The striatum, or corpus striatum (also called the neostriatum and the striate nucleus) is a nucleus (a cluster of neurons) in the subcorticalbasal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamatergic and dopaminergic inputs from different sources; and serves as the primary input to the rest of the basal ganglia.
The striatum is the largest structure of the basal ganglia.The striatum is divided into a ventral and a dorsal subdivision, based upon function and connections.
The ventral striatum is composed of the nucleus accumbens and the olfactory tubercle. The nucleus accumbens is made up of the nucleus accumbens core and the nucleus accumbens shell, which differ by neural populations. The olfactory tubercle receives input from the olfactory bulb but has not been shown to play a role in processing smell. In non-primate species, the islands of Calleja are included. The ventral striatum is associated with the limbic system and has been implicated as a vital part of the circuitry for decision making and reward-related behavior.
Dendritic spines on medium spiny neuron of striatum
Types of cells in the striatum include:
Medium spiny neurons (MSNs), which are the principal neurons of the striatum. They are GABAergic
and, thus, are classified as inhibitory neurons. Medium spiny
projection neurons comprise 95% of the total neuronal population of the
human striatum. Medium spiny neurons have two characteristic types: D1-type MSNs and D2-type MSNs. A subpopulation of MSNs contain both D1-type and D2-type receptors, with approximately 40% of striatal MSNs expressing both DRD1 and DRD2mRNA.
Cholinergicinterneurons
release acetylcholine, which has a variety of important effects in the
striatum. In humans, other primates, and rodents, these interneurons
respond to salient environmental stimuli with stereotyped responses that
are temporally aligned with the responses of dopaminergic neurons of
the substantia nigra. The large aspiny cholinergic interneurons themselves are affected by dopamine through D5 dopamine receptors.
There are many types of GABAergic interneurons. The best known are parvalbumin expressing interneurons, also known as fast-spiking interneurons, which participate in powerful feedforward inhibition of principal neurons. Also, there are GABAergic interneurons that express tyrosine hydroxylase, somatostatin, nitric oxide synthase and neuropeptide-y. Recently, two types of neuropeptide-y expressing GABAergic interneurons have been described in detail, one of which translates synchronous activity of cholinergic interneurons into inhibition of principal neurons. These neurons of the striatum are not distributed evenly.
There are two regions of neurogenesis in the brain – the subventricular zone in the lateral ventricles, and the dentate gyrus. Neuroblasts that form in the lateral ventricle adjacent to the striatum, integrate in the striatum. This has been noted in the human striatum following an ischemic stroke.
Injury caused to the striatum stimulates the migration of neuroblasts
from the subventricular zone, to the striatum, where they differentiate
into adult neurons. The normal passage of SVZ neuroblasts is to the olfactory bulb but this traffic is diverted to the striatum after an ischemic stroke. However, few of the new developed neurons survive.
Inputs
Simplified diagram of frontal cortex to striatum to thalamus pathways – frontostriatal circuit
Overview
of the main circuits of the basal ganglia. The striatum is shown in
blue. Picture shows 2 coronal slices that have been superimposed to
include the involved basal ganglia structures. + and – signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.
The largest connection is from the cortex, in terms of cell axons. Many parts of the neocortexinnervate the dorsal striatum. The cortical pyramidal neurons projecting to the striatum are located in layers II-VI, with the most dense projections come from layer V. They end mainly on the dendritic spines of the spiny neurons. They are glutamatergic, exciting striatal neurons.
Another well-known afferent is the nigrostriatal connection arising from the neurons of the substantia nigra
pars compacta. While cortical axons synapse mainly on spine heads of
spiny neurons, nigral axons synapse mainly on spine shafts.
In primates, the thalamostriatal afferent comes from the central
median-parafascicular complex of the thalamus (see primate basal ganglia system). This afferent is glutamatergic. The participation of truly intralaminar neurons is much more limited.
The striatum also receives afferents from other elements of the basal ganglia such as the subthalamic nucleus (glutamatergic) or the external globus pallidus (GABAergic).
Striatal outputs from both the dorsal and ventral components are primarily composed of medium spiny neurons (MSNs), a type of projection neuron, which have two primary phenotypes: "indirect" MSNs that express D2-type receptors and "direct" MSNs that express D1-type receptors.
The basal ganglia core is made up of the striatum along with the
regions to which it projects directly, via the striato-pallidonigral
bundle. The striato-pallidonigral bundle is a very dense bundle of
sparsely myelinated axons, giving a whitish appearance. This projection
comprises successively the external globus pallidus (GPe), the internal globus pallidus (GPi), the pars compacta of the substantia nigra (SNc), and the pars reticulata of substantia nigra (SNr).
The neurons of this projection are inhibited by GABAergic synapses from
the dorsal striatum. Among these targets, the GPe does not send axons
outside the system. Others send axons to the superior colliculus.
Two others comprise the output to the thalamus, forming two separate
channels: one through the internal segment of the globus pallidus to the
ventral oralis nuclei of the thalamus and from there to the cortical supplementary motor area and another through the substantia nigra to the ventral anterior nuclei of the thalamus and from there to the frontal cortex and the oculomotor cortex.
Metabotropicdopamine receptors are present both on spiny neurons and on cortical axon terminals. Second messenger
cascades triggered by activation of these dopamine receptors can
modulate pre- and postsynaptic function, both in the short term and in
the long term. In humans, the striatum is activated by stimuli associated with reward, but also by aversive, novel, unexpected, or intense stimuli, and cues associated with such events. fMRI evidence suggests that the common property linking these stimuli, to which the striatum is reacting, is salience under the conditions of presentation.
A number of other brain areas and circuits are also related to reward,
such as frontal areas. Functional maps of the striatum reveal
interactions with widely distributed regions of the cerebral cortex
important to a diverse range of functions.
The interplay between the striatum and the prefrontal cortex is relevant for behavior, particularly adolescent development as proposed by the dual systems model.
An association has been observed between striatal expression of variants of the PDE10A gene and some bipolar I disorder patients. Variants of other genes, DISC1 and GNAS, have been associated with bipolar II disorder.
