November 2003

Everyone is somewhere on the Neurodevelopmental Spectrum. Where are you on it .... where do you want to be?

Accelerated neurodevelopment allows us the ability to maximize and use our intellectual, physical, and emotional strengths simultaneously, no matter where we begin on the spectrum.

When accelerating brain power, daily tasks such as working, studying, and sports become easier to do and manage. The brain is functioning at optimal levels and is able to make quick attentional shifts on demand.

This is the state of mind that peak performers call "the zone" and is accessible at will.

Asthma Symptoms Linked to Infection Low-grade bacterial infections may play a role in asthma, according to a study. In the study, 31 out of 55 patients with chronic, stable asthma also had a low-grade airway infection with mycoplasma pneumoniae, bacteria that commonly cause pneumonia in people younger than 40 years of age, or another bacteria called chlamydia (not associated with the sexually transmitted kind). The infected patients were treated with antibiotics for six weeks and had significant improvements in lung function. Although some researchers view the findings as controversial, more and more experts are noting the importance of the association and a large study to further examine the topic has been launched. Asthma is becoming an increasing problem in the United States, with the number of asthma patients doubling from 1982 to 1998. Some 20 million Americans had asthma in 2001, and the condition costs the United States $14 billion annually. Mouse experiments are also being used to explore the link between bacteria, allergy and asthma. In asthma, airways get inflamed and hyperreactive, or "twitchy." Further, according to researchers, asthma patients with mycoplasma infection had a six-fold higher number of mast cells, which are associated with allergies, than asthma patients with no infection. In a mouse with mycoplasma infection, its airways become hyperreactive and inflamed as well. When the mouse gets over the illness, in about two weeks, it is then sensitized to mycoplasma allergen and the airway's hyperreactive response is blocked when subsequent exposure to the allergen occurs. However, researchers noted that if a mouse becomes sensitized to the allergen before the mycoplasma infection, the airways become much more reactive. According to researchers, this illustrates the hygiene hypothesis, which says that children who are exposed to germs are less likely to develop allergies and asthma than children who grow up in very clean environments. Researchers conclude that people with new-onset asthma should be evaluated for a possible infectious component. It was also noted that since it is possible to get mycoplasma infection but not wind up with asthma, those who do are likely genetically susceptible to the condition. Further genetic research may show that asthma cases follow different courses and may require different therapies to be treated effectively. Pittsburgh Post Gazette, PA June 10, 2003 The theory was developed by Dr. Thomas Brown over 50 years ago. He treated over 10,000 patients before he died in 1989. Dr. Brown believed that rheumatoid arthritis was in large part caused by the same mycoplasma organisms. That is why the antibiotics used in the treatment protocol are derivatives of tetracycline, because those are the drugs of choice for mycoplasma. Normally, asthma is not that difficult to treat. Optimizing your diet and removing sugars, grains and all fluids but water is typically a remarkable step in the right direction. Adding omega-3 fish oils is also another potent tool to help normalize asthma. When choosing your fish oil or cod liver oil, it is important to remember that not all brands are the same. So what is the difference between fish oil and cod liver oil? In short, fish oil should be consumed in warm weather months and warm climates, while cod liver oil should be consumed in cool weather months and cool climates. Cod liver oil is high in vitamin D (and vitamin A); those in cool weather climates do not generally get enough vitamin D. However, in warm weather, their vitamin D is usually sufficient, as sunshine is one of the primary methods of obtaining this vitamin; if you consume too much vitamin D in these warm weather months, you do risk overdosing. A reasonable dose for both fish oil and cod liver oil is one teaspoon for every 50 pounds of body weight daily.

EEG and behavioral changes following neurofeedback treatment in learning disabled children. Clin Electroencephalogr. 2003 Jul;34(3):145-52.Fernandez T, Herrera W, Harmony T, Diaz-Comas L, Santiago E, Sanchez L, Bosch J, Fernandez-Bouzas A, Otero G, Ricardo-Garcell J, Barraza C, Aubert E, Galan L, Valdes R. Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Juriquilla, QRO. 76230, Mexico. Neurofeedback (NFB) is an operant conditioning procedure, by which the subject learns to control his/her EEG activity. On one hand, Learning Disabled (LD) children have higher values of theta EEG absolute and relative power than normal children, and on the other hand, it has been shown that minimum alpha absolute power is necessary for adequate performance. Ten LD children were selected with higher than normal ratios of theta to alpha absolute power (theta/alpha). The Test Of Variables of Attention (TOVA) was applied. Children were divided into two groups in order to maintain similar IQ values, TOVA values, socioeconomical status, and gender for each group. In the experimental group, NFB was applied in the region with highest ratio, triggering a sound each time the ratio fell below a threshold value. Noncontingent reinforcement was given to the other group. Twenty half-hour sessions were applied, at a rate of 2 per week. At the end of the 20 sessions, TOVA, WISC and EEG were obtained. There was significant improvement in WISC performance in the experimental group that was not observed in the control group. EEG absolute power decreased in delta, theta, alpha and beta bands in the experimental group. Control children only showed a decrease in relative power in the delta band. All changes observed in the experimental group and not observed in the control group indicate better cognitive performance and the presence of greater EEG maturation in the experimental group, which suggests that changes were due not only to development but also to NFB treatment. University Of Wisconsin Study Reports Sustained Changes In Brain And Immune Function After Meditation Source: University Of Wisconsin-Madison 2003-02-04 MADISON – In a small but highly provocative study, a University of Wisconsin-Madison research team has found, for the first time, that a short program in "mindfulness meditation" produced lasting positive changes in both the brain and the function of the immune system. The findings suggest that meditation, long promoted as a technique to reduce anxiety and stress, might produce important biological effects that improve a person's resiliency. Richard Davidson, Ph.D., Vilas Professor of psychology and psychiatry at UW-Madison, led the research team. The study, conducted at the biotechnology company Promega near Madison, will appear in an upcoming issue of the journal Psychosomatic Medicine. "Mindfulness meditation," often recommended as an antidote to the stress and pain of chronic disease, is a practice designed to focus one's attention intensely on the moment, noting thoughts and feelings as they occur but refraining from judging or acting on those thoughts and feelings. The intent is to deepen awareness of the present, develop skills of focused attention, and cultivate positive emotions such as compassion. In the UW study, participants were randomly assigned to one of two groups. The experimental group, with 25 subjects, received training in mindfulness meditation from one of its most noted adherents, Jon Kabat-Zinn, Ph.D. (Kabat-Zinn, a popular author of books on stress reduction, developed the mindfulness-based stress reduction program at the University of Massachusetts Medical Center.) This group attended a weekly class and one seven-hour retreat during the study; they also were assigned home practice for an hour a day, six days a week. The 16 members of the control group did not receive meditation training until after the study was completed. For each group, in addition to asking the participants to assess how they felt, the research team measured electrical activity in the frontal part of the brain, an area specialized for certain kinds of emotion. Earlier research has shown that, in people who are generally positive and optimistic and during times of positive emotion, the left side of this frontal area becomes more active than the right side does. The findings confirmed the researchers' hypothesis: the meditation group showed an increase of activation in the left-side part of the frontal region. This suggests that the meditation itself produced more activity in this region of the brain. This activity is associated with lower anxiety and a more positive emotional state. The research team also tested whether the meditation group had better immune function than the control group did. All the study participants got a flu vaccine at the end of the eight-week meditation group. Then, at four and eight weeks after vaccine administration, both groups had blood tests to measure the level of antibodies they had produced against the flu vaccine. While both groups (as expected) had developed increased antibodies, the meditation group had a significantly larger increase than the controls, at both four and eight weeks after receiving the vaccine. "Although our study is preliminary and more research clearly is warranted," said Davidson, "we are very encouraged by these results. The Promega employees who took part have given us a wonderful opportunity to demonstrate a real biological impact of this ancient practice." Davidson, who is integrally involved with the HealthEmotions Research Institute at UW, plans further research on the impact of meditation. He is currently studying a group of people who have been using meditation for more than 30 years. His research team is also planning to study the impact of mindfulness meditation on patients with particular illnesses.

