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Sunday, July 21, 2019

Criticism of the War on Terror

From Wikipedia, the free encyclopedia

Criticism of the War on Terror addresses the morals, ethics, efficiency, economics, as well as other issues surrounding the War on Terror. It also touches upon criticism against the phrase itself, which was branded as a misnomer. The notion of a "war" against "terrorism" has proven highly contentious, with critics charging that participating governments exploited it to pursue long-standing policy/military objectives, reduce civil liberties, and infringe upon human rights. It is argued that the term war is not appropriate in this context (as in War on Drugs), since there is no identifiable enemy and that it is unlikely international terrorism can be brought to an end by military means.

Other critics, such as Francis Fukuyama, note that "terrorism" is not an enemy, but a tactic: calling it a "war on terror" obscures differences between conflicts such as anti-occupation insurgents and international mujahideen. With a military presence in Iraq and Afghanistan and its associated collateral damage Shirley Williams maintains this increases resentment and terrorist threats against the West. Other criticism include United States hypocrisy, media induced hysteria, and that changes in American foreign and security policy have shifted world opinion against the US.

Terminology

Various critics dubbed the term "War on Terror" as nonsensical. For example, billionaire activist investor George Soros criticized the term "War on Terror" as a "false metaphor." Linguist George Lakoff of the Rockridge Institute argued that there cannot literally be a war on terror, since terror is an abstract noun. "Terror cannot be destroyed by weapons or signing a peace treaty. A war on terror has no end."

Jason Burke, a journalist who writes about radical Islamic activity, describes the terms "terrorism" and "war against terrorism" in this manner:
There are multiple ways of defining terrorism and all are subjective. Most define terrorism as 'the use or threat of serious violence' to advance some kind of 'cause'. Some state clearly the kinds of group ('sub-national', 'non-state') or cause (political, ideological, religious) to which they refer. Others merely rely on the instinct of most people when confronted with an act that involves innocent civilians being killed or maimed by men armed with explosives, firearms or other weapons. None is satisfactory and grave problems with the use of the term persist. Terrorism is after all, a tactic. The term 'war on terrorism' is thus effectively nonsensical. As there is no space here to explore this involved and difficult debate, my preference is, on the whole, for the less loaded term 'militancy'. This is not an attempt to condone such actions, merely to analyze them in a clearer way.

Perpetual war

Former U.S. President George W. Bush articulated the goals of the War on Terror in a September 20, 2001 speech, in which he said that it "will not end until every terrorist group of global reach has been found, stopped and defeated."  In that same speech, he called the war "a task that does not end", an argument he reiterated in 2006 State of The Union address.

Preventive war

One justification given for the invasion of Iraq was to prevent terroristic, or other attacks, by Iraq on the United States or other nations. This can be viewed as a conventional warfare realization of the War on Terror. 

A major criticism leveled at this justification is that it does not fulfill one of the requirements of a just war and that in waging war preemptively, the United States undermined international law and the authority of the United Nations, particularly the United Nations Security Council. On this ground, by invading a country that did not pose an imminent threat without UN support, the U.S. violated international law, including the UN Charter and the Nuremberg principles, therefore committing a war of aggression, which is considered a war crime. Additional criticism raised the point that the United States might have set a precedent, under the premise of which any nation could justify the invasion of other states. 

Richard N. Haass, president of the Council on Foreign Relations, argues that on the eve of U.S. intervention in 2003, Iraq represented, at best, a gathering threat and not an imminent one. In hindsight he notes that Iraq did not even represent a gathering threat. "The decision to attack Iraq in March 2003 was discretionary: it was a war of choice. There was no vital American interests in imminent danger and there were alternatives to using military force, such as strengthening existing sanctions." However, Haass argues that U.S. intervention in Afghanistan in 2001 began as a war of necessity—vital interests were at stake—but morphed "into something else and it crossed a line in March 2009, when President Barack Obama` decided to sharply increase American troop levels and declared that it was U.S. policy to 'take the fight to the Taliban in the south and east' of the country." Afghanistan, according to Haass, eventually became a war of choice.

War on Terror seen as pretext

Excerpts from an April 2006 report compiled from sixteen U.S. government intelligence agencies has strengthened the claim that engaging in Iraq has increased terrorism in the region.

Domestic civil liberties

Picture of Satar Jabar, one of the prisoners subjected to torture at Abu Ghraib. Abar was in Abu Ghraib for carjacking.

In the United Kingdom, critics have claimed that the Blair government used the War on Terror as a pretext to radically curtail civil liberties, some enshrined in law since Magna Carta. For example, the detention-without-trial in Belmarsh prison: controls on free speech through laws against protests near Parliament and laws banning the "glorification" of terrorism: and reductions in checks on police power, as in the case of Jean Charles de Menezes and Mohammed Abdul Kahar.