Autism spectrum disorder
Autism spectrum disorder
(ASD) is characterized by cognitive inflexibility and poor
understanding of social systems. This inflexible behavior originates in
defects in the pre-frontal cortex as well as the striatal circuits.
The defects in the striatum seem to specifically contribute to the
motor, social and communication impairments seen in ASD patients. In
mice which have an ASD-like phenotype induced via the overexpression of
the eukaryotic initiation of translation factor 4E,
it has been shown that these defects seem to stem from the reduced
ability to store and process information in the striatum, which leads to
the difficulty seen in forming new motor patterns, as well as
disengaging from existing ones.
Dysfunction
Dysfunction in the ventral striatum can lead to a variety of disorders, most notably, depression and obsessive-compulsive disorder.
Because of its involvement in reward pathways, the ventral striatum has
also been implicated in playing a critical role in addiction. It has
been well established that the ventral striatum is strongly involved in
mediating the reinforcing effects of drugs, especially stimulants,
through dopaminergic stimulation.
History
In the
seventeenth and eighteenth centuries, the term "corpus striatum" was
used to designate many distinct, deep, infracortical elements of the
hemisphere. In 1941, Cécile and Oskar Vogt simplified the nomenclature by proposing the term striatum for all elements built with striatal elements (see primate basal ganglia system): the caudate, the putamen, and the fundus striati, that ventral part linking the two preceding together ventrally to the inferior part of the internal capsule.
The term neostriatum was forged by comparative anatomists
comparing the subcortical structures between vertebrates, because it was
thought to be a phylogenetically newer section of the corpus striatum.
The term is still used by some sources, including Medical Subject Headings.
Other animals
In birds the term used was the paleostriatum augmentatum, and in the new avian terminology listing (as of 2002) for neostriatum this has been changed to the nidopallium.
In non-primate species, the islands of Calleja are included in the ventral striatum.
Schematic of the HPA axis (CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone).
Hypothalamus, pituitary gland and adrenal cortex.
The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland (a pea-shaped structure located below the thalamus), and the adrenal (also called "suprarenal") glands (small, conical organs on top of the kidneys).
These organs and their interactions constitute the HPA axis, a major neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system,
mood and emotions, sexuality, and energy storage and expenditure. It is
the common mechanism for interactions among glands, hormones, and parts
of the midbrain that mediate the general adaptation syndrome (GAS).
While steroid hormones are produced mainly in vertebrates, the
physiological role of the HPA axis and corticosteroids in stress
response is so fundamental that analogous systems can be found in
invertebrates and monocellular organisms as well.
The anterior lobe of the pituitary gland. In particular, CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone (ACTH), once known as corticotropin. ACTH in turn acts on:
the adrenal cortex, which produces glucocorticoid hormones (mainly cortisol
in humans) in response to stimulation by ACTH. Glucocorticoids in turn
act back on the hypothalamus and pituitary (to suppress CRH and ACTH
production) in a negative feedback cycle.
CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence.
CRH is transported to the anterior pituitary through the portal blood
vessel system of the hypophyseal stalk and vasopressin is transported by
axonal transport to the posterior pituitary gland.
There, CRH and vasopressin act synergistically to stimulate the
secretion of stored ACTH from corticotrope cells. ACTH is transported by
the blood to the adrenal cortex of the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids such as cortisol from cholesterol.
Cortisol is a major stress hormone and has effects on many tissues in
the body, including the brain. In the brain, cortisol acts on two types
of receptor – mineralocorticoid receptors
and glucocorticoid receptors, and these are expressed by many different
types of neurons. One important target of glucocorticoids is the hypothalamus, which is a major controlling centre of the HPA axis.
Vasopressin can be thought of as "water conservation hormone" and
is also known as "antidiuretic hormone." It is released when the body
is dehydrated and has potent water-conserving effects on the kidney. It
is also a potent vasoconstrictor.
Important to the function of the HPA axis are some of the feedback loops:
Cortisol produced in the adrenal cortex will negatively feedback
to inhibit both the hypothalamus and the pituitary gland. This reduces
the secretion of CRH and vasopressin, and also directly reduces the
cleavage of proopiomelanocortin (POMC) into ACTH and β-endorphins.
Epinephrine and norepinephrine (E/NE) are produced by the adrenal medulla through sympathetic
stimulation and the local effects of cortisol (upregulation enzymes to
make E/NE). E/NE will positively feedback to the pituitary and increase
the breakdown of POMCs into ACTH and β-endorphins.
Function
Release of CRH from the hypothalamus is influenced by stress, physical activity, illness, by blood levels of cortisol and by the sleep/wake cycle (circadian rhythm).
In healthy individuals, cortisol rises rapidly after wakening, reaching
a peak within 30–45 minutes. It then gradually falls over the day,
rising again in late afternoon. Cortisol levels then fall in late
evening, reaching a trough during the middle of the night. This
corresponds to the rest-activity cycle of the organism. An abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome, insomnia and burnout.
The HPA axis has a central role in regulating many homeostatic
systems in the body, including the metabolic system, cardiovascular
system, immune system, reproductive system and central nervous system.
The HPA axis integrates physical and psychosocial influences in order to
allow an organism to adapt effectively to its environment, use
resources, and optimize survival.
Anatomical connections between brain areas such as the amygdala, hippocampus, prefrontal cortex and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the amygdala's central nucleus,
which then projects out to several parts of the brain involved in
responses to fear. At the hypothalamus, fear-signaling impulses activate
both the sympathetic nervous system and the modulating systems of the HPA axis.
Increased production of cortisol during stress results in an increased availability of glucose in order to facilitate fighting or fleeing.
As well as directly increasing glucose availability, cortisol also
suppresses the highly demanding metabolic processes of the immune
system, resulting in further availability of glucose.
Glucocorticoids have many important functions, including modulation of stress reactions, but in excess they can be damaging. Atrophy
of the hippocampus in humans and animals exposed to severe stress is
believed to be caused by prolonged exposure to high concentrations of glucocorticoids. Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress.
