example, overcoming fatigue through personal willpower alone is a learnable ability that is characteristic of superior athletes and that would be beneficial for military personnel as well (see Chapter 5).

Many fields of clinical medicine are directly concerned with the diseases of the brain. The branches of medicine most closely associated with neuroscience from the perspectives of this report are neurology (the study of the degenerative

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Nerve cells of the central and peripheral nervous systems.



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2 Neuroscience and the army This chapter provides a brief overview of neuroscience society’s 37th annual meeting and more than 15,000 research a nd neuroscience technology, including the definition presentations were made. At this time, national societies of of neuroscience used by the committee for the study. It neuroscience exist throughout the world, and there exists a describes major applications areas that were considered by Federation of European Neuroscience Societies. the study and provides rationale for not considering some Neuroscience incorporates a number of interacting areas, applications. including cognitive neuroscience, systems neuroscience, cellular and molecular neuroscience, developmental neuro- science, clinical neuroscience, theoretical neuroscience, and hisTory, scoPe, aNd deFiNiTioN computational neuroscience. Operations involving neurons1 oF NeuroscieNce form the basis for all of these areas and take place on four “Neuroscience” refers to the multiple disciplines that fundamental hierarchical levels: molecular, cellular, systems, carry out scientific research on the nervous system to and behavioral. These levels rest on the principle that neurons u nderstand the biological basis for behavior. Modern communicate chemically by the activity-dependent secre- studies of the nervous system have been ongoing since the tion of “neurotransmitters” at specialized points of contact middle of the nineteenth century. Neuroanatomists studied called “synapses.” In order for the brain to perform its mul- the brain’s shape, its cellular structure, and its circuitry; tiple functions, the mental operations of the brain rely on a neurochemists studied the brain’s chemical composition, properly functioning and integrated system of autonomous including its lipids and proteins; neurophysiologists studied bodily functions, monitored by the brain and modified by the brain’s bioelectric properties; and psychologists and behavioral operations only when the autonomous regula- neuropsychologists investigated the organization and neural tory systems—thermal control, control of blood nutrients, substrates of behavior and cognition. orientation of the body and limbs in space while moving, The term “neuroscience” was introduced in the mid- gesturing, and transporting, control of the salt and water 1960s, signaling the start of an era when these disciplines balance, and so on—are compromised. would work together cooperatively, sharing a common The autonomous peripheral systems monitored by the language, common concepts, and a common goal: to under- brain and over which it has ultimate control allow for an stand the structure and function of the normal and abnormal extreme but generally subconscious interaction between brain. Neuroscience today spans a wide range of research the body’s physical fitness and the brain’s emotional and endeavors, from the molecular biology of nerve cells, which cognitive powers to drive the body’s performance under contain the genes that command production of the proteins demanding conditions. For example, overcoming fatigue needed for nervous system function, to the biological bases through personal willpower alone is a learnable ability that of normal and disordered behavior, emotion, and cognition, is characteristic of superior athletes and that would be ben- including the mental properties of individuals as they interact eficial for military personnel as well (see Chapter 5). with each other and with their environments. Many fields of clinical medicine are directly concerned Neuroscience is one of the fastest growing areas of with the diseases of the brain. The branches of medicine most science, and the brain is sometimes referred to as the last closely associated with neuroscience from the perspectives frontier of biology. In 1971, for example, the first meeting of this report are neurology (the study of the degenerative of the Society for Neuroscience was attended by only 1,100 scientists; in 2007, 26,000 scientists participated at the 1Nerve cells of the central and peripheral nervous systems. 2

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 NeUROSCIeNCe AND THe ARMY sensory and motor diseases of the brain), neurosurgery (the one to hypothesize experimental results on one level based study of the surgical treatment of neurological disease), and on experimental findings and observations from other levels. psychiatry (the study of behavioral, emotional, and mental This ability extends to hypothesizing neuronal operations or diseases). Other fields of medicine also make important neuronal diseases based on data that would predict results contributions to neuroscience, including neuroradiology, at the behavioral level given the results of a perturbation which is the use of radiation for imaging the brain—initially or other experimental manipulation at a lower level. Such with X-rays and, more recently, with positron emitters, radio- results are strongly supported in the literature (Aston-Jones frequency, and electromagnetic waves—for clinical studies and Cohen, 2005a, 2005b). and microscopic study of samples from diseased neural One might predict from experimental results in animals, tissue. for example, that the thin axons that establish functional properties of the noradrenergic system might also be one of the brain fiber systems most vulnerable to the percus- hierarchical levels of Neuroscience sive damage of traumatic brain injuries (TBI), such as A t the molecular level, one examines the interac - might result from an improvised explosive device (IED). tion of molecules—typically proteins—that regulate gene As discussed in the Chapter 5 section on brain injury, this is expression and translation into proteins. Proteins mediate indeed the case, and the ability to translate between levels neurotransmitter synthesis and storage and release other of neuroscience has proven helpful in the treatment of TBI essential neuronal molecular functions such as the recep- and its emotional effects. tors by which neurons respond to neurotransmitters. Most drugs used for the treatment of neurological or psychiatric NeuroscieNce TechNoloGies diseases work by either enhancing or diminishing the effects of neurotransmitters. Until the advent of modern computer-based technol- At the cellular level of neuroscience, one examines the ogy, the primary noninvasive tools used to understand the interactions between neurons through their synaptic connec- workings of the central and peripheral nervous system were tions and between neurons