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Wednesday, May 18, 2022

Irreligion in India

From Wikipedia, the free encyclopedia
 

Atheism and agnosticism have a long history in India and flourished within the Śramaṇa movement. Indian religions like Jainism, Hinduism and Buddhism consider atheism to be acceptable. India has produced some notable atheist politicians and social reformers. According to the 2011 Census of India, 99.76% of Indians identified with a religion while 0.24% did not state their religious identity. According to the 2012 WIN-Gallup Global Index of Religion and Atheism report, 81% of Indians were religious, 13% were non-religious, 3% were convinced atheists, and 3% were unsure or did not respond.

History

Ancient India

Several śramaṇa movements are known to have existed in India before the 6th century BCE (pre-Buddha, pre-Mahavira), and these influenced both the āstika and nāstika traditions of Indian philosophy. Martin Wiltshire states that the Śramaṇa tradition evolved in India over two phases, namely Paccekabuddha and Savaka phases, the former being the tradition of individual ascetic and latter of disciples, and that Buddhism and Jainism ultimately emerged from these as sectarian manifestations. These traditions drew upon already established Brahmanical concepts, states Wiltshire, to formulate their own doctrines. Reginald Ray concurs that Śramaṇa movements already existed and were established traditions in pre-6th century BCE India, but disagrees with Wiltshire that they were nonsectarian before the arrival of Buddha.

Schools of Philosophy

In Indian philosophy, there are six major orthodox (astika) schools of Hindu philosophyNyaya, Vaisheshika, Samkhya, Yoga, Mīmāṃsā and Vedanta, and five major heterodox (nāstika) schools of ŚramaṇaJain, Buddhist, Ajivika, Ajñana, and Cārvāka. The four most studied Nāstika schools, those rejecting the doctrine of Vedas, are Jainism, Buddhism, Cārvāka, and Ājīvika.

Charvaka

There is no heaven, no final liberation, nor any soul in another world, Nor do the actions of the four castes, orders, etc., produce any real effect.

— from the Sarvadarśanasaṅ̇graha, attributed to Brhaspati

The Cārvāka school originated in India around the 6th century BCE. It is classified as a nāstika school. It is noteworthy as evidence of a materialistic movement in ancient India. Followers of this school only accepted pratyakşa (perception) as a valid pramāna (evidence). They considered other pramāna like sabda (testimony), upamāna (analogy), and anumāna (inference) as unreliable. Thus, the existence of a soul (ātman) and God were rejected, because they could not be proved by perception. They also considered everything to be made of four elements: earth, water, air and fire. The Cārvāka pursued enjoyment of life and elimination of physical pain. So, they can be considered hedonistic. All of the original Cārvāka texts are considered lost. A much quoted sūtra (Barhaspatya sutras) by Brhaspati, who is considered the founder of the school, is thought to be lost. The Tattvopaplavasimha by Jayarāśi Bhaṭṭa (8th century CE) and the Sarvadarśanasaṅ̇graha by Madhavacarya (13th century) are considered important secondary Cārvāka texts.

Samkhya

Sāṃkhya is an āstika school, but has some atheistic elements. Sāṃkhya is a radically dualist philosophy. They believed that the two ontological principles, puruṣa (consciousness) and prakriti (matter), to be the underlying foundation of the universe. The objective of life is considered the achievement of separation of pure consciousness from matter (kaivalya). The reasoning within this system led to the Nir-isvara Sāṃkhya (Sāṃkhya without God) philosophy, which deemed the existence of God as unnecessary. There is the opposing reasoning which accepts God, called Sesvara Sankhya (Sāṃkhya with God). Samkhya Karika (c. 350 CE) is the earliest known systematic text of this philosophy.

Mīmāṃsā

Mīmāṃsā (meaning exegesis) is also an astika school. They believed the Vedas to be author-less and self-authenticating. They did not accept the Vedas as being composed by any ṛishi (saint), they considered them to not be authored by anyone (apauruṣeya). They accepted the minor deities of the Vedas but resisted any notion of a Supreme Creator. They only concentrated on upholding the ṛta (order) by following the duties of the Vedas. The foundational text of this school is the Mīmāṃsā Sutra by Jaimini (c. 200 BCE - 200 CE).

Ājīvika

Ājīvika is yet another nastika school with an atheistic outlook. None of their scriptures survive and there is some question as to whether or not the accounts of them in secondary sources (often hostile) are accurate. They believed in a naturalistic atomic theory and held that the consequence of natural laws led to a deterministic universe. They denied karma, but upheld the atman. They lived in ascetic communities and existed in southern India until at least the 14th century.

Buddhism and Jainism

Jainism rejects the idea of a creator deity responsible for the manifestation, creation, or maintenance of this universe. According to Jain doctrine, the universe and its constituents (soul, matter, space, time, and principles of motion) have always existed. All the constituents and actions are governed by universal natural laws and an immaterial entity like God cannot create a material entity like the universe. Jainism offers an elaborate cosmology, including heavenly beings (devas), but these beings are not viewed as creators; they are subject to suffering and change like all other living beings, and must eventually die. Jains define godliness as the inherent quality of any soul characterising infinite bliss, infinite power, Kevala Jnana (pure infinite knowledge) and Perfect peace. However, these qualities of a soul are subdued due to karmas of the soul. One who achieves this state of soul through right belief, right knowledge and right conduct can be termed a god. This perfection of soul is called kevalin. A soul thus becomes a liberated soul – liberated of miseries, cycles of rebirth, world, karmas and finally liberated of body as well. This is called moksha.

Gautama Buddha rejected the existence of a creator deity, refused to endorse many views on creation and stated that questions on the origin of the world are not ultimately useful for ending suffering. Buddhism instead emphasises the system of causal relationships underlying the universe, pratītyasamutpāda, which constitute the dhamma and source of enlightenment. No dependence of phenomena on a supernatural reality is asserted in order to explain the behaviour of matter.

Philosophers and ancient texts

Ajita Kesakambali was a materialist philosopher. He is mentioned in the Samaññaphala Sutta. He rejected gods, an afterlife and karma. Payasi is a character, referred to as a prince, who appears in the Buddhist text Digha Nikaya in the Payasi Sutta. He didn't believe in rebirth or karma. He debated Kassapa, a disciple of Buddha, and lost according to Buddhist sources.

Jabali's speech from the Ramayana

In the Hindu epic Ramayana (Ayodhya Khanda), when Bharata goes to the forest to convince Rama to return home, he was accompanied by a sophist called Jabali ("जाबालिः"). Jabali uses nihilistic reasoning to convince Rama. He also says that rituals are a waste of food and scriptures were written by smart men so that people will give alms. But Rama calls him a deviant from the path of dharma ("धरमपथात"), refuses to accept his "nastika" views and blame his own father for taking Jabali into service. He also equates the Buddha to a thief. On hearing Rama's retort, Jabali retracts his statements, saying that he was merely arguing like a nihilist. However, these verses referring to the Buddha are considered a later interpolation, as those verses use a different metre.

The Carvaka incident in the Mahabharata

A character described as a Carvaka briefly appears in the Mahabharata (in the Shanti Parva). As Yudhishthira enters the city of Hastinapur, a brahmin, referred to as Carvaka, accuses him of killing his own kinsmen and says that he would suffer for it. The accuser is revealed to a rakshasa in disguise, who was a friend of Duryodhana. He had existed since the Satya Yuga by virtue of a boon from the god Brahma, that he could only be killed when he is showing contempt towards brahmins. He was killed by other brahmins by the chanting of sacred hymns and Yudhishthira was assured that his actions were within the kshatriya code. This event may be a possible denigration of the Carvaka philosophy.

Medieval India

In the 9th century CE, Jain philosopher Jinasena wrote the Mahapurana. The book contains the following often quoted words,

Some foolish men declare that a creator made the world. The doctrine that the world was created is ill-advised, and should be rejected. If God created the world, where was he before creation? If you say he was transcendent then, and needed no support, where is he now?

