Epigenetics of anxiety and stress–related disorders

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Epigenetics_of_anxiety_and_stress%E2%80%93related_disorders

Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), obsessive–compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.

Epigenetic modifications play a role in the development and heritability of these disorders and related symptoms. For example, regulation of the hypothalamus-pituitary-adrenal axis by glucocorticoids plays a major role in stress response and is known to be epigenetically regulated.

As of 2015 most work has been done in animal models in laboratories, and little work has been done in humans; the work is not yet applicable to clinical psychiatry. Stress-induced epigenetic changes, particularly to genes that effect the hypothalamic–pituitary–adrenal (HPA) axis, persist into future generations, negatively impacting the capacity of offspring to adapt to stress. Early life experiences, even when generations removed, can cause permanent epigenetic modifications of DNA resulting in changes in gene expression, endocrine function and metabolism. These heritable epigenetic modifications include DNA methylation of the promoter regions of genes that affect sensitivity to stress.

Mechanism

Epigenetic modification in response to stress results in molecular and genetic alterations that in turn results in mis-regulated or silenced genes. Heterochromatin is the protein that controls the silencing of these genes epigenetically. For example, epigenetic modifications to the gene BDNF (brain derived neurotrophic factor), as well as Drosophila ATF-2 (dATF-2), as a result of stress can be passed on to offspring. Chronic variable stress induces offspring hypothalamic gene expression modifications, including elevated methylation levels of the BDNF promoter in the hippocampus. This methylation will also occur in the heterochromatin, causing a disrupted heterochromatin to be passed on to the child. Maternal separation and postnatal maternal abuse also increases DNA methylation at regulatory regions of BDNF genes in the prefrontal cortex and hippocampus, leading to potential stress vulnerability in future generations.

Stress can also result in inheritable changes DNA methylation in the promoter regions of the estrogen receptor alpha (ERα), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). These changes lead to altered expression of these genes in offspring that in turn leads to decreased stress tolerance.

Stress and the HPA axis

Gene regulation as it relates to the HPA axis has been implicated in transgenerational stress effects. Environmental prenatal stress exposure, for example, alters glucocorticoid receptor gene expression, gene function, and future stress response in F1 and F2 generations. Maternal care likewise contributes to HPA-related epigenetic modifications. Epigenetic re-programming of gene expression alters stress response in offspring later in life when exposed to decreased maternal care. Inattentive mothering has led to increased levels of gene methyl marks, compared to attentive mothers. Female offspring with low licking-grooming mothers have decreased promoter methylation and increased histone acetylation, leading to increased glucocorticoid receptor expression. Epigenetic modifications as a result of absent maternal care lead to decreased estrogen receptor alpha expression, due to increased methylation at the gene's promoter.

Epigenetic writers, erasers, and readers

Epigenetic changes are performed by enzymes known as writers, which can add epigenetic modifications, erasers, which erase epigenetic modifications, and readers, which can recognize epigenetic modifications and cause a downstream effect. Stress-induced modifications of these writers, erasers, and readers result in important epigenetic modifications such as DNA methylation and acetylation.

DNA methylation

During DNA methylation, cytosine is methylated.

DNA methylation is a type of epigenetic modification in which methyl groups are added to cytosines of DNA. It is located on the fifth position of cytosine which has importance in the development of mammals. DNA methylation is an important regulator of gene expression and is usually associated with gene repression. DNA Methylation is a mechanism which can suppress gene expression. It can be inherited through cell divisions in development, and is involved with cell memory. Changes in methylation occur due to mutated or deregulated chromatin regulators. This process is also used in marking cancers for diagnosis.

MeCP2

Laboratory studies have found that early life stress in rodents can cause phosphorylation of methyl CpG binding protein 2 (MeCP2), a protein that preferentially binds CpGs and is most often associated with suppression of gene expression. Stress-dependent phosphorylation of MeCP2 causes MeCP2 to dissociate from the promoter region of a gene called arginine vasopressin (avp), causing avp to become demethylated and upregulated. This may be significant because arginine vasopressin is known to regulate mood and cognitive behavior. Additionally, arginine vasopressin upregulates corticotropin-releasing hormone (CRH), which is a hormone important for stress response. Thus, stress-induced upregulation of avp due to demethylation might alter mood, behavior, and stress responses. Demethylation of this locus can be explained by reduced binding of DNA methyl transferases (DNMT), an enzyme that adds methyl groups to DNA, to this locus.

MeCP2 is known to have interactions with several other enzymes that modify chromatin (for example, HDAC-containing complexes and co-repressors) and in turn regulate activity of genes that modulate stress response either by increasing or decreasing stress tolerance. For example, epigenetic upregulation of genes that increase stress response may cause decreased stress tolerance in an organism. These interactions are dependent on the phosphorylation status of MeCP2, which as previously mentioned, can be altered by stress.

DNMT1

DNA methyltransferase 1 (DNMT1) belongs to a family of proteins known as DNA methyltransferases, which are enzymes that add methyl groups to DNA. DNMT1 is specifically involved in maintaining DNA methylation; hence it is also known as the maintenance methylase DNMT1. DNMT1 aids in regulation of gene expression by methylating promoter regions of genes, causing transcriptional repression of these genes.

DNMT1 is transcriptionally repressed under stress-mimicking exposure both in vitro and in vivo using a mouse model. Accordingly, transcriptional repression of DNMT1 in response to long-term stress-mimicking exposure causes decreased DNA methylation, which is a marker of gene activation. In particular, there is decreased methylation of a gene called fkbp5, which plays a role in stress response as a glucocorticoid-responsive gene. Thus, chronic stress may cause demethylation and hyperactivation of a stress-related gene, causing increased stress response.

Additionally, DNMT1 gene locus has increased methylation in individuals who were exposed to trauma and developed post-traumatic stress disorder (PTSD). Increased methylation of DNMT1 did not occur in trauma-exposed individuals who did not develop PTSD. This may indicate an epigenetic phenotype that can differentiate PTSD-susceptible and PTSD-resilient individuals after exposure to trauma.

Transcription factors

Transcription factors are proteins that bind DNA and modulate the transcription of genes into RNA such as mRNA, tRNA, rRNA, and more; thus they are essential components of gene activation. Stress and trauma can affect expression of transcription factors, which in turn alter DNA methylation patterns.

For example, transcription factor nerve growth-induced protein A (NGFI-A, also called NAB1) is up-regulated in response to high maternal care in rodents, and down-regulated in response to low maternal care (a form of early life stress). Decreased NGFI-A due to low maternal care increases methylation of a glucocorticoid receptor promoter in rats. Glucocorticoid is known to play a role in downregulating stress response; therefore, downregulation of glucocorticoid receptor by methylation causes increased sensitivity to stress.

Histone acetylation

During histone acetylation, lysines are acetylated.

Histone acetylation and deacetylation is a type of epigenetic modification in which acetyl groups are added to lysine on histone tails. Histone acetylation, performed by enzymes known as histone acetyltransferases (HATs), removes the positive charge from lysine and results in gene activation by weakening the histone's interaction with negatively-charged DNA. In contrast, histone deacetylation performed by histone deacetylases (HDACs) results in gene deactivation.

HDAC

Transcriptional activity and expression of HDACs is altered in response to early life stress. For animals exposed to early life stress, HDAC expression tends to be lower when they are young and higher when they are older. This suggests an age-dependent effect of early life stress on HDAC expression. These HDACs may result in deacetylation and thus activation of genes that upregulate stress response and decrease stress tolerance.

