In Search of a Deep Psychobiology of Hypnosis:

Visionary Hypotheses for a New Millennium

Ernest Lawrence Rossi, Ph.D.

This search for the deep psychobiological foundations of hypnosis begins with a review of some of the paradoxes of historical hypnosis and the impasse of current theory. It is proposed that further progress requires a deeper investigation of how psychosocial cues can modulate the mechanisms of healing at the CNS, autonomic, neuroendocrine and cellular-genetic levels. The dynamics of hypnotic communication and healing from the cognitive-behavior level to the cellular-genetic are outlined in four stages: (1) Information transduction between the experiences of consciousness and the limbic-hypothalamic-pituitary system; (2) The psychosomatic network of messenger molecules and their receptors; (3) The immediate early gene protein cascade; and (4) State dependent memory, learning and behavior. Neuroscience research is outlined for its contributions toward a mathematical model of how a psychobiological approach to the therapeutic applications of hypnosis and the placebo response could facilitate neurogenesis in the human hippocampus and healing at the cellular-genetic-protein level throughout the body.  A series of ten hypotheses is proposed as a guide for theory and research in therapeutic hypnosis utilizing DNA chip technology in the new millennium.

Neuroscience in this decade of the brain is setting the stage for an important updating of our understanding of the psychobiological foundations of hypnosis. We first review the problems and paradoxes of historical hypnosis as well as the impasse of current theories when they are limited to the cognitive-behavioral level. Ten hypotheses are then proposed to expand the domain of hypnosis to include the psychobiology of mind-body communication and healing on all levels from the cognitive-behavioral to the cellular-genetic. Implications are drawn from chronobiology and neurobiology to infer the types of research that are now needed to explore the psychobiological parameters of the therapeutic applications of hypnosis in the future.

Historical Context: Activity-Passivity Paradox of Hypnosis

In 1846 James Braid adopted the term "hypnotism" and is credited with defining its mechanism of action as "psychophysiology" with these words.

"With the view of simplifying the study of reciprocal actions and reactions of mind and matter upon each other... the influence of concentrated attention, or dominant ideas, in modifying physical action, and these dynamic changes re-acting on the mind of the subject...I adopted the term "hypnotism" or nervous sleep (p. 369)... And finally as a generic term, comprising the whole of these phenomena which result from the reciprocal actions of mind and matter upon each other, I think no term more appropriate than psychophysiology." (Braid in Tinterow, 1970, p. 372).

It is surprising for some students to learn that it was Braid, the same physician who popularized the term "hypnotism," who apparently coined the word "psychophysiology" to describe how hypnosis achieved its therapeutic effects. In a later volume, The Physiology of Fascination and the Critics Criticized published in 1855, Braid notes his quandary about the role of fascination as well as voluntary and involuntary behavior in hypnosis.

"The power possessed by serpents to fascinate birds has always been a source of interest and admiration...by what means is this remarkable result effected?...Is it a voluntary, or an involuntary process... After due consideration, I feel satisfied that the approach and surrender of itself by the bird, or other animal, is just another example of the monoideo-dynamic, or unconscious muscular action from a dominant idea possessing the mind" (Tinterow, 1970, 365).

Braid’s concept of the monoideo-dynamic was an anticipation of the modern view that it is the fixation of attention, the patient’s intense focus on the words and ideas of the clinician using hypnosis, that is the stimulus for the psychophysiological healing. Braid’s questions about the role of active, conscious, and voluntary responsiveness versus more passive, involuntary or unconscious processes in hypnosis remains a central question in current theories. Until recently Braid’s emphasis on the significance of fascination in hypnosis fell into the oblivion of folklore about the "evil eye." As we shall soon see, however, fascination during enriching life experiences may be fundamental in the focusing of attention, brain growth and the deep psychobiological dynamics of hypnosis.

The primitive state of psychophysiology during the first century of hypnosis meant that it could be conceptualized only as some sort of reflex or pathology. Bernheim (1886/1957, p. 138), the leader of the Nancy school in France, for example, described hypnosis as the "exaltation of the ideo-motor reflex excitability, which effects the unconscious transformation of the thought into movement, unknown to the will ... The mechanism of suggestion in general, may then be summed up in the following formula: increase of the reflex ideo-motor, ideo-sensitivity, and ideo-excitability." The idea that hypnosis involved an increase in "sensitivity" and "excitability" is in striking contrast to the view of the Salpêtriêre school in Paris led by Charcot who maintained, to the contrary, that hypnosis was a pathological condition of passivity that progressed from lethargy and catalepsy to somnambulism.

This paradox in understanding the fundamental nature of hypnosis -- Is hypnosis heightened activity or passivity? -- continued into the next generation of leading researchers. Pavlov, for example, believed hypnosis was a state of cerebral inhibition, a kind of "partial sleep" while Clark Hull maintained the opposite view that hypnosis is a state of arousal.

"We seem forced to the view that hypnosis is not sleep...Thus the extreme lethargic state is not hypnosis, but true sleep: only the alert stage is hypnotic. Lastly, evidence has been presented which indicates not only that conditioned reflexes may be set up during hypnosis, but that this may perhaps be accomplished with even greater ease than in the waking state. This probably disproves Pavlov’s hypothesis that hypnosis is a state of partial sleep in the sense of a partial irradiation of inhibition." (Hull, 1933/1986, p. 221).

Milton H. Erickson, who was a student of Clark Hull, developed innovative approaches to hypnosis that could utilize either the passive, relaxed and sleep-like tendencies of his patients ("You don’t even have to listen to my voice") or their more active, compulsive, "acting out" behavior such as pacing around the therapy office in an agitated manner. Erickson taught that the appropriate choice of hypnotic induction should be a function of the patient’s mood, attitudes and behavior in the therapy session. Erickson described the great variety of approaches to hypnosis that made use of the full range of the patient’s ongoing behavior as the "naturalistic" (Erickson, 1958/1980) or the "utilization" approach (Erickson, 1959, 1980) in his typically lengthy 90 to 120 minute therapeutic sessions. As we shall soon see 90-120 minutes corresponds to a basic rest activity cycle (Kleitman, 1969; Kleitman and Rossi, (1992) that is associated with many psychobiological processes on all levels from the cognitive-behavioral to the genetic that may be related to the therapeutic possibilities of hypnosis as well as the activity-passivity paradox.

One of the first efforts to understand the psychobiological basis of the activity-passivity paradox of hypnosis came from Erickson's colleague Bernard Gorton in his papers on the physiology of hypnosis (1957, 1958). A review of the existing literature suggested to Gorton that "vasomotor activity" and the autonomic nervous system (ANS) with its two main branches, the sympathetic system (arousal) and the parasympathetic system (relaxation) was the major avenue of the physiological effects of hypnosis. More recent research supports Gorton’s view that there is "A positive correlation between hypnotic susceptibility and autonomic responsiveness during hypnosis..." (DeBenedittis et al., 1994, p 140) and the nature of the "physiological responsiveness [arousal or relaxation] is dependent on the type of suggestions during hypnosis..." (Sturgis & Coe, 1990, p 205).

Even today, however, the use of hypnotic suggestion to modulate the active as well as the passive branches of the ANS is not well understood by researchers who report the "paradoxical" nature of their results. Weinstein and Au (1991), for example, reported that norepinephrine levels were significantly higher in a hypnotized group of patients undergoing angioplasty than in the control group. They report that this was "unexpected and seemed paradoxical (p 29) ... One would expect that if hypnosis does cause relaxation, then those patients who were hypnotized would have a lower arterial catecholamine level than their controls. This was not the case. Just the opposite occurred and is hard to explain" (p 35). This so-called paradox is hard to explain only if one assumes, as these and other authors do (Lazarus and Mayne, 1991), that hypnosis is essentially a state of relaxation. The importance of arousal in hypnosis was emphasized by Amigo (1994) who presented evidence for "self-regulation therapy" as a "cognitive-behavioral approach to hypnosis" that involves the "voluntary reproduction of the stimulant effects of epinephrine." Likewise Harris et al., (1992) found that "both branches of the autonomic nervous system may contribute to hypnotic susceptibility. This accumulating research on how hypnosis can utilize both branches of the ANS resolves the activity-passivity paradox of hypnosis and leads to an expanded model of the psychobiological domain of hypnosis.