Former Liberal Democrat Leader Sir Menzies Campbell has also condemned Blair's inaction over the controversial U.S. practice of extraordinary rendition, arguing that the human rights conventions to which the UK is a signatory (e.g. European Convention on Human Rights) impose on the government a "legal obligation" to investigate and prevent potential torture and human rights violations.

Unilateralism

U.S. President George W. Bush's remark of November 2001 claiming that "You're either with us or you are with the terrorists," has been a source of criticism. Thomas A. Keaney of Johns Hopkins University's Foreign Policy Institute said "it made diplomacy with a number of different countries far more difficult because obviously there are different problems throughout the world."

As a war against Islam

Since the War on Terror revolved primarily around the United States and other NATO states intervening in the internal affairs of Muslim countries (i.e. in Iraq, Afghanistan, etc.) and organisations, it has been labelled a war against Islam by ex-United States Attorney General Ramsey Clark, among others. After his release from Guantanamo in 2005, ex-detainee Moazzam Begg appeared in the Islamist propaganda video 21st Century CrUSAders and claimed the U.S. was engaging in a new crusade:
I think that history is definitely repeating itself and for the Muslim world and I think even a great part of the non-Muslim world now, are beginning to recognize that there are ambitions that the United States has on the lands and wealth of nations of Islam.

Methods

Protestors dressed as hooded detainees and holding WCW signs in Washington DC on January 4, 2007

Aiding terrorism

Each month, there are more suicide terrorists trying to kill Americans and their allies in Afghanistan, Iraq, as well as other Muslim countries than in all the years before 2001 combined. From 1980 to 2003, there were 343 suicide attacks around the world and at most 10 percent were anti-American inspired. Since 2004, there have been more than 2,000, over 91 percent against U.S. and allied forces in Afghanistan, Iraq, as well as other countries.
Robert Pape
 
University of Chicago professor and political scientist, Robert Pape has written extensive work on suicide terrorism and states that it is triggered by military occupations, not extremist ideologies. In works such as Dying to Win: The Strategic Logic of Suicide Terrorism and Cutting the Fuse, he uses data from an extensive terrorism database and argues that by increasing military occupations, the US government is increasing terrorism. Pape is also the director and founder of the Chicago Project on Security and Terrorism (CPOST), a database of every known suicide terrorist attack from 1980 to 2008. 

In 2006, a National Intelligence Estimate stated that the war in Iraq has increased the threat of terrorism. The estimate was compiled by 16 intelligence agencies and was the first assessment of global terrorism since the start of the Iraq war.

Cornelia Beyer explains how terrorism increased as a response to past and present military intervention and occupation, as well as to 'structural violence'. Structural violence, in this instance, refers to economic conditions of backwardness which are attributed to the economic policies of the Western nations, the United States in particular.

British Liberal Democrat politician Shirley Williams wrote that the United States and United Kingdom governments "must stop to think whether it is sowing the kind of resentment which is the seedbed of future terrorism." The United Kingdom ambassador to Italy, Ivor Roberts, echoed this criticism when he stated that President Bush was "the best recruiting sergeant ever for al Qaeda." The United States also granted "protected persons" status under the Geneva Convention to the Mojahedin-e-Khalq, an Iranian group classified by the U.S. Department of State as a terrorist organization, sparking criticism. Other critics further noted that the American government granted political asylum to several alleged terrorists and terrorist organizations that seek to overthrow Fidel Castro's regime, while the American government claims to be anti-terrorism.

In 2018, New York Times terrorism reporter Rukmini Callimachi said "there are more terrorists now than there are on the eve of September 11, not less...There are more terror groups now, not less."

Hypocrisy of the Bush Administration

The alleged mastermind behind the September 11, 2001 attacks was part of the mujahideen who were sponsored, armed, trained and aided by the CIA to fight the Soviet Union after it intervened in Afghanistan in 1979.

Venezuela accused the U.S. government of having a double standard towards terrorism for giving safe haven to Luis Posada Carriles. Some Americans also commented on the selective use of the term War on Terrorism, including 3 star general William Odom, formerly President Reagan's NSA Director, who wrote:
As many critics have pointed, out, terrorism is not an enemy. It is a tactic. Because the United States itself has a long record of supporting terrorists and using terrorist tactics, the slogans of today's war on terrorism merely makes the United States look hypocritical to the rest of the world. A prudent American president would end the present policy of "sustained hysteria" over potential terrorist attacks..treat terrorism as a serious but not a strategic problem, encourage Americans to regain their confidence and refuse to let al Qaeda keep us in a state of fright.