Immune system
There is bi-directional communication and feedback between the HPA axis and immune system. A number of cytokines,
such as IL-1, IL-6, IL-10 and TNF-alpha can activate the HPA axis,
although IL-1 is the most potent. The HPA axis in turn modulates the
immune response, with high levels of cortisol resulting in a suppression
of immune and inflammatory reactions. This helps to protect the
organism from a lethal overactivation of the immune system, and
minimizes tissue damage from inflammation.
The CNS is in many ways "immune privileged," but it plays an important role in the immune system and is affected by it in turn. The CNS regulates the immune system through neuroendocrine pathways, such as the HPA axis. The HPA axis is responsible for modulating inflammatory responses that occur throughout the body.
During an immune response, proinflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and can pass through the blood brain barrier where they can interact with the brain and activate the HPA axis. Interactions between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression, and mood changes. Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
When the HPA axis is activated by stressors, such as an immune response, high levels of glucocorticoids are released into the body and suppress immune response by inhibiting the expression of proinflammatory cytokines (e.g. IL-1, TNF alpha, and IFN gamma) and increasing the levels of anti-inflammatory cytokines (e.g. IL-4, IL-10, and IL-13) in immune cells, such as monocytes and neutrophils.
The relationship between chronic stress and its concomitant
activation of the HPA axis, and dysfunction of the immune system is
unclear; studies have found both immunosuppression and hyperactivation
of the immune response.
Stress
Schematic
overview of the hypothalamic-pituary-adrenal (HPA) axis.Stress
activates the HPA-axis and thereby enhances the secretion of
glucocorticoids from the adrenals.
Experimental studies have investigated many different types of
stress, and their effects on the HPA axis in many different
circumstances.
Stressors can be of many different types—in experimental studies in
rats, a distinction is often made between "social stress" and "physical
stress", but both types activate the HPA axis, though via different
pathways. Several monoamine neurotransmitters are important in regulating the HPA axis, especially dopamine, serotonin and norepinephrine (noradrenaline). There is evidence that an increase in oxytocin, resulting for instance from positive social interactions, acts to suppress the HPA axis and thereby counteracts stress, promoting positive health effects such as wound healing.
The HPA axis is a feature of mammals and other vertebrates. For example, biologists studying stress in fish showed that social subordination leads to chronic stress, related to reduced aggressive interactions, to lack of control, and to the constant threat imposed by dominant
fish. Serotonin (5HT) appeared to be the active neurotransmitter
involved in mediating stress responses, and increases in serotonin are
related to increased plasmaα-MSH levels, which causes skin darkening (a social signal in salmonoid fish), activation of the HPA axis, and inhibition of aggression. Inclusion of the amino acidL-tryptophan, a precursor of 5HT, in the feed of rainbow trout made the trout less aggressive and less responsive to stress. However, the study mentions that plasma cortisol was not affected by dietary L-tryptophan. The drug LY354740 (also known as Eglumegad, an agonist of the metabotropic glutamate receptors2 and 3)
has been shown to interfere in the HPA axis, with chronic oral
administration of this drug leading to markedly reduced baseline cortisol levels in bonnet macaques (Macaca radiata); acute infusion of LY354740 resulted in a marked diminution of yohimbine-induced stress response in those animals.
Studies on people show that the HPA axis is activated in
different ways during chronic stress depending on the type of stressor,
the person's response to the stressor and other factors. Stressors that
are uncontrollable, threaten physical integrity, or involve trauma tend
to have a high, flat diurnal profile of cortisol release (with
lower-than-normal levels of cortisol in the morning and
higher-than-normal levels in the evening) resulting in a high overall
level of daily cortisol release. On the other hand, controllable
stressors tend to produce higher-than-normal morning cortisol. Stress
hormone release tends to decline gradually after a stressor occurs. In post-traumatic stress disorder
there appears to be lower-than-normal cortisol release, and it is
thought that a blunted hormonal response to stress may predispose a
person to develop PTSD.
It is also known that HPA axis hormones are related to certain
skin diseases and skin homeostasis. There is evidence shown that the HPA
axis hormones can be linked to certain stress related skin diseases and
skin tumors. This happens when HPA axis hormones become hyperactive in
the brain.
Stress and development
Schematic
overview of the hypothalamic-pituary-adrenal (HPA) axis. Stress
activates the HPA-axis and thereby enhances the secretion of
glucocorticoids from the adrenals.
Prenatal stress
There is evidence that prenatal stress
can influence HPA regulation. In animal experiments, exposure to
prenatal stress has been shown to cause a hyper-reactive HPA stress
response. Rats that have been prenatally stressed have elevated basal
levels and abnormal circadian rhythm of corticosterone as adults.
Additionally, they require a longer time for their stress hormone
levels to return to baseline following exposure to both acute and
prolonged stressors. Prenatally stressed animals also show abnormally
high blood glucose levels and have fewer glucocorticoid receptors in the hippocampus.
In humans, prolonged maternal stress during gestation is associated
with mild impairment of intellectual activity and language development
in their children, and with behaviour disorders such as attention deficits, schizophrenia, anxiety and depression; self-reported maternal stress is associated with a higher irritability, emotional and attentional problems.
There is growing evidence that prenatal stress can affect HPA
regulation in humans. Children who were stressed prenatally may show
altered cortisol
rhythms. For example, several studies have found an association between
maternal depression during pregnancy and childhood cortisol levels. Prenatal stress has also been implicated in a tendency toward depression and short attention span in childhood. There is no clear indication that HPA dysregulation caused by prenatal stress can alter adult behavior.
Early life stress
The
role of early life stress in programming the HPA Axis has been
well-studied in animal models. Exposure to mild or moderate stressors
early in life has been shown to enhance HPA regulation and promote a
lifelong resilience to stress. In contrast, early-life exposure to
extreme or prolonged stress can induce a hyper-reactive HPA Axis and may
contribute to lifelong vulnerability to stress.