Transgenerational epigenetic influences

Genome-wide association studies have shown that psychiatric disorders are partly heritable; however, heritability cannot be fully explained by classical Mendelian genetics, but rather epigenetics. There are many components in understanding the heritability of psychiatric disorders. Understanding epigenetic modifications and its ability to impact epigenomes over generations is vital in analyzing potential behavioral disorders. But we must acknowledge the concept of transgenerational epigenetics (epigenetic inheritance) which is the occurrence in which parents are able to transfer traits not present in their DNA sequencing to their offspring; it is the passing of environmentally manipulated traits for two or more generations without direct DNA alteration. For example, one study found transmission of DNA methylation patterns from fathers to offspring during spermatogenesis. Similarly, several studies have shown that traits of psychiatric illnesses (such as traits of PTSD and other anxiety disorders) can be transmitted epigenetically Parental exposure to various stimuli, both positive and negative, can cause transgenerational epigenetic and behavioral effects.

Parental exposure to trauma and stress

Trauma and stress experienced by a parent can cause epigenetic changes to its offspring. This has been observed both in population and experimental studies.

Biological vulnerability and HPA axis alterations may be observed after maternal epigenetic programing during pregnancy, leading to similar modifications in future generations. Child abuse exposure, for example, is associated with lower baseline infant cortisol levels as well as modified HPA axis function. Human studies investigating posttraumatic stress disorder (PTSD) and its effects on offspring have illustrated similar molecular and HPA axis modification and function. PTSD patients who experienced trauma from genocides or terrorist attacks frequently exhibited aggressive or neglectful behavior toward offspring during critical developmental periods, possibly contributing to permanent glucocorticoid deregulation in offspring. PTSD mothers and children illustrate lower basal cortisol levels and glucocorticoid receptors and increased mineralocorticoid receptors when exposed to stress. Therefore, developmental experiences, such as stress exposure, may have critical effects on neuromodulatory mechanisms transgenerationally.

Strong relationships between maternal care and subsequent epigenetic modification in offspring, similar to that found in animal models, has been observed in humans. Severe emotional trauma in the mother, for example, often leads to modified methylation patterns of DNA in subsequent offspring generations. PTSD exposed offspring illustrate epigenetic modifications similar to that seen in PTSD mothers, with an increased NR3C2 methylation in exon 1 and increased CpG methylation in the NR3C2 coding sequence, leading to alterations in mineralocorticoid receptor gene expression. Additionally, investigation of post mortem hippocampal tissue indicates decreased levels of neuron-specific glucocorticoid receptor mRNA and decreased DNA methylation in promoter regions among suicidal individuals with lifelong stress or abuse exposure.

Epigenetic mechanisms as a result of early life stress may be responsible for neuronal and synaptic alterations in the brain. Developmental stress exposure has been shown to alter brain structure and behavioral functions in adulthood. Evidence of decreased complexity in the CA1 and CA3 region of the hippocampus in terms of dendritic length and spine density after early-life stress exposure indicates transgenerational stress inheritance. Therefore, environmental and experience-dependent synaptic reorganization and structure modifications may lead to increased stress vulnerability and brain dysfunction in future generations.

Transgenerational Stress Effects

Human models illustrating transgenerational stress effects are limited due to relatively novel exploration of the topic of epigenetics as well as lengthy follow-up intervals required for multi-generational studies. Several models, however, have investigated the role of epigenetic inheritance and transgenerational stress effects. Transgenerational stress in humans, as in animal models, induces effects influencing social behavior, reproductive success, cognitive ability, and stress response. Similar to animal models, human studies have investigated the role of epigenetics and transgenerational inheritance molecularly as it relates to the HPA system. Prenatal influences, such as emotional stress, nutrition deprivation, toxin exposure, hypoxia, increased maternal HPA activity, and cortisol levels may activate or affect HPA axis activity of offspring, despite placental barrier.

Paternal stress inheritance

Paternal stress is an important factor in the determination of inheritance of genes as well as maternal stress inheritance. Factors such as environment and experiences can alter the epigenetic of paternal genes as well as in sperm. Epigenetic changes to the DNA in sperm ("epigenetic tags") prior to conception can be passed to offspring. The paternal phenotype will be inherited into the offspring due to genetic information being stored in the sperm. In studies, it is shown as rodent offspring are fostered mono-parentally and have no direct exposure with their fathers, offspring born of stressed male rodents provide a good model for transgenerational stress inheritance. Direct injection of sperm RNAs to wild type oocytes results in reproducible stress-related modifications. Small non-coding RNAs may serve as a potential mechanism for stress-related genetic changes in offspring. Mouse models of traumatic early life stress exposure result in microRNA modifications and subsequent differences in gene expression and metabolic function. This effect was reproducible by sperm RNA injection, leading to similar gene modifications in future generations. The novelty of this research suggests direct mechanisms capable of altering epigenetics by stress-related factors.

Phenotypic effects

Early life experiences and environmental factors may lead to epigenetic modification at specific gene loci, leading to altered neuronal plasticity, function, and subsequent behavior. As mentioned, there are genetic markers in all living organisms. There can also be the presence of epigenetically marks and this are basically areas of modification on DNA that in with gene expression. Certain exposures within the environment can lead to the expression of genes in various ways which can contribute to behavioral plasticity patterns that can potentially also change the ways in which organism functions when under normal conditions. Chromatin remodeling in rodent offspring and altered gene expression within the limbic brain regions that may contribute to depression, stress, and anxiety-related disorders in future generations. Variations in maternal care, such as maternal licking and grooming, indicates reduced HPA axis reactivity in subsequent generations. Such HPA axis modifications lead to decreased anxiety-like behavior in adulthood and increased glucocorticoid receptor levels leading to negative feedback on HPA reactivity and further behavioral modifications. Rodent models of maternal separation also reveal increased depressive-like behavior in offspring, decreased stress coping abilities, and changes in DNA methylation.

Irene Shashar, a Holocaust survivor of the Warsaw Ghetto, addressing MEPs

Holocaust

An epidemiological study investigating behavioral, physiological, and molecular changes in the children of Holocaust survivors found epigenetic modifications of a glucocorticoid receptor gene, Nr3c1. This is significant because glucocorticoid is a regulator of the hypothalamus-pituitary-adrenal axis (HPA) and is known to affect stress response. These stress-related epigenetic changes were accompanied by other characteristics that indicated higher stress and anxiety in these offspring, including increased symptoms of PTSD, greater risk of anxiety, and higher levels of the stress hormone cortisol. The offspring demonstrate greater risk of developing PTSD in response to their own trauma or traumas. Offspring with maternal exposure to the Holocaust during the mother's childhood has demonstrated significantly lower site 6 methylation. The site 6 methylation impacts the stress response. In addition to PTSD risks in response to individual trauma in offspring, there has also been an increase in nightmares of offspring related to persecution and torment.

Experimental evidence

The effect of parental exposure to stress has been tested experimentally as well. For example, male mice who were put under early life stress through poor maternal care—a scenario analogous to human childhood trauma—passed on epigenetic changes that resulted in behavioral changes in offspring. Offspring experienced altered DNA methylation of stress-response genes such as CB1 and CRF2 in the cortex, as well as epigenetic alterations in transcriptional regulation gene MeCP2. Offspring were also more sensitive to stress, which is in accordance with the altered epigenetic profile. These changes persisted for up to three generations.

In another example, male mice were socially isolated as a form of stress. Offspring of these mice had increased anxiety in response to stressful conditions, increased stress hormone levels, dysregulation of the HPA axis which plays a key role in stress response, and several other characteristics that indicated increased sensitivity to stress.

