1

Challenges to free will: transgenerational epigenetic information,

unconscious processes and vanishing twin syndrome
Reviews in the Neurosciences, In press
1
Bókkon, I., 2Vas J. P., 3Császár, N., 4Lukács, T.
2013
∗
1
Professor at Vision Research Institute, USA ∗Corresponding author
2
Supervisor Psychotherapist, Head of Psychotherapy Department, Borsod University Hospital,
Miskolc, Hungary
3
Head of Psychotherapy Department, National Center for Spinal Disorders, Budapest, Hungary
4
Special family therapist and consultant, Budapest, Hungary

∗
Corresponding author: István BÓKKON
His mail address: Hungary, H-1238, Budapest, Láng E. 68.
His email address: bokkoni@yahoo.com
His phone number: +36 30/506 5272
His fax number: +36 1 217-0914

Abstract
Here, we present various research results and thoughts with the intention of challenging
notions about free choice. Namely, we describe the concept of transgenerational transmission
of epigenetic information and discuss its nonconscious effects on cognitive abilities,
behavioral and emotional patterns and responses with regards to one's life and decisions, and
the impact these have on the concept of free will. In addition, we discuss the essential role of
unconscious mechanisms in human decision processes. We also show that twin loss in the
womb can have a powerful life-long impact on the surviving twin through nonconscious
context-dependent epigenetic changes. Finally, we hypothesize that human explicit self-
consciousness may be an active executer that intermediates between unconsciousness and the
external environment by means of feedback and feed-forward interactions. This executive
function makes it possible for self-consciousness to continuously develop in self-organized
evolution.

Keywords: free will, transgenerational epigenetic information, unconscious mechanisms,

vanishing twin syndrome
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Introduction
Free will is one of the most confusing philosophical questions. In classical philosophy, the
existence of free choice involves a debate between compatibilism and incompatibilism.
Compatibilists claim that free will can be compatible with determinism, while
incompatibilists argue the opposite (Caruso, 2012). The general opposition to compatibilism
is that it repeals moral responsibility. According to compatibilism, all causes of our choices
have previous causes and prior conditions such as genetic and environmental factors which
are beyond our control and form our character. In contrast, Spinoza and Laplace as hard
incompatibilists believed that we do not have free will because determinism is real. In
contrast, soft incompatibilists such as Eccles and Penrose claim that we have free will because
determinism is false (De Ridder et al., 2013). The free will debate is essentially dependent on
the belief that free choice is necessary for moral responsibility.
However, it is probable that the question of real free will cannot be understood if we
look at it exclusively from ethical, philosophical or moral grounds. This is analogous to
denying the discovery of atomic energy on behalf of moral responsibility, as the existence and
application of atomic energy has major and significant effects on our lives and on the fate of
the world. In addition, if there is no real freedom of choice it does not mean that there are no
consequences, since we live in an interconnected and self-regulating system (i.e. the world,
universe) in which all pieces of the system can mutually define each other and determine
behaviors and relationships. Any given individual is a complex part of a very complex living
and non-living world. If a person wants to make himself/herself separate from the world (with
a really and completely free choice), he/she could not exist, because an individual can exist
only in relation to other existing living and non-living entities (Bókkon, 2003). In the next
sections we raise some scientific results and novel thoughts that may challenge our notion
about the existence of real free will.

Epigenetics and transmission of transgenerational epigenetic information

Epigenetics is considered a bridge between genotype and phenotype and refers to changes in
the phenotype (appearance) or gene expression created by mechanisms other than changes in
the underlying DNA sequence. In other words, epigenetics refers to the heritable changes in
our genome that are transmitted through mitosis and meiosis by stable mechanisms and take
place without altering the DNA sequence (genetic code) itself. Epigenetics processes include
direct covalent methylation of DNA, post-translational modification of histone proteins tails,
including methylation, acetylation, ubiquitination and phosphorylation, regulatory non-coding
 3

RNAs such as microRNA (miRNA), PIWI-interacting RNA (piRNA)) and long noncoding
RNAs (lncRNAs) as well as hormones (Grentzinger et al., 2012; Shilatifar, 2006; Zhang and
Ho, 2011; Nelson and Nadeau, 2010; Csaba, 2011; Mercer and Mattick, 2013). Epigenetics
mechanisms concurrently change the chromatin structure and dynamically modulate gene
expression. Chromatin fibers are composed of repeating units of nucleosomes where DNA is
wound around histone octamers’ cores such as H2A, H2B, H3, and H4 (Kornberg and Lorch,
1999; Richmond and Davey, 2003). Histone modifications can directly influence chromatin
structure, gene transcription and epigenetic information, and are linked to various cellular
processes such as chromosome condensation, gene expression, and DNA repair (Cayuso Mas
et al., 2011; Gu et al., 2010; Banerjee and Chakravarti, 2011). Inheritance of DNA
methylation patterns is an essential mechanism involved in epigenetic cell memory
transmission from mother cell to daughter cell (Weaver et al., 2004; Champagne, 2008).
These epigenetic processes allow cells to obtain and maintain a molecular fingerprint in
response to internal or external factors. Several studies suggested that anomalous epigenetic
states (epimutations) are linked to human diseases (Whitelaw and Whitelaw, 2008). Other
studies have revealed diverse factors such as environmental agents, parental behaviors,
maternal physiology, nutrition, and xenobiotics as capable of producing epigenetic changes
which can be transmitted to subsequent generations without continued exposition (Nadeau,
2009).
It is important to distinguish the difference between “context-dependent” (within the
individual’s own life history, mitotically stable, non-germline epigenetic imprint) and
“germline-dependent” (inherited from previous generations, meiotic stable, germline
epigenetic imprint) epigenetic modifications when we study epigenetic processes (Crews,
2008). In addition, germline-dependent epigenetic modifications are not tantamount to
genomic imprinting where genes are monoallelically expressed and depended on the parent-
of-origin of alleles (Davies et al., 2008). Genomic imprinting, also referred to as gametic or
parental imprinting, represents a subset of genes that are silenced and influence development,
however, silencing of genes is not conveyed to the next generation.