This quote was also featured later in Carl Sagan's book, Cosmos. In the 14th century, philosopher Madhavacarya wrote the Sarvadarśanasaṅ̇graha, which is a compilation of all Indian philosophies, including Carvaka, which is described in the first chapter.

Modern India

19th century

Between 1882 and 1888, the Madras Secular Society published a magazine called The Thinker (Tattuvavivesini in Tamil) from Madras. The magazine carried articles written by anonymous writers and republished articles from the journal of the London Secular Society, which the Madras Secular Society considered itself affiliated to.

20th century

The Yukthivadi in 1929 was the first atheist/rationalist magazine published in Malayalam.

Periyar E. V. Ramasamy (1879 - 1973) was an atheist and rationalist leader of Self-Respect Movement and Dravidar Kazhagam. His views on the irreligion are based on the eradication of the caste system, religion must be denied to achieve the obliteration of caste system.

Vinayak Damodar Savarkar (1883 –1966) was an eminent Hindu nationalist leader of the Indian independence movement. He was also an atheist and a staunch rationalist who disapproved of orthodox Hindu belief, dismissing cow worship as superstitious. Being Hindu, for him, was a cultural and political identity.

Meghnad Saha (1893 – 1956) was an atheist astrophysicist best known for his development of the Saha equation, used to describe chemical and physical conditions in stars.

Jawaharlal Nehru (1889–1964), India's first Prime Minister was a self-described scientific humanist. He wrote in his autobiography, Toward Freedom (1936), about his views on religion and superstition.

Bhagat Singh (1907-1931), an Indian revolutionary and socialist nationalist who was hanged for using violence against British government officials, was a staunch atheist. He laid out his views in the essay Why I Am an Atheist, written in jail shortly before his execution.

Goparaju Ramachandra Rao (1902-1975), better known by his nom de guerre "Gora," was a social reformer, anti-caste activist, atheist and desciple of Mahatma Gandhi. He and his wife, Saraswathi Gora (1912-2007) who was also an atheist and social reformer, founded the Atheist Centre in 1940. The Atheist Centre is an institute working for social change. Gora expounded his philosophy of positive atheism as a way of life. He later wrote more about positive atheism in his 1972 book, Positive Atheism. Gora also organised the first World Atheist Conference in 1972. Subsequently, the Atheist Centre has organised several World Atheist Conferences in Vijayawada and other locations.

Khushwant Singh (1915-2014), a prominent and prolific writer, of Sikh extraction, was avowedly non-religious.

In 1997, the Federation of Indian Rationalist Associations was founded.

21st century

E.A.Jabbar and M. M. Akbar during the debate, Adv Anil Kumar,President Kerala Yukthivadi Sangham in middle
 
Declaration of Ex-Muslims day by Ex-Muslims of Kerala, From left 1.Jazla Madassery,2.Mini,3.Liyakkathali CM,4.Arif Hussain,5.Shafeeq
 
Askar Ali (Hudavi),a 24 year old Muslim maulvi from Kerala who was also an imam at a mosque, who left Islam and become a rationalist and freethinker.He faced murder attempts from Muslims and goondas of Islamic ummah of his native place Malappuram.His video has got one million views on YouTube in a week it has published

Amartya Sen (1933-), an Indian economist, philosopher and Nobel laureate, is an atheist and he holds that this can be associated with one of the atheist schools in Hinduism, the Lokayata.

Sunday Sapiens, the successor of Maharashtra Rationalist Association, is actively involved in developing scientific temper and eradicating superstition.

In 2008, the website Nirmukta was founded. It later became an organisation aiming to promote free thought and secular humanism in India.

In 2009, historian Meera Nanda published a book entitled "The God Market". It examines how Hindu religiosity is gaining more popularity among the rising middle class, as India is liberalising the economy and adopting globalisation.

In March 2009, in Kerala, a pastoral letter addressing the laity was issued by the Kerala Catholic Bishops' Council urging the members to not vote for political parties which advocate atheism. In July 2010, another similar letter was issued.

On 10 March 2012, Sanal Edamaruku investigated a so-called miracle in Vile Parle, where a Jesus statue had started weeping and concluded that the problem was caused by faulty drainage. Later that day, during a TV discussion with some church members, Edamaruku accused the Catholic Church of miracle-mongering. On 10 April, Angelo Fernandes, President of the Maharashtra Christian Youth Forum, filed a police complaint against Edamaruku under the Indian Penal Code Section 295A. In July while on a tour in Finland, Edamaruku was informed by a friend that his house was visited by the police. Since the offence is not bailable, Edamaruku stayed in Finland.

On Friday 7 July 2013, the first "Hug an Atheist Day" was organised in India by Nirmukta. The event aimed to spread awareness and reduce the stigma associated with being an atheist.

On 20 August 2013, Narendra Dabholkar, a rationalist and anti-superstition campaigner, was shot dead by two unknown assailants, while he was out on a morning walk.

On 9th Jan 2021, E.A.Jabbar, freethinker, atheist, and rationalist from Kerala and Islamic preacher M.M. Akbar were engaged in a debate on Quran. Both sides claimed to have defeated the other debater even as there was no clear verdict. Manoj John, an internationally reputed atheist activist, was dragged into a controversy after Liyakhathali CM alleged that the former took money from M.M. Akbar to tilt the debate in Akbar's favour. International atheist organisations immediately conducted a four-month long investigation and absolved Manoj John of having any link with Islamic organisations or having accepted money from them. It later turned out to be a false allegation to tarnish Manoj John's rising reputation and recognition in the global freethought movement, showing at the same time the dissaray among the irreligion camp in Kerala state of India.

In August 2021, Abdul Khader Puthiyangadi, an Indian citizen, a rationalist from Kerala, He was arrested by UAE police in 2021 without bail and sentenced to prison in UAE for 3 years for criticizing Islam on social media in his native language Malayalam. Liyakhathali CM, who was working towards the release of Puthiyangadi without authorisation by the latter's family, has been accused of unauthorised and intransparent fund collection for this purpose by many secular activists but the allegations have not yet been proven.

On 10 January 2022, ex-Muslim rationalist Aneesh Jasy from Tamil Nadu was arrested without bail over his Facebook posts against Islam. 

Rise of ex-Muslims of Kerala

In 2021 in Kerala, several ex-Muslims formed an organisation called Ex-Muslims of Kerala. It is an organisation founded in 2021 by E. A. Jabbar, Liyakkathali CM, Arif Hussain, and a few others who left Islam in Kerala. The organisation gives support to those who left Islam, a minority that is facing persecution from the Islamic community, just because they left the religion. The organisation conducts debates with Islamic scholars and fundamentalists on various topics. Ex-Muslim of Kerala observes 9 January as ex-Muslim day, by conducting seminars on atheism and Islam.

Legal status, rights and laws

Atheism and irreligion are not officially recognised in India. Apostasy is allowed under the right to freedom of religion in the Constitution, and the Special Marriage Act, 1954 allows the marriage of people with no religious beliefs, as well as non-religious and non-ritualistic marriages. However, there are no specific laws catering to atheists and they are considered as belonging to the religion of their birth for administrative purposes. In forms, the box in which you need to fill in 'caste' and 'religion' is still present in a lot of forms. Some of these boxes on forms are also compulsory, and you do not always have the option of leaving them empty. The closest option you get is 'Choose not to say' or 'Other' as an answer to these boxes.

Ravi Kumar, an atheist from Haryana is another person who is struggling and fighting to be officially and legally irreligious and caste-less in India. He went to court to declare him officially atheist and he got one certificate in which it was mentioned that he had "No Caste, No Religion, & No God". Later, Justice Tejinder Singh Dhindsa of the Punjab and Haryana High Court said they had exceeded their authority and asked heim to return the certificate; he refused to do so. The Fatehabad district authorities who issued the cewrtificate wthdrew it in April 2019. Kumar plans to continue his quest to be officially declared an atheist.

Sneha Parthibaraja, a lawyer from Vellore was the first citizen in India to get an official 'no religion, no caste' certificate. She won this right on February 5, 2019, after a 9-year court battle. Indian actor Kamal Haasan, who is known for his atheism, congratulated her on Twitter for this achievement.