Inheritance of small-noncoding RNA

Studies have found that early life stress induced through poor maternal care alters sperm epigenome in male mice. In particular, expression patterns of small-noncoding RNAs (sncRNAs) are altered in the sperm, as well as in stress-related regions of the brain. Offspring of these mice exhibited the same sncRNA expression changes in the brain, but not in the sperm. These changes were coupled with behavioral changes in the offspring that were comparable to behavior of the stressed fathers, especially in terms of stress response. Additionally, when the sncRNAs in the fathers' sperm were isolated and injected into fertilized eggs, the resulting offspring inherited the stress behavior of the father. This suggests that stress-induced modifications of sncRNAs in sperm can cause inheritance of stress phenotype independent of the father's DNA.

Parental exposure to positive stimulation

Exercise

Just as parental stress can alter epigenetics of offspring, parental exposure to positive environmental factors cause epigenetic modifications as well. For example, male mice that participated in voluntary physical exercise resulted in offspring that had reduced fear memory and anxiety-like behavior in response to stress. This behavioral change likely occurred due to expressions of small non-coding RNAs that were altered in sperm cells of the fathers. Participation in aerobic exercise led to decreased cortisol levels in males.

Stress effect reversal

Additionally, exposing fathers to enriching environments can reverse the effect of early life stress on their offspring. When early life stress is followed by environmental enrichment, anxiety-like behavior in offspring is prevented. Similar studies have been conducted in humans and suggest that DNA methylation plays a role. Other studies have been conducted to find drugs such as T2D and PPArG can be used as an epigenetic regulation for tissues associated with diabetes. These drugs used show evidence for the therapies that can be associated with the stress effect reversal.

Childhood exposure to trauma

Early life development and childhood trauma

Mental health disorders that can be caused by epigenetic alterations

Healthy development early in life is critical. Early life is characterized by rapid development and increased susceptibility to modifications. Childhood trauma can severely affect the development of the brain, resulting in the alteration of neural circuits which are involved in emotional regulation and threat detection. Childhood trauma has been associated with a wide array of mental health disorders such as bipolar disorder, anxiety, post traumatic stress disorder (PTSD), and depression.

PTSD Inheritability

Research involving PTSD in those who experienced childhood trauma had a 25% to 60% inheritability rate, which is a relatively low to moderate rate. This study suggests that other factors play a role in the contribution to this disorder such as gene interactions involving epigenetic modifications. These epigenetic modifications, specifically DNA methylation can lead to the phenotypic expression of mental disorders.

Changes to the HPA Axis Due to Childhood Trauma

Hypothalamic-pituatary-adrenal (HPA) axis is essential component of the neuroendocrine system that regulates stress response. Persistent dysregulation of the stress response pathway resulting from childhood trauma causes alterations in the (HPA). These alterations lead to prolonged harmful physiological and physical changes.

Postmortem Brain Tissue DNA Methylation

A DNA methylation study was done by Labonte on postmortem human brain tissue comparing humans with or without a history of childhood abuse who died by suicide. Childhood abuse and trauma was associated with increased cytosine methylation of the NR3C1 promoter resulting in the decrease of GR expression. The NR3C1 gene encodes glucocorticoid receptor (GR) which is essential for glucose regulation and managing stress response through both genetic and epigenetic pathways.

Post-traumatic stress disorder (PTSD)

Post-traumatic stress disorder (PTSD) is a stress-related mental health disorder that emerges in response to traumatic or highly stressful experiences. It is believed that PTSD develops as a result of an interaction between these traumatic experiences and genetic factors. The signs and symptoms of PTSD can include avoidance behaviors, invasive thoughts, and significant alterations in normal behavior and thinking. There is evidence suggesting PTSD formation is associated with epigenetic changes such as DNA methylation and acetylation of histone proteins. Increased DNA methylation has been found to regulate the induction of fear conditioning behaviors associated with PTSD triggers. Histone modifications, like acetylation and deacetylation, play an important role in the development of PTSD, which is related to fear memory from traumatic events. Recent research has also found that cultural factors—including differences in self-representation within individualistic and collectivist cultures—can impact such neural mechanisms of PTSD, including fear processing and regulation, leading to different modulation, presentation, and efficacy of treatment for PTSD symptoms.

The DSM-5 asserts that PTSD manifests differently in children over six years old than in adults. Specifically that their flashbacks or intrusive memories may be explained by recreating their traumatic event(s) through their play. They may also experience reoccurring nightmares that are indirectly related to the event. Additionally, there is a separate criteria altogether for PTSD in children under six years old.

Epigenetic modifications

DNA methylation

Epigenetic DNA Methylation

Through a number of human studies, PTSD is known to affect DNA methylation of CpG islands in several genes involved in numerous activities, including stress responses and neurotransmitter activity. CpGs are used to describe cytosine-guanine adjacent nucleotides within the same strand of DNA. CpG islands are defined by computer algorithms as being made up of at least 60% CpGs and being anywhere between 200 and 3000 base pairs in size. The methylation of these CpG islands can cause histone modifications which can lead to the condensation of chromatin which can ultimately alter gene expression.

DNMT enzyme

DNA methyltransferase, DNMT, is an enzyme responsible for increased methylation of DNA. It has been found that DNMT and its associated increased methylation can regulate risk for memory consolidation and fear conditioning.

TET enzyme

The removal of methyl groups from cytosine is initiated by a TET enzyme. TET is an enzyme known to oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) within the genome. This reaction initiates active DNA demethylation to ultimately alter gene expression. It has been found that the TET enzyme exists as two isoforms which are differentially regulated and expressed across brain regions. The regulation of these isoforms can affect synaptic connections and ultimately memory formation. The manipulation of the TET enzymes' expression levels has become a potential source of interest for PTSD medication.

The table below identifies differentially methylated regions (DMRs) across the genome which undergo PTSD-induced epigenetic changes which alter gene expression.

Human Studies Supporting the Role of DNA Methylation in PTSD

Genetic Loci	Finding(s)
SLC6A4	Following trauma exposure, low methylation levels of SLC6A4 increases risk of PTSD; high methylation levels decreases risk of PTSD
MAN2C1	Higher MAN2C1 methylation is correlated to greater risk of PTSD in individuals exposed to traumatic events
TPR, CLEC9A, APC5, ANXA2, TLR8	PTSD is associated with increased global methylation of these genes
ADCYAP1R1	Higher methylation is associated with PTSD symptoms in individuals exposed to trauma
LINE-1, Alu	Higher methylation of these loci is observed in postdeployed veterans who developed PTSD compared to those who do not develop PTSD
SLC6A3	High SLC6A3 promoter methylation, combined with a nine-repeat allele of SLC6A3, is correlated to higher PTSD risk
IGF2, H19, IL8, IL16, IL18	Higher methylation of IL18 but lower methylation of H19 and IL18 is associated with deployed veterans who developed PTSD
NR3C1	Lower methylation levels of NR3C1 1B and 1C promoters is associated with PTSD; Fathers with PTSD have offspring with higher NR3C1 1F promoter methylation; Lower levels of NR3C1 1F promoter methylation is associated with PTSD in combat veterans; Higher levels of NR3C1 methylation in male (but not female) Rwandan genocide survivors is associated with decreased PTSD risk
SPATC1L	Higher methylation is associated with PTSD symptoms.
HLA-DPB1	Higher methylation is associated with PTSD symptoms.

Histone modifications

Histone acetylation is performed by histone acetyl transferases (HATs) and histone deacetylation is carried out by histone deacetylases (HDACs). In rodent PTSD models, it has been found that an increase in histone acetylation is associated with fear conditioning. Histone acetylation can be involved in all parts of fear memory, including the development to memory extinction. It can also play a role in long-term potentiation (LTP). It was also observed that HDACs increase memory formation in fear extinction and HDAC inhibitors (HDACi) have shown evidence for modifying memory extinction, a possible treatment for PTSD.