and the supporting cells, the glia. the recording of electrical signals from the scalp (electro- Research at the cellular level strives to determine the neural encephalography [EEG]) and X-ray imaging of the soft pathways by which specific neurons are connected and which tissue of brain as distinguished from bone and compart- of their most proximate synaptic connections might medi- ments containing cerebral spinal fluid (CSF). EEG allowed ate a behavior or behavioral effects of a given experimental detecting epileptogenic foci that could subsequently be perturbation. managed surgically if a discrete region was involved in the At the systems level, one examines the interconnected initiation of seizures or pharmacologically if the region was neural pathways that integrate the body’s response to envi- more generalized. The X-ray imaging allowed detection and ronmental challenges. The sensory systems include the localization of lesions because the lesions displaced readily specialized senses for hearing, seeing, feeling, tasting, and identified portions of the brain. However, these technologies balancing the body. The motor systems control trunk, limb, provided very limited insight into neural information pro- eye, and fine finger motions. Internal regulatory systems cessing related to cognition, the central mechanisms involved are responsible for, among other things, control of body in the perception of pain, or other higher-order brain activi- temperature, cardiovascular function, appetite, and salt and ties. The pioneering work of Penfield and his colleagues was water balance. an exception: It combined EEG with invasive brain surgery At the behavioral level of neuroscience research, one to associate the visual and auditory auras that accompanied examines the interactions between individuals and their seizures to specific regions in the visual, auditory, or tempo- collective environment. Research at this level centers on the ral cortices (Penfield and Perot, 1963). systems that integrate physiological expressions of learned, The two decades from the late 1980s to the present have reflexive, or spontaneous behavioral responses. Behavioral seen the rapid rise of technologies that can provide high- research also looks at the cognitive operations of higher resolution structural images of the gray and white matters of mental activity, such as memory, learning, speech, abstract brain as distinct from one another, clearly delineating details reasoning, and consciousness. Research over the past three as small as the foci of white-matter disease and inflamma- decades has established that the brain is highly adaptable (this tory changes. These technologies are capable of imaging ability is commonly termed “neuroplasticity”) at each level the metabolic processes that are associated with functional of operation: the activity-dependent ability to change gene activity of the brain in response to specific stimuli (positron expression, to change transmitter production and response, emission tomography [PET] and functional magnetic reso- to change cellular structure and strength of connections nance imaging [fMRI]); the orientation and dimensions of between neurons, and to change behaviors by learning. axonal fiber bundles connecting one brain region to another An important consequence of organizing neuroscience (diffusion tensor imaging); and the electrophysiological research at four vertical hierarchical levels is that it enables localization of brain activation (magnetoencephalography

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 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS FIGURE 2-1 Various noninvasive imaging technologies provide insight into the brain (anatomy) and mind (function). Resolution boundaries are approximate. Currently, high resolution requires invasive procedures or injection of pharmacological agents not approved by the Food and Drug Administration; such technologies are outside the scope of Army applications, but some discussion is provided in Chapter 7. Note that useful measurements are performed at any point in the brain-mind plane. SOURCE: Adapted from Genik et al., 2005. [MEG] and visual and auditory evoked potentials). Most of imaging time of less than 10 minutes in a series of planes. the newer methodologies depend on computer-driven signal Recognizing that a large neuron cell body has a diameter of averaging across a time span of seconds to provide an under- 20-30 microns, each 100-micron element is likely to con- standing of brain structure and function. tain eight neurons and a much larger number of glia. Also The advancement of noninvasive neural measurement recognizing that each dendrite of a large neuron (Purkinje cell or motor neuron or pyramidal cell) may contain 10 3 techniques has opened new windows to the study of the to 104 synaptic connections, the number of information- functioning human brain. Figure 2-1 illustrates how neuro- science technologies provide insight into the brain (anatomy) processing elements contained within the small pixel volume and the mind (function). The spatial resolution of a given is large. There are very few 7-T MRI instruments avail- technology defines the largest and smallest brain structures able for human imaging at this time. The majority of MRI that can be observed, while the temporal resolution defines machines are 1.5 T and 3 T. The resolution for these instru- the elements of mind function to be measured. Academic and ments nominally decreases proportionally with static field, commercial research are primarily geared to improving reso- assuming a similar image acquisition time. Longer imaging lution, although important measurements for the prediction times can yield higher resolution, but the trade-off is that any of behavior can be made at any point in the brain-mind plane. movement of the head by the subject markedly decreases the Chapter 7 contains further details of neuroscience technolo- resolution. The limits of structural resolution are therefore gies, including a discussion of more invasive modalities and spatiotemporal limitations. the future direction of noninvasive imaging research. The diffusion tensor imaging allows examining the The spatial resolution of the structural imaging modali- pathways along which groups of axonal fibers travel from ties that could be achieved with the human brain in 2008 one brain region to another and the vectorial direction of the approximates 100 microns per side in three-dimensional fiber bundle group. This information is essentially a mapping pixel elements when a 7-tesla (T) MRI system is employed, of the potential for information exchange between regions which is the highest-field whole-body scanner currently and the tracing of the bundles that could carry information. in commercial production. This resolution requires a total No information is provided about the actual informational