Hate speech laws and irreligion

Notable verdicts

On 29 October 2013, the Bombay High Court judged in favour of an atheist school teacher from Nashik. Sanjay Salve had been employed by the state-funded Savitribai Phule Secondary School since 1996. In June 2007, during a prayer session, Salve didn't fold his hands during the pledge or prayer. The school management called this indiscipline and refused him a higher pay grade in 2008 when Salve became eligible for it. Salve sought legal recourse citing the article 28 (a) of the Constitution which states "no person attending any educational institution recognised by the State or receiving aid out of State funds shall be required to take part in any religious instruction that may be imparted in such institution or to attend any religious worship that may be conducted in such institution". The court ruled in Salve's favour and directed the school to release his dues by 31 January 2014.

On 23 September 2014, the Bombay High Court declared that the government cannot force a person to state a religion on any document or form. The court also stated any citizen has the right to declare that he/she doesn't belong to any religion. The decision came in response to a Public Interest Litigation (PIL) filed by Ranjit Mohite, Kishore Nazare and Subhash Ranware, representing an organisation called Full Gospel Church of God, after the Maharashtra state printing press refused to issue them a gazette notification stating that they belonged to no religion. The petitioners stated that the organisation had 4000 members, and that they believe in Jesus Christ but they do not follow Christianity or any religion. Responding to the petition, the Maharashtra and the central governments had stated that "no religion" cannot be treated as a religion on official forms. The court cited the Article 25 of the Constitution, which guarantees right to freedom of conscience, while passing the verdict.

Persecution and attacks

Narendra Nayak, an advocate of atheism, has claimed to have been attacked three times and had his scooter damaged twice, with one of the attacks leaving him with head injuries. This compelled him to take self-defence lessons and carry a nunchaku. Megh Raj Mitter's house was surrounded by a mob after he debunked the Hindu milk miracle, forcing him to call the police.

On 15 March 2007, a bounty of 700,000 (equivalent to 1.8 million or US$24,000 in 2020) was announced on atheist Bangladeshi author Taslima Nasrin, while living in India, by a Muslim cleric named Maulana Tauqeer Raza Khan for allegedly writing derogatory statements about Prophet Mohammad in her work. In December 2013, an FIR was filed against Nasrin in Bareilly by a cleric named Hasan Raza Khan, for hurting religious sentiments. Nasrin had allegedly tweeted on Twitter that "In India, criminals who issue fatwas against women don't get punished." Raza Khan said that by accusing clerics of being criminals, Nasrin had hurt religious sentiments.

On 2 July 2011, the house of U. Kalanathan, secretary of the Kerala Yukthivadi Sangham, was attacked in Vallikunnu after he suggested on television that the temple treasures of Padmanabhaswamy Temple should be used for public welfare. On 20 August 2013, Narendra Dabholkar, a rationalist and anti-superstition campaigner, was assassinated.

On 16 February 2015, rationalist Govind Pansare and his wife were attacked by unknown gunmen. He later died from the wounds on 20 February. On 30 August 2015, M. M. Kalburgi, a scholar and rationalist, was shot dead at his home. He was known for his criticism of superstition and idol worship. Soon afterwards, another rationalist and author, K. S. Bhagwan, received a threatening letter. He had offended religious groups by criticizing the Gita.

In March 2017, 31-year-old A Farooq, an Indian Muslim youth from Coimbatore who became an atheist, was killed by members of a Muslim radical group.

Demographics

Indian government census

The Indian census does not explicitly count atheists. In the 2011 Census of India, the response form required the respondent to choose from six options under religion. The "Others" option was meant for minor or tribal religions as well as atheists and agnostics.

The religion data from 2011 Census of India was released in August 2015. It revealed that about 2,870,000 people had stated no religion in their response, about 0.27% of the nation's population. However, the number included atheists, rationalists and also those who believed in a higher power. K. Veeramani, a Dravidar Kazhagam leader, said that it was the first time the number of non-religious people was recorded in the census. However, he added that he believed that the number of atheists in India was actually higher as many people don't reveal their atheism out of fear.

Different surveys

World Values Survey (2006)

According to the 2006 World Values Survey, conducted by the Dentsu Communication Institute Inc, Japan Research Center (2006), 6.6% of Indians stated that they had no religion.

WIN-Gallup Global Index of Religion and Atheism

According to the 2005 Global Index of Religion and Atheism report from WIN-Gallup, 87% of Indians were religious and 4% called themselves atheists. According to the 2012 report by the same organisation, 81% of Indians were religious, 13% were non-religious, 3% were convinced atheists and 3% were unsure or did not respond.

Worldviews and Opinions of Scientists in India (2007)

In 2007, a survey was conducted by the Institute for the Study of Secularism in Society and Culture of the Trinity College with the help of Center for Inquiry (India) called Worldviews and Opinions of Scientists in India. 1100 scientists surveyed from 130 institutes. Most of them identified themselves as secular (59%) or somewhat secular (16%) but refused to be labelled irreligious. 83% defined secularism, as it appears in the Indian constitutions, as the separation of state and religion. But, 93% also defined it as tolerance of other religious philosophies. 20% equated secularism to atheism. Only 11% called themselves completely not spiritual. However, 8% reportedly said they would refuse to do stem cell research based on religious or moral convictions. Y. S. Rajan commented on this saying that most Indians don't feel there is a conflict between science and religion. Other the hand, Innaiah Narisetti, chairman of Centre for Inquiry (India) and Pushpa Bhargava, the former director of the Centre for Cellular and Molecular Biology, pointed out the lack of scientific temper among Indian scientists.

Religion Among Scientists in an International Context (2014)

In a survey conducted by Elaine Howard Ecklund of Rice University, it was found that:


India United Kingdom
Scientists who identified as nonreligious 6% 65%
Scientists who attend religious services on a regular basis (once a month or more) 32% 12%
Scientists who never attend religious services 19% 68%
Scientists who believe that there are basic truths in many religions 73% 49%
Scientists who believe in God 27% 11%
Scientists who believe in a higher power of some kind 38% 8%

The ongoing study has surveyed 1,581 scientists from UK and 1,763 from India.

Tuesday, May 17, 2022

Neuroepigenetics

From Wikipedia, the free encyclopedia

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

Mechanisms

Neuroepigenetic mechanisms regulate gene expression in the neuron. Often, these changes take place due to recurring stimuli. Neuroepigenetic mechanisms involve proteins or protein pathways that regulate gene expression by adding, editing or reading epigenetic marks such as methylation or acetylation. Some of these mechanisms include ATP-dependent chromatin remodeling, LINE1, and prion protein-based modifications. Other silencing mechanisms include the recruitment of specialized proteins that methylate DNA such that the core promoter element is inaccessible to transcription factors and RNA polymerase. As a result, transcription is no longer possible. One such protein pathway is the REST co-repressor complex pathway. There are also several non-coding RNAs that regulate neural function at the epigenetic level. These mechanisms, along with neural histone methylation, affect arrangement of synapses, neuroplasticity, and play a key role in learning and memory.

Methylation

DNA methyltransferases (DNMTs) are involved in regulation of the electrophysiological landscape of the brain through methylation of CpGs. Several studies have shown that inhibition or depletion of DNMT1 activity during neural maturation leads to hypomethylation of the neurons by removing the cell's ability to maintain methylation marks in the chromatin. This gradual loss of methylation marks leads to changes in the expression of crucial developmental genes that may be dosage sensitive, leading to neural degeneration. This was observed in the mature neurons in the dorsal portion of the mouse prosencephalon, where there was significantly greater amounts of neural degeneration and poor neural signaling in the absence of DNMT1. Despite poor survival rates amongst the DNMT1-depleted neurons, some of the cells persisted throughout the lifespan of the organism. The surviving cells reaffirmed that the loss of DNMT1 led to hypomethylation in the neural cell genome. These cells also exhibited poor neural functioning. In fact, a global loss of neural functioning was also observed in these model organisms, with the greatest amounts neural degeneration occurring in the prosencephalon.