BRAIN PLASTICITY

BRAIN PLASTICITY   "To learn is to change. Education is a process that changes the learner." George Leonard The Wall Street Journal reported this past week, "Scientists have discovered the first strong evidence that intellectual stimulation can significantly increase the number of brain cells in a crucial region of the mind..."     This was in response to the April 3 1997, issue of Nature which has an article by Bruce McEwen of Rockefeller University. The article states, "...significantly more new neurons exist in the dentate gyrus of mice exposed to an enriched environment compared with littermates housed in standard cages." The Nature article suggests that this is biological confirmation of the importance of education and contradicts the previous dogma that the number of active brains cells is essentially fixed early in life. Similar tests were performed in the 1970s by psychologist William Greenough at the University of Illinois and they reached this same conclusion. Roger Penrose in his book The Emperor's New Mind describes the relevance of synaptic firing in the phenomenon of brain plasticity. He states, "It is actually not legitimate to regard the brain as simply a fixed collection of wired-up neurons. The interconnections between neurons are not in fact fixed but are changing all the time. I am referring to the synaptic junctions where the communication between different neurons actually takes place. Often these occur at places called dendrite spines, which are tiny protuberances on dendrites at which contact with synaptic knobs can be made. Here , 'contact' means not just touching, but leaving a narrow gap (synaptic cleft) of just the right distance - about one forty-thousandth of a millimeter. Now under certain conditions, these dendrite spines can shrink away and break contact, or they (or new ones) can grow to make new contact." It is estimated the you have about one hundred billion neurons in your brain, about ten billion of which are in your neo-cortex. It has been speculated that you lose about one thousand neurons each day after you reach forty. Research is finding that this loss can be offset by stimulating the brain regularly. A nerve is not like a simple relay circuit. Whether it fires or not depends on a complex interplay of many inputs. These can be inhibitory or exhibitory influences from the neurons surrounding it, or the intracellular fluid that fills the synaptic gap. If a neuron doesn't get enough excitatory input from the neurons connected to it, or gets too many neurotransmitters that inhibit neural action, it will do nothing. Other research has found that if a neuron is being used, it secretes substances that affect nearby cells responsible for the neuron's nourishment. These cells, in turn, produce a chemical that appears to preserve the neuron from destruction. If the neuron does not get that substances, it dies. In concert with this effect, Leif Finkel and Gerald M. Edelman of Rockefeller University have discovered that neurons do not act randomly but as a network. They tend to organize themselves into groups and specialize for different kinds of information processing. For example, when a touch stimuli comes in from the finger it first comes into the neural network. The information activates some groups of neurons more than others, and this high level of activity causes the connections among the group of excited neurons to be reinforced. As more and more similar patterns come through the network, the connections among the activated group of neurons becomes stronger and stronger, and eventually the group becomes specialized for processing that one finger's sense of touch. As far back as 1949 Canadian neurophysiologist Donald Hebb proposed in his work Organization of Behavior that, "When an axon of cell A is near enough to excite a cell B, and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency as one of the cells firing B is increased." In other words, if one neuron sends a lot of signals that excite another neuron, the synapse between the two neurons is strengthened. The more active the two neurons are, the stronger the connection between them grows; thus, with every new experience, your brain slightly rewires its physical structure. In working with nerve tissue scientists have also found that if two connected neurons are stimulated at the same time, the amount of signal passing from one neuron to the other can double. This is known as long-term potentiation or LTP. Whether this is permanent or not has yet to be verified. But work with aplysia, a sea-slug, by Eric Kandel of Columbia University, verified that the animal's neurons grew stronger as it learned to associate a food it disliked with the presence of a beam of light. The internet is replete with more information on neural networks and brain plasticity. A simple search engine inquiry into either of these subjects will give more detailed information and lead to specific scientific articles. This purpose of this site is to provide a simple method to 'exercise' the brain daily and make new connections. The brain's plasticity is becoming more apparent in cognitive science. More and more evidence is surfacing to validate the idea of "use it or lose it." Though this is something that common sense might dictate, there are very few mechanisms created that will allow us to use our brains in unfamiliar ways each day. Doing different puzzles will produce different kinds of thought processes as you search for solutions. Puzzles are useful because they do have solutions, therefore you can test your ability to find a resolve because there is one. The ability to flex the mind in whatever direction is necessary to find resolve is what leads to true creative thinking. Creativity is not just coming up with something that is different, but with something that is coherent, useful and relevant to whatever stimulated the need for a creative thought. Learning to think creatively is a skill that anyone can learn. Test yourself and see how flexible your mind is. Try this method for six months and see if you are able to think more clearly and apply either logical or analogical thought at will to any situation that arises. © J.L. Read, 1997. All Rights Reserved.

NEUROTRANSMITTER NEWS

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Emotional instability but intact spatial cognition in adenosine receptor 1 knock out mice [Research report] Undine E. Lang, Florian Lang, Kerstin Richter, Volker Vallon, Hans-Peter Lipp, Jürgen Schnermann and David P. Wolfer Behavioural Brain Research, (June 10, 2003), 10.1016/S0166-4328(03)00108-6 Abstract Several lines of evidence point to the involvement of adenosine in the regulation of important central mechanisms such as cognition, arousal, aggression and anxiety. In order to elucidate the involvement of the adenosine A1 receptor (A1AR) in spatial learning and the control of exploratory behaviour, we assessed A1AR knockout mice (A1AR-/-) and their wild-type littermates (A1AR+/+) in a place navigation task in the water maze and in a battery of forced and free exploration tests. In the water maze, A1AR-/- mice showed normal escape latencies and were indistinguishable from controls with respect to measures of spatial performance during both training and probe trial. But despite normal performance they showed increased wall hugging, most prominently after the relocation of the goal platform for reversal training. Quantitative analysis of strategy choices indicated that wall hugging was increased mainly at the expense of chaining and passive floating, whereas the frequency of trials characterised as direct swims or focal searching was normal in A1AR-/- mice. These results indicate intact spatial cognition, but mildly altered emotional reactions to the water maze environment. In line with this interpretation, A1AR-/- mice showed normal levels and patterns of activity, but a mild increase of some measures of anxiety in our battery of forced and free exploration paradigms. These results are in line with findings published using a genetically similar line, but demonstrate that the magnitude of the changes and the range of affected behavioural measures may vary considerably depending on the environmental conditions during testing.

EEG/ERP

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Electrical activity and development of neural circuits Li I. Zhang1 & Mu-ming Poo2 1. Keck Center of Integrative Neuroscience, University of California, San Francisco, California 2. Department of Molecular and Cell Biology, University of California, Berkeley, California November 2001 Volume 4 Number Supp pp 1207 - 1214 A distinct feature of the nervous system is the intricate network of synaptic connections among neurons of diverse phenotypes. Although initial connections are formed largely through molecular mechanisms that depend on intrinsic developmental programs, spontaneous and experience-driven electrical activities in the developing brain exert critical epigenetic influence on synaptic maturation and refinement of neural circuits. Selective findings discussed here illustrate some of our current understanding of the effects of electrical activity on circuit development and highlight areas that await further study. Since the pioneering work of Hubel and Wiesel on the effect of visual deprivation on the development of visual systems1, it has become increasingly clear that electrical activity is essential for the development of neural circuits in many parts of the brain. Both spontaneous activity present early in the embryonic brain and experience-driven activity during the postnatal period are critical for circuit development2. Here we begin with a discussion of various forms of electrical activity found in the developing brain and potential cellular actions of activity. This is followed by a summary of the effects of activity on the initial formation of synaptic contacts, the maturation of synapses and the structural refinement of connectivity. For activity-dependent synaptic modification, there is substantial evidence for an instructive role of electrical activity, with the instruction coded in the spatiotemporal pattern of activity. We thus review recent findings on the role of spike timing and the issue of input-specificity in the activity-induced synaptic modification, and discuss their implications for circuit development. Besides local synaptic effects, we also address more global effects of electrical activity on neurons, including changes in intrinsic excitability, gene expression and protein synthesis. Finally, we discuss the possibility that neurotrophins, a group of growth factors whose expression and secretion are regulated by activity, may serve as activity pattern-dependent morphogenic factors for shaping the developing connections. Selective coverage of this review reflects the authors' own research interests. More extensive discussion on electrical activity and circuit development may be found in several recent reviews2-6. Spontaneous and experience-dependent activity Electrical activity in the nervous system occurs in two general forms: spontaneous activity independent of sensory inputs or motor outputs, and experience-driven or use-dependent activity. Both types of activity regulate the development of neural circuits. For example, before an animal has any visual experience, spontaneous activity is found in various parts of the embryonic retina and thalamus7-9. These activities are thought to contribute to the refinement of neural circuits in the lateral geniculate nucleus (LGN)10 and primary visual cortex, resulting in orientation selectivity and ocular dominance in the newborn visual cortex2, 11. Activity associated with sensory experience during the postnatal critical period further refines and consolidates these circuits into mature forms. Spontaneous electrical activity has been examined in some detail12, 13 in the developing neocortex, thalamus, hippocampus, locus coeruleus, retina and spinal cord by direct recording of