1. The Role of Microtubules in Psychopathology
Massimo Pregnolato
Dipartimento di Scienze del Farmaco
Università degli Studi di Pavia (IT)
Web : http://www.quantumbiolab.org
e-mail: maxp@quantumbionet.org
"A Long Shadow over the Soul"
Molecular and Quantum Approaches to Psychopathology
An Interdisciplinary Dialog with Psychiatrists
Fano. March, 31, 2012

2. Is it possible that psychopathological diseases such as
depression (Cocchi, 2010) and psychosis (van
Woerkom, 1990; Benitez-King, 2004) involve
different states of consciousness (Morin, 2006)
through the biological interface called:
"Cytoskeletal Quantum Nanowire-Network"?

4. Quantum Cytoskeleton Nanowire Network
MTs and Actin filaments can be viewed as computationally relevant nanowire
networks that operate within neurons providing several functions among them the
connection of the cell nucleus with the postsynaptic density (Woolf, 2010).
Potential computational modes for MTs and actin filaments are beginning to be
understood, with two main quantum models for MT information processing having
been proposed.

6. The Penrose-Hameroff Orch OR model of consciousness
Microtubules are protein polymers inside brain neurons proposed to
act as quantum computers
Stuart Hameroff
Roger Penrose

7. Tubulin
Tubulin is a globular
protein and the
fundamental component
of microtubules.
Microtubules (MTs)
constitute the
cytoskeleton of all the
eukaryotic cells and are
supposed to be involved in
many key cellular
functions

8. Microtubules (MTs)
Microtubules are cylindrical polymers composed by alpha and beta-
tubulin dimers. MTs diameter is around 15 nm and their length can
vary from a few nm up to some cm.
MTs have optical, electrical and
quantum properties that might
explain long-distance intracellular
communication processes

9. Excitation of vibration in microtubules in living cells
ration in microtubules in living cells.
Jiří Pokorný May 13, 2011
In recent years coherent excitations have been found in living cells emanating
from microtubules at 8 Megahertz
P
Pokorný, J. (2004) Excitation of vibration in microtubules in living cells. Bioelectrochem. 63: 321-326.

10. Experimental and Computational Studies on Biophysical Properties
of Microtubules
Resonance - Microtubules: sharp (0,30 Hz) peak of mechanical
resonance at a frequency of 1510 MHz
- Tubulin and control solution did not show any
reaction
MT molecular tubular structure can be responsible
for the observed amplification of the signal
Birefringence
MTs react to electromagnetic fields in a different
way than tubulin and control: birefringence effect is
always higher in MTs than in tubulin and control,
with statistical significance
This suggests again that the molecular structure of MTs could
be the cause of their reaction to electro-magnetic fields
Pizzi R, Strini G, Fiorentini S, Pappalardo V and Pregnolato.M Evidences Of New Biophysical Properties
of Microtubules. Focus on Artificial Neural Networks cap. 9. pag. 191-207. Edited by John A. Flores. Nova
Science Publisher Inc. 2011

11. Physico-Chemical Computational Simulation
SONNIA (Self-Organizing Neural Network for Information Analysis)
ITSOM (Inductive Tracing Self-Organizing Map) network
MTs which in the dynamic evolution at zero field tend to move off their initial
position, under the influence of the electric field tend to return to the starting
position and to stabilize.
MTs spatial organization is stronger than tubulin alone even in absence of
field. The presence of electric field causes a decrease of conflicts, indicating
a better structural organization, confirmed both by SONNIA and by the ITSOM
attractors, that show a high regularity and compactness.
Pizzi R, Fiorentini S, Strini G and Pregnolato M. Exploring Structural and Dynamical Properties of
Microtubules by Means of Artificial Neural Networks. Complexity Science, Living Systems and Reflexing
Interfaces: New Models and Perspectives. edited by Franco Orsucci and Nicoletta Sala. IGI Global
publisher , 2012. in press.