Expanding the Domain of Hypnosis: The Deep Psychobiological Model

The deep psychobiological model of hypnotic suggestion is consistent with a generation of research that firmly established, contrary to popular belief, that there is no transcendence of normal abilities in hypnosis (Wagstaff, 1986). Researchers openly acknowledge, however, that they have no adequate theory of the source and parameters of hypnotic performance. Naish (1986, p165-166), for example, has summarized this limitation of the cognitive-behavioral approach as follows: "As [hypnotic] susceptibility is normally assessed, a high scorer is one who produces the behavior, the reason for its production remains unknown...the claim was frequently made that cognitive processes are involved in the production of 'hypnotic' effects. However, the exact nature of these processes generally remained obscure." The psychobiological model of hypnosis proposes that what seems to be an extension of the normal parameters of mind-body performance skills via hypnosis is actually the optimization of the individual's normal range of abilities in response to the general process of adaptation to challenge and stress by the ANS and related systems.

The limitations of cognitive-behavioral level in conceptualizing suggestibility and hypnosis have been discussed by a number of researchers. Hilgard (1991, p. 45-46), for example, summarized the current dilemma with these words, "...hypnotic behavior cannot be defined simply as a response to suggestion... Although hypnotic-like behaviors are commonly responses to suggestion, the domain of suggestion includes responses that do not belong within hypnosis, and the phenomena of hypnosis covers more than specific responses to suggestion." Hilgard seems to be saying that the domain of hypnotic suggestion as currently defined on the cognitive-behavioral level is not adequate or complete. Eysenck (1991, p. 87) emphasizes the problem more pungently, "There is no single, unitary trait of suggestibility, no one uniform type of reaction to different kinds of suggestion in human subjects. There are several, or possibly many different suggestibilities that bear no relation to each other. These are uncorrelated and, in turn, correlate differentially with other cognitive and emotional variables. This finding is of considerable interest and importance... It does make books containing in their title the word ‘suggestibility’ of rather doubtful value!"

Researchers who began their careers by defining hypnosis as a cognitive-behavioral response to suggestion and then, after a lifetime of research, reversing themselves and concluding, in effect, (1) hypnosis cannot be operationally defined simply as responsiveness to suggestion, and (2) there is no unitary human trait of suggestibility, has led to a fundamental impasse in current theory. Balthazard & Woody (1992, p. 22), for example, have stated, "Although a fair amount of factor analytic work has been done with the hypnosis scales this work appears to be at an impasse methodologically, and it has failed to yield any consistent picture of the mechanisms that underlie performance on the hypnosis scales." Kirsch and Lynn (1995, p. 854) emphasize this impasse as follows. "Is there a uniquely hypnotic state that serves as a background or gives rise to the altered subjective experiences produced by suggestion? Having failed to find reliable markers of trance after 50 years of careful research, most researchers have concluded that this hypothesis has outlived its usefulness."

Paradox and impasse in science frequently indicate where theory and practice need to be revised and expanded in some fundamental way. The psychobiological model of hypnosis expands the domain of suggestion beyond the cognitive-behavioral level to include all systems of mind-body communication and healing at the molecular level that are responsive to psychosocial cues. It has been proposed that the major path of mind-body communication is the hormonal or messenger molecule-cell receptor system of the neuroendocrine, neuropeptide, autonomic and immune systems that mediate stress, emotions, memory, learning, personality, behavior and symptoms in a "Psychosomatic Network" (Pert et al. 1985, 1989; Rossi, 1972/1985/2000, 1986/1993, 1996) as illustrated in Figure One. This leads to our first hypothesis about the expanded psychobiological domain of hypnosis.

Figure One illustrates four major levels of the communication process of information transduction between mind, brain and body that are hypothesized as the psychobiological domain of hypnosis. Let us review what is currently known about the psychobiological mechanisms of hypnosis at each level and the types of research that are now needed for further progress.

Papez (1937) traced the anatomical pathways by which emotional experience of the brain was transduced into the physiological responses of the body in a circuit of brain structures that are now generally recognized as the limbic-hypothalamic-pituitary system. The Scharrers (1940) documented how secretory cells within the hypothalamus could mediate molecular information transduction between brain and body. Cells within the hypothalamus transduce the electrochemical impulses of neurons of the cerebral cortex that encode the phenomenological experience of "mind" into the hormonal or "primary messenger molecules" of the endocrine system. These primary messenger molecules of the neuroendocrine system flow through the blood stream to signal receptors on cells of the brain and body to modulate their responsiveness in a cybernetic loop of information transduction illustrated in Figure One. The current consensus is that corticotrophin releasing factor (CRF) is the central psychobiological coordinator of the generalized arousal and stress response (Felker and Hubbard, 1998). CRF signals the anterior pituitary to induce proopiomelanocortin (POMC) that is cleaved into about a dozen messenger molecules including adrenocorticotropic hormone (ACTH) and beta-endorphin that have varying effects upon the psychobiology of arousal, stress, memory, learning and relaxation (Brush & Levine, 1989).

Fig. 1 The Four-Stage Mind-Body Communication loop illustrating the “Unification Hypothesis of Chronobiology” wherein the quasi-periodic rhythmical flow of messenger molecules of the neuroendocrine system (hormones associated with stress, relaxation, sexual hormones, immune system etc.) mediates communication between the mind-brain, brain-body and cellular genomic levels in ultradian time (less that 20 hours). (1) Information from the outside world encoded in the neurons  of the brain is transformed within the limbic hypothalamic pituitary system into the hormones (messenger molecules) that travel through the blood stream to signal receptors on all cells of the brain and body. (2) The receptors on the surface of cells transmit the signal via 2nd messengers to the nucleus of the cell where immediate early genes signal other activity dependent genes to transcribe their code into messenger RNAs. (3) The messenger RNAs serve as blueprints for the synthesis of proteins that will function as (a) the ultimate healing structures - the materia of the body, (b) enzymes to facilitate energy dynamics and (c) receptors and messenger molecules for the informational dynamics of the cell. (4) Messenger molecules function as a type of "molecular memory" that can evoke psychological experiences of mind as state dependent memory, learning and behavior (SDMLB). SDMLB is expressed in the neural networks of the brain (illustrated as the rectangular array of letters A to L on the top) that receive molecular signaling through the Extra Cellular Fluid (ECF) of the brain that may be regarded as a field of complex, self-organizing communication processes that are the psychobiological basis of mind, meaning, memory, learning, psychosomatic medicine and healing.  From Rossi, 2002.

Recent experiments document how such psychobiological mechanisms operate in the transition between waking and sleeping in a manner that may be of relevance for the therapeutic applications of hypnosis. Born et al. (1999), for example, investigated what we may call the "human alarm clock effect" which enables some people to awaken at a specific time in the morning without using an alarm clock. Awakening from a night of sleep is related to a daily (circadian) rhythm in the release of the pituitary and adrenal hormones. This circadian rhythm is in turn made up of a series of ultradian rhythms wherein there is a peak in the release of ACTH and cortisol every 90-120 minutes through out the day and night. Normally this release of ACTH and cortisol increases during the later stages of sleep and reaches a daily peak just before the time of awakening in the morning. Born et al. (1999) demonstrated that the conscious intentionality or anticipation of awakening at a specific time in the morning could shift the ultradian peak in the release of ACTH to that specific time. That is, a conscious intentionality or expectancy of awakening at a specific time could pervade sleep and modulate the expression of a normally autonomous or involuntary rhythm of hormone regulation across the limbic-hypothalamic-pituitary system at locus one in Figure One. This is a clear example of information transduction between the phenomenological experiences of consciousness and the flow of information through the body via hormones (also called "messenger molecules" or "information substances") (Rossi, 1986/1993, 2002). It would be of great interest to determine whether hypnosis achieves its mind-body effects by utilizing the same type of psychobiological mechanisms at the hormonal level when a posthypnotic suggestion is administered to awaken from a night of sleep at a specific time. This type of research would integrate hypnosis with the vast database and methodology of modern neuroscience (Barabasz, 2002;  Rainville et al., 1997, 1999).  Such research could, for example, provide experimental data to assess a mathematical model of the chronobiological mechanisms of hypnosis as proposed later in Figure Nine.

Such research motivates us to take a closer look at the typical dynamics of some of the other major systems of mind-body communication that may be operative in the psychobiological domain of hypnosis. Figures Two through Seven illustrate half a dozen interrelated life processes from the cellular-genetic level to the psychosocial including self-hypnosis. A superficial glance suggests these systems are all very different. A more careful examination, however, indicates that much of their apparent difference is due to the fact that (1) they were sampled with different numbers of data points on (2) different time scales that (3) are not strictly regular in their periodicity but manifest, rather, what is now called "quasi-periodic." Quasi-periodic behavior is found when two or more rhythms with different periods interact to produce oscillations that never repeat themselves exactly. Many physical systems such as the two-coupled pendulum, most biological processes, and brain dynamics are quasi-periodic (Rossi, 1996). Quasi-periodicity is the signature of the nonlinear dynamics of communication in the highly adaptive processes of life on all levels from the psychosocial to the cellular-genomic (Lloyd and Rossi, 1992; Newtson, 1994; Vallacher and Nowak, 1994). What all psychobiological systems have in common is that they may be modeled by the quasi-periodic dynamics of circadian (about 24 hours) and ultradian rhythms (less than 20 hours). This leads to conjectures about the non-linear dynamics of future mathematical models of the entire range of psychobiological states that are now loosely called "therapeutic hypnosis."