Epigenetic regulation of brain function: Transgenerational epigenetic information and

its nonconscious effects
Epigenetic regulation plays crucial roles in most of brain functions and can mediate various
experience-driven changes in the central nervous system (CNS) which are later manifested at
molecular, cellular, neural network, and behavioral levels in the adult brain. Several
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experiments have revealed that epigenetic mechanisms are essential contributors in neuronal
gene expression, synaptic plasticity, long-term memory formation, cognitive functions,
emotional health (behavioral plasticity), as well as in the pathophysiology of several
neurodevelopmental and neurodegenerative diseases and psychiatric disorders (Gräff and
Mansuy, 2008; Franklin and Mansuy, 2010; Puckett and Lubin, 2011; Miller and Sweatt,
2007; Lubin et al., 2011; Bredy et al., 2007; Grinkevich. 2012; Crews et al., 2012).
Epigenetics affects important regulatory mechanisms to convey long-lasting effects on
hormonal and environmental factors that take control sexual differentiation in the developing
brain (Matsuda et al., 2012).
The amygdala is an assemblage of nuclei located within the temporal lobe of the brain
that regulates a variety of emotions such as fear, depression and anxiety. The amygdala plays
a major role in emotional memory processing and reactivity of the hypothalamo–pituitary–
adrenal (HPA) axis to stress (Whalen and Phelps, 2009). Recent studies have provided
evidence for a role of epigenetic alterations in the reconsolidation of an amygdala-dependent
Pavlovian fear memory. The consolidation of conditioned fear induces upregulation of several
genes necessary for long-term memory formation. Monsey et al. (2011) found that auditory
fear conditioning regulates histone H3 acetylation and DNMT3A (DNA (cytosine-5-)-
methyltransferase 3 alpha) expression in an ERK/MAPK-dependent and associative way in
the lateral nucleus of the amygdala (LA) in the rat (MAPK = Mitogen-activated protein
kinases, originally called ERK= Extracellular signal-regulated kinases, which add phosphate
groups to a neighboring protein that acts as an "on" or "off" switch.). Maddox et al. (2010)
revealed the role of EGR-1 (early growth response gene-1) in the initial consolidation as well
as in the reconsolidation of auditory fear memories in the LA. Koshibu et al. (2011)
demonstrated that protein phosphatase 1 (PP1, that is abundant in many brain structures
among them in the amygdala) acts as a suppressor of fear memory and synaptic plasticity in
the amygdala and that PP1 can control chromatin remodeling via posttranslational
modifications of histones and the expression of many memory-associated genes. These
alterations correlated with enhanced fear memory, and with an increase in long-term
potentiation (LTP) that is transcription-dependent. Synaptic plasticity and memory
consolidation are dynamically directed by the activation of immediate early gene (IEG)
expression. Homer1 is an IEG that is required for memory formation and was isolated as a
neural activity-regulated gene product from seizure-stimulated rat hippocampus (Brakeman et
al., 1997). Mahan et al. (2012) examined if Homer1a can be necessary for Pavlovian cued fear
conditioning in mice and provided evidence for dynamic epigenetic regulation of Homer1a
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following BDNF-induced plasticity and during a BDNF-dependent learning process in