Misleading information

In the months leading up to the invasion of Iraq, President Bush and members of his administration indicated they possessed information which demonstrated a link between Saddam Hussein and al-Qaeda. Published reports of the links began in late December 1998. In January 1999, Newsweek magazine published a story about Saddam Hussein and al-Qaeda joining forces to attack U.S. interests in the Gulf Region. ABC News broadcast a story of this link soon after. The Bush Administration believed there was a possibility of a potential collaboration between al Qaeda and Saddam Hussein's Ba'ath regime following the U.S. led invasion of Afghanistan. Amnesty International Secretary General Irene Khan criticized the use of pro-humanitarian arguments by Coalition countries prior to its 2003 invasion of Iraq, writing in an open letter: "This selective attention to human rights is nothing but a cold and calculated manipulation of the work of human rights activists. Let us not forget that these same governments turned a blind eye to Amnesty International's reports of widespread human rights violations in Iraq before the Gulf War."

Torture by proxy

The term "torture by proxy" is used by some critics to describe situations in which the CIA and other US agencies transferred supposed terrorists, whom they captured during their efforts in the 'War on terrorism', to countries known to employ torture as an interrogation technique. Some also claimed that US agencies knew torture was employed, even though the transfer of anyone to anywhere for the purpose of torture is a violation of US law. Nonetheless, Condoleezza Rice (then the United States Secretary of State) stated that:
the United States has not transported anyone and will not transport anyone, to a country when we believe he will be tortured. Where appropriate, the United States seeks assurances that transferred persons will not be tortured.
This US programme also prompted several official investigations in Europe into alleged secret detentions and unlawful inter-state transfers involving Council of Europe member states, including those related with the so-called War on Terrorism. A June 2006 report from the Council of Europe estimated that 100 people were kidnapped by the CIA on EU territory with the cooperation of Council of Europe members and rendered to other countries, often after having transited through secret detention centres ("black sites"), some located in Europe, utilised by the CIA. According to the separate European Parliament report of February 2007, the CIA has conducted 1,245 flights, many of them to destinations where these alleged 'terrorists' could face torture, in violation of article 3 of the United Nations Convention Against Torture.

Religionism and Islamophobia

One aspect of the criticism regarding the rhetoric justifying the War on Terror was religionism, or more specifically Islamophobia. Theologian Lawrence Davidson, who studies contemporary Muslims societies in North America, defines this concept as a stereotyping of all followers of Islam as real or potential terrorists due to alleged hateful and violent teaching of their religion. He goes on to argue that "Islam is reduced to the concept of jihad and Jihad is reduced to terror against the West." This line of argument echoes Edward Said’s famous piece Orientalism in which he argued that the United States sees the Muslims and Arabs in an essentialized caricatures – as oil supplies or potential terrorists.

Decreasing international support

In 2002, strong majorities supported the U.S.-led War on Terror in Britain, France, Germany, Japan, India and Russia, according to a sample survey conducted by the Pew Research Center. By 2006, supporters of the effort were in the minority in Britain (49%), Germany (47%), France (43%) and Japan (26%). Although a majority of Russians still supported the War on Terror, that majority had decreased by 21%. Whereas 63% of Spaniards supported the War on Terror in 2003, only 19% of the population indicated support in 2006. 19% of the Chinese population still supports the War on Terror and less than a fifth of the populations of Turkey, Egypt, as well as Jordan support the efforts. The report also indicated that Indian public support for the War on Terror has been stable. Andrew Kohut, while speaking to the U.S. House Committee on Foreign Affairs, noted that and according to the Pew Research Center polls conducted in 2004, "the ongoing conflict in Iraq continues to fuel anti-American sentiments. America’s global popularity plummeted at the start of military action in Iraq and the U.S. presence there remains widely unpopular."

Marek Obrtel, former Lieutenant Colonel in Field Hospital with Czech Republic army, returned his medals which he received during his posting in Afghanistan War for NATO operations. He criticized the War on Terror as describing the mission as "deeply ashamed that I served a criminal organization such as NATO, led by the USA and its perverse interests around the world."

Role of U.S. media

Researchers in communication studies and political science found that American understanding of the "War on Terror" is directly shaped by how mainstream news media reports events associated with the conflict. In Bush's War: Media Bias and Justifications for War in a Terrorist Age political communication researcher Jim A. Kuypers illustrated "how the press failed America in its coverage on the War on Terror." In each comparison, Kuypers "detected massive bias on the part of the press." This researcher called the mainstream news media an "anti-democratic institution" in his conclusion. "What has essentially happened since 9/11 has been that Bush has repeated the same themes and framed those themes the same whenever discussing the War on Terror," said Kuypers. "Immediately following 9/11, the mainstream news media (represented by CBS, ABC, NBC, USA Today, The New York Times, as well as The Washington Post) did echo Bush, but within eight weeks it began to intentionally ignore certain information the president was sharing and instead reframed the president's themes or intentionally introduced new material to shift the focus." 

