The I Journalof PsychosocIal and culTural GenomIcs ... · of health and disease as well as...

Vol. 3 Issue III - 2017

The InTernaTIonal Journalof PsychosocIal and culTural GenomIcs

conscIousness & healTh research

Psychotherapy as never seen before and its epigenetic effects

An Appreciation of the Role of Space in the Transformation of Consciousness: Integrating the implied directive and set theory with the utilization of creativity, opposites, and compassion

The Physiological Foundation of Ego States: Future Perspectives for Research

A Holistic Therapy of Ancient India for mental disorders in view of aromatherapy

Establishing novel drug Leads of Prostate Cancer and from the phytocompounds of Centella asiatica and Annona muricata

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2 The International Journal of Psychosocial and Cultural Genomics, Consciousness & Health Research / Vol. 3, Issue III, 2017

Editorial

Over the past few years, a great number of research projects have focused on the study of the mechanisms involved in integrated treatments and their effectiveness; similarly, chronic diseases, stress-related conditions and the major psychiatric disorders have been increasingly framed within multifactorial gene-environment interactions.

It has been widely documented that genesinteract with the environment in order to modulate behavior and cognition in sickness and health (Hsieh, J., & Eisch, A.J. , 2010) by way of complex mechanisms which regulate their activity.

These interactions have been proven to involve a particular class of genes, frequently referred to as activity or experience-dependent genes, which can be activated by signals from the physical and psychosocial environment to modulate the complex functions of physiology and psychology (Rossi, 2002, 2004, 2007; Lloyd & Rossi, 1992, 2008).

[...]

Mauro Cozzolino

2

MAURO COZZOLINO,ERNEST ROSSI,GIOVANNA CELIA,KATHRYN ROSSI

MAURO COZZOLINO

MAURO COZZOLINO, ERNEST ROSSI,GARRET YOUNT, ROBERTO TAGLIAFERRI,GIOVANNA CELIA, KATHRYN ROSSI, ROXANNA ERICKSON KLEIN,STEFANO CASTIGLIONE

MAURO COZZOLINO,GIOVANNA CELIA

TERESA MAIA MOTTA

JAN DYBA

PREENON BAGCHI

JIE JOLY

TOD A. CURRY

RICHARD HILL, JANE MORTIMER

TIM GUIMOND

ANNINO ISIDORO, HAYNAUT YANNICK

ROBERTO FABRIZI, ANGELA CICATELLI, FRANCESCO GUARINO

ANTONIO DE ROSA

RINO CONTE

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The International Journal of Psychosocial Genomics,

Counsciousness andHealth Research

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Vol. 3, Issue III, 2017Salerno University,via Giovanni Paolo II, n. 132,CAP 84084, Fisciano (Salerno), Italy,prof. Mauro Cozzolino, Editorial Director,four montly journal.

http://www.psychosocialgenomics.com/

3The International Journal of Psychosocial and Cultural Genomics, Consciousness & Health Research / Vol. 3, Issue III, 2017

EDITORIALPsychotherapy as never seen before and its epigenetic effectsMauro Cozzolino

INTERVIEWS AND REVIEWSA holistic therapy of ancient india for mental disorders in view of aromatherapyRajesh.T.S and Somashekhar.R

HYPNOSIS AND PSYCHOSOCIAL GENOMICSThe Physiological Foundation of Ego States: Future Perspectives for ResearchBart Walsh

An Appreciation of the Role of Space in the Transformation of Consciousness: Integrating the implied directive and set theory with the utilization of creativity, opposites, and compassion Bruce Gregory

PSYCHOSOCIAL GENOMICS, MATH AND PHYSICS

Establishing Novel Drug Leads of Prostate Cancer and from the phytocompounds of Centella Asiatica and Annona MuricataShylesh Murthy I.A., Anuradha M. and Preenon Bagchi

NEUROSCIENCE RESEARCH

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PSYCHOTHERAPY AS NEVER SEEN BEFORE AND ITS EPIGENETIC EFFECTS

MAURO COZZOLINO Editor in Chief: [email protected]

Over the past few years, a great number of research projects have focused on the study of the mechanisms involved in integrated treatments and their effectiveness; similarly, chronic diseases, stress-related conditions and the major psychiatric disorders have been increasingly framed within multifactorial gene-environment interactions.

It has been widely documented that genes interact with the environment in order to modulate behavior and cognition in sickness and health (Hsieh, J., & Eisch, A.J. , 2010) by way of complex mechanisms which regulate their activity.

These interactions have been proven to involve a particular class of genes, frequently referred to as activity or experience-dependent genes, which can be activated by signals from the physical and psychosocial environment to modulate the complex functions of physiology and psychology (Rossi, 2002, 2004, 2007; Lloyd & Rossi, 1992, 2008).

Psychosocial stressors have been shown to produce dynamic experience-dependent effects on gene expression via the involvement of a great number of interrelated circuits (e.g. the Hypothalamic-Pituitary-Adrenal axis, the autonomous nervous system, inflammatory and immune messengers) which mediate the psychosocial stress effects on physiology, cellular biology and ultimately on gene expression (Morita, K. et al., 2005).

As illustrated by the studies which utilized genome-wide transcriptional profiling of leukocytes, it may be possible to identify a common pattern related to an increase in pro-inflammatory gene expression in stress and sickness.

Several studies, including the ones carried out by our team, hypothesize that positive psychosocial experiences, such as psychotherapy, can actually improve mental and physical health via the same stress response pathways (Dusek J.A., et al., 2008); (Antoni, M.H., et al., 2012); (Cozzolino, M., et al., 2015).

These studies show that the administration of specific mind-body practices may result in changes in the transcriptional dynamics of leukocytes in people who are ill. A number of mind-body therapies, for example, are able to reduce stress levels by modulating gene expression. This results in a reduced expression of the genes associated with inflammatory response and stress-related pathways (Bhasin, M.K., et al., 2013). Also, the effects associated with these practices have been shown to counteract the processes involved in cancer growth and progression in that they reduce inflammation and promote cellular immune response (Antoni, M.H., 2013), which ultimately results in improving cancer patients’ quality of life as well as increasing their life expectancy (Andersen, B.L., et al., 2008).

The evidence from our research on our therapeutic approach is in line with these studies. Our original 2008 pilot study posited that a creatively oriented, positive experience of therapeutic hypnosis - which was then called “The Creative Psychosocial Genomic Healing Experience” (CPGHE) - could modulate the expression of activity or experience-dependent genes as measured by DNA microarrays (Rossi, Iannotti, Cozzolino, Castiglione, Cicatelli, & Rossi, 2008). DNA microarrays are a new technology that allows researchers to identify and assess the biological and psychological states and changes in activity or experience-dependent gene expression in cells and tissues of the brain and body in health and sickness with a single experiment (Rossi, 2005/2006). We reviewed the new epigenetic models of how this DNA technology can be applied to a new era of foundational research on the clinical applications of therapeutic hypnosis and psychotherapy (Rossi, 2002, 2004, 2007). The limitation of this study was a cohort of three subjects (two females and one male).

Further research was subsequently carried out with a view to studying the connection between our mind-body model (MBT-T) and possible epigenetic effects (Cozzolino et al.,2017).

mailto:mcozzolino%40unisa.it?subject=


According to our hypothesis, we intended to determine if epigenetic variations would be found in relation to our group therapeutic intervention in addition to gene expression modulation, as already observed in our previous studies.

By using biomolecular investigations and specific Bayesian biostatistics approaches, we were able to establish an epigenetic response related to the treatment in a group of 20 subjects (Cozzolino et al., 2017). Specifically, the analyses we performed indicate that if before the treatment the subjects showed a certain level of epigenetic variability (they were clustered in three meta-populations), 1 hour after and, even more so, 24 hours after the treatment a significant increase was found in the epigenetic profile homogeneity, which was shown by the progressive clustering of all subjects (except one) in a single meta-population. Therefore, these results illustrate that the epigenetic status of individuals can be affected by MBT-T.

In another study carried out on groups, gene expression patterns characteristic of experience-dependent genes related to stem cell activation and to reduced cellular stress and inflammation were found in response to a single session of this therapeutic protocol (Mind Body Tranformations Therapy – MBT-T). Furthermore, the bioinformatics analyses performed to conduct an in-depth study of the differentially expressed genes have shown that the pathways involved were those related to cellular growth, apoptosis, inflammation and immune response (Cozzolino et al., 2014). We documented significant changes in the expression of the genes associated with stress-related conditions and those associated with the promotion of mind-body healing (Rossi et al., 2008; Atkinson et al., 2010; Cozzolino et al., 2015).

The Neuroscientific-oriented Strategic Psychotherapy results from the integration of the Strategic-integrated perspective in psychotherapy and the Psychosocial and Cultural Genomics approach. Over the last few years, this innovative and effective psychotherapy model has reached the highest standards in the fields of clinical practice, research and training.

From a holistic perspective encompassing physical, psychological and genomic aspects of health and disease as well as neuroscience, psychotherapy and genomics, we have developed both an innovative mind-body therapeutic approach, the Mind-Body Transformations Therapy (MBT-T), and an interdisciplinary research method to investigate the translational mechanisms of healing on all levels from mind, brain and ultimately up to genes.

Recent functional genomics studies have shown interesting connections between mind-body interventions and the immune system,

highlighting how these therapies are able to reduce the expression of pro-inflammatory genes related to stress pathways (Bhasin et al., 2013) as well as the translational dynamics of leukocytes in patients.

Consistent with this field of study our research team utilized gene microarrays and bioinformatics software to explore the molecular-genomic basis of our mind-body therapeutic protocol (MBT-T). Gene expression patterns characteristic of experience-dependent genes related to stem cell activation and reduced cellular stress and inflammation, as well as epigenetic variations, were found in response to a single session of our therapeutic protocol.

On the basis of the clinical and empirical results obtained so far, it is possible to state that our neuroscientific update of strategic psychotherapy has allowed the development of an evidence-based psychotherapy model, which is able to facilitate mind-body healing, effectively addressing not only mental disorders but also psychosomatic and/or physical diseases.

Epigenetics is a new field of research that investigates the interaction between genes and the environment. It explores the way the environment can directly interact with genome through a variety of molecular mechanisms and processes that modulate gene expression, inducing long-term changes in the genome which in turn can modulate behavior and cognition in sickness and health.

The gene-environment interactions involve a special class of genes, often described as activity or experience-dependent genes, which can be activated by signals from the physical and psychosocial environment. This is why research is now studying the epigenetic effects of psychosocial stressors on gene expression and an increasing number of studies are focusing on the effects of mind-body therapies on human physiology and gene expression.

Generally, results show that just as stress is able to activate specific inflammatory pathways, in an opposite way positive psychosocial experiences including psychotherapy and mind-body treatments, may improve mental and physical health through the modulation of the stress response patterns, thus reducing the expression of pro-inflammatory genes. Indeed, many functional genomics studies have precisely shown how various mind-body practices and therapies are able to generate an overall reduction of the expression of genes related to the inflammatory response, such as NF-kB, as well as regulate numerous pathways involved in apoptosis and cell proliferation.

Consistent with other studies in the field, the research we have carried out over the last ten years within the Psychosocial and Cultural Genomics approach utilized DNA microarrays


and bioinformatics software to explore the molecular-genomic basis of an innovative mind-body therapeutic protocol (MBT-T) with the aim to explain how psychosocial experiences can modulate gene expression to facilitate behavioral change at the molecular-genomic level after that. As observed in many other studies, our research documented that also this kind of mind-body therapy influenced the expression of many genes mainly through a down-regulation process, although we have not yet reached a full understanding of the molecular mechanisms underlying the positive effects of mind-body interventions.

Contrary to most of the published research which focuses on the analysis of the genome-wide transcriptional profiling, we preferred to address the changes to the epigenome by assessing DNA methylation changes in mind-body interventions.

With the aim to increase our understanding of the genomic determinants and the molecular pathways related to mind-body therapies, we conducted a specific study of the epigenetic response to a mind-body therapeutic approach, the MBT-T protocol, which is a preliminary research in the field of mind-body treatments and epigenetic response.

The study was conducted on 20 individuals who experienced the Mind-Body Transformation Therapy protocol (MBT-T), an evidence-based method for the treatment of mind-body illnesses and a therapeutic approach for facilitating human resilience and resourcefulness for health and rehabilitation characterized by a structured protocol based on the four-stage creative process, the ultradian rhythms, the basic rest-activity cycle (BRAC), and the neuronal and biological plasticity.

Each individual provided DNA samples at three different times, prior to (TIME A), 1 hour after (TIME B) and 24 hours after the treatment (TIME C) in order to assess the epigenetic variations of the subjects in response to the MBT-T treatment. Specifically, DNA samples were analyzed from the bio-molecular point of view by means of an epigenetic marker, called “MSAP molecular tool”, in order to estimate the different statuses of methylation. This analysis provided information on two different levels associated with MBT-T, epigenetic variations and DNA methylation status, processed through different biostatistics approaches: the Bayesian statistics approach, in order to estimate the membership clustering of the subjects (Structure), and the statistical estimation of the DNA methylation level (MSAP statistical tool).

The structure analysis revealed that the clusters and their membership changed along the three time points moving from a higher heterogeneous distribution to a higher

homogeneous cluster. The results showed that 1 hour after and 24 hours after the MBT-T treatment the number of meta-populations decreased from three to two. Moreover, the membership was more homogeneous at time C than at time B. In fact, before the treatment the subjects’ epigenetic profiles were heterogeneous whereas after the mind-body treatment we found that the epigenetic profiles converged toward a homogeneous DNA methylation status.

The results from these and other studies (Cole Steven W., 2013) show that more neuroscientifically oriented mind-body psychotherapies are greatly capable of inducing epigenetic effects.

This novel finding provides a completely different way of thinking about psychotherapy, its effects and the processes involved.

It is becoming increasingly clearer that the studies on psychotherapy effects (in terms of process-outcome) should not be framed in terms of psychological outcomes only, but also genomic and epigenetic outcomes.

This novel vision of mind-body research prompts us to think about a translational psychotherapy that is also capable of transferring its psychological interventions to deeper levels, involving brain, genes and new protein synthesis.

For all these reasons, we can state that we are witnessing the emergence of psychotherapy as never seen before, which dramatically sets itself apart from past, but also present psychotherapy.


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A randomized clinical trial. Cancer , 113(12): 3450–34.Antoni, M.H. (2013). Psychosocial intervention effects on adaptation, disease course and biobehavioral

processes in cancer. Brain, Behavior, and Immunity , 30 (Suppl.), S88-S98.Antoni, M.H., et al. (2012). Biological Psychiatry. Cognitive-behavioral stress management reverses

anxiety-related leukocyte transcriptional dynamics , 71(4), 366-372.Atkinsons, D., et al. (2010). A New Bioinformatics Paradigm for the Theory, Research, and Practice of

Therapeutic Hypnosis. American Journal of Clinical Hypnosis , 53:1.Bhasin, M.K., et al. (2013). Relaxation Response Induces Temporal Transcriptome Changes in Energy

Metabolism, Insulin Secretion and Inflammatory Pathways. PLoS ONE , 8(5).Cole Steven W. (2013). Nervous system regulation of the cancer genome . Brain, behavior, and

immunity , 30 Suppl. (13): S10-8. .Cozzolino M.; et al. (2014). The New Quantum Mind-Body Therapy with the Creative Psychosocial

Genomic Healing Experience. The International Journal of Psychosocial and Cultural Genomics , 1, 1-12.

