Genome Wide Expressions

Consciousness and Cognition 21 (2012) 13221344
Contents lists available at SciVerse ScienceDirect
Consciousness and Cognition

journal homepage: www.elsevier.com/locate/concog
Genome-wide expression changes in a higher state of consciousness

Metka Ravnik-Glavac a,b,, Sonja Hraovec a, Jure Bon c, Jurij Dreu c, Damjan Glavac a
a
b
c
University of Ljubljana, Faculty of Medicine, Institute of Pathology, Department of Molecular Genetics, Ljubljana, Slovenia
University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Ljubljana, Slovenia
University Medical Centre, Department of Neurology, Laboratory for Cognitive Neuroscience, Ljubljana, Slovenia
a r t i c l e
i n f o
Article history:
Received 5 January 2012
Available online 27 June 2012
Keywords:
Whole genome gene expression
Higher state of consciousness
EEG monitoring
a b s t r a c t
Higher states of consciousness in which the human mind can transcend the boundaries of
logic and reason are envisioned as natural to the experience and potential growth of every
human being. So far they have been mostly monitored by electrophysiological methods. In
this study we were particularly interested in discovering the molecular transcriptional
basis of higher states of consciousness. In addition to phenomenological reports of meditators who participated in this study the generated higher states of consciousness were also
EEG recorded. We assessed the whole genome gene expression analysis of long-term meditators in four separate trials and detected signicant differential gene expression in association with higher states of consciousness. The number of differently expressed genes as
well as high proportion of genes themselves differed between meditators. Despite this,
gene ontology enrichment analysis found signicant biological and molecular processes
shared among meditators higher state of consciousness.
2012 Elsevier Inc. All rights reserved.
1. Introduction
Science and spirituality have been becoming closer and closer in recent years. Increasing basic scientic interest in the
effects of meditation, especially on the brain, has led to a dialogue between neuroscientists and prominent members of
the Buddhist tradition in order to foster research that aims at understanding in particular the neuroscientic aspects of consciousness and thus combines neuroscientic knowledge with more experiential or phenomenological perspective of meditators. It is important that science has accepted the role of introspection, or reporting personal mental experience as a form
of data (Barinaga, 2003). A neurophenomenology approach (Lutz, Brefczynski-Lewis, Johnstone, & Davidson, 2008; Lutz,
Lachaux, Martinerie, & Varela, 2002; Lutz, Slagter, Dunne, & Davidson, 2008; Varela, 1996) thus combines quantitative measures of neural activity with specic and stable experiential and phenomenal categories of the meditator who is generating
and describing them.
Several recent studies have reported the inuence of meditation on neural function (Brefczynski-Lewis, Lutz, Schaefer,
Levinson, & Davidson, 2007; Chan, Han, & Cheung, 2008; Hankey, 2006; Lutz, Greischar, Rawlings, Ricard, & Davidson,
2004; Lutz et al., 2008; Lutz et al., 2008; Pagnoni & Cekic, 2007; Travis & Shear, 2010). However, there are not many studies
on how meditation inuences peripheral biological processes important for health and illness, especially on the molecular
level using modern molecular approaches. It was shown recently with a gene expression studies that long-term and shortterm meditation practitioners may regulate immunity, metabolic rate, response to oxidative stress, cell death (Dusek, Otu,
Wohlhueter, Bhasin, & Zerbini, 2008; Engel, Fries, & Singer, 2001; Li, Li, Garcia, Johnson, & Feng, 2005; Sharma et al., 2008).
Althoug similar genomic pattern changes occurred overall, indicating a common relaxation response state in practitioners
Corresponding author.
E-mail address: metka.ravnik-glavac@mf.uni-lj.si (M. Ravnik-Glavac).
1053-8100/$ - see front matter 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.concog.2012.06.003
M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344
1323
regardless of the techniques used to elicit it, it was not clear from these studies what subjective levels of meditation were
achieved by different practices and practitioners. Larger groups of meditators are essential for the generalization of original
ndings, although it may unfortunately result in an averaging out of important details that might be specic to more advanced stages of consciousness developed by meditation techniques.
Meditation can be considered to be a universal human capacity, which, it is proposed, fosters clear thinking and openheartedness, thereby developing a greater sense of emotional balance and well-being (Ludwig & Kabat-Zinn, 2008). However,
there are reports of further states of the human mind, known to oriental thinkers for many centuries, in which the brain can
transcend the boundaries of logic and reason, and experience states of extended awareness, commonly unrecognized (Ramamurthi, 1995). The culminating state of awareness is a state of thoughtless awareness also known as the advanced stage of meditation (Hankey, 2006), the fourth state of consciousness (Ramamurthi, 1995), pure consciousness (Bloomeld, Cain, & Jaffe,
1975), Samadhi, Dhyana-Yoga, or enlightenment (Deshmukh, 2006). Maharishi Mahesh Yogi has systemized the understanding of the seven states of consciousness described in the ancient Vedic literature. English names for these states, on a continuum
from least aware to most aware, are deep sleep, dreaming sleep, waking, transcendental consciousness, cosmic consciousness, rened cosmic consciousness, and unity consciousness. These seven states are envisioned as natural to the
experience and potential growth of every human being. However, without a special technique or techniques, the top four states
are rarely if ever experienced. A few individuals in any generation may spontaneously experience one or more of the four higher
states, but during the present age, for most people these states are accessible only as a result of regular practice of a meditation
technique (Alexander et al., 1990; Travis & Pearson, 2000; Travis & Shear, 2010; Travis, Tecce, Arenander, & Wallace, 2002).
Gaining access to appropriate long-term meditators with authentic experience in advanced stages of consciousness is
rare. However, long-term meditators of Transcendental meditation techniques are described who have experienced periods
of pure consciousness characterized by breath suspension episodes without compensatory hyperventilation, accompanied
by high intra- and interhemispheric EEG coherence in alpha and theta frequencies, especially in the frontal areas of the brain,
periods of low metabolic rate and stable autonomic activity (Alexander et al., 1990; Orme-Johnson & Haynes, 1981; Travis &
Shear, 2010). They could also sustain the state of pure consciousness during sleeping and walking states indicating the
growth towards cosmic consciousness (Travis et al., 2002).
In this study, we were particularly interested in discovering the molecular transcriptional basis of higher states of
consciousness.
We designed this preliminary study in such a way as to show whether differences in the subjective perception of a precisely experienced and dened higher states of consciousness are connected with signicant and specic/consistent molecular genetic changes. In addition to phenomenological reports of the two long-term meditation practitioners who have
generated higher states of consciousness in four separate experiments these states of consciousness were EEG recorded
on a digital EEG system with a 128-channel cap using active electrodes. We report here the results of a whole genome
expression study of the higher states of consciousness compared to ordinary states of consciousness of a long-term meditator who is living ordinary life and a long-term Buddhist lama.
2. Subjects and methods
The study was approved in writing by the meditators in this study and National Medical Ethics Committee (Ref.: KME
164/07/09a).
2.1. Meditator 1
The meditation practitioner was a 52-year old Caucasian male with 23 years of meditation practices in several various
meditation techniques including Zen, Kriya yoga, Kundalini yoga, and Pranayama. His reports of clear experience of higher
states of consciousness corresponded well with other descriptions of this state (Alexander et al., 1990; Bloomeld et al.,
1975). He could retain higher state of consciousness (extended awareness) while living normal life for a few days after spontaneous switch into this state during meditation. He used Zen meditation technique according to Charles Brener (Berner &
Sosna, 2005) and Kundalini meditation.
2.2. Meditator 2
The meditation practitioner was a 41-year old Caucasian male who is involved in daily Buddhist meditation practices
since he was 16 years of age. According to his testifying he is trying to sustain the state of extended awareness most of
his time. For the purpose of this study he meditated on mental quietness and visualization of Buddha to enter into higher
states of consciousness.
2.3. Electroencephalography (EEG) monitoring
Meditators were comfortably seated on a chair in a sound attenuating, dimly lit chamber. EEG was recorded during rest
and meditation on a digital EEG system with a 128-channel cap using active electrodes (BrainAmp MR plus, ActiCAP, Brain
1324
Products GmbH). Before recording the subjects scalp was gel-abraded under each electrode to lower impedances under
5 kX. The analogue EEG signals were digitized at 500 Hz. The recording reference was at the FCz position, the ground electrode was at the AFz position. One-hundred and twenty-two electrodes were attached to the scalp with an additional six
positioned on the face and neck (one under each eye, two at the corners of the mouth and two on the neck just below
the ears).
The raw EEG data was rst visually inspected for overt artifacts, electrode pop or otherwise bad channels which were
excluded from subsequent analyses but were later interpolated back with spherical splines from the remaining good channels. The EEG was then ltered using a bandpass butterworth zero-phase lter (lower bound: 0.15 Hz at 48 dB/Oct; upper
bound: 30 Hz at 24 dB/Oct). Eye movement and blink artifacts were corrected using an Independent Component Analysis
(ICA) based method implemented in the Brain Analyzer 2 software (Brain Products GmbH) which was also used for all other
data analyses.
The FCz-recorded EEG was then either re-referenced to the average reference (AvrREF) (Niedermeyer & da Silva, 2005) or
transformed using the Spherical Spline Laplacian (SSL) (Nunez & Srinivasan, 2006) to increase spatial resolution and better
show the power changes in higher frequency ranges. All subsequent analyses, group comparisons and data depictions are
thus either AvrREF or SSL transformed EEG data. Changes in signal power were calculated by Complex Demodulation method
as averages for consecutive 50 s time intervals.
2.4. Sample preparation and processing
We obtained blood samples from Meditator 1 from two separate events. In both cases a blood sample was taken on the
next day, 15 h after switch to higher state of consciousness happened during previous evening meditation (test sample).
Control samples were taken during his ordinary state of consciousness (control sample). The spontaneous switch to higher
state of consciousness of Meditator 1 happened twice during our 1 year monitoring.
Blood samples from Meditator 2 were also obtained from two separate events. In both cases a blood sample was taken
before meditation (control sample) and 1 h after higher state of consciousness was generated through meditation (test
sample).
All blood samples were taken at approximately the same time of the day each time (between 12.30 pm and 2 pm) in order
to avoid circadian interference. The whole blood samples were transferred to PAXgene Blood RNA Tubes (BRT, PreAnalytix,
Qiagen), which contained a proprietary reagent composition based on a patented RNA stabilization technology. That reagent
composition protects RNA molecules from degradation by RNases and also minimizes ex vivo changes in gene expression.
Total RNA isolation was performed using a PAXgene Blood RNA Kit according to the manufacturers protocol. Concentration
and integrity inspection was performed on ND-1000 (Nanodrop, USA) and Agilent2100 using RNA 6000 Nano Labchip
(Agilent).
RNA samples were then further analyzed for transcriptional differences between different states of consciousness.
Those differences were assessed by micro array analysis. All four samples of Meditator 1 were used for cDNA synthesis
and hybridized on Affymetrix HG-U133 Plus 2.0 Gene Chips, visually inspected after the scanning process, during which no
artefacts were observed. Analysis of the quality of the GeneChips was also performed.
The ArrayStar Human LncRNA Array v2 was used to proling both LncRNAs (data not shown) and 30,215 coding RNA
transcripts in four samples (two test and two control samples) of Meditator 2. Sample labeling and array hybridization were
performed according to the Agilent One-Color Microarray-Based Gene Expression Analysis protocol (Agilent Technology)
with minor modications. Briey, mRNA was puried from 1 lg total RNA after removal of rRNA (mRNA-ONLY Eukaryotic
mRNA Isolation Kit, Epicentre). Then, each sample was amplied and transcribed into uorescent cRNA along the entire
length of the transcripts without 30 bias utilizing a random priming method. The labeled cRNAs were puried by RNAeasy
Mini Kit (Qiagen). The concentration and specic activity of the labeled cRNAs (pmol Cy3/lg cRNA) were measured by NanoDrop ND-1000. 1 lg of each labeled cRNA was fragmented by adding 11 ll 10 Blocking Agent and 2.2 ll of 25 Fragmentation Buffer, then heated the mixture at 60 C for 30 min, nally 55 ll 2 GE Hybridization buffer was added to dilute the
labeled cRNA. 100 ll of hybridization solution was dispensed into the gasket slide and assembled to the expression microarray slide. The slides were incubated for 17 h at 65 C in an Agilent Hybridization Oven. The hybridized arrays were washed,
xed and scanned with using the Agilent DNA Microarray Scanner (part number G2505B).
2.5. Data and statistical analysis
Normalization was performed using Affymetrix GeneChip Microarray Analysis Suite 5.0 (MAS5) software.
The data was loaded into Nexus Expression software (version 1, BioDiscovery Inc.) to identify a set of signicantly differentially expressed probes between group T and group N of the Meditator 1. Data was rst ltered for low variance probes
and all probes with variance less than 0.1 across selected samples were removed. We also ltered low intensity probes and