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 NeUROSCIeNCe AND THe ARMY transactions between brain regions or the temporal events In PET imaging, a solution containing a small amount associated with such transactions. of a radioactive element is injected into the subject’s blood- The MRI system depends on alignment of the bulk stream. Signals from the decaying isotopes will show local- water dipole in the magnetic field and the perturbation of this ized concentration, which could be due to increased blood alignment by a radiofrequency pulse. The realignment of the flow, say, or perhaps to glucose metabolism, depending on dipole following the radiofrequency pulse provides the signal the tracer used. PET functional images are acquired at 3- to of interest. What MRI then permits resolving is the relative 4-mm isotropic resolution, and because very little tracer is water content of each compartment in the brain, spinal cord, used (to protect the subject), they require a few minutes to or organ system that is being studied. The white matter has tens of minutes of averaging to show a significant signal, the least free water content, the gray matter has intermediate again, depending on the tracer used. The significant advan- levels, and the CSF compartments have the greatest amount tage of PET over fMRI is that specific metabolic reactions of water. These compartments can be readily resolved. The can be targeted for measurement rather than merely observ- loss of myelin accompanying multiple sclerosis or other ing changes in blood flow. Additionally, with proper calibra- white-matter disease is also readily discerned for this rea- tion, an absolute measure of change in brain function can son, as are other diseases due to neurodegenerative changes be determined, even in different scanning sessions, whereas and cell loss. (MRI is to soft tissue as a computerized axial with fMRI only changes relative to a baseline condition are tomography [CAT] scan is to bone. These methods are observable. The main disadvantage of PET is that the physi- essentially noninvasive.) ology that produces transient signals of short duration, akin Imaging of the brain based on X-ray methods (CAT to noise, cannot be observed. Moreover, to avoid any adverse scans or X-ray scans) also have a high resolution but do not effects of radiation on the subject, PET studies on a given readily differentiate white from gray matter as does an MRI individual are limited to three or four experiments per year device. This approach has proven to be very useful for thread- depending on the amount of emitter injected. The functional ing catheters intravascularly to within 1 mm of any location properties of the brain have been shown to have relevance in the brain, for localizing tumors in the cranial cavity and for detecting a loss of situational awareness in individuals region of the spinal cord, and for visualizing new blood from subjected to total sleep deprivation for more than 24 hours hemorrhages. The two modalities taken together offer exqui- (Belenky et al., 2003). site timing of tumor, infection, and bleeding developments. Some of the noninvasive imaging technologies have The technologies for structural imaging provide the characteristics that may limit their use in military applica- basis for understanding the brain regions of interest obtained tions. PET, for example, requires injection of a positron by functional images. Functional images are lower resolu- emitter into the human subject. On the other hand, fMRI is tion than structural images in order to facilitate acquiring truly noninvasive in that no contrast agents or radioisotopes many repetitions in a short time. Typical 3-T fMRI acquires are injected in the subject. 2- to 3-mm isotropic resolution whole-brain images every A recent study by Bakker et al. (2008) demonstrated that 1 or 2 seconds, while cutting-edge hardware can acquire activation of the fMRI in hippocampal regions was related to 1-mm isotropic resolution whole-brain images in 1 second. the detection by human subjects of minor changes to objects By acquiring the images in a time-locked fashion with in the visual field. Detection of changes in the visual field by stimulation, one can interpret the activation of brain regions an unconscious mind might be applied to the identification as a response to stimulation. The fMRI signal is generated of IEDs implanted in the terrain. A clear understanding of by the loss of oxygen from hemoglobin (the deoxygenated the mechanisms by which an individual can become alerted hemoglobin is paramagnetic, while the oxygenated is not) to such activations when hippocampal neurons fire might and the change in blood flow in the activated region. The enhance the mission success of Army personnel. blood flow response continues for several seconds, enabling Electrophysiological events accompanying brain stimu- detection of very fast physiological events using this rather lation can be recorded in real time (milliseconds) from the slow temporal sampling. This is called blood oxygen level- cortex but not from deep brain structures, and the spatial dependent (BOLD) imaging. resolution is 5 mm per recording element. For noninvasive The more repeatable the brain response and, thus, the studies with the calvarium intact, the recordings are essen- blood flow response, the better localized activations can be tially averaging events in the top millimeter of cortex and observed, because one can average over several trials. If one across a diameter of 5 mm or more. The evoked potential can constantly stimulate a response in a block of time, say the is a signal-averaging methodology that examines rates of visual cortex with a flashing checkerboard, an activated state event-related depolarization across spatial domains of the lasts longer and is easier to detect. However, some cognitive scalp associated with a specific stimulus presentation—for processes are inherently transient and are better observed example, a checkerboard flicker, a flash, or an auditory sig- in so-called event-related experiments. Which experimental nal. It is possible to detect changes in such events that are method to use depends on the physiology of the reaction one due to changes in information processing (or to central ner- wishes to study (Friston et al., 1999; Otten et al., 2002). vous system lesions). Because vectorial electrical events are

