Nonlinear dynamical systems effects of homeopathic remedies on multiscale entropy and correlation dimension of slow wave sleep EEG in young adults with histories of coffee-induced insomnia

Background: Investigators of homeopathy have proposed that nonlinear dynamical systems (NDS) and complex systems science offer conceptual and analytic tools for evaluating homeopathic remedy effects. Previous animal studies demonstrate that homeopathic medicines alter delta electroencephalographic (EEG) slow wave sleep. The present study extended findings of remedy-related sleep stage alterations in human subjects by testing the feasibility of using two different NDS analytic approaches to assess remedy effects on human slow wave sleep EEG.

Methods: Subjects (N=54) were young adult male and female college students with a history of coffee-related insomnia who participated in a larger 4-week study of the polysomnographic effects of homeopathic medicines on home-based all-night sleep recordings. Subjects took one bedtime dose of a homeopathic remedy (Coffea cruda or Nux vomica 30c). We computed multiscale entropy (MSE) and the correlation dimension (Mekler-D2) for stages 3 and 4 slow wave sleep EEG sampled in artifact-free 2-min segments during the first two rapid-eye-movement (REM) cycles for remedy and post-remedy nights, controlling for placebo and post-placebo night effects.

Results: MSE results indicate significant, remedy-specific directional effects, especially later in the night (REM cycle 2) (CC: remedy night increases and post-remedy night decreases in MSE at multiple sites for both stages 3 and 4 in both REM cycles; NV: remedy night decreases and post-remedy night increases, mainly in stage 3 REM cycle 2 MSE). D2 analyses yielded more sporadic and inconsistent findings.

Conclusions: Homeopathic medicines Coffea cruda and Nux vomica in 30c potencies alter short-term nonlinear dynamic parameters of slow wave sleep EEG in healthy young adults. MSE may provide a more sensitive NDS analytic method than D2 for evaluating homeopathic remedy effects on human sleep EEG patterns.

Keywords

Homeopathy - Polysomnography - Electroencephalography - Coffea cruda - Nux vomica - Nonlinear dynamics - Multiscale entropy - Correlation dimension - Slow wave sleep - Complex systems - Time-dependent sensitization

• References

• 1 Owen D. Principles and practice of homeopathy: the therapeutic and healing process. Churchill Livingstone; 2007.
• 2 Grabia S., Ernst E. Homeopathic aggravations: a systematic review of randomised, placebo-controlled clinical trials. Homeopathy Apr 2003; 92 (02) 92-98.
• 3 Bertani S., Lussignoli S., Andrioli G., Bellavite P., Conforti A. Dual effects of a homeopathic mineral complex on carrageenan-induced oedema in rats. Br Homeopath J 1999; 88 (03) 101-105.
• 4 Hyland M. Extended network generalized entanglement theory: therapeutic mechanisms, empirical predictions, and investigations. J Alternative Compl Med 2003; 9 (06) 919-936.
• 5 Hyland M.E., Lewith G.T. Oscillatory effects in a homeopathic clinical trial: an explanation using complexity theory, and implications for clinical practice. Homeopathy 2002; 91 (03) 145-149.
• 6 Bell IR. Homeopathy as systemic adaptational nanomedicine: the nanoparticle-cross-adaptation-sensitization model. Am J Homeopath Med 2012; in press.
• 7 Vithoulkas G. The science of homeopathy. N.Y.: Grove Weidenfeld; 1980.
• 8 Bell I.R., Koithan M. Models for the study of whole systems. Integr Canc Ther 2006; 5 (04) 293-307.
• 9 Brien S.B., Harrison H., Daniels J., Lewith G. Monitoring improvement in health during homeopathic intervention. Development of an assessment tool based on Hering's Law of Cure: the Hering's Law Assessment Tool (HELAT). Homeopathy Jan 2012; 101 (01) 28-37.
• 10 Vithoulkas G., van Woensel E. Levels of health: practical applications and cases. International Academy of Classical Homeopathy; 2010.
• 11 Dantas F., Fisher P., Walach H. et al. A systematic review of the quality of homeopathic pathogenetic trials published from 1945 to 1995. Homeopathy Jan 2007; 96 (01) 4-16.
• 12 Sherr J. The dynamics and methodology of homeopathic provings. 2nd edn. Malvern, UK: Dynamis Books; 1994.
• 13 Brooks A.J., Bell I.R., Howerter A., Jackson N., Aickin M. Effects of homeopathic medicines on mood of adults with histories of coffee-related insomnia. Forsch Komplementarmed Klass Naturheilkd 2010; 17: 250-257.