12. 2007 - Schrodinger's protein evidences (1)

13. 2010 - Schrodinger's protein evidences (2)

14. 2010 - Schrodinger's protein evidences (3)

15. Tubulin: a Scrodinger’s protein
Tubulin exist in quantum superposition of different states and function like
a quantum bit, or qubit
Hameroff, S, Penrose, R (1995) Orchestrated reduction of quantum coherence in brain microtubules: A model for
consciousness. Neural Network World, Vol. 5(5): 793-804.
Hameroff, S (2007) Orchestrated Reduction of Quantum Coherence in Brain Microtubules. NeuroQuantology. 5 (1) 1–8.)

16. Penrose observed that quantum superposition – an object in two places/states
simultaneously – equated to two spacetime curvatures in different directions:
a bubble or separation in the fabric of reality
But the separations are unstable, and after a time t (given by E=h/t) will spontaneously
self-collapse to one curvature or the other (an “objective reduction” – O.R.).

17. The Penrose-Hameroff model suppose that quantum-superposed states develop
in tubulins, remain coherent and recruit more superposed tubulins until a mass-
time-energy threshold, related to quantum gravity, is reached (up to 500 msec).
This model predicts dendritic webs of approximately 100,000 neurons for discrete
conscious moments, or frames, occurring every 25 ms in gamma synchrony.
Bing

18. Interior schematic of dendrites in quantum isolation phase. Actin has
polymerized into gel form and MAPs detached, shielding and isolating MTs
whose tubulins have evolved into quantum superposition

19. Molecular simulation of tubulin with Schematic tubulin with non-
beta tubulin (dark gray) on top and polar hydrophobic phenyl rings
alpha tubulin (light gray) on bottom. approximating actually phenyl
Non-polar amino acids phenylalanine and indole rings. Scale bar: 1
and tryptophan with aromatic phenyl nanometer.
and indole rings are shown.
(Travis Craddock and Jack Tuszynski)

20. 2011 - Hameroff-Penrose Theory Updates
Four versions of the schematic Orch OR tubulin bit (superpositioned qubit states not shown).
•Early version showing conformational change coupled to/driven by single hydrophobic
pocket with two aromatic rings.
•Updated version with single hydrophobic pocket composed of 4 aromatic rings.
•McKemmish (2009) mis-characterization of Orch OR tubulin bit as irreversible
conformational change driven by GTP hydrolysis.
•Current version of Orch OR bit with no significant conformational change (change occurs at
the level of atomic nuclei) and multiple hydrophobic pockets arranged in channels.

21. 2011 - Direct Experimental Evidence for the Quantum
States in Microtubules and Topological Invariance
Series of coherence resonance peaks in single microtubules
ranging from 12 kilohertz to 8 megahertz.
Anirban Bandyopadhyay
National Institute of Material Sciences in Tsukuba, Japan
Using nanotechnology they interface via AFM/STM electrodes to opposite ends of a single viable
microtubule (MT). They vary AC and DC conditions and study electronic transport properties at
temperatures ranging from 10K to room temperature. At specific conditions they found:
3)spontaneous MT growth leading to Frohlich condensation
4)ballistic electronic transport,
5)ferroelectric MT properties.
•Multilevel information processing and memory (beyond binary logic) in MT
•Efforts to understand room temperature coherent transport in terms of band energies.
•Challenges and resolution of detection of MT topological quantum bits, or qubits based on
Hemchandra/Fibonacci MT geometry at physiological temperature.
Bandyopadhyay A (2011) Direct experimental evidence for quantum states in
microtubules and topological invariance. Abstracts: Toward a Science of Consciousness
2011, Sockholm, Sweden, http://www.consciousness.arizona.edu