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 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS BoX 2-1 computational Processes in the human Brain The last half century has seen the emergence of multiple technologies that, when taken in total, can lead to new understanding of the human–machine interface and to improving our management of it as an interacting organism. The relatively concurrent development of high-speed computer data pro- cessing, anatomic mapping of the human brain, noninvasive imaging technology (capable of visualizing neural information processing at a resolution of 1 mm3 in three dimensions), decoding of the human genome, and nanotechnology (giving us the ability to prepare molecular entities that can self- assemble in predictable arrays) has permitted researchers and theoreticians to construct models of how human–machine interfaces can aid training, increase combat effectiveness, and speed up the acquisition of information by the mind. A summary of some of this can be found in Kurzweil (2005, pp. 122-128). Anatomic studies of the brain lead to an estimate that the brain contains about 1011 neurons (information-processing units) and that many neurons (Purkinje cells in the cerebellum or anterior motor neurons in the spinal cord) have 1,000 information input elements (synapses) and 10 output ele- ments (synapses), yielding about 1014 possible information transactions occurring in seconds (it is assumed that in a local circuit in the cerebellum there are rapid impulse and repolarization events). If we focus on the neural components that enable all human visual perception, the retina is the initial image capture and processing element. It is a structure about 2 cm wide by 0.5 mm thick and weighs about 20 mg. This volume of tissue will contain about 105 neurons. Local information processing occurs between the rod and cone cells, which are activated by the input from the visual field, and the ganglion cells, which transmit initially processed information to the occipital cortex of the brain for further processing. The retina provides initial processing capability such as rapid detection of edges of objects by center-surround inhibition/activation, the movement of elements in the visual field, and the perception of dark/light properties of the objects in the field. The range of light/dark information processing that can be detected is several orders of magnitude. During the next two decades it is likely that visual input devices will be developed that will be able to fuse visual data with auditory cues to allow the more rapid detection of threats. These devices will be able to sustain vigilance by fusing measures of decreases in situational awareness (obtained through electroencephalography (EEG), evoked potentials, or other cues from the soldier) with threats detected in the area of operations. accompanied by changes in the magnetic field perpendicular cation of the neuroscience tools currently available to tasks to the electrical path, it is possible to measure columnar such as the three mentioned above. electrical events in the sulci using MEG.2 The spatial resolu- The report thinks of technology as being in one (or tion with this method is on the order of centimeters, and the sometimes both) of two categories: technologies that are temporal resolution is on the order of fractions of seconds “mission-enabling” (deployable) instruments and those to seconds. Studies on the effects of various stressors on that are “research-enabling” instruments. The word “instru- cognitive ability using MEG with EEG provide evidence that ment” is used in the most general sense: It could refer to a this tool can detect decremented situational awareness. This pen-and-paper personality inventory, a software-controlled is important from a defense perspective since EEG-related skills survey, a reaction-time analysis method for training devices are portable and readily deployable on an individual assessment, a control interlock system to distribute infor- soldier while MRI devices are not (Box 2-1). mation to vehicle crew based on their current workload and Among the applications of modern neuronal imaging baseline cognitive capability, an in-helmet device designed and structural technologies to military needs are the assess- to monitor neural activity or cerebral blood flow, or a device ment of (1) when appropriate training-to-criterion on a given that advances an imaging technology. Neuroscience research skill set has been achieved; (2) when a soldier in the well- plays a major role in the development of instruments in both rested state has significantly degraded situational awareness categories of technology. of her/his capability; (3) early signatures of neural dysfunc- tion. While some of these methodologies may prove to have reliaBle Biomarkers For NeuroPsycholoGical application for the a priori assessment of highly desirable sTaTes aNd Behavioral ouTcomes traits such as leadership, persistence, and other successful warrior behaviors, there is little evidence to support appli- Recordings of the brain’s electrical activity and the images of neural activation regions that were described in the previous section on neural monitoring technologies are all methods to record changes in brain activity in a specific 2This is possible because in the cerebral cortex, information-processing location at a given time. Generally, these data on neural modules are composed of a column of neurons spanning the thickness of events are interpreted in terms of what they tell us not just the cortex.

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 NeUROSCIeNCe AND THe ARMY the term in other disciplines.5 To avoid confusion, the com- about that event but also about longer-lasting patterns of brain activity and brain structure—that is, about neural states mittee has adopted the following definition, published by and changes in neural state. A major, if not the primary, goal the Biomarkers Definitions Working Group of the National of studying neurophysiology with these techniques is to Institutes of Health (Atkinson et al., 2001, p. 91): understand the linkages among neural states, psychological Biological marker (biomarker): A characteristic that is states, and behavior. (Psychological states are traditionally objectively measured and evaluated as an indicator of normal self-reported; behavior is directly observable by others.) biological processes, pathogenic processes, or pharmaco- In short, the outputs of neural monitoring technologies are logic responses to a therapeutic intervention. indicators of neural state (and of changes in neural state) that can in turn be linked with behavior. In its report, the Biomarkers Definitions Working Group Typically, these linkages begin with relationships that focused on applications of biomarkers as surrogates for clini- have statistical significance on a group-averaged basis and cal end points in a study or clinical trial. This emphasis on a move, as the state of scientific knowledge progresses, to con- biomarker’s role as a surrogate for a physiological or behav- nections that hold on an individual basis.3 Ultimately, this ioral condition or outcome is evident in the Working Group’s refinement will lead to a reliable, scientifically defensible, definition of clinical end point as “a characteristic or vari- knowledge of necessary and sufficient causal conditions able that reflects how a patient feels, functions, or survives.” underlying and explaining the observed patterns of brain Common examples of biomarkers mentioned by the Working activity, mental experience, and behavior. But because that Group include elevated blood glucose concentration for the ultimate goal is still a long way off, care must be taken not diagnosis of diabetes mellitus, the concentration of prostate- to leap prematurely from a statistically significant correlation specific antigen in blood as an indicator of the extent of to conclusions about causality. prostate tumor growth and metastasis, and blood cholesterol In addition to brain activity signals and images, the concentration as a predictive and