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WEEK ONE: HOW DOES THE BRAIN WORK? | ESSAY THREE Mind in the Brain By Dr. Joy Hirsch The mind and brain are an inseparable unit. This amazing idea is the foundational principle of current neuroscience. In The Astonishing Hypothesis, Francis Crick eloquently illuminates this fundamental principle: "You, your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are, in fact, no more than the behavior of a vast assembly of nerve cells and their associated molecules." As Lewis Carroll’s Alice might have phrased it: "You’re nothing but a pack of neurons." This notion is potentially as powerful as Crick’s earlier discovery of the molecular structure of DNA and the genetic code that builds each of us. However the basic mechanisms that couple biology and behavior remain a relative frontier in science. That intimate coupling between molecules, cells, circuits and behavior is evident, for example, in the notable discoveries of the molecular basis of memory and smell by Eric Kandel and Richard Axel who each received recent Nobel prizes for these advances. Widespread and growing acceptance of this notion is also evident in the “neurocentric” vocabulary that enriches our everyday language with words like neuromarketing, neuroeconomics, neuropolitics, neurophilosophy, neuroethics, and neurolaw. As suggested by these hybrid words, the behavior of neurons is incorporated into mainstream conversation and thought, and traditional academic disciplines can now be considered “life sciences.” This includes disciplines such as economics, law, business, finance, marketing, and psychology, in addition to the traditional medical disciplines of neurology, psychiatry, surgery, medicine and radiology. New sciences have also emerged. The decision sciences, for example, have the potential to enhance our understanding of topics such as “personal identity and free will” in terms of executive control, and biases in situations of uncertainty and risk based on the behavior of neural systems. On the “home front,” this new neurocentric view has many advantages. We now have new cognitive tools to cope with everyday anxieties such as taking a plane or getting stuck in an elevator. These tools can be used to say “amygdala be still” when anxiety strikes. Motivation to resist a chocolate chip cookie can be conceptualized by recalling a neural model of cognitive control that translates this temptation into a “tug-of-war” between reward and executive control systems. From this point of view, a “tug” from the executive control branch of neural systems increases resistance to the tempting power of chocolate chip cookie. Answering a phone, reading email, and navigating life’s treacherous political landscapes become the putative handiwork of “a vast assembly of neurons” purposed for executive functions. Along the same lines, this astonishing hypothesis provides a context for important personal decision-making, such as choosing a life partner. For example, the “vast assembly of nerve cells and their assorted molecules” sprinkled with various neurochemical cocktails in my basal ganglia are presumably the basis for my love and attachment to my husband. Earlier in my academic journey I would have resisted this biological perspective on the grounds that a physical basis for such a complex life choice would diminish its grandeur and centrality. This dismissive view of the role of neurons relating to the quality of human experience is common in our culture. Crick’s rephrasing of Lewis Carroll’s famous quote--“You’re nothing but a pack of neurons” -- implies that a biological basis somehow diminished the value and meaning of our emotions and feelings. Emerging advances in neuroscience have not erased this notion, but have embraced the challenge of integrating neural machinery as an underpinning for behavior and emotion. However, we are now challenged to understand how the workings of a brain actually create “joys and sorrows and memories and ambitions, personal identity and free will” as well as shared love between life partners. This is the goal of the new “science of mind.” Science of mind starts with wonder: how can a “pack of neurons” achieve the biological perfection that yields the essence of our humanity, attachments, and inner lives? We have long been aware that feelings begin as signals from the outside world that bombard sensory systems with packets of energy. For example, sound pressure energy on the eardrums is transduced by delicate membranes in our inner ear and then communicated to neurons in Heschl's gyrus to create the foundation for the experience of sound. Further processing of those neural signals leads to language, music, meaningful information, and even emotions. Specialized neurons in the back of the eye convert energy from photons within a specific range of radio frequencies into the perception of light, and then to color, shape, objects in