In one widely replicated experiment, rats subjected to the moderate
stress of frequent human handling during the first two weeks of life had
reduced hormonal and behavioral HPA-mediated stress responses as
adults, whereas rats subjected to the extreme stress of prolonged
periods of maternal separation showed heightened physiological and
behavioral stress responses as adults.
Several mechanisms have been proposed to explain these findings in rat models of early-life stress exposure. There may be a critical period
during development during which the level of stress hormones in the
bloodstream contribute to the permanent calibration of the HPA Axis. One
experiment has shown that, even in the absence of any environmental
stressors, early-life exposure to moderate levels of corticosterone was
associated with stress resilience in adult rats, whereas exposure to
high doses was associated with stress vulnerability.
Another possibility is that the effects of early-life stress on
HPA functioning are mediated by maternal care. Frequent human handling
of the rat pups may cause their mother to exhibit more nurturant
behavior, such as licking and grooming. Nurturant maternal care, in
turn, may enhance HPA functioning in at least two ways. First, maternal
care is crucial in maintaining the normal stress hypo responsive period
(SHRP), which in rodents, is the first two weeks of life during which
the HPA axis is generally non-reactive to stress. Maintenance of the
SHRP period may be critical for HPA development, and the extreme stress
of maternal separation, which disrupts the SHRP, may lead to permanent
HPA dysregulation. Another way that maternal care might influence HPA regulation is by causing epigenetic
changes in the offspring. For example, increased maternal licking and
grooming has been shown to alter expression of the glutocorticoid
receptor gene implicated in adaptive stress response.
At least one human study has identified maternal neural activity
patterns in response to video stimuli of mother-infant separation as
being associated with decreased glucocorticoid receptor gene methylation
in the context of post-traumatic stress disorder stemming from early
life stress.
Yet clearly, more research is needed to determine if the results seen
in cross-generational animal models can be extended to humans.
Though animal models allow for more control of experimental
manipulation, the effects of early life stress on HPA axis function in
humans has also been studied. One population that is often studied in
this type of research is adult victims of childhood abuse. Adult victims
of childhood abuse have exhibited increased ACTH concentrations in
response to a psychosocial stress task compared to healthy controls and
subjects with depression but not childhood abuse.
In one study, adult victims of childhood abuse that are not depressed
show increased ACTH response to both exogenous CRF and normal cortisol
release. Adult victims of childhood abuse that are depressed show a
blunted ACTH response to exoegenous CRH.
A blunted ACTH response is common in depression, so the authors of this
work posit that this pattern is likely to be due to the participant's
depression and not their exposure to early life stress.
Heim and colleagues have proposed that early life stress, such as
childhood abuse, can induce a sensitization of the HPA axis, resulting
in particular heightened neuronal activity in response to stress-induced
CRF release.
With repeated exposure to stress, the sensitized HPA axis may continue
to hypersecrete CRF from the hypothalamus. Over time, CRF receptors in
the anterior pituitary will become down-regulated, producing depression
and anxiety symptoms. This research in human subjects is consistent with the animal literature discussed above.
The HPA Axis was present in the earliest vertebrate species, and
has remained highly conserved by strong positive selection due to its
critical adaptive roles.
The programming of the HPA axis is strongly influenced by the
perinatal and early juvenile environment, or “early-life environment.” Maternal stress and differential degrees of caregiving may constitute
early life adversity, which has been shown to profoundly influence, if
not permanently alter, the offspring's stress and emotional regulating
systems. Widely studied in animal models (e.g. licking and grooming/LG in rat pups),
the consistency of maternal care has been shown to have a powerful
influence on the offspring's neurobiology, physiology, and behavior.
Whereas maternal care improves cardiac response, sleep/wake rhythm, and
growth hormone secretion in the neonate, it also suppresses HPA axis
activity. In this manner, maternal care negatively regulates stress
response in the neonate,
thereby shaping his/her susceptibility to stress in later life. These
programming effects are not deterministic, as the environment in which
the individual develops can either match or mismatch with the former's
“programmed” and genetically predisposed HPA axis reactivity. Although
the primary mediators of the HPA axis are known, the exact mechanism by
which its programming can be modulated during early life remains to be
elucidated. Furthermore, evolutionary biologists contest the exact
adaptive value of such programming, i.e. whether heightened HPA axis
reactivity may confer greater evolutionary fitness.
Various hypotheses have been proposed, in attempts to explain why
early life adversity can produce outcomes ranging from extreme
vulnerability to resilience, in the face of later stress.
Glucocorticoids produced by the HPA axis have been proposed to confer
either a protective or harmful role, depending on an individual's
genetic predispositions, programming effects of early-life environment,
and match or mismatch with one's postnatal environment. The predictive
adaptation hypothesis (1), the three-hit concept of vulnerability and
resilience (2) and the maternal mediation hypothesis (3) attempt to
elucidate how early life adversity can differentially predict
vulnerability or resilience in the face of significant stress in later
life. These hypotheses are not mutually exclusive but rather are highly interrelated and unique to the individual.
(1) The predictive adaptation hypothesis:
this hypothesis is in direct contrast with the diathesis stress model,
which posits that the accumulation of stressors across a lifespan can
enhance the development of psychopathology once a threshold is crossed.
Predictive adaptation asserts that early life experience induces
epigenetic change; these changes predict or “set the stage” for adaptive
responses that will be required in his/her environment. Thus, if a
developing child (i.e., fetus to neonate) is exposed to ongoing maternal
stress and low levels of maternal care (i.e., early life adversity),
this will program his/her HPA axis to be more reactive to stress. This
programming will have predicted, and potentially be adaptive in a highly
stressful, precarious environment during childhood and later life. The
predictability of these epigenetic changes is not definitive, however –
depending primarily on the degree to which the individual's genetic and
epigenetically modulated phenotype “matches” or “mismatches” with
his/her environment.