monitoring biomarker for neurosciences and allied fields—ranging from genetics to heart disease risk (Atkinson et al., 2001, p. 91). molecular biology and traditional behavioral science—are Throughout the remainder of this report, the Committee exploring a wide range of phenomena that can be connected on Opportunities in Neuroscience for Future Army Applica- with neuropsychological states or changes in state. Just as a tions is primarily interested in biomarkers as objectively neuroimaging pattern can be used as an indicator or marker measured and evaluated indicators of either a neural state of neuropsychological state, so may other phenomena. or a behavioral outcome. For example, Chapters 3 and 5 Among the phenomena being studied for this purpose are discuss the use of neuroimaging as a source of biomarkers biologically active small molecules, proteins and related for individual response to particular environmental stressors. molecules (e.g., lipoproteins and metabolic residues or pre- Chapter 7 discusses the value for Army applications of find- cursors of proteins), genes and nonencoding regions of the ing biomarkers that can be measured under field conditions genome, physiological events or patterns outside the brain and that are reliable indicators of specific neural states that but within the organism, and responses to an environmental have been reliably linked to behavioral outcomes. These exposure (physical, chemical, biological, social, or psycho- biomarker applications differ from uses of biomarkers as logical). The variety and complexity of the hypotheses being surrogate clinical end points, which were the focus of the put forward and tested about such correlations are driving a Biomarkers Definitions Working Group. Nevertheless, the revolution in scientific understanding. Working Group’s caveats about biomarker applications are “Biomarker” is a term often used in the biomedical dis- useful cautions for any application. ciplines for a characteristic that can be used as an indicator For example, both the accuracy and precision of a of some biological condition or outcome that is ultimately biomarker as a surrogate measure of outcome must be of interest but difficult to ascertain directly, at least under demonstrated: conditions of interest to a particular application. A number of implicit and explicit definitions of “biomarker” are in definition from Merriam Webster, in which a biomarker is “a distinctive common circulation.4 There are also quite different uses of biological or biologically derived indicator (as a biochemical metabolite in the body) of a process, event, or condition (as aging, disease, or exposure 3For example, fMRI investigations typically begin by examining rela - to a toxic substance).” The usage example given is “age-related biomarkers tionships averaged over many trials per subject and then averaged over of disease and degenerative change.” The URL for this National Institutes multiple subjects. Once a statistically significant relationship is established of Health (NIH)-sponsored dictionary is www.nlm.nih.gov/medlineplus/ in this way, the typical next step is to show that the relationship holds for mplusdictionary.html. Accessed on November 23, 2008. 5In petroleum exploration, biomarkers are compounds found in geologic individual events in the group of subjects, and ultimately to individual events in each subject. extracts (including oil, rock, sediment, and soil extracts) that indicate a 4The National Cancer Institute defines a biomarker as “a biological mol - biological origin of some or all of the material. See “Using Oil Biomarkers ecule found in blood, other body fluids, or tissues that is a sign of a normal in Petroleum Exploration,” by Oiltracers LLC, available at www.oiltracers. or abnormal process, or of a condition or disease . . .” in its Dictionary of com/biomarker.html8. Accessed November 21, 2008. A similar use occurs Cancer Terms, available at http://www.cancer.gov/dictionary/. Accessed in planetary science and astrobiology, where a biomarker is a chemical that November 23, 2008. The MedlinePlus online medical dictionary uses a signals the presence of biological processes, often in the distant past.

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8 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS tion of reliability that exceeds mere statistical correlation. The utility of a biomarker as a surrogate endpoint [or as a surrogate for a neural state or behavioral outcome] requires In cases where the biomarker is a measured quantity that demonstration of its accuracy (the correlation of the measure correlates with a magnitude of outcome, that quantitative with the clinical endpoint [or the neural state or behavioral relationship must be accurate and reproducible under the outcome]) and precision (the reproducibility of the measure). conditions in which the biomarker will be assessed in prac- (Atkinson et al., 2001, p. 92; bracketed text added by the tice. In cases where the application involves a binary test committee) (the outcome or end point to be indicated either is or is not present), values of sensitivity and specificity close to unity Elsewhere in its report, the Biomarkers Definitions are required for reliability. Working Group notes as follows: army aPPlicaTioN areas Biomarkers that represent highly sensitive and specific indi- cators of disease pathways have been used as substitutes for Neuroscience represents at once both a challenge and a outcomes in clinical trials when evidence indicates that they great opportunity. It is a challenge because the breadth and predict clinical risk or benefit. (Atkinson et al., 2001, p. 90; complexity of contemporary neuroscience are so great; and it emphasis added by the committee) is an opportunity because neuroscience can arguably become an important vehicle on which the Army depends to achieve The attributes of sensitivity and specificity have rigorous its mission goals. definitions that can be applied across the range of physical, The formal pursuit of neuroscience is a theoretical biological, and even social characteristics that are or will be endeavor on the one hand and a practical area of application candidates for indicators of whether a condition such as a on the other. Imaging technologies that form the basis for neural state is present or not. In a binary test (in this case, advances in neuroscience have their roots in the medical whether the neural state of interest is or is not present), arena, and it is the Army Medical Research and Materiel “sensitivity” is defined mathematically as the number of test Command that has traditionally sponsored much of the basic instances in which the biomarker is positive and the neural neuroscience research of benefit to individuals in all military state is present, divided by the number of instances in which services. DOD-level recognition of the importance of neuro- the neural state was present whether or not the biomarker science research can be seen in the 2008 establishment of was positive. In other words, the measure of sensitivity is the Defense Centers of Excellence for Psychological Health