22. Extending microtubule A-lattice hydrophobic channels results in helical winding
patterns matching Fibonacci geometry.
Bandyopadhyay (2011) has evidence for ballistic conductance and quantum
inteference along such helical pathways which may be involved in topological
quantum computing. Quantum electronic states of London forces in hydrophobic
channels result in slight superposition separation of atomic nuclei, sufficient EG for
Orch OR. This image may be taken to represent superposition of four possible
topological qubits which, after time T=tau, will undergo OR, and reduce to
specific pathway(s) which then implement function.
Roger Penrose, and S. Hameroff. Consciousness in the Universe: Neuroscience, Quantum Space-Time
Geometry & Orch OR Theory. Journal of Cosmology Volume 14 Consciousness and the Universe. 2011

23. Summary of Bandyopadhyay results (2011)
1) Microtubules have 8 resonance peaks for AC stimulation (kilohertz to 10
megahertz) which appear to correlate with various helical conductance
pathways around the geometric microtubule lattice.
2) Excitation at these resonant frequencies causes microtubules to assemble
extremely rapidly, possibly due to Fröhlich condensation.
3) In assembled microtubules AC excitation at resonant frequencies causes
electronic conductance to become lossless, or 'ballistic', essentially quantum
conductance, presumably along these helical quantum channels. Resonance in
the range of kilohertz demonstrates microtubule decoherence times of at least
0.1 millisecond.
4) Eight distinct quantum interference patterns from a single microtubule, each
correlating with one of the 8 resonance frequencies and pathways.
5) Ferroelectric hysteresis demonstrates memory capacity in microtubules.
6) Temperature-independent conductance also suggests quantum effects.
If confirmed, such findings would demonstrate Orch OR to be biologically feasible!

24. The Craddock and Tuszynski model
Describe classical and quantum information
processing in MTs based on a double-well potential
in the interior of the tubulin dimer.
Mapping electrostatic partial charges in the interior
of tubulin dimer shows a region in the alpha
monomer near the neck to the beta monomer of two
areas of positive charge in the range of 100-150
meV.
Electrostatic map of a horizontal
slice through tubulin near the
“neck” between the alpha and
beta monomers shows a “double
well” of positive charge.
Craddock TJA, Beauchemin C, Tuszynski JA. Information processing mechanisms in microtubules at
physiological temperature: Model predictions for experimental tests. Biosystems 2009; 97: 28-34.
Craddock TJA, Tuszynski JA. A critical assessment of the information processing capabilities of
neuronal microtubules using coherent excitations. J Biol Phys 2010; 36: 53-70.

25. The best correlate of consciousness
(NCC) comes from EEG,
EEG is divided into
frequency bands:
Delta (< 4 Hz)
Theta (4 to 8 Hz)
Alpha (8 to 12 Hz)
Beta (13 to 30 Hz)
Gamma (> 30 Hz)
Coherence in gamma synchrony
among different brain regions is
the best correlate of consciousness

26. The conscious pilot
Refers to spatiotemporal envelopes of dendritic gamma synchrony (demarcated by gap-
junction-defined “dendritic webs”) moving through the brain as vehicle for a conscious
agent which can experience and control otherwise non-conscious (autopilot) cognitive
functions. The best measurable “neural correlate of consciousness” (NCC), is gamma
synchrony EEG, coherent field potential oscillations in the range from 30 to 90 Hz
(prototypical 40 Hertz). Gamma synchrony, along with consciousness, apparently moves
and evolves through various global distributions and brain regions (Hameroff, 2010).

27. I Networks Sensory-driven e Default Mode
• Percezioni sensoriali
• Controllo del comportamento
• Apprendimento, Memoria
• Attenzione, Sonno
• Linguaggio
• Intelligenza
• Viscerale/sessuale
possono essere NON CONSCI
Chalmers’ easy problems
Zombie
Auto-pilot

28. • Percezione sensoriale
• Comportamento
• Apprendimento
• Memoria Bing
• Attentione, Sonno
• Linguaggio
• Intelligenza Bing
• Viscerale, Sessuale
Bing
…o CONSCI

29. •Percezione sensoriale
• Comportamento
• Apprendimento
•Memoria Bing
• Attenzione, Sonno Bing
• Linguaggio
• Intelligenza
• Viscerale, Sessuale
Bing
muovendosi e ridistribuendosi nel cervello

30. • Percezione sensoriale
• Comportamento Bing
• Apprendimento, Memoria Bing
• Attenzione
• Linguaggio
• Intelligenza Bing
• Viscerale, Sessuale
muovendosi e ridistribuendosi nel cervello

31. • Percezioni sensoriali Bing
• Conportamento
• Apprendimento, Memoria
• Attenzione
• Linguaggio Bing
• Intelligenza
• Viscerale, Sessuale Bing
muovendosi e ridistribuendosi nel cervello
La coscienza si muove attraverso le aree del
cervello in zone di sincronia gamma!