Cozzolino, M., et al. (2015). The Mind-Body Healing Experience (MHE) is associated with Gene Expression in Human Leukocytes. International Journal of Physical and Social Sciences , 5 (5).

Cozzolino, M., Guarino, F., Castiglione, S., Cicatelli, A., Celia, G. (2017). PILOT STUDY ON EPIGENETIC RESPONSE TO A MIND-BODY TREATMENT. Translational Medicine @ UniSa 17(7), 40-44.

Cozzolino, M.; Iannotti, S.; Castiglione, S.; Cicatelli, A.; Rossi, E. (2014, October). A bioinformatic analysis of the molecular-genomic signature of therapeutic hypnosis. The International Journal of Psychosocial and Cultural Genomics, Consciousness & Health Research .

Dusek J.A., et al. (2008). Genomic Counter-Stress Changes Induced by the Relaxation Response. PLoS ONE , 3(7).

Hsieh, J., & Eisch, A.J. . (2010). Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: Unraveling the genome to understand the mind. Neurobiology of Disease , 39(1): 73-84.

Lloyd, D., & Rossi, E.L. (2008). Ultradian Rhythms From Molecules to Mind: A New Vision of Life. New York: Springer-Verlag.

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Rossi E. (2009). The Psychosocial Genomics of Therapeutic Hypnosis, Psychotherapy, and Rehabilitation. Am J Clin Hypn , 51(3) , 281-298.

Rossi, E. L.; Iannotti, S.; Rossi, K.; Cozzolino, M. (2006). The bioinformatics of integrative medical insights: the international psychosocial and cultural bioinformatics project. INTEGRATIVE MEDICINE INSIGHTS , 1, 7-26.

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Rossi, E., Cozzolino, M., Mortimer, J., Atkinson, D., Rossi, K. (2011). A Brief Protocol for the Creative Psychosocial Genomic Healing Experience: the 4-Stage Creative Process in Theapeutic Hypnosis and Brief Psychotherapy. American Journal of Clinical Hypnosis , 54, 133-152.

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AN APPRECIATION OF THE ROLE OF SPACE IN THE TRANSFORMATION

OF CONSCIOUSNESS: INTEGRATING THE IMPLIED

DIRECTIVE AND SET THEORY WITH THE UTILIZATION OF CREATIVITY, OPPOSITES, AND COMPASSION

BRUCE GREGORY, PH.D.

AbstractThis paper explores the role of space in the

transformation of consciousness. Set theory in general, and Erickson’s utilization of yes sets and the implied directive are highlighted in the context of integrating creativity, opposites and compassion in the focusing of attention. The perspectives of molecular biology, Tibetan Buddhist theory and meditation practice, and western psychotherapy are employed to illustrate the role of space, and to serve as the foundation for facilitating yes sets for space. The creative use of compassion is examined through an appreciation of the roles of permission, receiving and opening in the transformation of consciousness. The appreciation and roles of dependency, and the symbolic value of physiological resources that support the facilitation of the transformation of consciousness are discussed to enhance the trust of professionals in focusing attention through the novelty provided by the theme of space.

IntroductionThe role of space in the expansion and

transformation of consciousness has been appreciated and addressed from both eastern and western perspectives, explicitly and implicitly (Cox and Forshaw, 2011, Kafatos, et. al., 2011, Merrill-Wolff, 1973, Tulku, 1979, Wilbur, Engler, and Brown, 1985). Both perspectives have utilized logical inference, in hypnotherapy known as the implied directive, whose roots can be traced to Euclid, Aristotle, and Archimedes. The implied directive was a core component of Erickson’s approach to the

transformation of consciousness (Calinger, 1999, Erickson and Rossi, 1979, Hogkin, 2005). Merrill-Wolff, drawing from both the work of Kant and Shankara, the primary scholar of the Vedas, and Tulku, who developed the logic contained in dependent origination, one of the touchstones of Buddhism, arrived at the same conclusion; that space was not just valuable, but fundamental and primary. From a western psychotherapeutic perspective, Freud’s identification of the defences of the unconscious included reactivity as a form of acting out of anxiety, anger, etc. Reactivity was an expression of poor frustration tolerance, poor impulse control, and a lack of space within a person. A primary expression of reactivity was the acting out of anxiety with respect to a variety of experiences which included: anger, frustration, disappointment, uncertainty, and pressure (Masterson, 1976). The lack of space represented by the acting out, from the perspective of the implied directive, contained the seeds of a need for space, the value of space, and the capacity for utilizing space as source for comfort and transformation (Cotnoir, 2015, Erickson and Rossi, 1979, Garfield and Priest, 2009, Merrill Wolff, 1973). This was validated on a physiological level by the .01 second reaction time of the autonomic nervous system when acting out/ reactivity was occurring. (Kernberg, 1967, Masterson, 1976, Rossi, 1986). Freud’s recognition of the defences of the unconscious was one of the first examples of the need and value of space from a western psychotherapeutic perspective. A later example was Winnecott’s incorporation of the ‘squiggle’ game with children to facilitate empowerment with regard to


creativity and dealing with feelings of helplessness and pressure by facilitating a foundational environment of permission, which echoed the first stage of Poincare’s four stage creative process, which appreciated the need for a space of permission and experimentation (Poincare, 1905, Rossi, 1996, Winnecott, 1973). Erickson utilized an appreciation of the variable of space in his displacement of resistance (Erickson and Rossi, 1992).

The role of space, it’s value, and the knowledge implicitly available through space, on a molecular biological level, is reflected by nature’s organization of introns and exons on the DNA strand of the nucleus of cells, which contain 1.9 billion units of information. Exons are the coding regions for the DNA sequences, validating space as a subset of capacity. Introns are the noncoding regions of the strand, expressing space’s value in terms of the mystery component of nature’s choices, which is also expressed by the 635 proteins utilized in red blood cells, and the choice of twenty proteins for amino acids out of a possible 64 choices from the four DNA bases; adenine, guanine, cytosine and thymine. Space’s utilization and value is also demonstrated by the precise spatial way molecules combine on the cellular level to form adenylyl cyclase. Adenylyl cyclase is the enzyme that facilitates the conversion of ATP into cAMP, a molecule responsible for intracellular signal transduction. This process validates space as a subset of the sources for comfort. In addition, the information exchanges that occur intracellularly on the nano level reinforce the value of space, and its capacity (Loewenstein, 1999).

On a mathematical level Abbott, (Abbott, 1885), prior to the development of the Lorentz transformation, creatively utilized metaphor and dimensionality to illustrate space’s value. Abbott described a world in which geometric figures interacted in the context of frame of reference, which was in terms of the dimensionality of the figure; i.e. lines, triangles, rectangles, polygons, circles and spheres. The Lorentz transformation validated frame of reference mathematically, and was the cornerstone of Einstein’s theory of special relativity and the Dirac Equation (Farmelo, 2009, Isaacson, 2006). In addition to frame of reference (position), the transformation unified space and time, providing a fourth dimension, and demonstrated time’s relativity, both of which were utilized by Erickson therapeutically in hypnotic and non-hypnotic contexts (Erickson and Rossi, 1979, Haley, 1973). The value and utilization of space is appreciated by the eastern disciplines of yoga, Tai Chi, and Tibetan Buddhist meditation practice. Yoga emphasizes an alignment in space to appreciate the harmony of structure. The practice of Tai Chi values maintaining structure in relationship to motion, in conjunction with an appreciation of the joints, and their relative positions with regard to the focus of attention and to motion. The core principle of dependent origination in Tibetan Buddhism addresses the fallacy or thinking error of the ego’s position in space, and orients the focus of attention

toward the variables of space and time (Iyengar, 2009, Tulku, 1979, Yang, 1989).

From a meta-consciousness perspective, the consciousness of Space, or the space of Consciousness, have potential through the appreciation of novelty (Mathews and Butler, 2011, Rossi, 2002) for activating unconscious processes and activity dependent gene expression. This potential value is limited if a yes set for space is not established (Erickson and Rossi, 1979, Metcalfe and Shimamura, 1994, Rossi and Rossi, 2014, Wells and Matthews, 1997). Tulku (Tulku, 1979) has noted that one of the reasons for this has been that space, and its value has been minimized by incomplete cognitive logical processes. These incomplete logical processes have regulated space to be considered a background aspect of experience or simply an intervening distance between objects. They ignore an application of the appreciation of opposites, forgetting or overlooking that there is a distinction between a lower form of space, and Great Space, which represents infinite openness, acceptance and tolerance (Rossi, 1996, Tulku, 1979.

Physics has recognized the role of space on both macro and micro levels. Einstein’s general relativity addresses the flexibility of space in relation to it being curved by the effects of gravity (Green, 1999, Isaacson, 2006). Group theory, which plays a core role in the micro or quantum world, utilizes space through its recognition and appreciation of symmetry and dimensionality as reflected by the groups U1, SO2, and SO3. Hilbert Spaces appreciate the role of vector algebra in extending two and three dimensional spaces to spaces of infinite dimensions (Ash and Gross, 2006, Levitan, 2001). The intervals(spaces) between notes and the spacing of notes in musical composition to make chords, develop chords, and the creative use of chord progressions are expressions of the utilization and valuing of space. Certain areas of the brain, like Broca’s and Brodmann 44 and 47, have the capacity for receiving and processing language and the experience of pleasure (Levitin, 2006).

The Roles of Yes Sets, Set theory and the Implied Directive in the Application of Space In terms of its facets, space expresses;

• Permission• Openness• Possibilities• Lack of pressure• Inclusiveness

On a representational or symbolic level, these facets are polar opposites of defensiveness, compression, and tension. Space constitutes most of what is in the universe. On a macro level, space contains everything, Space communicates tolerance, allowing, and permission for things to be. Two examples of the application and value of permission, reflected in the quotes below, can be seen in stage 1 of Poincare’s four stage creative process (Poincare, 1905, Rossi, 1996) and Erickson’s utilization of


permissive suggestions (Erickson, 1964, Erickson and Rossi, 1979). Poincare’s and Erickson’s incorporation of permission were a function of their appreciation of its fundamental value.

“Now I don’t really care if you listen to me with your conscious mind, because it doesn’t understand your problem anyway, or you wouldn’t be here, so I just want to talk to your unconscious mind because it’s here and close enough to hear me, so you can let your conscious mind listen to the street noises or the planes overhead or the typing in the next room. Or you can think about any thought that comes into your conscious mind, systematic thoughts, random thoughts, because all I want to do is talk to your unconscious mind, and it will listen to me, because it is within hearing distance even if your conscious mind does get bored. Just be comfortable while I am talking to your unconscious mind, since I don’t care what your conscious mind does (Erickson, 1958/ 1980, p. 302).”

“There is another remark to be made about the conditions of this unconscious work; it is possible, and of a certainty it is only fruitful, if it is on the one hand preceded and on the other hand followed by a period of conscious work (stages one and four). These sudden inspirations (stage 3) never happen except after some days of voluntary effort which has appeared absolutely fruitless, and whence nothing good seems to have come, where the way taken seems totally astray. These efforts then have not been as sterile as one thinks, they have set agoing the unconscious machinery (stage 2/incubation) and without them it would not have moved and would have produced nothing.

The subliminal self is in no way inferior to the conscious self; it is not purely automatic; it is capable of discernment; it has tact, delicacy; it knows how to choose, to divine. What do I say? It knows better how to divine than the conscious self, since it succeeds where that has failed.” (Poincare, 1905, p. 390).

Space is open. It reflects and expresses openness, which becomes a primary consideration in dealing with defences and resistance, and in opening the focal setting in Tibetan Buddhist meditation practice (Tulku, 1979, Surya Das, 2012). Erickson recognized resistance as the polar opposite of receptivity, which is a state of openness. He recognized that resistance was a force with significant momentum. Erickson recognized the value of providing a space for validation, which can be considered a subset of space, or a type of space. Validation functioned

mathematically as a linear operator, containing and transforming the momentum, mistrust, and hostility into a state of receptivity or openness (Erickson, 1964, Gregory, 2011, 2015). By expressing openness, space implies the need, value, processes

and resource networks for opening, which include more harmonious relationships with time. These issues will be discussed in the next section.

By expressing possibilities, space implies the consideration of what kind of space, the design of the space, and its architecture. Examples of this may include Beethoven’s creative design of his symphonies, sonatas, and quartets (Sachs, 2010, Sullivan, 1960), Erickson’s creative design of treatment plans (Lankton and Lankton, 1983), and architecture in general, whether it is Michangelo’s design of St. Peter’s Basilica (King, 2003), or the role of the microtubules in cell architecture (Penrose and Hameroff, 2011). Further, in terms of treatment and the transformation of consciousness, the valuing of possibilities implies the opening of space for exploring, which may include the consideration of how patients may want to design conversations, or the processing of their experience. Space’s lack of pressure validates the need and worthiness of time, while implying the value of considering temporal rhythms, the utilization of time, a relationship with time, and the value of dimensionality. As such, space functions as a resource and subset of connection, as it is a bridge to time, which is validated by the Lorentz transformation (Isaacson, 2006, Gregory, 2017). Figure 1 below shows the equations for the Lorentz transformation, which describes the mathematical relationship between space and time..

These are the simplest forms. The Lorentz transformation for frames in standard configuration can be shown to be:

where:

• v is the relative velocity between frames in the x-direction,

• c is the speed of light, • Gamma is the Lorentz factor (Greek lowercase

gamma), Gamma is defined as one over the square root of 1- v squared/ c squared.

• Beta is the velocity coefficient (Greek lowercase beta), again for the x-direction. Beta is defined as v/c.

Figure 1. The Lorentz Transformation. http://en.wikipedia.org/Lorentz_Transformation.

The t’ and x’ aspects of the Lorentz transformation reflect the relativity of time, as a function of different reference frames (position/space) in the context of


uniform motion. In describing the interdependence between time and space the transformation implies the value of space in the transformation of consciousness, which often involves the expansion of time, and a reorganization in space as a consequence of the focusing of attention. In terms of types of space, the concepts of vectors from mathematics can be useful in utilizing truisms/axioms to facilitate unconscious healing processes, neurogenesis, and the transformation of consciousness. Vectors reflect a direction of focus, or in trigonometry, an angle, often notated as Theta. Angles reflect subsets of space. In aviation, they are known as headings, which are essential in order to arrive at a destination. By thinking in terms of vectors or angles, conversations and internal searches utilizing the unconscious can break out of rigid patterns, exploring new possibilities.

The appreciation of the role of yes sets is one of the fundamental variables that facilitate the utilization of space in the transformation of consciousness A yes set (Erickson and Rossi, 1979), which is comparable to a response set (Lynn & Sherman, 2000), refers to a state wherein a person’s unconscious has recognized and is responsive to the theme being addressed. The facilitation of a yes set is often supported by the utilization of truisms, true statements about the subject being addressed. These truisms, which are comparable to axioms in mathematics, often have the effect of the recipient of the communication nodding his head, enhancing receptivity. The activation of a yes set implies that the unconscious knowledge and

intelligence networks have access to information and resources relative to the receiving of comfort, and the transformation of one’s position relative to the theme being addressed (i.e. unconscious, space, time, trauma, receiving, learning, etc.) An example of the utilization of yes sets, truisms and learning sets is found in Erickson’s work with a student interested in learning about hypnosis.