Nervous system structures affected by PTSD

Hypothalamus-pituitary-adrenal axis

The hypothalamus-pituitary-adrenal (HPA) axis is a neuroendocrine system largely involved in ascertaining the levels of cortisol circulating the body at any given point in time. As cortisol plays a key role in the stress response, so does the HPA axis. The dysregulation of the HPA axis has been found to be characteristic of several stress disorders, including PTSD. This system works under a negative feedback loop structure. Hence, this HPA axis dysregulation may take the form of amplified negative inhibition and result in down-regulated cortisol levels. Epigenetic modifications play a role in this dysregulation, and these modifications are likely caused by the traumatic/stressful experience that triggered PTSD.

Immune dysregulation by HPA axis modifications

PTSD is often linked with immune dysregulation. Traumatic experiences can induce epigenetic changes at the gene loci that are immune-related which can lead to immune dysregulation and an increased risk of PTSD. Trauma exposure can also disrupt the HPA axis, thus altering peripheral immune function. The effect of PTSD on immune function arises in at least two ways: 1) Continuous disturbances on the HPA axis can dysregulate peripheral immune function, and 2) the effects of immune dysregulation in the periphery can lead to increased development of PTSD because of alterations in brain function.

PTSD-associated changes in immune cells found in blood or saliva can serve as biomarkers that trigger epigenetic changes which are involved in the pathogenesis of PTSD. These unique biomarkers serve as means of identifying PTSD subtypes. Beyond identifying subtypes, these distinct biomarkers can potentially be used to develop PTSD treatments.

Epigenetic modifications have been observed in immune-related genes of individuals with PTSD. For example, deployed military members who developed PTSD have higher methylation in the immune-related gene interleukin-18 (IL-18). This has interested scientists because high levels of IL-18 increase cardiovascular disease risk, and individuals with PTSD have elevated cardiovascular disease risk. Thus, stress-induced immune dysregulation via methylation of IL-18 may play a role in cardiovascular disease in individuals with PTSD.

Additionally, an epigenome-wide study found that individuals with PTSD have altered levels of methylation in the following immune-related genes: TPR, CLEC9A, APC5, ANXA2, TLR8, IL-4, and IL-2. This again shows that immune function in PTSD is disrupted, especially by epigenetic changes that are likely stress-induced.

Genes affected by PTSD

NR3C1

Nr3c1 is a transcription factor that encodes a glucocorticoid receptor (GR) and contains many GR response elements. Npas4 is another regulatory transcription factor also responsible for the regulation of GRs. Stress-induced changes in Nr3c1 and Npas4 methylation have been shown to alter stress sensitivity. This response differs between short-lived stress exposure and chronic stress exposure. In response to short lived stress, the NR3C1 promoter is more hydroxymethylated which is a modification associated with increased transcription of GR-associated genes. Thus, short lived stress exposure increases stress sensitivity. Conversely, in response to chronic stress, the Npas4 promoter has been presumed to be increased in methylation, a modification which is associated with inhibitory regulation of GRs. Thus, chronic stress exposure decreases stress sensitivity. These distinctions are important in understanding the epigenetic patterns of stress and genetic interactions with PTSD triggers. Overall, in the hippocampus of chronically stressed animals, the 3′-UTR (untranslated region of DNA) of the glucocorticoid receptor Nr3c1 showed increased hydroxymethylation, which led to increased transcription and thus, the disruption of stress tolerance and increased risk of disorders such as PTSD. However, early life stress increases methylation of the 1_F promoter in this gene (or the 1₇ promoter analog in rodents). Because of its role in stress response and its link to early life stress, this gene has been of particular interest in the context of PTSD and has been studied in PTSD of both combat veterans and civilians.

In studies involving combat veterans, those who developed PTSD had lowered methylation of the Nr3c1 1_F promoter compared to those who did not develop PTSD. Additionally, veterans who developed PTSD and had higher Nr3c1 promoter methylation responded better to long-term psychotherapy compared to veterans with PTSD who had lower methylation. These findings were recapitulated in studies involving civilians with PTSD. In civilians, PTSD is linked to lower methylation levels in the T-cells of exons 1_B and 1_C of Nr3c1, as well as higher GR expression. Thus, it seems that PTSD causes lowered methylation levels of GR loci and increased GR expression. The methylation of GR in T-cells are investigated because of its role in regulating cell immunity which, as such, stores cellular memory with environmental factors. T-cell fragments from individual cell populations are preferred over homogenized tissue because of the drastic variation in DNA methylation patterns between different cell fragments.

Although these results of decreased methylation and hyperactivation of GR conflict with the effect of early life stress at the same loci, these results match previous findings that distinguish HPA activity in early life stress versus PTSD. For example, cortisol levels of HPA in response to early life stress is hyperactive, whereas it is hypoactive in PTSD. Thus, the timing of trauma and stress—whether early or later in life—can cause differing effects on HPA and GR.

FKBP5

Fkbp5 encodes a GR-responsive protein known as Fk506 binding protein 51 (FKBP5). FKBP5 is induced by GR activation and functions in negative feedback by binding GR and reducing GR signaling. There is particular interest in this gene because some FKBP5 alleles have been correlated with increased risk of PTSD and development of PTSD symptoms—especially in PTSD caused by early life adversity. Therefore, FKBP5 likely plays an important role in PTSD.

As mentioned previously, certain FKBP5 alleles are correlated to increase PTSD risk, especially due to early life trauma. It is now known that epigenetic regulation of these alleles is also an important factor. For example, CpG sites in intron 7 of FKBP5 are demethylated after exposure to childhood trauma, but not adult trauma. Additionally, methylation of FKBP5 is alters in response to PTSD treatment; thus methylation levels of FKBP5 might correspond to PTSD disease progression and recovery.

ADCYAP1 and ADCYAP1R1

Pituitary adenylate cyclase-activating polypeptide (ADCYAP1) and its receptor (ADCYAP1R1) are stress responsive genes that play a role in modulating stress, among many other functions. Additionally, high levels of ADCYAP1 in peripheral blood is correlated to PTSD diagnosis in females who have experienced trauma, thus making ADCYAP1 a gene of interest in the context of PTSD.

Epigenetic regulation of these loci in relation to PTSD still require further investigation, but one study has found that high methylation levels of CpG islands in ADCYAP1R1 can predict PTSD symptoms in both males and females.

Alcohol use disorder

Alcohol use disorder is a type of brain disorder that requires one to have dependency on alcohol. Alcohol use disorder can vary in severity. Alcohol dependence can impact stress and other disorders in many ways. For example, stress-related disorders such as anxiety and PTSD are known to increase risk of alcohol use disorder (AUD), and they are often co-morbid. Mental disorders that pair with AUD can impacts the brain in many ways. For example, AUD can have the ability to aid those diagnosed with depression by alleviating depression symptoms such as insomnia, restlessness, and/ or the ability to re-engage in normal activities, and re-engage in hobbies. Bipolar disorder can cause manic episodes ranging fro different sudden mood changes. AUD can also be used to stall the same symptoms expressed in depression as well as with bipolar disorder. In some cases AUD can cause other brain disorders to worsen itself, or the symptoms of the disorder. An example of this can be seen in some with Obessive-Compulsive Disorder (can typically include anxiety "triggers" that often cause an individual to have very specific compulsions or obsessions). With this type of disorder, although it can help in ways by relieving symptomatic stress, it can also aid in promoting addiction to alcohol which can be a negative impact if uncontrolled. This may in part be due to the fact that alcohol can alleviate some symptoms of these disorders, thus promoting dependence on alcohol. Conversely, early exposure to alcohol can increase vulnerability to stress and stress-related disorders. AUD is a type of epigenetic influencing disorder, it is able to be passed down generation to generation epigenetically following a process mentioned before as transgenerational epigenetics. Moreover, alcohol dependence and stress are known to follow similar neuronal pathways, and these pathways are often unable to be regulated by similar epigenetic modifications.