removed all probes with a value below 4.0 for 100% of all samples. All further statistical analysis was also performed using
Nexus Expression software. Thereafter, we compared samples to identify genes with signicantly different expression across
group T and group N. By using the Student t-test (p < .05), which also remained signicant at a 5% false discovery rate (FDR)
we compared expression results obtained from group T and group N. Input le provided from Nexus after normalization and
ltering procedures consisted of 54.613 probes, which passed all above mentioned criteria for all samples. Value Threshold
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was set at 0.05 and Log-Ratio Threshold at 0.1. Out of 54613 probes the 2266 had statistically signicant different expression
prole between group T and group N. Differentially expressed genes between groups test and control were separately analyzed using Gene Set Enrichment Analysis. We thus identied a large number of biologically relevant categories belonging to
a particular gene ontology category, which appeared more often than expected if the distribution had been random.
Agilent Feature Extraction software (version 10.7.3.1) was used to analyze acquired ArrayStar Human LncRNA Array v2
images. Quantile normalization and subsequent data processing were performed with using the GeneSpring GX v11.5.1 software package (Agilent Technologies). After quantile normalization of the raw data mRNAs were chosen for further data analysis. Differentially expressed mRNAs with statistical signicance were identied through Volcano Plot ltering (Fold
Change P 1.3, p-value 6 .05). Hierarchical Clustering was performed using the Agilent GeneSpring GX software (version
11.5.1). GO analysis were performed in the standard enrichment computation method.
2.6. Gene expression proling using real-time quantitative PCR
To validate whole-genome expression results obained from microarrays we performed a real-time PCR using Human
Mitochondria R2 Proler PCR Array (SABiosciences, Qiagen). cDNA was synthesized from 1000 ng of total RNA. The nnal
reaction volume of 10 ll was prepared according to the manufacturers protocol and included gDNA elimination buffer,
5 RT buffer, primer and external control mix, RT enzyme and dH2O. After reverse transcription, an experimental coctail
was prepared. Briey, real-time PCR mix included 2 SABioscience RT2qPCR Master Mix, ve time diluted rst strand cDNA
and dH2O to nnal volume of 25 ll. The reaction conditions were: initial denaturation at 95 C for 10 min and 40 cycles for
15 s at 95 C and 60 s at 60 C.Thermal cycling and urescence detection were performed using an ABI 7900HT Detection
system (Applied Biosystems).
For data analysis we used freely available on-line PCR Array Data Analysis Web Portal, which automatically performed
calculation and interpretation of the control wells upon including threshold cycle data from a real-time instrument. The
method used was DDCt Method. Fold-change was calculated as 2^(DDCt).
3. Results
The aim of the study was to elucidate whether a subjective but very well experienced state of higher consciousness generated by an experienced meditator can be followed/determined with molecular genetic tools or, in other words, whether
signicant transcriptional changes are induced by the process of the mind. We wanted to isolate as far as possible the expression changes of a higher state of consciousness. Thus, in order to exclude the possibility of a differential genome expression
prole due to a different personal genetic background or due to personal subjective experiences of awareness, in this primary
study we analyzed separately two long-term meditation practitioners during their higher states of consciousness and during
their ordinary states of consciousness. We also recorded EEG data of both mediators during their higher sates of
consciousness.
3.1. EEG results
The EEG signal changes are shown as scalp topographies of average power in different frequency ranges, calculated for
consecutive 50 s time intervals.
3.1.1. Meditator 1
Data were recorded from Meditator 1 while he was sustaining higher state of consciousness with eyes opened for 25 min.
Signal power increased in theta (47 Hz) (Fig. 1) and alpha (812 Hz) frequency range in continuous manner during mediation, mainly in parieto-occipital and frontal or fronto-central regions. Power changes in alpha 1 frequency range (810 Hz)
were most consistent with the time course of meditation (Fig. 2).
3.1.2. Meditator 2
Data were recorded from Meditator 2, while he was continuously meditating with eyes closed for 25 min. Signal power
increased in theta (47 Hz) (Fig. 3) and alpha (812 Hz) frequency range in continuous manner during mediation, mainly in
occipital regions. Power changes in alpha 1 frequency range (810 Hz, Fig. 4) were consistent with the time course of
meditation.
3.2. Whole genome gene expression analysis results
3.2.1. Meditator 1
Over a period of several months, Meditator 1 experienced during his meditation two spontaneous switches to higher state
of consciousness known among meditators as the rst stage of enlightenment or transcendental/cosmic consciousness. He
could retain this state of extended awareness for few days to a week. At the beginning, blood samples were taken several
times in his ordinary state of awareness. For the rst trial, a peripheral blood sample taken 3 days before the meditation
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Fig. 1. EEG signal changes are shown as scalp topographies of average power in theta (47 Hz) frequency range, calculated for consecutive 50 s time
intervals (Meditator 1).
switch to higher sate of consciousness was a control sample. A blood sample which was taken during higher state of consciousness was a test sample. This switch to higher state of consciousness happened during previous day evening meditation
and was sustained through meditation during EEG monitoring and blood sample taken on the next day around 12.30 pm
approximately 15 h after the switch to higher state of consciousness happened. In the second trial, which happened
7 months later a test sample was again taken within the novel higher state of consciousness but the control blood sample
was taken 2 weeks later, after complete remission to the meditators ordinary state of awareness. During this time mediator
lived his ordinary life. Transcriptional differences between the two control samples and the two test samples were assessed
by micro array analysis. Heatmaps generated using differently expressed genes in the two control and the two test samples
exhibited remarkably consistent gene expression proles across the two groups of samples (Fig 5). We performed Gene Set
Enrichment Analysis (GESA) (Subramanian et al., 2005) to identify gene ontology (GO) categories that were signicantly enriched with gene sets for test versus control samples.
3.2.2.1. GO analysis. 2266 differently expressed probe sets corresponding to 1668 unique genes. Of the 1668 genes that were
signicantly differently expressed between test and control samples, 1176 (70.5%) genes associated with GO biological process terms, 1226 (73.5%) with GO cellular component terms, and 1299 (77.9%) with GO molecular function terms.
3.2.2.2. GO biological process terms analysis. Over-represented GO biological processes/pathways with higher signicance
associated with higher sate of consciousness are summarized in Table 1, together with specic genes differently expressed
in our data-sets. The most highly enriched biological process terms with higher gene count and signicant down-regulation
in the state of higher consciousness included mRNA processing, RNA splicing, ubiquitin-dependent protein catabolic process,
small GTPase mediated signal transduction, anti-apoptosis, ubiquitin cycle, protein transport, and response to stress (Fig. 6a).
The most highly signicantly enriched down-regulated specic biological pathway connected with the state of higher consciousness (p = 1.91E12) was a pathway that is dominantly used to translocate secretory and membrane proteins, a cotranslational protein targeting to membrane pathway conserved throughout all kingdoms of life. Six (LOC1, SRP14, SSR1,
TRAM1, ARL6IP1 and SSR3) out of nine genes known to be involved in this pathway in human were found to be underexpressed in the samples of the state of higher consciousness compared to control samples. Additional more specic
1327
Fig. 2. EEG signal changes are shown as scalp topographies of average power in alpha 1 (810 Hz) frequency range, calculated for consecutive 50 s time
enriched down-regulated biological processes comprised spliceosome assembly, mRNA splice site selection (SFRS9, FUSIP1,
SFRS1, PTBP2), membrane fusion (GCA, SNAP23, VPS4B, PLDN, VAPA, NAPG,), sphingolipid metabolic process (SPTLC1, SERINC1, SGMS1, SGPP1, SGMS2), RNA catabolic process (RNASE2, PPP1R8, HNRPD, RNASE6, ISG20), chromosome segregation
(RAD21, SRPK1, PSEN1, STAG2, MRPL3, SMC3, NSL1, ARL8B), negative regulation of caspase activity, cell recognition (CLEC7A,
VCAN, ChGn, CNTNAP3), postreplication repair (UBE2B, MSH2, UBE2B), calciummediated signaling (IL8, CAMKK2, PIP5K3,
MCTP1, MCTP2, RCAN3) (see also Table 1).
Among up-regulated enriched GO biological process terms we detected more specic processes associated with higher
state of consciousness including erythrocyte maturation and development (KLF1, EPB42), induction of positive chemotaxis
(IL8, AZU1), heme biosynthetic process (ALAS2, ERAF), induction of apoptosis by intracellular signals (HIPK2, CUL4A), oxygen
transport; oxygen homeostasis (HBZ, HBD, ALAS2), anion transport (SLC4A1, SLC4A4), regulation of cell adhesion (LAMA2,
IL8), defense response to bacterium (LOC728320, DEFA4, AZU1) (Table 1).
3.2.2.3. GO molecular function terms analysis. Larger signicantly enriched down-regulated GO molecular functions associated
with higher state of consciousness are summarized in Table 2. A higher signicance between tests versus controls was detected for RNA binding molecular function (p = 1.21E12). Genes with higher fold changes detected in this molecular category included CPEB2, NUDT21, FUBP1, ZRANB2, PAPOLA, QKI. Additional signicantly down-enriched GO molecular
functions were ubiquitin-protein ligase activity (TRIM23, FBXL3, BIRC3, KIAA1333, UBR5, UBE2D1) GTP binding, GTPase
activity (RAB18, TRIM23, RAB11A, RAB2A, RAB8B, GNAQ), ligase activity, phosphoinositide binding, transcription coactivator
activity. More specic GO molecular functions signicantly enriched and down-regulated during higher state of consciousness included protein serine/threonine phosphatase activity (MTMR6, PPM1B, PPM2C, PTEN, PPP3CA), SMAD binding (TOB1,
ZEB2, ACVR1, PURA, TGFBR1), 7S RNA binding (SRP14, SRP9, SRP54, SRP72), RNA splicing factor activity, transesterication
mechanism (SMNDC1, SFRS10, FUSIP1, SF3B1, SFRS2IP, SLU7, SFRS4), Tat protein binding (LOC399804, RARA, MDFIC), calcium ion transmembrane transporter activity (ATP2B1, ITPR1, ITPR2, SLC8A1), histone binding (DEK, IPO7, ASF1A, SMARCA5,
SET), IkappaB kinase activity (ERLIN1, CHUK), DNA bending activity (HMGB1, HMGB2, LEF1, TRERF1), double-stranded DNA
binding (HNRPDL, SMAD2, PURA, MSH2, CGGBP1, PURB) (Table 2).
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Fig. 3. EEG signal changes are shown as scalp topographies of average power in theta (47 Hz) frequency range, calculated for consecutive 50 s time
Signicantly enriched up-regulated GO molecular functions connected with higher state of consciousness included hemoglobin/heme binding (HBD, ERAF, HBZ, EIF2AK1), anion exchanger activity (SLC4A1, SLC4A4, SLC6A8), oxygen transporter
activity (HBZ, HBD), transferase activity (TAT, ALAS2), antioxidant activity (PRDX2), antigen binding (IGHD, IGL@), structural
constituent of cytoskeleton (KRT1, ANK1, EPB42) (see also Table 2 and Fig. 6b).
3.2.2.4. GO Cellular component terms analysis. Golgi apparatus, Golgi membrane, endosome, endoplasmic reticulum membrane, condensed chromosome, chromosome telomeric region, PML body, cytosol and centrosome were GO cellular components signicantly enriched with down-regulated genes in higher state of consciousness. Up-regulated GO cellular
component detected by Gene Enrichment Analysis in the state of higher consciousness were hemoglobin complex, extracellular matrix (LAMA2, ADAMTSL4) and integral to Golgi membrane (FUT2, ST6GALNAC4) (Table 3).
3.2.3. Meditator 2
Meditator 2 is a Buddhist lama who is sustaining the state of extended awareness most of his time. In a period of few
months he came twice for monitoring EEG and taken of blood sample during higher states of consciousness. He generated
higher state of consciousness during 25 min meditations. Blood samples taken for gene expression analysis each time before
meditation were control samples and samples taken during higher state of consciousness were test samples. Transcriptional
differences between the two control samples and the two test samples were assessed by micro array analysis. We performed
a Volcano Plot ltering between test samples group and control samples group to identify differentially expressed mRNAs
with statistical signicance. The threshold was Fold Change P 1.3, p-value 6 .05. (Fig 7). 608 different genes passed these
criteria, 338 being signicantly up-regulated and 270 being signicantly down-regulated. We therefore did a Gene Set
Enrichment Analysis (GESA) (Subramanian et al., 2005) to identify gene ontology (GO) categories that were signicantly enriched with gene sets for test versus control samples. Fishers exact test was used to nd if there is more overlap between the
differently expressed list and the GO annotation list than would be expected by chance. The p-value 6 .05 denotes the signicance of GO terms enrichment in the differently expressed genes.
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Fig. 4. EEG signal changes are shown as scalp topographies of average power in alpha 1 (810 Hz) frequency range, calculated for consecutive 50 s time
Fig. 5. Analysis of differently expressed genes. Heatmap of 2266 signicantly differently regulated probe sets (p < 0.05, FDR 6 5%) between two states of
higher state of consciousness (1T and 2T, respectively) and two ordinary states of awareness (1N and 2N, respectively). Rows represent probe sets and
columns represent samples (controls: 1N, 2N; tests: 1T, 2T).
3.2.4.1. GO analysis. Of the 608 genes that were signicantly differently expressed in higher state of consciousness, 472
(77.6%) genes associated with GO biological process terms, 483 (79.4%) with GO molecular function terms, and 511 (84%)
with GO cellular component terms.
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Table 1
Gene Enrichment Analysis of signicantly differently regulated genes by biological processes (Meditator 1).
Process
p-Value
Fold
enrichment
Present
Total
Genes
Down regulated genes