“When you first went to kindergarten, grade school, this matter of learning letters and numerals seemed to be a big insurmountable task. To recognize the letter A to tell a Q from an O was very, very difficult. And then too, script and print were so different. But you learned to form a mental image of some kind. You didn’t know it at the time, but it was a permanent mental image”. (Erickson, Rossi and Rossi, 1976, pp. 6,7). Erickson also utilized these principles with respect to the subsets of learning relative to reading and walking (Erickson, Rossi, and Rossi, 1976, Rosen, 1982).

Accompanying the implication regarding unconscious knowledge are the implications that the receiver is opening and receiving. These two sets of opening and receiving, when yes sets have been established for them, can function, along with permission, as foundational aspects, sets of process resource networks for the appreciation of the role of space in the transformation of consciousness. These sets of resources for the transformation of consciousness, and their complementary relationships are represented by Figure 2 below.

Figure 2. Fundamental Subsets, Facets and Implications of Space by Bruce Gregory©2018.


The primary polarity with respect to internal spaces and relationships with the unconscious is safe, benevolent, trusting vs. unsafe, adversarial, suspicious. Questions that explore these kinds of internal spaces include;

• When you close your eyes, can you allow an image of a form that reflects the landscape inside of you relative to your relationship with your unconscious?

• Is it more like a pasture, a forest, a jungle, an ocean, a desert, or ….?

• What associations do you have with this environment?

Figure 3. Subsets of Space in Relationship to Utilization of Opposites by Bruce Gregory©2018.

• Does your experience of your internal environment shift ever so slightly, significantly, or not at all if you shift your frame of reference from either being in the center, on its edge, or above or below it?

• Have you ever imagined what your internal space is like in relation to your unconscious?

• Is it more like a valley, a forest, a glacier, or a swamp?

The sets of permission, receiving and opening are

resources, functioning metaphorically, as enzymes in the utilization of opposites, in their relationships to pressure and the various forms of resistance. This role in the utilization of opposites is reflected by Figure 3 below.

They can further the appreciation of the psychobiological aspects of the process, which continuously reflect the capacity and utilization of opening and receptivity. In addition, this activation is often accompanied by a spontaneous unconscious search process, which utilizes the resource networks of the limbic system and hippocampus, similar to a Google search, that explores sources of the problem being addressed, resource networks for solving the problem, strategies and needs relative to the transformation being sought.

The primary yes sets utilized in the transformation of consciousness for which yes sets are established

implicitly and explicitly depending on the orientation being employed include;

• Unconscious• Resources• Resistance/shadow/unhealthy parts• Motion• Connection• Time• Space

(Erickson and Rossi, 1979, Gregory, 2015, 2016, Rossi, 1986, 1996, 2002).


A yes set for space recognizes that space has value, and can be either a bridge to, or source for new forms of comfort. Once a yes set for space is established, the application of set theory (Dunham, 1991) can function, in mathematical terms, as a linear operator, in biological terms as an enzyme, and in psychological terms as a transformative force. When the implied directive and set theory are applied to a yes set for space, a number of pathways are suggested that include; the exploration of the subsets and types of space, and what is the nature of space (Erickson and Rossi, 1979, Joseph, 2011, Merrill-Wolff, 1973). One example of this, from the perspectives of opposites and subsets, is the distinction of lower space and Great Space, as subsets of space. Lower space, being the intervening distance between objects and a background component, has its value minimized. Great Space is considered a higher order variable that represents infinite openness, acceptance and tolerance, Along with time, Great Space functions as a primary source of experience (Tulku, 1979). Other examples of types of space include; from a mathematical perspective, Euclidean spaces, Hilbert spaces, Minkowski space/time, and curved space/time (Isaacson, 2006). From western psychology, there are the spaces reflected by disharmonious conversations. Spatially, disharmonious conversations can go in circles, be stuck in cement or quicksand, spiral out of control, or simply be going in the wrong direction, which would be, in mathematical terms, proceeding along the wrong vector.

Other types of spaces include, as previously noted, the internal spaces within human beings that reflect their relationships with their unconscious, the spaces between thoughts, and the spaces between people. These subsets of space can be explored through either the utilization of opposites or basic accessing questions (Rossi, 1986, 1996, 2002). The different moves in Tai Chi, and the ‘giant body exercise’ are other examples of the application of the appreciation of space (Tulku, 1979, Yang, 1989).

The same questions can be utilized to explore the landscape of interpersonal conversations.

An example of utilizing a yes set for space from a mathematical perspective would be exploring whether a conversation could be examined from x, y, and z dimensions.

This type of exploration can have the effect of interrupting rigid patterns of processing conversations, which introduces novelty, and can facilitate unconscious search processes (Erickson and Rossi, 1979, Rossi, 2002).

Examples of basic accessing questions that can be utilized include;

• Have you imagined or considered how the conversations might be perceived from twenty, fifty or a hundred feet up?

• Have you considered how the conversations might be perceived from behind or to the side of either person?

• If you were ten feet below the conversations, looking up, how might the conversations be perceived differently?

The same process applied to space, can also be applied to the exploration and deepening of trust, valuing and appreciation of permission, opening and receiving with respect to their nature, and their subsets. The exploration of these sets of process resource networks can open abundant possibilities for focusing attention in novel ways, which facilitate unconscious processes and as a consequence a transformation of consciousness. This transformation is a reflection of new learning and integration with respect to the valuing and utilization of the themes of permission, receiving and opening.

The implied directive, a primary tool of Erickson (Erickson and Rossi, 1979), an essential aspect of meditation theory and practice (Tulku, 1979), and a fundamental aspect of mathematical proofs, known as the rules of inference (Calinger, 1999, O’Connor and Robertson, 1996), when appreciated, can be applied repeatedly in the utilization of space for facilitating activity dependent gene expression, creative problem solving, new forms of comfort, and the transformation of consciousness.

The implications contained within space include; • The appreciation of the value of possibilities, once

a yes set is established for facilitating unconscious processes.

• Being open, and opening have value. • The unconscious has relevant information about

opening.• Receiving is opening.• Capacity for opening.• Opening contains subsets.• Recognition of needs and resources for opening,

courage, and reassurance.• Possibilities for dealing with fear and pressure. • Possibilities connected to dealing with pressure

creatively.• Permission to be, open up, and to face issues.• Opening to fear, and its subsets, which include the

fear of the experience of suffering.• How to creatively communicate no pressure.• Recognition of the value of healthy dependency.• Utilization of triviality

The appreciation of the implied directive offers multiple directions to creatively focus attention. The focusing is dependent on the depth and quality of the professional’s trust in facilitating the focus, as evidenced by Erickson’s work with a variety of complex problems, and Tulku’s descriptions of the dynamics involved in meditations around space and time.


The Roles of Receiving and Openingin the application of Spacein the transformation of consciousnessIn his resistance protocol Erickson (Erickson, 1964,

Gregory, 2011, 2015) demonstrated how resistance could be transformed into receptivity by appreciating that;

• The resistance was a force with momentum.• The mathematical appreciation of validation

could contain and transform the resistance.• Validation worked as an enzyme in focusing

attention.• Validation met core needs of the patient.• The receiving of the validation could be recognized

by visual cues. These recognitions validate receiving as a stage

in the transformation of consciousness, and contain their own series of implications that can be utilized. These implications include;

• Receiving and opening are complementary.• Resource networks support the receiving process.• Receiving and opening can be understood as

positions in space

Figure 4. Progression of Consciousness in Terms of Focus of Attention by Bruce Gregory©2018.

The establishment of yes sets for receiving and opening continue the opening up of possibilities for the creative focusing of attention and the enhancement of trust within the professional to focus attention. These new directions may reflect a different stage in the transformation of consciousness from the perspective that attention now becomes focused around processes, which now become resources themselves. This opens up thinking about what resources are, not limiting resources to just being things, operating at different levels of depth (i.e. organs vs. molecules or quantum/ fundamental particles). The effect of this is consistent with processes from Tai Chi and Tibetan Buddhist meditation practices which orient the focus of attention toward the processes of experience with respect to the unfolding of experiences and the processes involved in motion that affect connections, and penetrating the present as opposed to reaching a goal in linear time. From a western therapeutic perspective, focusing on process and the present was emphasized by Perls (Perls, 1973). Focusing on processes appreciates the value of opening up the present, which is an indirect method on continuing the reduction of pressure to do and the valuing of being. This reduction of pressure reflects the expansion of internal permission and the reduction of anxiety, mirroring the essence of space. Figure 4 below illustrates a progression in consciousness with respect to the focus of attention.


Examples of the above are reflected by the Tai Chi process of push hands and roll back, and Tibetan Buddhist mindfulness practices of responding to thoughts, and the exploration of the tripartite nature of time in relation to experiences. Every moment has a past, a present and future, and shifting focus of attention from the center toward the future to either the future back to the present, or from the past to the present can soften and deconstruct some of the rigid default settings of focusing attention from the present toward the future (Tulku, 1979, Yang, 1996).

When there is a yes set for opening, the process of opening has value. Then attention can be focused around the process itself (Merrill-Wolff, 1973). This points like a vector to what kinds of opening, levels of opening, the timing of opening processes, and the resource networks for facilitating such opening. In Tai Chi this is expressed by the concept of rooting, which focuses attention on the feet, in order to facilitate an opening of a connection to the earth. By opening to an appreciation of the feet, their connection to earth, and their position, the feet become resources that function as bridges to comfort. This process is repeated by focusing attention to the waist, elbows and shoulders (Gregory, 2012, Man Ch’ing, 1985, Yang, 1981).

Types of opening relevant to the transformation of consciousness include;

• Opening to attention relative to the validation of resistance, and experience.

• Opening to the unconscious.• Opening to the resources of the unconscious.• Opening to the fear of being hurt, or feeling pain.• Opening to the hurt and pain.• Opening to opening.• Opening to quantum variables.• Opening to process.

Basic accessing questions that can support the exploration of receiving and opening, and the facilitation of yes sets include:

• What resources are supporting the receiving?• What is the rhythm of the opening process?• What resources support the exploration of the

process of opening?• What is being received that facilitates the

opening?• What are some of the different kinds of opening?• Does opening to the possibilities facilitate more

space, and time, and hope?• Does opening to the value of permission stimulate

unconscious processing?• Can opening to recognizing fear without

judgment be a bridge to exploring needs?• How does focusing on processes reduce pressure?

Tulku highlighted the process of opening in three major directions; opening the focal setting away from a rigid self/object and linear time frame of reference,

opening to the value of space and time, and their relationship to knowledge, and the opening up of different aspects of experience (i.e. thoughts, feelings, perceptions, objects) (Tulku, 1979). By opening to details of motion with respect to space and time, the practice of Tai Chi highlights the importance of the levels of opening, and the implicit possibilities for accessing vast amounts of comfort, as a consequence of more integrated harmonic connections (Man Ch’ing, 1985, Yang, 1989).

Implications of opening include:

• Safety• Capacity for receiving, trusting• Source of comfort• The subsets of comfort that can be accessed

through the process of opening.• Opening to what resources, the depth of the

resources, and sources of resources that provide the comfort (Erickson and Rossi, 1979, Gregory, 2011, 2017, Tulku, 1979).

When ‘opening’ is trusted and valued, the professional’s trust in focusing attention may expand, and curiosity can be applied to it, opening more space, which opens time, and reduces pressure. The open ended questions that may emerge as a result of this shift in consciousness are; what am I in the process of opening to? What do I need to open to? Both of these questions imply a reduction in fear and more internal safety. This shifts the temporal orientation more toward the present, away from the future, and implies an opening of the need for, and value of time. When sufficient yes sets for receiving and opening have been established, further subsets of the possibilities for organizing and representing the process resource networks of permission, receiving and opening emerge. These subsets open up ways of considering and exploring the relationships between permission, receiving and opening, which naturally expands the connection and trust of opening as a resource network. Two possibilities for organizing and representing the relationship between the processes of permission, receiving and opening are reflected in Figure 5 and 6 below.

An example of the application of the trust of ‘opening’ and some of the reasoning behind it is as follows; from a hypnotherapeutic perspective (Erickson and Rossi, 1979), experiences, symptoms, and resistance can be utilized to focus attention, activating unconscious healing processes. These processes can be in any one of the five stages outlined by Erickson and Rossi; fixation of attention, depotentiation, unconscious search, unconscious reorganization, and integration. In addition to facilitating the unconscious processes through basic accessing questions (Rossi, 1986, 2002), an appreciation of receiving and opening can support the continued shifting of the focusing of attention (Erickson and Rossi, 1979, Goswamy, 2003, Merrill-Wolf, 1973, Mindell, 2000, Tulku, 1979) toward the


processes of receiving and opening themselves. The shifting of the focus of attention toward process can naturally take the patient more into the present toward an experience of being, and the levels of comfort connected to the trust of being (Erickson and Rossi, 1979, Merrill-Wolff, 1973, Tulku, 1979).

An example of the shifting of the focus of attention to process is:

That’s right…. I wonder what you are receiving now, and what resource networks are supporting the opening involved in the receiving. That’s right, …. What needs are being satisfied in order to receive and continue receiving, and what genes are supporting the continuing receiving and opening? Have you ever wondered what is the rhythm of your receiving, and the rhythm of sending resources and information that support this receiving and opening? Have you ever wondered if the same genes support receiving and opening, or if there are different genes for receiving and opening?

A Specific Subset of Space:The reduction of pressure throughthe application of Compassion and Triviality.The experience of compassion is often a function

of the appreciation of the quality, and depth of suffering, which may include the accumulated effects of suffering over time. The appreciation of suffering implies an appreciation of the polarity between pressure and permission. Erickson demonstrated this through his utilization of conversation induction and multi-embedded metaphor (Erickson and Rossi, 1979, Lankton and Lankton, 1983). Both of these processes bypass the difficulties and resistances when pressure, the projections associated with the pressure (Masterson, 1976) and its accompanying momentum are active

(Gregory, 2011). From a set theory perspective, these processes can be considered as subsets for facilitating the reduction of pressure and anxiety, hence creating more space. Erickson exhibited an appreciation of the value of the small vs. the large, a metaphor for pressure reduction, in his utilization of geometric progression in his treatment of the phantom limb case (Erickson and Rossi, 1979). This corresponded to an appreciation of the butterfly effect in chaos theory, and the value of fundamental particles, especially in the case of metaphorical implications of the electron’s capacity for quantum entanglement (Gregory, 2016, 2017). In addition, it is found in the role of small details in the practice of Tai Chi in moving toward more progressive states of harmony and the physiological resources supporting activity dependent gene expression (Gregory, 2012, Mindell, 2000, Rossi, 1996).

