Psychotherapy and the Single Synapse 19 cells (Figure 1–5). By contrast, after long-term habituation, only 30% of the sensory neurons produced detectable connections onto the motor cell, and this effect lasted for over a week; these connections were only partially re- stored at 3 weeks. Thus, fully functioning synaptic connections were inacti- vated for over a week as a result of a simple learning experience—several brief sessions of habituation training of 10 trials each. Thus, whereas short-term habituation involves a transient decrease in synaptic efficacy, long-term habituation leads to prolonged and profound functional inactivation of a previously existing connection. These data pro- vide direct evidence that long-term change in synaptic efficacy can underlie a specific instance of long-term memory. Moreover, at a critical synapse such as this one, relatively few stimuli produce long-term synaptic depression. Sensitization Sensitization, the opposite of habituation, is the process whereby an animal learns to increase a given reflex response as a result of a noxious or novel stimulus. Thus, sensitization requires the animal to attend to stimuli that po- tentially produce painful or dangerous consequences. Like habituation, sen- sitization can last from minutes to days and weeks, depending on the pattern of stimulation (Pinsker et al. 1973). In this discussion, I will focus on the short-term form. At the cellular level, sensitization also involves altered transmission at the synapses made by the sensory neurons on their central target cells. Spe- cifically, sensitization involves a mechanism called presynaptic facilitation, whereby the neurons mediating sensitization end on the terminals of the sensory neurons and enhance their ability to release transmitter (Figure 1–6). Thus, the same synaptic locus is regulated in opposite ways by opposing forms of learning: it is depressed by habituation and enhanced by sensitiza- tion. The transmitter released by the neurons that mediate presynaptic facil- itation (which is thought to be serotonin) acts on the terminals of the sensory neurons to increase the level of cyclic AMP (cAMP). Cyclic AMP, in turn, acts (perhaps through phosphorylation of a membrane channel) to in- crease calcium influx and thereby enhance transmitter release (Brunelli et al. 1976; Cedar and Schwartz 1972; Cedar et al. 1972; Hawkins et al. 1976; Klein and Kandel 1978; Schwartz et al. 1971) (Figure 1–7). How effective a restoring force is sensitization? Can it restore the com- pletely inactivated synaptic connections produced by long-term habitua- tion? We have found that study sensitization not only reversed the depressed behavior but restored the effectiveness of synapses that had been function- ally disconnected and would have remained so for over a week (Carew et al. 1979) (Figure 1–6B). 20 Psychiatry, Psychoanalysis, and the New Biology of Mind Psychotherapy and the Single Synapse 21 Thus, in these simple instances, learning does not involve a dramatic anatomic rearrangement in the nervous system. No nerve cells or even syn- apses are created or destroyed. Rather, learning of habituation and sensitiza- tion changes the functional effectiveness of previously existing chemical synaptic connections and, in these instances, does so simply by modulating calcium influx in the presynaptic terminals. Thus, a new dimension is intro- duced in thinking about the brain. These complex pathways, which are genetically determined, appear to be interrupted not by disease but by expe- rience, and they can also be restored by experience. Implications for the Classification and Understanding of Psychiatric Disorders The finding that dramatic and enduring alterations in the effectiveness of connections result from sensory deprivation and learning leads to a new way of viewing the relation between social and biologic processes in the genera- tion of behavior. There is a tendency in psychiatry to think that biologic de- terminants of behavior act on a different “level of the mind” than do social and functional determinants. For example, it is still customary to classify psychiatric illnesses into two major categories: organic and functional. The organic mental illnesses include the dementias and the toxic psychoses; the functional illnesses include the various depressive syndromes, the schizo- phrenias, and the neuroses. This distinction stems from studies in the nine- teenth century, when neuropathologists examined the brains of patients at autopsy and found a disturbance in brain architecture in some diseases and a lack of disturbance in others. The diseases that produced clear (gross) ev- FIGURE 1–5. Long-term habituation (opposite page). In A, a synaptic connection between a sensory neuron (S.N.) and the motor neuron (M.N.) L7 is compared in control (untrained) animals and in animals that have been subjected to long-term habituation training. In control animals, the synaptic connec- tions produce a large excitatory synaptic potential. The synaptic connection in habit- uated animals is undetectable. The sensory neuron was depolarized intracellularly to trigger a single action potential and evoke a synaptic potential in the gill motor neu- ron L7. In B, the mean percentage of detectable connections is shown in control and habitu- ated animals tested at three intervals after long-term habituation training. The error bars indicate the S.E.M. Source. Adapted from Castellucci VF, Carew TJ, Kandel ER: “Cellular Analysis of Long-Term Habituation of the Gill-Withdrawal Reflex of Aplysia californica.” Science 202:1306–1308, 1978. Used with permission. 