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8 Long-Term Trends in Research Chapters 3 through 6 identified and discussed near- to • Recognizing opportunities from the vertical integra- medium-term research opportunities that the committee tion of neuroscience levels. judges could have high value for Army applications. The • Gaining new insights into the behaviors of committee’s specific recommendations on these opportuni- adversaries. ties are presented in Chapter 9. Task 4 of the statement of task asks the committee to “determine trends in research and Trend 1: Discovering AND VALIDATINg commercial development of neuroscience technologies that bIOMARKERS OF neural stateS LINKED TO are likely to be of importance to the Army in the longer term.” SOLDIERS’ PERFORMANCE OUTCOMES Important long-term trends in technology development were discussed in Chapter 7, along with specific technology oppor­ As discussed in Chapters 3 through 6, the cognitive and tunities evaluated by the committee. This chapter presents behavioral performance of soldiers in many areas—training important long-term trends in neuroscience research, includ- and learning, decision making, and responding to a variety of ing research aimed at expanding our fundamental under- environmental stressors—has substantial neurological com- standing and applied research that has particular relevance ponents. How the brain functions, even how it is functioning for the Army. The committee believes the Army should moni- at a particular time, makes a difference in these and other tor the progress of research in these areas and evaluate the types of performance essential to the Army’s missions. The results for promising Army-relevant applications. In addition techniques used to study and understand brain functioning to the research trends themselves, the chapter describes the at all levels—from the molecular and cellular biology of the type of mechanism needed for monitoring progress in both brain to observable behavior and soldier interactions with research and technology development. other systems—are providing an ever-increasing number The soldier is the centerpiece of every Army operation, of potential indicators of neural status relevant to Army and the Army will always depend on its soldiers to accom- tasks. The Army will need to monitor these techniques plish its missions. Just as physics and chemistry are the foun- and technologies for their potential to serve as biomarkers dational sciences for military ballistics and platform systems, of differences in neural state that reliably correlate with neuroscience as defined in this report is the foundational changes in performance status. To illustrate this tendency science for the soldier. The foremost research objectives for performance biomarkers to emerge from the methods of of the Army should include increasing the survivability of studying the brain, three broad kinds of such methods are dis- soldiers, both in combat and under the other extreme condi- cussed here: genomic and proteomic markers, ­neuroimaging tions in which they operate, while sustaining and enhancing techniques, and physiological indicators of neural state or their performance. behavioral outcome. With these soldier-focused objectives in mind, the com- mittee has identified four trends to represent the breadth and Genetic, Proteomic, and Small-Molecule Markers potential importance of research in neuroscience: The development and functioning of the central and • Discovering and validating biomarkers for neural peripheral nervous systems of all animals, including ­humans, states linked to soldiers’ performance outcomes. are regulated by genomic and proteomic factors. The • Using individual variability to optimize unit g ­ enomic factors are associated with the nucleic acids of every performance. cell. From embryonic development through senescence, the 93

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94 OPPORTUNITIES IN NEUROSCIENCE FOR FUTURE ARMY APPLICATIONS inherited genome and epigenetic modifications of it regulate quantify one or more neural (cognitive/behavioral) states the expression of proteins critical for neural cell functions. relevant to the status of the individual’s current abilities. This regulated gene expression produces signaling elements Neurohormones and neuropeptides—biologically active (transmitters), signal receivers (receptors), guidance of com- molecules much smaller than proteins or the nucleic acids munication processes (axons and dendrites), and cell–cell of the genome—are another emerging class of markers of recognition materials. neurological and cognitive state and of psycho­physiological Known genetic markers may, for example, allow iden- r ­ esponse to stress. A study of candidates for the U.S. Navy tification of individuals at greater risk of damage from Sea, Air, and Land Forces (SEALs) found that candidates exposure to chemical agents or more likely to succumb to with strong stress-hormone reactions to behavioral chal- post-traumatic stress disorder. The cost of genetic tests is lenges like abrupt changes or interruptions are less likely likely to decrease substantially in the next decade, while their