This goes beyond reporting alternate points of view, which is an important function of the press. "In short," Kuypers explained, "if someone were relying only on the mainstream media for information, they would have no idea what the president actually said. It was as if the press were reporting on a different speech." The study is essentially a "comparative framing analysis." Overall, Kuypers examined themes about 9-11 and the War on Terror that President Bush used and compared them to themes that the press used when reporting on what he said.

"Framing is a process whereby communicators, consciously or unconsciously, act to construct a point of view that encourages the facts of a given situation to be interpreted by others in a particular manner," wrote Kuypers. These findings suggest that the public is misinformed about government justification and plans concerning the War on Terror. 

Others have also suggested that press coverage contributed to a public confused and misinformed on both the nature and level of the threat to the U.S. posed by terrorism. In his book, Trapped in the War on Terror political scientist Ian S. Lustick, claimed, "The media have given constant attention to possible terrorist-initiated catastrophes and to the failures and weaknesses of the government's response." Lustick alleged that the War on Terror is disconnected from the real but remote threat terrorism poses and that the generalized War on Terror began as part of the justification for invading Iraq, but then took on a life of its own, fueled by media coverage. Scott Atran writes that "publicity is the oxygen of terrorism" and the rapid growth of international communicative networks renders publicity even more potent, with the result that "perhaps never in the history of human conflict have so few people with so few actual means and capabilities frightened so many."

Media researcher Stephen D. Cooper's analysis of media criticism Watching the Watchdog: Bloggers As the Fifth Estate contains several examples of controversies concerning mainstream reporting of the War on Terror. Cooper found that bloggers' criticisms of factual inaccuracies in news stories or bloggers' discovery of the mainstream press' failure to adequately verify facts before publication caused many news organizations to retract or change news stories. 

Cooper found that bloggers specializing in criticism of media coverage advanced four key points:
  • Mainstream reporting of the War on Terror has frequently contained factual inaccuracies. In some cases, the errors go uncorrected: moreover, when corrections are issued they usually are given far less prominence than the initial coverage containing the errors.
  • The mainstream press has sometimes failed to check the provenance of information or visual images supplied by Iraqi "stringers" (local Iraqis hired to relay local news).
  • Story framing is often problematic: in particular, "man-in-the-street" interviews have often been used as a representation of public sentiment in Iraq, in place of methodologically sound survey data.
  • Mainstream reporting has tended to concentrate on the more violent areas of Iraq, with little or no reporting of the calm areas.
David Barstow won the 2009 Pulitzer Prize for Investigative Reporting by connecting the Department of Defense to over 75 retired generals supporting the Iraq War on television and radio networks. The Department of Defense recruited retired generals to promote the war to the American public. Barstow also discovered undisclosed links between some retired generals and defense contractors. He reported that "the Bush administration used its control over access of information in an effort to transform the analysts into a kind of media Trojan horse".

British objections

The Director of Public Prosecutions and head of the Crown Prosecution Service in the UK, Ken McDonald, Britain's most senior criminal prosecutor, stated that those responsible for acts of terrorism such as the 7 July 2005 London bombings are not "soldiers" in a war, but "inadequates" who should be dealt with by the criminal justice system. He added that a "culture of legislative restraint" was needed in passing anti-terrorism laws and that a "primary purpose" of the violent attacks was to tempt countries such as Britain to "abandon our values." He stated that in the eyes of the UK criminal justice system, the response to terrorism had to be "proportionate and grounded in due process and the rule of law":
London is not a battlefield. Those innocents who were murdered...were not victims of war. And the men who killed them were not, as in their vanity they claimed on their ludicrous videos, 'soldiers'. They were deluded, narcissistic inadequates. They were criminals. They were fantasists. We need to be very clear about this. On the streets of London there is no such thing as a war on terror. The fight against terrorism on the streets of Britain is not a war. It is the prevention of crime, the enforcement of our laws and the winning of justice for those damaged by their infringement.
Stella Rimington, former head of the British intelligence service MI5 criticised the War on Terror as a "huge overreaction" and had decried the militarization and politicization of U.S. efforts to be the wrong approach to terrorism. David Miliband, former UK foreign secretary, has similarly called the strategy a "mistake". Nigel Lawson, former Chancellor of the Exchequer, called for Britain to end its involvement in the War in Afghanistan, describing the mission as "wholly unsuccessful and indeed counter-productive."