electrical activity or fluorescence imaging of Ca2+ transients. In general, this activity consists of bursts of action potentials that last for tens to hundreds of milliseconds, separated by intervals of a few minutes, and involves correlated firing of large populations of neurons. The activity may spread from one region to another in the form of propagating electrical waves, such as those observed in the developing retina8, or it may remain localized to discrete domains, as in the neocortex14 and the spinal cord13. Correlative spontaneous activity in the developing retina, spinal cord and hippocampus is generated by excitatory synaptic connections, whereas gap junctions mediate coactivation of the neurons within discrete domains in the developing neocortex, in locus coeruleus and, to a limited extent, in the retina. The correlated excitation of neurons is usually self-terminated, perhaps due to synaptic fatigue, and recovers in the interval between episodes of bursting discharges. Synaptically correlated activity is mediated mainly by excitatory transmitters acetylcholine and glutamate. Inhibitory transmitters GABA and glycine also contribute to the excitation in the embryonic and neonatal brain15 by their depolarizing actions on developing neurons that have high intracellular Cl- concentrations. Electrical activity evoked by sensory inputs usually consists of spike trains of varying frequencies. As an example, we describe its characteristics in the developing tectum of Xenopus tadpoles16, 17. Light stimulus induces brief spike trains (with frequencies up to 100 Hz), which terminate quickly as a result of a combinations of factors, including rapid fatigue of excitatory synapses, the clamping action of GABAergic and glycinergic activity, and a slow after-hyperpolarization mediated by K+ channels. The light-evoked spike trains are similar in appearance to spontaneous bursts of discharges in the same tectal cell, but occur with a latency of about 100 ms following the stimulus and a 10–20 ms variation in the onset of the discharge. The relatively precise timing of the onset of evoked activity suggests that information associated with rapidly modulated visual inputs can be used for spike-timing-dependent modification of developing synapses (see below). The early presence of evoked GABAergic activity is also likely to be important for circuit development, as depolarizing action of GABA in the embryonic and neonatal cortex results in Ca2+ influx15 and large-scale Ca2+ wave18. Calcium waves and oscillations are found in many developing neural circuits14, 18-20. These Ca2+ transients may arise from Ca2+ influx triggered by membrane depolarization or Ca2+ release from internal stores. The widespread coupling between developing cells by gap junctions allows intercellular spread of Ca2+ and production of Ca2+ waves through regenerative Ca2+-induced Ca2+ release from internal stores, independent of plasma membrane depolarization. Moreover, Ca2+ waves through electrically coupled glial cells may result in secretion of factors that regulate maturation and functions of synaptic connections21. In developing neurons, Ca2+ transients modulate nerve growth20 and stimulate neuronal differentiation22. Potential cellular actions of activity How do various forms of electrical activity described above exert their effects on developing circuits? Activity-induced Ca2+ elevation can be central in both pre- and postsynaptic neurons (Fig. 1a). Depolarization-induced Ca2+ elevation triggers presynaptic secretion of transmitters and proteins. Postsynaptic Ca2+ elevation resulting from transmitter receptor activation or depolarization may also induce secretion of retrograde and autocrine factors from the postsynaptic cell. Activation of cytoplasmic effectors by Ca2+ or by receptors for secreted factors can produce short- or long-term modification of synaptic efficacy23, neuronal excitability24 and trafficking of cytoplasmic proteins25 and membrane receptors26. Activity-induced changes in gene expression and protein synthesis can be mediated by calcium22, 27, through its cytoplasmic effectors, as well as by other signaling events triggered by transmitters and secreted proteins, resulting in changes in the molecular composition of the neuron during circuit development. The level of cAMP, a second messenger responsible for regulating a wide range of neuronal functions28, can also be influenced by Ca2+ through the activity of Ca2+-dependent adenylate cyclase. In addition to the effects mediated directly or indirectly through Ca2+ elevation in both pre- and postsynaptic neurons, electrical activity may also exert direct effects on the transduction efficacy of non-ionophoric membrane proteins (Fig. 1b). The finding of voltage-sensitive but Ca2+-independent adenylate cyclase29 suggests that, in analogy to voltage-dependent ion channels, the conformation of transmembrane proteins may be affected to varying degrees by changes in membrane potential. There is also evidence that depolarization-induced Na+ influx may directly stimulate the activity of Ca2+-independent adenylate cyclase30. In principle, membrane potential-dependent conformational changes may affect ligand–receptor binding, receptor dimerization, tyrosine phosphorylation, intracellular interaction of the membrane receptor with cytoplasmic adaptor proteins, and internalization of ligand–receptor complexes. Neurotrophin-induced potentiation of transmitter release at developing neuromuscular synapses is facilitated by presynaptic membrane depolarization in a manner independent of Ca2+ influx31. Whether binding of the neurotrophin with the tyrosine kinase receptor (Trk), subsequent signal transduction or receptor internalization is directly affected by membrane depolarization remains to be determined. Ionic currents associated with neuronal and synaptic activity generate local electric fields in the cytoplasm and extracellular space of the neuron. These fields may induce migration of charged cellular components in the membrane or cytoplasm by in situ electrophoresis32. Charged or uncharged components may also be `dragged' by the solvent flow created by the flow of ions, a process known as electro-osmosis. Both types of electrokinetic migration can result in redistribution of cell surface receptors and cytoplasmic components (Fig. 1c). For inducing lateral redistribution of membrane proteins such as ACh receptors32, the effective extracellular electric field is on the order of 1 V/cm, which is within the range of the field generated by the focal current sink associated with repetitive synaptic currents33. Direct physical actions of synaptic currents are inescapable consequences of electrical activity and have long been postulated to serve for activity-dependent synaptic modification33, 34. Similar to the role of physical forces involved in many inductive and morphogenetic events during development, nonspecific actions of physical forces create gradients in the distribution of molecules and organelles, which set the stage for specific molecular interactions. Formation of synaptic contacts The formation of neural networks begins with growing axons finding their path, then recognizing their targets and finally establishing synaptic contacts. Evidence from neuromuscular synapse formation suggests that functional synaptic contacts can be established rapidly before the appearance of morphological specialization of synapses35. We can thus define `synapse formation' as the establishment of functional synaptic communication, separate from `synapse maturation,' which involves a much more protracted process of functional and morphological differentiation. We here consider the role of electrical activity in various phases of synapse development. Path finding of growing axons is generally thought to be independent of electrical activity and to require molecular guidance signals provided by the surrounding developing tissues. However, recent findings have shown that electrical activity may be required for growing thalamic axons to reach their appropriate cortical target area36 and for axons of cortical pyramidal neurons to form layer-specific intracortical connections37. In these latter studies, it is difficult to determine with certainty whether the activity is involved in axon path finding per se or target selection of the axon after it has reached the target cell. Definitive evidence that electrical activity can influence path finding of axons before the synaptic contact was provided by an in vitro study. A brief train of action potentials in cultured Xenopus spinal neurons resulted in marked alterations in the turning response of the growth cone induced by gradients of several repulsive guidance cues38, converting repulsive turning into attraction. This study showed that brief spiking activity can leave an imprint in the neuronal cytoplasm that persists for a period of about 30 min, involving Ca2+-dependent elevation of cAMP, which is known to regulate growth cone behavior in response to many guidance cues. On the other hand, there is also evidence against the role of activity in axon guidance in other systems. In mice that are deficient in odorant-evoked neuronal activity, projection of olfactory sensory axons to specific glomeruli in the olfactory bulb is largely unaffected39, although minor aberrant path finding was observed for some axons40. Thus, the guidance behavior of different axons may exhibit differential sensitivity to modulation by electrical activity, and the role of electrical activity in the path finding of axon remains an open issue. The establishment of synaptic contacts can be influenced by the motility of filopodial protrusions from axonal growth cones and postsynaptic dendrites. Electrical activity, through depolarization-induced Ca2+ influx, can regulate filopodial motility and thus alter the frequency and stability of axon–dendritic filopodial contacts41. Two interesting questions arise. Does functional synaptic transmission begin immediately after the filopodial contact? Is early synaptic activity involved in modifying the structure and stability of synaptic contacts? The answers to both questions appear to be positive. In vivo two-photon imaging of pyramidal neurons in the developing rat barrel cortex showed that spines and filopodial protrusions on dendrites appear, disappear and change shape over tens of minutes42. Because this dendritic motility is reduced after sensory deprivation, electrical activity associated with sensory inputs seems to be capable of modulating growth cone and dendrite dynamics during the early period of synaptogenesis. Studies on the development of axonal and dendritic arbors in the developing tectum also showed that early synaptic activity mediated by NMDA subtype of glutamate receptors promotes dendritic arbor growth of immature tectal neurons4, and thus facilitates the formation of additional synaptic contacts. As synapses mature, synaptic activity further exerts a stabilizing action on the existing dendrites by reducing spine motility through membrane depolarization43 or glutamate receptor activation44. It seems that the level of synaptic activity, mediated through Ca2+-calmodulin-dependent kinase II (CaMKII), is responsible for a switch of the activity's role from growth promotion to arbor stabilization4. Maturation of synaptic structures Electrical activity in growing axons can trigger secretion of neurotransmitters from growth cones, a process that allows immediate initiation of synaptic activity following contact between growth cones and target neurons possessing appropriate receptors on their surface45. Early spontaneous and evoked transmitter release at the contact site, together with anterograde and retrograde factors secreted in association with synaptic activity, may trigger a cascade of cytosolic processes that lead to pre- and postsynaptic differentiation. The assembly of presynaptic secretion machinery, postsynaptic receptor clusters and subsynaptic complexes within the postsynaptic density