to complete training successfully than those with weak effectiveness will increase markedly. Of the 20,000-25,000 r ­ eactions (Taylor et al., 2006, 2007). Another example is the genes in the human genome, more than 100 are involved in work discussed in Chapter 3 on oxytocin, a neuropeptide axonal guidance alone (Sepp et al., 2008). At least 89 genes signal, which is released when an individual experiences a have been shown to be involved in the faulty formation of the sense of trust (Kosfeld et al., 2005; Zak et al., 2005). Hor- axon’s myelin sheath (dysmyelination), associated with the monal markers are easily gathered with simple blood draws. development of schizophrenia (Hakak et al., 2001). Under­ The level in the bloodstream of a neural signaling molecule standing the human genes associated with development of such as oxytocin has at best a very indirect relationship to the brain and peripheral nervous system can shed light on its level in the brain; it may be necessary to figure out how differential human susceptibilities to brain injury and may to monitor its release in the hypothalamus. The monitoring aid in predicting which pharmacological agents will be use- of neurohormones and neuropeptides is likely to be a power- ful for sustaining performance. The Army should position ful means of identifying individuals who are well suited to itself to take advantage of the continuing scientific progress particular tasks and may lend itself to assessing candidates in this area. for Special Operations training in particular. A proteomic marker (a type of biomarker) is a protein (generally an enzyme) whose concentration, either systemi- Neuroimaging Techniques cally or in specific tissues, can serve as a reliable and readily measurable indicator of a condition or state that is difficult Neuroimaging technologies available in the 2008-2010 or even impossible to assay directly. Small variations in time frame allow visualization of brain regions that are acti- gene structure (polymorphisms) are often associated with vated during action-guiding cognitive processes such as deci- differences in concentration of a particular protein in a par- sion making. These activation patterns enable brain activity ticular tissue of a particular individual, so there are important to be correlated with behavior. These imaging technologies linkages between genetic factors and proteomic markers. and techniques include structural magnetic resonance imag­ However, specific enzyme concentrations (including tissue- ing for volumetric analysis of brain regions, functional specific concentration) can also be influenced (upregulated magnetic resonance imaging (fMRI) for cognitive control or downregulated) in response to environmental factors that networks, diffusion tensor imaging for transcranial fibers, vary on timescales of hours, or roughly the timescale of and hyperspectral electroencephalography (EEG). preparation for and conduct of an Army operation. Thus, proteomic markers can vary with recent or current conditions Applications to Soldier Training (environmental stressors, for example) and can also reflect the genetic traits of an individual soldier. As an example relevant to evaluation of training, fMRI Proteomic markers known to signal a change in scans before and after training sessions can be compared to vigilance or cognitive behavior include salivary amylase, examine changes in the brain’s response to novel training- blood homovanillic acid (which correlates with dopamine related stimuli. Novel visual and auditory inputs activate m ­ etabolism), and lactic acid (a metabolic product of the brain in specific regions. An analysis of event-related glucose ­ metabolism that increases as a result of intense potentials combined with fMRI before and after novel audi- muscle ­exercise). Proteomic factors associated with fatigue tory cues revealed that a particular event-related potential (a resistance include microtubule-associated protein 2 and P300-like potential, which is to say a positive potential occur­ the ­ muscarinic acetylcholine receptor. Comparison of an ring approximately 300 msec after a triggering stimulus) is individual’s current concentration (titer) of one of these associated with fMRI patterns of activity in the bilateral foci proteomic markers with his or her baseline titer could 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 An a strong response of the second type also have fMRI scans epigenetic modification refers to changes in gene expression from mechanisms other than alteration of the underlying DNA sequence. showing activation in the right prefrontal cortex. These