The valuing of the small implies a reduction in pressure and is consistent with the 70% rule in Taoist practices of chi gung (Frantzis, 1995). The continued application of the implied directive in terms of set theory opens up the exploration of what other subsets exist for the reduction of pressure, in

conjunction with the extensive varieties of pressure (i.e. pressure to do, pressure to do fast, pressure not to be, pressure not to resist, and the pressure to be perfect, which includes the pressure not to disappoint or make a mistake). The utilization of triviality in the context of compassion may serve as an additional subset for reducing pressure, facilitating the receiving of messages within patients of permission to be, which in turn can facilitate more receptivity to following redirection of attention. Seen this way triviality can be seen as embodying two polarities; one, an unhealthy one, where triviality is used to avoid facing risks; while in the other, it is used in a healthy manner, to communicate compassion by not requiring any performance or risks on the patient’s part. From the perspective of vectors/angles, and frame of reference one direction for compassion is the suffering, and the length, and kind of suffering, which is a recognition and validation of experience. There is also compassion related to the combination of suffering and pressure to not be.

SummaryThe role of space in the transformation of

consciousness has been explored from the perspectives of set theory and the implied directive. The utilization of yes sets and the utilization of opposites are discussed in terms of enhancing the trust of professionals to creatively focus attention around the themes of permission, receiving and opening. Within the discussion parallels have been drawn between Ericksonian hypnotherapy, Tai Chi, and Tibetan Buddhist theory and practice. Attention is drawn to the relevance and application of compassion and dependency in the utilization of space to facilitate the transformation of consciousness.


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Mathematical terms are utilized to highlight the logical processes involved in the creative focusing of attention. The appreciation of inferences is utilized to highlight the parallels between psychotherapy, mind-body hypnotherapy, classical music composition theory, tai chi, and Tibetan Buddhist meditation practices in the context of reinforcing space’s role in the transformation of consciousness.


THE PHYSIOLOGICAL FOUNDATION OF EGO STATES:

FUTURE PERSPECTIVES FOR RESEARCH

BART WALSH - PORTLAND, OREGON, USA

This script addresses those familiar with most of the process I describe as well as those unfamiliar with the themes presented here. As such, I will present process and theme information intended to bring all to a similar reference base. This includes reviewing the context upon which my thinking developed, describing a method for communicating directly with the unconscious and defining components of the human psyche known as ego-states. Because I yet have no scientific evidence to substantiate the hypothesis presented here, this can only be considered a theory in need of proof.

In my professional work I commonly use ideomotor/ideodynamic questioning (Rossi & Cheek, 1988; Cheek, 1994; Cheek & LeCron, 1968; Walsh,1997, 2005, 2016; Ewing & Eimer, 2006) to engage the unconscious mind. Direct communication with the unconscious engages a rich source of remedial information and resources. Most commonly I help clients develop yes and no finger signals with the unconscious, such that one finger lifts up, free of conscious volition, as a “yes” response and a different finger lifts up as a “no” response from the unconscious. Once these finger signals are in place, questions and possibilities can be posed to the unconscious with responses coming through finger signals. Most of us experience the unconscious expressing “yes” and “no” without conscious volition when our head nods “yes” or shakes “no” in conversation with another. Developing ideomotor finger signals is simply a variation on this common theme.

When working with the unconscious, I will often communicate directly with intra-psychic parts of an individual known as ego-states. We all have many sub-components that make us who we are. Most of us have said “part of me wants to do this and

Presented here is a hypothesis which poses specific types of cell nuclei to be the physiological basis for sub-components of the psyche known as ego-states. A means of directly communicating with the unconscious and specific ego-states is described. A case example substantiating this hypothesis is shared. The most recent science illustrating the mechanism of muscle memory and inspiring development of this hypothesis is summarized.

another part of me wants to do that’. I use the terms parts and ego-states interchangeably. The process of communicating with parts is derived from ego-state therapy (Watkins & Watkins, 1997). To understand ego-state theory and therapy, as previously explained (Walsh, 2010), consider how an individual’s inner reality, that navigating fund of learning, experience, knowledge, perception, belief and inclination, is being constructed piece by piece as the body develops from infancy to adulthood. Through the growing up years, each new experience becomes a piece of the inner reality foundation. Some pieces of foundation are held by particular resources created for this purpose. John and Helen Watkins (1997) call these resources “ego-states”, or parts of the greater self. These ego-states contribute to a fluid, responsive interplay of resources useful in navigating through life. Helen Watkins (1993) summarizes ego-state therapy as a psychodynamic approach in which techniques of family or group therapy are employed to resolve conflicts between various “ego-states” that constitute a “family of self” within the individual. The foundation of inner reality is thus seen not only as a network of perception, emotion, thought and behavior tied to experience, but also as ego-states that hold, connect or express experience. The experiential functional flow and communication between these ego-states and their respective purpose determines much about how a person functions.

A few important elements of the history of psychiatry relate to this discussion of parts work. The two men credited with fathering what came to be known as psychiatry, Sigmund Freud (1950) and Carl Jung (1973, 1959, 1933), made wonderful contributions to the field. As Freud used hypnosis, he learned much about repressed and suppressed


memory and other psychic dynamics. Freud stopped using hypnosis after both uncovering child abuse and recognizing the powerful transference hypnotic subjects can develop toward the practitioner. Freud and Jung recognized that there were many different aspects to the human psyche. Jung conceptualized these variations as complexes. As a way of capturing and categorizing these different aspects, Freud developed the tripartite theory which groups various aspects of human experience, awareness and psychic functioning into one of three categories. These categories are the ego, the id and the superego. Without delving into the many facets of Freud’s work, it is important to mention contributions made by one of his disciples named Paul Federn.

Paul Federn (1952) continued using hypnosis after Freud abandoned it. Federn realized he could communicate directly with specific entities of a person involved in the person’s struggle. He encountered many of these entities with distinct characteristics and functions. Federn concluded these entities were subcomponents of the ego. He called these subcomponents ego-states. Hypnosis allowed him to have very direct communication with these ego-states. One of Federn’s colleagues, Eduardo Weiss (1960), elaborated on the psychic underpinnings of ego-states. John and Helen Watkins expanded significantly on the ideas of Federn and Weiss as they constructed ego-state theory and therapy (1997, 1993, 1992, 1987). Consider for a moment how John Watkins (1997) described an ego state as: “an organized system of behavior and experience whose elements are bound together by some common principle, and which is separated from other such states by a boundary that is more or less permeable.”

Yet another variation on this theme of parts deserves mention. An Italian contemporary and student of both Freud and Jung named Roberto Assagioli (1973, 1965/1975) developed an entirely different concept from his mentors. He believed that all humans have many sub-personalities, as there is a multiplicity of the mind. These sub-personalities have specific functions and can be engaged directly. Assagioli developed ways of working with these sub-personalities. His work ultimately came to be known as psychosynthesis.

Whether I am communicating with a single ego-state or a group of ego-states, responses from these parts are made through the established finger signals. Experience taught me that ego-states need a purpose or function and become distressed without such focus. Ego-states hold emotion, belief, memory and most often want to do what they believe is in the best interest of the entire system. Sometimes parts, deliberately isolated from the rest of the system in order to hold a difficult emotional experience (i.e.: post traumatic stress disorder or PTSD, dissociative identity disorder or DID) will create serious symptoms. Questioning these parts has revealed to me how symptom production is often an attempt by these parts to get attention, in hopes of somehow getting

out of isolation. Even these parts seem to have an honorable purpose at their foundation. On other occasions, parts have revealed how the intensity of emotion they carried was so significant they could simply not contain it all. When treating PTSD I most often find at least one group of isolated parts holding the trauma experience with its emotion. Symptoms are usually resolved as isolated parts release the emotion they carry and leave isolation. Most of the time parts are quite responsive to logic and negotiation.

Over the years I have been mystified by how parts know how to change blood calcium levels, or how to create dysfunction in the thyroid gland and other parts of the endocrine system, or how to develop an allergy or how to develop severe localized pain. How parts then reverse the problematic dynamics they’ve created to remedy the symptom is equally mystifying. Parts seem to have access to, and facility with, some of the deepest levels of functioning and communication in the human system.

Another piece of context has to do with muscle cells and memory, or muscle memory. Muscle cells are the largest cells in the human body. When challenged, through load testing or some other demand, muscle cells acquire more than one nucleus. The muscle cell robs surrounding stem cells (known as satellite cells) or their nuclei. As a challenged muscle cell acquires more nuclei, it grows bigger and stronger. When that same muscle cell atrophies because of inactivity, it retains those additional nuclei. If that same atrophied muscle cell is once again challenged, it will rather quickly restore its previous larger size and strength ( Egner et al, 2013; Gundersen et al, 2016; Bruusgaard et al, 2010). Control studies found that the muscle cell with additional nuclei grows significantly faster than a cell, challenged in the same way, that did not have additional nuclei. This is scientifically substantiated and provides evidence for what many call muscle memory. The extra nuclei in a muscle cell seem to remember its potential for growth.

Kristian Gundersen (2016) eloquently describes this process with the following abstract. “Memory is a process in which information is encoded, stored, and retrieved. For vertebrates, the modern view has been that it occurs only in the brain. This review describes a cellular memory in skeletal muscle in which hypertrophy is ‘remembered’ such that a fiber that has previously been large, but subsequently lost its mass, can regain mass faster than naive fibers. A new cell biological model based on the literature, with the most reliable methods for identifying myonuclei, can explain this phenomenon. According to this model, previously untrained fibers recruit myonuclei from activated satellite cells before hypertrophic growth. Even if subsequently subjected to grave atrophy, the higher number of myonuclei is retained, and the myonuclei seem to be protected against the elevated apoptotic activity observed in atrophying muscle tissue. Fibers that have acquired a higher number of myonuclei grow faster when subjected to overload


exercise, thus the nuclei represent a functionally important ‘memory’ of previous strength.”

As you consider the experience of communicating directly with responsive parts or ego- states and the discovery of muscle cell nuclei carrying muscle cell memory, I can now share an experience with you.

A client I’ll call Tom, recently seen in my psychotherapy practice, has a chronic anxiety condition. Tom is motivated, intelligent and practices skills he learns in treatment. Tom has effectively learned to manage his anxiety disorder. During our visit, Tom said he had shut down the source of his anxiety, resolved the anxiety and was feeling very comfortable within. His concern, as he explained, was not being able to get his legs to relax. He said his leg muscles were very tight and wanting to run, as if very anxious. He tried everything he knew to relax the legs and nothing helped.

I began to question Tom’s unconscious using ideomotor signaling. There was no specific event or series of events from the past to which the body was responding. There was no belief at the source of the leg tension. However, the legs would not relax.

Then I asked “Are there particular parts (ego-states) within the leg muscles that are continuing to carry anxiety?” Yes was the answer. I continued “Are these parts within the muscle cells?” Yes was the response. Questioning continued with “Are these parts needing to remember the anxiety the muscle cells experienced?” I received another yes. “Are these parts needing to remember all the experience of these muscle cells?” Another affirmative response was given. I commented to these parts about the remarkable and challenging job they were doing. I also reflected on how difficult it must be for them to remember anxiety accurately without experiencing anxiety at the same time. I spoke of how perspective plays such a great role with anxiety and how the perspective influences physiological change and how this can pose a big problem when trying to maintain a memory of anxiety without feeling anxious. The yes finger lifted several times as I was making the above comments.

I then asked these parts “Will it be OK to remember the effect and experience of anxiety, like the tight muscles and tension and desire to flee, without experiencing the anxiety?” The yes finger lifted. I then asked the unconscious “Will the process these parts use now be adjusted to allow them to remember the effect of the experience of anxiety without being anxious?” The yes finger lifted and in less than a minute my client smiled and said his legs relaxed.

I was excited about this experience and felt my client had really taught me something. Never before had I encountered parts whose job was solely about muscle memory. I have worked much with parts carrying body memory from trauma and more. This was different. What was the connection between these parts carrying muscle memory and the nuclei of muscle cells carrying muscle memory? Are these two entities one and the same? Are the nuclei really the physiological foundation of ego-states?

As I considered the possibility of nuclei being parts, many quandaries began to make sense. This would certainly explain how parts could both disrupt and resolve the many complex physiological conditions I have witnessed in my practice. Each nucleus has a great warehouse of information about systemic physiological functioning within. This is an enormously exciting possibility. Those who have worked directly with ego-states likely see a certain logic to this hypothesis, as it could explain much about how ego-states do what they do. This would also explain more about about somatic disturbances experienced by those with post-traumatic stress disorder. Since the time of Janet (1907, 1925), many have noted how client somatic distress resolves once repressed traumatic memory is processed adequately (Koch et al, 2012; Levine & Frederick, 1997; Miller, 2006; Rothschild, 2000; Scaer, 2007; van der Kolk, 2005, 2014) . The somatic distress is known by many as “body memory”.

Consider two types of memory we all experience (Brown, Schelin & Hammond, 1998). Explicit or declarative memory is memory of facts and events and what happened. It is what we recall consciously and what most of us think of as memory. Implicit or procedural memory is the unconscious remembrance of skills and functions and how to do things. Implicit memory particularly applies to movements and functions of the body, such as brushing teeth or playing a musical instrument or swimming. These memories involve automatic sensorimotor sequences of which we have no conscious awareness. These automatic procedures are yet another form of body memory.

The presence of somatic symptoms such as body memories is often an indication that trauma has occurred and is encoded as a memory. Because explicit memory of trauma could significantly destabilize the affected individual, it becomes amnesic. The resulting implicit memory (Brown, Scheflin & Hammond, 1998) serves to maintain stability and may be represented in body memories. Traumatic experience can thus be deeply encoded into implicit memory, out of conscious awareness. This protective function allows the system to remain stable. Experience has shown me that isolated parts, or parts separated from the rest of the system, hold and express these trauma memories in the body. When faced with trauma or any potentially destabilizing emotional experience, the human system seems to have the capacity to quickly create ego-states for the sole purpose of remotely holding the challenging experience with its respective emotion. These parts are indefinitely banished to isolation. PTSD and DID (Ross, 1996; Kluft 1984,1987,1999 ) are extreme examples of this dynamic. Might these parts destined for isolation be materialized from stem cells?

We can weave together the recent research on muscle cell nuclei accounting for muscle memory, the long history of somatic complaints or body memories being resolved with appropriate trauma treatment,


the capacity to communicate directly with ego-states through unconscious signaling, ego-states carrying trauma experience, resolution of somatic symptoms via negotiation with ego-states, the role of implicit memory and the case of muscle anxiety illustrated here. If ego-states really are born of cell nuclei, there exists a physiological component for and oversight of repressed memory and many somatic complaints.

How could this be proven scientifically? What kind of experiment would set up the right conditions and evidence to support this notion? How might ideomotor signaling and negotiation with parts result in a measurable outcome reflecting expression and response from specific nuclei? Research considerations raise many questions.

Next, it seemed important to question my own unconscious about this notion. As I considered what question to start with, a clear statement came into my conscious mind which was “Its about time”. Then, using ideomotor signaling, I asked my unconscious the following questions:

• Are there parts of me whose foundation really is cell nuclei?

Answer: Yes.• Are parts of me derived from muscle cell nuclei?

Answer: Yes.• Are there parts of me derived from blood cell

nuclei?Answer: Yes.

• Are there parts of me derived from bone cell nuclei?Answer: Yes.