Fig. 2  The Cellular Genomic Level.  In this series of graphs it can be seen that Kleitman's (1969; Kleitman & Rossi, 1992) Basic Rest Activity Cycle - typically a 90-120 minute  quasi-periodic ultradian  rhythm - is fundamental in cell growth and replication.  The approximately 20 minute  peak in Maturation Promoting Factor (MPF), the protein  Cyclin and the enzyme H1 kinase act in concert to signal the final stage of genetic replication and cell division (mitosis) (From Murray et al., 1989).  Some researchers propose that this may be the basic ultradian pacemaker that sets all other levels such as the metabolic, neuroendocrinological, cognitive-behavioral  and the socio-cultural as illustrated below.

Fig. 3  The Endocrine-Behavior Level.  An example of the interaction between the cognitive-behavioral  and hormonal levels. The typical 90-120 minute  ultradian  rhythms  in the pulsate expression of the endocrine  renin-angiotensin-aldosterone system have their higher amplitude peaks shifted to the right by an 8-hour delay of the sleep-wake cycle in the lower graph.  The small inset on the upper part of each graph illustrates the relationship between plasma renin and the stages of waking consciousness , Rapid Eye Movement  Sleep (REM Dreaming state) and the four major levels of sleep depth (From Brandenberger, 1992).

Fig. 4a Neuroendocrine Level - ACTH & Cortisol.  Hormonal profiles of the ultradian  rhythms  in ACTH and Cortisol in two subjects when blood samples were taken at 10 minute intervals over a 24 hour period (From Brandenberger, 1992).  While there are obvious differences, both individuals manifest 90-120 minute  pulsate rhythms  with varying amplitudes.  The lower profile, which is perhaps the more typical, illustrates how these two hormonal messenger molecules  that mediate states of arousal  tend to their highest peaks in the early morning hours and gradually dwindle in the afternoon and evening when our energy levels are lower.

Fig. 4b  The ultradian and circadian time parameters of an acute stressor (forced swimming in mice).  Notice the initial peak of stress induced acetylcholinesterase activity during the typical time frame of Kleitman's 90-120 minute Basic Rest Activity Cycle (BRAC) in the hippocampus (hipp) that is followed by a peak in the cortex (cort) when the symptoms of PTSD become manifest.  This figure is reproduced with permission from Kaufer et al., 1998.

Fig. 5  The Endocrine-Energy-Metabolic Level.  These three graphs illustrate how the blood Glucose (left), C-peptide (middle) and insulin  (right) obtained at two minute intervals during an 8-hour fasting period have rapid 10-15 minute oscillations that are shown superimposed on the approximately 90-120 ultradian  rhythms  which were obtained by a best-fit curve with a regression algorithm (From Sturis et al., 1992). 

Fig. 6   The Behavioral-Social-Cultural (Psychosocial) Level. Time series illustrating the ultradian  rhythms  of the locomotion (about 80 minutes), object change (about 65 minutes) and social contacts (about 103 minutes) for the Indian child “Ram” in a natural  setting in a small village in India.  Similar ultradian rhythms  are found in a child of !Ko Bushmen and social synchronization in a village community of Colombian Indians as well as free play in highly urbanized children  in Germany.  (From Meier-Koll, 1992). 

Fig. 7a The Cognitive-Behavioral-Hypnosis Level.  An illustration of the quasi-periodic 180 minute ultradian rhythms of self hypnosis that were recorded by 9 subjects in their diaries in a pilot study that now requires independent confirmation (From Rossi, 1992).  

Fig. 7b The Basic Rest Activity Cycle (BRAC) found in the time series of 7 subjects who were instructed to simply enjoy an “ultradian healing response” whenever they felt a need to throughout the day in a pilot study that now requires independent confirmation (From Rossi, 1992).  

The nonlinear relationship between performance and arousal illustrated on the right of Figure Eight, called the Yerkes-Dodson Function (1908), and is one the earliest and most well established laws in psychology. All life processes go through an initial phase of arousal, they reach a peak where performance is optimized, and then relax back to a basal level. Guastello (1995) has updated the significance of the Yerkes-Dodson function in psychophysics and sensory-perceptual systems as well as the nonlinear dynamics of creativity, work and social organizations. We hypothesize that this intensively researched Yerkes-Dodson function models the arousal (high phase) and relaxation (low phase) aspects of hypnosis as well. An outline of the parameters of this mathematical model adapted from chronobiology is presented in Figure Nine. Figure Ten illustrates how this quasi-periodic model could integrate many of the apparently paradoxical phenomena and conflicting theories of high and low phase hypnosis in a complementary manner (Rossi, 1996, 2002).

Fig. 8  Linear and nonlinear dynamics in psychobiology. The typical linear approach is illustrated on the left with the straight line cutting through a cloud of data points is the "best linear fit," of the data. Traditionally each of the data points is said to be a combination of a measurable psychological factor and experimental error or "noise." The nonlinear dynamics systems approach, however, recognizes that many apparently random deviations of so-called "noise" actually may be the signature of quasi-periodicity and deterministic chaos in the natural and highly adaptable ultradian rhythms of mind-body communication and healing that are responsive (easily entrained by) psychosocial cues of stress, trauma, arousal, and relaxation.  This responsiveness, adaptation, or entrainment of biological processes by psychosocial cues (communications) is the essence of psychosomatic medicine, mind-body healing, and so-called "alternative, complementary or holistic medicine."

Fig. 9 Towards a quasi-periodic mathematical model of hypnosis.

Fig. 9 The parameters of a possible mathematical model of how the therapeutic applications of hypnosis may entrain and utilize the quasi-periodic psychobiological dynamics of adaptation to stress, arousal, and relaxation are as follows.

Amplitude refers to the absolute value of the height or depth of a quasi-periodic rhythm of behavior: it measures how far rhythm deviates from its mean level. The amplitude may correspond to the degree to which hypnosis may optimize performance variables that require psychobiological arousal (sympathetic system) or healing (parasympathetic system).

Period is the time required for one complete cycle of adaptation on all levels from the cognitive-behavioral to the cellular-genetic. The period is a quasi-periodic parameter of psychobiological rhythms that may be contracted, stretched or "phase locked" in the therapeutic applications of hypnosis. The frequency is the reciprocal of the period.

Phase identifies parts of natural quasi-periodic psychobiological rhythms of adaptation that may be accessed, entrained and utilized by hypnosis. The crest or peak phase is associated with the activation (sympathetic system) dynamics of "high phase hypnosis," while the trough phase of relaxation (parasympathetic system) may be entrained by "low phase hypnosis." The number C/B, called the phase shift, is a measure of the degree to which certain portions of chronobiological behavior can be entrained and modulated with hypnosis.

Entrainment or synchronization refers to the interaction of psychobiological rhythms (x and y below) with psychosocial cues such as hypnosis (z below). Many therapeutic applications of hypnosis may be conceptualized as the entrainment of portions of the Basic Rest-Activity Cycle (BRAC) that are utilized for enhancing performance or facilitating healing.

A mathematical model adapted from the field of chronobiology (Kronauer, 1984) is used to illustrate how the hypnotic entrainment of quasi-periodic psychobiological rhythms may operate. In the equations below  F_zy is the "influence" or entrainment coefficient; w _x and w _y are the natural frequencies of quasi-periodic psychobiological rhythms x and y; k may be a constant associated with hypnotic susceptibility; that is, the entrainability of a particular psychobiological process by highly focused psychosocial cues.

Note that this is not yet a complete mathematical model of therapeutic hypnosis!  It is merely the initial conceptual stage where we are assuming that therapeutic hypnosis actually engages the natural ultradian psychosomatic network on all levels from mind to gene expression and neurogenesis as proposed by the new discipline that I call "Psychosocial Genomics: How psychosocial processes can modulate immediate early, activity dependent, and behavior state related gene expression." (Rossi, 2002).   A series of iterative steps integrating theory and experiment are now required to assess, modify, and retest the value of this possible math model of therapeutic hypnosis (Borrelli and Coleman, 1998)

Fig. 10 The continuum of therapeutic hypnosis to be assessed by DNA chip technology ranges from the quasi-periodic ultradian peaks of performance of (1) high phase hypnosis with its active focus on problem solving as described by social-psychological theorists to (2) the apparently passive periods of deep inner absorption and ultradian healing with low phase hypnosis emphasized by special state theorists. A complete cycle of hypnotic work usually consists of an initial high phase of sympathetic system arousal as the subject becomes engaged in problem solving. With the resolution of a problem the subject spontaneously slips into low phase hypnosis wherein parasympathetic system dominance is experienced as relaxation and healing (Rossi, 1996, 1972/1985/2000, 2002).