Other studies showed a trend for DNMT3a and DNMT3b. However, these DNMT's add new methyl marks on unmethylated DNA, unlike DNMT1. Like DNMT1, the loss of DNMT3a and 3b resulted in neuromuscular degeneration two months after birth, as well as poor survival rates amongst the progeny of the mutant cells, even though DNMT3a does not regularly function to maintain methylation marks. This conundrum was addressed by other studies which recorded rare loci in mature neurons where DNMT3a acted as a maintenance DNMT. The Gfap locus, which codes for the formation and regulation of the cytoskeleton of astrocytes, is one such locus where this activity is observed. The gene is regularly methylated to downregulate glioma related cancers. DNMT inhibition leads to decreased methylation and increased synaptic activity. Several studies show that the methylation-related increase or decrease in synaptic activity occurs due to the upregulation or downregulation of receptors at the neurological synapse. Such receptor regulation plays a major role in many important mechanisms, such as the 'fight or flight' response. The glucocorticoid receptor (GR) is the most studied of these receptors. During stressful circumstances, there is a signaling cascade that begins from the pituitary gland and terminates due to a negative feedback loop from the adrenal gland. In this loop, the increase in the levels of the stress response hormone results in the increase of GR. Increase in GR results in the decrease of cellular response to the hormone levels. It has been shown that methylation of the I7 exon within the GR locus leads to a lower level of basal GR expression in mice. These mice were more susceptible to high levels of stress as opposed to mice with lower levels of methylation at the I7 exon. Up-regulation or down-regulation of receptors through methylation leads to change in synaptic activity of the neuron.

Hypermethylation, CpG islands, and tumor suppressing genes

CpG Islands (CGIs) are regulatory elements that can influence gene expression by allowing or interfering with transcription initiation or enhancer activity. CGIs are generally interspersed with the promoter regions of the genes they affect and may also affect more than one promoter region. In addition they may also include enhancer elements and be separate from the transcription start site. Hypermethylation at key CGIs can effectively silence expression of tumor suppressing genes and is common in gliomas. Tumor suppressing genes are those which inhibit a cell's progression towards cancer. These genes are commonly associated with important functions which regulate cell-cycle events. For example, PI3K and p53 pathways are affected by CGI promoter hypermethylation, this includes the promoters of the genes CDKN2/p16, RB, PTEN, TP53 and p14ARF. Importantly, glioblastomas are known to have high frequency of methylation at CGIs/promoter sites. For example, Epithelial Membrane Protein 3 (EMP3) is a gene which is involved in cell proliferation as well as cellular interactions. It is also thought to function as a tumor suppressor, and in glioblastomas is shown to be silenced via hypermethylation. Furthermore, introduction of the gene into EMP3-silenced neuroblasts results in reduced colony formation as well as suppressed tumor growth. In contrast, hypermethylation of promoter sites can also inhibit activity of oncogenes and prevent tumorigenesis. Such oncogenic pathways as the transformation growth factor (TGF)-beta signaling pathway stimulate cells to proliferate. In glioblastomas the overactivity of this pathway is associated with aggressive forms of tumor growth. Hypermethylation of PDGF-B, the TGF-beta target, inhibits uncontrolled proliferation.

Hypomethylation and aberrant histone modification

Global reduction in methylation is implicated in tumorigenesis. More specifically, wide spread CpG demethylation, contributing to global hypomethylation, is known to cause genomic instability leading to development of tumors. An important effect of this DNA modification is its transcriptional activation of oncogenes. For example, expression of MAGEA1 enhanced by hypomethylation interferes with p53 function.

Aberrant patterns of histone modifications can also take place at specific loci and ultimately manipulate gene activity. In terms of CGI promoter sites, methylation and loss of acetylation occurs frequently at H3K9. Furthermore, H3K9 dimethylation and trimethylation are repressive marks which, along with bivalent differentially methylated domains, are hypothesized to make tumor suppressing genes more susceptible to silencing. Abnormal presence or lack of methylation in glioblastomas are strongly linked to genes which regulate apoptosis, DNA repair, cell proliferation, and tumor suppression. One of the best known examples of genes affected by aberrant methylation that contributes to formation of glioblastomas is MGMT, a gene involved in DNA repair which encodes the protein O6-methylguanine-DNA methyltransferase. Methylation of the MGMT promoter is an important predictor of the effectiveness of alkylating agents to target glioblastomas. Hypermethylation of the MGMT promoter causes transcriptional silencing and is found in several cancer types including glioma, lymphoma, breast cancer, prostate cancer, and retinoblastoma.

Neuroplasticity

Neuroplasticity refers to the ability of the brain to undergo synaptic rearrangement as a response to recurring stimuli. Neurotrophin proteins play a major role in synaptic rearrangement, amongst other factors. Depletion of neurotrophin BDNF or BDNF signaling is one of the main factors in developing diseases such as Alzheimer's disease, Huntington's disease, and depression. Neuroplasticity can also occur as a consequence of targeted epigenetic modifications such as methylation and acetylation. Exposure to certain recurring stimuli leads to demethylation of particular loci and remethylation in a pattern that leads to a response to that particular stimulus. Like the histone readers, erasers and writers also modify histones by removing and adding modifying marks respectively. An eraser, neuroLSD1, is a modified version of the original Lysine Demethylase 1(LSD1) that exists only in neurons and assists with neuronal maturation. Although both versions of LSD1 share the same target, their expression patterns are vastly different and neuroLSD1 is a truncated version of LSD1. NeuroLSD1 increases the expression of immediate early genes (IEGs) involved in cell maturation. Recurring stimuli lead to differential expression of neuroLSD1, leading to rearrangement of loci. The eraser is also thought to play a major role in the learning of many complex behaviors and is way through which genes interact with the environment.

Neurodegenerative diseases

Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease known to progressively affect memory and incite cognitive degradation. Epigenetic modifications both globally and on specific candidate genes are thought to contribute to the etiology of this disease. Immunohistochemical analysis of post-mortem brain tissues across several studies have revealed global decreases in both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in AD patients compared with controls. However, conflicting evidence has shown elevated levels of these epigenetic markers in the same tissues. Furthermore, these modifications appear to be affected early on in tissues associated with the pathophysiology of AD. The presence of 5mC at the promoters of genes is generally associated with gene silencing. 5hmC, which is the oxidized product of 5mC, via ten-eleven-translocase (TET), is thought to be associated with activation of gene expression, though the mechanisms underlying this activation are not fully understood.

Regardless of variations in results of methylomic analysis across studies, it is known that the presence of 5hmC increases with differentiation and aging of cells in the brain. Furthermore, genes which have a high prevalence of 5hmC are also implicated in the pathology of other age related neurodegenerative diseases, and are key regulators of ion transport, neuronal development, and cell death. For example, over-expression of 5-Lipoxygenase (5-LOX), an enzyme which generates pro-inflammatory mediators from arachidonic acid, in AD brains is associated with high prevalence of 5hmC at the 5-LOX gene promoter region.

Amyotrophic Lateral Sclerosis

DNA modifications at different transcriptional sites have been shown to contribute to neurodegenerative diseases. These include harmful transcriptional alterations such as those found in motor neuron functionality associated with Amyotrophic Lateral Sclerosis (ALS). Degeneration of upper and lower motor neurons, which contributes to muscle atrophy in ALS patients, is linked to chromatin modifications among a group of key genes. One important site that is regulated by epigenetic events is the hexanucleotide repeat expansion in C9orf72 within the chromosome 9p21. Hypermethylation of the C9orf72 related CpG Islands is shown to be associated with repeat expansion in ALS affected tissues. Overall, silencing of the C9orf72 gene may result in haploinsufficiency, and may therefore influence the presentation of disease. The activity of chromatin modifiers is also linked to prevalence of ALS. DNMT3A is an important methylating agent and has been shown to be present throughout the central nervous systems of those with ALS. Furthermore, over-expression of this de novo methyl transferase is also implicated in cell death of motor-neuron analogs.