22 Psychiatry, Psychoanalysis, and the New Biology of Mind Psychotherapy and the Single Synapse 23 idence of brain lesions were called organic, and those that lacked these fea- tures were called functional. Studies of the critical developmental period and of learning have shown that this distinction is artificial. Sensory deprivation and learning have profound biologic consequences, causing effective disrup- tion of synaptic connections under some circumstances and reactivation of connections under others. Instead of distinguishing between mental disor- ders along biologic and nonbiologic lines, it might be more appropriate to ask, in each type of mental illness, to what degree is this biologic process de- termined by genetic and developmental factors, to what degree is it due to infectious or toxic agents, and to what degree is it socially determined? In each case, even in the most socially determined neurotic illness, the end re- sult is biologic. Ultimately, all psychologic disturbances reflect specific alter- ations in neuronal and synaptic function. And insofar as psychotherapy works, it works by acting on brain functions, not on single synapses, but on synapses nevertheless. Clearly, a shift is needed from a neuropathology also based only on structure to one based on function. An Overview Cellular studies of the critical stages of development and of learning have shown that genetic and developmental processes determine the connections between neurons; what they leave unspecified is the strength of the connec- tions. It is this factor—the long-term efficacy of synaptic connections—that is played on by environmental effects such as learning. What learning ac- complishes in the instances so far studied is to alter the effectiveness of pre- existing pathways, thereby leading to the expression of new patterns of behavior. As a result, when I speak to someone and he or she listens to me, we not only make eye contact and voice contact but the action of the neu- FIGURE 1–6. Scheme of circuit for presynaptic facilitation (A) and restoration of synaptic transmission and behavior by a sensi- tizing stimulus after long-term habituation (B) (opposite page). In A, stimuli to the head activate neurons that excite facilitative interneurons (Fac. Int.). The facilitating cells, in turn, end on the synaptic terminals of the sensory neu- rons (S.N.), where they modulate transmitter release. Exc. Int. denotes excitatory in- terneurons, and M.N. motor neuron. In B, a typical undetectable excitatory synaptic potential from a habituated animal and a typical detectable excitatory postsynaptic potential from a sensitized animal are shown. Source. Adapted from Carew T, Castellucci VF, Kandel ER: “Sensitization in Aplysia: Restoration of Transmission in Synapses Inactivated by Long-Term Habituation.” Sci- ence 205:417–419, 1979. Used with permission. 27 COMMENTARY “A NEW INTELLECTUAL FRAMEWORK FOR PSYCHIATRY” Thomas R. Insel, M.D. In “A New Intellectual Framework for Psychiatry,” Eric Kandel aims to inte- grate psychiatry with the biological insights of 1998, specifically addressing the relationship of cognition and behavior to brain processes (Kandel 1998). He notes the need to enhance psychiatric training with neuroscientific ex- pertise and describes the importance of biology for a comprehensive under- standing of mental processes. Kandel provides five principles that frame this understanding, some of which may have seemed provocative in 1998: 1) all mental processes are neural, 2) genes and their protein products determine neural connections, 3) experience alters gene expression, 4) learning changes neural connections, and 5) psychotherapy changes gene expression. He con- cludes this thoughtful paper with a description of “unconscious” processing in patients with hippocampal lesions, noting that neuroscience might pro- vide a new framework for psychoanalysis as well as psychiatry in general. In the 7 years since Kandel’s paper, biology has been transformed by sev- eral landmark events and discoveries, rendering Kandel’s call for integration 28 Psychiatry, Psychoanalysis, and the New Biology of Mind even more important. The most historic event occurred in 2003 when the Human Genome Project published the full sequence of the human genome, mapping 30,000 genes across nearly 3 billion bases of DNA. The human se- quence not only provides an unprecedented opportunity to study how our species differs from its mammalian relatives, it also demonstrates the re- markable sequence similarity across humans, with 99.9% homology be- tween individuals. A current project, the International Haplotype Mapping Project, is working to describe