amygdala and hippocampus (BDNF=Brain-derived neurotrophic factor is a secreted
neurotrophin proteins that can induce the survival, development and function of neurons
(Reichardt, 2006)). Experiments by Maddox and Schafe (2011) also support that epigenetic
processes such as histone acetylation and DNA methylation have key roles in the regulation
of auditory fear memory reconsolidation in the LA. Si et al. (2012) studies indicated that
inhibition of transcription factor NF-κB in the basolateral amygdala after memory reactivation
reduces the retention of amygdala-dependent auditory fear conditioning.
Animal studies revealed that in the developing brain limbic regions are specially
sensitive to exposure to the stress hormone cortisol (cortisol steroid hormon (or
hydrocortisone) is the most important human glucocorticoid). The amygdala and
hippocampus develop at an early embryonic period and are associated with many
neurodevelopmental and psychopathological disorders and can be very sensitive to elevated
levels of glucocorticoids during development. There is evidence that intrauterine exposure to
elevated glucocorticoids increases risk for affective disorders in humans and animals
(Wyrwoll and Holmes, 2011). Previous observations revealed that there is approximately 13%
difference in amygdala volume between clinically depressed patients and healthy volunteers
(Lange and Irle, 2004). Recently, Buss et al. (2012) demonstrated that higher maternal cortisol
concentrations in early gestation are associated with larger right amygdala volume and
affective problems in 7 year old girls. However, no association was observed between
maternal cortisol in pregnancy and child hippocampus volume in either sex. According to
Buss et al. (2012), “In conclusion, findings from the present study provide support for the
premise that susceptibility for affective disorders may, in part, be programmed in utero, and
that this effect may be mediated through changes in anatomy of the amygdala.”
During the prenatal period, as well as in peri- and early postnatal development
responses babies give to stressful stimuli of environment are built up in the babies’ stress
coping and self-regulatory processes as nonconscious functions. This nonconscious functions
will serve as a fractal phenomenon on the base of self-similarity principle against new stress
situations, and become nonconscious implicit procedural somatic memory (Vas and Császár,
2011a; 2011b). This nonconscious epigenetic inherited and obtained information in pre-, peri-
and in early postnatal states essentially predisposes a subject, not only to the different
diseases, but can also determine the development of individual brain structures, cognitive
abilities, and behavioral and emotional (mood) patterns and responses. Consequentially, at an
adult age our freedom choice, as a response (as a reaction) to a given external or internal
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event, is fundamentally dependent on nonconscious inherited and nonconsciously obtained

information, in addition to the given spatiotemporal context where we execute our freedom of
choice. Thus, epigenetic information can be transmitted in a form of a maternal response to
her fetus’s or newborn baby’s immediate reaction to environmental stimuli. This type of
transmission can be effective in a way that epigenetic patterns of culture (beliefs, rites, social
norms, cultural inheritance of ancestors of a given family) are mediated by the maternal
response. Transgenerational transmission of epigenetic information and its nonconscious
effects (through its influence on cognitive abilities, behavioral and emotional patterns and
responses) on one's life and decisions can question the true existence of free will.

Cellular memory may be analogous to behavioral memory in the central nervous

1
system
As mentioned, there is increasing experimental evidence that epigenetic modifications inside
neurons are essential mechanisms for the formation and storage of behavioral memory
(Nelson and Monteggia, 2011; Lipsky, 2012; Zovkic et al., 2013; Rudenko and Tsai, 2013).
Recent studies support the concept that epigenetic modulation of the genome is required for
the neuronal plasticity and long-term memory (Feng et al., 2007). Chromatin arrangement can
represent a memory and allow for temporal integration of spaced signals or metaplasticity of
synapses (Levenson and Sweatt, 2005). According to Arshavsky (2006) the cognitive and
memory functions are achieved, not only by neural networks, but also by intrinsic processes
of neurons. The concept of synaptic plasticity (neural networks) does not contradict the
influence of epigenetics, as neural networks can operate as variable information channels
among neurons while long-term memory can have an epigenetic basis in individual neurons.
Latest experiments also support that memories can be stored in individual neurons
(Liu et al., 2012). The researchers labelled a population of hippocampal dentate gyrus neurons
by optogenetic manipulation of neurons (with channelrhodopsin-2, ChR2) so that they were
sensitive to light. Mice got an electric shock to create a fear memory in the hippocampus area
of the brain and later these neurons were optically reactivated in different contexts. During
light stimulation, previously fear- conditioned and optogenetic manipulated mice showed
increased freezing indicating light-induced fear memory recall. In non-fear-conditioned mice
that also expressed ChR2 in a similar proportion of neurons freezing was not detected. In a
context that was not associated with fear activation of labelled neurons did not evoke freezing
in mice.
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According to Levenson and Sweatt (2005), “Several classic examples illustrate the
importance of epigenetic mechanisms in information storage at the cellular level. They
indicate that epigenetic mechanisms are widely used for the formation and storage of cellular
information in response to transient environmental signals. We present these examples to
emphasize that the storage of cellular information is in some ways analogous to memory
storage in the adult nervous system. Moreover, the lasting cellular changes are triggered by a
transient signal in each case, which is also analogous to the formation of behavioral memory
in the CNS.” This behavioral memory may be viewed as tantamount to implicit procedural
somatic memory mentioned earlier (Vas and Császár, 2011a; 2011b).