Mutations in the FUS gene, that encodes an RNA/DNA binding protein, are causally linked to ALS. ALS patients with such mutations have increased levels of DNA damage. The protein encoded by the FUS gene is employed in the DNA damage response. It is recruited to DNA double-strand breaks and catalyzes recombinational repair of such breaks. In response to DNA damage, the FUS protein also interacts with histone deacetylase I, a protein employed in epigenetic alteration of histones. This interaction is necessary for efficient DNA repair. These findings suggest that defects in epigenetic signalling and DNA repair contribute to the pathogenesis of ALS.

Neuro-oncology

A multitude of genetic and epigenetic changes in DNA profiles in brain cells are thought to be linked to tumorgenesis. These alterations, along with changes in protein functions, are shown to induce uncontrolled cell proliferation, expansion, and metastasis. While genetic events such as deletions, translocations, and amplification give rise to activation of oncogenes and deactivation of tumor suppressing genes, epigenetic changes silence or up-regulate these same genes through key chromatin modifications.

Neurotoxicity

Neurotoxicity refers to damage made to the central or peripheral nervous systems due to chemical, biological, or physical exposure to toxins. Neurotoxicity can occur at any age and its effects may be short-term or long-term, depending on the mechanism of action of the neurotoxin and degree of exposure.

Certain metals are considered essential due to their role in key biochemical and physiological pathways, while the remaining metals are characterized as being nonessential. Nonessential metals do not serve a purpose in any biological pathway and the presence and accumulation in the brain of most can lead to neurotoxicity. These nonessential metals, when found inside the body compete with essential metals for binding sites, upset antioxidant balance, and their accumulation in the brain can lead to harmful side effects, such as depression and intellectual disability. An increase in nonessential heavy metal concentrations in air, water and food sources, and household products has increased the risk of chronic exposure.

Acetylation, methylation and histone modification are some of the most common epigenetic markers. While these changes do not directly affect the DNA sequence, they are able to alter the accessibility to genetic components, such as the promoter or enhancer regions, necessary for gene expression. Studies have shown that long-term maternal exposure to lead (Pb) contributes to decreased methylation in areas of the fetal epigenome, for example the interspaced repetitive sequences (IRSs) Alu1 and LINE-1. The hypomethylation of these IRSs has been linked to increased risk for cancers and autoimmune diseases later in life. Additionally, studies have found a relationship between chronic prenatal Pb exposure and neurological diseases, such as Alzheimer's and schizophrenia, as well as developmental issues. Furthermore, the acetylation and methylation changes induced by overexposure to lead result in decreased neurogenesis and neuron differentiation ability, and consequently interfere with early brain development.

Overexposure to essential metals can also have detrimental consequences on the epigenome. For example, when manganese, a metal normally used by the body as a cofactor, is present at high concentrations in the blood it can negatively affect the central nervous system. Studies have shown that accumulation of manganese leads to dopaminergic cell death and consequently plays a role in the onset of Parkinson's disease (PD). A hallmark of Parkinson's disease is the accumulation of α-Synuclein in the brain. Increased exposure to manganese leads to the downregulation of protein kinase C delta (PKCδ) through decreased acetylation and results in the misfolding of the α-Synuclein protein that allows aggregation and triggers apoptosis of dopaminergic cells.

Research

The field has only recently seen a growth in interest, as well as in research, due to technological advancements that facilitate better resolution of the minute modifications made to DNA. However, even with the significant advances in technology, studying the biology of neurological phenomena, such as cognition and addiction, comes with its own set of challenges. Biological study of cognitive processes, especially with humans, has many ethical caveats. Some procedures, such as brain biopsies of Rett Syndrome patients, usually call for a fresh tissue sample that can only be extricated from the brain of deceased individual. In such cases, the researchers have no control over the age of brain tissue sample, thereby limiting research options. In case of addiction to substances such as alcohol, researchers utilize mouse models to mirror the human version of the disease. However, the mouse models are administered greater volumes of ethanol than humans normally consume in order to obtain more prominent phenotypes. Therefore, while the model organism and the tissue samples provide an accurate approximation of the biology of neurological phenomena, these approaches do not provide a complete and precise picture of the exact processes underlying a phenotype or a disease.

Neuroepigenetics had also remained underdeveloped due to the controversy surrounding the classification of genetic modifications in matured neurons as epigenetic phenomena. This discussion arises due to the fact that neurons do not undergo mitosis after maturation, yet the conventional definition of epigenetic phenomena emphasizes heritable changes passed on from parent to offspring. However, various histone modifications are placed by epigenetic modifiers such as DNA methyltransferases (DNMT) in neurons and these marks regulate gene expression throughout the life span of the neuron. The modifications heavily influence gene expression and arrangement of synapses within the brain. Finally, although not inherited, most of these marks are maintained throughout the life of the cell once they are placed on chromatin.

Hypokinesia

From Wikipedia, the free encyclopedia
 
Hypokinesia
SpecialtyPsychiatry, neurology

Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a symptom of Parkinson's disease shown as muscle rigidity and an inability to produce movement. It is also associated with mental health disorders and prolonged inactivity due to illness, amongst other diseases.

The other category of movement disorder is hyperkinesia that features an exaggeration of unwanted movement, such as twitching or writhing in Huntington's disease or Tourette syndrome.

Spectrum of disorders

Hypokinesia describes a variety of more specific disorders:

Hypokinetic disorder Characteristics
Akinesia (α- a-, "without", κίνησις kinēsis, "motion") Inability to initiate voluntary movement.
Bradykinesia (βραδύς bradys, "slow", κίνησις kinēsis, "motion") Slowness of initiation of voluntary movement with a progressive reduction in speed and range of repetitive actions, such as voluntary finger-tapping. It occurs in Parkinson's disease and other disorders of the basal ganglia. It is one of the four key symptoms of parkinsonism, which are bradykinesia, tremor, rigidity, and postural instability.
Dysarthria A condition which affects the muscles necessary for speech, it causes difficulty in speech production despite a continued cognitive understanding of language. Often caused by Parkinson's disease, patients experience weakness, paralysis, or lack of coordination in the motor-speech system, causing respiration, phonation, prosody, and articulation to be affected. Problems including tone, speed of communication, breath control, volume, and timing are displayed. Hypokinetic dysarthria particularly affects the volume of speech, prompting treatment with a speech language pathologist.
Dyskinesia This is characterized by a diminished ability for voluntary movements, as well as the presence of involuntary movements. The hands and upper body are the areas most likely to be affected by tremors and tics. In some cases, Parkinson's patients experience dyskinesia as a negative side effect of dopamine medications.
Dystonia A movement disorder characterised by sustained muscle contractions, frequently causing twisted and repetitive movements, or abnormal postures.
Freezing This is characterized by an inability to move muscles in any desired direction.
Neuroleptic malignant syndrome Resulting from heavy exposure to drugs that block dopamine receptors, victims can experience fever, rigidity, mental status change, dysautonomia, tremors, dystonia, and myoclonus. While this disorder is extremely rare, immediate attention is necessary because of the high risk of death.
Rigidity Resistance to externally imposed ("passive") joint movements, such as when a doctor flexes a patient's arm at the elbow joint. It does not depend on imposed speed and can be elicited at very low speeds of passive movement in both directions. Cogwheel rigidity and leadpipe rigidity are two types identified with Parkinson's disease:
  • Leadpipe rigidity is sustained resistance to passive movement throughout the whole range of motion, with no fluctuations.
  • Cogwheel rigidity is jerky resistance to passive movement as muscles tense and relax.

Spasticity, a special form of rigidity, is present only at the start of passive movement. It is rate-dependent and only elicited upon a high-speed movement. These various forms of rigidity can be seen in different forms of movement disorders, such as Parkinson's disease.

Postural instability A disturbance in balance that impairs the ability to maintain an upright posture when standing and walking. In Parkinsons disease it is correlated with greater disability and more depression, as well as with frequency of falls and fear of falls (which, itself, can be significantly disabling).

A person with medication-induced dystonia

Causes

The most common cause of Hypokinesia is Parkinson's disease, and conditions related to Parkinson's disease.