(2) Three-Hit Concept of vulnerability and resilience:
this hypothesis states that within a specific life context,
vulnerability may be enhanced with chronic failure to cope with ongoing
adversity. It fundamentally seeks to explicate why, under seemingly
indistinguishable circumstances, one individual may cope resiliently
with stress, whereas another may not only cope poorly, but consequently
develop a stress-related mental illness. The three “hits” –
chronological and synergistic – are as follows: genetic predisposition
(which predispose higher/lower HPA axis reactivity), early-life
environment (perinatal – i.e. maternal stress, and postnatal – i.e.
maternal care), and later-life environment (which determines
match/mismatch, as well as a window for neuroplastic changes in early
programming).
(Figure 1) The concept of match/mismatch is central to this
evolutionary hypothesis. In this context, it elucidates why early life
programming in the perinatal and postnatal period may have been
evolutionarily selected for. Specifically, by instating specific
patterns of HPA axis activation, the individual may be more well
equipped to cope with adversity in a high-stress environment.
Conversely, if an individual is exposed to significant early life
adversity, heightened HPA axis reactivity may “mismatch” him/her in an
environment characterized by low stress. The latter scenario may
represent maladaptation due to early programming, genetic
predisposition, and mismatch. This mismatch may then predict negative
developmental outcomes such as psychopathologies in later life.
Ultimately, the conservation of the HPA axis has underscored its
critical adaptive roles in vertebrates, so, too, various invertebrate
species over time. The HPA Axis plays a clear role in the production of
corticosteroids, which govern many facets of brain development and
responses to ongoing environmental stress. With these findings, animal
model research has served to identify what these roles are – with
regards to animal development and evolutionary adaptation. In more
precarious, primitive times, a heightened HPA axis may have served to
protect organisms from predators and extreme environmental conditions,
such as weather and natural disasters, by encouraging migration (i.e.
fleeing), the mobilization of energy, learning (in the face of novel,
dangerous stimuli) as well as increased appetite for biochemical energy
storage. In contemporary society, the endurance of the HPA axis and
early life programming will have important implications for counseling
expecting and new mothers, as well as individuals who may have
experienced significant early life adversity.
Methylphenidate (Ritalin) 10 mg Pill (Ciba/Novartis), a drug commonly prescribed to treat ADHD
Attention deficit hyperactivity disorder (ADHD) controversies
include concerns about its existence, causes, perceived overdiagnosis,
and methods of treatment, especially with the use of stimulant
medications in children. These controversies have surrounded the subject
since at least the 1970s.
Status as a disorder
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5), the leading authority in the US on clinical diagnosis and
psychological behavior published by the APA in 2013, ADHD is a neurodevelopmental disorder with a prevalence rate in most cultures of about 5% in children and 2.5% in adults. Today, the existence of ADHD is widely accepted, but controversy around the disorder has existed since at least the 1970s. Adult ADHD continues to be a source of debate. According to the DSM-5, symptoms must be present before age 12, but it's not uncommon for ADHD to continue into adulthood.
Parents and educators sometimes still question a perceived
overdiagnosis in children and the effectiveness of treatment options,
especially stimulant medications. However, according to sociology professor Vincent Parrillo,
"Parent and consumer groups, such as CHADD (Children and Adults with
Attention Deficit Hyperactivity Disorder), tend to support the medical
perspective of ADHD."
In 2009, Dr. Leon Eisenberg, who had coined the term ADDD in the 1950s, said "ADHD is a prime example of a fictitious disease". Snopes, a popular fact checking website found this to be mostly true.
Causes
The pathophysiology of ADHD is unclear and there are a number of competing theories.
ADHD as a biological illness
Frequently observed differences in the brain between ADHD and non-ADHD patients have been discovered, but it is uncertain if or how these differences give rise to the symptoms of ADHD. Results from various types of neuroimaging techniques suggest there are differences in the brain, such as thinner regions of the cortex, between individuals with and without ADHD.
ADHD is said to be highly heritable: twin studies suggest that genetics explain 70-80% in the variation of ADHD.
However, interest in the potential role of gene-environment
interactions in ADHD is also increasing; maternal alcohol or tobacco use
during pregnancy may be one contributor. It has also been argued that ADHD is a heterogeneous disorder
with multiple genetic and environmental factors converging on similar
neurological changes. Authors of a review of ADHD etiology in 2004
noted: "Although several genome-wide searches
have identified chromosomal regions that are predicted to contain genes
that contribute to ADHD susceptibility, to date no single gene with a
major contribution to ADHD has been identified." However, many further studies have occurred since, and the same is true for many other heritable human traits (e.g., schizophrenia).
The Online Mendelian Inheritance in Man (OMIM) database has a listing
for ADHD under autosomal dominant heritable conditions, claiming that
multiple genes contribute to the disorder. As of 2014, OMIM listed 6
genes with variants that have been associated with ADHD.
Social construct theory of ADHD
It has been argued that even if it is a social construct,
this does not mean it is not a valid condition; for example obesity has
different cultural constructs but yet has demonstrable adverse effects
associated with it.
A minority of these critics maintain that ADHD was "invented and not
discovered". They believe that the disorder does not exist and that the
behavior observed is not abnormal and can be better explained by
environmental causes or just the personality of the "patient".
Diagnosis
Methods of diagnosis
There is no blood test or brain scan for ADHD. Diagnosis is based on a clinical interview with the child and parents.
Over the past two decades more research on the functioning of the
brain is being done to help support the idea that Attention Deficit
Hyperactivity Disorder is an executive dysfunction issue.
The brains of males and females are showing differences, which could
potentially help to explain why ADHD presents differently in boys and
girls. Studies conducted using EEGs between boys and girls suggest that
we can no longer ignore sex difference between boys and girls when
identifying ADHD. There are EEG differences between girls and boys in
their maturational pattern and this suggests that more studies regarding
sex differences in ADHD should be conducted.
Over- and under-diagnosis
Overdiagnosis
typically refers to children who are diagnosed with ADHD but should not
be. These instances are termed as "false positives". However, the
"presence of false positives alone does not indicate overdiagnosis".
There may be evidence of overdiagnosis if inaccuracies are shown
consistently in the accepted prevalence rates or in the diagnostic
process itself. "For ADHD to be overdiagnosed, the rate of false
positives (i.e., children inappropriately diagnosed with ADHD) must
substantially exceed the number of false negatives (children with ADHD
who are not identified or diagnosed)."