Cotranslational protein targeting to membrane
mRNA processing
1.91E12
1.92E11
5.786
1.757
6
49
9
242
RNA splicing
2.89E12
1.794
43
208
SRP-dependent cotranslational protein targeting to

membrane
Ubiquitin-dependent protein catabolic process
.003
5.786
TLOC1, SRP14, SSR1, TRAM1, ARL6IP1, SSR3

NUDT21, ZRANB2, YTHDC1, PAPOLA, QKI,
SFRS12, FUSIP1, etc.
SNRPN, SFRS12, FUSIP1, SMNDC1, PTBP2,
LOC643167, PRPF4B, etc.
SRP14, SRP9, SRP54, SRP72
.004
1.774
28
137
Small GTPase mediated signal transduction
.005
1.564
42
233
Anti-apoptosis
.006
1.689
29
149
Spliceosome assembly
.009
3.254
16
Ubiquitin cycle
.009
1.394
67
417
Protein transport
.010
1.366
76
483
mRNA splice site selection

ER to Golgi vesicle-mediated transport
.010
.014
4.339
1.816
4
18
8
86
Protein refolding
Response to chemical stimulus
Chondroitin sulfate proteoglycan and polysaccharide
biosynthetic process
Blastocyst growth
Regulation of protein ubiquitination
Vesicle organization, biogenesis and fusion
Negative regulation of translational elongation
Negative regulation of T-helper 2 cell differentiation
Negative regulation of caspase activity
Cell recognition
Postreplication repair
Membrane fusion
Sphingolipid metabolic process
RNA catabolic process
Chromosome segregation
.015
.015
.015
8.679
8.679
8.679
2
2
2
2
2
2
.015
.015
.015
.015
.015
.016
.025
.027
.027
.028
.036
.040
8.679
8.679
6.943
8.679
8.679
3.857
3.471
4.339
2.604
2.712
2.712
2.104
2
2
4
2
2
4
4
3
6
5
5
8
2
2
5
2
2
9
10
6
20
16
16
33
Regulation of ossication
Negative regulation of cellmatrix adhesion
Macrophage activation
Regulation of MAPK activity
RNA polyadenylation
Response to X-ray
Negative regulation of gene expression; epigenetic
Negative regulation of cytokine secretion
Regulation of lipid kinase activity
Calcium-mediated signaling
.041
.041
.041
.041
.041
.041
.041
.041
.041
.042
5.786
5.786
5.786
5.786
5.786
5.786
5.786
5.786
5.786
2.367
2
2
2
2
2
2
2
2
2
6
3
3
3
3
3
3
3
3
3
22
Regulation of phosphoprotein phosphatase activity

Response to stress
.043
.045
3.719
1.621
3
17
7
91
.001
.001
.004
2.893
2.893
1.736
2
2
2
6
6
10
KLF1, EPB42
IL8, AZU1
ALAS2, ERAF
.005
.006
.012
.013
.017
1.335
1.736
0.868
0.827
4.339
2
3
2
2
1
13
15
20
21
2
HIPK2, CUL4A
HBZ, HBD, ALAS2
SLC4A1, SLC4A4
LAMA2, IL8
HIPK2
.017
4.339
Up regulated genes
Erythrocyte maturation and development
Induction of positive chemotaxis
Heme biosynthetic process; hemoglobin metabolic
process
Induction of apoptosis by intracellular signals
Oxygen transport; oxygen homeostasis
Anion transport
Regulation of cell adhesion
Positive regulation of transforming growth factor beta
receptor signaling pathway
Monocyte activation
PSMC6, USP6, USP32, USP10, UBR5, UBE2D1,

UBR5, etc.
RAB18, RIT1, TRIM23, RAP2C, LRRK2, RIT1,
PDK1, etc.
TXNDC1, BIRC3, BCL2A1, FAS, HIPK3, BNIP2,
HMGB1, etc.
SRPK2, SMNDC1, SNRPD2, SNRPE, SNRPG,
SFRS2IP
MIB1, RNF138, SENP6, USP6, UFM1, USP32,
FBXL3, etc.
RAB18, VPS36, CCDC91, RANBP6, CHMP5,
STAM2, STXBP3, etc.
SFRS9, FUSIP1, SFRS1, PTBP2
TXNDC1, GOPC, RAB2A, SEC24A, ERGIC2,
SEC23A, ERGIC2, etc.
HSP90AA1, MALAT1
RPS6KA5, BCL10
GALNACT-2, ChGn
NBN, CCDC16
RNF139, UBQLN1
ZFYVE16, EPS15, LRMP, EEA1
SRP14, SRP9
SOCS5, BCL6
HBXIP, DNAJB6, SFRS2, BIRC4
CLEC7A, VCAN, ChGn, CNTNAP3
UBE2B, MSH2, UBE2B
GCA, SNAP23, VPS4B, PLDN, VAPA, NAPG
SPTLC1, SERINC1, SGMS1, SGPP1, SGMS2
RNASE2, PPP1R8, HNRPD, RNASE6, ISG20
RAD21, SRPK1, PSEN1, STAG2, MRPL3, SMC3,
NSL1, ARL8B
ACVR1, PTGER4
RASA1, BCL6
TLR4, TLR1
TRIB1, TRIB2
PAPOLA, PAPOLG
MSH2, IKIP
CREBZF, EPC1
NLRP12, SRGN
RB1, RBL2
IL8, CAMKK2, PIP5K3, MCTP1, MCTP2,
RCAN3, etc.
PPP1R2, SAPS3, C13orf18, etc.
TXNDC1, PRKRIR, SERP1, HIF1A, PPP3CA,
CROP, SGK, etc.
AZU1
1331
Table 1 (continued)
Process
p-Value
Fold
enrichment
Present
Total
Glycerophospholipid metabolic process

Regulation of retroviral genome replication
Nitric oxide transport
Glycolipid metabolic process
Maintenance of epithelial cell polarity
Response to light stimulus
Complement activation; lectin pathway
G1/S transition of mitotic cell cycle
Defense response to bacterium
Regulation of vascular permeability
Glial cell migration
Hemopoiesis
Positive regulation of MHC class II biosynthetic process
Cellular extravasation
Negative regulation of proteolysis
Virushost interaction
Tetrapyrrole biosynthetic process
Regulation of mitochondrial membrane potential;
permeability
Aspartyl-tRNA aminoacylation
Macrophage chemotaxis
Cellular ion homeostasis
Regulation of embryonic development
Tyrosine catabolic process
Ceramide biosynthetic process
Neutrophil activation
Neurotransmitter uptake
Amino acid and derivative metabolic process
Negative regulation of survival gene product activity
.017
.017
.017
.017
.017
.017
.017
.023
.025
.025
.025
.033
.033
.033
.033
.033
.042
.042
4.339
4.339
4.339
4.339
4.339
4.339
4.339
0.620
0.347
2.893
2.893
2.170
2.170
2.170
2.170
1.736
2.170
1.736
1
1
1
1
1
1
1
2
3
1
1
2
1
1
1
1
1
1
2
2
2
2
2
2
2
28
75
3
3
34
4
4
4
4
5
4
.042
.042
.042
.042
.042
.042
.050
.050
.050
.050
1.736
1.736
1.736
1.736
1.736
1.446
1.446
1.446
1.446
1.446
1
1
1
1
1
1
1
1
1
1
5
5
5
5
5
5
6
6
6
6
Genes
PIP4K2A
IL8
HBD
ST6GALNAC4
ANK1
FECH
KRT1
GSPT1, CUL4A
LOC728320, DEFA4, AZU1
AZU1
AZU1
HBD, ERAF
AZU1
AZU1
CLN8
HIPK2
ALAS2
BCL2L1
C20orf27
AZU1
SLC4A1
LAMA2
TAT
CLN8
IL8
SLC6A8
TAT
BCL2L1
Fig. 6. GO enrichment analysis: (a) enriched down-regulated GO biological process terms with higher signicance and higher gene count and (b) enriched
up-regulated GO molecular function terms with higher signicance and higher gene count (Meditator 1).
3.2.4.2. GO biological process terms analysis. Over-represented down-regulated GO biological processes/pathways with higher
signicance and higher gene count associated with higher state of consciousness were regulation of cellular process, regulation of biological process, regulation of primary metabolic process, regulation of gene expression, signaling process, chromatin modication (Fig. 8a). Among up-regulated GO biological process terms enrichment was found in regulation of cell
death and apoptosis, negative regulation of cell death and apoptosis, signal transmission, immune system process and regulation of immune response, regulation of response to stimulus and regulation of response to stress (Table 4). More specic
down-regulated biological processes together with specic genes differently expressed in test versus control samples are
summarized in Table 4. and include catecholamine secretion (SNCA, GDNF, LY6E), T cell activation (ITGAL, IL7, SP3, JMJD6,
ERBB2, IL12A, NCK2, SLK, MAP3K7) ventricular cardiac muscle tissue development (LY6E, TNNC1, TNNC1), regulation of
nucleobase, nucleoside, nucleotide and nucleic acid metabolic process (GRIP1, ZMYND11, DNMT3A, DR1, D1, ZNF148, CALR,
ELK3, CREM, CRX), regulation of transcription, positive regulation of synaptic transmission,dopaminergic (GRIA4, SLC24A2,
1332
Table 2
Gene Enrichment Analysis of signicantly differently regulated genes by molecular function (Meditator 1).
Process
p-Value
Fold
enrichment
Present
Total
Genes

RNA binding
1.21E12
1.655
119
665
Protein serine/threonine phosphatase activity
.002
2.973
28
Ubiquitin-protein ligase activity
.002
1.822
26
132
SMAD binding
7S RNA binding
GTP binding
.002
.004
.005
3.964
5.285
1.443
6
4
56
14
7
359
RNA splicing factor activity; transesterication mechanism
.010
2.815
23
Tat protein binding