32. The above-described coherent framework reflects the meaning of the
ability of a quantitative approach to psychopathology.
Is there any correlation between hallucination and cell-molecular
interactions, or any cause for changing the conscious state that may be
detected by measuring the gamma synchrony, which is better
correlated to consciousness and which has already provided a
variability of responses in different psychopathological conditions and
meditation?
Flynn G, Alexander D, Harris A, Whitford T, Wong W, Galletly C, Silverstein S, Gordon E, Williams
LM. Increased absolute magnitude of gamma synchrony in first-episode psychosis.
Schizophr Res. 2008 Oct;105(1-3):262-71.

34. Ecstasy
Neuro Correlate of Consciousness
Hyper alert
Levels of Ordinary State of
(i.e. Gamma Synchrony ?)
Stupor
Pure biological level
Consciousness
Bio-eco-logical level
Mnemonic extended level
Identity level
Mystery level of the ego
Lethargic
Anesthesia
Coma
Unconsciousness

36. The role of microtubules in psychopathology
According to Woolf et al. MTs dysfunction occurring in mental illness might be expected to
cause abnormal tubulin oscillations between polymerization-depolymerization cycles resulting
in different arrays mixtures (classified by Craddock as types I–IV behaviors).
Depression could results from too little type IV behavior which is associated with information
processing systems. Billions of quantum computations in MTs would be responsible for moving
millions of proteins over nanometer distances, with the most salient among the collective
effects affecting neural activity on millisecond time scales.
Woolf concluded that: “….classical and quantum information processing in brain MTs could be
impaired in mental illness, to the extent that such information processing modes are validated
by experimental support”.
Woolf N, Craddock T, Friesen D, Tuszynski J. Neuropsychiatric illness: a case for impaired neuroplasticity
and possible quantum processing derailment in microtubules. NeuroQuantology 2010; 8(1): 13-28.

37. Major depressive disorder
Major depressive disorder (also
known as recurrent depressive
disorder, clinical depression, major
depression, unipolar depression, or
unipolar disorder) is a mental disorder
characterized by an all-encompassing
low mood accompanied by low self-
esteem, and by loss of interest or
pleasure in normally enjoyable
activities.
The diagnosis of major depressive
disorder is based on the patient's self-
reported experiences, behavior
reported by relatives or friends, and a
mental status exam. There is no
laboratory test for major depression,
although physicians generally request
tests for physical conditions that may
cause similar symptoms. Vincent van Gogh's 1890 painting
At Eternity's Gate

38. Ipotesi molecolare della Depressione
Acido Arachidonico, Fluidità di Membrana e Serotonina
Cocchi et al hanno tentato di spiegare il possibile ruolo della fluidità della
membrana delle piastrine nella modulazione dei livelli di serotonina nel
cervello, con un processo che coinvolge l’acido arachidonico (AA).
In questi lavori è stata dimostrata l‘importanza di tre acidi grassi nei fosfolipidi
della membrana delle piastrine di sangue prelevato a pazienti depressi.
Acido Palmitico (PA)
Acido linoleico (LA)
Acido Arachidonico (AA) Massimo Cocchi
(2008)