scenes, and visual contexts that meaningfully connect us to the visible world. Similarly, the smell of coffee starts as an airborne molecule that is captured by dedicated neurons in the epithelial layer of nasal passages and converted to a delightful aroma. The unrestrained joy conveyed by wet and cold kisses from a dog who has been waiting all day for you to return starts with mechanical receptors in the face and hands. Those receptors signal sensory motor neurons to start an orchestra of neural signals to generate visual, auditory, and emotional components that integrate to convey a moment of unconditional love. Yes, at the root of who we are and how we experience the universe, neurons rule. But how do they do it? Historically, quantum leaps in science have been made in conjunction with advances in imaging technology. The microscope enabled views of infinitely small subunits of life forms, and the telescope enabled views of infinitely large solar systems. Each extended the boundaries of the human eye and mind, and our scientific understanding of the principles that govern life and the universe. Current brain imaging technology is equally revolutionary. Functional MRI (fMRI) provides views of the brain while dynamically engaged, enabling neuroscientists to discover the relationships between specific mental operations and the associated working parts of the brain. Although a relatively new discipline, functional neural imaging has taken us far into the unknown territory of the biology that underlies who we are, altering how we think about ourselves and each other. I think of this technology as a “mindoscope”, a “scope” to reveal the mind in the landscape of the brain. It marries two disciplines: imaging sciences and behavioral sciences. A conventional MRI uses a magnetic resonance signal to reveal the structure of a living human brain. Functional MRI uses the same signal to track oxygen levels in the blood, and, because active neural tissue consumes more metabolites than resting neural tissue and uses more oxygen, increases in the flow of oxygenated blood indicate neural activity. This occurs when the brain is engaged during a specific task. Figure 1 shows a research volunteer preparing for a functional imaging study of the languagesensitive regions of the brain. Figure 1. Functional MRI study A research subject is shown preparing to go into the Hirsch Laboratory fMRI scanner at Columbia University School of Medicine. The task that he will perform while in the scanner is to silently name the pictures (illustrated on the side panels) as they are presented to him via a back projection screen. The object naming task employs “internal or silent speech” to avoid the head movements associated with spoken speech. The pictures are presented in 15 second blocks that alternate with 15 second rest epochs. ©AMNH Enlarge image » Findings from functional imaging studies are commonly represented as yellow and orange points and clusters of points on magnetic images of the brain. These colors identify active regions and become the data for neural imaging studies. Figure 2 illustrates this process. Functional magnetic resonance imaging, fMRI, exploits the most fundamental principle of brain organization, the “real estate” principle: specific clusters of neurons perform specific types of functions. The biology that underlies the roots of conscious experience including perception, thought, and actions, is isolated by experiments that selectively engage specific neural tissue called to action during specific functional tasks. Carefully designed experiments enable scientists to test hypotheses about the mechanisms of signaling between coordinated brain areas. Figure 3 illustrates a few of the well-known functional specificities of brain regions, and much current research is now focused on how these areas communicate to share information. Figure 2. Active areas of the brain The left panel shows an image representing a horizontal slice (axial section) of the subject’s brain. The top of the image is the front of the brain and the right of the image in the left hemisphere. The grid represents the resolution of the image where the voxel (volume element) is 1.5 x 1.5 mm. Each grid box in the figure represents a 5 x 5 array of voxels. The yellow and red regions represent voxels with MR signals that statistically exceed baseline (rest) levels during the object naming task relative to the signal during rest. The panel on the right illustrates such a signal from a single voxel located at (x = 90, y = 35) which is located in the inferior frontal gyrus, left hemisphere, an area known as Broca’s Area as indicated by the label. Broca’s Area is known as a region associated with speech production and language comprehension. ©Joy Hirsch Enlarge image » Figure 3. Brain regions with well-known functions A general illustration of the important principle of functional specialization where specific areas