the ratio of true positive tests to the sum of the true positive and Traumatic Brain Injury under the assistant secretary of and false negative tests. (False negative tests are those that defense for health affairs. should have been positive.) “Specificity” is defined as the The Army Research Institute for the Behavioral and number of instances in which the biomarker was negative Social Sciences (ARI) has traditionally conducted research and the neural state was absent, divided by the number of in support of personnel testing and assessment, but neither instances in which the neural state was absent whether or not ARI nor the Army’s main research arm, the Army Research the biomarker was present. The measure of sensitivity is thus Laboratory (ARL), possesses in-house facilities to perform the ratio of true negative tests to the sum of the true negative basic neuroscience research. In light of a growing awareness and the false positive tests. A reliable biomarker for this kind of neuroscience potential in military applications, however, of binary application is one that has both high sensitivity and the ARL is planning to establish a collaborative technology high specificity; that is, both ratios are close to unity. alliance on cognition and neuroergonomics, which will take With respect to how biomarkers may be used, they can a multidimensional approach (e.g., genetics, computational be current, retrospective, or predictive (prospective) indica- modeling, neuroimaging, and performance) to optimizing tors or measures, depending on whether the condition or end information transfer between the system and the soldier, point for which they are used as a surrogate occurs at the identifying mental states and individual differences that same time, before, or after the assessment of the biomarker. impact mission-relevant decision making, and developing Demonstrating the reliability of a biomarker for an applica- technologies for individualized analyses of neurally based tion typically requires the same temporal relationship as the processing in operational environments.6 intended application. Neuroscience advances have already led to a broad As the report by the Biomarkers Definitions Working array of commercial applications and sparked centers for Group also notes, often several biomarkers must be combined neuroscience research at academic institutions throughout to get a reliable indicator or measure of outcome (Atkinson the country and the world. Table 2-1 lists sample objectives et al., 2001, p. 93). For applications of practical value to the in important Army application areas likely to benefit from Army, such as field-deployable indicators of neural state, neuroscience advances. To respond to the statement of task, this approach, assessing multiple biomarkers, may often be required (see Chapter 7 for further discussion). In summary, applications of biomarkers as surrogates for 6Kaleb McDowell, U.S. Army Research Laboratory, “ARL Research in neural states or behavioral outcomes require a demonstra- Neuroscience,” presentation to the committee, December 18, 2007.

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9 NeUROSCIeNCe AND THe ARMY TABLE 2-1 Prospective Army Applications for Neuroscience Application Areas Sample Objectives Training and learning Training paradigms and methods Shorten training cycles; assess training effectiveness Performance assessments of individuals and groups Detect individual performance degradation; assess group–individual interactions Identification of training candidates Improve success rates Training effectiveness measures Predict optimal performance; anticipate degraded performance Optimizing decision making Individual and unit readiness Utilize neural-state indicators Adversary assessment and prediction Act inside adversary decision cycle; disrupt adversary decision making (psychological operations) Setting objectives Reduce risk by matching goals with performance Sustaining soldier performance Recovery and reset Mitigate effect of sleep deprivation on recovery; neuropharmacological intervention to mitigate trauma response Counterstress Insulate immune system; moderate disease; modify brain functions to contend with combat rigors Fatigue and pain Nutritional countermeasures; minimize effects of sleep deprivation; drug therapies Brain injury Intervene early to mitigate acute and long-term deficits due to trauma Improving cognitive and behavioral performance Soldier skills Optimize brain–machine interfaces; improve image interpretation capabilities Information utilization and management Personalize data fusion; prevent information overload the applications are organized in four categories: training participation) associated with the identification of disease and learning, optimizing decision making, sustaining soldier potential and susceptibility to stress, and so the downside of performance, and improving cognitive and behavioral perfor- such information has become of social concern. mance. There is no question that neuroscience research has great potential for the Army’s future, but there are societal ethical considerations issues, including ethical considerations and cultural impedi - ments, that must be overcome to realize its full potential. One consequence of the genetic screening of large numbers of healthy persons for susceptibility to treatable or manageable disease is that subsequent studies may reveal socieTal issues that the same gene predisposes to an untreatable disease. A The decoding of the human genome and the emergence case in point is the screening of individuals for a particular of new imaging modalities are making possible the identifi- allele of apolipoprotein E4, which was known in the 1980s cation of proteomic, genomic, and imaging biomarkers asso- to be associated with high risk for cardiovascular disorder. ciated with susceptibility to a specific disease, with environ- In the early 1990s it was found that an apolipoprotein E4 mental stressors, or with neuropsychological vulnerabilities also was associated with higher risk for Alzheimer’s disease (e.g., pain, reduced perception, anxiety). The aggregate of (Corder et al., 1993). Patients who wanted to reduce the multiple biomarkers may provide a susceptibility profile that risk of cardiovascular disease and signed a consent form for would not be achievable through testing for any single marker such analysis became aware of their increased susceptibil- alone. These aggregate data can help in monitoring the rate ity to Alzheimer’s, a then untreatable neurological disorder. of progression of clinical disorders or response to treatment. Such information was not wanted and caused distress for a Creating a susceptibility profile of such signatures for a significant number of people. patient can allow for personalized medicine tailored to indi- Another consequence of learning one’s susceptibility to vidual need. The nature (e.g., mutation sites, triplet repeats, a nontreatable disease is the still-healthy patient’s inability proteomic signatures, and structural and functional imaging to anticipate the effect of such information on lifestyle and