Other conditions may also cause slowness of movements. These include hypothyroidism and severe depression. These conditions need to be carefully ruled out, before a diagnosis of Parkinsonism is made.

The remainder of this article describes Hypokinesia associated with Parkinson's disease, and conditions related to Parkinson's disease.

Pathophysiology

Associated neurotransmitters

Dopamine

The main neurotransmitter thought to be involved in hypokinesia is dopamine. Essential to the basal ganglionic-thalamocortical loop, which processes motor function, dopamine depletion is common in these areas of hypokinesic patients. Bradykinesia is correlated with lateralized dopaminergic depletion in the substantia nigra. The dopamine pathway in the substantia nigra is essential to motor function, and commonly a lesion in this area correlates with displayed hypokinesia. Tremor and rigidity, however, seem to be only partially due to dopamine deficits in the substantia nigra, suggesting other processes are involved in motor control. Treatments for hypokinesia often either attempt to prevent dopamine degradation by MAO-B or increase the amount of neurotransmitter present in the system.

GABA and glutamate

The inhibitory neurotransmitter GABA and the excitatory glutamate are found in many parts of the central nervous system, including in the motor pathways that involve hypokinesia. In one pathway, glutamate in the substantia nigra excites the release of GABA into the thalamus, which then inhibits the release of glutamate in the cortex and thereby reduces motor activity. If too much glutamate is initially in the substantia nigra, then through interaction with GABA in the thalamus and glutamate in the cortex, movements will be reduced or will not occur at all.

Another direct pathway from the basal ganglia sends GABA inhibitory messages to the globus pallidus and substantia nigra, which then send GABA to the thalamus. In the indirect pathway, the basal ganglia send GABA to the globus pallidus which then sends it to the subthalamic nucleus, which then disinhibited sends glutamate to the output structures of the basal ganglia. Inhibition of GABA release could disrupt the feedback loop to the basal ganglia and produce hypokinesic movements.

GABA and glutamate often interact with each other and with dopamine directly. In the basal ganglia, the nigrostriatal pathway is where GABA and dopamine are housed in the same neurons and released together.

Neurobiology

Hypokinetic symptoms arise from damage to the basal ganglia, which plays a role in producing force and computing the effort necessary to make a movement. Two possible neural pathways enable the basal ganglia to produce movement. When activated, the direct pathway sends sensory and motor information from the cerebral cortex to the first structure of the basal ganglia, the putamen. That information directly inhibits the globus pallidus internal and allows free movement. The indirect pathway, traveling through the putamen, globus pallidus external, and subthalamic nucleus, activates the globus pallidus internal threshold and inhibits the thalamus from communicating with the motor cortex, producing hypokinetic symptoms.

Basal ganglia (red) and related structures (blue)

When levels of dopamine decrease, the normal wave-firing pattern of basal ganglia neural oscillations changes and the tendency for oscillations increases, particularly in the beta wave of the basal ganglia. Recent research indicates, when oscillations fire simultaneously, processing is disrupted at the thalamus and cortex, affecting activities such as motor planning and sequence learning, as well as causing hypokinetic tremors.

Treatments

Dopaminergic drugs

Dopaminergic drugs are commonly used in the early stages of the hypokinesia to treat patients. With increased intake, though, they can become ineffective because of the development of noradrenergic lesions. While initially the dopaminergic drugs may be effective, these noradrenergic lesions are associated with hypokinesic gait disorder development later on.

Some Parkinson's patients are unable to move during sleep, prompting the diagnosis of "nocturnal hypokinesia". Physicians have experienced success treating this sleep disorder with slow-release or night-time dopaminergic drugs, and in some cases, continuous stimulation by the dopamine agonist rotigotine. Despite improved mobility during sleep, many Parkinson's patients report an extremely uncomfortable sleeping experience even after dopaminergic treatments.

Deep brain stimulation

Once the reaction to dopaminergic drugs begins to fluctuate in Parkinson's patients, deep brain stimulation (DBS) of the subthalamic nucleus and internal globus pallidus is often used to treat hypokinesia. DBS, like dopaminergic drugs, initially provides relief, but chronic use causes worse hypokinesia and freezing of gait. Lower-frequency DBS in irregular patterns has been shown to be more effective and less detrimental in treatment.

Parkinson surgery

Posteroventral pallidotomy (PVP) is a specific kind of DBS that destroys a small part of the globus pallidus by scarring the neural tissue, reducing brain activity and therefore tremors and rigidity. PVP is suspected to recalibrate basal ganglia activity in the thalamocortical pathway. PVP in the dominant hemisphere has been reported to disrupt executive function verbal processing abilities, and bilateral PVP may disturb processes of focused attention.

Many akinesia patients also form a linguistic akinesia in which their ability to produce verbal movements mirrors their physical akinesia symptoms, especially after unsuccessful PVP. Patients are usually able to maintain normal levels of fluency, but often stop midsentence, unable to remember or produce a desired word. According to a study of Parkinson's patients with articulatory hypokinesia, subjects with faster rates of speech experienced more problems trying to produce conversational language than those who normally spoke at slower rates.

Methylphenidate

Methylphenidate, commonly used to treat ADHD, has been used in conjunction with levodopa to treat hypokinesia in the short term. The two work together to increase dopamine levels in the striatum and prefrontal cortex. Methylphenidate mainly inhibits dopamine and noradrenaline reuptake by blocking presynaptic transporters, and levodopa increases the amount of dopamine, generally improving hypokinesic gait. Some patients, however, have adverse reactions of nausea and headache to the treatment and the long-term effects of the drug treatment still need to be assessed.

Stem cells

New treatments include increasing the number of dopamine cells by transplanting stem cells into the basal ganglia or stimulating endogenous stem cell production and movement to the basal ganglia. The successful integration of stem cells can relieve hypokinetic symptoms and decrease the necessary dose of dopaminergic drugs. However, a variety of complications, including possible tumor formation, inappropriate cell migration, rejection of cells by the immune system, and cerebral hemorrhage are possible, causing many physicians to believe the risks outweigh the possible benefits.

NOP receptor antagonists

Another treatment, still in an experimental stage, is the administration of nociception FQ peptide (NOP) receptor antagonists. This treatment has been shown to reduce hypokinesia in animal studies when increasing nociception FQ in the substantia nigra and subthalamic nucleus. Low doses can be taken with dopaminergic treatment to decrease the amount of L-dopa needed, which can reduce its long-term side effects and improve motor performance.

Dance therapy

Dance therapy has also been shown to reduce hypokinesic movements and rigidity, though targeted more at the muscular aspects of the disorder than the neural activity.

Associations

Cognitive impairment

Bradykinesia has been shown to precede impairment of executive functions, working memory, and attention. These cognitive deficiencies can be tied to nonfunction of the basal ganglia and prefrontal cortex, which is also linked to the motor-dysfunction of hypokinesia. Tremor and rigidity have not had observable connections to cognitive impairments, supporting the idea that they are not as involved in the dopamine pathway in the basal ganglionic-thalamocortical loop. Dopaminergic treatments have shown improvement in cognitive functions associated with hypokinesia, suggesting they are also dependent on dopamine levels in the system.

Motor motivation

Often debated is whether the efficiency, vigor, and speed of movements in patients with hypokinesia are tied to motivation for rewarding and against punishing stimuli. The basal ganglia have been tied to the incentives behind movement, therefore suggesting a cost/benefit analysis of planned movement could be affected in hypokinesia. Rewards have not been shown to change the aspects of a hypokinesic individual's movement. In fact, the motor planning and control of a patient with hypokinesia is already as efficient as possible (as shown by slightly faster, but generally the same movement after deep brain stimulation of the subthalamic nucleus). This suggests that hypokinetic individuals simply have a narrower range of movement that does not increase relative to motivation.

Other studies have come to the same conclusion about rewards and hypokinesia, but have shown that aversive stimuli can, in fact, reduce hypokinesic movement. Dopamine is either less involved or has a more complex role in the response to punishment than it does to rewards, as the hypodopaminergic striatum allows more movement in response to aversive stimuli.