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LONG-TERM TRENDS IN RESEARCH 95 observations suggest that an indicator based on combining E ­ xpected improvements in the next 5 years include advanced fMRI and event-related potential could be used to assess designs for multichannel data collection from cortical ­sources. training to criterion. At criterion—for example, when 90 per- In the 10- to 20-year time frame, one R&D opportunity is to cent of the appropriate responses are exhibited in response to use NIRS for more accurate imaging of the deeper brain. a cue—effective training will no longer elicit a “novel-type” brain functional response or event-related potential response Physiological Indicators of Neural-Behavioral State (Opitz et al., 1999). Fear is a critical response to threat that can compromise Physiological indicators include individual character- appropriate action of an individual soldier or an entire Army istics such as age, gender, muscle power, neuroendocrine unit. To incorporate desensitization to fear-invoking situa- effects, neuromuscular function, vascular tone, and circadian tions into soldier training, fMRI scans could be compared cycling. While neural information processing is primarily b ­ efore and after training to determine which environments a result of brain functioning and can be revealed by brain elicit fear-correlated neural activity patterns. A prime imaging, the general wellness and physiological condition e ­ xample is the response of soldiers in Operation Desert of the entire human organism can affect combat capability Shield and Operation Desert Storm when sensors for chemi- and response to threat. This is true in large part because the cal warfare agents indicated that the environment might brain depends on nutrient input (e.g., glucose and oxygen) contain an active agent. These fear-invoking events led to via the circulatory system and on neuroendocrine function significant disorganization of military units, even when the involving other organ systems. (The complex interactions sensor warnings were false positives. between the brain and other organ systems of the body were discussed in Chapters 2 and 5.) For Army applications, physiological indicators of Tracking Change in the Visual Field neural state are important because they are often more read- The ability to track dynamic changes in objects present ily accessible and measurable in the field than more direct in a soldier’s visual field is of great benefit to Army person- indicators of neural state derived from neuroimaging tech- nel. Examples include the sudden appearance of a potential niques. As discussed in Chapter 2 in the section on reliable threat on a Force XII Battle Command Brigade and Below biomarkers for neurophysiological states and behavioral display and the apparent change of terrain indicating recent outcomes and in Chapter 7 in the section on field-deployable placement of an improvised explosive device (IED). Jeremy biomarkers, the idea is to find a monitorable physiological Wolfe of Harvard has demonstrated that the visual system condition that correlates to a neural state with sufficient must focus on only a very limited region within the ­visual a ­ ccuracy and precision to be useful as a reliable sign of that field to detect change (Angier, 2008). To accommodate state. Often, the laboratory studies that define the neural state h ­ uman limitations, fMRI neurotechnology could be used and establish the correlation will begin with neuroimaging to detect minor changes in the visual field and correlate techniques (such as fMRI). them with activation events in the hippocampus (Bakker et al., 2008). Related research has shown that shifts in visual Trend 2: Using Individual Variability To attention to objects in a field of view tend to occur either Optimize Unit Performance as a series of microsaccades (rapid naturally occurring eye movements) or in response to cueing signals in the field of Early systems neuroscience experiments used functional view. Recent studies suggest that the latter is more important neuroimaging tools—fMRI, positron emission tomography, (Horowitz et al., 2007). EEG, or magnetoencephalography—to learn how the vari- ous brain systems process cognitive and affective functions (Van Horn et al., 2004). It has become increasingly clear that Leveraging Opportunities for Neuroimaging Techniques individuals do not process tasks in the same way but instead EEG and EEG image processing will continue to engage different brain systems, with the particular systems a ­ dvance, and EEG will be incorporated in multimodal engaged depending in part on the underlying default brain imaging equipment with magnetic resonance imaging and state (Greicius et al., 2003; Esposito et al., 2006). Neuro- magnetic encephalography. The high-payoff opportunity scientists are increasingly appreciating the importance of here is to leverage this work to develop a sensor array that interindividual variability regarding which neural signals can be used on a free-moving subject. A good initial goal for are operative during various tasks. Instead of being discour- proof-of-concept would be the collection of stable trace data aged by this variability, investigators have begun to use its from a treadmill runner. enormous potential for optimizing training and performance. For neuroimaging with near-infrared spectroscopy Paying attention to this variability helps in understanding (NIRS), DARPA has been active in R&D on NIRS ­ sensor how different individuals learn differently when acquiring a ­ rrays that can be worn in situ. This is an opportunity to a skill or how they organize their behavior when faced with a ­ dvance a noninvasive cerebral blood monitoring tool. extreme conditions.