Histone acetylation

HDAC

Histone acetylation is dysregulated by alcohol exposure and dependence, often through dysregulated expression and activity of HDACs, which modulate histone acetylation by removing acetyl groups from lysines of histone tails. For example, HDAC expression is upregulated in chronic alcohol use models. Monocyte-derived dendritic cells of alcohol users have increased HDAC gene expression compared to non-users. These results are also supported by in vivo rat studies, which show that HDAC expression is higher in alcohol-dependent mice that in non-dependent mice. Furthermore, knockout of HDAC2 in mice helps lower alcohol dependence behaviors. The same pattern of HDAC expression is seen in alcohol withdrawal, but acute alcohol exposure has the opposite effect; in vivo, HDAC expression and histone acetylation markers are decreased in the amygdala.

Dysregulation of HDACs is significant because it can cause upregulation or downregulation of genes that have important downstream effects both in alcohol dependence and anxiety-like behaviors, and the interaction between the two. A key example is BDNF (see "BDNF" below).

BDNF

Brain-derived neurotrophic factor (BDNF) is a key protein that is dysregulated by HDAC dysregulation. BDNF is a protein that regulates the structure and function of neuronal synapses. It plays an important role in neuronal activation, synaptic plasticity, and dendritic morphology—all of which are factors that may affect cognitive function. Dysregulation of BDNF is seen both in stress-related disorders and alcoholism; thus BDNF is likely an important molecule in the interaction between stress and alcoholism.

For example, BDNF is dysregulated by acute ethanol exposure. Acute ethanol exposure causes phosphorylation of CREB, which can cause increased histone acetylation at BDNF loci. Histone acetylation upregulates BDNF, in turn upregulating a downstream BDNF target called activity-regulated cytoskeleton associated protein (Arc), which is a protein responsible for dendritic spine structure and formation. This is significant because activation of Arc can be associated with anxiolytic (anxiety-reducing) effects. Therefore, ethanol consumption can cause epigenetic changes that alleviate stress and anxiety, thereby creating a pattern of stress-induced alcohol dependence.

Alcohol dependence is exacerbated by ethanol withdrawal. This is because ethanol withdrawal has the opposite effect of ethanol exposure; it causes lowered CREB phosphorylation, lowered acetylation, downregulation of BDNF, and increase in anxiety. Consequently, ethanol withdrawal reinforces desire for anxiolytic effects of ethanol exposure. Moreover, it is proposed that chronic ethanol exposure results in upregulation of HDAC activity, causing anxiety-like effects that can no longer be alleviated by acute ethanol exposure.

Potential epigenetic drug treatments

See also: Epigenetic therapy

The most common treatments for anxiety disorders at the moment are benzodiazepines, Buspirone, and antidepressants. However, around one/third of patients with anxiety disorders do not respond well to the current anxiolytics, and many others have treatment-resistant anxiety disorders. Recent research surrounding DNA methylation changes in genes in genes encoding proteins associated with the HPA axis, histone modifications, and sncRNAs point to epigenetic drugs potentially being effective treatment methods for anxiety disorders.

HDACi

Histone deacetylase inhibitors (HDACi) fall into five different classes, not to be confused with the four different classes of HDACs. The five classes of HDACi consist of (I) hydroxamic acids, (II) short-chain fatty acids, (III) benzamides, (IV) cyclic tetrapeptides, and (V) sirtuin inhibitors. The three classes of HDACs are class I, consisting of HDAC1, HDAC2, HDAC3, HDAC8, class II, consisting of HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10, class III, consisting of NAD+-dependent HDACS, and class IV, consisting of HDAC11. While most HDACi inhibit only specific classes of HDACs, certain HDACi can act against all classes, making them pan-inhibitors.

HDACi are currently being researched as potential anxiolytics. At the moment, the mechanism of action of HDAC inhibitors in the treatment of anxiety disorders is not clear, as they affect several targets and have multiple pharmacological effects besides the inhibition of HDACs. However, they have been shown to cause DNA demethylation, possibly due to an increase in the levels of TET1, which is a demethylating enzyme. In the human peripheral cells of patients with anxiety disorders and in animal models of anxiety disorders, genes such as GAD1, NR3C1, BDNF, MAOA, HECA, and FKBP5 are shown to be hypermethylated. As such, the mechanism of action of HDACi in anxiety disorders could, in part, be potentially explained by the demethylation of those genes.

Valproate

Valproate is a drug that acts as an HDACi on class I and II HDACs. Six clinical trials surrounding its use as an anxiolytic have been performed so far. Five of the six trials were performed on patients with anxiety disorders, and one of the trials used healthy subjects with no anxiety disorders. Of the five trials performed on patients with anxiety disorders, three found that Valproate decreases panic disorder, one found that Valproate decreases social anxiety, and one found that Valproate reduces generalized anxiety. The trial performed on healthy subjects found that Valproate reduces anxiety and also acts as a nerve conduction inhibitor, which could be an explanation for some of its anxiety-reducing effects.

D-cycloserine, Trichostatin-a, Suberoylanilide hydroxamic acid, sodium butyrate, and valproic acid

Various preclinical drug trials using other HDAC inhibitors have also been performed, with most drugs targeting HDAC classes I and II and a select few targeting classes IV and III. The HDACi drug, d-cycloserine, was found to reduce fear in 129S1/SvImJ mice, which are mice that show poor extinction acquisition and recovery of fear-induced suppression of heart-rate variability, enlarged dendritic arbors in basolateral amygdala neurons, and functional abnormalities in cortico-amygdala circuitry that mediates fear extinction. Trichostatin-a was normalized BDNF and Arc expression in the central and the medial nucleus of the amygdala in rats experiencing alcohol withdrawal. Suberoylanilide hydroxamic acid significantly reversed anxiety-like behaviors and stress-induced gastrointestinal hypersensitivity and fecal pellet output. Anxiety-like and depression-like behaviors caused by immobilization stress or nicotine addiction were also reduced in mice treated with the HDACi sodium butyrate and valproic acid.

Lactate

Lactate, a metabolite that is naturally produced during exercise, was found to function as an HDAC II and III modulator in a pre-clinical trial. The trial was performed on C57BL/6 mice, which are mice that were exposed to chronic stress in the form of daily defeat by a CD-1 aggressive mouse. While control mice exhibited increased social avoidance, anxiety, and susceptibility to depression, mice that received lactate before each defeat demonstrated resilience to depression and stress and reduced social avoidance and anxiety. Lactate promoted this resilience by restoring regular hippocampal class I HDAC levels and activity.

sncRNA

Preliminary research has been done about therapy involving small non-coding RNAs, demonstrating that they can regulate epigenetic mechanisms of gene expression and could present as biomarkers for disease. One therapy option is for the sncRNAs in patients with anxiety disorders to be targeted for upregulation. Another option is to inhibit the miRNAs in order to reduce their effects, potentially using antisense oligonucleotides or antagomirs as inhibitors.

Hydrocortisone

The medication hydrocortisone is a synthetic form of cortisol, and is typically an anti inflammatory. In recent years, the administration of hydrocortisone has been tested as a possible preventative measure for the onset of PTSD symptoms. Ideally, it should be administered immediately after a traumatic event. The efficacy of hydrocortisone as a preventative intervention for PTSD has been confirmed by a meta-analysis of eight separate studies, and researchers believe the best results are obtained when hydrocortisone is administered within the first six hours of exposure to the traumatic event. At this time, however, no curative properties have been discovered. Hydrocortisone's potential operates on two bases: restoration of normal HPA axis functioning and interference with memory consolidation.