gamma-Aminobutyric acid

From Wikipedia, the free encyclopedia

gamma-Aminobutyric acid
Simplified structural formula
GABA molecule
Names
Preferred IUPAC name
4-Aminobutanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.235
EC Number 200-258-6
KEGG
MeSH gamma-Aminobutyric+Acid
PubChem CID
RTECS number ES6300000
UNII
Properties
C4H9NO2
Molar mass 103.120 g/mol
Appearance white microcrystalline powder
Density 1.11 g/mL
Melting point 203.7 °C (398.7 °F; 476.8 K)
Boiling point 247.9 °C (478.2 °F; 521.0 K)
130 g/100 mL
log P −3.17
Acidity (pKa)
  • 4.031 (carboxyl; H2O)
  • 10.556 (amino; H2O)
Hazards
Main hazards Irritant, Harmful
Lethal dose or concentration (LD, LC):
LD50 (median dose)
12,680 mg/kg (mouse, oral)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

gamma-Aminobutyric acid, or γ-aminobutyric acid /ˈɡæmə əˈmnbjuːˈtɪrɪk ˈæsɪd/, or GABA /ˈɡæbə/, is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.
GABA is sold as a dietary supplement.

Function

Neurotransmitter

GABA metabolism, involvement of glial cells
 
In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known:
The production, release, action, and degradation of GABA at a stereotyped GABAergic synapse
 
Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands. In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.

GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane potential), or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarizing. When the net flow of chloride is close to zero, the action of GABA is shunting. Shunting inhibition has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing the electrical resistance of the cell's membrane. Shunting inhibition can "override" the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA between neonatal and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory.

Brain development

While GABA is an inhibitory transmitter in the mature brain, its actions were thought to be primarily excitatory in the developing brain. The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl ions from the cell (that is, a depolarizing current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses.

In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator. The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.

GABA regulates the proliferation of neural progenitor cells the migration and differentiation the elongation of neurites and the formation of synapses.

GABA also regulates the growth of embryonic and neural stem cells. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression. GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.

Beyond the nervous system

mRNA expression of the embryonic variant of the GABA-producing enzyme GAD67 in a coronal brain section of a one-day-old Wistar rat, with the highest expression in subventricular zone (svz)
 
Besides the nervous system, GABA is also produced at relatively high levels in the insulin-producing β-cells of the pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighboring islet α-cells and inhibits them from secreting glucagon (which would counteract insulin’s effects).

GABA can promote the replication and survival of β-cells and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.

GABA has also been detected in other peripheral tissues including intestines, stomach, Fallopian tubes, uterus, ovaries, testes, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons or β-cells. GABAergic mechanisms have been demonstrated in various peripheral tissues and organs, which include the intestines, the stomach, the pancreas, the Fallopian tubes, the uterus, the ovaries, the testes, the kidneys, the urinary bladder, the lungs, and the liver.

Immune cells express receptors for GABA and administration of GABA can suppress inflammatory immune responses and promote "regulatory" immune responses, such that GABA administration has been shown to inhibit autoimmune diseases in several animal models.

In 2018, GABA has shown to regulate secretion of a greater number of cytokines. In plasma of T1D patients, levels of 26 cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.

In 2007, an excitatory GABAergic system was described in the airway epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of asthma. GABAergic systems have also been found in the testis and in the eye lens.

GABA occurs in plants.

Structure and conformation

GABA is found mostly as a zwitterion (i.e. with the carboxyl group deprotonated and the amino group protonated). Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favored due to the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighboring molecules. In solution, five different conformations, some folded and some extended, are found as a result of solvation effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.

History

In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.

In 1950, GABA was discovered as an integral part of the mammalian central nervous system.

In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibers GABA acts like stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.

Biosynthesis

GABAergic neurons which produce GABA
 
GABA is primarily synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter).

GABA can also be synthesized from putrescine by diamine oxidase and aldehyde dehydrogenase.

Traditionally it was thought that exogenous GABA did not penetrate the blood–brain barrier, however more current research indicates that it may be possible, or that exogenous GABA (i.e. in the form of nutritional supplements) could exert GABAergic effects on the enteric nervous system which in turn stimulate endogenous GABA production. The direct involvement of GABA in the glutamate–glutamine cycle makes the question of whether GABA can penetrate the blood-brain barrier somewhat misleading, because both glutamate and glutamine can freely cross the barrier and convert to GABA within the brain.

Catabolism

GABA transaminase enzyme catalyzes the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.

Pharmacology

Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects. Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.