1
Footnote: Examples about cellular information can be in some ways analogous to memory storage in the
nervous system

A possible example for the storage of lasting memory at the cellular level is mammalian cellular differentiation.
When an embryonic precursor cell starts to differentiate into a given cell type and becomes terminally
differentiated, this cell and its daughter cells can be undergo thousands of cell divisions throughout the lifetime
of the animal. This cell can keep its specific acquired pattern of gene expression across cellular generations by
’heritable’ epigenetic mechanisms. Another possible example can be T cells in the mammalian immune system.
T-lymphocyte precursors can differentiate to a variety of T cells with different patterns of gene expression that is
started by epigenetic mechanisms such as DNA methylation and histone modifications (Smale, 2003). In
addition, Christof Koch in his book (1999) presented several detailed experimental and theoretical findings as
individual neurons can multiply, integrate, or delay synaptic inputs and that information can be encoded in the
voltage across the membrane, i.e. how an individual neuron can perform logical computations. In this context,
recently we also raised a new notion that also supports cellular memory as analogous to memory in the central
nervous system (Bókkon and Vimal, 2010). To date, mitochondria are considered cellular energy sources and are
described as little round organelles with dimensions much smaller than those of the cell. However, vertebrate
mitochondria of connective, muscular, or neuronal tissue are mostly filamentous (Skulachev, 2001). It is has
been proven that mitochondrial networks can be electrically coupled and can coordinate and synchronize each
other (Skulachev, 2001) Mitochondria frequently fuse and divide and are functionally connected and constitute a
dynamical network inside neuronal cells (Müller et al., 2005). Aon et al. (2008) revealed that mitochondria work
as metabolic and redox hubs and are key integration centers of cellular signaling pathways in eukaryotic cells.
Tong (2007) proposed that the spatiotemporal dynamic patterns of mitochondrial distribution can act as a
“mitochondrial memory code” that dictates the potentiation of specific synapses and the plasticity of the
neuronal network. There is a direct coupling between synaptic activity and mitochondrial organization
movement-activity (Mattson, 2007). Based on the above mentioned information, we have pointed out (Bókkon
and Vimal, 2010) that since sensory information processes are linked to mitochondrial (energetic) processes
spatiotemporal mitochondrial networks within neurons can also reflect representations during sensory
experiences.