Children aged 8 to 15 years living in the community, indicated an ADHD
prevalence rate of 7.8%. However, only 48% of the ADHD sample had
received any mental health care over the past 12 months.
Evidence also exists of possible differences of race and
ethnicity in the prevalence of ADHD. The prevalence of ADHD dramatically
varies across cultures despite the fact that the same methodology has
been used. Some believe this may be due to different perceptions of what
qualifies as disruptive behavior, inattention and hyperactivity.
It is argued that over-diagnosis occurs more in well-off or more
homogeneous communities, whereas under-diagnosis occurs more frequently
in poorer and minority communities due to lack of resources and lack of
financial access. Those without health insurance are less likely to be
diagnosed with ADHD. It is further believed that the "distribution of
ADHD diagnosis falls along socioeconomic lines", according to the amount
of wealth within a neighborhood. Therefore, the difficulty of applying
national, general guidelines to localized and specific contexts, such as
where referral is unavailable, resources are lacking or the patient is
uninsured, may assist in the establishment of a misdiagnosis of ADHD.
Development can also influence perception of relevant ADHD
symptoms. ADHD is viewed as a chronic disorder that develops in
childhood and continues into adulthood. However, some research shows a
decline in the symptoms of ADHD as children grow up and mature into
adulthood. As children move into the stage of adolescence, the most
common reporters of ADHD symptoms, parents and teachers, tend to focus
on behaviors affecting academic performance. Some research has shown
that the primary symptoms of ADHD were strong discriminators in parent
ratings, but differed for specific age groups. Hyperactivity was a
stronger discriminator of ADHD in children, while inattentiveness was a
stronger discriminator in adolescents.
Issues with comorbidity is another possible explanation in favor
of the argument of overdiagnosis. As many as 75% of diagnosed children
with ADHD meet criteria for some other psychiatric diagnosis. Among children diagnosed with ADHD, about 25% to 30% have anxiety disorders, 9% to 32% have depression, 45% to 84% have oppositional defiant disorder, and 44% to 55% of adolescents have conduct disorder. Learning disorders are found in 20% to 40% of children with ADHD.
Another possible explanation of over-diagnosis of ADHD is the
"relative-age effect", which applies to children of both sexes. Younger
children are more likely to be inappropriately diagnosed with ADHD and
treated with prescription medication than their older peers in the same
grade. Children who are almost a year younger tend to appear more
immature than their classmates, which influences both their academic and
athletic performance.
The debate of underdiagnosis, or giving a "false negative", has
also been discussed, specifically in literature concerning ADHD among
adults, girls and underprivileged communities. It is estimated that in
the adult population, rates of ADHD are somewhere between 4% and 6%. However, as little as 11% of these adults with ADHD actually receive assessment, and furthermore, any form of treatment.
Between 30% and 70% of children with ADHD report at least one
impairing symptom of ADHD in adulthood, and 30% to 50% still meet
diagnostic criteria for an ADHD diagnosis.
Research on gender differences also reveals an argument for
underdiagnosis of ADHD among girls. The ratio for male-to-female is 4:1
with 92% of girls with ADHD receiving a primarily inattentive subtype
diagnosis.
This difference in gender can be explained, for the majority, by the
different ways boys and girls express symptoms of this particular
disorder. Typically, females with ADHD exhibit less disruptive behaviors and more internalizing behaviors.
Girls tend to show fewer behavioral problems, show fewer aggressive
behaviors, are less impulsive, and are less hyperactive than boys
diagnosed with ADHD. These patterns of behavior are less likely to
disrupt the classroom or home setting, therefore allowing parents and
teachers to easily overlook or neglect the presence of a potential
problem.
The current diagnostic criteria appear to be more geared towards males
than females, and the ADHD characteristics of men have been
over-represented.
This leaves many women and girls with ADHD neglected. Studies have
shown that girls with ADHD, especially those with signs of impulsivity,
were three to four times more likely to attempt suicide when compared
with female controls. Additionally, these girls were two to three times
more likely to engage in self-harming behaviors.
As stated previously, underdiagnosis is also believed to be seen
in more underprivileged communities. These communities tend to be poorer
and inhabit more minorities. More than 50% of children with mental
health needs do not receive assessment or treatment. Access to mental
health services and resources differs on a wide range of factors, such
as "gender, age, race or ethnicity and health insurance". Therefore,
children deserving of an ADHD diagnosis may never receive this
confirmation and are not identified or represented in prevalence rates.
In 2005, 82 percent of teachers in the United States considered
ADHD to be over diagnosed while three percent considered it to be under
diagnosed. In China 19 percent of teachers considered ADHD to be over
diagnosed while 57 percent considered it to be under diagnosed.
Treatment
ADHD management recommendations vary by country and usually involves some combination of counseling, lifestyle changes, and medications.
The British guideline only recommends medications as a first-line
treatment in children who have severe symptoms and for them to be
considered in those with moderate symptoms who either refuse or fail to
improve with counseling.
Canadian and American guidelines recommend that medications and
behavioral therapy be used together as a first-line therapy, except in
preschool-aged children.
Stimulants
The National Institute of Mental Health recommends stimulants for the treatment of ADHD, and states that, "under medical supervision, stimulant medications are considered safe".
A 2007 drug class review found no evidence of any differences in
efficacy or side effects in the stimulants commonly prescribed.
Between 1993 and 2003 the worldwide use of medications that treat ADHD increased almost threefold. Most ADHD medications are prescribed in the United States.
In the 1990s, the US accounted for 90% of global use of stimulants such
as methylphenidate and dextroamphetamine. By the early 2000s, this had
fallen to 80% due to increased usage in other countries.
In 2003, doctors in the UK were prescribing about a 10th of the amount
per capita of methylphenidate used in the US, while France and Italy
accounted for approximately one twentieth of US stimulant consumption. These assertions appear to contradict the 2006 World Drug Report published by the United Nations Office on Drugs and Crime, which indicate the US constituted merely 17% of the world market for dextroamphetamine. They assert that in the early 2000s amphetamine use was "widespread in Europe."