of the brain are specialized for specific functions. This illustration shows the left hemisphere and includes the area specialized for speech production (as illustrated in a real image in Figure 2). In truth the regional specializations are observed on a much finer grain than suggested by this graphic. ©AMNH/Richard Tibbits Enlarge image » Does this explain, “how they do it?” Every neuroimaging tool—including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), electroencephalography (EEG), magnetoencepheography (MEG), and optical imaging—is limited. Many of the hardest questions, like how neurons turn energy packets captured from the environment and absorbed by neural transducers into conscious experience remain beyond our reach at the present time. Nonetheless, current “mindoscopes” segment the healthy brain according to task-related systems. When coupled with rigorously designed experiments, these systems reveal dynamical mechanisms of top-down and bottom-up pathways that influence one another to execute tasks and modulate performance. For example, scientists have recently applied fMRI to discover within-brain processes that modulate behavior, revealing mechanisms that suppress emotional responses, boost detection processes, improve focus on cognitive tasks, and resolve conflict. Several examples of these findings are included in the bibliography at the end. A floodgate of new opportunities to advance how we think about ourselves and our behavior has opened as a result of functional brain imaging studies, and ultimately will translate into advances in patient care and quality of life. A few examples follow. Eating disorders, obesity, and addictions can be studied in terms of the neural circuitry sensitive to reward and executive control. Anxiety disorders and post-traumatic stress may be diagnosed, prevented, and treated by image-guided approaches that reveal the circuitry related to fear. Functional image guided methods may lead to better diagnosis and treatment of developmental disorders such as autism. Figure 4 illustrates ways in which the language system in autistic brains differs from that of typical brains. Note the reduction of brain activity in the frontal areas of autistic subjects. Psychiatric disorders, including dementia, schizophrenia, depression, obsessive-compulsive, and panic disorders may also be diagnosed by characteristic patterns of the neural circuitry, which will inform personalized treatment strategies. Patients whose traumatic brain injury has caused disorders of consciousness can be “given a voice” by reading brain responses to specific passive stimulations or task-related requests. Figure 4. Horizontal (axial) and side (sagittal) views of group images for typical (control) and autistic children Of note is the neural activity within the circled regions that highlight Broca’s Area in left Inferior Frontal Gyrus, LIFG of both sets of images. The children were all age-matched and hearing normal and all participated in an fMRI experiment where they passively listened to a recording of a parent talking to them. Control subjects demonstrate robust activity in LIFG in response to listening to the speech whereas the homologous regions in the autistic children did not respond. These data are consistent with an emerging consensus that neural information processing in autism involves reduced representation in frontal lobe structures for spoken language. ©Joy Hirsch Enlarge image » The applications extend beyond frontiers in medicine. Neural systems engaged when healthy individuals make economic decisions respond with biases related to fear, emotional arousal, and losses and gains. This could alert financial managers to risky or problematic financial decisions. Value and preference may have neural underpinnings, as well as political attitudes, prejudices, and moral judgments. Learning may be guided by neural tendencies, and compensatory mechanisms for memory loss may be neurally guided and strategically enhanced. Even political policy may be thought of in terms of neural responses to variables such as altruism, personal comfort, and perceived safety. The transformative effects of art, poetry and music may also be credited in part to contributions from gifted neurons endowed with complex abilities to connect highly valued stimuli to neural emotiongenerators in the brain. The bibliography also includes a few examples of these findings. As these examples suggest, we can expect a vast array of questions, insights, and medical advances to emerge from the teams of scientists, physicians, and students joined together in the discovery of brain processes that define our humanity. In the context of this new scientific framework and based on the astonishing unity of brain and behavior, we all become students and together travel the “neurojourney” along the road to the mind. This journey leads us to unprecedented opportunities to understand ourselves as