Unconscious processes may precede voluntary actions and decisions

In 1965 Kornhuber and Deecke (1965) discovered that an electrical potential (on the order of
micro volts) can be observable in the brain before a subject flexes a finger. This observable
slow negative potential shift in electroencephalogram (EEG) activity that may precede
voluntary movement has been termed "Bereitschaftspotential" or “readiness potential” (RP)
and originates from the supplementary motor area (SMA). Later, Libet et al. (1983) showed
that the RP precedes conscious awareness of initiating the movement. Libet et al. produced a
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circulating dot on an oscilloscope screen and asked volunteers to note the position of the
circulating dot when he/she was aware of the conscious decision to move a finger. Libet et al.
found that the awareness of the decision emerged 200 ms before the motor action. Explicitly,
RP begins 550 ms before the movement but the first awareness (certain brain activity) arises
at 350 ms before the movement. Libet et al. concluded that unconscious processes preced
voluntary actions. Libet’s interpretations of his experiments with regards to free will have
recieved much criticism related to the method of time estimation (Trevena and Miller, 2002).
In addition, the RP is produced by the SMA, which only gives information about late stages
of motor planning.
Traditionally, cognitive functions have been thought to be the result of isolated
operations of single brain regions. In contrast, recent studies support the concept that
cognition is the outcome of dynamic interactions of distributed brain regions operating in
large-scale networks. The so called default mode network (DMN) is a network in the brain
that is active when a person is not focused on the outside world and the brain is at wakeful
rest. When subjects perform stimulus-based tasks, there is an activity increases in the
executive network (EN) and a decreases in DMN (Fox et al., 2005; Fox, Corbetta et al., 2006;
Golland et al., 2007; Lin et al., 2011). Bressler and Menon (2010) revealed that unconscious
conflicting primes not only increase activation in specific executive areas, but these occur
concomitantly with deactivation of DMN components. This suggests that executive control
does not absolutely require consciousness and that the DMN indirectly regulates task
execution, in other words the EN can be modulated by unconscious demands. Further, these
results suggest that executive functions cannot be solely linked to consciousness and free will
(Dehaene and Naccache, 2001; Jack and Shallice, 2001; Haggard, 2008; De Pisapia et al.,
2012) and that unconscious information can activate and influence executive control.
Soon et al. (2008) directly studied some areas in the brain that can predetermine
conscious intentions when subjects began shaping a motor decision. Soon et al. (2008)
performed motor-decision tasks while subjects’ brain activity was measured by functional
magnetic resonance imaging (fMRI). These experiments showed that the effect of a decision
can be revealed via activity of prefrontal and parietal cortex up to 10 s before it enters
awareness. These experiments indicate that the earliest predictive information is encoded in
specific areas of the frontopolar and parietal cortex, and not in the SMA. Soon et al. suggested
that time delay likely occurred due to the processes of a network in high-level control areas
that started to organize an upcoming decision long before it enters the subject’s awareness.
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In 2011, Bode et al. (2011) replicated Soon et al.’s (2008) experiments by ultra-high
field fMRI (7 Tesla scanner) and presented further evidence that motor intentions were
encoded in the frontopolar cortex (FPC), up to seven seconds before participants were aware
of their decisions. The FPC is a brain region that can shape conscious decisions long before
subjects are able to reach conscious awareness.
In current experiments by Soon et al. (2013) the intended action was a nonmotor,
abstract mental operation. Researchers studied the emergence of spontaneous abstract
intentions and revealed that the brain may begin preparing for a voluntary action up to a few
seconds before the decision can enter into awareness. These results cannot be elucidated
through motor preparation or general attention-based processes. In addition, the authors found
a partial spatial overlap between the choice-predictive brain areas and the DMN, which
indicates that preparatory signals were not due to conscious engagement with the task and that
the DMN could take part in unconscious choice preparation. According to Soon et al. (2013),
“We found that frontopolar and precuneus/ posterior cingulate encoded the content of the
upcoming decision, but not the timing. In contrast, the pre-SMA (presupplementary motor
area) predicted the timing of the decision, but not the content.”
The unconscious-thought effect is defined as improved judgments and complex
decisions after a period of distraction (de Vries et al., 2010). The prevailing elucidation about
this effect is that unconscious mechanisms continue to deal with a problem during the period
of distraction. It is proposed that unconscious thinkers may be merely recalling a decision that
was formed on-line (i.e., during information acquisition). Recently, Strick et al. (2010)
demonstrated that a period of unconscious thought improved judgments that were formed
earlier on-line. Thus, the effect of the unconscious thought takes place off-line, and not on-
line.
According to the integrate-and-fire attractor-based model of decision-making by Rolls
and Deco (2011), ”the noise generated by the randomness in the spiking times of neurons can
be used to predict a decision for 0.5 s or more before the decision cues are applied”. Namely,
model analysis by Rolls and Deco (2011) suggests that: …“random neuronal firing times can
influence a decision before the evidence for the decision has been provided”.
In addition, without going into details, we have to mention the global workspace
theory (GWT) (Baars, 1988, 2005) that is a cognitive model about how the consciousness can
emerge from the unconscious. GWT suggests that conscious contents are widely distributed in
the brain and that the conscious could emerge by the parallel and coherent activation of
multiple modular brain networks with fronto-parietal associative cortices as key areas.
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Hassin (2013) claims that: “unconscious processes can perform the same fundamental,
high-level functions that conscious processes can perform”: Hassin discusses several
significant experiments and thoughts as subliminal information processes, problem solving,
motivation, decisions mechanisms or working memory, etc. can take place and operate
unconsciously, outside of conscious awareness. (Hassin et al., 2009 Hassin, 2013).
Similarly, van Gaal et al. (2008) revealed that: “unconscious stimuli can influence
whether a task will be performed or interrupted, and thus exert a form of cognitive control”.
Although the neural correlates of consciousness have conventionally assigned a essential role
to the prefrontal cortex, current neuroscientific experiments have revealed that the prefrontal
cortex can be activated unconsciously (van Gaal et al., 2008), which challenges the
elementary function of the prefrontal cortex in consciousness (van Gaal and Lamme, 2012). It
seems that specific brain regions (cognitive modules) can support specific cognitive roles, but
that consciousness is independent of this (van Gaal and Lamme, 2012). In addition, Horga and
Maia (2012) suggested that conscious and unconscious processes may share common
mechanisms and differ mostly in the quality of the representations.
We basically agree with Hassin’s thoughts (Hassin et al., 2009; Hassin, 2013) as
computationally conscious and unconscious processes are very similar. It is logical that
nonconscious epigenetic inherited and obtained information in pre-, peri- and in early
postnatal states cannot be recalled consciously although can interact and influence
unconscious processes, which later predisposes the adult subject to the various diseases,
cognitive abilities, as well as to behavioral and emotional patterns and responses.
Although the existence of unconscious processes are still controversial (Abadie et al.
2013), the research discussed may portray and support essential roles for unconscious
mechanisms in our everyday decision processes, and challenge traditional views concerning
the proposed relationship between awareness and cognitive control.

The developing brain can be affected by stress in the womb

Brain development starts around 3 weeks after conception, develops throughout the
pregnancy, and continues to develop outside the womb after birth. Cortisol is a steroid
glucocorticoid hormone which is the primary end-product of the hypothalamic-pituitary-
adrenal (HPA) axis and an important signal component of the stress system. While exposure
to glucocorticoids is necessary for the normal development of the HPA axis, stressful factors
can produce excessive concentration levels of cortisol, which is conveyed by the placentas
into its inactive form before reaching the fetus (Charil et al., 2010). However, the human fetus
 11

is not completely protected against direct exposure to increased cortisol concentrations,