In general, GABA does not cross the blood–brain barrier, although certain areas of the brain that have no effective blood–brain barrier, such as the periventricular nucleus, can be reached by drugs such as systemically injected GABA. At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH). GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual. Certain pro-drugs of GABA (ex. picamilon) have been developed to permeate the blood–brain barrier, then separate into GABA and the carrier molecule once inside the brain. Prodrugs allow for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism.

GABA enhanced the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats. It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.

Chemistry

Although in chemical terms, GABA is an amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term "amino acid", when used without a qualifier, refers specifically to an alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon so it is not incorporated into proteins.

GABAergic drugs

GABAA receptor ligands are shown in the following table:
Activity at GABAA Ligand
Orthosteric Agonist Muscimol, GABA, gaboxadol (THIP), isoguvacine, progabide, piperidine-4-sulfonic acid (partial agonist)
Positive allosteric modulators Barbiturates, benzodiazepines, neuroactive steroids niacin/niacinamide,, nonbenzodiazepiness (i.e. z-drugs, e.g. zolpidem, eszopiclone), etomidate, etaqualone, alcohol (ethanol),, theanine, methaqualone, propofol, stiripentol,, and anaesthetics (including volatile anaesthetics), glutethimide
Orthosteric (competive) Antagonist bicuculline, gabazine, thujone, flumazenil
Uncompetitive antagonist (e.g. channel blocker) picrotoxin, cicutoxin
Negative allosteric modulators neuroactive steroids (Pregnenolone sulfate), furosemide, oenanthotoxin, amentoflavone

Additionally, carisoprodol is an enhancer GABAA activity. Ro15-4513 is a reducer of GABAA activity. 

GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol, which then acts via the GABAA receptor.

skullcap and valerian are plants containing GABAergic substances. Furthermore, the plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.

Other GABAergic modulators include:

In plants

GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes. Evidence also suggests a role in cell signalling in plants.

Primary motor cortex

From Wikipedia, the free encyclopedia
 
Primary motor cortex
Ba4.png
Brodmann area 4 of human brain.
Blausen 0103 Brain Sensory&Motor.png
Primary motor cortex shown in green.
Details
Part ofPrecentral gyrus
ArteryAnterior cerebral Middle cerebral
Identifiers
Latincortex motorius primus
NeuroNames1910
NeuroLex IDnlx_143555
FMA224854

Animation. Primary motor cortex (Brodmann area 4) of the left cerebral hemisphere shown in red.
 
The primary motor cortex (Brodmann area 4) is a brain region that in humans is located in the dorsal portion of the frontal lobe. It is the primary region of the motor system and works in association with other motor areas including premotor cortex, the supplementary motor area, posterior parietal cortex, and several subcortical brain regions, to plan and execute movements. Primary motor cortex is defined anatomically as the region of cortex that contains large neurons known as Betz cells. Betz cells, along with other cortical neurons, send long axons down the spinal cord to synapse onto the interneuron circuitry of the spinal cord and also directly onto the alpha motor neurons in the spinal cord which connect to the muscles. 

At the primary motor cortex, motor representation is orderly arranged (in an inverted fashion) from the toe (at the top of the cerebral hemisphere) to mouth (at the bottom) along a fold in the cortex called the central sulcus. However, some body parts may be controlled by partially overlapping regions of cortex. Each cerebral hemisphere of the primary motor cortex only contains a motor representation of the opposite (contralateral) side of the body. The amount of primary motor cortex devoted to a body part is not proportional to the absolute size of the body surface, but, instead, to the relative density of cutaneous motor receptors on said body part. The density of cutaneous motor receptors on the body part is generally indicative of the necessary degree of precision of movement required at that body part. For this reason, the human hands and face have a much larger representation than the legs. 

For the discovery of the primary motor cortex and its relationship to other motor cortical areas, see the main article on the motor cortex.

Structure

The human primary motor cortex is located on the anterior wall of the central sulcus. It also extends anteriorly out of the sulcus partly onto the precentral gyrus. Anteriorly, the primary motor cortex is bordered by a set of areas that lie on the precentral gyrus and that are generally considered to compose the lateral premotor cortex. Posteriorly, the primary motor cortex is bordered by the primary somatosensory cortex, which lies on the posterior wall of the central sulcus. Ventrally the primary motor cortex is bordered by the insular cortex in the lateral sulcus. The primary motor cortex extends dorsally to the top of the hemisphere and then continues onto the medial wall of the hemisphere. 

The location of the primary motor cortex is most obvious on histological examination due to the presence of the distinctive Betz cells. Layer V of the primary motor cortex contains giant (70-100 µm) pyramidal neurons which are the Betz cells. These neurons send long axons to the contralateral motor nuclei of the cranial nerves and to the lower motor neurons in the ventral horn of the spinal cord. These axons form a part of the corticospinal tract. The Betz cells account for only a small percentage of the corticospinal tract. By some measures they account for about 10% of the primary motor cortex neurons projecting to the spinal cord or about 2-3% of the total cortical projection to the spinal cord. Though the Betz cells do not compose the entire motor output of the cortex, they nonetheless provide a clear marker for the primary motor cortex. This region of cortex, characterized by the presence of Betz cells, was termed area 4 by Brodmann.