requires proper localization of specific cellular components and mechanisms that allow functional matching of pre- and postsynaptic specializations46, 47. How the neuron accomplishes the complex task of trafficking and selective trapping of specific components to the heterogeneous synaptic sites on the axons and dendrites, and whether electrical activity regulates these processes, are interesting areas for further study. Many aspects of the maturation and refinement of central synapses are likely to be similar to that at the developing neuromuscular junction (for review, see ref. 35), which is much better understood in cellular and molecular terms. The role of neuronal or synaptic activity on the maturation of the synapse has been a controversial subject, as experimental findings have supported opposite conclusions. On the negative side, under conditions of chronic receptor blockade, one finds apparently normal development of some aspects of postsynaptic differentiation, such as clustering of muscle nicotinic receptors35. Morphologically normal presynaptic structures also appear at some synapses in Munc-18 mutant mice in which transmitter secretion is absent48. On the positive side, there is clear evidence for the effects of synaptic activity on postsynaptic differentiation. In cultured spinal neurons, blocking glycine receptors or L-type Ca2+ channels inhibits clustering of glycine receptors and gephyrin, an `anchoring' protein responsible for stable localization of glycine receptors49. At Drosophila neuromuscular junctions, the presence of spontaneous transmitter (glutamate) secretion correlates with the clustering of junctional glutamate receptors during development50. Synaptic activation causes recruitment26 or removal51 of synaptic glutamate receptors, as well as rapid redistribution of cytoplasmic proteins such as CaMKII25 to the synaptic site. Selective recruitment of cellular components to the synaptic site is achieved by specific binding and `anchoring' of the components with pre-existing `scaffolds' at the synaptic sites, a process that may be facilitated by their electrokinetic accumulation driven by synaptic currents (Fig. 1c). Because the site of synapse formation on the dendrite is not predetermined, the first signal for synaptic localization presumably comes from axon–dendritic interactions, which must induce a relatively stable localized scaffold, for subsequent cascades of molecular localization in both the presynaptic nerve terminal and the postsynaptic cytoplasm. The identity of the `first signal' and the `earliest scaffold' remains elusive. Studies of synapse maturation in the developing tectum and cortex have provided insights into the involvement of synaptic activity in the maturation of central excitatory synapses. Newly formed glutamatergic synapses are mediated by NMDA receptors and more synapses acquire AMPA receptors as the neuron matures52, 53. The immature synapses may be `silent' unless sufficient depolarization is provided, through strong correlated inputs or depolarizing GABA/glycine transmission. The depolarization may result in the recruitment of AMPA receptors to the synapse in a manner similar to that found in the induction of long-term potentiation (LTP) in the CA1 region of the hippocampus54. The parallel between developmental maturation of synapse and LTP is further supported by the finding that disrupting (but not blocking) NMDA receptor function with infusion of low-level NMDA, a condition that prevents induction of hippocampal LTP, results in a reduction of AMPA and kainate receptor activity and long-lasting synaptic depression55. Thus, synapse maturation may require a tight correlation between a robust NMDA receptor activation and afferent activity, similar to that required for the induction of LTP, whereas low-level NMDA receptor activation prevents maturation in a manner similar to that found in long-term synaptic depression (LTD). NMDA receptor activity also modulates the maturation of GABAergic transmission in the colliculus by regulating the expression of GABA synthesizing enzyme glutamate decarboxylase56. Besides the effects on functional maturation, the early NMDA receptor activity in the postsynaptic neuron also helps to stabilize dendritic arbors, through the activation of CaMKII4. Similar NMDA receptor-dependent morphological effect was observed in cultured tectal neurons that have established functional synapses57. Postsynaptic activity mediated by both NMDA receptors and CaMKII also result in growth inhibition of presynaptic axonal arbors4. Thus, there is an intricate interplay between functional and structural maturation during the early phase of synaptogenesis. There is an additional twist in the maturation of GABAergic and glycinergic synapses. During embryonic and early postnatal period, GABA and glycine are depolarizing, capable of elevating intracellular Ca2+ concentration and triggering action potentials15. Due to a developmental shift in the reversal potential for Cl- currents, which results from changes in the expression of a Cl- transporter KCC2 (ref. 58), there is a switch of GABAergic actions from excitatory to inhibitory over the first two weeks of postnatal life. This developmental switch can be largely prevented by blockade of GABAA receptors and accelerated by increasing GABA release24, whereas blocking glutamatergic transmission has little effect. Furthermore, GABAergic activity also regulates the level of KCC2 mRNA and modifies the activation properties of voltage-gated Ca2+ currents. Thus, electrical activity associated with GABAA receptor activation acts on the postsynaptic cell to alter the property of synaptic transmission, and GABA itself serves as a maturation factor for the development of inhibitory synapses. Refinement of synaptic connectivity Following the initial formation of synaptic connections, many developing circuits undergo a period of refinement, through which some connections are eliminated while others are strengthened35, 59, 60. This rewiring of connectivity depends on the pattern of electrical activity in the circuit and involves cooperative and competitive interactions between converging inputs on the postsynaptic cell2, 35. Hebb61 postulated many years ago that strengthening of a synapse might be achieved by repetitive presynaptic activation that leads to postsynaptic firing. Hebb's postulate was later transformed into a simple correlation rule—coincident pre- and postsynaptic activity leads to synapse strengthening. To account for activity-dependent rearrangements of connectivity in the developing visual system, Hebb's rule was further extended by assuming that noncoincident pre- and postsynaptic activity leads to synapse weakening62. Modeling studies showed that the correlation-based Hebb's rule, under the constraint of self-normalization, can indeed explain activity-dependent refinement of developing visual circuits63, 64. However, experimental evidence for the validity of Hebb's rule came mainly from studies of activity-induced functional changes of synaptic efficacy, rather than changes in the connectivity. The findings of homosynaptic LTP and heterosynaptic LTD at some developing synapses65, where strengthening of coactive pathways is accompanied by weakening of non-coactive converging inputs onto the postsynaptic cell, do provide cooperative and competitive mechanisms for synaptic interaction. However, is activity-dependent structural rearrangement of connectivity mechanistically related to LTP and LTD? The strongest evidence for a positive answer came from studies of the dependence of circuit refinement on the activation of NMDA receptors: blocking NMDA receptors prevented segregation of ON/OFF sub-layers in LGN66 and the formation of eye-specific stripes in the tectum of the three-eyed frog67. The same requirement for NMDA receptor activation is found for the induction of LTP/LTD at developing retinogeniculate68 and retinotectal16, 69 synapses. Repetitive visual stimuli can induce NMDA receptor-dependent LTP of retinotectal synapses16, suggesting that natural experience-driven activity is capable of inducing LTP-like synaptic modification. Furthermore, the composition of NMDA receptor undergoes experience-dependent developmental regulation in the visual system70, and there is a correlation between the susceptibility of developing synapses to the induction of LTP/LTD and the susceptibility of the developing circuits to refinement during the critical period71, 72. Despite these correlations, whether LTP/LTD is relevant or even a prelude to structural refinement in the visual system remains controversial73. In activity-dependent synapse elimination at the developing muscle, there seems to be a causal link between functional modification and structural rearrangement: local inactivation of postsynaptic receptors results in a physical withdrawal of terminals covering the inactive area74, and functional weakening of inputs precedes synapse elimination75. Importance of the temporal pattern of activity The pattern of electrical activity is instructive in the development of ocular dominance and orientation selectivity of the primary visual cortex. Rearing kittens with induced squint (strabismus), which alters the pattern but not the absolute level of activity, results in striking changes in the binocular property of cortical cells1. Artificially imposing synchronous activity on optic nerves from the two eyes prevents segregation of thalamocortical projections into ocular dominance columns, whereas asynchronous activity allows segregation (M.P. Stryker and S.L. Strickland, Invest. Ophthalmol. Vis. Sci. 25S, 278, 1984). Similarly, synchronous activation of optic nerves blocks the development of topographic maps in the optic tectum76 and reduces orientation selectivity in the cortex77. Moreover, rewiring visual inputs into the auditory cortex induces the formation of visual orientation modules in the auditory cortex78. All these findings indicate that information coded in the temporal patterns of activity is critical in shaping developing circuits. Although simple correlation-based Hebb's rule has been successful in modeling the rearrangements of developing circuits by activity63, it is not clear how these events depend on the precise timing of the activity in the circuit. In the last few years, Hebb's postulate has been further tested experimentally in both temporal and spatial aspects79. The temporal specificity in the correlated activity required for the induction of LTP/LTD was examined in several systems69, 72, 80-83, showing that the temporal order in the spiking of pre- and postsynaptic neurons must be considered in addition to the extent of coincidence in spiking. Furthermore, the inherent notion in the original Hebb's postulate that activity-induced synaptic modification is input- (or synapse-) specific may not be valid under some circumstances. The implications of these new findings with respect to activity-induced modifications of neural circuits remain to be clarified. The importance of the temporal pattern of activity in modifying developing synapses is best illustrated by the findings on the Xenopus retinotectal system69. Synaptic modification of convergent retinotectal inputs by repetitive retinal activation depends on the temporal order of spiking in pre- and postsynaptic neurons; inputs that are activated within 20 ms before spiking of the tectal neuron become potentiated, whereas inputs that fail to induce postsynaptic spiking and are activated within 20 ms after spiking become depressed (Fig. 2). Similar to LTP/LTD at some central synapses induced by conventional tetanic stimulation or pairing protocols, spike-timing-dependent LTP/LTD depends on the activation of NMDA receptors, and LTD induction also requires activation of L-type calcium channels82. Postsynaptic Ca2+ is critical in determining the polarity of modification: high-level Ca2+ transients result in LTP, whereas sustained low-level Ca2+ elevations lead to LTD23. Imaging studies have