because about 50–90% of maternal cortisol is converted to inactive cortisone in the human
placenta. This excess cortisol can perturb fetal development and growth, retard the
development of neurons and result in reduced hippocampal sizes. Prenatal stress mainly
affects on some specific brain regions such as the hippocampus, amygdala, corpus callosum,
anterior commissure, cerebral cortex, cerebellum and hypothalamus.
Prenatal stress produces abnormalities in the development and integration of forebrain
dopaminergic and glutamatergic projections that may the development of schizophrenia and
other psychotic disorders (Berger et al., 2002; Previc, 2007; Rodrigues et al., 2011). Prenatal
stress can also alter the serotonin (5-HT) regulation in the developing brain that can lead to
mood and behavioral disorders in children and adults. The placenta is involved in the
synthesis of serotonin from maternally derived tryptophan (TRP) that make it possible that
genetic and environmental perturbations directly affecting placental TRP metabolism may
cause abnormal brain neural networks in the developing embryo, and therefore predispose to
the aggressive, fearful or anxious behaviors, as well as to the psychiatric disorders (Velasquez
et al., 2013; Dennis et al., 2013).
The developing hippocampus is especially vulnerable to prenatal stress-induced
elevations of glucocorticoids (Charil et al., 2010; Takahashi, 1998). The mammalian
hippocampal neurons are responsible for the formation of long-term memories and the adult
hippocampus is an important area of the brain for storage of stem cells and active
neurogenesis. In addition, hippocampal neurons are very sensitive to environmental and
glucocorticoid stress hormones (Weaver et al., 2006; 2004). It seems that reduced
hippocampal volume may determine susceptibility to Posttraumatic Stress Disorder (PTSD)
(Gross and Hen, 2004). In addition, as described above, the amygdala is also very vulnerable
to prenatal stress.
Prenatal stress can cause various physiological and behavioral alterations such as
enhancement of secretion of stress hormones, decreases in levels of steroid receptors that bind
endogenous glucocorticoids, and increases in reactivity or emotionality in stressful situations.
Thus, during pregnancy, maternal stress can strongly influence the brain development
resulting in permanent alterations that can contribute to increased susceptibility to subsequent
cognitive or neuropsychiatric diseases, as well as impairment of the normal adult adaptive
responses to acute or chronic stress (Fumagalli et al., 2005; 2007). For example, prenatal
stress produces lifelong effects on synaptic function through modulation of fibroblast growth
factor (FGF-2) gene expression. The environmental prenatal stress can also affect fetuses
 12

through maternal behavior that produces long-lasting perturbed hormonal, behavioral and
neuroanatomical alterations in the offspring which are revealed when offspring reach maturity
(Pérez-Laso et al., 2008).
Since the prenatal environmental and maternal stress can produce various
physiological, behavioral, and emotional alterations that are nonconscious processes, this also
questions the existence of real free will. It is known from clinical studies that mental disorders
stemming from prenatal stress can be healed by special methods. We suggest that
nonconscious epigenetic information based on prenatal stress can be modified and
transformed by body psychotherapy (Vas and Császár, 2013a; 2013b).

Vanishing twin syndrome may produce nonconscious life-long emotional/ behavioral

stress patterns and/or diseases as well as context-dependent epigenetic modifications in
the survivor twin
Fusion of an ovum with a sperm leads to the formation of a diploid zygote cell. Next, the
zygote start to divide and form a blastocyst and when it reaches the uterus, it achieves
implantation in the endometrium. Monozygotic twins can be develop from one zygote when it
splits and forms two embryos, but dizygotic twins develop from two different zygotes, each
fertilized by separate sperms. Gametes (ovum and sperm) not only carry epigenetic hereditary
information, but their epigenetic pattern can be continuously modified in the uterus and by the
means of the maternal environment.
In 1945 Stoeckel revealed that the rate of multiple gestations is greater than the birth
rate, or in other words twins are more often conceived than born. In 1986 Landy et al.
suggested the vanishing twin syndrome (fetal resorption) concept. In other words, during an
early stage of pregnancy, one of a set of twin/multiple fetuses often die and then are
reabsorbed (and/or form a blighted ovum) by the body, before the mother is even aware that
she was carrying multiples. Since vaginal bleeding is a frequent obstetric complication in the
first trimester, estimated to occur in 15–25% of all pregnancies and representing an increased
risk of pregnancy loss (Stabile et al., 1987; Falco et al., 1996), twin loss can happen during
common vaginal bleeding without any knowledge of mother. Thus, it is not surprising that
vaginal bleeding or spotting is reported in association with disappearance of an embryo or a
gestational sac. Vanishing twin syndrome has been diagnosed more frequently since the use
of ultrasonography and transvaginal sonography in early pregnancy and has revealed that
spontaneous reduction of a twin pregnancy to a singleton pregnancy (vanishing twin
phenomenon) is a rather frequent incidence (10–40%) in early pregnancy (Landy and Keith,
 13