Pathway

As the motor axons travel down through the cerebral white matter, they move closer together and form part of the posterior limb of the internal capsule

They continue down into the brainstem, where some of them, after crossing over to the contralateral side, distribute to the cranial nerve motor nuclei. (Note: a few motor fibers synapse with lower motor neurons on the same side of the brainstem). 

After crossing over to the contralateral side in the medulla oblongata (pyramidal decussation), the axons travel down the spinal cord as the lateral corticospinal tract

Fibers that do not cross over in the brainstem travel down the separate ventral corticospinal tract, and most of them cross over to the contralateral side in the spinal cord, shortly before reaching the lower motor neurons.

Corticomotorneurons

Corticomotorneurons are neurons in the primary cortex which project directly to motor neurons in the ventral horn of the spinal cord. Axons of corticomotorneurons terminate on the spinal motor neurons of multiple muscles as well as on spinal interneurons. They are unique to primates and it has been suggested that their function is the adaptive control of the distal extremities (e.g. the hands) including the relatively independent control of individual fingers. Corticomotorneurons have so far only been found in the primary motor cortex and not in secondary motor areas.

Blood supply

Branches of the middle cerebral artery provide most of the arterial blood supply for the primary motor cortex

The medial aspect (leg areas) is supplied by branches of the anterior cerebral artery.

Function

Homunculus

There is a broadly somatotopic representation of the different body parts in the primary motor cortex in an arrangement called a motor homunculus (Latin: little person). The leg area is located close to the midline, in interior sections of the motor area folding into the medial longitudinal fissure. The lateral, convex side of the primary motor cortex is arranged from top to bottom in areas that correspond to the buttocks, torso, shoulder, elbow, wrist, fingers, thumb, eyelids, lips, and jaw. The arm and hand motor area is the largest, and occupies the part of precentral gyrus between the leg and face area. 

These areas are not proportional to their size in the body with the lips, face parts, and hands represented by particularly large areas. Following amputation or paralysis, motor areas can shift to adopt new parts of the body.

Neural input from the thalamus

The primary motor cortex receives thalamic inputs from different thalamic nuclei. Among others:

Alternative maps

Map of the body in the human brain
 
At least two modifications to the classical somatotopic ordering of body parts have been reported in the primary motor cortex of primates. 

First, the arm representation may be organized in a core and surround manner. In the monkey cortex, the digits of the hand are represented in a core area at the posterior edge of the primary motor cortex. This core area is surrounded on three sides (on the dorsal, anterior, and ventral sides) by a representation of the more proximal parts of the arm including the elbow and shoulder. In humans, the digit representation is surrounded dorsally, anteriorly, and ventrally, by a representation of the wrist.

A second modification of the classical somatotopic ordering of body parts is a double representation of the digits and wrist studied mainly in the human motor cortex. One representation lies in a posterior region called area 4p, and the other lies in an anterior region called area 4a. The posterior area can be activated by attention without any sensory feedback and has been suggested to be important for initiation of movements, while the anterior area is dependent on sensory feedback. It can also be activated by imaginary finger movements and listening to speech while making no actual movements. This anterior representation area has been suggested to be important in executing movements involving complex sensoriomotor interactions. It is possible that area 4a in humans corresponds to some parts of the caudal premotor cortex as described in the monkey cortex.

In 2009, it was reported, that there are two evolutionary distinct regions, an older one on the outer surface, and a new one found in the cleft. The older one connects to the spinal motorneurons through interneurons in the spinal cord. The newer one, found only in monkeys and apes, connects directly to the spinal motorneurons. The direct connections form after birth, are dominant over the indirect connections, and are more flexible in the circuits they can develop which allows the post-natal learning of complex fine motor skills. "The emergence of the 'new' M1 region during evolution of the primate lineage is therefore likely to have been important for the enhanced manual dexterity of the human hand."

Common misconceptions

Certain misconceptions about the primary motor cortex are common in secondary reviews, textbooks, and popular material. Three of the more common misconceptions are listed here.