What is the type of data that could be used to assess this mathematical model of high and low phase hypnosis? While the therapeutic applications of hypnosis have traditionally focused on relaxation or low phase hypnosis, a pair of research reports by Hautkappe & Bongartz (1992) and Unterweger, Lamas & Bongartz (1992) supports the idea that hypnosis involves a significant "work function" that operates differently in high and low hypnotic susceptibility subjects.  Hautkappe & Bongartz (1992) found that heart rate variability was a useful physiological parameter for discriminating high and low hypnotic susceptibility; high susceptible hypnotic subjects have less heart rate variability (p. 82-83). This implies, "High susceptible subjects do not have to work as hard on passing a suggestion as do low susceptibles" (Unterweger et al., 1992, p. 87). High hypnotic susceptibility is apparently associated with a more efficient psychobiological use of information and/or energy.  From a historical perspective this may be interpreted as consistent with Braid's conception of hypnosis as facilitating "monoideism" (Tinterow, 371).  

In Ericksonian terms high susceptible subjects have higher "response attentiveness" or selective focus so their mind-body system does not require an indiscriminate massive arousal to do certain tasks (Erickson and Rossi, 1979). Erickson pioneered the use of psychological shocks and creative moments (Rossi, 1973) to focus attention in what we would now call "high phase" hypnosis. More recent clinical and experimental research by Barabasz and Barabasz (1996) has documented how such "alert hypnosis" can facilitate the neurotherapy (neural biofeedback) of children with attention deficit hyperactivity disorder (ADHD) by enhancing their skills in shifting from a predominantly theta to beta modes of functioning as measured by their eeg. Further research is now needed to explore the relationships between high and low susceptible hypnotic subjects with the use of high and low phase hypnosis. One wonders, for example, whether high susceptible hypnotic subjects are more efficient in turning on and focusing the activating (sympathetic branch or high phase hypnosis) as well as the relaxation (parasympathetic branch or low phase hypnosis) of their neuroendocrine system. What are the relative merits of (1) The Stanford and Harvard Hypnotic Susceptibility Scales that may induce low phase hypnosis with their emphasis on sleep; (2) The Barber Scale the and Spiegle Hypnotic Induction Profile that may induce high phase hypnosis with their emphasis on focused attention, versus (3) Rossi’s (1986) Indirect Trance Assessment Scale (ITAS) that seeks to eliminate a bias toward either high or low phase hypnosis in the therapeutic applications of hypnosis?

At the limbic-hypothalamic-pituitary level any powerful physical or psychosocial stimulus leads within minutes to the release of CRF which in turn initiates an ACTH-Cortisol-Beta-endorphin cascade that coordinates a variety of adaptive psychobiological processes on the organ, tissue and cellular-genetic levels. One of the most prominent of these is the 90-120 Basic Rest Activity Cycle (BRAC) associated with the quasi-periodicity of hormonal systems of mind-body regulation during waking (Lloyd and Rossi, 1992, 1993), sleep and dreaming (Kleitman, 1969; Kleitman and Rossi, 1992; Rossi 1972/1986/2000). Available evidence indicates that the highly adaptable quasi-periodic 90-120 minute ultradian cycle consists of an initial phase of psychobiological arousal, work and performance mediated by the ACTH-cortisol phase of the BRAC. The relaxation phase of the BRAC is then mediated by beta-endorphin that signals a molecular cascade at the cellular-genetic-protein level to facilitate restoration and healing. Iranmanesh et al. (1989, p. 1019), for example report that "...cortisol was considered to lead B-endorphin by 20 or 30 minutes. We conclude that B-endorphin is released physiologically in a pulsate manner with circadian and ultradian rhythmicity and a close temporal coupling to cortisol." Such research is consistent with the hypothesis that arousal or high phase hypnosis is associated with the cortisol peak of the BRAC while relaxation or low phase hypnosis is associated with the subsequent B-endorphin response. Research is now required to continuously monitor the release of ACTH, cortisol, B-endorphin and related messenger molecules during the quasi-periodic phases of hypnosis as described previously (Rossi, 1988,1990 a & b, 1996; Rossi and Cheek, 1988). This leads to a pair of hypotheses about relationships between the quasi-periodic parameters of adaptation, stress, hypnosis and healing.

The proof of the principle that we can now trace pathways of communication between mind and body to the genetic level is evident in emerging virtual models of systems biology where researchers are creating interactive computer simulations of the molecular dynamics of the entire cell (Davidson et al., 2002; Kitano, 2002).  ( http://www.cellular-signaling.org/  http://www.sbml.org/  http://www.genome.ad.jp/).  Noble (2002), for example, describes the current status of "Modeling the heart - from genes to cells to the whole organ" and behavior that has implications for the deep psychobiology of therapeutic hypnosis.

"Successful physiological analysis requires an understanding of the functional interactions between the key components of cells, organs, and systems, as well as how these interactions change in disease states.  This information resides neither in the genome nor even in individual proteins that genes code for.  It lies at the level of protein interactions within the context of subcellular, cellular, tissue, organ, and system structures.  There is therefore no alternative to copying nature and computing these interactions to determine the logic of healthy and diseased states.  The rapid growth in biological data bases; models of the cells, tissues, and organs; and the development of powerful computing hardware and algorithms have made it possible to explore functionality in a quantitative manner all the way to the level of genes to physiological function of whole organs and regulatory systems.

The amount of biological data generated over the past decade by new technologies has completely overwhelmed our ability to understand it.  Genomics has provided us with a massive "parts catalogue" for the human body; proteomics seeks to define these individual "parts" and the structures they form in detail.  But there is as yet no "user's guide" describing how these parts are put together to allow these interactions that sustain life or cause disease.  In many cases, the cellular, organ, and system functions of genes and proteins are unknown, although clues often come from similarity in the gene sequences. . . 

An important strength of models based on reconstructing the functional properties of proteins is that it is possible for the models to reach down to the genetic level, for example, in reconstructing the effects of particular mutations when these are characterized by changes in protein function.  An example of this approach is the use of multistate (Markov) models of the sodium channel in which models of the wild-type ["normal" as typically found in nature] and a mutant sodium channel were formulated and validated. . . This causes major prolongation of repolarization and the development of arrhythmogenic early afterpolarizations at slow pacing rates, a behavior that is consistent with the clinical presentation of bradycardia-related arrhythmogenic episodes during sleep or relaxation in LQT3 patients."  (Pp. 1678-1679)

These relationships between systems of molecular interactions at all levels from the rhythms of the gene expression- protein cycle (figure 1) to mind and behavior such as "sleep and relaxation" point to new ways of validating our deep psychobiological model therapeutic hypnosis.  The current challenge is to include the cognitive-behavioral approaches of therapeutic hypnosis in the emerging virtual models of the cell that are being developed in systems biology (Davidson et al., 2002).  These virtual computer models will become our new tool for bridging the so-called "Cartesian gap between mind and body."   Meanwhile we can review some basic research on hypnosis that is consistent with  the experimental associations found between "arrhythogenic episodes during sleep or relaxation," described above, as but one example of the more general finding of "chronic desynchronization" found in psychosomatic problems that may be ameliorated by therapeutic hypnosis.

Hypothesis Four: Psychobiological stress engendered by the chronic desynchronization of circadian and ultradian dynamics such as the quasi-periodic 90-120 minute Basic Rest Activity Cycle by traumatic and/or excessive work loads is a major etiology for psychosomatic problems that may be ameliorated by the therapeutic applications of hypnosis.

Well replicated work on the normal psychobiological dynamics of the major systems of mind-body regulation and healing is evolving out of time parameter research on many levels ranging from the molecular biology of the cell cycle to the neuroendocrinal and the behavioral levels as illustrated in Figures Two through Seven (Lloyd and Rossi, 1992, 1993). It now appears that many of the highly adaptive processes of psychobiological regulation that manifest a natural quasi-periodic circadian/ultradian variability are modifiable by psychosocial cues and hypnosis (Rossi, 1982, 1986/1993, 1996). This implies that what has been traditionally called "hypnotic suggestion" may be, from a chronobiological perspective, the accessing and utilization of the quasi-periodic variability of ultradian and circadian processes on all levels from the cognitive-behavioral to the molecular that respond to psychosocial cues. Within this framework, many of the classical phenomena of hypnosis may be conceptualized as extreme manifestations and/or preservations of quasi-periodic psychobiological processes that are responsive to psychosocial cues. That is, what the clinician using hypnosis calls "therapeutic suggestion" is what the chronobiologist calls "the entrainment of biological processes by psychosocial cues."