• 14 Torres J.L. Homeopathic effect: a network perspective. Homeopathy 2002; 91 (02) 89-94.
• 15 Torres J.L., Ruiz M.A.G. Stochastic resonance and the homeopathic effect. Br Homeopath J 1996; 85 (03) 134-140.
• 16 Shepperd J. Chaos theory: implications for homeopathy. J Am Inst Homeopathy 1994; 87 (04) 22.
• 17 Bellavite P., Signorini A. The emerging science of homeopathy. Complexity, biodynamics, and nanopharmacology. 2nd edn. Berkeley: North Atlantic Books; 2002.
• 18 Bellavite P. Complexity science and homeopathy: a synthetic overview. Homeopathy 2003; 92 (04) 203-212.
• 19 Bell I.R., Baldwin C.M., Schwartz G.E.R. Translating a nonlinear systems theory model for homeopathy into empirical tests. Alternative Ther Health Med 2002; 8 (03) 58-66.
• 20 In: Witt C., Albrecht H. New Directions in Homeopathy Research. 2009. Essen, Germany: KVC Verlag.;
• 21 Milgrom L.R. Vitalism, complexity, and the concept of spin. Homeopathy 2002; 91 (01) 26-31.
• 22 Koithan M., Bell I.R., Niemeyer K., Pincus D. A complex systems science perspective for whole systems of CAM research. Forsch Komplementarmed Klass Naturheilkd 2012; 19 (Suppl. 01) 7-14.
• 23 Bell I.R., Koithan M., Pincus D. Research methodological implications of nonlinear dynamical systems models for whole systems of complementary and alternative medicine. Forsch Komplementarmed Klass Naturheilkd 2012; 19 (Suppl. 01) 15-21.
• 24 Bell IR, Schwartz GE, Koithan M, Brooks AJ. Adaptational nanomedicine and hormesis: homeopathic remedies as nanoparticles and low intensity systemic stressors. Am Homeopath, in press.
• 25 Guastello S.J., Koopmans M., Pincus D. Chaos and complexity in psychology: the theory of nonlinear dynamical systems. New York, NY: Cambridge University Press; 2009.
• 26 Bar-Yam Y. Dynamics of complex systems. Reading, MA: Perseus Books; 1997.
• 27 Mitchell M. Complexity: a guided tour. NY: Oxford University Press; 2009.
• 28 Burggren W.W., Monticino M.G. Assessing physiological complexity. J Exp Biol 2005; 208 Pt (17) 3221-3232.
• 29 Vasquez A., Dobrin R., Sergi D., Eckmann J.P., Oltvai Z.N., Barabasi A.L. The topological relationship between the large-scale attributes and local interaction patterns of complex networks. Proc Natl Acad Sci U S A 2004; 101 (52) 17940-17945.
• 30 Barabasi A.L. Linked. How everything is connected to everything else and what it means for business, science, and everyday life. Cambridge, MA: Plume; 2003.
• 31 Barabasi A.L., Bonabeau E. Scale-free networks. Sci Am 2003; 288 (05) 60-69.
• 32 Bar-Yam Y. Making things work: solving complex problems in a complex world. Knowledge Press; 2004.
• 33 Pincus D. Self-organizing biopsychosocial dynamics and the patient-healer relationship. Forsch Komplementarmed Klass Naturheilkd 2012; 19 (Suppl. 01) 22-29.
• 34 Woyshville M.J., Calabrese J.R. Quantification of occipital EEG changes in Alzheimer's disease utilizing a new metric: the fractal dimension. Biol Psychiatry 1994; 35 (06) 381-387.
• 35 Ferri R., Pettinato S., Nobili L., Billiard M., Ferrillo F. Correlation dimension of EEG slow-wave activity during sleep in narcoleptic patients under bed rest conditions. Int J Psychophysiol Oct 1999; 34 (01) 37-43.
• 36 Jardanhazy A., Jardanhazy T. Non-linear quantitative electroencephalographic (qEEG) changes during processing of chemo-sensory stimulations: a preliminary study. Behav Brain Res Dec 12 2008; 194 (02) 162-168.
• 37 Jelles B., Scheltens P., van der Flier W.M., Jonkman E.J., da Silva F.H., Stam C.J. Global dynamical analysis of the EEG in Alzheimer's disease: frequency-specific changes of functional interactions. Clin Neurophysiol Apr 2008; 119 (04) 837-841.
• 38 Kawasaki H., Morinushi T., Yakushiji M., Takigawa M. Nonlinear dynamical analysis of the effect by six stimuli on electroencephalogram. J Clin Neurophysiol Feb 2009; 26 (01) 24-38.