In 1999, a study constructed with 1,285 children and their
parents across four U.S. communities has shown 12.5% of children that
met ADHD criteria had been treated with stimulants during the previous
12 months.
In May 2000, the testimony of DEA Deputy Director Terrance Woodworth has
shown that the Ritalin quota increased from 1,768 kg in 1990 to
14,957 kg in 2000. In addition, IMS Health also revealed the numerous
use of Adderall prescription have increased from 1.3 million in 1996 to
nearly 6 million in 1999.
Adverse effects
Some parents and professionals have raised questions about the side effects of drugs and their long-term use. Magnetic resonance imaging
studies suggest that long-term treatment with amphetamine or
methylphenidate decreases abnormalities in brain structure and function
found in subjects with ADHD, and improves function of the right caudate nucleus.
On February 9, 2006, the U.S. Food and Drug Administration voted to recommend a "black-box" warning describing the cardiovascular risks of stimulant drugs used to treat ADHD.
Subsequently, the USFDA commissioned studies which found that, in
children, young adults, and adults, there is no association between
serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the medical use of amphetamine or other ADHD stimulants.
The effects of amphetamine and methylphenidate on gene regulation are both dose- and route-dependent.
Most of the research on gene regulation and addiction is based upon
animal studies with intravenous amphetamine administration at very high
doses.
The few studies that have used equivalent (weight-adjusted) human
therapeutic doses and oral administration show that these changes, if
they occur, are relatively minor.
The long-term effects on the developing brain and on mental health
disorders in later life of chronic use of methylphenidate is unknown.
Despite this, between 0.51% to 1.23% of children between the ages of 2
and 6 years take stimulants in the US. Stimulant drugs are not approved
for this age group.
In individuals who experience sub-normal height and weight gains
during stimulant therapy, a rebound to normal levels is expected to
occur if stimulant therapy is briefly interrupted. The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.
Effectiveness
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. An evidence review noted the findings of a randomized controlled trial of amphetamine treatment for ADHD in Swedish children following 9 months of amphetamine use. During treatment, the children experienced improvements in attention,
disruptive behaviors, and hyperactivity, and an average change of +4.5
in IQ. It noted that the population in the study had a high rate of comorbid
disorders associated with ADHD and suggested that other long-term
amphetamine trials in people with less associated disorders could find
greater functional improvements.
A 2008 review found that the use of stimulants improved teachers'
and parents' ratings of behavior; however, it did not improve academic
achievement.
The same review also indicates growth retardation for children
consistently medicated over three years, compared to unmedicated
children in the study. Intensive treatment for 14 months has no effect on long-term outcomes 8 years later. No significant differences between the various drugs in terms of efficacy or side effects have been found.
School enforcement
Some schools have attempted to require treatment with medications before allowing a child to attend school. The United States has passed a bill against this practice.
Potential for misuse
Stimulants used to treat ADHD are classified as Schedule II controlled substances in the United States.
Controversy has surrounded whether methylphenidate is as commonly abused as other stimulants with many
proposing that its rate of abuse is much lower than other stimulants.
However, the majority of studies assessing its abuse potential scores
have determined that it has an abuse potential similar to that of cocaine and d-amphetamine.
Both children with and without ADHD abuse stimulants, with ADHD
individuals being at the highest risk of abusing or diverting their
stimulant prescriptions. Between 16 and 29 percent of students who are
prescribed stimulants report diverting their prescriptions. Between 5
and 9 percent of grade/primary and high school children and between 5
and 35 percent of college students have used nonprescribed stimulants.
Most often their motivation is to concentrate, improve alertness, "get
high," or to experiment.
Stimulant medications may be resold by patients as recreational drugs, and methylphenidate (Ritalin) is used as a study aid by some students without ADHD.
Non-medical prescription stimulant use is high. A 2003 study
found that non prescription use within the last year by college students
in the US was 4.1%.
A 2008 meta analysis found even higher rates of non prescribed
stimulant use. It found 5% to 9% of grade school and high school
children and 5% to 35% of college students used a nonprescribed
stimulant in the last year.
As of 2009, 8% of all United States Major League Baseball
players had been diagnosed with ADHD, making the disorder common among
this population. The increase coincided with the League's 2006 ban on stimulants,
which has raised concern that some players are mimicking or falsifying
the symptoms or history of ADHD to get around the ban on the use of
stimulants in sport.
Russell Barkley, a well-known ADHD researcher who has published diagnostic guidelines, has been criticized for his works because he received payment from pharmaceutical companies for speaking and consultancy fees.
In 2008, it was revealed that Joseph Biederman
of Harvard, a frequently cited ADHD expert, failed to report to Harvard
that he had received $1.6 million from pharmaceutical companies between
2000 and 2007. E. Fuller Torrey,
executive director of the Stanley Medical Research Institute which
finances psychiatric studies, said "In the area of child psychiatry in
particular, we know much less than we should, and we desperately need
research that is not influenced by industry money."
Children and Adults with Attention-Deficit/Hyperactivity Disorder, CHADD,
an ADHD advocacy group based in Landover, MD received a total of
$1,169,000 in 2007 from pharmaceutical companies. These donations made
up 26 percent of their budget.
Stigma
Russell Barkley
believes labeling is a double-edged sword; there are many pitfalls to
labeling but by using a precise label, services can be accessed. He also
believes that labeling can help the individual understand and make an
informed decision how best to deal with the diagnoses using
evidence-based knowledge.
Furthermore studies also show that the education of the siblings and
parents has at least a short-term impact on the outcome of treatment.
Barkley states this about ADHD rights: "... because of various
legislation that has been passed to protect them. There are special
education laws with the Americans with Disabilities Act, for example,
mentioning ADHD as an eligible condition. If you change the label, and
again refer to it as just some variation in normal temperament, these
people will lose access to these services, and will lose these hard-won
protections that keep them from being discriminated against. ..."