This matching of the domains of chronobiological and hypnotic phenomena leads to important falsifiability tests about the relevance of quasi-periodic parameters in hypnotic work. In brief, if one could find a single chronobiological phenomenon (aspects of memory, emotions, learning, behavior and self-regulation, for example) that can be entrained by psychosocial cues that is not responsive to hypnotic suggestion then one would have disproved the relevance of quasi-periodic parameters for the psychobiological model of hypnosis. The reverse is also true. If one could find a single psychobiological process modifiable by hypnotic suggestion that does not have a natural quasi-periodic ultradian/circadian rhythmicity then one would have disproven the relevance of chronobiological parameters for the psychobiological model of hypnosis. Rossi (1996) has discussed an unintended but highly informative example of this falsifiablity test with the event-related P300 brain wave potential. Initially the P300 wave was found to be modifiable by hypnosis (Barabasz and Lonsdale, 1983; Spiegel and Barabasz, 1988). Later in unrelated research the P300 wave was found to have a 90-120 minute ultradian periodicity (Escera et al., 1992). This is exactly what our matching of the domains of chronobiological and hypnotic phenomena that are responsive to psychosocial cues would predict.

Research consistent with the significance of quasi-periodic parameters in hypnosis has been reported by a number of investigators in the past decade. Aldrich and Bernstein (1987) who found that "time of day" was a statistically significant factor in hypnotic susceptibility initially assessed it. They reported a bi-modal distribution of scores on The Harvard Group Scale of Hypnotic Susceptibility in college students with a sharp major peak at 12 noon and a secondary, broader plateau around 5 to 6 p.m. Further research found a very prominent circadian rhythm with a peak between noon and 1 p.m. in the self-hypnosis as well as an ultradian periodicity of about 90 to 180 minutes throughout the day that approximates Kleitman’s 90-120 minute Basic Rest Activity Cycle (BRAC) (Rossi, 1992). The pilot data of Figure Seven suggests that self-hypnosis usually lasts about 20 minutes.

It is interesting and probably not coincidental that much research assessing the therapeutic value of the various modalities of alternative medicine such as acupuncture, biofeedback, imagery, meditation, music, therapeutic touch, etc. also use a core 20 minute therapeutic period (Green and Green, 1987). While this core therapeutic period may be condensed or extended depending on practical exigencies, it is rarely extended beyond the Kleitman’s typical 90-129 Basic Rest Activity Cycle. Similar quasi-periodic parameters were found associated with hypnosis (Brown, 1991 a & b; Lippincott, 1992,1993; Osowiec, 1992; Rossi, 1982,1992; Sommer, 1993; Wallace, 1993) and imagery (Wallace and Kokoszka, 1995). Two studies (Mann and Sanders, 1995; Saito and Kano, 1992) were correct in emphasizing that a narrow interpretation of Rossi’s original chronobiological hypothesis - that hypnotic susceptibility was a function of strictly periodic or statistically uniform ultradian rhythms (Rossi, 1982) - would be incorrect. The experimental results of these two studies, however, are entirely consistent with the current hypothesis about the quasi-periodic or nonlinear dynamics of hypnotic susceptibility. Further research utilizing more efficient mathematical algorithms for detecting the synchronization of psychobiological rhythms (Schäfer et al., 1998) are now required to examine how hypnosis can assess and entrain the natural quasi-periodic dynamics of mind-body communication and healing.

The most revealing demonstrations of how psychosocial stress can modulate the actual mechanisms of gene expression in the immune system are a series of papers by Glaser et al. (1990, 1993).  Recently this research team (Kiecolt-Glaser, 2001) and others (Gruzelier et al., 2001) have demonstrated how hypnosis could successfully modulate cellular immune dysregulation.  Their research traces the effects of psychological stress (experienced by medical students during examinations) in down regulating the transcription of the interleukin-2 receptor gene and interleukin-2 mRNA production. Since interleukin-2 is a messenger molecule of the immune system, its down regulation by psychological stress is the first demonstration of how the immune system’s optimal functioning can be impaired at the cellular-genetic level by psychosocial cues. Glaser’s research gains even more profound significance for a general theory of mind-body communication and healing when we realize that other independent medical researchers (Rosenberg and Barry, 1992) found that interleukin-2 is a messenger molecule of the immune system that "tells" white blood cells to attack pathogens and cancer cells. This means that traditional medical research represented by Rosenberg and mind-body medicine represented by Glaser have found the same bottom line of mind-gene communication and healing in psychoimmunology.

This molecular-genetic essence of communication in psychoimmunology is now know to be mediated by immediate early genes (IEGs) that typically turn on within a minute of the onset of psychological arousal and stress and operate for about and hour and a half or so (Schlingensiepen et al., 1995). Further evidence of how the immune system can be impaired at the cellular-genetic level was provided when Glaser et al. (1993) found that academic stress led to the down regulation of the two IEGs (also called proto-oncogenes) c-myc and c-myb in peripheral blood leukocytes. The IEG c-myc is part of an informational loop at the cellular level that activates oncogenes that are involved with breast cancer as well as stomach and lung cancers and leukemia. Such research detailing how psychosocial cues can modulate immediate early gene expression provides at least a clue about the mechanisms of hypnosis that could optimize the functioning of the immune system to facilitate the remission of cancer as is occasionally reported in a well documented manner (Crasilneck, 1997).

The most obvious research frontier in this area of psychoimmunology is to document the reverse of the Glaser protocol outlined above. We need to design experimental protocols to assess whether an hypnotic intervention designed to reduce psychosocial stress could lead to a facilitation of the expression of the Interleukin-2 receptor gene and mRNA. 

in 2002.  In the very same issue of The American Journal of Clinical Hypnosis in which this paper appeared there was an abstract of a experimental study by Castes et al., (1999)  that took a step in this direction.  Castes et al. (1999) reported that a 6-month program of relaxation, guided imagery, and self-esteem workshops with a group of asthmatic children led to significantly reduced number of illness episodes and the use of bronchodilator medication compared with a control group.  The experimental group also showed an increase in the gene expression of the T-cell receptor for interleukin-2 (precisely as predicted above as a test of the mind-gene pathway of healing that would be the reverse of the Glaser protocol) as well as a significant increase in natural killers cells and other immune system factors associated with psychosocial stress. 

Recent advances in genomic technology (Brown, 1999) now make further research on the positive utilization of psychosocial genomics easily within the reach of clinicians and researchers in hypnosis.  Gene expression microarrays present up to 10,000 genes (including the interleukin-2 gene) on a single "DNA chip" that can be used to assess the patterns of gene expression associated with varying experimental conditions. A prototype of such research assessing interleukin-2 gene expression as well as the ultradian time dynamics of early, intermediate and late activated genes in human peripheral blood mononuclear cells (including the major cells of the immune system such as T and B-lymphocytes, monocytes, natural killer cells, and dendritic cells) is available on the internet (Incyte, 1999). Most research using DNA chip technology at the present time has been carried out to assess purely biological variables at the molecular level in medical and pharmaceutical studies. We propose that in the near future, however, this DNA chip technology will be adapted as the ultimate test of the efficacy of all psychosocial variables in facilitating mind-body healing and therapeutic hypnosis at the level of gene expression and new protein formation.

Hypothesis Five: The final common path to healing by the traditional model of physical medicine as well as many therapeutic applications of hypnosis involves the expression of genes coding for the formation of proteins that are the bottom line of healing on the material, energetic and informational levels.

The source of this hypothesis is in the history of our understanding of the role of proteins in life processes and healing. Originally the albuminoids, called "proteins" by G.J. Mudler in 1838, were described as the structural or material substance of life. Proteins were later recognized as playing an essentially energetic role as enzymes catalyzing the metabolism of the cell. Currently proteins are understood to function also as informational and computational processors of life at the molecular level (Brey, 1995). The nonlinear dynamics of proteins are described as the informational, autopoietic or self-organizational systems of life at the cellular-genetic-protein level (Kauffman, 1995).