• 39 Kobayashi T., Madokoro S., Wada Y., Misaki K., Nakagawa H. Human sleep EEG analysis using the correlation dimension. Clin Electroencephalogr Jul 2001; 32 (03) 112-118.
• 40 Tsirka V., Simos P.G., Vakis A. et al. Mild traumatic brain injury: graph-model characterization of brain networks for episodic memory. Int J Psychophysiol 2011; 79 (02) 89-96.
• 41 Dimpfel W. The ultra low dose combination medication ULDCM-310 triggers electro-encephalographic patterns in the rat brain in a dose and time dependent manner. Eur J Integr Med 2010; 2 (04) 227-228.
• 42 Bell I.R., Brooks A.J., Howerter A., Jackson N., Schwartz G.E. Short term effects of repeated olfactory administration of homeopathic Sulphur or Pulsatilla on electroencephalographic alpha power in healthy young adults. Homeopathy 2011; 100 (04) 203-211.
• 43 Bell I.R., Lewis 2nd D.A., Schwartz G.E. et al. Electroencephalographic cordance patterns distinguish exceptional clinical responders with fibromyalgia to individualized homeopathic medicines. J Alternative Compl Med 2004; 10 (02) 285-299.
• 44 Ruiz-Vega G., Perez-Ordaz L., Leon-Hueramo O., Cruz-Vazquez E., Sanchez-Diaz N. Comparative effect of Coffea cruda potencies on rats. Homeopathy 2002; 91: 80-84.
• 45 Ruiz-Vega G., Poitevin B., Pérez-Ordaz L. Histamine at high dilution reduces spectral density in delta band in sleeping rats. Homeopathy 2005; 94 (02) 86-91.
• 46 Ruiz-Vega G., Perez-Ordaz L., Cortes-Galvan L., Juarez-G F.M. A kinetic approach to caffeine–Coffea cruda interaction. Homeopathy 2003; 92 (01) 19-29.
• 47 Ruiz G., Torres J.L. Homeopathic effect on the sleep pattern of rats. Br Homeopath J 1997; 86: 201-206.
• 48 Sukul A., Sinhabau S.P., Sukul N.C. Reduction of alcohol induced sleep time in albino mice by potentized Nux vomica prepared with 90% ethanol. Br Homeopath J 1999; 88 (02) 58-61.
• 49 Bell I.R., Howerter A., Jackson N., Aickin M., Baldwin C.M., Bootzin R.R. Effects of homeopathic medicines on polysomnographic sleep of young adults with histories of coffee-related insomnia. Sleep Med May 2011; 12 (05) 505-511.
• 50 Costa M., Goldberger A.L., Peng C.K. Multiscale entropy analysis of complex physiologic time series. Phys Rev Lett 2002; 89 (68102): 068101-068104.
• 51 Costa M., Priplata A.A., Lipsitz L.A. et al. Noise and poise: enhancement of postural complexity in the elderly with a stochastic-resonance-based therapy. Europhys Lett 2007; 77: 68008.
• 52 Costa M., Goldberger A.L., Peng C.K. Multiscale entropy analysis of biological signals. Phys Rev E 2005; 71 (21906): 1-18.
• 53 Mekler A. Calculation of EEG correlation dimension: large massifs of experimental data. Comput Methods Programs Biomed 2008; 92: 154-160.
• 54 Kobayashi T., Madokoro S., Ota T. et al. Analysis of the human sleep electroencephalogram by the correlation dimension. Psychiatry Clin Neurosci Jun 2000; 54 (03) 278-279.
• 55 Yang H., Wang Y., Wang C.J., Tai H.M. Correlation dimensions of EEG changes during mental tasks. Conf Proc IEEE Eng Med Biol Soc 2004; 1: 616-619.
• 56 Morrison R. Desktop guide to keynotes and confirmatory symptoms. Albany, CA: Hahnemann Clinic Publishing; 1993.
• 57 Roy R., Tiller W., Bell I.R., Hoover M.R. The structure of liquid water: novel insights from materials research and potential relevance to homeopathy. Mater Res Innovat 2005; 9 (04) 557-608.
• 58 Rao M.L., Roy R., Bell I.R. The defining role of structure (including epitaxy) in the plausibility of homeopathy. Homeopathy 2007; 96 (03) 175-182.
• 59 Rao M., Roy R., Bell I.R. Characterization of the structure of ultra dilute sols with remarkable biological properties. Mater Lett 2008; 62: 1487-1490.
• 60 Rey L. Thermoluminescence of ultra-high dilutions of lithium chloride and sodium chloride. Phys Stat Mech Appl 2003; 323: 67-74.