1998; Dickey et al., 2002). However, the real frequency of the vanishing twin is difficult to
assess and estimated frequencies emerged from 3.7% to over 60%. These significant
differences in estimated frequencies are possibly due to varying patient populations,
sonographic methods and outcome data. According to Boklage (1995) the loss of one member
of a twin pair can be understood quite simply as part of the highly imperfect biology of human
reproduction. Most human conceptions fail before birth. It is no different and no more
mysterious for twins”.
As we have seen above, factors such as maternal stress, nutrition, and the maternal
environment can produce serious life-long epigenetic stress patterns in the offspring. When
twin loss, for example in the first trimester, occurs in the womb and the deceased twin is
reabsorbing, this may cause very strong and complex toxic and nonconscious emotional stress
that can produce context-dependent epigenetic changes in the surviving twin embryo. This is
because the zygote, embryo, and foetus are very susceptible to various stress-related factors
(Hussain, 2012). Thus, twin loss can have deep and long-lasting consequences on mental
health and risk of diseases in the later life of the survivor twin.
The mammalian hippocampal neurons have crucial role in the formation of long-term
memories and the amygdale has key role in the modulation and consolidation of memory by
emotions (Winocur et al. 2010; Bird and Burgess N, 2008; Roozendaal and McGaugh, 2011).
The amygdala affect memory extinction, memory recall, and working memory and can
regulates memory consolidation via its efferent projections to several brain regions
(Roozendaal and McGaugh, 2011). The amygdala mediates the memory-modulating effects of
adrenal stress hormones (epinephrine and glucocorticoids) and various neurotransmitters that
converge in modulating the noradrenergic processes in the amygdala (McGaugh, 2004).
Since the amygdala and hippocampus are especially sensitive to the stress in the
developing brain, twin loss can produce nonconscious stress related (toxic and nonconscious
emotional stress created by the dead twin embryo) epigenetic information in these limbic
parts that predispose the survivor twin to diverse neurodevelopmental and psychopathological
disorders in amygdala and hippocampus dependent manner.
According to Segal (2009) loss of a twin has been largely overlooked by bereavement
counselors and clinicians. This particular type of loss is also poorly understood among the
public”. Research has also revealed that twin loss has negative lifelong impacts on diseases
and relationships. The powerful attachment between twins is different from that between other
siblings, and it also endures beyond the confines of the uterus. Following the death of one
twin, morbidity in the surviving twin can be produced by hypotensive ischemia of the brain
 14

due to hemorrhage (bleeding or the abnormal flow of blood) through placental vascular
anastomoses (Okamura, 1994).
Joan Woodward's twin study (1998) included interviews with 219 survivor twins
whose uterine siblings deaths' happened at stages from prenatal to adulthood. Although
Woodward did not focus on twin losses in the uterus, there are several relevant cases
concerning early losses of uterine siblings that produced painful, long-term distress and
caused lonely feelings in the survivor twins for life. The surviving twin, without knowing
his/her lost twin in the womb, unconsciously searched for the lost twin and strived anxiously
to make connections with people.

Assisted reproduction technologies (ART)

Multiple pregnancies significantly increased in the last few decades, due to advances in
artificial reproductive technology. The use of assisted reproductive technology (ART) around
the world is estimated at about from 1 to 3% of births. ART is a reproductive method used
primarily in infertility treatments which can achieve pregnancy by artificial or partially
artificial fertilization such as in vitro fertilization, cryopreservation, intracytoplasmic sperm
injection (ICSI) or intrauterine insemination (IUI) (Owen and Segars, 2009). ART can be
associated with hyper- and hypomethylation, with imprinting changes occurring at paternal as
well as maternal alleles, and can stimulate epigenetic alterations and affect fetal growth and
development (Horsthemke and Ludwig, 2005). Many imprinting disorders such as Beckwith–
Wiedemann syndrome, Angelman syndrome and the maternal hypomethylation syndrome
arise at higher frequencies in children conceived with the use of ART than in children
conceived spontaneously (Owen and Segars, 2009; Skora and Frankfurter, 2012) but the real
cause of these epigenetic imprinting disorders induced by ART is not clear. In Europe, 22% of
all pregnancies by ART are twin pregnancies due to transfer of more than one embryo
(Pinborg, 2005). Landy and Keith (1998) and Tummers et al. (2003) performed research on
213 and 1597 clinical ART pregnancies and revealed by transvaginal sonography in
gestational week 8 that 12–30% of twin pregnancies ended as a singleton birth, 60–83% as
twin deliveries and 5–10% as spontaneous abortions of both fetuses. A recent study by
Pinborg et al. (2005) included 8542 women with IVF (in vitro fertilization) /ICSI
(intracytoplasmic sperm injection) pregnancies using transvaginal sonography in gestational
week 8. About one in 10 singleton deliveries after ART originated from a vanishing twin
pregnancy.
 15

It is very possible that ART can cause human imprinting syndromes and produce
stress related, context-dependent epigenetic changes (Horsthemke and Ludwig, 2005) that
may create life-long nonconscious behavior and emotional problems and other types of
diseases. Since the gametes may virtually perform complex single cell memory systems, what
could be the effect of ART? The freezing of sperm cells, ICSI, in vitro culture and mechanical
stimulation, among them, are strong environmental stress to living sperm cells that can induce
compelled stress adaptive context-dependent epigenetic responses that may produce life-long
increased susceptibility to various nonconscious disturbed cognitive, emotional and behavior
processes as well as to neuropsychiatric and other type of diseases in persons (Xu et al., 2013;
Kohda and Ishino, 2013; van Montfoort et al., 2012; Ciapa and Arnoult, 2011). In reality, it is
possible that all kinds of ART may produce various stress related context-dependent
epigenetic changes that can be manifested through nonconscious and emotional mechanisms
and other types of diseases.