• Are there parts of me derived from immune system cell nuclei?

Answer: Yes.• Are there parts of me derived from nerve cell nuclei?

Answer: No.• Are there parts of me derived from endocrine

system cell nuclei?Answer: Yes.

• Are there parts of me derived from liver cell nuclei?Answer: Yes.

• Are there parts of me derived from gastro-intestinal system cell nuclei?

Answer: Yes.• Are there parts of me derived from kidney cell

nuclei?Answer: No.

• Are there parts of me derived from skin cell nuclei?Answer: No.

• Are there parts of me derived form gonad, sex organ, cell nuclei?

Answer: Yes.

I was baffled by the “no” response to nerve cell nuclei. Is this a peculiarity with my system or common with most human beings? As I questioned my unconscious about this, it indicated that parts oversee the nervous system and use it for movement and both internal and external communication. My questioning continued.

• How many parts typically develop from one nuclei?

Answer: One.• How is the nervous system employed by parts?(This

question summarizes a series of yes/no questions I asked to arrive at the following answer.)

Answer: The nervous system is used for communication among parts, for information storage, for expression and for movement.

• Do parts perceive themselves as components of a greater system?

Answer: Yes.• If there are not parts derived from skin cell nuclei,

do parts experience touch?Answer: Yes.

• Is it muscle cell nuclei parts that experience touch?Answer: Yes.

• Do parts experience touch by accessing nerve cell receptor sites?

Answer: No.• Do these parts experience touch by accessing the

dendrites or axons of nerve cells?Answer: Yes.

• How do parts navigate space?(This question summarizes a series of yes/no questions I asked to arrive at the following answer.)

Answer: Spacial orientation for parts is guided by the nervous system, as they have no spacial orientation themselves.

• How do parts orient to space? i.e.: Parts that are isolated or not isolated. (This question summarizes a series of yes/no questions I asked to arrive at the following answer.)

Answer: For parts, isolation is not an orientation to space but rather an emotional/sensory/intellectual experience which holds loneliness.

• Is there a central hub or switchboard or filter through which parts transmit and receive information?

Answer: Yes. The hub is the body and the central nervous system is employed by the body.

• Is all communication happening between ego states of a biochemical nature?

Answer: Yes. All ego state communication within the system is of a biochemical nature.

• Do ego states use the circulatory system for communication among themselves?

Answer: Yes. The circulatory system, much like the nervous system, is used to communicate information, store information and enact change in the system.

• Is there a particular group of parts that oversee the whole system?

Answer: Yes. This group is who responds when I ask questions of “the unconscious”. This group is located in the circulatory system and is always moving.

• Are ego states formed from a number of different kinds of blood cell nuclei?

Answer: Yes.• Do parts selectively choose to receive or dismiss

information coming from outside the system? (This question summarizes a series of yes/


no questions I asked to arrive at the following answer.)

Answer: Yes. Parts can shield themselves and prevent information from going out of the system or allow information to venture out. Parts can also decide to receive information from outside the system or not.

This is now the substance of a new hypothesis about cell nuclei being the physiological basis of at least a large portion of ego-states or parts. I believe science now has the means to prove this. If proven, this will establish anatomical evidence of that as yet intangible entity we know to be the human mind. We have been searching for physical evidence of mind far longer than our current search for evidence of dark matter. My thoughts are now being directed toward what kind of experiment will provide evidence to support this hypothesis and how to fund the research.


ReferencesAssagioli, R. (1973). The act of will. New York: Penguin Books.Assagioli, R. (1975). Psychosynthesis: A manual of principles and techniques. London: Turnstone Press. (Original

work published in 1965.)Brown, D., Schelin, A.W., Hammond, D.C. (1998). Memory, Trauma Treatment, and the Law. New York; Norton

Professional BooksBruusgaard, J.C., Johansen, I.B., Egner, I.M., Rana, Z.A., and Gundersen, K. (2010) Myonuclei acquired by overload

exercise precede hypertrophy and are not lost on detraining. Proceedings of the National Association of Sciences August 24, vol. 107 | no. 34 | 15115

Cheek, D. B. (1994). Hypnosis: The Application of ideomotor techniques. Needham Heights, Massachusetts: Allyn & Bacon.

Cheek, D.B. & Le Cron, L.M. (1968). Clinical hypnotherapy. New York: Grin & StrattonEgner, I. M., Bruusgaard, J. C., Eftestøl, E. and Gundersen, K. (2013). A cellular memory mechanism aids overload

hypertrophy in muscle long after an episodic exposure to anabolic steroids. J. Physiol. 591, 6221-6230.Ewin, D.M. & Eimer, B.N. (2006) Ideomotor signals for rapid hypnoanalysis. Springfield, IL; Charles C.Thomas-

Publisher.Federn, P. (1952). In E. Weiss (Ed.), Ego psychology and the psychoses. New York: Basic.Freud, S. (1950). Collected Papers, Vol. IV, London: The Holgarth Press & The Institute of Psycho-analysis.Gundersen, K (2016). Muscle memory and a new cellular model for muscle atrophy and hypertrophy. Journal

of Experimental Biology 219, 235-242 doi:10.1242/jeb.124495Janet, P. (1925). Psychological Healing (Vol. 2). New York: Macmillan.Janet, P. (1907). The major symptoms of hysteria. New York: Macmillan.Jung, C.G. (1973). Letters (Bollingen Series XCV) Vol. I, Trans. R.F.C. Hull. Ed. G. Adler, A. Jaffe. Princeton; Princeton

University PressJung, C. G. (1933). Modern Man in Search of a Soul. New York: Harcourt, Brace & World, Inc.Jung, C.G. (1959). The Archetypes and the Collective Unconscious. New York: Princeton, Bollingen.Kluft, Richard P. (1987) An Update on Multiple Personality Disorder Psychiatric Services. April 01Kluft, Richard P.(1984) Treatment of multiple personality disorder: A study of 33 cases. Psychiatric Clinics of

North America, Vol 7(1), Mar 1984, 9-29.Kluft, R.P. (1999) An overview of the psychotherapy of dissociative identity disorder. American Journal of

Psychiatry 53(3):289-319.Koch, S. C., Fuchs, T., Summa, M. and Mu ller, C. (2012). Body Memory, Metaphor and Movement. Amsterdam:

John Benjamins B.V.Levine, P. & Frederick, A. (1997). Walking the tiger. New York: North Atlantic BooksMiller, A. (2006). The body never lies: The lingering effects of cruel parenting. New York: W. W. Norton & Company.Ross, C.A. (1996) Dissociative identity disorder. New York; WileyRossi, E.L. (1986). The psychobiology of mind-body healing. New York: W.W. Norton & Company, Inc.Rossi, E.L. & Cheek, D.B. (1988). Mind body therapy: Ideodynamic healing in hypnosis. New York: W.W. Norton &

Co.Rothschild, B. (2000). The body remembers: The psychophysiology of trauma and trauma treatment. New York:

Norton Professional Books.Scaer, R. (2007). The body bears the burden: Trauma, dissociation, and disease. New York: Routledge. van der Kolk,

B. A. (2005). Developmental trauma disorder: Towards a rational diagnosis for children with complex trauma histories. Retrieved from http://www.traumacenter.org/products/pdf_files/preprint_dev_trauma_disorder.pdf.

van der Kolk, B. (2014). The body keeps the score: Brain, mind, and body in the healing of trauma. New York: VikingWalsh, B.J. (1997) Goldfinger: A framework for resolving affect using ideomotor questioning. American Journal

of Clinical Hypnosis, Vol. 40,j No. 1, July.Walsh, B.J. (2003) Utilization sobriety: Brief, individualized substance abuse treatment employing ideomotor

questioning. American Journal of Clinical Hypnosis, Vol.45, No. 3, January.Walsh, B.J. (2010) Rapid remission of anorexia nervosa and unconscious communication. American Journal of

Clinical Hypnosis, Vol. 52(4), April, 319-333Walsh, B.J. (2016) Emotional regulation using signals of self. Portland, Oregon: Peaceful Pilgrim PressWatkins, J. G. & Watkins, H.H. (1997). Ego states: Theory and therapy. New York: W.W. W.W. Norton & Co..Watkins, H.H. (1993). Ego-state therapy: An overview. American Journal of Clinical Hypnosis, 35(4), 232-240.Weiss, E. (1960). The structure and dynamics of the human mind. New York: Grune & Stratton.

http://www.traumacenter.org/products/pdf_files/preprint_dev_trauma_disorder.pdf

http://www.traumacenter.org/products/pdf_files/preprint_dev_trauma_disorder.pdf


A HOLISTIC THERAPY OF ANCIENT INDIA FOR MENTAL DISORDERS

IN VIEW OF AROMATHERAPY

RAJESH.T.S 1* AND SOMASHEKHAR.R2

ABSTRACTA mental disorder, also called a mental illness or

psychiatric disorder is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Around 450 million people currently suffer from such conditions, placing mental disorders among the leading causes of ill-health and disability worldwide. From the vedic period India has treated these mental disorders, depression, migraine, epilepsy, hysteria, paralysis, memory loss, insomnia, anxiety, convulsion etc with traditional knowledge which sourced from Atharvaveda. Dhupana and homa are seems to be designed by the ancient scholars to fight with the diseases of the brian. The ayurvedic medicinal plants as psychotherapeutic agents used in these Yagna therapy/aromatherapy/herbal smoke treatment were aimed to the central nervous system through nasal route root ie directly delivering the drug to central nervous system to increase the drug bio-availabity and efficacy. In view of scriptural and scientific citations it is evident that the holistic healing of Indian system will prove its efficiency in treating many psychosomatic disorders. From the data it is evident that the holistic healing of Indian system is not just delivers the drug but it also increases the vital immunity and stabilize the mind to receive the drug in the brain metabolism pathway. The current review is focused on to understand the Indian holistic method of healing a mental disease (mind and body linkage) with the scientific background.

INTRODUCTION According to ayurveda each herb on this earth

can be used as medicine for some problems. In spite of this about 60-70millioin Indians suffer from severe and common mental disorder and receive treatment for their condition[1]. According to an estimate there is a prevalence level of 22% individual developing one or more mental or behavioral disorder in their life time[2]. Whether we accept it or not, most of us

1 Research Scholar, School of Sciences, Career Point University, Kota,Rajastan India, Email: [email protected] Career Point University, Kota, Rajastan India1 Sanatana Yoga Vignana Kendra (affiliated to VYASA), Bengaluru, Karnataka.

do not possess a perfectly sound mental health these days. Though the extent and level of manifestation may be different, but almost every adult is suffering from mental pressures and disorders in varieties of forms-tensions, stress, anger depression, desplair, frustration, anxiety, apprehension, excition, aggression, restlessness, whimsical mood-swings, frequent metnal irritation, suspicion lack of confidence, disintrest, dullness, etc. (yagya therapy)[3]. Psychiatric disorders account for 12% of the Global Burden and this is likely to increase to 15% by 2020[1]. It is also said that by 2025, mental illness will catch up with heart disease or may even overtake it as the biggest global health concern (World Health Report, 2001). It is rightly accepted that the nature has best answers to all the diseases affecting human body from time to time.

Right from the vedic period, in India the traditional knowledge on medicinal plants has been passed on through generations[4]. The Yajur-Veda contains the knowledge of the principles and methods of performing yagyas as part of spiritual and scientific experiments for global welfare. The Sam-Veda focuses on the musical chanting patterns of the mantras that deal with the subtle forms of yagya pertaining to mental oblation in the deeper core of emotions[5]. The hymns nos. 1 to 29 in chapter 18 of the Yajur Veda describe Yagya as the basis of good agriculture, physical, mental and spiritual and intellectual progress, prosperity in the botanical kingdom of the earth, prosperity in food and cereals produce, good health and pure environment through removal of pollution[6]. Four hundred yagyas are described in the Vedas, of which 21 are deemed compulsory. These compulsory Yagyas are also called nityakarmas. The rest of the yagyas are optional and are performed for kamyakarma (particular wishes and benefits)[7]. The Aupasana Yagya, though not a part of these 21, is still compulsory .The first seven Yagyas are called Paka-Yagyas or cooked sacrifices. The next seven are

mailto:trajeshsr%40gmail.com?subject=


called Havir-Yagyas or oblations (burnt offerings) related Yagyas and the remaining seven are called Soma-Yagyas[8].in the Vedas and vedic scriptures like the Brahmanas and Ayurvedic texts especially in “Charak Samihta”, “Bhavprakash” and “Naighantu” Yagya is regarded as the sustainer of all living beings and hence it is also referred as bhujyu and provider of safety and security to life. It is mentioned here that therapeutic yagyas should be performed to eliminate the effect of contagious/epidemic diseases, which usually occur with the change of seasons.

The traditional system of treatment of physical diseases employ medicine which are mostly administered orally. Bioavailability of this orally transmitted drug is less since it depends on many factors. When a drug is intravenous adverse side effects are often more pronounced[9]. White corpuscles of the blood resent intrusion of any foreign bodies into the blood, and sometimes the reaction of the system to the sudden, massive and direct intrusion of foreign matter into the blood through injection proves most serious, and even fatal. It has been clinically proved that the treatment of high blood pressure using synthetic medicines is having a negative impact on their patient’s mental health[10]. When the synthetic drugs fail to be effective or show serious side effects it is the plant medicine which brings relief. Many of the plant species distributed throughout the world, have some pharmacological action on the body. Herbal treatment is the natural form of healing therapy to cure the diseases of mankind[11]. In some of the rituals medicines and herbs are vaporized by offering them into the sacrificial fire, and they enter the human body in a gaseous form through the nose, lungs and the pores of the skin[12]. Inhalation of the medicinal vapors, gases and thin colloid-like fume of yagya soothingly activates the neuronal and hormonal system and helps rejuvenate the mind-body functions harmoniously. This might be proved to be easiest, least taxing, least risky and most effective method of administering a medicine so as to reach every Single cell of the body [7].

Therefore the whole world is looking towards ancient science of ayurveda to explore safe, alternative cost effective treatment as well as reliable cure with no side effects for psychiatric disorders. In the current review is focused on to understand the Indian holistic method of healing a mental disease (mind and body linkage) with the scientific background.