The hypothesis of gene-protein dynamics as the final common path to healing integrates traditional physical medicine with the mind-body models of "alternative or holistic medicine." The facilitation of gene-protein dynamics becomes an important criterion for evaluating all forms of therapeutic communication and healing - biofeedback, body work, emotional catharsis, EMDR, imagery, active imagination, hypnosis, meditation, prayer, ritual, yoga or whatever - with a common yardstick. Whatever the therapeutic method, we can test whether it has really facilitated healing with relatively simple DNA chip assays to determine whether the appropriate immediate early genes and their target genes are expressed in the form of mRNAs that serve as "blueprints" for the synthesis of proteins. A dramatic example of a psychosocial intervention that can modulate gene expression and growth protein formation is provided by Schanberg (1995) who found that premature and isolated human babies had significant gains in weight development and sympatho-adrenal maturation when they were administered maternal touch. He reports in an animal model (preweanling rat pups) that the absence of nurturing touch suppresses ODC [ornithine decarboxylase] gene transcription by interfering with a cells ability to transduce the hormone receptor activated signal. This is takes place when the lack of adequate maternal behavior (lack of physical contact and touch) leads to a down regulation of specific IEGs for synthesizing the protein for this growth regulating enzyme.

Touch and "therapeutic passes," of course, have a long and honorable place in the history of hypnosis (Edmonston, 1986). It is estimated that 40,000 nurses and caregivers in the United States have eagerly embraced "therapeutic touch" with an erroneous theory attributing its value to "energy fields" (Rosa et al., 1998) in a striking parallelism with the false attribution of healing to magnetism in Mesmerism 200 years ago. Can hypnosis now reclaim its psychophysiological heritage in Braid by investigating the psychobiology of hypnosis at the genetic-protein level? The current research literature implies that both touch and verbal suggestion can initiate immediate early gene protein cascades to facilitate growth and healing. As we shall soon see, further research in this area with the new DNA chip technology could become a new methodology for differentiating between the relative merits of the many approaches to hypnosis and their therapeutic applications.

The time required to make new proteins in adaptive responses to stress and trauma provides an important window into the informational and healing dynamics of mind-body communication at level three in Figure One. Todorov’s research (1990) on how cells maintain their stability in response to environmental demands reveals three major phases of gene transcription and translation in response to physical trauma and stress. Immediate-early genes are turned on first to initiate the formation of M (Metabolism) proteins within a hour to produce proteins required for energy dynamics (ATP in Figure One). The next R (Ribosomal) block of proteins are turned on to facilitate a heightened state of mRNA translation processes of healing within a few hours. The third stage produces the N (Nuclear) proteins such as DNA polmerases and histones required for deeper healing in a slower process requiring 12 hours to a day or more. The previously cited model of gene expression (Incyte, 1999) is a more recent example of these ultradian time dynamics in the expression of early-activated gene expression (30 minutes to an hour), intermediate-activated genes (one to two hours), and late-activated genes (two to four hours).

A new research frontier for the psychobiological model of hypnosis is to demonstrate how these typical ultradian time stages physical stress at the genetic-protein level are found in response to sever psychological trauma and stress as well. This response to trauma and stress is but one illustration of the quasi-periodic dynamics for a complete ultradian healing cycle noted in Figures One through Seven.  Figure 4a compares the typical ultradian rhythms of ACTH and cortisol  which mediate the stress response at the neuroendocrine level in two human subjects during Kleitman's Basic Rest Activity Cycle (90 - 120 minutes) in the normal routines of everyday life.  Figure 4b illustrates the ultradian and circadian time parameters of an acute stressor (forced swimming in mice).  Notice the initial peak of activity in the hippocampus followed by a later peak of activity in the cortex when symptoms of PTSD typically become manifest as described by Kaufer et al. (1998).

These ultradian time parameters for gene expression in response to acute stress reported by Kaufer et al. are similar to those reported in the utilization of therapeutic hypnosis to ameliorate trauma and stress (Rossi, 2002).  Dabney Ewin (1986), a former president of The American  Society of Clinical Hypnosis, has documented, for example, how hypnotic suggestions for cooling administered within two hours (a typical ultradian time BRAC) of a severe burn can reduce inflammation and facilitate healing to a much greater degree than when hypnotic suggestion is used more than two hours after the burn. Research is now needed to assess the hypothesis that the mechanism of this therapeutic application of hypnosis may be in modulating gene expression  and the formation of "stress proteins" whose over-production after two hours complicates the healing process in burn patients (e.g., bradykinin-like substances that mediate inflammation, Pardue et al., 1989).

Level four of Figure One illustrates how messenger molecules that have their origin in the processing of larger protein "mother-molecules" such as POMC may be stored within cells as a kind of molecular memory. Messenger molecules from the peripheral cells of the body, such as epinephrine and norepinephrine from the adrenals, are released into the blood stream. There they can complete the SDMLB loop of information transduction from all parts of the body to the brain’s neural networks illustrated by the block of letters A through L at the top of Figure One. It has been theorized that messenger molecules can diffuse as much as 15 mm through the extracellular fluid (ECF) to any site in the cerebral cortex (Schmitt, 1984) to modulate memory, emotions and behavior at the cellular-genetic level within neurons of the brain (Routtenberg and Meberg, 1998).

Neurobiological research indicates that most forms of learning (Pavlovian, Skinnerian, imprinting, sensitization, etc.) utilize messenger molecules of arousal and stress (such as ACTH, epinephrine etc.) in the construction and reconstruction of memory (Izquierdo et al., 1988). Insofar as these classical forms of learning use messenger molecules, they ipso facto have a state dependent (SDMLB) component (McGaugh, 1989). SDMLB can be turned on or off by purely biological approaches (injecting a messenger molecule such as ACTH or epinephrine) as well as psychological-behavioral approaches (positive or negative reinforcement with food, electric shock etc.). When memory and new learning is encoded under conditions of high emotional arousal, shock, surprise, stress or trauma, it tends to become state dependent (SDMLB) to that psychobiological condition. This state dependent memory becomes dissociated or apparently "lost" after the person apparently recovers when the stress hormones or drugs are metabolized out of the system. Reactivating stress in another context, however, has a tendency to reestablish the original SDMLB encoding condition to reactivate the cognitions, emotions and behaviors associated with it with varying degrees of memory.

It is important to recognize how SDMLB completes the information transduction loop of mind-body communication in Figure One so that the psychosomatic network that may be accessed and modulated by hypnosis becomes a two way street. One theoretical objection to the idea that the psychosomatic network is a two way street is that the brain has long been regarded as a "privileged organ" that has a "blood-brain barrier" that normally protects the brain from toxic substances that may be circulating throughout the rest of the body. This would imply that many messenger molecules from the body could be blocked from entering the brain by the blood-brain barrier. Recent research, however, has demonstrated that during highly stressful emotional conditions the blood-brain barrier is lowered so that many messenger molecules and other substances can enter the brain (Soreq and Friedman, 1997).

The two way street hypothesis proposes a major mechanism of how the molecules of the body can modulate mental experience as well as how mental experience such as hypnotic suggestion can modulate the expression of genes and other molecules of the body. SDMLB is the quintessential psychobiological concept that bridges the so-called Cartesian dichotomy between mind and body. What is most significant about research in SDMLB is that it enables us to study the parameters of "reversible amnesia," which is the fundamental psychobiological phenomenon that theories of hypnosis and psychoanalysis have always tried to explain (Rossi, 1996). Most experiments in SDMLB demonstrate that "reversible amnesia" is only partial (that is, there is usually some memory/learning available even in the dissociated condition after the messenger molecules return to normal levels). Likewise much hypnotic literature documents that hypnotic amnesia is usually fragile and partial in character. Since the earliest days of psychoanalysis it has been noted that a sudden fright, shock, trauma and stress could evoke "hypnoidal states" that were somehow related to amnesia, dissociated and neurotic behavior. A full amnesia that is completely reversible, however, is relatively rare in SDMLB research as well as in psychoanalysis and therapeutic hypnosis (Rossi and Cheek, 1988). In the historical literature of hypnosis and psychoanalysis this same fragile and partial character of reversible amnesia has been responsible for many of the paradoxes of dissociation and memory. SDMLB is the first experimental model that can account for the paradoxes of dissociation in a manner consistent with current neurobiological research on the effects of stress on mind, memory and healing (Rossi and Ryan, 1986).

Hypothesis Seven: The clinical application of hypnosis, psychoanalysis and the therapeutic arts in general engages the patient’s state dependent mental experience (SDMLB) that is encoded and continually modulated by the molecular genetic dynamics of the CNS, ANS, neuropeptide and immune systems of the psychosomatic network. This is the psychobiological foundation of the classical concepts of depth psychology such as dissociation, reversible amnesia, repression, and emotional complexes.