Psychiatrist Harvey Parker, who founded CHADD, states, "we should be
celebrating the fact that school districts across the country are
beginning to understand and recognize kids with ADHD, and are finding
ways of treating them. We should celebrate the fact that the general
public doesn't look at ADHD kids as "bad" kids, as brats, but as kids
who have a problem that they can overcome". However, children may be ridiculed at school by their peers for using psychiatric medications including those for ADHD.
Perspectives on ADHD
Medical perspectives outside of North America
In
2009, the British Psychological Society and the Royal College of
Psychiatrists, in collaboration with the National Institute for Clinical
Excellence (NICE), released a set of diagnosis and treatment guidelines
for ADHD.
These guidelines reviewed studies by Ford et al. that found that 3.6
percent of boys and 0.85 percent of girls in Britain qualified for a
diagnosis of ADHD using the American DSM-IV criteria. The guidelines go on to state that the prevalence drops to 1.5% when using the stricter criteria for the ICD-10 diagnosis of hyperkinetic disorder used mainly in Europe.
A systematic review of the literature in 2007 found that the
worldwide prevalence of ADHD was 5.29 percent, and that there were no
significant differences in prevalence rates between North America and
Europe. The review did find differences between prevalence rates in
North America and those in Africa and the Middle East, but cautioned
that this may be due to the small number of studies available from those
regions.
Norwegian National Broadcasting (NRK)
broadcast a short television series in early 2005 on the increase in
the use of Ritalin and Concerta for children. Sales were six times
higher in 2004 than in 2002. The series included the announcement of a
successful group therapy program for 127 unmedicated children aged four
to eight, some with ADHD and some with oppositional defiant disorder.
Politics and media
North America
The
validity of the work of many of the ADHD experts (including Biederman)
has been called into question by Marcia Angell, former editor in chief
of the New England Journal of Medicine, in her book review, "Drug Companies & Doctors: A Story of Corruption." Newspaper columnists such as Benedict Carey, science and medical writer for The New York Times, have also written controversial articles on ADHD.
In 1998, the US National Institutes of Health (NIH) released a
consensus statement on the diagnosis and treatment of ADHD. The
statement, while recognizing that stimulant treatment is controversial,
supports the validity of the ADHD diagnosis and the efficacy of
stimulant treatment. It found controversy only in the lack of sufficient
data on long-term use of medications and in the need for more research
in many areas.
In 2014, a preliminary retrospective analysis on the effect of increased use of methylphenidate among children in Quebec due to a policy change found little evidence of positive effects and limited evidence of negative effects.
United Kingdom
The National Institute for Health and Care Excellence (NICE)
concluded that while it is important to acknowledge the body of
academic literature which raises controversies and criticisms
surrounding ADHD for the purpose of developing clinical guidelines, it
is not possible to offer alternative methods of assessment (i.e. ICD 10
and DSM IV) or therapeutic treatment recommendations. NICE stated that
this is because the current therapeutic treatment interventions and
methods of diagnosis for ADHD are based on the dominant view of the
academic literature. NICE further concluded that despite such criticism, ADHD represented a valid clinical condition, with genetic, environmental, neurobiological, and demographic factors. The diagnosis has a high level of support from clinicians and medical authorities.
BaronessSusan Greenfield,
a leading neuroscientist, wanted a wide-ranging inquiry in the House of
Lords into the dramatic increase in the diagnosis of ADHD in the UK and
its possible causes.
This followed a BBC Panorama programme in 2007 which highlighted US
research (The Multimodal Treatment Study of Children with ADHD by the
University of Buffalo showing treatment results of 600) suggesting drugs
are no better than therapy for ADHD in the long-term. In the UK medication use is increasing dramatically. Other notable individuals have made controversial statements about ADHD. Terence Kealey, a clinical biochemist and vice-chancellor of University of Buckingham, has stated his belief that ADHD medication is used to control unruly boys and girls behavior.
The British Psychological Society
said in a 1997 report that physicians and psychiatrists should not
follow the American example of applying medical labels to such a wide
variety of attention-related disorders: "The idea that children who
don't attend or who don't sit still in school have a mental disorder is
not entertained by most British clinicians."
The National Institute for Health and Care Excellence (NICE), in
collaboration with others, release guidelines for the diagnosis and
treatment of ADHD. They are currently devising an update for 2018.
Scientology
An article in the Los Angeles Times stated that "the uproar over Ritalin was triggered almost single-handedly by the Scientology movement." The Citizens Commission on Human Rights, an anti-psychiatry
group formed by Scientologists in 1969, conducted a major campaign
against Ritalin in the 1980s and lobbied Congress for an investigation
of Ritalin. Scientology
publications claimed the "real target of the campaign" as "the
psychiatric profession itself" and said that the campaign "brought wide
acceptance of the fact that (the commission) [sic] and the Scientologists are the ones effectively doing something about ... psychiatric drugging".
Tom Cruise has described the medications Ritalin (methylphenidate) and Adderall (a mixed-salt amphetamine formulation) as "street drugs".
Ushma S. Neill criticized this view, stating that the doses of
stimulants used in the treatment of ADHD do not cause addiction and that
there is some evidence of a reduced risk of later substance addiction
in children treated with stimulants.
Other
In the UK, Susan Greenfield spoke out publicly in 2007 in the House of Lords
about the need for a wide-ranging inquiry into the dramatic increase in
the diagnosis of ADHD, and possible causes. Her comments followed a BBCPanorama program that highlighted research that suggested medications are no better than other forms of therapy in the long term. In 2010, the BBC Trust criticized the 2007 Panorama
program for summarizing the research as showing "no demonstrable
improvement in children's behaviour after staying on ADHD medication for
three years" when in actuality "the study found that medication did
offer a significant improvement over time" although the long-term
benefits of medication were found to be "no better than children who
were treated with behavior therapy." In 2017, Senator Johnny Isakson
was criticized by his constituents when he stated that ADD is not a
learning disability but a "parental deficit disorder", and that it is a
result of parents not "raising their kids like they should".
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