Summary and Conclusions

Without any final opinion about the existence of free will, we have presented some research
outcomes and concepts that may challenge the existence and nature of real free choice.
All information obtained through transgenerational epigenetic processes cannot be
recalled consciously. In addition, all information during the prenatal period, as well as in peri-
and early postnatal development with surrounding environmental effects, is essentially
nonconscious information in persons that have also never been able to recall consciously in
their lifetime. This nonconscious epigenetic inherited and obtained information can essentially
predispose a subject, not only to the different diseases, but also to determine the development
of individual brain structures, cognitive abilities, behavioral and emotional patterns, as well as
responses and decisions. This all questions the existence of real free will.
We briefly described many studies that may indicate essential roles of unconscious
mechanisms in our daily decision processes and defy traditional views concerning the
proposed relationship between awareness and cognitive control. This research also questions
the existence of freedom of our choice.
We also pointed out that twin loss in the womb can have a powerful life-long impact
on the surviving twin through complex, context-dependent, epigenetic changes such as
exposition to toxins, perturbed nonconscious and emotional mechanisms, and to other types of
diseases. In these processes stress related epigenetic changes in the amygdala and
hippocampus can have key roles. These early losses of uterine siblings can cause painful,
 16

long-term distress in the surviving twin. The surviving twins are unconsciously searching for
the lost twin and anxiously trying to make connections with people. In general, in the case of
recognized twin loss the mental assistance is made to the mother, although the real mental
injury is to the survivor twin, because the attachment between twins is much stronger than
between the mother and her surviving twin child. If we consider the frequency of the
vanishing twin phenomenon is 10%, without any knowledge of the mother (Landy and Keith,
1998; Dickey et al., 2002) this suggests that millions of people may be mentally living alone
in the world, without he/she knowing why. Twin lost may be the basis for mental illness. The
frequency of twin loss and it’s nonconscious effects on the surviving twin also question the
existence of real free will.
Regarding the assisted reproductive technology (ART) we showed that ART not only
can disturb natural imprinting, and cause human imprinting syndromes, but may also create
stress-related context-dependent epigenetic patterns that may produce serious life-long
nonconscious behavior and emotional problems in the adult person. This early shaping of the
person also questions the existence of real free will.
Furthermore, it is possible that freedom of will is an “inner perception” (Hallet, 2007)
rather than an “initiating force”. Namely, we think we have real free will because we are
aware of the intent to move, but in reality that intention/aim is produced through unconscious
mechanisms and only reaches awareness at a later stage.
The existence of free will cannot be determined and understood exclusively in terms of
moral, religious or philosophical points of view. All pieces of our world and universe can
exist only in interactions, in which each part, to a smaller or larger extent, mutually defines
and determines the other. The free choice may be a self-determined and relative process. In
our adult age, in a given situation, our freedom choice, as a response (as a reaction) to a given
external or internal event is fundamentally depend on the nonconscious inherited and obtained
information (emotional patterns), on learned information, as well as on the spatiotemporal
context where we perform our actual free choice. Free choice (a given conscious decision)
may be essentially a convergent and integrated spatiotemporal manifestation of millions of
subjective unconscious processes while a subject interacts with environmental factors. Since
the conscious (explicit) mind may have originated from pre-conscious (implicit) or proto-
conscious processes (Bókkon and Mallick, 2012, Hobson, 2009) in evolution, this suggests
that consciousness may be a dynamic and convergent manifestation of unconscious
neurocomputation processes. Furthermore, even if in a given situation we could truly perform
free choice, we cannot know and cannot make a distinction that it was our true free choice or
 17

if it was determined by large number of unconscious processes and epigenetic-linked factors

as presented throughout this article. Free will may be considered as a way of manifested
behavior between one’s genetic features and epigenetic information mediated by culture. To
find out the narrow or wide path between these two entities depends on one’s self-knowledge
and self-regulation along with his/her lifetime.
We hypothesize that human explicit self-consciousness may be an active executer that
intermediates between implicit nonconscious and unconsciousness and the external
environment by means of feedback and feed-forward interactions. This executive function
makes it possible for self-consciousness to continuously develop in self-organized evolution.
In the waking state, human self-consciousness may be an abstract, language-dependent
manifestation of the unconscious. Our self-conscious thinking, and every decision made at a
given moment, may be a coherent and convergent dynamic (discrete events) manifestation of
our unconscious processes.

Declaration of interest: The authors report no conflicts of interest. The authors alone are
responsible for the content.

Acknowledgements: Authors gratefully thank critical comments for Christian Agrillo

(Department of General Psychology, University of Padova Padova, Italy), and critical
comments and editing for Alexis Pietak (Queen's University, Kingston, Ontario, Canada).

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