These hypothesized relationships between the molecular genetic dynamics of the psychosomatic network and SDMLB suggest a new research frontier for the psychobiological investigation of classical psychoanalytic concepts of repression, dissociation, and emotional complexes that is in keeping with the dissociated control theory of hypnosis (Spiegel, 1998; Woody and Farvolden, 1998) as well as the cortical and subcortical pathways of hypnosis and the placebo response (Price, 1998; Rainville et al., 1997). A new paradigm for such research has been provided by Cahill et al. (1994) who compared the effects of the beta-adrenergic receptor antagonist propranolol hydrochloride on the long-term memory for an emotionally arousing versus an emotionally neutral short story. Their results were consistent with the hypothesis that the messenger molecules of beta-adrenergic (fight or flight) dynamics of SDMLB mediate the enhanced memory associated with the emotionally arousing metaphors of a short story. Such research could become a more effective psychobiological approach for investigating the relative merits of the direct and indirect, metaphorical approaches to hypnosis (Erickson et al., 1976)

Frontiers in the Psychobiology of Hypnosis: Behavioral State-Related Gene Expression

Many lines of research suggest that immediate-early genes (IEGs) are the newly discovered mediators between nature and nurture at the cellular-genetic level (Merchant, 1996; Rossi, 1996, 1997; Tölle et al., 1995). Immediate-early genes act as transducers allowing signals (sometimes called primary response genes or third messengers) from the external environment to regulate the adaptive transcription of target gene expression at the cellular level. Immediate-early genes can initiate a series of molecular-genetic transformations that can transduce relatively brief signals from the environment into enduring changes in the physical structure of the developing nervous system and the formation of new memory and learning throughout life (Morimoto and Jacob, 1998; Tölle et al., 1995). To coin a metaphor, IEGs seem to function as a "steering committee" mediating between stimuli from the outside world and the inner conditions of the cells in processes of creative adaptation at the genetic-protein level. Novel, arousing or stressful environmental stimuli, for example, can induce the expression of immediate early genes such as c-fos and c-jun and the proteins they code for within neurons of the brain. In response to conditions prevailing within the neurons, the fos and jun proteins associate to form the transcription factor activator protein-1 (AP-1) DNA-binding complex.

As Bentivoglio and Grassi-Zucconi (1999, p. 236), who have done considerable laboratory research on the role of IEG expression in sleep and wakefulness describe it, "The AP-1 recognition sequence is found in a variety of promoter regions of target genes and modulates their transcription, thus mediating neuronal responses to many different extracellular signals." As we have seen above, many of these "extracellular signals" have their ultimate origin from psychobiologically arousing signals from the outside world that activate the expression of immediate early genes. We now need research to document how such extracellular signals that activate IEGs may include the heightened expectancy provided by the psychobiologically arousing and arresting psychosocial cues of hypnosis. This orchestration of target gene expression by outer world psychosocial signals is translated into the formation of proteins that carry on the adaptive life dynamics of energy, information, and structure at the molecular level - what is commonly called "stress," "work" and "healing" by the psychotherapist. "Behavioral state-related gene expression" (Bentivoglio and Grassi-Zucconi, 1999, p. 245) via IEGs such as c-fos and c-jun, among others, is associated with a wide range of normal behavioral states of consciousness, sleep and dreaming as well as heightened states of psychological arousal, novelty, physical stress and trauma.

While more than 100 IEGs have been reported, many of their functions in activating the target genes associated with behavioral states in health and illness remain unknown. The complex range of interrelated biological and psychological functions that immediate-early genes are already known to serve, however, recommends a central role for IEGs and their target genes in the deep psychobiology of hypnosis that can now be explored with the new DNA chip technology. Hypnosis has been characterised as a continuum of mind-body states (DeBenedittis et al., 1994; Rossi, 1996). Mass screenings of large samples of subjects of varying degrees of hypnotic susceptibility with the new DNA chip technology would be an ultimate way of precisely specifying what we mean by defining hypnosis as an altered state. We would expect that varying patterns of genes expression would be associated with the continuum of phenomenological states we call hypnosis.

Similar mass screenings of medical patients with a variety of stress related dysfunctions would reveal what patterns of gene expression are associated with the various psychosomatic problems. It would then be a straight forward task to match the patterns of gene expression in hypnosis with those found in stress related medical conditions to determine which patients are most likely to benefit from hypnosis. It should not escape our notice that this would provide a new scientific criterion for assessing the therapeutic efficacy of hypnosis and related approaches to mind-body healing. Whatever the approach to medical, psychological or "alternative" healing the crucial question to answer remains the same: What patterns of gene expression are facilitated to optimize what pathway of mind-body healing?

Hypothesis Eight: The therapeutic applications of hypnosis facilitate the psychosocial genomics of encoding new experience, memory, learning and behavior at the neural-genetic-protein level in the quasi-periodic ultradian/circadian time parameters of long term potentiation.

Most arousing environmental stimuli that have been studied can induce IEGs within minutes in neurons of the CNS, their concentrations typically peak within fifteen to twenty minutes and their effects usually last for an hour or two. These are the same time parameters of the psychobiological model of memory and learning called "Long Term potentiation" (LTP). It is now known that LTP takes place in many regions of the brain associated with stress and emotional learning (McKernan and Shinnick-Gallagher, 1997). LTP operates in the same quasi-periodic ultradian time frame of about 90-120 minutes (Bailey et al. 1996) that is typical of many dynamical processes of mind-body healing and hypnosis discussed above. We hypothesize that changes in the orchestration of patterns of gene transcription and new protein formation initiated by the therapeutic applications of hypnosis could lead to lasting changes in the central nervous system by converting short term memory to long lasting learning and behavior (Tully, 1996).

IEGs are now used as markers or indicators of changes in neuronal activity in depression and schizophrenia. Anti-psychotic drugs are currently being designed to modulate the effects of IEGs on pathways leading to the production and utilization of neurotransmitters such as dopamine, serotonin and noradrenaline that are implicated in the "dopamine hypothesis" of schizophrenia (Merchant, 1996). Most drugs dealing with pain as well as related addictive drugs such as cocaine, amphetamine and the opiates are also mediated by immediate-early genes.  A few brief quotes from Ziegelgaensgerger (1998) at the Max Planck Institute of Psychiatry, Munich , Germany outlines many of the molecular pathways by which the psychological experience of pain evokes activity dependent gene expression as follows.

"The earliest short-term responses following nociceptor [PAIN] activation are reflected in rapid changes of neuronal discharge activity in a variety of pharmacologically and anatomically distinct systems in the central nervous system. In these systems long-term changes most commonly require alterations in gene expression. The activity dependent modulation of gene expression is a characteristic feature of highly integrated systems such as the pain matrix...Each of the levels of integration of nociceptive information probably receives and is the origin of modulatory mechanisms conveyed by afferent segmental or descending pathways. Besides “classical” neurotransmitters, biologically active molecules such as peptide hormones, neurosteroids, adenosine, trophic factors or cytokines released synaptically or non-synaptically from terminals, neighboring neurons, glia cells or components of the immune system or from the circulation participate in the integration of somatosensory information...A major facilitator effect of the central nervous system responding to noxious stimuli involves the interaction between L-glutamate and substance P, a neuropeptide long thought to have a role in pain perception. Immediate early genes (IEGs) are thought to participate as third messengers in the late phase of the stimulus-transcription cascade. They code for transcription factors and alter gene expression and translation into the corresponding protein products such as enzymes, receptors or neurotransmitters. The amount of several IEG coded proteins, produced by central neurons, is proportional to the degree of synaptic excitation following somatic and visceral acute noxious stimulation and is reduced by morphine application before the stimulation. Protein phosphorylation of ligandgated channels appears as a major mechanism in the regulation of neuronal plasticity." (Italics added here)

The implication of Ziegelgaensgerger's summary of the many levels involved in pain experience from mind to molecule is that immediate early genes are central in mediating the psychobiology of pain and its associated emotions such as depression and behavioral addictions. There are as yet no studies of the effects of hypnosis on IEGs but recent reviews on the relation of c-fos and nerve growth factor-induced A (NGFI-A) in the wake-sleep cycle (Bentivoglio and Grassi-Zucconi, 1999) implies they may be related to the quasi-periodic parameters of hypnosis. It has been found, for example, "that the expression of c-fos during waking is strictly dependent on the level of activity of the noradrenergic system...high levels of c-fos during forced and spontaneous waking and...low levels during sleep" (Cirelli et al., 1998, pp. 46). While most research has been done with animals, it is tempting to hypothesize that stimulation of the noradrenergic system and IEG expression may be the molecular-genetic basis of Braid’s (1855/1970) "psychophysiology of fascination" as a pathway to healing in the clinical applications of hypnosis. This new field of mind-gene communication that we might call "psychosocial genomics" – how psychosocial cues can signal mind-body responsiveness at the level of gene transcription and the formation of new proteins in health and optimal performance as well as illness – has very broad implications for a new understanding of the phenomenology of creative life experience (Rossi, 1972/1985/2000, 2002).