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96 OPPORTUNITIES IN NEUROSCIENCE FOR FUTURE ARMY APPLICATIONS How the Individual Variability Insight Affects the Army levels of brain-derived neurotrophic factors or other factors expressed in brain tissue). Western and Eastern cultures pro- The significance for the Army of this paradigm-shifting cess mathematics differently (Tang et al., 2006), and there insight from neuroscience is profound. Understanding in a is every reason to expect that such cultural differences will systematic way the variability among individuals in brain also exist in other cognitive processing tasks. Identifying and processing when performing the same task is an initial step understanding these differences will be critical in such appli- toward understanding the systematic differences from one cations as interacting with noncombatants in peacekeeping or individual to another in how they respond in similar circum- in security and stability operations (SASO) missions, as well stances. For example, some individuals engage emotional as in predicting adversary responses and decision making. processing areas even in simple but challenging cognitive A still-open question is whether such cultural and tasks (McIntosh et al., 1996; Beauregard et al., 2001). It individual differences exist all the way down to the genetic/­ would be important to determine whether activation of cellular level or whether they disappear at some level. To these emotional processing areas helps or interferes with use the deception example, even if cultural conditioning (or the cognitive task at hand. If it helps in performing the task, specific training) means that some individuals do not show perhaps others can learn to enhance their performance on “normal” physiological or neural indicators of deliberate that type of task if they are trained by methods that activate lying, is there some type of monitoring that could detect if the emotional processing areas. If such activation interferes a subject being interrogated is responding in a “contrary-to- with the cognitive task, one might implement training strate- truth” manner? gies that attenuate the effects of emotional processing. Most important, however, whether performance of a cognitive task is enhanced or degraded by emotional processing may differ TREND 3: RECOGNIZING Opportunities from the across groups of individuals. In this case, an optimal training Vertical Integration of Neuroscience Levels program would develop modulation strategies tailored for a As discussed in Chapter 2, neuroscience exists on four particular group. hierarchical levels, which are now being vertically integrated, The significance of individual variability for optimiz- from the levels of molecules and cells to the levels of behavior ing task performance extends to areas other than training and systems. Increasingly, discoveries and advances at one and learning. Chapter 4, for example, noted that individuals level are leading directly to discoveries and advances at levels show traitlike (i.e., stable for the individual over time) differ- higher and lower in the hierarchy. Given this trend, the Army ences in decision-making styles. Chapter 5 emphasized the needs to remain cognizant of research in multiple fields that importance of individual variability in neurophysiological could impact neuroscience applications on multiple levels. responses to stressors typical in Army mission environments One such opportunity will serve as a simple example: and in responses to countermeasures to those stressors. Given At the level of behavioral research, a variety of methodolo- that what needs to be optimized from the standpoint of Army gies can be used to assess soldier response. Among these are operations is performance of the unit, not the individual, the measures of the efficiency with which a task is performed, insight from neuroscience is that a higher optimum may be subjective self-assessments, and psychophysiological cor- achievable and sustainable by learning to work with and relates. Often the outcomes from these separate methodolo- exploit individual variability rather than treating soldiers gies more or less converge. For instance, as an individual’s as interchangeable parts to be mass-produced on a training performance of a task degrades, the individual also sub- assembly line. jectively feels more stressed by the demands of the task. Convergence of the assessment results increases confidence Neural Correlates for Cultural Differences in Behavior that we understand the responses. However, what happens when methodologies from the same or different levels in the Even as it comes to accept this insight into the sub- hierarchy produce results that do not converge? Divergence stantial neurological basis for interindividual variability, raises the question of which technique is a better indicator the Army will still need to look for some general patterns of the subject’s real condition, that is, of the “ground truth” in variability from which to draw statistically valid general (Yeh and Wickens, 1988; Hancock, 1996). Often the ques- conclusions—that is, the conclusions might be expressed in tion can be answered by moving up or down in the hierarchy terms of a distribution in a given population or culture rather of integrated levels to determine, for example, which of the than as single-point characterizations or predictions. As a divergent neuroimaging results is consistent with a behavior simple example, there are cultural differences in attitudes conventionally used to define a neural state of interest. Or, to deception that often depend on the social role of the indi- one might test whether seemingly similar behaviors are truly vidual. There are also well-established gender differences in the same by examining activation patterns from one or more neural correlates of behaviors, such as social responsiveness neuroimaging techniques. (Proverbio et al., 2008) and reward anticipation (Hoeft et al., Another example of an opportunity derived from the ver- 2008), and some differences are linked to proteomics (e.g., tical integration hierarchy is this: The neuroscience literature