indeed shown that summation of postsynaptic Ca2+ elevation is supralinear when presynaptic activation immediately precedes postsynaptic spiking and is sublinear when the temporal order is reversed84. Spike-timing-dependent synaptic modification endows a sensitivity of neural circuits to the temporal pattern of neuronal activity, with a time resolution in the range of 5–20 ms. A relatively symmetric potentiation and depression time window (Fig. 2) allows a `self-normalization' of synaptic strength, which helps to prevent saturation of synaptic changes and to stabilize output firing rate of the circuit85. In principle, spike-timing dependency can offer useful features for the activity-dependent development of complex circuit properties. Computational modeling demonstrated that neural circuits can use spike-timing-dependent plasticity to develop directional sensitivity to moving stimuli86 and precise temporal discrimination in the auditory system87. Recent experiments have shown that following repetitive presentation of stimuli moving in a particular direction across the receptive field of young Xenopus tadpole tectal neurons, the neurons become selectively tuned to the conditioned direction (F. Engert et al., Soc. Neurosci. Abs., 27, 27.17, 2001). Spontaneous activity in the embryonic brain (for example, wave-like activity observed in the retina and LGN2, 9) may evoke sequential excitation of neighboring neurons that helps not only to refine the existing topographic projections but also to shape more complex circuitry for specific computational tasks. Inhibitory activity may also have an important regulatory role in the refinement of developing circuits. In GAD65-deficient mice lacking ocular dominance plasticity, neurons often exhibited prolonged discharges in response to visual stimuli88, a phenomenon not observed in wild-type mice. Increased GABA inhibition in diazepam-treated mutant mice caused a reduction in prolonged discharges and allowed the appearance of ocular dominance plasticity88. The shortening of stimulus-evoked discharges sharpens the temporal pattern of the response, which may in turn facilitate spike-timing-dependent refinement of neural circuits. In addition to the overall reduction of excitation and increased precision in spike timing, shunting of specific excitatory inputs may be achieved by selective distribution of inhibitory synapses. It would be of interest to determine how nascent inhibitory connections, while playing important regulatory roles in refining excitatory connections, can themselves be consolidated into the mature circuit. Global effects of electrical activity In addressing activity-induced synaptic changes, an outstanding issue is the synapse (input) specificity of synaptic modification—whether only the activated synapse is modified. There is increasing evidence that activity-induced LTP/LTD observed in many systems is not strictly input-specific, but may spread to adjacent synapses (for review, see ref. 79). A modeling study showed that both spike-timing dependent LTP and its presynaptic spread is necessary for the development of the computational map of interaural time differences in the barn owl89. However, the extent to which the spread of LTP/LTD influences activity-dependent refinement of developing circuits in general remains largely unclear. During early stages of development in the Xenopus retinotectal system, theta burst stimulation (TBS, which induces 100 Hz bursts resembling spontaneous activity) results in LTP that spreads to other unstimulated converging inputs on the same tectal neuron17. Interestingly, as the animal develops, LTP induced by the same TBS becomes input-specific, a change that correlates with the increased complexity of tectal dendrites. In contrast, LTP induced by low-frequency correlated pre- and postsynaptic spiking is input specific at these retinotectal connections during the same period of development. The difference between TBS and low-frequency correlated spiking may reside in the extent of dendritic spread of high-level Ca2+ transients; global Ca2+ elevation accompanies the spread of TBS-induced LTP in young tectal neurons, but is absent following correlated spiking. Moreover, the emergence of input specificity of TBS-induced LTP in more mature tectal neurons correlates with a more restricted dendritic domain of Ca2+ elevation evoked by each retinal input. These results suggest that the spread of TBS-induced LTP among converging inputs in young tectal neurons may provide a cooperative mechanism for establishing multiple converging functional inputs during early development, whereas spike-timing-dependent synaptic modification is responsible for input-specific refinement of the circuit. Besides modifying synaptic connections, electrical activity also induces changes in the global properties of the neuron such as intrinsic excitability and patterns of gene expression and protein synthesis. Studies of lobster stomatogastric ganglion have shown that neuronal firing patterns are under constant neuromodulatory and homeostatic control; stable firing characteristics of ganglionic circuits are regulated by activity-induced, Ca2+-dependent modulation of various ion channels over a duration of several days90. The overall level of electrical activity of cortical neurons in cell cultures also regulates the expression of synaptic glutamate receptors, a `scaling' effect that may allow homeostatic control of the average level of excitation in the neural circuit91. In developing circuits formed by cultured hippocampal neurons, repetitive correlated activity results in a rapid and persistent enhancement of the intrinsic excitability of the presynaptic neuron, leading to a decreased threshold for spiking and a reduced variability of interspike intervals92. Furthermore, such modification depends on the temporal order of pre- and postsynaptic spiking and requires PKC-dependent global modification of sodium channels in the presynaptic neuron. Rapid activity-induced changes in intrinsic excitability are due to post-translational modifications of ion channels, whereas activity-dependent homeostatic control of excitability involves gene regulation and expression of proteins involved in neuronal functions. Activity-dependent changes in gene expression and protein synthesis are often triggered by activity-induced elevation of Ca2+ and cAMP22. During the late phase of LTP, cAMP induces new gene transcription through cAMP-responsive element binding protein (CREB)93. Sensory experience-driven activity also affects expression of immediate early genes in the visual cortex94. What are the specific gene products regulated by the activity in the developing circuits? Electrical activity regulates expression of many proteins relevant to synaptic maturation and functions27 such as NMDA receptors, CaMKII and glutamic acid decarboxylase (GAD). Activity also induces expression of some `candidate plasticity-related genes27, 95, such as class I major histocompatibility antigen (class I MHC) and cpg15. These gene products may be important for circuit refinement, as mice deficient in class I MHC show abnormal layer segregation in lateral geniculate nucleus96, and overexpression of cpg15 leads to increased dendritic arbor growth of developing tectal neurons97. Finally, activity upregulates expression of neurotrophins (NTs), which are proteins that regulate synaptic function and axon/dendrite morphology98-102. Secreted NTs bind to their respective Trks, triggering cytoplasmic signaling events. Complexes of NT-Trk are internalized and transported within the neuron in both anterograde and retrograde directions. Long-range trafficking of NT–Trk complexes within and across neurons may be important in global modulation of developing circuits102. Neurotrophins: activity-dependent morphogens? NTs, a family of growth factors known for their effects on neuronal survival, are attractive candidates for linking electrical activity to functional and structural modification of synaptic connections98-102. Electrical activity or sensory inputs can upregulate the expression of NTs in many regions of the brain. Neurotrophin secretion from neurons and muscle cells can be triggered by depolarization or synaptic activity. In some preparations, extracellularly applied NTs can potentiate excitatory synaptic transmission and depress inhibitory transmission. Of particular relevance here, NTs induce marked morphological changes in developing axons and dendrites101. For example, perfusion with excessive NTs or chelating endogenous NTs with Trk–IgG in the primary visual cortex disrupts the formation of ocular dominance columns, suggesting that an appropriate level of extracellular NTs is necessary for activity-dependent refinement of developing thalamocortical projections103. Following the induction of LTP, morphological changes observed on postsynaptic dendrites (for example, formation of new spines6) resemble those induced by exogenously applied NTs. Due to their highly basic structure, secreted NTs are likely to be tightly bound to cell surface, and their synaptic modulatory actions are restricted to synapses near the site of secretion104. Moreover, local protein synthesis in developing dendrites can be triggered by NTs105. Neurotrophins thus may serve as activity-dependent morphogenic factors in promoting localized formation of new synaptic connections. In serving its function for synaptic refinement, how do NTs' actions depend on the temporal pattern of activity? One possibility is that NT secretion at the synapse is spike-timing-dependent, in the same manner as is required for the induction of LTP/LTD. High-level evoked NT secretion may occur only when high-level Ca2+ transients are induced postsynaptically at those coactive inputs that initiate postsynaptic spiking immediately following coactivation. Non-coactive inputs arriving at a time beyond the window for synaptic potentiation (Fig. 2) do not evoke postsynaptic NT secretion (due to low-level Ca2+ elevation) and receive no benefit from NT secreted at other coactive synapses (thanks to the localized action of NT). Under the assumptions that, first, the total postsynaptic pool of NT-containing vesicles is conserved—increased secretion at coactive synapses depletes the pool for constitutive and evoked NT secretion at nearby non-coactive synapses; second, a low-level, constitutive NT secretion is required for maintaining the stability of the synapse; and third, increased NT secretion promotes synapse strengthening/formation whereas reduced constitutive and evoked NT secretion leads to synapse weakening/elimination, NTs may serve for the refinement of developing circuits in a manner that depends on the temporal patterns of electrical activity. Conclusion There is little doubt that electrical activity in the nervous system is important in the formation and refinement of developing neural circuits. However, with the exception of activity-induced LTP/LTD, our understanding of how electrical activity affects the structure and function of developing circuits is very limited. There are many outstanding questions. How does the activity regulate the synthesis and localization of cellular components required for the formation, maturation and elimination of synaptic connections in a manner that depends on the spatiotemporal pattern of activity? What are the cellular substrates that endow the developing circuit the plasticity for structural refinement during the critical period of development? How do the spatiotemporal patterns of excitatory and inhibitory activities within the nascent circuits interact to shape the circuit architecture appropriate for their mature function? Is the plasticity of mature circuits associated with integrative brain functions such as learning and memory a remnant of developmental plasticity of the circuit and subjected to the same rules of activity-dependent regulation? A combination of molecular, cellular and system approaches are likely to be required to answer these questions.