GDP binding
Calcium ion transmembrane transporter activity
Glucuronylgalactosylproteoglycan 4-beta-Nacetylgalactosaminyltransferase activity
Ceramide cholinephosphotransferase activity
Double-stranded telomeric DNA binding
Sphingomyelin synthase activity
mRNA binding
.011
.011
.012
.012
5.549
5.549
4.111
9.249
3
3
4
2
5
5
9
2
CPEB2, NUDT21, FUBP1, ZRANB2,

PAPOLA, QKI, DDX3Y, etc.
MTMR6, PPM1B, PPM2C, PTEN, PPP3CA,
PPP6C, PPM1D, etc.
TRIM23, FBXL3, BIRC3, KIAA1333, UBR5,
UBE2D1, UBE2W, etc.
TOB1, ZEB2, ACVR1, PURA, TGFBR1, PURB
SRP14, SRP9, SRP54, SRP72,
RAB18, TRIM23, RAP2C, LRRK2, RIT1,
ARL5A, RAB11A, etc.
SMNDC1, SFRS10, FUSIP1, SF3B1, SFRS2IP,
SLU7, SFRS4
LOC399804, RARA, MDFIC
TRIM23, ARL8B, RRAGC
ATP2B1, ITPR1, ITPR2, SLC8A1
GALNACT-2, ChGn
.012
.012
.012
.014
9.249
9.249
9.249
2.921
2
2
2
6
2
2
2
19
Protein self-association
GTP-dependent protein binding
GTPase activity
.021
.026
.030
4.624
3.363
1.441
3
4
31
6
11
199
Small conjugating protein ligase activity
.032
1.884
11
54
Histone binding
Poly(A) binding
Phospholipase A2 inhibitor activity
Hypoxanthine phosphoribosyltransferase activity
Apoptotic protease activator activity
Inositol 1;4;5-triphosphate-sensitive calcium-release
channel activity
IkappaB kinase activity
Protein-L-isoaspartate (D-aspartate) O-methyltransferase
activity
Ligase activity
.033
.033
.034
.034
.034
.034
2.720
3.964
6.166
6.166
6.166
6.166
5
3
2
2
2
2
17
7
3
3
3
3
SGMS1, SGMS2
TERF1, PURA
SGMS1, SGMS2
FMR1, GRSF1, HNRPD, PTBP2, PURB,
RBM25
BCL10, VIL2, DYRK1A
CDC42, EEA1, FNIP1, RAPGEF6
RAB18, TRIM23, RAB11A, RAB2A, RAB8B,
GNAQ, GNA13, etc.
UBE2D1, UBE2W, UBE2J1, UBE2Q2,
MRPL3, UBE2D2, RWDD4A, etc.
DEK, IPO7, ASF1A, SMARCA5, SET
TIA1, HNRPDL, SYNCRIP
ANXA1, ANXA3
HPRT1, MSH2
EBAG9, CASP8AP2
ITPR2, ITPR1
.034
.034
6.166
6.166
2
2
3
3
ERLIN1, CHUK
PCMT1, PCMTD1
.040
1.356
39
266
Guanyl nucleotide binding

Phosphoinositide binding
.041
.044
2.569
1.850
5
10
18
50
Transcription coactivator activity
.046
1.415
28
183
DNA bending activity

Double-stranded DNA binding
.047
.049
2.846
2.088
4
7
13
31
Caspase inhibitor activity

GTPase binding
.049
.049
3.468
3.468
3
3
8
8
MIB1, RNF138, SHPRH, KIAA1333, UBE1C,

UBR5, TOPORS, etc.
GNAI3, RAB5A, GNA13, GNAQ, GNAS
PIK3C2A, SGK3, SNAG1, SNX10, SNX13,
SNX14, SNX2, etc.
SUB1, ZEB1, ATF2, MED13, ZFX, NRIP1,
JMY, etc.
HMGB1, HMGB2, LEF1, TRERF1
HNRPDL, SMAD2, PURA, HMGB2, MSH2,
CGGBP1, PURB
TNFAIP8, SFRS2, BIRC4
RASA1, DOCK9, DOCK11
.001
.003
.006
.007
.008
.008
3.700
1.682
1.233
1.156
9.249
9.249
2
2
2
2
1
1
5
11
15
16
1
1
HBD, ERAF
SLC4A1, SLC4A4
HBZ, HBD
TAT, ALAS2
PSMF1
ST6GALNAC4
.008
.008
.008
.008
.015
.015
.015
.015
9.249
9.249
9.249
9.249
4.624
4.624
4.624
4.624
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
FECH
TAT
CTSB
HYI
C16orf35
ALAS2
ANK1
PRDX2
Up regulated genes
Hemoglobin binding
Anion exchanger activity
Oxygen transporter activity
Transferase activity; transferring nitrogenous groups
Proteasome inhibitor activity
(Alpha-N-acetylneuraminyl-2;3-beta-galactosyl-1;3)-Nacetyl-galactosaminide 6-alpha activity
Ferrochelatase activity
Tyrosine transaminase activity
Cathepsin B activity
Hydroxypyruvate isomerase activity
Alkylbase DNA N-glycosylase activity
5-Aminolevulinate synthase activity
Spectrin binding
Thioredoxin peroxidase activity
1333
Table 2 (continued)
Process
p-Value
Fold
enrichment
Present
Total
Genes
Anion transmembrane transporter activity

Creatine:sodium symporter activity
Toxin binding
Galactoside 2-alpha-L-fucosyltransferase activity
Selenium binding
Antigen binding
Interleukin-8 receptor binding
Eukaryotic translation initiation factor 2alpha kinase
activity
Sodium:bicarbonate symporter activity
Protease binding
Structural constituent of cytoskeleton
1-Aminocyclopropane-1-carboxylate synthase activity
Ucleoside-diphosphatase activity
Aspartate-trna ligase activity
Virion binding
Heme binding
.023
.023
.023
.023
.024
.025
.030
.030
3.083
3.083
3.083
3.083
0.597
0.578
2.312
2.312
1
1
1
1
2
2
1
1
3
3
3
3
31
32
4
4
SLC4A1
SLC6A8
AZU1
FUT2
HBD, SELENBP1
IGHD, IGL@
IL8
EIF2AK1
.030
.030
.033
.038
.038
.038
.045
.048
2.312
2.312
0.305
1.850
1.850
1.850
1.541
3
1
1
3
1
1
1
1
3
4
4
91
5
5
5
6
106
SLC4A4
ADAMTSL4
KRT1, ANK1, EPB42
TAT
ENTPD5
C20orf27
HIPK2
HBZ, HBD, EIF2AK1
Table 3
Gene Enrichment Analysis of signicantly differently regulated genes by cellular component (Meditator 1).
Process
pValue
Fold
enrichment
Present
Total
Genes

Golgi apparatus
.001
1.883
39
201
Centrosome
.046
1.941
12
60
Endosome
.003
1.906
32
163
Early endosome
.003
3.235
27
Golgi trans cisterna

Signal recognition particle; endoplasmic
reticulum targeting
Golgi membrane
.006
.009
7.28
4.853
3
4
4
8
SLC35A3, C4orf18, ATP7A, GOPC, RAB2A, RPGR,

SACM1L, etc.
NUDT21, PPP4R2, MARCKS, PCGF5, CEP57, NIN, APC,
etc.
TMEM55A, VPS36, SCYL2, ZFYVE16, PTP4A1, STX7,
RAB11A, etc.
RAB14, CLCN3, CHMP1A, ZFYVE16, SLC9A6, RAB5A,
RAB22A, etc.
SGMS1, GNAS, B4GALT1
SRP14, SRP9, SRP54, SRP72
.012
2.427
11
44
Nuclear chromosome; telomeric region

Lipopolysaccharide receptor complex
Condensed chromosome
Chromosome; telomeric region
Endoplasmic reticulum membrane
.014
.014
.018
.019
.024
9.706
9.706
3.467
3.065
2.069
2
2
5
6
13
2
2
14
19
61
PML body
Cytosol
.033
.034
3.033
1.478
5
51
16
335
Nuclear inner membrane

Autophagic vacuole
Trans-Golgi network transport vesicle
.039
.040
.040
6.471
4.16
4.16
2
3
3
3
7
7
Up regulated genes
Hemoglobin complex
Azurophil granule
Extra cellular matrix
Integral to Golgi membrane
Nuclear body
.094
.008
.035
.041
.048
2.24
9.706
0.539
0.498
1.618
3
1
2
2
1
13
1
36
39
6
COPB1, VDP, SLC35A1, TRIM23, MON2, SEC23A,

ARFGEF2, etc.
PURA, POT1
TLR4, BCL10
H2AFY, HMGB1, HMGB2, PAM, SMARCA5
HNRPD, NBN, POT1, RIF1, TERF1, TNKS2
TXNDC1, KTN1, SERINC1, DPM1, ASPH, LRMP,
ERLIN2, etc.
RB1, RNF6, MRPL3, SFRS2, ISG20
PSMC6, AKAP7, ANKRA2, ARFIP1, PTPN12, MALAT1,
SDPR, etc.
LOC727839, ATP11B
ATG5, MAP1LC3B, GABARAPL1
RAB14, ATP7A, GOPC
HBZ, HBD, ERAF

AZU1
LAMA2, ADAMTSL4
FUT2, ST6GALNAC4
HIPK2
SNCA), G1/S transition of mitotic cell cycle, cardiac muscle contraction, circadian rhythm (PER1, CREM, CRX, CYP7B1), bone
remodeling (IL7, ACP5, MITF), cortical actin cytoskeleton organization (EPB41, CALR), chromatin modication (HRAC1,
DNMT3A, CPA4, MORF4L1, EYA3, UBE2A, SNCA, JMJD6, EPC2, KDM5C), steroid hormone receptor signaling pathway, RNA stabilization (GDNF, ZBP1), phosphoinositide 3-kinase cascade, calcium ion transport (STIM2, SNCA, SLC24A2, SLK, CAMK2B,
CACNA1G), respiratory gaseous exchange (TNNC1, PSAP), DNA repair (PARP2, SLK, JMY, SMC5, RRM2B), glucose metabolic
process.
1334
Fig. 7. Volcano Plot of test versus control sets of Meditator 2. It visualizes the relationship between fold-change (magnitude of change) and statistical
signicance (which takes both magnitude of change and variability into consideration). The vertical lines correspond to 1.3-fold up and down, respectively,
and the horizontal line represents a p-value of .05. So the red point in the plot represents the differentially expressed mRNAs with statistical signicance.
(For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article.)
Fig. 8. GO enrichment analysis: (a) enriched down-regulated GO biological process terms with higher signicance and higher gene count and (b) enriched
up-regulated GO molecular function terms with higher signicance and higher gene count (Meditator 2).
Up-regulated specic GO biological process terms detected in connection with higher state of consciousness include glycerol metabolic process (GPD2, MGAT3, COQ3, MGAT2), regulation of lipid catabolic process (APOA5, MLYCD, GIMAP1, GIMAP5), positive regulation of JUN kinase activity (ERCC6, PAK1, SYK), regulation of T cell activation (GIMAP1, GIMAP5,
EFNB1, HGF, SYK, ADORA2A, SIT1), positive regulation of MAP kinase activity (HGF, ERCC6, PAK1, SYK, PAK1, PDGFB), positive
regulation of defense response (MICA, HGF, GIMAP1, GIMAP5, TLR2), mitochondrial transport (MTX2, TOMM5, TIMM8A),
negative regulation of apoptosis (GF, BCL2A1, SON, FAIM3, PIK3R2, ADORA2A, WFS1, XRCC4, HGF, AKT1S1), lipoprotein metabolic process (RABGGTA, PIGF, PIGV, APOA5, APOL1), positive regulation of calcium ion transport (GIMAP1, GIMAP5, WFS1),
protein targeting to mitochondrion (TIMM8A, MTX2, TOMM5), brain morphogenesis (GSX2, MKKS), sensory perception of
sound (MKKS, KCNE1, MYO7A, WFS1, KCNQ4), collagen biosynthetic process, regulation of membrane potential, positive regulation of ion transport, negative regulation of neuron apoptosis, membrane depolarization, ncRNA processing, ribonucleoprotein complex biogenesis. More detailed list of signicantly enriched up-regulated GO biological process terms together
with most signicantly differently expressed genes is summarized in Table 4.
3.2.4.3. GO molecular function terms analysis. Larger signicantly enriched down-regulated GO molecular function terms
associated with higher state of consciousness comprised protein binding, protein phosphatase binding, transcription factor
binding, kinase activity, transferase activity, transferring phosphorus-containing groups, calcium ion binding, cytoskeletal
1335
Table 4
Gene Enrichment Analysis of signicantly differently regulated genes by biological processes (Meditator 2).
Process
p-Value
Fold
Present
enrichment
Total
Genes