Disease and treatment according to ayurveda According to yoga philosophy we are all made of

5 bodies called sheaths. They are annamaya sheath, pranamaya sheath, manomaya sheath, vijnanamaya sheath and anandamaya sheath[13]. In anandamaya kosa a man is healthiest with perfect harmony and balance of all his faculties. At vijnanamaya kosa there are movements, but are channelized in the right direction. As such, it is the imbalances in manomaya level will disturb the homeostasis of the body metabolism which leads to the diseases[14]. Adhis

(primary diseases) are twofold samanya (ordinary) and Sara (essential). The former includes the diseases incidental to the body while the later is responsible for rebirth to which all men are subject[14]. The Samanya are normally produced during the interactions with the world, these may be termed as psychosomatic ailments. When dealt with by suitable techniques and congenial atmosphere, Adhis of the ordinary type will vanish. Along with it are destroyed the physical ailments i.e. the vyadhis caused by these Adhis-Adhijah vyadhaya. The subtler adhis of the essential type (sara) which cause the birth of the physical body can be destroyed only by the realization of causal states of mind and corresponding ability to live in vijnanamaya and anandamaya kosas. In that state man transcends the cycle of birth and death. The second category ailments are anadhija, vyadhajah[15] those not originated by mind. These would probably include the infections and contagious diseases. The text says that anadhija vyadhis can be handled through conventional medicines (chemotherapy and ayurveda). An entire body of literature in the ayurvedic texts deals with the nervous system and disorders, called ‘VataVyadhi’ in Sanskrit[16], were thought to be brought on by imbalance of Vata, the biological air humor, the energy that moves through the brain and the nerves (the ancients considered nerve impulses to be a kind of wind or air traveling through the body) controlling both voluntary and involuntary fusions. Hence Vata derangements always involve some weakness, disturbance, or hypersensitivity of the nervous system[17]. The unique anatomical arrangement of blood vessels and sinuses in the human skull and the brain, the prevalence of a high density of skin appendages in the scalp communicating with the brain via emissary veins. Seven major sinuses within the skull are inter connected by a number of anatomising veins, which finally drain intracranial into jugular veins giving ample scope for the diffusion of the drug molecules into the nerve tissue of the brain[18]. Most importantly, the way that the scalp is used in ayurvedic medical system in treating disease associated with the brain show that a drug could be transcranially delivered and targeted to the brain through the scalp[19].

As aetiology of mental disorders is concern emotional disturbances, volitional transgression, unwholesome food are said to be the causes of mental disorders, in general[20]. For ubhayatmaka vikara like un made, apasmara, mada, murcha etc.symptoms and signs have been described in detail in the texts. Diseases have been broadly classified into 3 broad catagories. 1.sarira vikara (physical disease) jvara (fever), atisara (diarrhea) etc. manasavikara (mental disorders), like kama (desire), soka (grief ), abhyasuya(jealousy) an others and ubhayatmaka vikara (diseases whererin both body and mind are affected) like, unmade (psychosis), apasmara (epilepsy). Ayurveda mentiones three types of Chikitsa(treatment) for treating mental illnesses. 1.Daivavyapasraya chikitsa: this refers to measure


like mantra,(incantation/chanting), Ausadhi(wearing scared herbs), mani (wearing precious gems), mangala (propitiatory rites), bali (oblations), homa (fire sacrifice), upahara (offerings), niyama (vows), prauascitta (ceremonial penitence), upavasa (fasts), swastyayana (prostrations), pranipata (surrender), gamana (pilgrimage). The prescription of these depends on the nature, faith, religiosity, culture and educational level of the patient for both psychosis and neurosis. 2. Yuktivyapasraya chikitsa: in this type different food articles like ksira(milk), ghrta (ghee), draksa (grapes), panasa (jack fruit), Brahmi (Centella asiatica), Mahishamamsa(buffalo meat), Sarpamamsa (snake meat), kurmamamsa (tortoise meat), vastuka (ghoose goot), barhimamsa(cuckoo meat), Mahakusmanda (ash gourd), Kapittha (wood apple) are beneficial in various mental disorders. 3. Sattvavajaya Chikitsa or it is a treatment by Self Control. Charaka defines it as a mind controlling therapy in which a stress has been laid on restraining of mind from unwholesome objects[21] [22]. Thus, it includes all the methods of Manonigraha and Astanga Yoga (Yogic techniques) too. Indian philosophy portrays Astanga Yoga as a primary tool to control mind; hence it can be used as Satvavajaya Chikitsa[20].

Yagna therapy as solutionThe process of yagya for the treatment of

physical and metnal diseases/disorders comprises of decomposition and transformation of havan samagri(yagna inputs) and release of healthy phytochemicals and medicinal vpour/gases/colloids[23]. The temperature attained by the kunda varies between 250C and 600C, while in the actual flames it can rise as high as 1200C to 1300C. At their boiling points, the volatile constituents vaporize and their gaseous forms get diffused. Also, when cellulose and other carbohydrates undergo combustion, steam is formed in copious quantities by the combination of the hydrogen of the decomposed organic molecules with the oxygen. This is how the substances like thymol, eugenol, pinene, terpinol etc., are dispersed to in the surroundings and the aroma of a yagna can be smelt at a considerable distance. In addition to steam, smoke is emitted in large quantities and solid particles existing in a decomposed state offer sufficient scope for its diffusion[12]. Thus smoke also functions as a colloidal vehicle for the spreading of volatile aromatic substances. This process depends on the inside and surrounding temperature and on the direction of the wind. The medicinal wood pieces and healthy nutritional substances offered in the fire of yagya are also synergistically processed to induce increased vigor and immunity[24]. The medicinal and nourishing output of the yagya are naturally inhaled through the nose and mouth. It is well known fact that the substance when taken in their vapor or gaseous form through the nostrils have much greater efficacy many hundred times more[3]. The use of CO2 as a cerebral stimulant to

assist the patients suffering from lack of ventilation is common in medical world. Its use to control and cure many metnal disorders is also known to medical science. Small amount of CO2 inhaled by the persons performing yagna/hawan acts as a stimulant and more and more aromatic fumes are in haled which help in curing mental disorders[23]. Sesamum indicum, Sesamin is a well known antioxidant from sesame seeds and it scavenges free radicals and significantly decreased ROS[25]. Nitric oxide(NO) is an important neurotransmitter and also related to synaptic plasticity, neuronal excitability regulation and epileptic activity[26].the higher NO level is able to increase the induction of generalized epilepsy. NO is known as a molecule that can easily react with O2 radiclas in the brain and reduce the oxidative stress induced damage bia deleting free radicals[27]. It has been reported in a study that Hawan causes a reduction in NO levels in the atmosphere83. The reduction in level of NO may be helpful in reducing the epileptic seizures. Other components of Hawan materials have also been reported to reduce NO levels through various mechanisms. Methanol extracts of Nardostachys jatamansi have been shown to exert inhibitory effect on nitric oxide(NO) production. The NO level dcreased from 100% to 5.8% and this decreased levels could prove to have antiepileptic effect[23].

Herbal smoking treatmentDhupana(Herbal smoking) is a process explained

from time immemorial form the period of samhitas. It is widely used not just in ayurveda pharmaceutics for disinfecting the drug store (Bheshajagara) to prevent degredation of raw drugs[28]. Different Dhupa kalpas are explained in treatises that are used in various ailments for curative purpose and also Dhupas are employed for prevention of disease.

In Ayurveda, the term krumi has been used in broader sense; it includes all pathogenic and non pathogenic organisms covering wide range of infection and infestation. They are explained under the tittle of oupasargarogas, which spread through different routes. To get prevention from krumi (microbes), Rakshoghnavidhi is indicated in our classics. In this various medicinal plants were burnt on fire and the smoke generated from it used to make starilization of different areas where chance of infections are more. The references of janapadodwansarogas, Method of treating vrana (Wound management), vranitaagara (Casuality), sutikagara (Labour theatre) and shastrakarmaghruha (Operation theatre) by various dhoopanadravyas like rakshoghnadhupa, elaborately has been explained by acharyas.

Disease treatment through aroma oil Aromatherapy derived it name from the word

aroma, it is the therapeutic use of plantderived, aromatic essential oils to promote physical and psychological wellbeing[29]. Since various kinds of


essential oils such as true lavender, rose, mandarin, sweet organge, sandalwood, geranium, etc have anxiolytic activity, aromatherapy has been used for the relief of depression and anxiety[30]. It is sometimes used in combination with massage and other therapeutic techniques as part of a holistic treatmentapproach. This therapy is a natural way of healing a person’s mind, body and soul. Many ancient civilizations like Egypt, china and India have used this as a popular complementary and alternative therapy form at least 6000 years[31]. In ayurvedic science medicine the use of herbs and aromatics was an important part of philosophy of healing. The term aromatherapy coined in 1920 by Rene-Maurice Gattefosse a French cosmetic chemist. He plunged his arm into a vessel of lavender oil, mistakenly assuming it was water. To his surprise, the pain ceased within movements and with regular application of lavender oil, the wound healed without a scar. When he analysed the lavender oil, he discovered many chemical constituents or components, which he concluded had tremendous healing properties. Essential oils are aromatic volatile liquids distilled from shrubs, flowers, trees, bushes, and seeds. They contain highly oxygenating molecules. Essential oils are called “essential” because the plant would die without them. They are made up of oxygen, amino acids and minerals whose function is to carry nutrients directly into the cell nucleus. For centuries the essential oils have found their importance as a fragrance with a curative potential on the body, mind and spirit. These aroma molecules are very potent organic plant chemicals that make the surroundings free from disease, bacteria, virous and fungus. Their versatile character of antibacterial , antiviral, anti-inflammatroy nature along with immune booster body with hormonal, glandular, emotional, circulatory by many scientists[32]. These oils have some stimulation properties with the hormones because of its structural similarity[9]. The mechanism of their action involves integration of essential oils into a biological signal of the receptor cells in the nose when inhaled. The signal is transmitted to limbic and hypothalamus parts of the brain via olfactory bulb. These signals cause brain to release neuro messengers like serotonin, endorphin etc., to link our nervous and other body systems assuring a desired change and to provide a feeling of relief. Serotonin, endorphin and noadrenalin are released from calming oil, euphoric and stimulating oil respectively to give effect on mind and body[9]. Pathirana et.al concluded that transcranial brain targeted delivery of methadone base in the form of an oil based non aqueous solution results in statistically significant antinoceptive effects under experimental conditions. Therefore it is possible to deliver central nervous system drugs through the proposed transcranial route when suitably formulated[19]. Researchers on essential oils

concluded that use of aromatherapy massage as complementary and alternative medicine on cancer patients has assisted relaxation and reduced physical and emotional symptoms[33] [34].

Role of PUFA in Brain DevelopmentOver half of the brain’s dry weight is comprised

of lipids, and it is especially enriched in logh-chain omega-3(n-3) polyunsaturated fatty acids, suggesting a key role for these molecules in the optimal, maturation and aging of neural structures and networks[35]. DHA is enriched in membranes structures found at synaptic terminals, mitochondria and endoplasmic reticulum[36], and it can ultimately affect cellular characteristics and physiological processes including membrane fluidity, lipid raft function, neurotransmitter release, transmembrane receptor function, gene expression, signal transduction, myelination, neuroinflamamation and neuronal differentiation and growth[37] [38]. Therefore maintaining optimal lipid composition in these brain regions, and specifically DHA levels is not only important during the development and maturation of the brain form gestation though childhood and adolescence[39] [40], but such maintenance is also critical for successful aging of the adult brain[41] [42]. The human brain metabolizes approximately 4mg of DHA per day, resulting in an estimated half-life of brain DHA of 2.5years[43], much longer than that of DHA in peripheral tissues. Therefore many researchers conclude that preformed DHA consumption is required for reaching and maintaining ideal brain DHA concentration and related neurological functions[44] [45] [46]. DHA also likely has cardiovascular benefits throughout adulthood leading to better perfusion of the brain. These benefits include lower blood pressure, improved vaso reactivity, dampened hepatic triglyceride synthesis, and reduced platelet aggregation[47] [48]. In addition researchers also found that both increased blood Hcy levels which is a risk factor for cardiovascular disease and reduced serum DHA levels were associated with decreased cognitive performance in healthy elderly. DHA can alter the expression of genes encoding enzymes important for Hcy metabolism, methionine adenosyltransferase(MAT) and methylenetetrahydrofolate reductase (MTHFR) and plasma Hcy and MTHFR polymorphism are risk factor for dementia[49]

A Scientific view on Plant based psychotherapeutic agents usedin holistic healingNature is the best combinatorial chemist and

possibly has answers to all disease of mankind, failure of some synthetic drugs and its side effect have prompted many researchers to go back to ancient healing methods which use herbal medicines to give relief. Many of the thousands of


plant species growing throughout the world have a direct pharmacological action on the body[50] [51]. Currently the world is looking towards brain healing prescriptions of traditional medicines, including ayurveda for a reliable cure with no or minimal side effects for psychiatric disorders. ayurvedic medicines, improve the concentration and other mental capabilities. Popularly the extract of Saffron (Crocus sativus)-increase in seizure threshold, increase GABA-ergic neurotransmission, inhibit absence seizures [52] [53],Coconut(Cocos nucifera)- increase GABA level, Serotonin level[54]. Anticonvulsant[55], Sesame seeds(Sesamum indicum)- Decrease Reactive oxygen species, Malondialdehyde in epileptics[25]. Clove (Eugenia caryophyllus)-Delay onset on seizures, increase GABAergic and glycinergic activity[56] [57]. Nutmeg(Myristica fragrans)-Reduce severity of seizures[58], Jatamansi(Nardostachys jatamansi)-inhibit electroshock convulusions[59],increase GABA[59] [23], 5-HT, 5-HIAA, Brahmi, Acorus calamus (vach), Celasaturs paniculatus(jyotismati)[10],Sweet Bacha[60], Banyan fruit[10], pulp of Bera (Indian plum)[61], Giloya[62], Gorakhamundi[63], , Kakajangha[64], Khiraiti- seed, Maulsri-bark skin[65], Malkangani[66], Fresh leaf of Pipala[67], sarpagandha, Sankhapuspi[68], Satawar[69], Tamarind seed[70] are considered extremely beneficial in strengthening mental condition according to astangasangraha written by Srimadbhattacharya.

CONCLUSIONThe yagna therapy/herbal smoking treatment/

traditional aromatherapy are ethno botanical inhalation therapy derived from the ancient medical science of India. The multiple benefits of yagna experiments include purification of atmospheric environment, healthy fertilization of soil and therapeutic applications. Treatment of disease being necessary for all class of people will have to be low cost and accessible to the common man. It should be noted that durg delivery through nasal root is studied in the vedic period. In this view Indian vedic traditions has worked a lot in ayurveda to have effective medicine and also available cheaply. Since the treatment method requires the presence of mind and body helps in preventing the disease. Studies say yagna can be used as therapy for mental disorders, respiratory disorders, increasing the immunity, etc. in view of the scriptural citations and scientific affirmation by clinical trials, case studies, laboratory tests the therapy assumes great significance in today’s world where we are facing threatening challenges of ever new viral infections, psychosomatic disorders, dreaded diseases like cancer and unabated air water soil pollutions. In this regard there is a need to approach scientifically for the vedic traditional practice which gives the holistic healing. Instead extracting an active component and reformulating the same with many other unnecessary chemicals and introducing to human system again.


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ESTABLISHING NOVEL DRUG LEADS OF PROSTATE CANCER AND FROM THE

PHYTOCOMPOUNDS OF CENTELLA ASIATICA AND ANNONA MURICATA

SHYLESH MURTHY I.A*1,2, ANURADHA M1 AND PREENON BAGCHI1,2

1DEPT. OF BIOTECHNOLOGY, PADMASHREE INSTITUTE OF MANAGEMENT & SCIENCES, BENGALURU, INDIA. 2VASISHTH ACADEMY OF ADVANCED STUDIES & RESEARCH, SARVASUMANA ASSOCIATION, BENGALURU, INDIA.