HPa axis homeostasis

Our standard understandings of PTSD may suggest elevated glucocorticoid levels during and directly following events of trauma. However, multiple studies have indicated that overall HPA axis activity and cortisol levels are depleted in the critical aftermath and extended period after trauma. Moreover, research has also indicated that an appropriate release of glucocorticoids following acute stress may restore homeostatic equilibrium of the HPA axis, thereby preventing gradual sensitization, which is responsible for persistent cortisol reduction and increased PTSD susceptibility. Thus, the appropriately-dosed administration of hydrocortisone promptly following the traumatic incident would normalize the HPA axis and potentially prevent PTSD onset.

Disruption of memory consolidation

In the absence of memory reactivation, hydrocortisone's effectiveness within a six-hour window supports the consolidation theory, which asserts that memory is labile even immediately after trauma. It is assumed that the medication is disrupting initial memory consolidation of the traumatic event. However, its exact mechanism within this context remains largely unknown.

Although trials have proven promising, there is much more research to be done. Further comprehensive studies are required amidst more diverse populations under different traumatic conditions in order to ascertain factors of optimal usage of the drug and clarify the PTSD subgroups hydrocortisone is beneficial to.

Rodent models used to study PTSD medication

Stress-enhanced fear learning (SEFL)

The observation of epigenetic modifications and their role in regulating fear learning is an active area of research. The use of stress-enhanced fear learning (SEFL) paradigms are important for forming preclinical models of PTSD because one is able to observe the epigenetic changes in rodents and PTSD associated changes in fear learning after stress exposure.

Single-prolonged stress (SPS)

The single-prolonged stress (SPS) model is a tool in which a complex stressor is consistently presented. This tool is used to explore the complexity of PTSD, particularly its impaired fear extinction.

Susceptible factors to PTSD

Despite high levels of individuals exposed to trauma, only about one third of exposed individuals develop PTSD. This suggest that individuals differ in their susceptibility to PTSD. This might arise from differences in the epigenetic modifications that they generate in response to traumatic experiences. Furthermore, a large area of research regarding increased susceptibility to PTSD investigates the transgenerational inheritance of epigenetic modifications resulting from trauma. A recent review of PTSD susceptibility suggested that a range as wide as 30% to 70% of susceptibility to PTSD can be attributed to heritability. From our observations of mice in transgenerational research, we have seen that the epigenetic modifications that stem from trauma can be passed down multiple generations. Epigenetic modifications due trauma are not the only heritable factors that affect PTSD susceptibility. General histories of health deficiencies, both physical and psychological, have also been associated with a higher PTSD susceptibility. Sociodemographic factors may come into play as well. Particularly, ethnic minorities and women are more susceptible to development of PTSD.

Telepathy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Telepathy

The Ganzfeld experiments that aimed to demonstrate telepathy have been criticized for lack of replication and poor controls.

Telepathy (from Ancient Greek τῆλε (têle) 'distant' and πάθος/-πάθεια (páthos/-pátheia) 'feeling, perception, passion, affliction, experience') is the purported vicarious transmission of information from one person's mind to another's without using any known human sensory channels or physical interaction. The term was first coined in 1882 by the classical scholar Frederic W. H. Myers, a founder of the Society for Psychical Research (SPR), and has remained more popular than the earlier expression thought-transference.

Telepathy experiments have historically been criticized for a lack of proper controls and repeatability. There is no good evidence that telepathy exists, and the topic is generally considered by the scientific community to be pseudoscience. Telepathy is a common theme in science fiction.

Origins of the concept

According to historians such as Roger Luckhurst and Janet Oppenheim the origin of the concept of telepathy in Western civilization can be traced to the late 19th century and the formation of the Society for Psychical Research. As the physical sciences made significant advances, scientific concepts were applied to mental phenomena (e.g., animal magnetism), with the hope that this would help to understand paranormal phenomena. The modern concept of telepathy emerged in this context.

Psychical researcher Eric Dingwall criticized SPR founding members Frederic W. H. Myers and William F. Barrett for trying to "prove" telepathy rather than objectively analyze whether or not it existed.

Thought reading

In the late 19th century, the magician and mentalist Washington Irving Bishop would perform "thought reading" demonstrations. Bishop claimed no supernatural powers and ascribed his powers to muscular sensitivity (reading thoughts from unconscious bodily cues). Bishop was investigated by a group of scientists including the editor of the British Medical Journal and the psychologist Francis Galton. Bishop performed several feats successfully, such as correctly identifying a selected spot on a table and locating a hidden object. During the experiment, Bishop required physical contact with a subject who knew the correct answer. He would hold the hand or wrist of the helper. The scientists concluded that Bishop was not a genuine telepath but was instead using a highly trained skill to detect ideomotor movements.

Another famous thought reader was the magician Stuart Cumberland. He was famous for performing blindfolded feats such as identifying a hidden object in a room that a person had picked out or asking someone to imagine a murder scene and then attempt to read the subject's thoughts and identify the victim and reenact the crime. Cumberland claimed to possess no genuine psychic ability and his thought-reading performances could only be demonstrated by holding the hand of his subject to read their muscular movements. He came into dispute with psychical researchers associated with the Society for Psychical Research who were searching for genuine cases of telepathy. Cumberland argued that both telepathy and communication with the dead were impossible and that the minds of people cannot be read through telepathy, but only by muscle reading.

Case studies

Gilbert Murray conducted early telepathy experiments.

In the late 19th century the Creery Sisters (Mary, Alice, Maud, Kathleen, and Emily) were tested by the Society for Psychical Research and believed to have genuine psychic ability. However, during a later experiment they were caught utilizing signal codes and they confessed to fraud. George Albert Smith and Douglas Blackburn were claimed to be genuine psychics by the Society for Psychical Research but Blackburn confessed to fraud:

For nearly thirty years the telepathic experiments conducted by Mr. G. A. Smith and myself have been accepted and cited as the basic evidence of the truth of thought transference... ...the whole of those alleged experiments were bogus, and originated in the honest desire of two youths to show how easily men of scientific mind and training could be deceived when seeking for evidence in support of a theory they were wishful to establish.

Between 1916 and 1924, Gilbert Murray conducted 236 experiments into telepathy and reported 36% as successful. However, it was suggested that the results could be explained by hyperaesthesia as he could hear what was being said by the sender. Psychologist Leonard T. Troland had carried out experiments in telepathy at Harvard University which were reported in 1917. The subjects produced below chance expectations.

Arthur Conan Doyle and W. T. Stead were duped into believing Julius and Agnes Zancig had genuine psychic powers. Both Doyle and Stead wrote that the Zancigs performed telepathy. In 1924, Julius and Agnes Zancig confessed that their mind reading act was a trick and published the secret code and all the details of the trick method they had used under the title of Our Secrets!! in a London newspaper.

In 1924, Robert H. Gault of Northwestern University with Gardner Murphy conducted the first American radio test for telepathy. The results were entirely negative. One of their experiments involved the attempted thought transmission of a chosen number between one and one-thousand. Out of 2,010 replies, none was correct. This is below the theoretical chance figure of two correct replies in such a situation.

In February 1927, with the co-operation of the British Broadcasting Corporation (BBC), V. J. Woolley, who was at the time the Research Officer for the SPR, arranged a telepathy experiment in which radio listeners were asked to take part. The experiment involved 'agents' thinking about five selected objects in an office at Tavistock Square, whilst listeners on the radio were asked to identify the objects from the BBC studio at Savoy Hill. 24,659 answers were received. The results revealed no evidence of telepathy.