• 61 Rey L. Can low-temperature thermoluminescence cast light on the nature of ultra-high dilutions?. Homeopathy 2007; 96 (03) 170-174.
• 62 Elia V., Niccoli M. Thermodynamics of extremely diluted aqueous solutions. Ann N Y Acad Sci 1999; 879: 241-248.
• 63 Elia V., Niccoli M. New physico-chemical properties of extremely diluted aqueous solutions. J Therm Anal Calorim 2004; 75: 815-836.
• 64 Elia V., Napoli E., Germano R. The ‘Memory of Water’: an almost deciphered enigma. Dissipative structures in extremely dilute aqueous solutions. Homeopathy 2007; 96 (03) 163-169.
• 65 van Wijk R., Bosman S., van Wijk E.P. Thermoluminescence in ultra-high dilution research. J Altern Complement Med Jun 2006; 12 (05) 437-443.
• 66 Chikramane P.S., Suresh A.K., Bellare J.R., Kane S.G. Extreme homeopathic dilutions retain starting materials: a nanoparticulate perspective. Homeopathy 2010; 99 (04) 231-242.
• 67 Montagnier L., Aissa J., Ferris S., Montagnier J.-L., Lavallee C. Electromagnetic signals are produced by aqueous nanostructures derived from bacterial DNA sequences. Interdisciplinary Sci Comput Life Sci 2009; 1: 81-90.
• 68 Bhattacharyya S.S., Mandal S.K., Biswas R. et al. In vitro studies demonstrate anticancer activity of an alkaloid of the plant Gelsemium sempervirens . Exp Biol Med (Maywood) Dec 2008; 233 (12) 1591-1601.
• 69 Lancet. The end of homeopathy. Lancet 2005; 366: 690.
• 70 Frei H., Everts R., von Ammon K. et al. Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial. Homeopathy Jan 2007; 96 (01) 35-41.
• 71 Möllinger H., Schneider R., Walach H. Homeopathic pathogenetic trials produce specific symptoms different from placebo. Forsch Komplementmed Klass Naturheilkd 2009; 16 (02) 105-110.
• 72 Rechtschaffen A., Kales A. A manual of standardized terminology, techniques, and scoring system for sleep stages of human subjects. Los Angeles, CA: UCLA BIS/BRI Publications; 1968.
• 73 Costa M., Goldberger A.L., Peng C.K. Multiscale entropy to distinguish physiologic and synthetic RR time series. Comput Cardiol 2002; 29: 137-140.
• 74 Grassberger P., Procaccia I. Measuring the strangeness of strange attractors. Phys Nonlinear Phenom 1983; 9 (01/02) 189-208.
• 75 Baumgartner S. The state of basic research on homeopathy. In: Witt C., Albrecht H. New Directions in Homeopathy Research. 2009. Essen, Germany: KVC Verlag; 107-130.
• 76 Spiegler A., Kiebel S.J., Atay F.M., Knosche T.R. Bifurcation analysis of neural mass models: impact of extrinsic inputs and dendritic time constants. Neuroimage Sep 2010; 52 (03) 1041-1058.
• 77 Whelan R., Conrod P.J., Poline J.B. et al. Adolescent impulsivity phenotypes characterized by distinct brain networks. Nat Neurosci Apr 29 2012
• 78 Sporns O. The non-random brain: efficiency, economy, and complex dynamics. Front Comput Neurosci 2011; 5: 5.
• 79 Priano L., Saccomandi F., Mauro A., Guiot C. Non-linear recurrence analysis of NREM human sleep microstructure discloses deterministic oscillation patterns related to sleep stage transitions and sleep maintenance. Conf Proc IEEE Eng Med Biol Soc 2010; 2010: 4934-4937.
• 80 Ruiz-Vega G., Perez-Ordaz L., Proa-Flores P., Aguilar-Diaz Y. An evaluation of Coffea cruda effect on rats. Br Homeopath J 2000; 89 (03) 122-126.
• 81 Sukul N.C., Ghosh S., Sinhababu S.P., Sukul A. Strychnos nux-vomica extract and its ultra-high dilution reduce voluntary ethanol intake in rats. J Alternative Compl Med 2001; 7 (02) 187-193.
• 82 Grassberger P. Information and complexity measures in dynamical systems. In: Atmanspacher H., Scheingraber H. Information Dynamics. 1991. New York: Plenum Press; 15-33.
• 83 Sherr J. Dynamic materia medica. Syphilis: a study of syphilitic miasm through remedies. Great Malvern Worcestershire, England: Dynamis Books; 2002.
• 84 Sankaran R. The synergy in homoeopathy. Mumbai, India: Homoeopathic Medical Publishers; 2012.