*corrisponding author email: [email protected]

AbstractGenes associated with prostate cancer viz.,

ACPT,BRCA1,BRCA2,HOXB13,FGFFR4, RNASEL and TUSC3 are downloaded from genbank and virtually screened with the phytocompounds from the plants Annona muricata and Centellina asiatica; these plants have anti-cancer activity. It is seen that the compounds anomuricine, stepharine and asiatic acid docks best with most receptor of prostate cancer and also satisfy Lipinski rule of five for drugs evidenced from ADME studies. Hence the compounds anomuricine, stepharine and asiatic acid can successfully used as ligands for prostate cancer receptors.

Keywords: Prostate Cancer, Phytocompounds, annona muricata, Centellina asiatica, Lipinski rule for drugs, ADME

IntroductionCancer is the one of the major cause of death

worldwide and prostate cancer exhibits tremendous differences in incidence among populations; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold. The asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 cases per 100,000 men. Higher incidence rates are usually seen in northern European countries. African and African- American men, however, have the highest incidence of prostate cancer in the world. Prostate cancer affects the prostate gland which produces some of the fluid in semen and plays a role in urine control in men. Although several break-through have been made in the treatment and control of cancer progression, significant deficiencies and room for improvement remain [1]. Currently, a few plant products are being used to treat cancer [2-5]. Several genes and chromosomal regions have

been found to be associated with prostate cancer in genome-wide association studies (GWAS), linkage and case-control studies including ad mixture mapping studies. Genes identified and used in this work are: BReast CAncer susceptibility gene (BRCA1 and BRCA2), Ribonuclease L (RNASEL), Tumour Suppressor Candidate 3 (TUSC3), Acid Phosphatase Testicular (ACPT), Fibroblast Growth Factor Receptor 4 (FGFR4) and Homeobox B13(HOXB13) [6-25]. This cancer and its treatments affect patients’ quality of life in enormous spheres and issues such as sexual dysfunction, urinary incontinence, bowel changes, fatigue, pain, hot flashes, body image changes, and forced lifestyle changes lead to psychosocial distress. The psychosocial reaction-diagnosis in older population of men would depend on available supports, psychiatric history, and other significant life events such as a recent death of a spouse, divorce, entering dating situations as older partner, retirement, or previously losing loved ones to cancer [26].

Methodology3d structures of the receptor proteins BRCA1,

BRCA2, RNASEL, TUSC3, ACPT, FGFR4 and HOXB13 were modeled using Modeller [27, 28] and verified using Ramachandran Plot [29]. The best receptor model was docked with the phytocompounds from Centella asiatica and Annona muricata. The best docked phytocompounds were subjected to ADME screening [30, 31]. The phytocompounds showing no violation in ADME screening were chosen as the best drug leads for prostate cancer.

Results and discussionHomology modeling [27, 28] was performed on

the receptors in Table 1. Using BLAST, the homologous templates for each receptor were selected (Table 1).

mailto:shyleshias%40gmail.com?subject=


GENES ACCESION NUMBER Homologous templatesACPT NP149059 2HPA, 1ND5, 1RPABRCA 1 AAI06746 1JM7, 2YSL, 4TKP BRCA2 AIC83585 1IYJ, 1MJE, 1MIUFGFR4 ACF47639 1RY7, 4J23, IEV2HOXB13 AAH70233 5EDN, 5EEA, 5EF6 RNASEL AAH90934 40AU, 4010, 4G8KTUSC3 Q13454 4M90, 4M91, 4M8G

Table 1: Gens withbtheir NCBI Accesion number.

Modeller generated 10 models for each protein. Based on Rampage Ramachandran Plot [29] analysis, the best protein model was selected. The best model is analyzed based least number of residues in the outlier region and maximum number of residues in the favored region.

ACPT Number of residuesin favoured region(~98.0% expected)

Number of residuesin allowed region( ~2.0% expected)

Number of residuesin outlier region

MODEL 1 397 ( 93.6%) 16 ( 3.8%) 11 ( 2.6%)MODEL 2 388 ( 91.5% 19 ( 4.5%) 17 ( 4.0%)MODEL 3 386 ( 91.0%) 26 ( 6.1%) 12 ( 2.8%)MODEL 4 385 ( 90.8%) 28 ( 6.6%) 11 ( 2.6%)MODEL 5 388 ( 91.5%) 18 ( 4.2%) 18 (4.2%)MODEL 6 388 ( 91.5%) 20 ( 4.7%) 16 ( 3.8%)MODEL 7 387 ( 91.3%) 22 ( 5.2%) 15 ( 3.5%)MODEL 8 399 (94.1%) 19 ( 4.5%) 6 ( 1.4%) SELECTEDMODEL 9 397 ( 93.6%) 17 ( 4.0%) 10 ( 2.4%MODEL 10 390 ( 92.0%) 19 ( 4.5%) 15 ( 3.5%)

MODEL 1 434 (92.1%) 26 ( 5.5%) 11 ( 2.3%)MODEL 2 191 ( 89.7%) 15 ( 7.0%) 7 ( 3.3%)MODEL 3 189 ( 88.7%) 18 ( 8.5%) 6 ( 2.8%)MODEL 4 433 ( 91.9%) 28 ( 5.9%) 10 ( 2.1%)MODEL 5 435 ( 92.4%) 27 ( 5.7%) 9 ( 1.9%)MODEL 6 433 ( 91.9%) 24 ( 5.1%) 14 ( 3.0%)MODEL 7 444 ( 94.3%) 21 ( 4.5%) 6 ( 1.3%) SELECTEDMODEL 8 440 ( 93.4%) 20 ( 4.2%) 11 ( 2.3%)MODEL 9 432 ( 91.7%) 32 ( 6.8%) 7 ( 1.5%)MODEL 10 444 ( 94.3%) 19 ( 4.0%) 8 ( 1.7%)

MODEL 1 192 ( 90.1%) 16 ( 7.5%) 5 ( 2.3%)MODEL 2 191 ( 89.7%) 15 ( 7.0%) 7 ( 3.3%)MODEL 3 189 ( 88.7%) 18 ( 8.5%) 6 ( 2.8%)MODEL 4 185 ( 86.9%) 18 ( 8.5%) 10 ( 4.7%)MODEL 5 194 ( 91.1%) 15 ( 7.0%) 4 ( 1.9%) SELECTEDMODEL 6 187 ( 87.8%) 17 ( 8.0%) 9 ( 4.2%)MODEL 7 188 ( 88.3%) 20 ( 9.4%) 5 ( 2.3%)MODEL 8 189 ( 88.7%) 16 ( 7.5%) 8 ( 3.8%)MODEL 9 184 ( 86.4%) 25 ( 11.7%) 4 ( 1.9%)MODEL 10 191 ( 89.7%) 12 ( 5.6%) 10 ( 4.7%)

MODEL 1 395 ( 89.0%) 34 ( 7.7%) 15 ( 3.4%) SELECTEDMODEL 2 396 ( 89.2%) 27 ( 6.1%) 21 ( 4.7%)MODEL 3 390 ( 87.8%) 35 ( 7.9%) 19 ( 4.3%)MODEL 4 391 ( 88.1%) 33 ( 7.4%) 20 ( 4.5%)MODEL 5 382 ( 86.0%) 40 ( 9.0%) 22 ( 5.0%)MODEL 6 388 ( 87.4%) 40 ( 9.0%) 16 ( 3.6%)MODEL 7 399 ( 89.9%) 28 ( 6.3%) 17 ( 3.8%)MODEL 8 389 ( 87.6%) 38 ( 8.6%) 17 ( 3.8%)MODEL 9 394 ( 88.7%) 28 ( 6.3%) 22 ( 5.0%)MODEL 10 392 ( 88.3%) 33 ( 7.4%) 19 ( 4.3%)

MODEL 1 269 ( 95.1%) 9 ( 3.2%) 5 ( 1.8%)MODEL 2 275 ( 97.2%) 8 ( 2.8%) 0 ( 0.0%)MODEL 3 272 ( 96.1%) 9 ( 3.2%) 2 ( 0.7%)MODEL 4 273 ( 96.5%) 5 ( 1.8%) 5 ( 1.8%)MODEL 5 279 (98.6%) 3 ( 1.1%) 1 ( 0.4%)MODEL 6 275 ( 97.2%) 4 ( 1.4%) 4 ( 1.4%)MODEL 7 270 ( 95.4%) 10 ( 3.5%) 3 ( 1.1%)MODEL 8 272 ( 96.1%) 8 ( 2.8%) 3 ( 1.1%)MODEL 9 276 ( 97.5%) 3 ( 1.1%) 4 ( 1.4%)MODEL 10 271(95.8%) 10(3.5) 2(0.7) SELECTED

MODEL 1 625 ( 96.2%) 20 ( 3.1%) 5 ( 0.8%)MODEL 2 624 ( 96.0%) 18 ( 2.8%) 8 ( 1.2%)MODEL 3 625 ( 96.2%) 20 ( 3.1%) 5 ( 0.8%)

BRCA1

BRCA2

FGFR4

HOXB13

RNASEL

Table 2: Ramachandran Plot Analysis of the receptors in Table 1.


ACPT Number of residuesin favoured region(~98.0% expected)

Number of residuesin allowed region( ~2.0% expected)

Number of residuesin outlier region

MODEL 1 397 ( 93.6%) 16 ( 3.8%) 11 ( 2.6%)MODEL 2 388 ( 91.5% 19 ( 4.5%) 17 ( 4.0%)MODEL 3 386 ( 91.0%) 26 ( 6.1%) 12 ( 2.8%)MODEL 4 385 ( 90.8%) 28 ( 6.6%) 11 ( 2.6%)MODEL 5 388 ( 91.5%) 18 ( 4.2%) 18 (4.2%)MODEL 6 388 ( 91.5%) 20 ( 4.7%) 16 ( 3.8%)MODEL 7 387 ( 91.3%) 22 ( 5.2%) 15 ( 3.5%)MODEL 8 399 (94.1%) 19 ( 4.5%) 6 ( 1.4%) SELECTEDMODEL 9 397 ( 93.6%) 17 ( 4.0%) 10 ( 2.4%MODEL 10 390 ( 92.0%) 19 ( 4.5%) 15 ( 3.5%)

MODEL 1 434 (92.1%) 26 ( 5.5%) 11 ( 2.3%)MODEL 2 191 ( 89.7%) 15 ( 7.0%) 7 ( 3.3%)MODEL 3 189 ( 88.7%) 18 ( 8.5%) 6 ( 2.8%)MODEL 4 433 ( 91.9%) 28 ( 5.9%) 10 ( 2.1%)MODEL 5 435 ( 92.4%) 27 ( 5.7%) 9 ( 1.9%)MODEL 6 433 ( 91.9%) 24 ( 5.1%) 14 ( 3.0%)MODEL 7 444 ( 94.3%) 21 ( 4.5%) 6 ( 1.3%) SELECTEDMODEL 8 440 ( 93.4%) 20 ( 4.2%) 11 ( 2.3%)MODEL 9 432 ( 91.7%) 32 ( 6.8%) 7 ( 1.5%)MODEL 10 444 ( 94.3%) 19 ( 4.0%) 8 ( 1.7%)

MODEL 1 192 ( 90.1%) 16 ( 7.5%) 5 ( 2.3%)MODEL 2 191 ( 89.7%) 15 ( 7.0%) 7 ( 3.3%)MODEL 3 189 ( 88.7%) 18 ( 8.5%) 6 ( 2.8%)MODEL 4 185 ( 86.9%) 18 ( 8.5%) 10 ( 4.7%)MODEL 5 194 ( 91.1%) 15 ( 7.0%) 4 ( 1.9%) SELECTEDMODEL 6 187 ( 87.8%) 17 ( 8.0%) 9 ( 4.2%)MODEL 7 188 ( 88.3%) 20 ( 9.4%) 5 ( 2.3%)MODEL 8 189 ( 88.7%) 16 ( 7.5%) 8 ( 3.8%)MODEL 9 184 ( 86.4%) 25 ( 11.7%) 4 ( 1.9%)MODEL 10 191 ( 89.7%) 12 ( 5.6%) 10 ( 4.7%)

MODEL 1 395 ( 89.0%) 34 ( 7.7%) 15 ( 3.4%) SELECTEDMODEL 2 396 ( 89.2%) 27 ( 6.1%) 21 ( 4.7%)MODEL 3 390 ( 87.8%) 35 ( 7.9%) 19 ( 4.3%)MODEL 4 391 ( 88.1%) 33 ( 7.4%) 20 ( 4.5%)MODEL 5 382 ( 86.0%) 40 ( 9.0%) 22 ( 5.0%)MODEL 6 388 ( 87.4%) 40 ( 9.0%) 16 ( 3.6%)MODEL 7 399 ( 89.9%) 28 ( 6.3%) 17 ( 3.8%)MODEL 8 389 ( 87.6%) 38 ( 8.6%) 17 ( 3.8%)MODEL 9 394 ( 88.7%) 28 ( 6.3%) 22 ( 5.0%)MODEL 10 392 ( 88.3%) 33 ( 7.4%) 19 ( 4.3%)

MODEL 1 269 ( 95.1%) 9 ( 3.2%) 5 ( 1.8%)MODEL 2 275 ( 97.2%) 8 ( 2.8%) 0 ( 0.0%)MODEL 3 272 ( 96.1%) 9 ( 3.2%) 2 ( 0.7%)MODEL 4 273 ( 96.5%) 5 ( 1.8%) 5 ( 1.8%)MODEL 5 279 (98.6%) 3 ( 1.1%) 1 ( 0.4%)MODEL 6 275 ( 97.2%) 4 ( 1.4%) 4 ( 1.4%)MODEL 7 270 ( 95.4%) 10 ( 3.5%) 3 ( 1.1%)MODEL 8 272 ( 96.1%) 8 ( 2.8%) 3 ( 1.1%)MODEL 9 276 ( 97.5%) 3 ( 1.1%) 4 ( 1.4%)MODEL 10 271(95.8%) 10(3.5) 2(0.7) SELECTED

MODEL 1 625 ( 96.2%) 20 ( 3.1%) 5 ( 0.8%)MODEL 2 624 ( 96.0%) 18 ( 2.8%) 8 ( 1.2%)MODEL 3 625 ( 96.2%) 20 ( 3.1%) 5 ( 0.8%)

BRCA1

BRCA2

FGFR4

HOXB13

RNASELMODEL 1 625 ( 96.2%) 20 ( 3.1%) 5 ( 0.8%)MODEL 2 624 ( 96.0%) 18 ( 2.8%) 8 ( 1.2%)MODEL 3 625 ( 96.2%) 20 ( 3.1%) 5 ( 0.8%)MODEL 4 626 ( 96.3%) 15 ( 2.3%) 9 ( 1.4%)MODEL 5 624 ( 96.0%) 21 ( 3.2%) 5 ( 0.8%)MODEL 6 631 ( 97.1%) 15 ( 2.3%) 4 ( 0.6%) SELECTEDMODEL 7 615 ( 94.6%) 24 ( 3.7%) 11 ( 1.7%)MODEL 8 626 ( 96.3%) 15 ( 2.3%) 9 ( 1.4%)MODEL 9 617 ( 94.9%) 21 ( 3.2%) 12 ( 1.8%)MODEL 10 627 ( 96.5%) 17 ( 2.6%) 6 ( 0.9%)

MODEL 1 325 ( 93.9%) 13 ( 3.8%) 8 ( 2.3%)MODEL 2 326 ( 94.2%) 13 ( 3.8%) 7 ( 2.0%)MODEL 3 322 ( 93.1%) 19 ( 5.5%) 5 ( 1.4%)MODEL 4 318 ( 91.9%) 20 ( 5.8%) 8 ( 2.3%)MODEL 5 325 ( 93.9%) 18 ( 5.2%) 3 ( 0.9%)MODEL 6 322 ( 93.1%) 20 ( 5.8%) 4 ( 1.2%)MODEL 7 322 ( 93.1%) 18 ( 5.2%) 6 ( 1.7%)MODEL 8 326 ( 94.2%) 17 ( 4.9%) 3 ( 0.9%)MODEL 9 320 ( 92.5%) 16 ( 4.6%) 10 ( 2.9%)MODEL 10 327 ( 94.5%) 15 ( 4.3%) 4 ( 1.2%) SELECTED

TUSC3

RNASEL


Fig. 1: Ramachandran Plot Analysis and model structure of the best receptors 3d structures of the compounds in table 3 were virtually screened [29] against the selected receptors table 2. The best docked structure (interaction between the receptor with the phyto-compound) with their docking scores was noted (Table 4, Fig. 2).