Regulation of cellular process
2.8E05
1.289
6759
136
1.265
7036
139
.000151
1.236
7412
143
Regulation of primary metabolic process
.002876
1.355
3310
70
Catecholamine secretion
T cell activation
.003025
.003576
10.114
2.956
19
195
3
9
Ventricular cardiac muscle tissue

development
Ventricular cardiac muscle tissue
morphogenesis
Cardiac ventricle morphogenesis
Regulation of macromolecule metabolic
process
Regulation of nucleobase, nucleoside,
nucleotide and nucleic acid metabolic
process
Regulation of transcription
.004057
9.150
21
CCNG1, GRIP1, ZMYND11, DNMT3A, DR1, ZNF148,

CALR, DUSP4, MAP3K7, RAPGEF2, etc.
CCNG1, GRIP1, ZMYND11, DNMT3A, DR1, ZNF148,
CALR, MAP3K7, IL12A, SNCA, etc.
CCNG1, GRIP1, ZMYND11, DNMT3A, DR1, ID1,
ZNF148, CALR, DUSP4, MAP3K7, etc.
GRIP1, ZMYND11, DNMT3A, DR1, ID1, ZNF148, CALR,
ELK3, CREM, CRX, REM2, ZNF610, etc.
SNCA, GDNF, LY6E
ITGAL, IL7, SP3, JMJD6, ERBB2, L12A, NCK2, SLK,
MAP3K7
LY6E, TNNC1, TNNC1
Regulation of biological process
5.8E05
Biological regulation
.004057
9.150
21
LY6E, TNNC1, TNNC1
.004644
.005314
8.735
1.330
22
3274
3
68
.005689
1.362
2822
60
.005848
1.381
2598
56
Cardiac ventricle development

Positive regulation of synaptic transmission
Regulation of cellular biosynthetic process
.005966
.005966
.006405
8.007
8.007
1.345
24
24
2952
3
3
62
G1/S transition of mitotic cell cycle

Cardiac muscle contraction
Regulation of nitrogen compound metabolic
process
Negative regulation of cellular biosynthetic
process
Covalent chromatin modication
.006577
.006702
.006905
5.338
7.686
1.350
48
25
2847
4
3
60
.007143
1.938
562
17
.007184
3.135
143
Regulation of biosynthetic process
.007334
1.337
2970
62
Cardiac muscle tissue morphogenesis

Muscle tissue morphogenesis
Circadian rhythm
Regulation of gene expression
.00749
.00749
.007599
.007972
7.391
7.391
5.124
1.341
26
26
50
2866
3
3
4
60
Cardiac chamber morphogenesis

Catecholamine transport
Positive regulation of transmission of nerve
impulse
Negative regulation of biosynthetic process
.008331
.008331
.008331
7.117
7.117
7.117
27
27
27
3
3
3
.008581
1.900
573
17
Regulation of metabolic process
.008605
1.286
3635
73
Signaling
.008764
1.258
4174
82
Cardiac chamber development

Positive regulation of neurological system
process
Positive regulation of endocytosis
Regulation of macromolecule biosynthetic
process
Negative regulation of biological process
.009225
.009225
6.863
6.863
28
28
3
3
.009225
.009287
6.863
1.336
28
2829
3
59
.009568
1.443
1820
41
Regulation of cellular metabolic process
.009849
1.289
3478
70
Dopamine secretion
Regulation of dopamine secretion
Signal release
Intracellular receptor-mediated signaling
pathway
.010055
.010055
.010055
.011642
12.811
12.811
12.811
3.681
10
10
10
87
2
2
2
5
LY6E, TNNC1, TNNC1

SNCA, ELK3, CREM, CRX, REM2, etc.
LY6E, TNNC1, TNNC1
GRIA4, SLC24A2, SNCA
RCC1, PPP6C, CAMK2B, CUL2
CACNA1G, TNNC1, TNNC1
AES, NCOR2, ELK3, RLIM, PER1, etc.
DNMT3A, CPA4, MORF4L1, EYA3, UBE2A, SNCA,
JMJD6
LY6E, TNNC1, TNNC1
LY6E, TNNC1, TNNC1
PER1, CREM, CRX, CYP7B1
ELK3, CREM, CRX, REM2, ZNF610,0, etc.
LY6E, TNNC1, TNNC1
SNCA, GDNF, LY6E
AES, NCOR2, ELK3, RLIM, PER1, , etc.
ZNF148, CALR, SNCA, ELK3, CREM, CRX, , etc.
ELK3, DUSP4, MAP3K7, RAPGEF2, GDNF, SNCA,
YWHAZ, AES, MITF, CSNK1G1, BAIAP2, etc.
LY6E, TNNC1, TNNC1
CALR, SNCA, CBLL1
GDNF, IL7, SNCA, YWHAZ, CBLL1, etc.
ZNF148, CALR, SNCA, ELK3, CREM, CRX, REM2, etc.
SNCA, GDNF
GDNF, SNCA
SNCA, GDNF
GRIP1, GRIP1, NCOA1, CALR, CREM
(continued on next page)
1336
Table 4 (continued)
Process
p-Value
Fold
Present
enrichment
Up regulated genes
Glycerol metabolic process
Alditol metabolic process
Regulation of lipid catabolic process
Response to X-ray
Regulation of response to stress
4
4
4
3
12
24
26
28
15
272
9.808
9.053
8.407
11.769
2.596
Total
Genes
0.000662
0.000906
0.001209
0.001896
0.002431
Positive regulation of JUN kinase activity

Regulation of alpha-beta T cell activation
Positive regulation of alpha-beta T cell
differentiation
Regulation of T cell activation
Regulation of JUN kinase activity
Photoreceptor cell maintenance
T cell activation
4
4
3
34
34
18
6.923
6.923
9.808
GPD2, MGAT3, COQ3, MGAT2

MGAT3, COQ3, MGAT2, GPD2
APOA5, MLYCD, GIMAP1, GIMAP5
IKBIP, ERCC6, XRCC4
MICA, KLK3, HGF, GIMAP1, GIMAP5, TLR2, ERCC6,
PAK1, SYK, PDGFB, etc.
0.002528 ERCC6, PAK1, SYK, PAK1
0.002528 GIMAP1, GIMAP5, ADORA2A, SYK
0.003275 GIMAP1, GIMAP5, SYK
7
4
3
9
116
38
22
195
3.551
6.194
8.024
2.716
0.003648
0.003817
0.00588
0.006188
Regulation of alpha-beta T cell differentiation

Polyol metabolic process
Positive regulation of MAP kinase activity
Positive regulation of alpha-beta T cell
activation
Positive regulation of defense response
Positive regulation of innate immune
response
Activation of JUN kinase activity
Cilium assembly
Regulation of defense response
Mitochondrial transport
Positive regulation of T cell activation
Regulation of cell activation
3
4
6
3
23
45
101
24
7.676
5.231
3.496
7.356
0.006678
0.007024
0.007502
0.007537
5
4
72
47
4.086
5.008
0.007554 MICA, HGF, GIMAP1, GIMAP5, TLR2

0.008191 MICA, GIMAP1, GIMAP5, TLR2
3
3
7
5
5
8
25
25
137
75
75
172
7.061
7.061
3.007
3.923
3.923
2.737
0.008459
0.008459
0.008934
0.008946
0.008946
0.009209
Cellular component maintenance

Alpha-beta T cell activation
Immune response
3
4
22
26
49
759
6.790
4.804
1.706
0.009444
0.009477
0.010261
Regulation of MAP kinase activity

Negative regulation of apoptosis
7
13
141
370
2.921
2.068
0.010373
0.010824
Regulation of humoral immune response

Subpallium development
Positive regulation of CD4-positive, alpha
beta T cell differentiation
Regulation of mitochondrial membrane
permeability
Regulation of lymphocyte activation
Negative regulation of programmed cell
death
Positive regulation of T cell differentiation
Regulation of neuron apoptosis
Negative regulation of cell death
2
2
2
10
10
10
11.769
11.769
11.769
0.01183
0.01183
0.01183
ERCC6, PAK1, SYK

BBS10, MKKS, IFT172
MICA, KLK3, HGF, GIMAP1, GIMAP5, TLR2, ADORA2A
MTX2, TOMM5, TIMM8A, GIMAP1, GIMAP5
GIMAP1, GIMAP5, EFNB1, HGF, SYK
PDGFB, GIMAP1, GIMAP5, EFNB1, HGF, SYK,
ADORA2A, SIT1
ERCC6, BBS10, MKKS
GIMAP1, GIMAP5, SYK, ADORA2A
MICA, TLR2, HGF, GIMAP1, GIMAP5, MNX1, YTHDF2,
XRCC4, SYK, etc.
HGF, GPS1, ERCC6, PAK1, SYK, PDGFB, PAK1
HGF, BCL2A1, SON, FAIM3, PIK3R2, ADORA2A, WFS1,
XRCC4, etc.
GIMAP1, GIMAP5
MKKS, GSX2
GIMAP1, GIMAP5
10
11.769
0.01183
GIMAP1, GIMAP5
7
13
145
375
2.841
2.040
3
5
13
29
82
379
6.087
3.588
2.018
Mitochondrial membrane organization

Positive regulation of calcium ion transport
Cilium morphogenesis
3
3
3
30
30
30
5.885
5.885
5.885
GIMAP1, GIMAP5, EFNB1, HGF, SYK, ADORA2A, SIT1

ERCC6, PAK1, SYK, PAK1
ERCC6, BBS10, MKKS
GIMAP1, GIMAP5, XRCC4, EFNB1, HGF, SYK, MICA,
etc.
GIMAP1, GIMAP5, SYK
MGAT3, COQ3, MGAT2, GPD2
HGF, ERCC6, PAK1, SYK, PAK1, PDGFB
GIMAP1, GIMAP5, SYK
0.011975 GIMAP1, GIMAP5, EFNB1, HGF, SYK, ADORA2A, SIT1