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LONG-TERM TRENDS IN RESEARCH 97 contains many cases in which neurological signals indicate the Army in terms of both the overarching implications of that an attentive brain has processed a signal but the subject, such understanding and the concrete mechanisms of neuro- when asked, denies any conscious knowledge of such pro- logical changes. Understanding the neural correlates of this cessing. Are such cases of divergence between assessments change may, for example, help an intelligence analyst to also exhibited at different levels—perhaps a general pattern predict when responses of potential adversaries (or of non­ of response divergence—or are they a function of the task combatants potentially allied with the Blue or Red force) that is imposed, of differences in the assessment methods, will reverse direction. of characteristics of the individual being tested, or of some other combination of factors? A Mechanism for MoNITORING Neuroscience Divergence of results is likely to become more frequent, RESEARCH AND TECHNOLOGY at least for a time, as neuroscience assessment methods proliferate. When results from multiple neuroimaging Neuroscience research and applications are advancing techniques diverge, is this evidence that the physical signal at a lightning-like pace, and the Army needs to continually to which a neuroimaging technique is responding is inher- assess the potential of these advances. The growing knowl- ently different from the signal to which another technique edge base will have many direct and indirect applications is responding? Or, is it instead an idiographic characteristic to soldiers, applications that will increase their operational of the individual being tested, or perhaps just an artifact of effective­ness. A neuroscience monitoring group, consist- nuances in the imposed task and the task environment? As ing of recognized leaders in neuroscience research in both they have throughout the history of any scientific discipline, the ­ academic and business communities, would help those such divergences spur and orient further inquiry into the m ­ aking Army science and technology funding decisions to methodologies themselves and whether the phenomena they assess the relevance of progress in nonmilitary neuroscience transduce as an information signal are in fact correlates of to Army applications. Research results and emerging tech- the same underlying reality (here, brain function or process- nology can be relevant, whether through direct adaptation ing event). The Army can leverage the ongoing research for Army use or as a starting point for further Army-oriented efforts on neuroscience methods, especially with regard to R&D, funded or otherwise fostered by the Army. To ensure the method(s) it selects for field implementation. In short, as that this monitoring group remains sensitive to and keeps neuroscience applications come to use two or more neuro- abreast of Army needs, its membership should include Army imaging techniques, the Army can benefit from the natural civilians and soldiers with appropriate backgrounds and inter- direction of inquiry, which is to investigate and resolve seem- ests to participate meaningfully in the group’s deliberations. ingly divergent results. The committee envisions that such a monitoring group would operate mainly by attending and reporting on the pre- sentations at conferences and other meetings of professional TREND 4: GAINING New Insights INTO societies for the neuroscience-relevant disciplines. Of course, Adversary Response the journals of these societies are also important sources of Negative social interactions, such as the emergence and information, but they may not contain ideas, research accom­ growth of distrust or the initiation of hostile behavior, are a plishments, or information on commercial products, all of relevant aspect of social neuroscience. The neural correlates which can be gathered by participation in and interactions of these types of social behavior are not yet well understood. at professional meetings. Once the nascent and emerging However, fairly simple interventions at the neural level hot topics are identified, the published literature becomes a can have substantial, if temporary, effects on higher-level useful tool for documenting them and covering their prog- functioning, such as the administration of thiopental sodium ress. The monitoring group would be alert to neuroscience (Pentothal), a medical anesthetic for psychotherapy under advances and opportunities reported through national and seda­tion in order to recover repressed memories together with international societies and organizations promoting neuro­ the emotion that accompanied the repressed experience. science and neuroscience-related research and collabora- The work with the neuropeptide oxytocin, described tions of value to the Army. Examples of such organizations in Chapter 3, indicates that