the nature of human variation, identifying where the 0.1% of difference between individuals emerges across the 3 billion bases of DNA (The International HapMap Consortium 2003). With the advent of new technologies for high-throughput sequencing, projects that in 1998 required tens of thousands of hours (such as the sequencing of a new microbe) now are routinely completed by a single postdoctoral fellow in a day. The past 7 years can also be considered an era of biological pluralism, sometimes noted as the era of systems biology. Decades of studying a single gene or a single neurotransmitter have given way to techniques that permit the measurement of thousands of RNAs or proteins simultaneously. Recall that the entire body of scientific literature in this field prior to 1998 focused on roughly 1% of the genome. Indeed, the few neurotransmitters, receptors, and transporters studied in neuroscience totaled perhaps 30 amines and pro- teins, products of less than 0.1% of the genome. We now suspect that 20,000 genes are expressed in the brain, with as many as 6,000 expressed exclu- sively in the brain. Not surprisingly, in the past 6 years, much of biology has moved into a discovery phase, exploring which genes are expressed in the brain, where and when they are expressed, and how they respond to experi- ence. Neuroanatomic maps of cytoarchitecture can now be redrawn based on molecular fingerprints of individual cells and brain nuclei (Zirlinger et al. 2001). There is no doubt that, as Kandel stated in 1998, 1) genes and pro- teins determine neural connections and 2) experience, including psycho- therapy, alters gene expression. The molecular players and the cellular rules by which neural systems develop and experience alters gene expression are just being revealed. One thing is already clear: serotonin and dopamine will be only two of hundreds of important factors that future psychiatrists will need to know about. Systems neuroscience has also advanced beyond the study of single elec- trodes and single brain regions to the widespread use of multielectrode ar- rays and various new imaging techniques to visualize multiple brain regions simultaneously. The simplistic (and even the complex) network diagrams of hierarchical organization in the brain have given way to dynamic models of neural activity, involving abundant recursive connections between brain re- gions and subtle temporal and state changes that have been hypothesized to A New Intellectual Framework for Psychiatry 29 underlie mental function (Abbott 2001). While there is no question that, as Kandel stated, “all mental processes are neural,” we are now beginning to understand how neural activity measured in ensembles of cells or in field po- tentials of millions of cells binds information together to create memory, at- tention, or consciousness (Reynolds and Desimone 2003). While molecular, cellular, and systems neuroscience have advanced so rapidly over the past 7 years, has psychiatry embraced or ignored this progress? Anyone reading the American Journal of Psychiatry during this time will rec- ognize the abundant findings of psychiatric genetics and the increasing im- pact of neuroimaging. The human genome map, the haplotype map, and rapid genotyping are already beginning to revolutionize our approach to psychiatric genetics, allowing gene findings from linkage studies and high- throughput studies of variations in candidate genes associated with psychi- atric illness. While almost no one expects that genetics will discover a Men- delian “cause” for any of the major mental illnesses, the discovery of variations associated with vulnerability should reveal the architecture for each of these illnesses that predisposes for risk, just as we have seen for hy- pertension and other genetically complex medical disorders. Similarly, the profile of gene expression in schizophrenia and bipolar disorder can be in- vestigated by interrogating thousands of genes in select brain areas (Middle- ton et al. 2002). Neuroimaging of regional function, in vivo neurochemistry, and connec- tivity have allowed psychiatric researchers to peer inside the “black box” of the brain. In this research area, part of the integration with neuroscience that Kandel hoped for in 1998 has arrived, although thus far cognitive scientists, not psychiatric patients, have been the chief beneficiaries. Studies with fMRI have provided remarkable insights into how the brain parses language, rec- ognizes faces, and encodes emotion. Recent studies have described the neu- robiology of repression (Anderson et al. 2004), romantic love (Bartels and Zeki 2000), and the unconscious (Henson 2003). But the technology, re- markable as it is, remains correlational with an unclear relationship to the millisecond world of neural function. PET studies of receptors and trans- porters may be more easily interpreted, but the field lacks many of the radi- oligands needed. And Kandel’s call for studies measuring changes in regional activity with psychotherapy or psychopharmacological treatment remains largely unanswered (note, however, Goldapple et al. 2004). While research in psychiatry has begun to embrace the power of molec- ular, cellular, and systems neuroscience, this scientific excitement has not yet influenced clinical practice by refining diagnosis or informing treatment. Furthermore, these advances have been conspicuously ignored by training programs. Most psychiatry residency programs remain focused on psycho- dynamic psychotherapy or applied psychopharmacology with little expo- This page intentionally left blank [...]