The entire history of holistic approaches to healing including ancient and modern spiritual rituals of exorcism, shamanism, fire walking and the still "mysterious methods" of acupuncture, body work, therapeutic touch, and biofeedback that evoke a positive experience of wonder and expectation are the experiential data base for this hypothesis about the role of psychological arousal and fascination in the clinical applications of hypnosis (Rossi and Nimmons, 1991). We speculate that psychobiological healing during ecstatic religious experiences of the "numinosum," consisting of a combined sense of fascination, the mysterious and the tremendous (Otto, 1923/50), has much in common with traditional and modern rituals of healing associated with the self-help groups, twelve step programs and the so-called "miracle cures" in clinical demonstrations of hypnosis (Barber, 1990). We hypothesize that just as negative states of emotional arousal can evoke the CNS, ANS, and neuropeptide systems of the psychosomatic network to initiate an IEG cascade leading to the synthesis of stress proteins and illness, so can positive psychological experiences initiate cascades of healing at the IEG protein level. This implies that the experience of positive fascination, novelty, mystery, surprise and insight experienced in hypnosis (Rossi, 1973) could access and facilitate an IEG cascade leading to the synthesis of healing proteins (Rossi, 1972/1986/2000).

In mature mice and primates the experience enriched environments and novelty initiate IEG cascades leading to the formation of new proteins and 15% more granule cell neurons along with increased synapses and dendrites in the dentate gyrus of the hippocampus that encode memory and learning (Kempermann et al., 1997; Gould et al., 1998). When combined with voluntary exercise such as running the number of newborn cells is doubled (Van Praag et al., 1999). Neurogenesis (the growth of new neurons) is now documented as taking place in the adult human hippocampus (Eriksson et al., 1998; Gould et al., 1999) as well. The significance of such experimental findings is that they provide an urgent rational for our new psychobiological paradigm to investigate the therapeutic applications of hypnosis in facilitating neurogenesis in the hippocampus of the human brain as well as mind-body healing at the cellular-genetic-protein level in stem cells throughout the body. 

Current research suggests that stem cells normally reside quietly  in most tissues of the mature organism.  When there is a traumatic injury or stress that damages healthy cells, stem cells are able to receive molecular signals to differentiate and produce new health cells to replace those that have been injured and died.  Stem cells thus function as "mother natures menders" (Vogel, 2000).  Stress, trauma, injury, and diseases of many types leave a trail of molecular signals that activate the gene expression-protein synthesis cycle in the stem cells still residing in malfunctioning tissues.   Nishimura et al. (2002) have summarized their research on the differentiation of stem cells into hair follicles as a clear example of how stem cells respond to molecular signals in their immediate environment (their niche).

Stem cells—which have the capacity to self-renew and generate differentiated progeny—are thought to be maintained in a specific environment known as a niche. The localization of the niche, however, remains largely obscure for most stem-cell systems. Melanocytes (pigment cells) in hair follicles proliferate and differentiate closely coupled to the hair regeneration cycle. Here we report that stem cells of the melanocyte lineage can be identified, using Dct-lacZ transgenic mice, in the lower permanent portion of mouse hair follicles throughout the hair cycle. It is only the population in this region that fulfils the criteria for stem cells, being immature, slow cycling, self-maintaining and fully competent in regenerating progeny on activation at early anagen (the growing phase of hair follicles). Induction of the re-pigmentation process in K14-steel factor transgenic mice demonstrates that a portion of amplifying stem-cell progeny can migrate out from the niche and retain sufficient self-renewing capability to function as stem cells after repopulation into vacant niches. Our data indicate that the niche has a dominant role in the fate determination of melanocyte stem-cell progeny.

I now hypothesize that the molecular messengers generated by stress, injury, and disease can activate immediate early genes within stem cells, so that they then signal the target genes required to synthesize the proteins that will transform (differentiate) the stem cells into mature, well-functioning tissues.  These new tissue cells can then replace injured, aging, and dysfunctional cells that die by a process of apoptosis—so-called “cell suicide” that takes place due to senescence, stress, injury, genetic mutations, etc. (McLaren, 2000; Temple, 2001).  Research is now needed to document the pathways by which molecular messengers associated with injury and stress and their modulation by therapeutic hypnosis could facilitate the differentiation of stem cells leading to healing during positive psychological experiences.  This implies a more general hypothesis about the role of IEGs and stem cells in the positive experiences of arousal in therapeutic hypnosis and the placebo response.

Placebo research is consistent in finding about 30% of subjects report themselves as experiencing a therapeutic benefit (Harrington, 1997; Quitkin et al., 1996). With psychiatric drugs such as the selective serotonin uptake inhibitors there is a relapse rate of only 45% after one year. This means that 55% of the subjects reported a significant placebo response even after one year (Moller and Volz, 1996). Is the placebo response merely wishful thinking or does this research reflect a 30% to 55% psychobiological healing effect that is measurable on the cellular-genetic-protein level? Since it is now known that psychobiological arousal, such as that provided by an enriched environment, can generate an IEG response, we propose that a "novelty immediate early gene protein placebo effect" could generate an IEG cascade leading to the synthesis of proteins for a genuinely healing placebo response at the cellular-genetic level within stem cells (Rossi, 1997, 2002).

We hypothesize that a heightened, positive sense of fascination, emotional arousal and expectation associated with a novel, brightly colored sugar pill can be just as effective as a new, mysterious therapeutic ritual introduced by a healer coming from a far away country. It is known that increased corticotrophin releasing factor (CRF mRNA) appears in the paraventricular nucleus of the hypothalamus to initiate an adaptive arousal response within minutes of experiencing an acute physical or psychological stressor (Brush and Levine, 1989; Lloyd and Rossi, 1992). We propose that a placebo can initiate these psychobiological dynamics to entrain the quasi-periodic parameters of a healing response at the cellular-genetic-protein level within stem cells. This accounts for the fact that the placebo response appears within minutes but may also disappear when its novelty effect wears out - just as is the case when the mind-body CRF-POMC-ACTH-Cortisol-Gene-Protein cascade is metabolized out of the system when novelty or a stressor is removed. Research with the new DNA chip technology is now needed to explore the parameters of how enriched life experiences and the novelty immediate early gene protein placebo effect could be facilitated with the therapeutic applications of hypnosis.

A recent brain imaging study by Petrovic et al. (2002) documents how placebos engage the same brain circuits as pain killing drugs.

            “It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opiate systems.  The rostral anterior cingulated cortex (ACC) and brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo.  In this [PET] study, we confirm that both opioid and placebo analgesia are associated with increased activity in the rostral ACC.  We also observe a covariation between activity in rostral ACC and brainstem during both opioid and placebo analgesia, but not during the pain only condition.  These findings indicate a related neural mechanism in placebo and opioid analgesia.”  (p. 923)

            Since we now know that pain and analgesia both engage gene expression (Rossi, 2002), this study is a model for future psychogenomic research as implied in Holden’s (2002) commentary on the Petrovic study.

            “Both the genuine analgesic and the placebo led to increased blood flow in areas of the brain known to be rich in opioid receptors:  the brainstem and the rostral anterior cingulated cortex (ACC), which exchanges information with a network of brain regions, including the orbitofrontal cortex, a relatively sophisticated part of the brain know to process emotions.  Furthermore, those people who responded most to the placebo – according to their ratings on a scale of 0 to 100 of how much it reduced pain – also showed more rostral ACC activation from the drug.  This . . . provides new fodder for the hypothesis that ‘high placebo responders have a more efficient opioid system. “  (p. 947, italics added).

Summary

We have reviewed how many of the problems and paradoxes of historical hypnosis and the impasse of current theory on the cognitive-behavioral level could be resolved by a deeper understanding of the natural psychobiological time parameters of mind-body communication and healing on the cellular-genetic-protein level. We propose an expansion of the psychological domain of therapeutic hypnosis to include the utilization of the entire cybernetic loop of information transduction between the psychosocial environment, the central nervous system and the psychosomatic networks of the autonomic, neuroendocrine and immune systems. Four levels of the general process of mind-body communication via messenger molecules and their receptors have been integrated into a broad picture of how psychosocial experiences such as hypnosis and the placebo response could initiate immediate early gene protein cascades to facilitate healing, memory, learning, creativity and behavior. Ten hypotheses integrating the traditional model of physical medicine with the psychobiological dynamics of therapeutic hypnosis are outlined as a guide for research using the new DNA chip technology to trace the pathways of mind-body communication on all levels from the cognitive-emotional to the cellular-genetic. The implication of such research is that the therapeutic applications of hypnosis in the new millennium may include the facilitation of neurogenesis in the human brain as well as mind-body healing at the cellular-genetic-protein level throughout the body.

References