39. La membrana piastrinica delle persone depresse è caratterizzata da
un grado più elevato di insaturazioni rispetto al gruppo di soggetti
clinicamente sani ed è emersa una correlazione diretta tra la
concentrazione di Acido Arachidonico nelle piastrine e nei neuroni ed
una correlazione inversa con la concentrazione di serotonina.
Kary Mullis (Nobel Prize 1993) said:
“It is a very important discovery. Just think
that, through this method it will be possible
to understand if a patient will have intention
to commit suicide. It is a philosophic,
medical and religious revolution.”
(Il Resto del Carlino, May 28, 2008).
39

40. Lipid rafts are specialised structures on the plasma membrane that have an
altered lipid composition as well as links to the cytoskeleton. S-Palmitoylation is
the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues
of membrane proteins including Gsα.
Il gruppo di ricerca di Rasenick che studia la
proteina Gsα nei neuroni di suicidi,
ha evidenziato i microdomini lipidici raft della
membrana quali elementi critici di
vulnerabilità dei neuroni nella
depressione. Recenti scoperte mostrano che
un circuito molecolare, a partire dalla
viscosità della membrana, può modulare la
cascata di segnalazione che coinvolge le
proteine Gsα e la tubulina.

41. Post-synaptic Density Interactome
Interactome is defined “as the whole
molecular interactions that take place in
an organism and allow the cascade of
regulatory molecules including the
mechanism of action of enzymes and
metabolic reactions”. The interactions
between different proteins are in fact the
basic physiological mechanisms that
regulate and monitor the performance of
all bodily functions. Protein interaction
network decomposition reveals
functional modules and motifs.
(Rual et al, 2005, Towards a proteome-scale map
of the human protein–protein interaction network,
Nature, 437: 1173-1178.)
Recent data estimate approximately 650,000 human interactions between proteins
Stumpf MPH, Thorne T, de Silva E, Stewart R, Hyeong JA, Lappe M, Wiuf C. Estimating the size of the human interactome.
PNAS 2008; 105: 6959-6964

42. Protein- Protein Interaction

43. L’interazione Gsα – Tubulin
La principale interazione proteica da prendere in considerazione nella densità
post-sinaptica dell’interattoma, è l'interazione Gsα-tubulina. L’aumento della
Gsα catalizza la polimerizzazione dei MTs. Nella Depressione Maggiore la
diminuzione dell'interazione Gsα – Tubulina causa una riduzione del network
citoscheletrico e dei fenomeni quantistici molecolari implicati negli stati di
coscienza.
Layden BT, Saengsawang W, Donati RJ, Yang S, Mulhearn DC, Johnson ME, Rasenick MM.
Structural model of a complex between the heterotrimeric G protein, Gsalpha, and tubulin. Biochim
Biophys Acta. 2008; Jun;1783(6):964-73.
Gsα Giα

44. Gli antidepressivi e gli antipsicotici mostrano il loro effetto terapeutico con
una latenza di 2-6 settimane. Il fatto che la prima parte di questo periodo
(2 settimane) corrisponda al tempo di riorganizzazione del citoscheletro
neuronale suggerisce che gli agenti psicofarmacologici possono esplicare i
loro effetti clinici attraverso l'alterazione del citoscheletro.
Woolf N, Craddock T, Friesen D, Tuszynski J. Neuropsychiatric illness: a case for impaired
neuroplasticity and possible quantum processing derailment in microtubules. NeuroQuantology
2010; 8(1): 13-28.

45. 3
1
2

47. Alzheimer’s Disease
•Alzheimer’s disease (AD) is a prevalent
neurodegenerative disorder, and the major
cause of dementia in the elderly.
•Early symptoms, including inability to form
new memories, confusion, and mood
swings, can lead to loss of language, long-
term memory, bodily functions, and death.
•Although numerous therapeutic
approaches have been implemented, no
significantly useful treatments or cures are
available, other than recommendations to
exercise one’s mental facilities.
•With tens of millions of AD patients
worldwide requiring care, and more and
more reaching mid-60’s and older ages
when AD usually strikes, the disease
presents global medical, social and
economic problems of enormous proportion.