Table 3: Herbs [2-5] used along with their active compounds (phytocompounds)

Centella asiatica Annona muricataAsiatic acid 2 Butenoic acidAsiaticoside 2 Hex ethyl acidBrahmic acid 2 Octenoic acidMadasiaticoside retinoic acid Alpha 2 terpinolTerminolic acid Ano muricineMadecassic acid Atherosperminine

CalarineCarophylleneCineoleCioclaurineCoreximineLinaloolLinalyl propionateMuricatinStepharine


Table 3: Herbs [2-5] used along with their active compounds (phytocompounds)

2-BUTENOIC ACID -1.33E+02 0 02 HEX ETHYL Acid -1.75E+02 0 02 OCTENOIC ACID -1.84E+02 1 ASP 2412 TERPINOL -1.75E+02 0 0ANOMURICINE -2.57E+02 3 GLN 274

GLY 360TYR 363

ATHERO SPERMINE -2.58E+02 1 LEU 359CALARINE -1.58E+02 0 0CARO PHYLLENE -1.54E+02 0 0CIINEOLE -1.43E+02 1 GLY 360COCLAURINE 4550 2 TYR 3630

VAL 331CIOREXIMINE -2.89E+02 2 GLN 274

GLY 360LINALOOL -1.55E+02 0 0LINAYL PROPIONATE -1.91E+02 0 0MURICATIN -2.15E+02 0 0STEPHARINE -2.25E+02 2

ASIATIC ACID -2.41E+02 1 ARG 415BRAHMIC ACID -2.32E+02 2 SER 158

ARG 415MADASIATICOSIDE_RETINOIC ACID -2.56E+02 5 ARG 275,

GLY 360,ASN 330ASP 327LEU 405

MADECASSIC ACID -2.32E+02 2 SER 158ARG 415

TERMINOLIC ACID -2.62E+02 2 SER 158ARG 415LEU 405GLY 360ASN 330ASP 327ARG 275

ARG 275LEU 405

ACPT receptor with Annona muricataLIGAND DOCKING SCORES

Kcal/mol NO. OF INTERACTIONS

Interacting amino acids

ACPT receptor with Centellina asiatica

5-3.27E+02ASIATICOSIDE


2-BUTENOIC ACID 2352 0 02 HEX ETHYL Acid 3076 0 02 OCTENOIC ACID 3524 0 02 TERPINOL 3204 0 0ANOMURICINE 4768 3 HIS 192

PHE 191TYR 272

ATHERO SPERMININE 4888 1 PRO 472CALARINE 3444 1 ASN 243CARO PHYLLENE 3746 1 SER 187CIINEOLE 3046 0 0COCLAURINE 4478 0 0CIOREXIMINE 4850 2 ARG 365

ARG 350LINALOOL 3310 2 SER 186

GLN 284LINAYL PROPIONATE 4324 0 0MURICATIN 3532 1 LYS 111STEPHARINE 4380 4 SER 229

ASN 243ASN 244THR 234

ASIATIC ACID 5734 2 GLN 284SER 186

BRAHMIC ACID 5796 5 THR 234ASN 243CYS 226GLY 172ASN 235

MADASIATICOSIDE_RETINOIC ACID 4940 0 0MADECASSIC ACID 5796 5 ASN 235

THR 234ASN 243ASN 244GLN 172

TERMINOLIC ACID 5936 5 SER 225THR 236ASN 230THR 234VAL 233

ASIATICOSIDE 5636 4 PRO 472VAL 412VAL 191GLY 284

BRCA1 receptor with Centellina asiatica

BRCA1 receptor with Annona muricata


2-BUTENOIC ACID -2834 0 02 HEX ETHYL Acid 3694 0 02 OCTENOIC ACID 3524 0 02 TERPINOL 376.5 1 ILE 200ANOMURICINE 4768 4 TYR 222

LEU 185PHE 191HIS 192

ATHERO SPERMININE 4418 3 LYS 169THR 114LEU 115

CALARINE 3344 1 GLU 212CARO PHYLLENE 3472 1 GLU 212CIINEOLE 2908 1 GLY 198COCLAURINE 4182 0 0CIOREXIMINE 4850 2 ARG 350

ARG 365LINALOOL 3146 1 ARG 183LINAYL PROPIONATE 3946 1 HIS 192MURICATIN 3198 3 ASN 195

LYS 186ASP 218

STEPHARINE 4022 3 HIS 192PHE 191GLY 193

ASIATIC ACID NO DOCK 0 0BRAHMIC ACID NO DOCK 0 0MADASIATICOSIDE_RETINOIC ACID NO DOCK 0 0MADECASSIC ACID NO DOCK 0 0TERMINOLIC ACID NO DOCK 0 0

2-BUTENOIC ACID -1.37E+02 2 ARG 63LYS 58

2 HEX ETHYL Acid -1.63E+02 1 LYS 1112 OCTENOIC ACID -1.83E+02 0 02 TERPINOL -1.64E+02 0 0ANOMURICINE -2.62E+02 0 0ATHERO SPERMININE -2.57E+02 1 LEU 126CALARINE -1.84E+02 0 0CARO PHYLLENE -1.84E+02 0 0CIINEOLE -1.55E+02 0 0COCLAURINE 4298 0 0CIOREXIMINE -2.53E+02 2 GLN 187

SER 129LINALOOL -1.72E+02 0 0LINAYL PROPIONATE -2.04E+02 0 0MURICATIN -2.27E+02 1 LYS 111STEPHARINE -2.45E+02 2 LEU 124

SER 129

FGFR4 receptor with Annona muricata

FGFR4 receptor with Centellina asiatica

BRCA2 receptor with Annona muricata


2-BUTENOIC ACID 2124 0 02 HEX ETHYL Acid 2448 0 02 OCTENOIC ACID 2756 0 02 TERPINOL NO DOCK 0 0ANOMURICINE 4248 3 LEU 222

LYS 274LYS 220

ATHERO SPERMININE 4240 0 0CALARINE NO DOCK 0 0CARO PHYLLENE NO DOCK 0 0CIINEOLE 2728 1 LLE 222COCLAURINE 3986 0 0CIOREXIMINE 4138 1 LYS 219LINALOOL NO DOCK 0 0LINAYL PROPIONATE NO DOCK 0 0MURICATIN 3112 2 ASN 267

LYS 220STEPHARINE 3732 2 ASN 267

ARG 218

ASIATIC ACID 4958 4 LYS 239LYS 220ILE 222ARG 218

BRAHMIC ACID 5066 4 TRY 224LYS 220ARG 218LYS 219

MADASIATICOSIDE_RETINOIC ACID 4624 2 GLO 233LYS 220

MADECASSIC ACID 5066 6 GLY 217ARG 218LYS 216ARG 221ASN 267TYR 224

TERMINOLIC ACID 4992 4 LYS 219 LYS 220TRY 224ARG 218

2-BUTENOIC ACID -1.40E+02 0 02 HEX ETHYL Acid -1.70E+02 0 02 OCTENOIC ACID -1.86E+02 0 02 TERPINOL -1.68E+02 0 0ANOMURICINE -3.16E+02 1 CYS 437ATHERO SPERMININE -2.81E+02 0 0CALARINE -1.79E+02 0 0CARO PHYLLENE -1.89E+02 0 0CIINEOLE -2.60E+02 2 ARG 400

GLN 487COCLAURINE 4474 0 0CIOREXIMINE -2.60E+02 2 ARG 400

GLN 487LINALOOL -1.72E+02 1 LYS 392LINAYL PROPIONATE -2.42E+02 0 0MURICATIN -2.22E+02 0 0STEPHARINE -2.24E+02 1 LYS 392

RNASEL receptor with Annona muricata

HOXB13 receptor with Annona muricata

HOXB13 receptor with Centellina asiatica


ASIATIC ACID 5868 4 ARG 400ASP 505ASP 503GLN 489

BRAHMIC ACID 5932 3 GLU 457ASP 452GLU 454

MADASIATICOSIDE_RETINOIC ACID 4942 2 PRO 196ARG 170

MADECASSIC ACID 5932 5 ASP 167TRP 181ALA 163THR 165ARG 185

TERMINOLIC ACID NO dockss 0 0ASIATICOSIDE 5372 3 SER 623

SER 637ASN 651

2-BUTENOIC ACID -1.41E+022 HEX ETHYL Acid -1.92E+02 0 02 OCTENOIC ACID -1.94E+02 0 02 TERPINOL -1.87E+02 0 0ANO MURICINE -2.92E+02 0 0ATHEROSPERMINE -2.83E+02 0 0CALARINE -1.86E+02 0 0CARO PHYLLENE -2.19E+02 0 0CIINEOLE -1.63E+02 0 0CIOCLAURINE 4300 1 THR 229CIOREXIMINE -2.62E+02 1 ASP 167LINALOOL -1.85E+02 0 0LINAYL PROPIONATE -2.37E+02 1 ARG 82MURICATIN -2.39E+02 0 0STEPHARINE -2.71E+02 0 0

ASIATIC ACID -2.91E+02 3 ALA 279LEU 285TYR 256

BRAHMIC ACID -2.99E+02 4 ASP 167ALA 163 TRP 181 ARG 185

MADASIATICOSIDE_RETINOIC ACID -2.56E+02 2 PRO 196ARG 170

MADECASSIC ACID -2.99E+02 5 ASP 167TRP 181 ARG 165THR 165ALA 163

TERMINOLIC ACID -2.72E+02 2 PRO 195ARG 162

ASIATICOSIDE -3.88E+02 2 THR 243ASN 227

RNASEL receptor with Centellina asiatica

TUSC3 receptor with Annona muricata

TUSC3 receptor with Centellina asiatica


Fig. 2: Docking Images ADME screening [30, 31] was performed on the selected compounds (Table 5). It is seen that phyto-compounds anomuricine, stepharine and asiatic acid satisfy lipinsky rule of five for drug evidenced from the ADME studies.

Table 5: ADME studies

COMPOUNDS miLogP TPSA natoms MW nON nOHNH volume nrotb nviolationsASIATIC ACID 4.7 97.98 35 488.71 5 4 487.79 2 0BRAHMIC ACID 3.78 118.21 36 504.71 6 5 495.83 2 1TERMINOLIC ACID 3.72 118.21 36 504.71 6 5 495.49 2 1MADECASSIC ACID 3.78 118.21 36 504.71 6 5 495.83 2 1Madasiaticoside retinoic acid 5.8 37.3 22 300.44 2 1 315.59 5 12 Butenoic acid 1.07 26.3 7 100.12 2 0 101.14 2 02 Hex ethyl acid 2.75 26.3 10 142.2 2 0 151.55 5 02 Octenoic acid 3.38 26.3 11 156.22 2 0 168.35 6 0Alpha terpinol 2.6 20.23 11 154.25 1 1 170.65 1 0Ano muricine 3.06 59.96 24 329.4 5 2 308.9 5 0Athero sperminine 4.26 21.71 23 309.41 3 0 302.6 5 0Calarine 4.84 0 15 204.36 0 0 224.47 0 0Carophyllene 5.17 0 15 204.36 0 0 229.95 0 1Cineole 1.8 29.46 12 170.25 2 1 174.71 0 0Coclaurine 2.31 61.72 21 285.34 4 3 285.34 3 0Co reximine 1.94 62.16 24 327.38 5 2 297.71 2 0Linalool 3.21 20.23 11 154.25 1 1 175.59 2 0Linalyl propionate 4.28 26.3 15 210.32 2 0 228.9 7 0Muricatin 1.66 47.57 22 297.35 4 1 272.35 2 0Stepharine 1.66 47.57 22 297.35 4 1 272.57 2 0

Legends: LogP: (octanol/water partition coefficient); TPSA: Molecular Polar Surface Area; natoms: number of atoms; MW: Molecular weight; nON: Number of ON; nOHNH: number of OHNH; volume: Molecular Volume, nrotb: Number of Rotatable Bonds; nviolations: number of violations.


ConclusionThe compounds anomuricine and stepharine from

plant Annona muricata docks best with all selected receptors of prostate cancer used in this work. The compound asiatic acid from Centellina asiatica docks best with most receptor of prostate cancer in this work. Also the compounds anomuricine, stepharine and asiatic acid satisfy lipinsky rule of 5 for drug evidenced from the ADME studies hence the compounds anomuricine, stepharine and asiatic acid can successfully used as ligands for prostate cancer receptors and further in vitro receptors binding can be done to establish the efficiency of the above ligands as drugs in treating prostate cancer .

Psychosocial Genomics of Cancer Research Psychosocial Genomics Research Program in

Oncology or cancer (PSGPO) aims to integrate psychological and medical knowledge at the ground level of neuro-scientific findings, genomic research and mind-body medicine and research in the psychosocial genomics of stress is achieving a quiet but significant breakthrough in understanding the fundamentals of the etiology and proliferation of a variety of human cancers including prostrate cancer. This research is a profound breakthrough in the theoretical and practical advances for the

amelioration and cure of cancer. Several studies have highlighted the role of neuroendocrine regulation of downstream physiological, psychological and biochemical pathways of cancer development which demonstrates how subjective the stressful experiences [32], may influence tumor growth and progression, via sympathetic nervous system (SNS) and hypothalamicpituitary- adrenal axis (HPA) activation. Functional genomics studies show interesting connections between mind-body therapies and immune system of cancer. We know that the chronic diseases, such as prostrate cancer, are complex conditions determined by a multiplicity of factors and so rarely can be treated by only surgical and/or pharmacological approaches. Treating prostrate cancer effectively means also taking into account the psychological and emotional challenges patients cope with. In particular when emotional distress becomes a mental disorder (e.g. depression, anxiety acc.) a comprehensive including cost-effective approach to treat co-morbidity is required to avoid polypharmacy that is frequent practiced especially in older patients and for this evidences we need to heal the chronic sources of stress, conflict, corruption and war within our own psychic nature which also requires a revolutionary shift in our social and spiritual values [32, 33].


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