A famous experiment in telepathy was recorded by the American author Upton Sinclair in his book Mental Radio which documents Sinclair's test of psychic abilities of Mary Craig Sinclair, his second wife. She attempted to duplicate 290 pictures which were drawn by her husband. Sinclair claimed Mary successfully duplicated 65 of them, with 155 "partial successes" and 70 failures. However, these experiments were not conducted in a controlled scientific laboratory environment. Science writer Martin Gardner suggested that the possibility of sensory leakage during the experiment had not been ruled out:

In the first place, an intuitive wife, who knows her husband intimately, may be able to guess with a fair degree of accuracy what he is likely to draw—particularly if the picture is related to some freshly recalled event the two experienced in common. At first, simple pictures like chairs and tables would likely predominate, but as these are exhausted, the field of choice narrows and pictures are more likely to be suggested by recent experiences. It is also possible that Sinclair may have given conversational hints during some of the tests—hints which in his strong will to believe, he would promptly forget about. Also, one must not rule out the possibility that in many tests, made across the width of a room, Mrs. Sinclair may have seen the wiggling of the top of a pencil, or arm movements, which would convey to her unconscious a rough notion of the drawing.

Frederick Marion who was investigated by the Society for Psychical Research in the late 1930–1940s.

The Turner-Ownbey long distance telepathy experiment was discovered to contain flaws. May Frances Turner positioned herself in the Duke Parapsychology Laboratory whilst Sara Ownbey claimed to receive transmissions 250 miles away. For the experiment Turner would think of a symbol and write it down whilst Ownbey would write her guesses. The scores were highly successful and both records were supposed to be sent to J. B. Rhine; however, Ownbey sent them to Turner. Critics pointed out this invalidated the results as she could have simply written her own record to agree with the other. When the experiment was repeated and the records were sent to Rhine the scores dropped to average.

Another example is the experiment carried out by the author Harold Sherman with the explorer Hubert Wilkins who carried out their own experiment in telepathy for five and a half months starting in October 1937. This took place when Sherman was in New York and Wilkins was in the Arctic. The experiment consisted of Sherman and Wilkins at the end of each day to relax and visualise a mental image or "thought impression" of the events or thoughts they had experienced in the day and then to record those images and thoughts on paper in a diary. The results at the end when comparing Sherman's and Wilkins' diaries were claimed to be more than 60 percent.

The full results of the experiments were published in 1942 in a book by Sherman and Wilkins titled Thoughts Through Space. In the book, both Sherman and Wilkins had written they believed they had demonstrated that it was possible to send and receive thought impressions from the mind of one person to another. The magician John Booth wrote that the experiment was not an example of telepathy as a high percentage of misses had occurred. Booth wrote it was more likely that the "hits" were the result of "coincidence, law of averages, subconscious expectancy, logical inference or a plain lucky guess". A review of their book in the American Journal of Orthopsychiatry cast doubt on their experiment, noting "the study was published five years after it was conducted, arouses suspicion on the validity of the conclusions.

In 1948, on the BBC radio Maurice Fogel made the claim that he could demonstrate telepathy. This intrigued the journalist Arthur Helliwell who wanted to discover his methods. He found that Fogel's mind reading acts were all based on trickery as he relied on information about members of his audience before the show started. Helliwell exposed Fogel's methods in a newspaper article. Although Fogel managed to fool some people into believing he could perform genuine telepathy, the majority of his audience knew he was a showman.

In a series of experiments Samuel Soal and his assistant K. M. Goldney examined 160 subjects over 128,000 trials and obtained no evidence for the existence of telepathy. Soal tested Basil Shackleton and Gloria Stewart between 1941 and 1943 in over five hundred sittings and over twenty thousand guesses. Shackleton scored 2890 compared with a chance expectation of 2308 and Gloria scored 9410 compared with a chance level of 7420. It was later discovered the results had been tampered with. Gretl Albert who was present during many of the experiments said she had witnessed Soal altering the records during the sessions. Betty Marwick discovered Soal had not used the method of random selection of numbers as he had claimed. Marwick showed that there had been manipulation of the score sheets and all experiments reported by Soal had thereby become discredited.

In 1979 the physicists John G. Taylor and Eduardo Balanovski wrote the only scientifically feasible explanation for telepathy could be electromagnetism (EM) involving EM fields. In a series of experiments the EM levels were many orders of magnitude lower than calculated and no paranormal effects were observed. Both Taylor and Balanovski wrote their results were a strong argument against the validity of telepathy.

Research in anomalistic psychology has discovered that in some cases telepathy can be explained by a covariation bias. In an experiment (Schienle et al. 1996) 22 believers and 20 skeptics were asked to judge the covariation between transmitted symbols and the corresponding feedback given by a receiver. According to the results the believers overestimated the number of successful transmissions whilst the skeptics made accurate hit judgments. The results from another telepathy experiment involving 48 undergraduate college students (Rudski, 2002) were explained by hindsight and confirmation biases.

In 1995, Rupert Sheldrake published his book on alleged telepathic phenomena Seven Experiments That Could Change the World, claiming among other things that dogs have the telepathic ability to know when their owners are coming home. In 1998, Richard Wiseman, Matthew Smith and Julie Milton published a paper putting forward other explanations for the behavior Sheldrake observed in animals while saying the results from their own experiments did not support Sheldrake's thesis.

In parapsychology

Within parapsychology, telepathy, often along with precognition and clairvoyance, is described as an aspect of extrasensory perception (ESP) or "anomalous cognition" that parapsychologists believe is transferred through a hypothetical psychic mechanism they call "psi". Parapsychologists have reported experiments they use to test for telepathic abilities. Among the most well known are the use of Zener cards and the Ganzfeld experiment.

Types

Several forms of telepathy have been suggested:

• Latent telepathy, formerly known as "deferred telepathy", describes a transfer of information with an observable time-lag between transmission and reception.
• Retrocognitive, precognitive, and intuitive telepathy describes the transfer of information about the past, future or present state of an individual's mind to another individual.
• Emotive telepathy, also known as remote influence or emotional transfer, describes the transfer of kinesthetic sensations through altered states.
• Superconscious telepathy describes use of the supposed superconscious to access the collective wisdom of the human species for knowledge.

Zener cards

Main article: Zener cards

Zener cards

Zener cards are marked with five distinctive symbols. When using them, one individual is designated the "sender" and another the "receiver". The sender selects a random card and visualizes the symbol on it, while the receiver attempts to determine that symbol telepathically. Statistically, the receiver has a 20% chance of randomly guessing the correct symbol, so to demonstrate telepathy, they must repeatedly score a success rate that is significantly higher than 20%. If not conducted properly, this method is vulnerable to sensory leakage and card counting.

J. B. Rhine's experiments with Zener cards were discredited due to the discovery that sensory leakage or cheating could account for all his results such as the subject being able to read the symbols from the back of the cards and being able to see and hear the experimenter to note subtle clues. Once Rhine took precautions in response to criticisms of his methods, he was unable to find any high-scoring subjects. Due to the methodological problems, parapsychologists no longer utilize card-guessing studies.

Dream telepathy

Parapsychological studies into dream telepathy were carried out at the Maimonides Medical Center in Brooklyn, New York led by Stanley Krippner and Montague Ullman. They concluded the results from some of their experiments supported dream telepathy. However, the results have not been independently replicated. The psychologist James Alcock has written the dream telepathy experiments at Maimonides have failed to provide evidence for telepathy and "lack of replication is rampant."

The picture target experiments that were conducted by Krippner and Ullman were criticized by C. E. M. Hansel. According to Hansel there were weaknesses in the design of the experiments in the way in which the agent became aware of their target picture. Only the agent should have known the target and no other person until the judging of targets had been completed, however, an experimenter was with the agent when the target envelope was opened. Hansel also wrote there had been poor controls in the experiment as the main experimenter could communicate with the subject.