wondrous works of nature in which fertile packs of neurons are responsible for a human spirit bursting with creativity, love, beauty, joys, and sorrows. Moment by moment thoughts, sensations, and actions emerge as if they were a bouquet of flowers from the garden of brain. An earlier version was published by the author in Portraits of Mind (edited by Carl Schoonover and published by Abrams, Chapter 7, 200-227, 2010) as a chapter titled “From Brain Structure to Brain Function.” Joy Hirsch, Ph.D. is Professor of Psychiatry and Neurobiology at Yale University School of Medicine REFERENCE BIBLIOGRAPHY Recommended as supplemental reading: Lai, G., Pantazatos, S.P., Schneider, H., Hirsch, J., Neural systems for speech and song in autism, Brain, 2012 Mar, 135(Pt 3):961-75. Summerfield, C., Egner, T., Greene, M., Korchlin, E., Mangels, J., Hirsch, J., Predictive Codes for Forthcoming Perception in the Frontal Cortex, Science (111, v.314, no.5803, 1311-1314), 2006. Egner, T., Hirsch, J., Cognitive control mechanisms resolve conflict through cortical amplification of Task-Relevant information, Nature Neuroscience, 8 (12), 1784-1790, 2005 Hirsch, J., Ruge, M.I., Kim, K.H.S., Correa, D.D., Victor, J.D., Relkin, N.R., Labar, D.R., Krol, G., Bilsky, M.H., Souweidane, M.M., DeAngelis, L.M., Gutin, P.H. An Integrated fMRI Procedure for Preoperative Mapping of Cortical Areas Associated with Tactile, Motor, Language, and Visual Functions. Neurosurgery, 2000, 47(3), 711-722. Kim, K.H.S., Relkin, N.R., Lee, K.M., Hirsch, J. Distinct cortical areas associated with native and second languages. Nature, 1997, 388, 171-174. Recommended for special interests related to the subjects discussed in the text: Karten A, Pantazatos S, Khalil D, Zhang X, Hirsch J. Brain Connectivity. Dynamic Coupling between the Lateral Occipital Cortex, Default Mode and Frontoparietal Networks During Bistable Perception. Brain Connectivity, 2013. doi:10.1089/brain.2012.0119. Pannese, A., Hirsch, J., Unconscious neural specificity for “self” and the brainstem, Journal of Consciousness Studies, 2013. Journal of Consciousness Studies, Volume 20, Numbers 1-2, 2013, pp. 169-179(11) Zhang, X., Hirsch, J., The temporal derivative of expected utility: a neural mechanism for dynamic decision-making, NeuroImage, 2013 Jan 15, 65:22330. Pantazatos, S.P., Talati, A., Pavlidis, P., Hirsch, J. Cortical functional connectivity decodes subconscious, task-irrelevant threat-related emotion processing, Neuroimage, 2012 Mar 28, 61(4):1355-1363. Lai, G., Schneider, H., Schwarzenberger, J., Hirsch, J. Speech stimulation during functional MR imaging as a potential indicator of autism. Radiology, 260(2):521-530, 2011 August. Rodriguez-Moreno, D., Hirsch, J., Giacino, J., Schiff, N., Kalmar, K. A network approach to assessing cognition in disorders of consciousness. Neurology, 75(21):1871-1878, 2010. PMID: 20980667. Rodriguez-Moreno, D., Hirsch, J. The Dynamics of deductive reasoning: an fMRI investigation, Neuropsychologia, 47: 949-961, 2009. PMID: 18835284. Rosenbaum, M., Sy, M., Pavlovich, K., Leibel, R., Hirsch, J. Leptin reverses weight loss– induced changes in regional neural activity responses to visual food stimuli, Journal of Clinical Investigation, 118(7): 2583-2591, 2008. PMID: 18568078. PMCID: PMC2430499. Kelly, C., Grinband, J., Hirsch, J. Repeated exposure to media violence is associated with diminished response in an inhibitory frontolimbic network, PloSONE, 2(12): e1268. Doi:10.1371/journal.pone.0001268, 5 December 2007. Wang, Y., Lin, L., Kuhl, P., Hirsch, J., “Mathematical and linguistic processing in native and second languages,” Brain Imaging and Behavior, 2007; 1: 6882. Kross, E., Egner, T., Ochsner, K., Downey, G., Hirsch, J., Neural dynamics of rejection sensitivity, Journal of Cognitive Neuroscience, 2007; 19(6): 945956. Etkin, A., Egner, T., Peraza, D.M., Kandel, E.R., Hirsch, J., Resolving emotional conflict: a model for amygdalar modulation by the rostral anterior cingulate cortex, Neuron, 51, 871-882, 2006. Grinband, J., Hirsch, J., Ferrera, V.P., A neural representation of categorization uncertainty in the human brain, Neuron, 2006, 49: 757-763. Schiff, N.D., Rodriguez-Moreno. D., Kamal, A., Kim, K.H.S., Giacino, J.T., Plum, F., Hirsch, J. fMRI Reveals Large Scale Network Activation in Minimally Conscious Patients, Neurology, 2005, Vol 64, 514-523. Nuñez, J.M., Casey, B. J., Egner, T., Hare, T., Hirsch, J., Intentional False Responding Shares Neural Substrates With Response Conflict and Cognitive Control, NeuroImage, 2005, Vol 25, 267-277. Etkin, A., Klemenhagen, K., Dudman, J., Rogan, M., Hen, R., Kandel, E., Hirsch, J. Individual Differences in Trait Anxiety Predict the Response of the Basolateral Amygdala to Unconsciously Processed Threat, Neuron, 2004, Vol 44, 1043-1055. Lai, G., Pantazatos, S.P., Schneider, H., Hirsch, J., Neural systems for speech and song in autism, Brain, 2012 Mar, 135(Pt 3):961-75.