48. The brains of AD patients have three types of neuropathological lesions:
3)Extracellularly, excessive accumulation of the ∼4 kD peptide, known as Aβ,
derived from the β-amyloid precursor protein (APP), leads to amyloid (senile)
plaques and oligomers associated with impairment of LTP and synaptic
function
4)At the intracellular level, cortical neurons in the AD brain accumulate hyper-
phosphorylated tau, a MAP, which triggers the formation of neurofibrillary
tangles (NFTs).
5)Neurons in AD brain demonstrate impaired axonal transport, motor protein
transport along axonal MTs, and compromised MT networks.
Woolf suggested an imbalance of MAPs throughout brain neurons lead to
cytoskeletal breakdown in AD
R.E. Tanzi and L. Bertram. Twenty years of the Alzheimers disease amyloid hypothesis: A genetic perspective. Cell,
120(4):545–555, 2005.
A.D. Cash, G. Aliev, S.L. Siedlak, A. Nunomura, H. Fujioka, X. Zhu, A.K. Raina, H.V. Vinters, M. Tabaton, A.B.
Johnson, M. Paula-Barbosa, J. Avla, P.K. Jones, R.J. Castellani, M.A. Smith, and G. Perry. Microtubule reduction in
Alzheimer’s disease and aging is independent of tau filament formation. Am J Pathol, 162(5):1623–1627, 2003.
N.J.Woolf, A. Priel, and J.A. Tuszynski. Nanotechnology, nanostructure, and nervous system disorders. In
Nanoneuroscience: Structural and Functional Roles of the Neuronal Cytoskeleton in Health and Disease, pages 177–
226. Springer, Berlin; Heidelberg; New York, 2010.

49. Transcranial ultrasound (TUS)
TUS application of mechanical vibrations to the scalp, e.g. in the temporal region, in
the range between 20,000 Hz and 30 megahertz, shown to have electrophysiological
and behavioral effects in animals. Microtubules have been shown to have
resonances precisely in the range of TUS (e.g. 8 MHz).
Thus, TUS may promote microtubule activity, and is a potential therapeutic tool for
the treatment of AD.
Stabilization of the MT cytoskeleton by drug induced redistribution of zinc, or via
ultrasonic techniques may not only prevent tauopathy and NFT formation, but, in a
more general context, also ameliorate cognition based on the proposed role MTs in
information processing.

50. Along with actin filaments and other cytoskeletal components, MTs grow, reshape
and modify neurons and synapses.
Generally considered as merely cytoskeletal structural support, MTs have been
proposed to also function as intra-cellular information processing devices in which
subunit states represent and process fundamental information bits.
Y. Tufail, A. Matyushov, N. Baldwin, M.L. Tauchmann, J. Georges, and et al. Transcranial pulsed ultrasound stimulates
intact brain circuits. Neuron, 66:681–694, 2010.
S.S. Yoo, A. Bystritsky, J.H. Lee, Y. Zhang, K. Fischer, and et. al. Focused ultrasound modulates region-specific brain
activity. Neuroimage, 56:1267– 1275, 2011.

51. CONCLUSION
It seems to be consistent the hypothesis that Schrödinger proteins
interactoma and in particular the cytoskeleton nanowire network is
the best biological interface for potential expression of
consciousness, being typical and specific for each animal species
and that consciousness is always a potential. It’s very fascinating to
think that every animal possess a primary Schrödinger proteins
complex (cytoskeleton) and even in the absence of circulating
serotonin there is a potential of consciousness that is essential to
the behavior of some life forms, while other species such as
invertebrates, procariotes and even archea possess expertise in
their own domain probably mediated by their own Schrödinger
proteins interactoma.

52. A great leader should mix Science & Art, Public & Private, Politics &
Religions and think that this is the Creativity of Life.
(Massimo Pregnolato)
Thanks
Massimo Cocchi, Lucio Tonello , Fabio Gabrielli,
Stuart Hameroff, Mark Rasenick,
Jack Tuszynski, Travis Craddock,
Eliano Pessa, Paola Zizzi, Donald Mender
www.quantumbionet.org