Chinese Herbal Prozac: Depression and Traditional Chinese Medicine by Brian Benjamin Carter In clinical setting we frequently see patients who are taking antidepressants like Prozac, Zoloft, Paxil, Effexor, and Wellbutrin. Chinese herbs like Albizzia may be an alternative to psychiatric drugs. Traditional Chinese Medicine (TCM) is a holistic medicine- it has never separated the mind and body, and so can comprehensively treat conditions with both physical and mental symptoms. Causes of Depression As with all disease, we need an accurate diagnosis before we can begin treatment. Depression has many causes. Not all of them will be helped by antidepressants. If your self-esteem is intact, your mood does not vary during the day, and you are not impaired socially, your depression may have a physical cause. Some physical/biomedical causes of depression are: chronic pain, chronic fatigue, normal grief, vitamin B12 deficiency anemia, folate deficiency anemia, viral disease, connective tissue/collagen disorders (arthritis), an organic brain disorder, drug side-effects, cancer, and endocrine abnormalities. Chinese Medicine can enhance the health of anyone with any of these conditions. Psychiatric Drug Therapy Controlling depression with pharmaceuticals usually requires weeks or months of experimentation with various drugs at different dosages. During this experimentation, the patient experiences physical and mental side-effects which can range from the annoying to the unbearable. Chinese herbal medicine, properly practiced, does not cause side-effects and so may ultimately be preferable to psychiatric medications. However, there are many grave situations where psychiatric pharmaceuticals are essential, and not taking them can endanger the well-being, or even the life of the patient. More and more M.D.'s are now working to minimize the amount of pharmaceuticals taken by each patient, and some are even working with OMD's to utilize acupuncture and chinese herbs to slowly take the patient off of drugs and cure the root problem. How Chinese Medicine Diagnoses Depression In Traditional Chinese Medicine (TCM), we always conduct a thorough evaluation of the patient. Symptoms and other diagnostic findings are like the pieces of a puzzle. The puzzle is a diagnosis that describes a patient&Mac185;s particular imbalances. Treatment arises naturally from this diagnosis. In TCM (unlike western biomedicine) there is a treatment for every diagnosis. One simple way to understand depression is to use TCM&Mac185;s 5-Element system. The 5 Elements are Wood, Fire, Earth, Metal, and Water. Each element is associated with a particular strength, weaknesses, color, sound, etc. Three common 5-Element types in depression are Earth, Water, and Wood. Earth types "can't keep up." They often experience digestive deficiency, become tired and overwhelmed easily, and are prone to worry and weight gain. They become depressed as a result of deficiency. Water types have deficiencies in their 'root' energy. This is most associated with old age, or extreme chronic illness. Wood types get depressed because "they are all bunched up." They are easy to anger.When anger is focused inward, it turns into depression. They are irritable, have short tempers, and tend to be skinnier than the Earth type.Wood types become depressed as a result of stagnation. Of course, a TCM diagnosis must be much more specific than this before treatment can begin. Then the practitioner moves from diagnosis "What is the disease?" to treatment principles "What strategies should we use to balance the patient?". For example, they may want to increase the patient&Mac185;s energy, move stagnation, and calm the spirit. Herbs and herb formulas are chosen that fit the patient&Mac185;s symptoms, diagnosis, and the practitioner&Mac185;s treatment principles. Albizzia - Chinese Herbal Prozac Alternative? Cortex Albizzia Julbrissin (mimosa tree bark) is a TCM herb in the åNourish the Heart and Calm the Spirit&Mac185; category. It is traditionally used to calm the spirit and relieve emotional constraint when the associated symptoms of bad temper, depression, insomnia, irritability and poor memory are present. It also relieves pain and dissipates abscesses and swelling due to trauma (including fractures). The flower of the mimosa tree is also used to relieve constrained Liver qi, and calm the spirit when the associated symptoms of insomnia, poor memory, irritability, epigastric pain, and feelings of pressure in the chest are present. Research has shown that the flower of the mimosa tree has a sedative effect. German scientists assert that mimosa tree bark is part of the heavily-guarded Coca Cola recipe (a concoction that has been making people happy for decades!). Understanding the meaning of "Spirit" In Chinese Medicine, "spirit" is conscious awareness, the more emotional and elusive aspect of being. The body must be in a good state of health, and there must be sufficient nourishment and balance for the spirit to be at peace. When improper diet, extreme emotions, trauma, and external diseases injure the body, the spirit does not have a comfortable place to rest. To address this problem, we balance the underlying problem, but in the meantime we also calm the spirit. Thus, in TCM, we treat the cause of the depression AND we calm the spirit so that the patient feels happier and more at peace. Conclusion It is safe to say that there are people on anti-depressant medications that do not need them. More exacting diagnosis by all healthcare practitioners will lead to more appropriate treatments. Psychiatric medications often cause unwanted side-effects. Proper TCM treatment does not cause side-effects. Because TCM is a holistic medicine that integrates the body and mind in its diagnostic process and treatment strategies, it is a viable solution for the treatment of depression. Brian Benjamin Carter is the Editor of The Pulse of Oriental Medicine, a writer for Being Well and an Intern at the Pacific College of Oriental Medicine. The Mechanism of Acupuncture - Beyond neurohumoral theory by Charles Shang ABSTRACT Acupuncture points and meridians have been discovered to have high electric conductance which is related to high density of gap junctions. Neurohumoral approach in acupuncture research was instrumental in establishing the scientific validity of acupuncture. However, it is largely descriptive with little prediction power. It also has not been able to explain many observations in acupuncture. Based on the morphogenetic singularity theory, acupuncture points originate from the organizing centers in morphogenesis. This theory explains several long-standing puzzles in both developmental biology and acupuncture research, including the distribution and non-specific activation of organizing centers and acupuncture points, the high electric conductance of acupuncture points, the polarity effect of electroacupuncture and side effect profile of acupuncture, as well as the ontogeny, phylogeny and physiological function of the meridian system and chakra system. Most of these have not been explained by any neurohumoral theory. In several ‘prospective blind trials’, main-stream biomedical researchers have confirmed its corollary on the role of singularity and separatrix in morphogenesis, the predictions on the high electric conductance and the high density of gap junction at the organizing centers. These advances have profound implications in biomedicine. Physical characteristics of the acupuncture points and meridian system According to the Standard Acupuncture Nomenclature proposed by the World Health Organization (WHO),[1] the meridian system in acupuncture consists of about 400 acupuncture points and 20 meridians connecting most of the points. Since the 1950s, it has been discovered and confirmed by researchers in several countries with refined techniques [2] that most acupuncture points correspond to the high electrical conductance points on the body surface [3,4,5,6,7] and vice versa.[8] The high skin conductance of the meridian system is further supported by finding of high density of gap junctions at the epithelia of the acupuncture points.[9,10,11,12] Gap junctions are hexagonal protein complexes that form channels between adjacent cells. It is well established in cell biology that gap junctions facilitate intercellular communication and increase electric conductivity.Acupuncture and meridian points have also been found to have higher temperature[13], higher metabolic rate and carbon dioxide release.[14] The neurohumoral approach In acupuncture analgesia, the peripheral nervous system has been shown to be crucial in mediating the effect. The analgesia can be abolished if the acupuncture site is affected by postherpetic neuralgia[15] or injection of local anesthetics[16]. In other effects of acupuncture such as anti-hyperglycemic effects, studies have shown that local blockade of peripheral nerves or denervation did not interfere with the acupuncture effect[17]. In the 70s, the relation between cerebral cortex and acupuncture alteration of visceral function was explored by examining the cortical evoked potentials, single unit discharges and neurochemistry associated with acupuncture. These studies brought forth the Meridian-Cortex-Viscera correlation hypothesis[18] which states that: 1. The meridian system is an independent system connected via the nervous system to the cerebral cortex. 2. It acts through neurohumoral mechanisms[19]. Recently, a more generalized acupoint-brain-organ model was proposed that acupuncture first stimulates the corresponding brain cortex via the nervous system, thereby controlling the chemical or hormone release to the disordered organs for treatment.[20] In the mid-70s, the discovery of endorphin induction in acupuncture analgesia and its blockade by naloxone played a key role in establishing the validity of acupuncture in main-stream science.[21,22] Animals which respond poorly to acupuncture analgesia can be rendered good responders by treatment with D-phenylalanine which inhibits the degradation of met-enkephalin[23]. A close relation between acupuncture and nervous system is also indicated by the large overlap between acupuncture points and trigger points - points of maximum tenderness in myofascial pain syndrome[24]. These results have led some practitioners to believe that the meridian system as described in the classic acupuncture literature does not exist and that all the effects of acupuncture are mediated through nervous system.[25,26] Other scholars regard the neurally mediated acupuncture phenomena as “not the central core of the mechanism of acupuncture”.[27] The current neurohumoral theory of acupuncture has been mostly descriptive with little prediction power. It has difficulty in explaining a number of phenomena in acupuncture: 1. The distribution of acupuncture points: For example, an auricle has no important nerves or blood vessels and no significant physiological function other than sound collection, it nevertheless has the highest density of acupuncture points. According to the WHO, 43 auricular points have proven therapeutic value, which consist of 10% of the acupuncture points of the whole body. 2. The non-specific activation of acupuncture points: Each type of nerve usually responds to certain specific modalities of stimuli. Therapeutic effect of acupuncture can be achieved by a variety of stimuli[28,29] including needling, temperature variation, laser[30], ultrasound, vacuum and pressure. 3. The bi-directional regulation effect of acupuncture: Conventional nerve stimulation usually result in uni-directional effect. For example, vagal stimulation slows down heart rate. Opioids inhibits gut motility. However, acupuncture at PC6 accelerates bradycardia and decelerates tachycardia. Acupuncture at ST36 suppresses hyperfunction (as in diarrhea) and stimulates hypofunction (as in constipation) of the gut motility.[31] Therefore, proper use of acupuncture causes few side effects[32,33,34,35] as demonstrated in randomized controlled trials[36,37], unlike most of the conventional nerve-stimulation therapies. The morphogenetic singularity theory The morphogenetic singularity theory[38] developed over the last 2 decades is compatible with the neurohumoral findings of acupuncture effect and also can explain many phenomena in acupuncture beyond the neurohumoral theory. Acupuncture points are singular points in surface bioelectric field Epithelia usually maintain a 30-100 mV voltage difference across themselves.[39] This voltage is the potential difference across cell layers, not membrane potential. An acupuncture point which has high density of gap junctions and local maximum electric conductance will also have locally maximum electric current density – a converging point of surface current. It is a singular point of abrupt change in electric current flow. A singular point is a point of discontinuity as defined in mathematics. It indicates abrupt transition from one state to another. Small perturbations around singular points can have decisive effects on a system. As James Maxwell observed: “Every existence above certain rank has its singular points ... At these points, influence whose physical magnitude is too small to be taken account of by a finite being, may produce results of the greatest importance.”[40] The pattern of electromagnetic field on the human scalp mapped by SQUID (Superconducting QUantum Interference Device)[41] shows that the acupuncture point GV20 Baihui is a singular point at the surface magnetic field where the surface magnetic flux trajectories converge and enter the inside of the body. (Dr. Magnus Lou, personal communication) The Governor Vessel is a converging pathway of magnetic flux on the scalp and also a separatrix which divides the surface magnetic field into two symmetrical domains of different flow directions. A separatrix is a trajectory or boundary between spatial domains in which other trajectories have different behavior.[42] Morphologically, the Governor Vessel is also the axis of symmetry on the scalp. This pattern is consistent with the pattern of the meridian system, but different from the distribution of any major nerve, lymphatic or blood vessel on the scalp. The morphogenetic singularity theory suggests that the meridian system is related to the bioelectric field in morphogenesis and growth control.[38] The role of electric field in growth control and morphogenesis A variety of cells are sensitive to electric fields of physiological strength.[43] Somite fibroblasts migrate to the negative pole in a voltage gradient as small as 7 mV/mm.[44] Asymmetric calcium influx is crucial in the migration which can be blocked or even reversed by certain calcium channel blockers and ionophores.