Demographic differentiation

Gender

More men than women typically develop hypokinesia, which is reflected in young and middle-aged populations where females have displayed higher levels of nigrostriatal dopamine than males. In the elderly, however, this differentiation is not present. Typically, women exhibit more tremor in the beginning development of hypokinesia. In the disorder, men tend to display more rigidity and women more bradykinesic motor behavior.

Age of onset

Hypokinesia is displayed in the brain and outwardly slightly different depending on when an individual is first affected. In young-onset hypokinesia (younger than 45 years of age), typically slightly more cell loss occurs in the substantia nigra with more displayed dystonia and muscle stiffness. In old-onset hypokinesia (older than 70 years of age), typically more of a hypokinesic gait and difficulty walking and no dystonia are seen. Both onsets can display resting tremor, although more generally found in old-onset cases.

Symptoms

Stress causes alterations of cerebral circulation, increasing blood flow in the supramarginal gyrus and angular gyrus of the parietal lobe, the frontal lobe, and the superior temporal gyrus of the left hemisphere. Also, an increase in cardiac activity and change in the tonus of the heart vessels occurs, which is an elementary indication of stress development. In patients with normal stress, an adaptive fight-or-flight response is usually triggered by sympathetic nervous system activation. Hypokinesia patients experience these typical stress symptoms on a regular basis because of damage to the basal ganglia system. Therefore, when a hypokinesia victim is under stress, he or she does not display a typical fight-or-flight response, placing the patient under greater danger from potentially harmful stimuli. Low-impact exercise, elimination of drug and alcohol use, and regular meditation can help to restore normal stress responses in hypokinesia patients.

Connections to other medical conditions

Though it is often most associated with Parkinson's disease, hypokinesia can be present in a wide variety of other conditions.

Condition Connection to hypokinesia
Stroke Damage to certain areas of the brain due to lack of oxygenation has been found to cause hypokinetic symptoms. Frontal and subcortical lesions caused by stroke are more likely to cause hypokinesia than posterior lesions.
Schizophrenia The lack of connections between the right supplementary motor area to the pallidum and the left primary motor cortex to the thalamus shown in patients with schizophrenia is thought to lead to hypokinesia.
Hyperammonemia Chronic hyperammonemia and liver disease can alter neurotransmission of GABA and glutamate by increasing the amount of glutamate in the substantia nigra and inhibiting movement.
Progressive supranuclear palsy Very similar to Parkinson's disease, supranuclear palsy does not actually display the hypokinetic characteristic of progressive loss of movement, despite small amplitude. Diagnosis of hypokinesia can help to distinguish this disorder from Parkinson's.

Alcohol and pregnancy

From Wikipedia, the free encyclopedia
 
Alcohol and pregnancy
Photo of baby with FAS.jpg
Baby with fetal alcohol syndrome, showing some of the characteristic facial features
SpecialtyGynaecology Neonatology Pediatrics Psychiatry Obstetrics Toxicology
ComplicationsMiscarriage Stillbirth

Alcohol use in pregnancy includes use of alcohol at any time during gestation, including the time before a mother-to-be is aware that she is pregnant. Alcohol use at some point during pregnancy is common and appears to be rising in prevalence.

Alcohol use during pregnancy has been associated with spontaneous abortion, stillbirth, low birthweight, and prematurity, along with a variety of birth defects and developmental abnormalities with ranging severity. Defects caused by gestational exposure to alcohol are collectively referred to as Fetal alcohol spectrum disorders (FASDs), with the most severe form termed fetal alcohol syndrome (FAS). However, not all pregnancies complicated by alcohol use will result in spontaneous abortion, stillbirth, low birthweight, and prematurity, and not all infants exposed to alcohol in utero will have FASDs or FAS.

The variance seen in outcomes of alcohol consumption during pregnancy is poorly understood, however genetic and social risk factors for more severe outcomes have both been suggested. The effect of quantity and gestational timing of alcohol consumption is also poorly understood. However, there is no amount of alcohol that is known to be safe to drink while pregnant, and there is no safe time point or trimester of pregnancy during which alcohol consumption has been proven to be safe. Therefore, medical consensus is to recommend complete abstinence from alcohol during pregnancy.

Some evidence suggests that the likelihood of FASD, FAS, miscarriage and stillbirth increases with higher quantity and longer duration of alcohol consumption during pregnancy. Therefore, it is never too late to reduce the likelihood of FASDs, FAS, and alcohol related pregnancy complications by avoiding or limiting alcohol use.

Embryology

Different body systems in the infant grow, mature and develop at specific times during gestation. The consumption of alcohol during one or more of these developmental stages may only result in one or few conditions.

During the first weeks of pregnancy babies grow at a rapid pace, even before the mothers know they are pregnant. From conception and to the third week, the most susceptible systems and organs are the brain, spinal cord, and heart. These crucial organs start forming in early stages of pregnancy, which are very sensitive and critical periods in human development. Though these body systems complete their development later in the pregnancy, the effects of alcohol consumption early in the pregnancy can result in defects to these systems and organs. During the fourth week of gestation, the limbs are being formed and it is at this point that alcohol can effect the development of arms, legs, fingers and toes. The eyes and ears also form during the fourth week and are more susceptible to the effects of alcohol. By the sixth week of gestation, the teeth and palate are forming and alcohol consumption at this time will affect these structures. Alcohol use in this window is responsible for many of the facial characteristics of fetal alcohol syndrome. By the 20th week of gestation the formation of organs and organ systems is well-developed. The infant is still susceptible to the damaging effects of alcohol. Therefore, it would be safer for women to stop drinking prior to trying to conceive.

The baby's brain, body, and organs are developing throughout pregnancy and can be affected by exposure to alcohol at any time. Because every pregnancy is different, drinking alcohol may hurt one baby more than another. A child that has been affected by alcohol before birth may appear 'normal' at birth. Intellectual disabilities may not appear until the child begins school.

According to a study done by the University of Houston, through the use of Speckle variance optical cohearance tomography (SVOCT), it was discovered that 45 minutes after pregnant mice were exposed to a binge like bolus of ethanol, a dramatic decrease in the size and number of blood vessels in the fetal brains of the mice was observed. Thus, demonstrating the magnitude of potential damage caused by a single prenatal alcohol exposure.

Alcohol during pregnancy

The developing fetus is exposed to the alcohol through the placenta and umbilical cord. Alcohol metabolizes slowly in the fetus and remains for a long time when compared to an adult because of re-uptake of alcohol-containing amniotic fluid. Alcohol exposure has serious implications on the developing fetus as well as the mother. When a woman is planning for pregnancy, she should keep in mind that there is no safe limit for alcohol consumption. It can lead to premature birth and problems may manifest later as the child continues to grow. One of the main problematic outcomes in the developing baby is fetal alcohol syndrome (FAS), which is characterized by: cleft palate and/or cleft lip, disproportionate physical development of the body, and various disabilities like attention deficiency, low memory and coordination ability, as well as improper functioning of various body organs like the kidneys, heart and bones. A large range of other developmental abnormalities are also associated with alcohol consumption during pregnancy, including an abnormal appearance, short height, low body weight, small head size, poor coordination, low intelligence, behavioral problems, hearing loss, and vision problems. These less severe outcomes are collectively termed Fetal alcohol spectrum disorders (FASDs). Those affected are more likely to have trouble in school, legal problems, participate in high-risk behaviors, and have trouble with alcohol and recreational drug use. Spontaneous abortion, stillbirth, low birthweight, and prematurity are other common outcomes, along with increased likelihood of domestic violence and potential harm to the infant.