An attempt to replicate the experiments that used picture targets was carried out by Edward Belvedere and David Foulkes. The finding was that neither the subject nor the judges matched the targets with dreams above chance level. Results from other experiments by Belvedere and Foulkes were also negative.

Ganzfeld experiment

When using the Ganzfeld experiment to test for telepathy, one individual is designated as the receiver and is placed inside a controlled environment where they are deprived of sensory input, and another person is designated as the sender and is placed in a separate location. The receiver is then required to receive information from the sender. The nature of the information may vary between experiments.

The Ganzfeld experiment studies that were examined by Ray Hyman and Charles Honorton had methodological problems that were well documented. Honorton reported only 36% of the studies used duplicate target sets of pictures to avoid handling cues. Hyman discovered flaws in all of the 42 Ganzfeld experiments and to access each experiment, he devised a set of 12 categories of flaws. Six of these concerned statistical defects, the other six covered procedural flaws such as inadequate documentation, randomization and security as well as possibilities of sensory leakage. Over half of the studies failed to safeguard against sensory leakage and all of the studies contained at least one of the 12 flaws. Because of the flaws, Honorton agreed with Hyman the 42 Ganzfeld studies could not support the claim for the existence of psi.

Possibilities of sensory leakage in the Ganzfeld experiments included the receivers hearing what was going on in the sender's room next door as the rooms were not soundproof and the sender's fingerprints to be visible on the target object for the receiver to see.

Hyman also reviewed the autoganzfeld experiments and discovered a pattern in the data that implied a visual cue may have taken place:

The most suspicious pattern was that the hit rate for a given target increased with the frequency of occurrence of that target in the experiment. The hit rate for the targets that occurred only once was right at the chance expectation of 25%. For targets that appeared twice the hit rate crept up to 28%. For those that occurred three times it was 38%, and for those targets that occurred six or more times, the hit rate was 52%. Each time a videotape is played its quality can degrade. It is plausible then, that when a frequently used clip is the target for a given session, it may be physically distinguishable from the other three decoy clips that are presented to the subject for judging. Surprisingly, the parapsychological community has not taken this finding seriously. They still include the autoganzfeld series in their meta-analyses and treat it as convincing evidence for the reality of psi.

Hyman wrote the autoganzfeld experiments were flawed because they did not preclude the possibility of sensory leakage. In 2010, Lance Storm, Patrizio Tressoldi, and Lorenzo Di Risio analyzed 29 ganzfeld studies from 1997 to 2008. Of the 1,498 trials, 483 produced hits, corresponding to a hit rate of 32.2%. This hit rate is statistically significant with p < .001. Participants selected for personality traits and personal characteristics thought to be psi-conducive were found to perform significantly better than unselected participants in the ganzfeld condition. Hyman (2010) published a rebuttal to Storm et al. According to Hyman "reliance on meta-analysis as the sole basis for justifying the claim that an anomaly exists and that the evidence for it is consistent and replicable is fallacious. It distorts what scientists mean by confirmatory evidence." Hyman wrote the ganzfeld studies have not been independently replicated and have failed to produce evidence for telepathy. Storm et al. published a response to Hyman claiming the ganzfeld experimental design has proved to be consistent and reliable but parapsychology is a struggling discipline that has not received much attention so further research on the subject is necessary. Rouder et al. 2013 wrote that critical evaluation of Storm et al.'s meta-analysis reveals no evidence for telepathy, no plausible mechanism and omitted replication failures. A 2016 paper examined questionable research practices in the ganzfeld experiments.

Twin telepathy

Twin telepathy is a belief that has been described as a myth in psychological literature. Psychologists Stephen Hupp and Jeremy Jewell have noted that all experiments on the subject have failed to provide any scientific evidence for telepathy between twins. According to Hupp and Jewell there are various behavioral and genetic factors that contribute to the twin telepathy myth "identical twins typically spend a lot of time together and are usually exposed to very similar environments. Thus, it's not at all surprising that they act in similar ways and are adept at anticipating and forecasting each other's reactions to events."

A 1993 study by Susan Blackmore investigated the claims of twin telepathy. In an experiment with six sets of twins one subject would act as the sender and the other the receiver. The sender was given selected objects, photographs or numbers and would attempt to psychically send the information to the receiver. The results from the experiment were negative, no evidence of telepathy was observed.

The skeptical investigator Benjamin Radford has noted that "Despite decades of research trying to prove telepathy, there is no credible scientific evidence that psychic powers exist, either in the general population or among twins specifically. The idea that two people who shared their mother's womb—or even who share the same DNA—have a mysterious mental connection is an intriguing one not borne out in science."

Scientific reception

A variety of tests have been performed to demonstrate telepathy, but there is no scientific evidence that the power exists. A panel commissioned by the United States National Research Council to study paranormal claims concluded that "despite a 130-year record of scientific research on such matters, our committee could find no scientific justification for the existence of phenomena such as extrasensory perception, mental telepathy or 'mind over matter' exercises... Evaluation of a large body of the best available evidence simply does not support the contention that these phenomena exist." The scientific community considers parapsychology a pseudoscience. There is no known mechanism for telepathy. Philosopher and physicist Mario Bunge has written that telepathy would contradict laws of science and the claim that "signals can be transmitted across space without fading with distance is inconsistent with physics".

Physicist John Taylor has written that the experiments that have been claimed by parapsychologists to support evidence for the existence of telepathy are based on the use of shaky statistical analysis and poor design, and attempts to duplicate such experiments by the scientific community have failed. Taylor also wrote the arguments used by parapsychologists for the feasibility of such phenomena are based on distortions of theoretical physics as well as "complete ignorance" of relevant areas of physics.

Psychologist Stuart Sutherland wrote that cases of telepathy can be explained by people underestimating the probability of coincidences. According to Sutherland, "most stories about this phenomenon concern people who are close to one another—husband and wife or brother and sister. Since such people have much in common, it is highly probable that they will sometimes think the same thought at the same time." Graham Reed, a specialist in anomalistic psychology, noted that experiments into telepathy often involve the subject relaxing and reporting the 'messages' to consist of colored geometric shapes. Reed wrote that these are a common type of hypnagogic image and not evidence for telepathic communication.

Outside of parapsychology, telepathy is generally explained as the result of fraud, self-delusion and/or self-deception and not as a paranormal power. Psychological research has also revealed other explanations such as confirmation bias, expectancy bias, sensory leakage, subjective validation, and wishful thinking. Virtually all of the instances of more popular psychic phenomena, such as mediumship, can be attributed to non-paranormal techniques such as cold reading. Magicians such as Ian Rowland and Derren Brown have demonstrated techniques and results similar to those of popular psychics, albeit without claiming paranormal skills. They have identified, described, and developed psychological techniques of cold reading and hot reading.

Psychiatry

The notion of telepathy is not dissimilar to three clinical concepts: delusions of thought insertion/removal and thought broadcasting. This similarity might explain how an individual might come to the conclusion that he or she were experiencing telepathy. Thought insertion/removal is a symptom of psychosis, particularly of schizophrenia, schizoaffective disorder or substance-induced psychosis. Psychiatric patients who experience this symptom falsely believe that some of their thoughts are not their own and that others (e.g., other people, aliens, demons or fallen angels, or conspiring intelligence agencies, or artificial intelligences) are putting thoughts into their minds (thought insertion). Some patients feel as if thoughts are being taken out of their minds or deleted (thought removal). Schizophrenic patients suffering from the form of alleged telepathy known as thought broadcasting believe that their private thoughts are being broadcast to other people against their informed consent. Along with other symptoms of psychosis, delusions of thought insertion may be reduced by antipsychotic medication. Psychiatrists and clinical psychologists believe and empirical findings support the idea that people with schizotypy and schizotypal personality disorder are particularly likely to believe in telepathy.