0.012004 HGF, BCL2A1, SON, FAIM3, PIK3R2, GIMAP1, HGF,
GIMAP5, etc.
0.012787 GIMAP1, GIMAP5, SYK
0.012861 ADORA2A, WFS1, XRCC4, AKT1S1, GRID2
0.013018 HGF, BCL2A1, SON, FAIM3, PIK3R2, GIMAP1, HGF,
GIMAP5, etc.
0.014033 TIMM8A, GIMAP1, GIMAP5
0.014033 GIMAP1, GIMAP5, WFS1
0.014033 BBS10, MKKS, IFT172
protein binding, DNA binding, sequence-specic DNA binding, enzyme binding. More specic down-regulated molecular
function included transcription cofactor activity. JMY, GRIP1, NCOA1, AES, DR1, ELK3, NFIL3, RLIM, NCOR2, CREM, ELK4 were
genes with higher fold changes detected in this molecular category. Genes involved in receptor signaling complex scaffold
activity, which was also found to be signicantly enriched molecular function down-regulated between tests and controls
included GRIP1, NCK2, G3BP2. Chromatin binding represented with differently expressed genes like MORF4L1, RCC1, CRX,
DNMT3A, MITF, SP3, NCOA1 was another GO molecular function signicantly down-regulated in association with higher
state of consciousness. More detailed list of enriched down-regulated GO molecular function terms together with most
highly differently expressed genes between test and control samples is summarized in Table 5.
1337
Signicantly differently up-regulated genes found enrichment in specic GO molecular function terms like structural constituent of ribosome (MRPL21, MRPL42, MRPL18, MRPS10, MRPS14, MRPL1, MRPL33), nuclease activity (EXOSC3, TSEN2,
RNASEN, OGG1, RAD51C, ASTE1, FANCM), racemase and epimerase activity (MCEE, AMACR), collagen binding (PAK1, PDGFB,
SERPINH1), acetylglucosaminyltransferase activity (MGAT3, MGAT2, B3GNT8), voltage-gated chloride channel activity
(CLCNKB, CLIC2), ionotropic glutamate receptor activity (GRIA3, GRID2), NADH dehydrogenase activity (NDUFA8, NDUFB5,
NDUFV3) (see Table 5 and Fig. 8b).
3.2.4.4. GO cellular component terms. Intracellular organelle, nucleus, intracellular membrane-bounded organelle, cytosol,
cytoskeleton, intracellular non-membrane-bounded organelle and membrane-enclosed lumen were signicantly enriched
down-regulated GO cellular component terms with most abundant gene count (see Table 6) in test set compared to control
set. More specic down regulated cellular down-enriched components included cell cortex (EPB41, SPTBN4, MPP1, SEPT6,
NCL, NEDD9, SNCA), peroxisomal part (AP2M1, IDE, MVD), stereocilium (MPP1, PCDH15), nuclear speck (PYHIN1, DDX3X,
PRPF40B, SFRS18, EFTUD2), cell projection (BAIAP2, PCDH15, ERBB2, C2CD3, ZBP1, NEDD9, PLD1, NEFL, SPTBN4, SNCA,
GRIA4, CACNA1G, MPP1, PDE9A, STAU1, IQGAP1).
Most signicantly enriched cellular component detected in associated with higher state of consciousness was mitochondrion. Additional enriched cellular component terms with signicant up-regulated gene sets included intracellular membrane-bounded organelle, organellar ribosome, voltage-gated potassium channel complex, cilium (MYO7A, PKD1, MKKS,
IFT172, NPHP4, CABYR), mitochondrial respiratory chain complex I (NDUFA8, NDUFB5, NDUFV3), very-low-density lipoprotein particle (APOA5, APOL1) (detailed list in Table 6).
The validation of genome expression results obained from microarrays is shown for two test and two control samples of
Meditator 2 with real-time PCR using R2 Proler PCR Array (Fig. 9).
4. Discussion
Meditation has become an increasingly popular practice worldwide. The criteria of successful meditation practice are
understood both in terms of properly practicing a specic technique and in terms of achieving the aim of the meditation,
such as stress reduction, calmness of mind or spiritual enlightenment (Ospina et al., 2007). The majority of studies to date
have focused on the effects of meditation on brain functions and have shown that the combination of neuroimaging and neurodynamics is a particularly promising methodological approach to revealing obvious neurophysiology changes induced by
meditation (Lutz, Slagter, et al., 2008). Furthermore, it was shown that different meditation techniques or categories, which
include focused attention, open monitoring and automatic self-transcending have been associated with different EEG frequency bands. Open monitoring meditation category was found to be associated with increased frontal midline theta EEG
frequency bands (58 Hz) and connected with Vipassana and Zen meditation techniques. Automatic self transcending category associated with increased frontal alpha 1 (810 Hz) power and coherence and was found in connection with Transcendental meditation technique (Travis & Shear, 2010). EEG monitoring results of Meditator 1 and Meditator 2 in our study
revealed signicantly increased in both theta (57 Hz) frequency band as well as alpha 1 (810 Hz) frequency band. Increased theta (57 Hz) EEG frequency bands of Meditator 1 and Meditator 2 in our study is consistent with their meditation
techniques used to elicit higher state of consciousness, while increased alpha 1 (810 Hz) frequency band is in concordance
with the state of higher (transcendental) consciousness reported so far only in connection with Transcendental meditation
practices and in one long-term Qigong practice meditator (Travis & Pearson, 2000; Travis & Shear, 2010). Meditator 1 in our
study has in both cases experienced the switch to higher state of consciousness during a 3 day meditation retreat to the
mountain area. Meditation technique used was a Zen meditation according to Charles Brener (Berner & Sosna, 2005) accompanied with Kundalini meditation that included rising of energy from lower parts of the body into the head mentally, by
breathing and visualization. Since he was out in the mountain, the blood sample was taken for genetic analysis as well as
EEG monitoring was performed on the next day between noon and 1 pm while he was still sustaining higher state of consciousness. Higher states of consciousness that were experienced during meditation and could subsequently co-existed with
walking and sleeping states were reported in long-term practitioners of the Transcendental meditation and were connected
with the so called stabilized higher states of consciousness (Mason et al., 1997; Travis et al., 2002). The state of the mind
during the higher state of consciousness, according to the report of the Meditator 1 in our study, is free from any selsh motivation, instinctual pressure and mental conict, a state in which the energy ow through the body is as if there is no resistance of the body and egotistic structures disappear. In this state one can live naturally with spontaneity, presence and
natural wisdom. It is unitary, undifferentiated, reality-consciousness, an essential being, which can only be experienced
by spontaneous intuition and self-understanding. There is a natural sense of well-being, with self-understanding, spontaneous joy, serenity, freedom, and self-fullment. In Maharishis interpretation of the Vedic literature on higher states of consciousness, the fourth state, transcendental consciousness, is also referred to as pure consciousness when it occurs without
thoughts, feelings, or perceptions. It is understood as awareness by itself, without content. With repeated experience of the
transcendental consciousness state, as happens for brief periods during each practice session of the Transcendental
Meditation technique, more of that transcendental consciousness begins to be experienced along with the active waking
state of consciousness. When the two states are nally present together at all times, this denes the fth state of consciousness, termed cosmic consciousness (Alexander et al., 1990). Meditator 1 of our study could sustain this state of higher
1338
Table 5
Gene Enrichment Analysis of signicantly differently regulated genes by molecular function (Meditator 2).
Process
p-Value
Fold
enrichment
Present
Total

Protein binding
.000105913
3.975052771
150
8137
Phosphatase binding
Transcription factor binding
.000599171
.002416536
3.45833729
3.222448985
5
16
46
480
Binding
.002526489
2.616806782
204
12540
Receptor signaling complex scaffold activity

Transcription cofactor activity
.002689572
.005790184
2.597482638
2.570316813
3
12
19
344
Protein complex scaffold

Chromatin binding
Transcription repressor activity
.005976164
.00621939
.006371612
2.237307617
2.22357751
2.2062522
3
7
11
25
145
305
Androgen receptor binding

Sugar binding
.007435228
.008421672
2.19575067
2.128705732
3
8
27
192
Guanylate kinase activity

Intramolecular transferase activity,
phosphotransferases
Kinase activity
.011232551
.011232551
2.074601673
1.949521587
2
2
11
11
.01171298
1.949521587
20
769
Transcription corepressor activity

Calcium channel regulator activity
Cytoskeletal adaptor activity
Ubiquitin protein ligase binding
Steroid hormone receptor binding
Nuclear hormone receptor binding
Phosphatidylinositol binding
Carboncarbon lyase activity
Heat shock protein binding
Transferase activity, transferring
phosphorus-containing groups
Carbohydrate kinase activity
Hormone receptor binding
Calcium ion binding
.017139052
.018044956
.018044956
.01901828
.020380558
.021798502
.023333945
.024781633
.024942728
.02746192
1.931332594
1.766013193
1.743644179
1.743644179
1.720828752
1.69078392
1.661573343
1.632011825
1.605870077
1.603056043
6
2
2
3
3
4
2
3
4
21
137
14
14
38
39
71
16
42
74
894
.032291042
.034607398
.036185363
1.561269108
1.490917937
1.460831053
2
4
21
19
82
921
Phosphoric diester hydrolase activity

Cytoskeletal protein binding
.037318698
.037817129
1.441467064
1.428073515
4
13
84
499
DNA binding
.037980755
1.422311442
45
2318
Phosphotransferase activity, alcohol group

as acceptor
Sequence-specic DNA binding
.038506213
1.420436411
17
710
.043368452
1.41446919
15
614
Nucleotide kinase activity

Phosphatase regulator activity
Pyridoxal phosphate binding
Vitamin B6 binding
Enzyme binding
.045953736
.047047209
.047047209
.047047209
.048416451
1.362826075
1.337679178
1.327466133
1.327466133
1.327466133
2
3
3
3
13
23
54
54
54
518
Vitamin binding
Tubulin binding
30 ,50 -Cyclic-nucleotide phosphodiesterase
activity
.048457245
.049353429
.049647977
1.315007052
1.314641284
1.306682672
5
4
2
132
92
24
Up regulated genes
Structural constituent of ribosome
.014705932
2.729476292
157
Nuclease activity
.014705932
2.729476292
157
Racemase and epimerase activity

Hexosaminidase activity
Collagen binding
Nucleoside kinase activity
.015746557
.018411169
.019184698
.021251013
10.20304233
9.418192918
5.247278912
8.745464853
2
2
3
2
12
13
35
14
Genes
DNAJB9, CALR, ERBB2, SLK, IL1RL1, ELK4, JMY,

GRIP1, NCOA1, etc.
STAU1, ERBB2, PIK3R1, SNX3, IQGAP1
ELK4, JMY, GRIP1, NCOA1, AES, DR1, ELK3, NFIL3,
RLIM, etc.
DNAJB9, CALR, CDK9, ZBP1, SEPT9, PDE10A,
LMTK3, REM2, DDX3X, etc.
GRIP1, NCK2, G3BP2
JMY, GRIP1, NCOA1, AES, DR1, ELK3, NFIL3, RLIM,
NCOR2, etc.
GRIP1, NCK2, G3BP2
MORF4L1, RCC1, CRX, DNMT3A, MITF, SP3, NCOA1
AES, DR1, ELK3, NFIL3, RLIM, NCOR2, GRIP1, ID1,
SP3, ZNF148, CALR
GRIP1, CALR, NCOA1
GK, GRIP1, GALNT1, CLEC2B, PSAP, PSAP, CALR,
CLEC2B
MPP1, CASK
PGM1, PGM2L1
ELK3, GK, GK, MPP1, CASK, HK1, LMTK3,
CSNK1G1, MAPK6, etc.
AES, DR1, ELK3, NFIL3, RLIM, NCOR2
TNNC1, STIM2
BAIAP2, NCK2
ERBB2, UBE2A, CUL2
GRIP1, CALR, NCOA1
GRIP1, CALR, NCOA1, GRIP1
EPB41, PIK3R1
MVD, CSAD, ACLY
ERBB2, MVD, SNCA, DNAJB9
ELK3, CHRAC1, GK, GK, MPP1, CASK, HK1, LMTK3,
CSNK1G1, etc.
GK, HK1
GRIP1, NCOA1, GRIP1, CALR
RASGRP1, SLC24A2, PLCB1, SLC24A2, GALNT1,
ITGAL, etc.
PLCB1, PLD1, PDE10A, PDE9A
JMY, EPB41, MYO1E, HK1, SPTBN4, TNNC1, MYOT,
TNNC1, etc.
SP3, ZNF148, ZBP1, SSBP3, FUBP1, CREM, CRX,
TSC22D3, etc.
ELK3, GK, GK, HK1, LMTK3, CSNK1G1, MAPK6,
MAP3K7, etc.
ELK3, MITF, NCL, ELK3, CREM, CRX, DR1, ELF2,
ELK4, etc.
MPP1, CASK
PPP2R5A, PPP4R1, ZEB2
ALAS1, CSAD, SHMT2
ALAS1, CSAD, SHMT2
PLD1, STAU1, PLK1S1, TNNC1, ERBB2, PIK3R1,
SNX3, etc.
ALAS1, CSAD, SHMT2, DHTKD1, P4HA1
HK1, SNCA, SLK, STMN1
PDE10A, PDE9A
MRPL21, MRPL42, MRPL18, MRPS10, MRPS14,