[45] In most cases, there is enhanced cell growth toward cathode and reduced cell growth toward anode in electric fields of physiological strength.[46,47] Fast growing cells tend to have relative negative polarity. This polarity is due to the increased negative membrane potential generated by the mitochondria at high rate of energy metabolism.[48] Imposed electric fields can cause polarization of mouse blastomeres,[49] reversal of anterior-posterior polarity[50] and dorsal-ventral polarity[51] in lower animal morphogenesis. Organizing centers have high electric conductance In development, the fate of a larger region is frequently controlled by a small group of cells, which is termed an organizing center.[52] Organizing centers are the high electric conductance points on the body surface:[38] The amphibian blastopore, a classic organizing center, has high electric conductance and current density.[53] Similar phenomena have also been observed in higher vertebrates.[54] The high conductance phenomenon is further supported by the finding of high density of gap junctions at the sites of organizing centers.[55,56,57,58] At the macroscopic level, organizing centers are singular points in the morphogen gradient and electromagnetic field.38 Disruption of electric field at the organizing center can cause malformation.[53] Change of electric activity at the organizing centers correlates with signal transduction and can precede morphologic change.[59,60] For example, in amphibians, an outward current can be detected at the site of a future limb bud (an organizing center) several days before the first cell growth.[61] Acupuncture points originate from organizing centers. Both acupuncture points and organizing centers have high electric conductance, current density, high density of gap junctions and can be activated by nonspecific stimuli. Therapeutic effect of acupuncture can be achieved by a variety of stimuli as mentioned above. Similarly, morphogenesis of organizing centers can be induced by various stimuli such as mechanical injury and injection of nonspecific chemicals.[52,62] Meridian – Separatrix - Boundary At early stages of embryogenesis, gap junction mediated cell-cell communication is usually diffusely distributed which results in the entire embryo becoming linked as a syncytium. As development progresses, gap junctions become restricted at discrete boundaries, leading to the subdivision of the embryo into communication compartment domains.[63] These boundaries are major pathways of bioelectric currents and divide the body into domains of different electric current directions. Separatrices can be folds on the surface or boundaries between different structures and often connect singular points.[38,64] Meridians are separatrices[38] and related to a under-differentiated,[9] interconnected cellular network that regulates growth and physiology. The attributes of separatrix is consistent with the observation in the Inner Classic (Nei Jing) that meridians lie at the boundaries between different muscles. For example, part of the lung meridian runs along the borders of biceps and brachioradialis. Part of pericardium meridian runs between palmaris longus and flexor carpi radialis. Part of gallbladder meridian runs between sternocleidomastoid and trapezius. Trigger points also tend to locate at the boundaries of muscles.[65] The Governor Vessel and the Conception Vessel are the axis of symmetry of the body surface and the boundaries of many different structures. They are also regarded as the convergence of all meridians in traditional acupuncture. In consistence with the under-differentiation of the meridians, it has been observed that the most apical part of folds remain undifferentiated in morphogenesis,66including organizing centers such as apical ectodermal ridge.[67] Why do auricles have the highest density of acupuncture points? The distribution of acupuncture points and organizing centers is closely related to the morphology of the organism. For example, the auricle, which has the most complex surface morphology, also has the highest density of acupuncture points. Although an auricle has no important nerves or blood vessels and no significant physiological function other than sound collection, its morphology is one of the most sensitive signs of malformations in other organs. Auricular malformation has been observed in Turner syndrome, Potter syndrome, Treacher-Collins syndrome, Patau syndrome, Edwards syndrome, Noonan syndrome, maternal diabetes, atherosclerosis,[68] Goldenharr syndrome, Beckwith syndrome, DiGeorge syndrome, Cri-du-chat syndrome and fragile X syndrome. It is recommended in a standard textbook of pediatrics that any auricular anomaly should initiate a search for malformations in other parts of the body.[69] Based on the phase gradient model in developmental biology, [38,70] many organizing centers are at the extreme points of curvature on the body surface such as the locally most convex points (e.g., the apical ectodermal ridge and other growth tips) or concave points (e.g., the zone of polarizing activity). Similarly, almost all the extreme points of the body surface curvature are acupuncture points, for example, the convex points include EX-UE11 Shixuan, EX-LE12 Qiduan, ST17 Ruzhong, ST42 Chongyang, ST45 Lidui, SP1 Yinbai, SP10 Xuehai, GV25 Suliao, EX-HN3 Yintang ... The concave points include CV17 Danzhong, KI1 Yongquan, LI5 Yangxi, LU 5 Chize, LU7 Lieque, LU8 Jingqu, LU10 Yuji, SI19 Tinggong, TE21 Ermen, GB20 Fengchi, GB30 Huantiao, BL40 Weizhong, HT1 Jiquan, SI18 Quanliao, BL1 Jingming, CV8 Shenque, ST35 Dubi ... The role of the meridian system in evolution and physiology In ontogeny, the development of organizing centers in the growth control system precedes the development of the nervous system and other physiological systems. The formation and maintenance of all the physiological systems are directly dependent on the activity of the growth control system. As the individual embryonic development recapitulates the evolution of the species,(ontogeny recapitulates phylogeny) the evolutionary origin of the meridian system as an intercellular signal transduction system of growth control is likely to have preceded all the other physiological systems, including the nervous system. Its genetic blueprint might have served as a template from which the newer systems evolved. Consequently, it overlaps and interacts with other systems but is not simply part of the nervous system. The meridian signal transduction is embedded in the activity of the function-based physiological systems. The regulation of many neural, circulatory or immune processes is through growth control mechanisms such as hypertrophy, hyperplasia, atrophy, apoptosis with shared messenger molecules and common signal transduction pathways involving growth control genes such as proto-oncogenes.[71,72,73,74,75] Acupuncture also induces the expression of proto-oncogene c-fos. [76,77] Many “non-excitable” cells have shown electrochemical oscillation, coupling, long range intercellular communication [60,78,79] and can participate in the meridian signal transduction. A unified basis of meridian system and chakra system Based on the morphogenetic singularity theory, the distribution of meridian system is related to both internal and external structures, and not solely determined by nerves, muscles or blood vessels. The distribution is a result of morphogenesis. Therefore, acupuncture points which are not at obvious extreme points of surface curvature or meridians which are not at obvious surface boundaries may be vestigial or more related to internal structures. The under-differentiated, inter-connected cellular network is not limited to the body surface. The distribution pattern of a certain type of primary tumors reflects the distribution of its normal counterpart. For example, the distribution of primary pheochromocytoma reflects the distribution of normal sympathetic ganglion cells. One type of the least differentiated cells is germ cell. The germ cell tumors [80,81] have a midline and para-axial distribution pattern which spans from the sacrococcygeal region, through anterior mediastinum, tongue, nasopharynx, to pineal gland. It appears to concentrate at 7 locations: sacrococcygeal region, gonads, retroperitoneum, thymus,[82] thyroid, [83] suprasellar region, and pineal gland.[84] The pattern resembles the chakra system used in yoga and acupuncture,[85] suggesting the existence of under-differentiated cells which may be highly inter-connected in a normal state as part of the “inner meridian system” and provide important regulatory functions.[86] Mechanism of meridian system based diagnosis and therapy As the electrical conductance of organizing centers varies with morphogenesis, the conductance of acupuncture points also varies and correlates with physiological change3 and pathogenesis.[87,88] The fact that the change in electric field precedes morphologic change61 and manipulation of the electric field can affect the change[89] may shed light on the diagnosis[90] and treatment of many diseases. According to the theory,[38] the network of organizing centers retain its regulatory function through high levels of intercellular communication correlated with relatively low levels of cell differentiation after embryonic development. This prediction is consistent with the finding that the high electric conductance persists at the organizing centers after early embryogenesis.[91] The organizing centers may communicate with other parts of the body to maintain proper forms and functions. Gap junctional communication has been shown to play a crucial role in morphogenesis.[92] The gap junction genes can also behave as classical tumor suppressor genes both in culture and in animal tests in restoring growth regulatory properties to metastatic cancer cells.[93] An anomaly inside the organizing center network may be detected by measuring the electrical parameters of some points on its surface at the early signal transduction stage and treated by manipulation of the interconnected organizing centers. The activation of organizing centers is likely to be involved in the restoration of proper form and function in wound healing and stress response. Acupuncture can speed up the wound healing process [94] and cause an exaggerated systemic wound healing and stress response.[95,96] The response can include excessive release of endorphin which stimulates epithelial cell growth[97] as well as analgesia. Other neuro-humoral factors induced by acupuncture such as serotonin[98] and ACTH[99] also have growth-control effects.[100] A principle in electroacupuncture is that positive (anode) pulse stimulation of a point inhibits its corresponding function while negative (cathode) pulse stimulation enhances the function.[101] This polarity effect is similar to the finding that cell growth is enhanced toward cathode and reduced toward anode,[46,47] consistent with the theory that the mechanism underlying acupuncture overlaps with that of growth control. Why does acupuncture has normalizing effect and few side effects? In acupuncture, the often nonspecific perturbation at singular points (acupuncture points) may not directly antagonize a pathological process but may indirectly adjust the process and restore normal function by activating the network of organizing centers in the organism. The activation of the self-organizing activity is less likely to cause the side effects resulted from directly antagonizing a pathological process which often overlap with other normal and beneficial physiological processes. Summary The morphogenetic singularity theory outlines the common ground shared among meridian system, chakra system and modern sciences. It is compatible with the findings from neurohumoral studies. It explains several long-standing puzzles in both developmental biology and acupuncture research. These include the distribution of meridian system, chakra system and germ cell tumors, the non-specific activation of acupuncture points and organizing centers, the high electric conductance of acupuncture points, the polarity effect of electroacupuncture and side effect profile of acupuncture, as well as the ontogeny, phylogeny and physiological function of the meridian system. Most of these have not been explained by any neurohumoral theory. In several ‘prospective blind trials’,[53,55,56,57,65] main-stream biomedical researchers, who were unaware of the theory, confirmed its corollary on the role of singularity and separatrix in morphogenesis, and its predictions of the high electrical conductance and high density of gap junctions at the organizing centers such as blastopore and zone of polarizing activity. Techniques involving the stimulation of the meridian system such as acupuncture and qigong[102,103] may activate the self-organizing system of an organism and improve its structure and function at a more fundamental level than symptomatic relief. Development of these techniques may enable the diagnosis and treatment of a pathologic process at the early signal transduction stage prior to the anatomical or morphological change. Prospects The advances reviewed above have broad implications in biomedicine beyond acupuncture. The current stage of research on acupuncture and medicine is analogous to that of physics in early 19th century – at the transition from Newtonian mechanics to electromagnetics. Many questions remain unanswered. More spectacular advances similar to that of relativity and quantum physics may await us in the next century and will depend on the further development of meridian “electromagnetics”. Many other areas such as psychophysiology, chronobiology,[104] and pulse analysis105 related to the meridian system are awaiting more rigorous studies. Many details of the current theories remain to be clarified and tested. Besides the neurohumoral studies, the following directions of research are likely to be important in further understanding acupuncture and meridian system: 1. Mapping of meridian system and the dynamics of its electromagnetic field with high resolution techniques such as SQUID. 2. The relation between the physical parameters of meridian system and various pathological or physiological changes, including changes during acupuncture and qigong practice. 3. Develop acupuncture related techniques of early diagnosis and treatment and establish their cost-effectiveness. 4. Clarify the role of meridian system in morphogenesis and growth control. 5. Cell differentiation and signal transduction in meridian system. 6. Mapping the body surface curvature through embryonic development with imaging techniques and study its relation with meridian system.