changes) and quantity of biomarkers involved could play an quality of life. Huntington’s disease is a clear example of this important role in screening for, diagnosing, and predicting effect. In the early part of the 1980s it became possible to disease. This same capability has made it possible to select screen patients and determine whether they would develop persons with a low risk of developing disease or succumbing the neurodegenerative disorder Huntington’s disease, a to a variety of stressors (toxic materials in the environment, dementia that does not appear until the fourth decade of life for instance). There may be adverse economic consequences or later and that is associated with an extensive triplet repeat (uninsurability, reduced rates of compensation) for the indi- of cytosine-adenine-guanine (CAG) (Myers et al., 1993). vidual and his or her career path progression (costly training Because the disease is autosomal dominant (all individuals programs may intentionally preclude high-risk persons from with the gene will develop Huntington’s disease), it was

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20 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS proposed that all conceptuses that had a parent or close rela- There is tension between the idea of “selecting out” indi- tive with Huntington’s disease should be tested for the gene. viduals for tasks based on presumed genetic susceptibilities Knowledge of whether one has a genetic predisposition and and the belief that extensive training can overcome inherited hence was certain to develop the disease could have a neutral, limitations and liabilities. The science-fiction film Gattaca beneficial, or adverse effect on the patient, with outcomes ( Columbia Pictures Corporation, 1997) confronts this ranging from acceptance to suicide. Undesired information dilemma with a dark view of the preselection concept. The on susceptibility to an untreatable disease might be a sword film was made during the early stages of the Human Genome of Damocles for a young soldier. Project and the first cloning of large animals. The positive aspects of knowing how one’s genetic heri- The U.S. military community traditionally aspires to tage impacts wellness and resilience to toxic insult can be select individuals for particular tasks or promote them based illustrated by the case of glutathione S-transferase genotype on excellence during training and performance in the field. (GST) and resistance of smokers to lung cancer. A significant Selecting in for extended service in closed platforms such number of studies reveal a twofold increase in the incidence as submarines is rigorous: The training periods are long of squamous cell carcinoma for patients having GST M1 and and there are particular social/psychological requirements. GST T1 null genotypes. GST and cytochrome P450 are two Despite this, very little research has been done on selecting classes of enzymes that metabolize and detoxify potential envi- in individuals who have a particular aptitude as assessed ronmental toxins. Patients with the null forms do not express by genetic and phenotype testing for a particular military active GST with the properties of GST M1 or GST T1, and the position or job. The decoding of the human genome and the absence of these enzyme variants might predispose them to advent of real-time imaging of neural information flow and the toxic effects of various chemicals, including some chemi- noninvasive tracing of major fiber pathways provide an oppor- cal warfare agents or toxic industrial materials. Restricting tunity to learn how we can use these novel methodologies the assignment of certain soldiers to areas of high risk might to enhance training and personalize it to meet the needs of protect them from exposure to such toxic materials; however, the soldier, to identify characteristics that are particularly it might also keep her/him from serving or being advanced well suited to complex and extreme environments, and to (promoted) in an area of specific interest, or it might prevent detect the early appearance of uncompensated responses to him/her from participating in important missions before any stress and emerging TBI and post-traumatic stress disorder clinical manifestation of illness. (PTSD). Federal laws and regulations contained in the Health The issues confronting the Army include training to Insurance Portability and Accountability Act (HIPAA) criterion (90 percent or better appropriate response to chal - protect patients and the community at large against the lenge), increasing data flow from deployed aerial and ground unwarranted and unnecessary disclosure of medical infor- sensors, human intelligence, electronic communications, mation that is directly or indirectly traceable to a particular and tempo of engagement with increasing capability of individual to unauthorized parties. The primary concerns lethality. The need to reduce casualties during force-on-force are that such disclosure might (1) affect the promotion of engagement drives the development of means for conducting military or civilian persons in their field of specialization, combat at large standoff distances and acquiring extensive (2) affect insurance rates and insurability of a given indi- awareness of the adversary’s deployment and capability. vidual, or (3) affect the psychological/social well-being At the same time, there is a perceived need to minimize of individuals with catastrophic diseases that are currently noncombatant casualties, which militates against extensive largely untreatable (e.g. Huntington’s disease, Alzheimer’s standoffs. These challenges call for a strategy that allows disease). These are but a few of the unintended consequences human cognitive capabilities to operate for 18-20 hours per of inappropriate disclosure. day, 7 days a week for 12 to 15 months at a high tempo of For additional information on ethical issues relevant to operations. The most affected group will be the command neuroscience research discussion in this report, the commit- organization, which is permitted little or no respite from tee recommends the following sources: Karanasiou et al., high-tempo decision making and little organized sleep. 2008; Fins and Shapiro, 2007; Illes, 2007a and 2007b. The use and abuse of socially sensitive cultural impediments demographic categories as indicators of Neural state and Performance capability The emergence of new bio- and neurotechnologies per- mits categorizing the human population into subsets having As the preceding discussions on societal issues sug- either increased or decreased susceptibility to disease and gest, the committee supports and encourages scientifi- stress on the basis of their genotype and their phenotype.7 cally validated neuroscience applications across the Army- relevant areas highlighted in Table 2-1 and addressed in detail throughout the report. Ethical considerations, such as 7Phenotype is the result of genes plus environment, and epigenetic changes those related to genetic screening or improper disclosure of that occur in the individual after conception may play an important role.