MRPL1, MRPL33
EXOSC3, TSEN2, RNASEN, OGG1, RAD51C, ASTE1,
FANCM
MCEE, AMACR
HYAL1, HYAL1
PAK1, PDGFB, SERPINH1
TK2, TK2
1339
Table 5 (continued)
Process
p-Value
Fold
enrichment
Present
Total
Genes
Acetylglucosaminyltransferase activity
Protein kinase C activity
Protein disulde oxidoreductase activity
Acylglycerol O-acyltransferase activity
Voltage-gated chloride channel activity
Ionotropic glutamate receptor activity
NADH dehydrogenase activity
NADH dehydrogenase (ubiquinone) activity
NADH dehydrogenase (quinone) activity
Extracellular-glutamate-gated ion channel
activity
Disulde oxidoreductase activity
Voltage-gated anion channel activity
Transferase activity, transferring amino-acyl
groups
DNA binding
.023863513
.024259701
.024259701
.024259701
.027431005
.034237331
.034901501
.034901501
.034901501
.037860669
4.83302005
8.162433862
8.162433862
8.162433862
7.652281746
6.802028219
4.173971861
4.173971861
4.173971861
6.444026734
3
2
2
2
2
2
3
3
3
2
38
15
15
15
16
18
44
44
44
19
MGAT3, MGAT2, B3GNT8

PRKD2, PAK1
CLIC2, GLRX
MGAT3, MGAT2
CLCNKB, CLIC2
GRIA3, GRID2
NDUFA8, NDUFB5, NDUFV3
GRIA3, GRID2
.037860669
.045519589
.045519589
6.444026734
5.830309902
5.830309902
2
2
2
19
21
21
GLRX, CLIC2
CLCNKB, CLIC2
TGM6, TGM6
.046594463
1.26767739
48
2318
Oxidoreductase activity, acting on NADH or

NADPH
Ion channel activity
.04694519
2.9502773
83
.048126047
1.772107352
11
380
ALKBH2, OGG1, DMRT2, GSX2, MNX1, ZNF167,

TBX1, MLX, etc.
CYB5R2, NDUFA8, NDUFB5, NDUFV3
GRIA3, GRID2, CLCNKB, CLIC2, TRPM5, KCNE1,
KCNQ4, etc.
consciousness for approximately a week each time after peak switch into this consciousness, then it gradually resolved into
his ordinary state of awareness. The similarities between the experience described by Meditator 1 and experiences of those
who are noticing the growth of cosmic consciousness through Transcendental Meditation (Alexander et al., 1990; Travis &
Pearson, 2000) are striking.
Meditator 2 in our study was a Buddhist lama who is living most of his time in a state of higher awareness. His EEG was
monitored during meditation aiming at achievement higher state of consciousness. Blood samples for this study were taken
in each trial before meditation and after meditation on the same day, approximately 1 h apart.
For the purpose of this study he did meditations of two kinds that included mental quietness, which aims at a maximum
pacication of the mind, very little thoughts and peace; and visualization, aiming at seeing oneself as a Buddha and keeping
this visualization as stable as possible. When either of the aim was achieved, according to Meditator 2, the mind was peaceful, concentrated without tension, without disturbed emotions like desire or irritation.
The results of our preliminary study indicated that there were distinct differences in gene expression between higher
states of consciousness of both Meditators compared to their ordinary states of awareness. However, the number of differently expressed genes as well as the majority of genes themselve associated with higher states of consciousness differed between Meditator 1 and Meditator 2. Despite this, differently expressed genes associated with both meditators higher states
of consciousness were found to be involved in some shared more general biological and molecular processes. The number of
signicantly differently expressed genes connected with higher state of consciousness of maditator 1 was 1668. The majority
of differently expressed genes 1559/1668 (93.5%) were found to be down-regulated in higher state of consciousness and
over-expression was detected in 109 (6.5%) genes. In higher sates of consciousness of Meditator 2 we detected 608 differently expressed genes, 338 (55.6%) being signicantly up-regulated and 270 (44.4%) being signicantly down-regulated.
Nevertheless, more than hundred (118) signicantly differently expressed similar genes have been detected to be shared
in association with higher states of consciousness of Meditator 1 and Meditator 2. Among over-expressed common genes we
found ankyrins (ANK), alkylation repair homologs (ALKBH), ADP-ribosylation factors ((ARF), laminins (LAMA). Ankyrins are a
family of proteins that link the integral membrane proteins to the underlying spectrinactin cytoskeleton and play key roles
in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains.
Multiple isoforms of ankyrin with different afnities for various target proteins are expressed in a tissue-specic, developmentally regulated manner. The Alkylation repair homologs (ALKBH) proteins are a sub-family of 2OG oxygenases that are
dened by homology to the Escherichia coli DNA-methylation repair enzyme AlkB which is a part of the adaptive response
mechanism of DNA alkylation damage repair. ADP-ribosylation factors ((ARF) belong to family of GTP-binding proteins with
possible role in membrane-associated intracellular trafcking and apoptosis. Laminins (LAMA), a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide
variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis (http://www.ncbi.nlm.nih.gov/gene/).
Results revealed that majority of common genes that showed connection with higher states of consciousness of both
meditators were under-expressed (110 genes). Selected shared genes and their products are summarized in Table 7.
ZNF148, ELK3, DR1, AES, ZEB2, are involved in negative regulation of transcription, BAZ1A, Elf2, ZNF600, JMY, SP3, MEF2A,
FUBP1 are involved in positive regulation of transcription. AES acts as dominant repressor of gene expression towards other
family members. It inhibits NF-kappa-B-regulated gene expression and may be required for the initiation and maintenance
1340
Table 6
Gene Enrichment Analysis of signicantly differently regulated genes by cellular component (Meditator 2).
Process
p-Value

Intracellular
2.07E05
Intracellular part
Present
Total
Genes
1.17465475
194
11049
4.45E05
1.176883632
188
10687
Intracellular organelle
.000194
1.203546239
162
9005
Organelle
.000212
1.201944536
162
9017
Nucleus
.000448
1.325938672
101
5096
Intracellular membrane-bounded
organelle
Membrane-bounded organelle
.002011
1.188277007
143
8051
.002086
1.187392104
143
8057
Cytoskeletal part
.003657
1.783071067
25
938
Cytosol
.003725
1.641738072
32
1304
Cytoskeleton
.00429
1.611479761
33
1370
Cell cortex
Non-membrane-bounded organelle
.004546
.005257
3.418290402
1.402968788
7
54
137
2575
Intracellular non-membranebounded organelle

Actin cytoskeleton
.005257
1.402968788
54
2575
.005557
2.593055289
10
258
Cell leading edge

Peroxisomal matrix
Microbody lumen
Organelle part
.007136
.013305
.013305
.015426
3.142991846
11.15013774
11.15013774
1.21936792
7
2
2
89
149
12
12
4883
Striated muscle thin lament

Intracellular organelle lumen
.01557
.017398
10.29243484
1.414708628
2
38
13
1797
Endocytic vesicle membrane

Stereocilium
Microvillus
Nuclear body
.017634
.017988
.020295
.021376
5.424391333
9.557260921
5.146217419
2.531382622
3
2
3
7
37
14
39
185
Cytoplasmic part
.022932
1.202711487
88
4895
Stereocilium bundle
Organelle lumen
.023261
.023953
8.362603306
1.383150928
2
38
16
1838
Cortical cytoskeleton
Nuclear speck
Cell cortex part
Membrane-enclosed lumen
.026244
.027344
.028207
.031211
4.66749952
2.96021356
3.475367608
1.356580259
3
5
4
38
43
113
77
1874
Microtubule cytoskeleton
.034024
1.724883186
14
543
Intracellular organelle part
.03559
1.184573003
86
4857
Microbody part
Peroxisomal part
Cell projection
Cytoplasm
.040629
.040629
.046877
.047888
3.935342732
3.935342732
1.585797368
1.120435235
3
3
16
124
51
51
675
7404
Nuclear chromatin
.049035
3.649135988
55
RASGRP1, ARFIP1, GLG1, ZDHHC3, PLD1, LPCAT1, PER1,

CBLL1, etc.
PPP2R5A, BAZ1A, RCC1, UBE2A, DNMT3A, TPX2, EIF2C1,
SCEL, KRT35, etc.
SCEL, KRT35, SEPT9, SNRPN, ACP5, ELK3, ALAS1, NNT, PSAP,
etc.
RASGRP1, ARFIP1, GLG1, ZDHHC3, SNRPN, ACP5, ELK3,
ALAS1, etc.
BAZ1A, RCC1, SNRPN, ANKLE2, EIF3A, PARP2, CDK9,
PYHIN1, DUSP4, etc.
PLCB1, SSBP3, PRPF40B, SFRS18, C10ORF137, EPC2, ZBTB20,
ID1, etc.
ALAS1, NNT, PSAP, GK, HK1, P4HA1, DHTKD1, ACOT13,
SHMT2, YWHAZ, etc.
TPX2, KRT35, SEPT9, EIF3A, CNKSR2, PLK1S1, IL1RL1, MPP1,
SFI1, etc.
PIK3R1, MAP3K7, IDE, NEFL, RASGRP1, AP2M1, PRICKLE1,
PLCB1, GRIP1, etc.
TPX2, SCEL, KRT35, SEPT9, EIF3A, CNKSR2, PLK1S1, IL1RL1,
MPP1, SFI1, etc.
EPB41, SPTBN4, MPP1, SEPT6, NCL, NEDD9, SNCA
BAZ1A, RCC1, PPP2R5A, UBE2A, DNMT3A, TPX2, SCEL,
KRT35, etc.
DNMT3A, TPX2, SCEL, KRT35, SEPT9, EIF3A, SMC5, PARP2,
CDK9, etc.
SEPT9, TNNC1, TNNC1, IQGAP1, EPB41, SPTBN4, MYO1E,
SNCA, etc.
BAIAP2, ZBP1, NEDD9, PLD1, PDE9A, JMY, IQGAP1
IDE, MVD
IDE, MVD
BAZ1A, RCC1, etc.
TNNC1, TNNC1
EIF3A, PARP2, CDK9, PYHIN1, DUSP4, GK, NCL, PTBP1,
CAMK2B, MPP1, etc.
AP2M1, GRIA4, CAMK2B
MPP1, PCDH15
MPP1, PCDH15, ERBB2
EFTUD2, SPTBN4, PYHIN1, DDX3X, PRPF40B, SFRS18,
NCOR2
EIF2C1, etc.
MPP1, PCDH15
CAMK2B, MPP1, etc.
EPB41, SPTBN4, MPP1
PYHIN1, DDX3X, PRPF40B, SFRS18, EFTUD2
EPB41, SPTBN4, MPP1, SEPT6
CAMK2B, etc.
TPX2, CNKSR2, PLK1S1, IL1RL1, MPP1, SFI1, CEP350, SEPT6,
etc.
BAZ1A, etc.
AP2M1, IDE, MVD
AP2M1, IDE, MVD
BAIAP2, PCDH15, ERBB2, C2CD3, ZBP1, NEDD9, PLD1, etc.
EIF2C1, TNNC1, etc.
DNMT3A, MORF4L1, RCC1
Up regulated genes
Mitochondrion
1.67E05
2.0870453
37
1067
.001728
1.1811412
158
8051
Intracellular membrane-bounded
organelle
Fold
enrichment
BIK, MTX2, GIMAP5, NLRX1, TOMM5, TIMM8A, GPD2,

NDUFA8, etc.
BET1, CHST14, GBGT1, SLC26A11, B3GNT8, MGAT2, MGAT3,
etc.
1341
Table 6 (continued)
Process
p-Value
Fold
enrichment
Present
Total
Genes
Membrane-bounded organelle
Organellar ribosome
Mitochondrial ribosome
Voltage-gated potassium channel
complex
Potassium channel complex
Mitochondrial part
.001797
.007591
.007591
.013615
1.1802616
5.122202
5.122202
3.5403455
158
4
4
5
8057
47
47
85
PNPLA8, SYBU, EXOSC3, TSEN2, SPESP1, SPAG8, PCGF2, etc.