... evaluation of the outcome of psychotherapy 40 Psychiatry, Psychoanalysis, and the New Biology of Mind I now consider each of these principles in turn and illustrate the experimental basis of this new framework and its implications for the theory and practice of psychiatry All Functions of Mind Reflect Functions of Brain This principle is so central in traditional thinking in biology and medicine (and has... profound impact on our understanding of mind This view is shared by students just beginning their scientific training Many of the very best graduate students in biology and the best M.D.-Ph.D students are drawn to neural science and particularly to the biology of mental processes for this very reason If the progress of the past few years and the continued influx of 54 Psychiatry, Psychoanalysis, and. .. Freud and their later elaboration and enrichment by others In contrast, Eric Kandel calls upon psychoanalysis to find ways to invigorate itself, to become a source of new ideas, and to enrich 59 60 Psychiatry, Psychoanalysis, and the New Biology of Mind the neurosciences by becoming part of the neuroscientific community, while preserving and expanding its knowledge and skill in mapping the conscious and. .. medicine and with the rest of biology The drift away from biology was not due simply to changes in psychiatry; it was in part due to the slow maturation of the brain sciences In the late 1940s, the biology of the brain was neither technically nor conceptually ma- A New Intellectual Framework for Psychiatry 35 ture enough to deal effectively with the biology of most higher mental processes and their disorders... Mayr, the great Harvard biologist and a friend of Franz Kallmann, a founder of psychiatric genetics, to come and talk to us I am providing here an oversimplified description of the weakness of an environment that had many excellent qualities and many strengths The intellectual quality of the house officers was remarkable, and the commitment of the faculty to the training of the house staff and to the. .. place the concepts of repetition-compulsion and resistance in a new light Shifts in philosophy of mind may be required on both sides of the current divide: an acceptance of mind- brain as a single Biology and the Future of Psychoanalysis 61 entity that can be investigated from different perspectives, rejection of a computational model in favor of nonlinear complexity, and full recognition of the power of. .. biologists, the details of the relationship between the brain and mental processes—precisely how the brain gives rise to various mental processes—is understood poorly, and only in outline The great challenge for biology and psychiatry at this point is to delineate that relationship in terms that are satisfying to both the biologist of the brain and the psychiatrist of the mind Second, the relationship of mind. .. second-order relatives—those who share 25 % of the patient’s genes, including aunts, uncles, nieces, nephews, and grandchildren Even the third-degree relatives, who share only 12. 5% of the patient’s genes, had a higher incidence of schizophrenia than the 1% found in the population at large These data strongly suggest a genetic contribution to schizophrenia 46 Psychiatry, Psychoanalysis, and the New Biology. .. After several thousand trials, the area of cortex devoted to the three fingers was greatly expanded at the expense of the area normally devoted to the other fingers (Figure 2 3) Practice alone, therefore, may not only strengthen the effectiveness of existing patterns of connections but also change cortical connections to accommodate new patterns of actions Psychotherapy and Pharmacotherapy May Induce... the east and west coasts of the country Our residency years the decade of the 1960s—marked a turning point in American psychiatry To begin with, new and effective treatments, in the 38 Psychiatry, Psychoanalysis, and the New Biology of Mind form of psychopharmacological drugs, began to be available Initially, a number of supervisors discouraged us from using them, believing that they were designed more . evalua- tion of the outcome of psychotherapy. 40 Psychiatry, Psychoanalysis, and the New Biology of Mind I now consider each of these principles in turn and illustrate the experi- mental basis of. qualities and many strengths. The intel- lectual quality of the house officers was remarkable, and the commitment of the faculty to the training of the house staff and to the treatment of the patients was. Psychoanalysis, and the New Biology of Mind Psychotherapy and the Single Synapse 23 idence of brain lesions were called organic, and those that lacked these fea- tures were called functional. Studies of the