this neural signaling agent is include these: associated with the bonding of offspring and parents and of intimate couples and that it is released under condi- • Cognitive Neuroscience Society, tions that evoke trust between individuals. Similarly, recent • Federation of European Neuroscience, neuro­science experi­ments have revealed that individuals • Human Factors and Ergonomics Society, show specific brain-related changes when engaging in • International Society for Magnetic Resonance in a ­ ltruistic behavior (Moll et al., 2006). Understanding how Medicine, the ­human brain changes as individuals turn to confrontation • Organization for Human Brain Mapping, from coopera­tion or turn an adversarial relationship into a • Radiological Society for North America (focuses on friendly one provides an important scientific opportunity for commercial imaging),

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98 OPPORTUNITIES IN NEUROSCIENCE FOR FUTURE ARMY APPLICATIONS • Society for Neuroscience, and Hancock, P.A. 1996. Effect of control order, augmented feedback, input • Society of Automotive Engineers. device and practice on tracking performance and perceived workload. Ergonomics 39(9): 1146-1162. Hoeft, F., C.L. Watson, S.R. Kesler, K.E. Bettinger, and A.L. Reiss. 2008. There are also regular conferences that the Army can Gender differences in the mesocorticolimbic system during computer monitor to track the rapidly developing field of computa- game-play. Journal of Psychiatric Research 42(4): 253-258. tional neuroscience. These include the Neural Information Horowitz, T.S., E.M. Fine, D.E. Fencsik, S. Yurgenson, and J.M. Wolfe. Processing (NIPS) conference, the biannual Statistical Anal- 2007. Fixational eye movements are not an index of covert attention. Psychological Science 18(4): 356-363. ysis of Neural Data (SAND) workshop, the annual Compu- Kosfeld, M., M. Heinrichs, P.J. Zak, U. Fischbacher, and E. Fehr. 2005. tational and Systems Neuroscience (Cosyne) meeting, the Oxytocin increases trust in humans. Nature 435(7042): 673-676. annual Computational Neuroscience meeting, and the annual McIntosh, A.R., C.L. Grady, J.V. Haxby, L.G. Ungerleider, and B. Horwitz. D ­ ynamical Neuroscience meeting. The meetings are a venue 1996. Changes in limbic and prefrontal functional interactions in a work- for discussions on recent work in the fields of computational ing memory task for faces. Cerebral Cortex 6(4): 571-584. Moll, J., F. Krueger, R. Zahn, M. Pardini, R. de Oliveira-Souza, and J. neuroscience modeling and signal processing. G ­ rafman. ������������������������������������������������������� 2006. Human fronto-mesolimbic networks guide decisions The number of Army representatives attending a con- about charitable donation. Proceedings of the National Academy of ference should be large enough to allow coverage of simul- Sciences of the United States of America 103(42): 15623-15628. taneous sessions that may contain relevant research: two Opitz, B., A. Mecklinger, A.D. Friederici, and D.Y. von Cramon. 1999. The or three persons for smaller conferences, six or more for functional neuroanatomy of novelty processing: Integrating ERP and fMRI results. Cerebral Cortex 9(4): 379-391. large gatherings. Each attendee could generate a report to Proverbio, A.M., A. Zani, and R. Adorni. 2008. Neural markers of a greater the Army and one of them could summarize the advances female responsiveness to social stimuli. BMC Neuroscience 9: 56. and identify possible Army applications. At least yearly, Sepp, K.J., P. Hong, S.B. Lizarraga, J.S. Liu, L.A. Mejia, C.A. Walsh, the ­ entire monitoring group would gather, together with and N. Perrimon. 2008. Identification of neural outgrowth genes using additional military guests, to share new Army needs and genome-wide RNAi. Available at info%3Adoi%2F10.1371%2Fjournal.pgen.1000111. Last accessed to discuss the group’s recent findings and expectations for August 19, 2008. Army-relevant neuroscience. Tang, Y., W. Zhang, K. Chen, S. Feng, Y. Ji, J. Shen, E.M. Reiman, and Y. Liu. 2006. Arithmetic processing in the brain shaped by cultures. Proceedings of the National Academy of Sciences of the United States References of America 103(28): 10775-10780. Angier, N. 2008. Blind to change, even as it stares us in the face. New York Taylor, M., A. Miller, L. Mills, E. Potterat, G. Padilla, and R. Hoffman. ������ 2006. Times, April 1, 2008, p. F2. Predictors of success in Basic Underwater Demolition/SEAL (BUD/S) Bakker, A., C.B. Kirwan, M. Miller, and C.E.L. Stark. 2008. Pattern �������������� training. Part I: What do we know and where do we go from here? 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Nature ­Neuroscience impact of active thinking. Brain Research Bulletin 70(4-6): 263-269. 7(5): 473-481. Greicius, M.D., B. Krasnow, A.L. Reiss, and V. Menon. 2003. Functional Yeh, Y.Y., and C.D. Wickens. 1988. Dissociation of performance and subjec- connectivity in the resting brain: A network analysis of the default mode tive measures of workload. Human Factors 30(1): 111-120. hypothesis. Proceedings of the National Academy of Sciences of the Zak, P.J., R. Kurzban, and W.T. Matzner. 2005. Oxytocin is associated with United States of America 100(1): 253-258. human trustworthiness. Hormones and Behavior 48(5): 522-527. Hakak, Y., J.R. Walker, C. Li, W.H. Wong, K.L. Davis, J.D. Buxbaum, V. Haroutunian, and A.A. Fienberg. 2001. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proceedings of the National Academy of Sciences of the United States of America 98(8): 4746-4751.