MRPL18, MRPS14, MRPL1, MRPL42
MRPL1, MRPL42, MRPL18, MRPS14
KCNE1L, KCNMB4, KCNE1, KCTD15, KCNQ4
.013615
.014631
3.5403455
1.7615378
5
18
85
615
Exosome (RNase complex)

Cilium
Ribosome
Intracellular
.016264
.017448
.017837
.022978
10.030979
2.9122197
2.4317525
1.0839885
2
6
8
199
12
124
198
11049
Intracellular part
.025034
1.0869162
193
10687
Mitochondrial respiratory chain

complex I
NADH dehydrogenase complex
Respiratory chain complex I
Cytoplasmic part
.034364
4.1990144
43
KCNE1L, KCNMB4, KCNE1, KCTD15, KCNQ4

BIK, MTX2, GIMAP5, NLRX1, TOMM5, TIMM8A, GPD2,
NDUFA8, etc.
EXOSC3, C1D
MYO7A, PKD1, MKKS, IFT172, NPHP4, CABYR
MRPL18, MRPS14, MRPL1, MRPL42, MRPL21, etc.
etc.
PNPLA8, SYBU, FBXO8, FBXO4, EXOSC3, C1D, TSEN2, PES1,
etc.
.034364
.034364
.040337
4.1990144
4.1990144
1.1680609
3
3
95
43
43
4895
Very-low-density lipoprotein particle

Triglyceride-rich lipoprotein particle
.042929
.042929
6.0185874
6.0185874
2
2
20
20

etc.
APOA5, APOL1
APOA5, APOL1
Fig. 9. Heatmap representing qRT-PCR results of two control and two test samples of Meditator 2 for validation of microarray results.
of the differentiated state. Forced expression of AES in healthy neurons resulted in cell death (Zhang, Chen, Jaramillo, Wang,
& Dmello, 2008). DR1 gene encodes a TBP- (TATA box-binding protein) associated phosphoprotein that represses both basal
and activated levels of transcription. The encoded protein is phosphorylated in vivo and this phosphorylation affects its
interaction with TBP. This protein contains a histone fold motif at the amino terminus, a TBP-binding domain, and a glutamine- and alanine-rich region. The binding of DR1 repressor complexes to TBP-promoter complexes may establish a mechanism in which an altered DNA conformation, together with the formation of higher order complexes, inhibits the assembly
of the preinitiation complex and controls the rate of RNA polymerase II transcription (http://www.ncbi.nlm.nih.gov/gene/).
BAZ1A gene encodes the accessory subunit of the ATP-dependent chromatin assembly factor (ACF), a member of the ISWI
(imitation switch) family of chromatin remodeling complexes (Racki et al., 2009). Junction-mediating and regulatory
protein (JMY) is a novel p53 cofactor that regulates p53 activity during stress. JMY interacts with p300/CBP, which are
ubiquitous transcriptional co-activators that interact with a variety of sequence-specic transcription factors, including
hypoxia-inducible factor-1a (HIF-1a). In addition, JMY is an actin-nucleating protein, which, through its WH2 domains,
stimulates cell motility. It was shown also that interplay between JMY and HIF-1a represent mechanism that controls cell
motility under hypoxic stress (Coutts et al., 2011).
Another common genes associated with test group of all samples belonged to signal transduction process. G3BP2, CD164,
ELK3, RASGRP1, NEDD9, RAPGEF2 were some of the representatives of these genes. RAPGEF2 for example is a member of the
RAS subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive
1342
Table 7
Selected shared genes and their products among both meditators in association with higher state of consciousness.
Gene
EntrezID
Product
UBE2A
BAZ1A
ZNF148
DNAJB9
SFRS18
G3BP2
CD164
CCNG1
ELK3
DR1
EIF3A
ZC3H13
HERPUD2
GK
ELF2
AES
DDX3X
SLK
RRM2B
ZNF600
RASGRP1
NEDD9
CLEC2B
GPBP1L1
GALNT1
RAPGEF2
P4HA1
ZBP1
ZEB2
PPP6C
JMY
SP3
MEF2A
FUBP1
ARFIP1
RICTOR
SNRPN
MAP3K7
7319
11177
7707
4189
25957
9908
8763
900
2004
1810
8661
23091
64224
2710
1998
166
1654
9748
50484
162966
10125
4739
9976
60313
2589
9693
5033
81030
9839
5537
133746
6670
4205
8880
27236
253260
6638
6885
Ubiquitin-conjugating enzyme E2A (RAD6 homolog)

Bromodomain adjacent to zinc nger domain, 1A
Zinc nger protein 148
DnaJ (Hsp40) homolog, subfamily B, member 9
Splicing factor, arginine/serine-rich 18
GTPase activating protein (SH3 domain) binding protein 2
CD164 molecule, sialomucin
Cyclin G1
ELK3, ETS-domain protein (SRF accessory protein 2)
Down-regulator of transcription 1, TBP-binding (negative cofactor 2)
Eukaryotic translation initiation factor 3, subunit A
Zinc nger CCCH-type containing 13
HERPUD family member 2
Glycerol kinase
E74-like factor 2 (ets domain transcription factor)
Amino-terminal enhancer of split
DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked
STE20-like kinase
Ribonucleotide reductase M2 B (TP53 inducible)
Zinc nger protein 600
RAS guanyl releasing protein 1 (calcium and DAG-regulated)
Neural precursor cell expressed, developmentally down-regulated 9
C-type lectin domain family 2, member B
GC-rich promoter binding protein 1-like 1
UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 1 (GalNAc-T1)
Rap guanine nucleotide exchange factor (GEF) 2
Prolyl 4-hydroxylase, alpha polypeptide I
Z-DNA binding protein 1
Zinc nger E-box binding homeobox 2
Protein phosphatase 6, catalytic subunit
Junction mediating and regulatory protein, p53 cofactor
Sp3 transcription factor
Myocyte enhancer factor 2A
Far upstream element (FUSE) binding protein 1
ADP-ribosylation factor interacting protein 1
RPTOR independent companion of MTOR, complex 2
Small nuclear ribonucleoprotein polypeptide N
Mitogen-activated protein kinase kinase kinase 7
GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF2, serve as RAS activators by
promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and
RAS activation (Rebhun, Castro, & Quilliam, 2000).
In addition, several genes involved in the cell cycle were signicantly differentially expressed in tests versus controls. In
this cell cycle part of the gene sets, the majority of genes encoded regulators of cell cycle progression, including CCNG1,
NEDD9, PPP6C, JMY. DNA repair function of genes like SLK, RRM2B, UBE2B were found to be suppressed in connection with
higher states of consciousness. This could be partly explained by detected overall down-regulation of several biological and
cellular processes associated with higher state of consciousness.
In association with higher states of consciousness of both meditators we also detected sets of transcripts signicantly enriched in epigenetic mechanisms. Genes involved in chromatin modication including HRAC1, DNMT3A, CPA4, MORF4L1,
EYA3, UBE2A, SNCA, JMJD6, EPC2, KDM5C were signicantly under-expressed in test samples of Meditator 2 and set of genes
involved in chromatin modication including SMARCA5, SMARCE1, CHD9, TLK1, ASF1A, CBX3, HMGB1, RB1, HDAC2, UBE2A,
JMJD6, BMI1, H2AFY, MLL3, RCBTB1, MORF4L2, EPC1, TBL1XR1, as well as those involved in histone acetylation including
EID1, H2AFV, H2AFY, H2AFZ, HAT1, HDAC2, HIF1A, PCAF, SET were signicantly down-regulated in test samples of Meditator
1, showing that some gene regulation mechanisms were mediated through epigenetic control.
Mitochondrion was a cellular component most signicantly (p = 1.666E05) differently enriched and over-regulated in
connection with higher state of consciousness of Meditator 2. Associated with higher state of consciousness of this Meditator
we detected also increased expression of genes involved in glutamate transport, glutamate receptors and calcium ion transport. All these events together might contribute to the initiation of the process of neurosynaptic plasticity (Cheng, Hou, &
Mattson, 2010) and showing on the molecular level that higher states of consciousness generated through meditation inuence synaptic plasticity of the brain.
We could hypothesize that differences in gene expression signature associated with higher states of consciousness of
Meditator 1 and Meditator 2 are mostly due to their different level of ordinary awareness connected to their way of living.
For Meditator 1, the spontaneous switch to higher state of consciousness during intensive process of meditation probably
1343
represented bigger difference for the molecular biology of his body than in the case of Meditator 2. Namely, Meditator 2
according to his phenomenological report is sustaining higher state of awareness during his normal life style. The EEG analysis of both Meditators during their higher state of consciousness revealed similar increase in frequency bands in theta and
alpha 1 frequency range. Increased Alpha 1 frequency band was previously connected with higher (transcendental) state of
consciousness (Travis & Shear, 2010). It is very likely also that different meditation techniques contributed to different
expression of genes. It is also possible that results of molecular genetic analyses more reected the differences the body
needed to overcome in order the mind senses the subjective state of higher state of consciousness than the state of mind
itself. It was proposed also that the rate of transcending to higher (transcendental) consciousness may vary from person
to person, and often from meditation to meditation, owning to the difference in the mind and body when meditator sits
to meditate (Travis & Shear, 2010).
We can conclude that we have shown for the rst time with our preliminary study that the higher state of consciousness
is associated with signicant changes in gene expression. We detected common and different GO biological process and
function terms associated with higher states of consciousness of different meditators. Common biological functions associated with higher states of consciousness of both meditators in this study included general down regulation of metabolic and
cell cycle processes, signaling, protein transport, regulation of gene expression, DNA repair, epigenetic mechanisms. Immune
system activity, apoptotic processes were both up and down-regulated, as well was the response to stress. We observed less
similarities in over-expressed molecular and biological processes among higher states of consciousness of both meditators
than in under-expressed processes. While the higher state of consciousness of Meditator 1 was characterized by up-regulation of genes involved in hemoglobin synthesis, transport of oxygen and nitric oxide, signicantly enrichment in glutamate
transport, ionotropic glutamate receptor activity as well as NADH dehydrogenase activity was observed in connection with
higher state of consciousness of Meditator 2.
Additional studies with more advanced meditation practitioners are needed to discover whether there is a common gene
expression prole generated by higher state of consciousness of meditators who are using similar meditation techniques, for
example transcendental meditation technique. The impact on health and well-being of the detected complex gene expression changes induced by higher state of consciousness is important to discover. It would also be interesting to discover
whether individual genetic background could inuence the ability to achieve higher state of consciousness among long-term
meditation practitioners.
Acknowledgments
We gratefully acknowledge the Meditators in this study. We also thank Andrej Zupan, Emanuela Botjancic and Gregor
Pir for technical assistance.
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Consciousness and Cognition

Genome-wide expression changes in a higher state of consciousness

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

Down regulated genes

SRP-dependent cotranslational protein targeting to

TLOC1, SRP14, SSR1, TRAM1, ARL6IP1, SSR3

Small GTPase mediated signal transduction

mRNA splice site selection

Regulation of phosphoprotein phosphatase activity

PSMC6, USP6, USP32, USP10, UBR5, UBE2D1,

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

Glycerophospholipid metabolic process

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

Down regulated genes

Protein serine/threonine phosphatase activity

Ubiquitin-protein ligase activity

RNA splicing factor activity; transesterication mechanism

Tat protein binding

CPEB2, NUDT21, FUBP1, ZRANB2,

Small conjugating protein ligase activity

Guanyl nucleotide binding

Transcription coactivator activity

DNA bending activity

Caspase inhibitor activity

MIB1, RNF138, SHPRH, KIAA1333, UBE1C,

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

Anion transmembrane transporter activity

Down regulated genes

Golgi trans cisterna

SLC35A3, C4orf18, ATP7A, GOPC, RAB2A, RPGR,

Nuclear chromosome; telomeric region

Nuclear inner membrane

COPB1, VDP, SLC35A1, TRIM23, MON2, SEC23A,

HBZ, HBD, ERAF

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

Down regulated genes

Regulation of primary metabolic process

Ventricular cardiac muscle tissue

CCNG1, GRIP1, ZMYND11, DNMT3A, DR1, ZNF148,

Regulation of biological process

LY6E, TNNC1, TNNC1

Cardiac ventricle development

G1/S transition of mitotic cell cycle

Regulation of biosynthetic process

Cardiac muscle tissue morphogenesis

Cardiac chamber morphogenesis

Regulation of metabolic process

Cardiac chamber development

Regulation of cellular metabolic process

LY6E, TNNC1, TNNC1

M. Ravnik-Glavac et al. / Consciousness and Cognition 21 (2012) 13221344

Positive regulation of JUN kinase activity

GPD2, MGAT3, COQ3, MGAT2

Regulation of alpha-beta T cell differentiation