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2 NeUROSCIeNCe AND THe ARMY personal medical information, are important constraints that T he work by Ursano et al. (2008) illustrates how need to be considered, even when the science is adequate the neurosciences can extend and inform behavior-based for a potential application. In addition, there are a number of findings—such as the PTSD studies cited above—by open- issues that require further consideration before being pursued ing the way to reliable indicators. Their work indicates that for possible Army application. the 5-HT2A receptor, p11 protein, and associated regulators One of these issues—the use of performance-enhancing may play a role in PTSD-related response to stress experi- pharmacological agents—was central to the committee’s ences. If this still-preliminary line of inquiry were to lead to decision to distinguish between uses of neuroscience-related suitably sensitive and specific indicators of PTSD suscepti- countermeasures (including pharmacological agents) to ame- bility, then those indicators would be candidate criteria for liorate a deficit in performance due to a stressor (Chapter 5) selection and assignment decisions, where gender is not. and uses of pharmacological agents to enhance performance In short, whether one is female or male is not the issue; it beyond an individual’s baseline capability (Chapter 6). is one’s neurophysiological sensitivity to a definable level Cautions and caveats appropriate for these two contexts of and type of environmental stress for which the Army needs application are included in both chapters. validated, reliable indicators. A second major area in which caution must be exercised Over the past half-century and longer, American society when considering application to Army-relevant problems has traveled a long and difficult road to break away from c oncerns statistically significant differences in group- unscientific stereotypes about gender, “race,” and other averaged neural states or activity patterns—or even differ- previously accepted ways of categorizing individuals to ences in behavior—between a demographically defined sub- define their suitability for various roles and responsibilities. population and a reference population. In the case of gender, The committee’s deliberations on how to deal with research such differences are typically expressed as a comparison of on gender differences and other demographic categories male and female subpopulations. For other subpopulations acknowledged these societal issues. In light of its concerns of societal interest, such as ethnocultural identity, age, or about applying group-averaged statistical differences to indi- socioeconomic status, comparisons may be drawn either viduals within a group, the committee decided to emphasize between one such category (e.g., African-Americans, young individual variability in neural-based traits and tendencies people between 18 and 25) and the general population or as a more appropriate way to address observed distribu- among subpopulation categories within a classification (e.g., tions in a population of interest. By focusing attention on comparisons among ethnocultural groups or age groups). individual variability and the search for reliable indicators In most cases, these differences, even when statistically of that variability, the committee hopes to avoid unscientific significant, represent differences in population distributions and unethical application of findings about behavior and where the distributions have substantial overlap. From an neurophysiology in ways that would negate our hard-won epidemiological perspective, the statistically significant dif- progress toward fair treatment and equal opportunity. ference in the distributions justifies identifying membership in certain subpopulation categories as a differential risk reFereNces factor. However, for purposes such as selecting, assign - Aston-Jones, G., and J.D. Cohen. 2005a. Adaptive gain and the role of the ing, or qualifying individuals for a task, the overlap in the locus coeruleus-norepinephrine system in optimal performance. Journal subpopulation distributions means that these categories lack of Comparative Neurology 493(1): 99-110. the sensitivity and specificity to be reliable indicators of the Aston-Jones, G., and J.D. Cohen. 2005b. An integrative theory of locus neural state or behavior of interest. Rather than relying on a coeruleus-norepinephrine function: Adaptive gain and optimal perfor- familiar but scientifically indefensible population category mance. Annual Review of Neuroscience 28: 403-450. Atkinson, A.J., Jr., W.A. Colburn, V.G. DeGruttola, D.L. DeMets, G.J. as a criterion, the appropriate use of neuroscience insights Downing, D.F. Hoth, J.A. Oates, C.C. Peck, R.T. Schooley, B.A. Spilker, is to seek out one or more truly reliable indicators for the J. Woodcock, and S.L. Zeger. 2001. Biomarkers and surrogate endpoints: variable of interest. Preferred definitions and conceptual framework. Clinical Pharmacology As a simple but germane example, a number of behavioral & Therapeutics 69(3): 89-95. epidemiologic studies have found that women are at greater Bakker, A., C.B. Kirwan, M. Miller, and C.E.L. Stark. 2008. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science risk for developing PTSD, given similar stress experiences, 319(5870): 1640-1642. than men (e.g., Breslau and Anthony, 2007; Turner et al. Belenky, G., N.J. Wesensten, D.R. Thorne, M.L. Thomas, H.C. Sing, D.P. 2007). Should this difference in relative risk be used, for Redmond, M.B. Russo, and T.J. Balkin. 2003. Patterns of performance example, to exclude women from high-stress combat situa- degradation and restoration during sleep restriction and subsequent tions? The committee’s position is that gender is not a suf- recovery: A sleep dose-response study. Journal of Sleep Research 12(1): 1-12. ficiently reliable indicator of the PTSD outcome to be used as Breslau, N., and J.C. Anthony. 2007. Gender differences in the sensitivity to a criterion in selecting and assigning individual women, even posttraumatic stress disorder: An epidemiological study of urban young though the studies establish being female as a risk factor for adults. Journal of Abnormal Psychology 116(3): 607-611. PTSD. The numbers of false positives and false negatives are too high; the correlation lacks sensitivity and specificity.

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