Human memory, cerebral hemispheres, and limbic system: A new approach. Vadim S. Rotenberg and Igor Weinberg Affiliation of authors: Prof., V. S. Rotenberg, MD, Ph D., is affiliated with the Sackler School of Medicine, Tel-Aviv University. Genetic, Social and General Psychology Monographs,1999,125(1):45-70. Abstract: This paper presents an integrative approach to human memory in context of brain asymmetry. According to the results of psychophysiological investigations it is suggested that the right hemisphere functioning is closely associated with the limbic system. Their close association leads to formation of polysemantic context. Polysemantic context is determined by multiple interconnections among its elements, whereas each concrete element bears the stamp of the whole context. This context sustains episodic, personal, and emotionally laden memories. The left hemisphere functioning leads to formation of monosemantic context, which is responsible for maintenance of semantic memories. This distinction in terms of general organization of material by hemispheres rises a number of explanation of such phenomena as memory disturbances among aged persons, the influence of emotions on memory, and confabulations. The right and the left hemispheres: The problem of context. Since the first investigations performed by Sperry, Gazzaniga and their associates (Sperry, Gazzaniga, & Bogen,1969; Gazzaniga, 1970) there was an ever increasing number of studies that focused on brain asymmetry. The first theoretical conceptualizations suggested that the left and the right hemispheres process qualitatively different information (Sperry, Gazzaniga, & Bogen, 1969; Gazzaniga, 1970). In particular, the left hemisphere was thought to be involved in processing of verbal material, signs, and symbols, whereas the right hemisphere was thought to be involved in handling non-verbal material, images, melodies, and spatial information. However, the results of other studies refute this point of view. Really, in split brain subjects the right hemisphere is able to process verbal constructions, if they are not too complicated (Ellis, Young, & Andersen, 1988). EEG activity of the right hemisphere predominates during reading stories, while EEG activity of the left hemisphere predominates during reading textbooks in science (Ornstein, Herron, Johnstone, Swencionis, 1979). Although all melodies belong to non-verbal information, right ear (e. g. the left hemisphere) is superior to the left ear in perception of dichotically presented melodies if they differ only in rhythm (Gordon, 1978). Split brain subjects are able to report their dreams (Hoppe, 1977), although dream is a visual experience. The left hemisphere is superior to the right one in perception of faces with some outstanding features (such as very long nose) (Parkin & Williamson, 1987). Deaf and dumb language signs are non-verbal. However, they are damaged by the left hemisphere strokes (Bellugi, Poizner, & Klima, 1983). According to another approach the human hemispheres differ in terms of information processing (Gordon, 1978). That is, the left hemisphere is involved in sequential information processing, whether verbal or non-verbal. The function of the right hemisphere is single-stage, parallel processing of many elements of information as a single whole. However, this point of view can not account for the findings according to which the left hemisphere is also able to grasp a series of data simultaneously, and as rapidly as the right hemisphere does (Polich, 1982). Yet another point of view (Goldberg & Costa, 1981) stresses that the left hemisphere is responsible for the maintenance of familiar forms of behavior, wereas the right hemisphere’s specialization includes the detection of novel and unexpected events. However even this approach cannot account for all existing data. Really, it cannot explain the advantage of the left hemisphere in identification of strange faces, nor the advantage of the right hemisphere in identification of normal faces with which the subject is familiar (Parkin & Williamson, 1987). In order to explain the diversity of results in the field it was suggested (Rotenberg,1979; Rotenberg & Arshavsky,1991) that in the most general form, the difference between the two fundamental and most important strategies of thinking (which are customarily associated with functions of the left and right hemispheres of the human brain), is reduced to the opposite modes of organizing the contextual connection between elements of information. Left-hemispheric or formal, logical thinking organizes any sign material (whether symbolic or iconic) so as to create a strictly ordered and unambiguously understood context. Its formation requires the active choice out of innumerable, real and potential connections between the multiform objects and phenomena of few definite connections which would not create internal contradictions. This choice would be the one most natural to facilitate a sequential analysis. A strategy of thinking of this type makes it possible to build a pragmatically convenient, but simplified model of reality. This model is based on probability forecasting and a search for concrete cause-and-effect relations. It is precisely for this model that the vector-time orientation exists. In contrast, the function of right-hemispheric or image thinking is to simultaneously "capture" an infinite number of connections and the formation, due to this capture, of an integral but ambiguous context. In this context the whole is not determined by its components, since all specific features of the whole are determined only by interconnections between these parts. On the contrary, any concrete element of such a context bears a determining stamp of the whole. Perception at each concrete moment is brought in line with the entire past experience, with the already shaped picture of the world, and with impacts to such a capture the status of thinking. Individual facets of images interact with each other on many semantic planes simultaneously. Examples of such contextual connections are the connections between images in sleep dreams. The advantages of this strategy of thinking manifest themselves only when the information itself is complex, internally contradictory and basically irreducible to an unambiguous context. In this case some of the existing connections, from the positions of formal logic, can be perceived as mutually exclusive and, accordingly, many of them remain unrealized, forming the basis for intuition and creative realization. Thus, the right hemisphere (and only the right hemisphere) functions according to the holographic model and to the model of neural networks with parallel connections. In this case overlap and crosstalk are a main advantages of the right hemisphere thinking, which provide the creation of the polysemantic context and the combination of two or more concepts in a unitary pattern. The complicated interaction between concepts only exists for the linear monosemantic left-hemisphere system. This is especially true if all these concepts are encoded by the same units of the system and an overlap appears. For this reason, only in a linear system the encoding of information must be successive and not parallel. Contrary to this, the parallel system for the encoding of information represented simultaneously in many units is a mechanism of a polysemantic context. The combination of different concepts, each represented in every unit of the holographic system, can be seen as illustrative of the proposition that the holographic system of the right hemisphere includes not the separate concept, but rather the holistic and mosaic picture of the world. Each separate concept is only a small component of this picture. This is why every newly perceived component is integrated in the mosaic picture together with all the other components. The process, therefore, is one of integration and not of inference. On the contrary, left hemisphere mechanisms bring about the distinguishing and structuring of some pragmatic monosematic results extracted from the polysemantic mosaic. It is apparent that the declared differences are most similar to the differences between the iconic and the symbolic systems of representation. The main distinction is that we emphasize the arrangement of contextual relations rather than the consequtiveness or simultaneity of the synthesis (Rotenberg, 1993; Schore, 1997). Research provides increasingly abundant evidence that the ability to arrange a polysemantic context is a specific, immanent function of the right human hemisphere and need not be further amplified by the brainstem reticular formation. Particularly, in healthy subjects tested under normal conditions, the left hemisphere is always more active than the right, as revealed by the frequency and the amplitude of the alpha-rhythm, or by the alpha-index. The intensity and uniqueness of daydream images show a positive correlation with the alpha-index (Kripke & Sonnenschein, 1978). Vivid mental visualization does not decrease EEG synchronization for persons who have well-developed image thinking (De Pascalis & Palumbo, 1986; Rotenberg & Arshavsky, 1991). In meditation, which corresponds to the right hemisphere pattern of thinking (Ornstein, 1972), alpha waves have a high amplitude and become generalized. When a person with a high creative potential succeeds in solving a problem that calls for imaginative and creative handling, his alpha-rhythm is very distinct, especially in the right hemisphere (Martindale, 1975). The left hemisphere data-processing pattern, contrary to that of the right hemisphere, requires higher cerebral activity - for the sole reason that it attempts to arrange the information available and distinguish the few relevant links in a multitude of irrelevant relations. Western culture assumes that an activity should always have a purpose; a known goal should be accomplished. However, activity of the right hemisphere, in creation of the polysemantic context, involves no statistical predictions and sets no cause- and-effect relations. The right hemisphere is responsible for predictions that extend beyond the actual statistics and thus come close to the experience brought about by insight. Its mechanism is yet to be identified. Right-