Segregated map of the body

One of the most common misconceptions about the primary motor cortex is that the map of the body is cleanly segregated. Yet it is not a map of individuated muscles or even individuated body parts. The map contains considerable overlap. This overlap increases in more anterior regions of the primary motor cortex. One of the main goals in the history of work on the motor cortex was to determine just how much the different body parts are overlapped or segregated in the motor cortex. Researchers who addressed this issue found that the map of the hand, arm, and shoulder contained extensive overlap. Studies that map the precise functional connectivity from cortical neurons to muscles show that even a single neuron in the primary motor cortex can influence the activity of many muscles related to many joints. In experiments on cats and monkeys, as animals learn complex, coordinated movements, the map in the primary motor cortex becomes more overlapping, evidently learning to integrate the control of many muscles. In monkeys, when electrical stimulation is applied to the motor cortex on a behavioral timescale, it evokes complex, highly integrated movements such as reaching with the hand shaped to grasp, or bringing the hand to the mouth and opening the mouth. This type of evidence suggests that the primary motor cortex, while containing a rough map of the body, may participate in integrating muscles in meaningful ways rather than in segregating the control of individual muscle groups. It has been suggested that a deeper principle of organization may be a map of the statistical correlations in the behavioral repertoire, rather than a map of body parts. To the extent that the movement repertoire breaks down partly into the actions of separate body parts, the map contains a rough and overlapping body arrangement.

M1 and primary motor cortex

The term "M1" and the term "primary motor cortex" are often used interchangeably. However, they come from different historical traditions and refer to different divisions of cortex. Some scientists suggested that the motor cortex could be divided into a primary motor strip that was more posterior and a lateral premotor strip that was more anterior. Early researchers who originally proposed this view included Campbell, Vogt and Vogt Foerster, and Fulton. Others suggested that the motor cortex could not be divided in that manner. Instead, in this second view, the so-called primary motor and lateral premotor strips together composed a single cortical area termed M1. A second motor area on the medial wall of the hemisphere was termed M2 or the supplementary motor area. Proponents of this view included Penfield and Woolsey. Today the distinction between the primary motor cortex and the lateral premotor cortex is generally accepted. However, the term M1 is sometimes mistakenly used to refer to the primary motor cortex. Strictly speaking M1 refers to the single map that, according to some previous researchers, encompassed both the primary motor and the lateral premotor cortex.

Betz cells as the final common pathway

The Betz cells, or giant pyramidal cells in the primary motor cortex, are sometimes mistaken to be the only or main output from the cortex to the spinal cord. This mistake is old, dating back at least to Campbell in 1905. Yet the Betz cells compose only about 2-3% of the neurons that project from the cortex to the spinal cord, and only about 10% of the neurons that project specifically from the primary motor cortex to the spinal cord. A range of cortical areas including the premotor cortex, the supplementary motor area, and even the primary somatosensory cortex, project to the spinal cord. Even when the Betz cells are damaged, the cortex can still communicate to subcortical motor structures and control movement. If the primary motor cortex with its Betz cells is damaged, a temporary paralysis results and other cortical areas can evidently take over some of the lost function.

Clinical significance

Lesions of the precentral gyrus result in paralysis of the contralateral side of the body (facial palsy, arm-/leg monoparesis, hemiparesis).

Movement coding

Evarts suggested that each neuron in the motor cortex contributes to the force in a muscle. As the neuron becomes active, it sends a signal to the spinal cord, the signal is relayed to a motorneuron, the motorneuron sends a signal to a muscle, and the muscle contracts. The more activity in the motor cortex neuron, the more muscle force. 

Georgopoulos and colleagues suggested that muscle force alone was too simple a description. They trained monkeys to reach in various directions and monitored the activity of neurons in the motor cortex. They found that each neuron in the motor cortex was maximally active during a specific direction of reach, and responded less well to neighboring directions of reach. On this basis they suggested that neurons in motor cortex, by "voting" or pooling their influences into a "population code", could precisely specify a direction of reach.

The proposal that motor cortex neurons encode the direction of a reach became controversial. Scott and Kalaska showed that each motor cortex neuron was better correlated with the details of joint movement and muscle force than with the direction of the reach. Schwartz and colleagues showed that motor cortex neurons were well correlated with the speed of the hand. Strick and colleagues found that some neurons in motor cortex were active in association with muscle force and some with the spatial direction of movement. Todorov proposed that the many different correlations are the result of a muscle controller in which many movement parameters happen to be correlated with muscle force. 

The code by which neurons in the primate motor cortex control the spinal cord, and thus movement, remains debated. 

Some specific progress in understanding how motor cortex causes movement has also been made in the rodent model. The rodent motor cortex, like the monkey motor cortex, may contain subregions that emphasize different common types of actions. For example, one region appears to emphasize the rhythmic control of whisking. Neurons in this region project to a specific subcortical nucleus in which a pattern generator coordinates the cyclic rhythm of the whiskers. This nucleus then projects to the muscles that control the whiskers.

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