• 85 Antelman S.M., Levine J., Gershon S. Time-dependent sensitization: the odyssey of a scientific heresy from the laboratory to the door of the clinic. Mol Psychiatr 2000; 5 (04) 350-356.
• 86 Antelman S.M., Caggiula A.R. Oscillation follows drug sensitization: implications. Crit Rev Neurobiol 1996; 10 (01) 101-117.
• 87 Bell I.R., Baldwin C.M., Schwartz G.E. Sensitization studies in chemically intolerant individuals: implications for individual difference research. Ann New York Acad Sci 2001; 933: 38-47.
• 88 Antelman S.M. Time-dependent sensitization in animals: a possible model of multiple chemical sensitivity in humans. Toxicol Ind Health 1994; 10 (04/05) 335-342.
• 89 Van Wijk R., Wiegant F.A. Postconditioning hormesis and the similia principle. Front Biosci (Elite Ed) 2011; 3: 1128-1138.
• 90 Fisher P. Does homeopathy have anything to contribute to hormesis?. Hum Exp Toxicol Jul 2010; 29 (07) 555-560.
• 91 Calabrese E.J., Jonas W.B. Homeopathy: clarifying its relationship to hormesis. Hum Exp Toxicol Jul 2010; 29 (07) 531-536.
• 92 Hahnemann S. Organon of the medical art. 6th edn. Redmond, WA: Birdcage Books; 1843.
• 93 Bell I.R., Lewis 2nd D.A., Lewis S.E., Brooks A.J., Schwartz G.E., Baldwin C.M. Strength of vital force in classical homeopathy: bio-psycho-social-spiritual correlates within a complex systems context. J Alternative Compl Med 2004; 10 (01) 123-131.
• 94 Lipsitz L.A., Goldberger A.L. Loss of ‘complexity’ and aging. Potential applications of fractals and chaos theory to senescence. JAMA 1992; 267: 1806-1809.
• 95 Goldberger A.L., Peng C.K., Lipsitz L.A. What is physiologic complexity and how does it change with aging and disease?. Neurobiol Aging Jan–Feb 2002; 23 (01) 23-26.
• 96 Pincus D., Metten A. Nonlinear dynamics in biopsychosocial resilience. Nonlinear Dynamics Psychol Life Sci 2010; 14 (04) 353-380.
• 97 Fredrickson B.L., Losada M.F. Positive affect and the complex dynamics of human flourishing. Am Psychol 2005; 60 (07) 678-686.
• 98 Losada M. The complex dynamics of high performance teams. Math Comput Model 1999; 30: 179-192.
• 99 Losada M., Heaphy E. The role of positivity and connectivity in the performance of business teams: a nonlinear dynamics model. Am Behav Sci 2004; 47 (06) 740-765.
• 100 Catarino A., Churches O., Baron-Cohen S., Andrade A., Ring H. Atypical EEG complexity in autism spectrum conditions: a multiscale entropy analysis. Clin Neurophysiol Dec 2011; 122 (12) 2375-2383.
• 101 Rossi E., Bartoli P., Bianchi A., Endrizzi C., Da Fre M. Homeopathic aggravation with Quinquagintamillesimal potencies. Homeopathy Apr 2012; 101 (02) 112-120.
• 102 Good L.B., Sabesan S., Marsh S.T., Tsakalis K., Treiman D.M., Iasemidis L.D. Nonlinear dynamics of seizure prediction in a rodent model of epilepsy. Nonlinear Dynamics Psychol Life Sci 2010; 14 (04) 411-434.
• 103 Lewith G.T., Watkins A.D., Hyland M.E. et al. Use of ultramolecular potencies of allergen to treat asthmatic people allergic to house dust mite: double blind randomised controlled clinical trial. BMJ 2002; 324 (7336): 520-523.
• 104 Pincus D. Coherence, complexity, and information flow: self-organizing processes in psychotherapy. In: Guastello S.J., Koopmans M., Pincus D. Chaos and Complexity in Psychology. The Theory of Nonlinear Dynamical Systems. 2009. NY: Cambridge University Press; 335-369.
• 105 Hayes A.M., Laurenceau J.P., Feldman G., Strauss J.L., Cardaciotto L. Change is not always linear: the study of nonlinear and discontinuous patterns of change in psychotherapy. Clin Psychol Rev 2007; 27 (06) 715-723.
• 106 Walach H., Mollinger H., Sherr J., Schneider R. Homeopathic pathogenetic trials produce more specific than non-specific symptoms: results from two double-blind placebo controlled trials. J Psychopharmacol Jul 2008; 22 (05) 543-552.