These effects can be magnified especially during the first and third trimester of pregnancy when the baby is growing rapidly. Alcohol consumption in the first trimester of pregnancy, which is a crucial developmental stage of fetal growth, can have serious consequences. The developing fetus can be exposed to alcohol in the earliest weeks of pregnancy. During the third week, alcohol can affect the heart and central nervous system of the fetus. If the mother continues to drink, the eyes, legs and arms of the fetus can be adversely affected. Continuous exposure further through the sixth week can have negative impact on ear and teeth development. palate and external genitalia can be affected if the mother persists drinking. During the twelfth week, frequent alcohol exposure can negatively impact the brain development which affects cognitive, learning and behavioral skills before birth. Consumption of excessive alcohol can lead to Fetal Alcohol Syndrome which can produce irreversible lifetime changes in physical, mental and neurobehavioral development of the fetus. Alcohol during pregnancy not only affects the developing fetus, but it also has adverse health outcomes on the mother as well. It can harm the fertility of women who are planning for pregnancy. Adverse effects of alcohol can lead to malnutrition, seizures, vomiting and dehydration. The mother can suffer from anxiety and depression which can result in child abuse/neglect. It has also been observed that when the pregnant mother withdraws from alcohol, its effects are visible on the infant as well. The baby remains in an irritated mood, cries frequently, doesn't sleep properly, has weakening of sucking ability and increased hunger.

Alcohol consumption during pregnancy may increase the risk that the child will develop acute myeloid leukemia at a young age.

In the past, alcohol was used as a common tocolytic agent. Tocolytic agents are drugs that are used to prevent preterm labor (born at less than 37 weeks gestation) by suppressing uterine contraction. However, alcohol is no longer used in current practice due to safety concerns for the mother and her baby. A Cochrane Systematic Review has also shown that ethanol is no better than placebo (sugar water) to suppress preterm birth and neonatal mortality. Not only is ethanol worse than other beta-mimetic drugs (type of tocolytic agents) at postponing birth, it also leads to a higher rate of low birthweight babies, babies with breathing problems at birth and neonatal death.

Signs and symptoms

When an infant is born and appears to be healthy, they may still have non-visible disorders and organ defects due to exposure to alcohol during gestation. Social problems in children have been found to be associated with their mothers' alcohol use during pregnancy. Alcohol is a cause of microcephaly. Alcohol use during pregnancy does not effect the ability to breastfeed the infant – in addition, an infant may breastfeed even if their mother continues to consume alcohol after giving birth. An infant born to a mother with an alcohol dependency may go through alcohol withdrawal after the birth.

One of the major effects of alcohol consumption during pregnancy is Fetal Alcohol Spectrum Disorders (FASDs), of which Fetal Alcohol Syndrome (FAS) is the most severe form. It is shown that small amounts of alcohol consumed during pregnancy does not show any health related issues in the face, but behavioral issues can be seen. There is a wide range of symptoms seen in persons suffering from FASDs which include:

  • Abnormal facial features, such as a smooth ridge between the nose and upper lip (this ridge is called the philtrum)
  • Small head size
  • Shorter-than-average height
  • Low birth weight
  • Poor coordination
  • Hyperactive behavior
  • Difficulty with attention
  • Poor memory
  • Difficulty in school (especially with math)
  • Learning disabilities
  • Speech and language delays
  • Intellectual disability or low IQ
  • Poor reasoning and judgment skills
  • Sleep and sucking problems as a baby
  • Vision or hearing problems
  • Problems with the heart, kidneys or bones.

There are five types of FASDs depending on the symptoms:

(1) Fetal Alcohol Syndrome;

(2) Alcohol-Related Neurodevelopmental Disorder;

(3) Alcohol-Related Birth Defects;

(4) Static Encephalopathy;

(5) Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure.

There are three approaches to treatment of FAS:

(1) At Home – A stable and loving home, along with a regular routine, simple rules to follow and where rewards are given for positive behavior, is a good environment for children with FAS.

(2) Medications – Medications are used to specifically treat symptoms of FASDs and not FAS entirely. Some of the medications used are antidepressants, stimulants, neuroleptics and anti-anxiety drugs.

(3) Counseling – Children with FAS benefit from behavioral and functional training, social skill training and tutoring. Support groups and talk therapy not only help the children suffering from FAS, but also help the parents and siblings of these children.

Treatment

A woman may elect to discontinue alcohol once she discovers that she is pregnant. However, women can experience serious symptoms that accompany alcohol withdrawal during pregnancy. According to the World Health Organization, these symptoms can be treated during pregnancy with brief use of benzodiazepine tranquilizers.

Medications

Currently, the FDA has approved three medications—naltrexone, acamprosate, and disulfiram—for the treatment of alcohol use disorder (AUD). However, there is insufficient data regarding the safety of these medications for pregnant women.

  • Naltrexone is a nonselective opioid antagonist that is used to treat AUD and opioid use disorder. The long-term effects of naltrexone on the fetus are currently unknown. Animal studies show that naltrexone administered during pregnancy increases the incidence of early fetal loss; however, there are insufficient data available to identify the extent to which this is a risk in pregnant women.
  • Acamprosate functions as both an antagonist of NMDA and glutamate and an agonist at GABAA receptors, although its molecular mechanism is not completely understood. Acamprosate has been shown to be effective at preventing alcohol relapse during abstinence. Animal data, however, suggests that acamprosate can have possible teratogenic effects on fetuses.
  • Disulfiram prevents relapse by blocking the metabolism of acetaldehyde after consumption of alcohol which leads to headache, nausea, and vomiting. Some evidence suggests that disulfiram use during the first trimester is associated with an increased risk of congenital malformations such as reduction defects and cleft palate. Additionally, the effects of disulfiram can involve hypertension which can be harmful to both the pregnant woman and the fetus.

American Psychiatric Association guidelines recommend that medications not be used to treat alcohol use disorder in pregnant women except in cases of acute alcohol withdrawals or other co-existing conditions. Instead, behavioral interventions are usually preferred as treatments for pregnant women with AUD.  Medications should only be used for pregnant women after carefully considering potential risks and harms of the medications versus the benefits of alcohol cessation.

Epidemiology

Alcohol consumption during pregnancy is relatively common, and its prevalence has been on the rise. An estimated 7.6% of pregnant women use alcohol, while 1.4% of pregnant women report binge drinking during their pregnancy. The highest prevalence estimates of reported alcohol use during pregnancy were among women who are aged 35–44 years (14.3%), white (8.3%), college graduates (10.0%), or employed (9.6%). Furthermore, alcohol-related congenital abnormalities occur at an incidence of roughly one out of 67 women who drink alcohol during pregnancy. The use of alcohol during pregnancy occurs at different rates across the world, potentially due to various cultural differences and legislation. The five countries with the highest prevalence of alcohol use during pregnancy are Ireland (60%), Belarus (47%), Denmark (46%), the UK (41%), and the Russian Federation (37%).

One of the biggest challenges in uncovering the true prevalence of FAS and the associated disorders is understanding how to recognize the syndrome, which largely depends on the age and physical features of the individual being diagnosed. Using medical and other records, CDC studies have identified 0.2 to 1.5 infants with FAS for every 1,000 live births in certain areas of the United States. A more recent CDC study analyzed medical and other records and found FAS in 0.3 out of 1,000 children from 7 to 9 years of age.

Public health recommendations

Starting in 1981, the Surgeon General of the United States started releasing a warning asking pregnant women to abstain from alcohol for the remainder of gestation. The American Academy of Pediatrics issued a set of recommendations in 2015: "During pregnancy no amount of alcohol intake should be considered safe; there is no safe trimester to drink alcohol; all forms of alcohol, such as beer, wine, and liquor, pose similar risk; and binge drinking poses dose-related risk to the developing fetus." The World Health Organization recommends that alcohol should be avoided entirely during pregnancy, given the relatively unknown effects of even small amounts of alcohol during pregnancy. The United Kingdom's National Institute for Health and Clinical Excellence recommends "that if you're pregnant or planning to become pregnant, the safest approach is not to drink alcohol at all to keep risks to your baby to a minimum."

There has been some controversy surrounding the zero-tolerance approach taken by many countries toward alcohol consumption during pregnancy. A 2000 article wrote that the concern about the risk of FAS may be inflated beyond the level warranted by existing evidence of its prevalence and impact and argued that equating a low level of drinking with unavoidable harm to the fetus may have negative social, legal and health impacts.

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