17. 15
Q: RAVENS PROGRESSIVE MATRICES
RPM is a kind of nonverbal intelligence test (other being Goodenough –
Harris draw a man test), which can be applied across culture; either
individually or in a group.
It covers from people aging 4 years to elderly adults.
Designed primarily as a measure of spearman’s g factor of general
intelligence.
The items of the tests consist of a set of matrices or arrangements of designs
into rows and columns, from each of which a part remains missing. The task
of the subject is to choose the missing insert from the given alternatives. The
easier items simply require accuracy of discrimination but the difficult ones
require some complex processes like analogies, permutations, alteration of
patterns and other logical relations. The test is usually administered with no
time limits.
RPM is available in three different types of forms:
1) The standard progressive matrices (SPM) - for average individuals
between age of 8 yrs and 60 yrs.
2) The coloured progressive matrices (CPM) – for younger children or
ones who cannot be tested with SPM.
3) The advanced progressive matrices (APM) – for above average
adolescents and adults.
Reliabilities and validities of RPM were high and satisfactory.
18. 16
Q: IQ TEST IMPORTANCE
An intelligence quotient (IQ) is a total score derived from one of several standardized
tests designed to assess human intelligence.
The abbreviation "IQ" was coined by the psychologist William Stern for the German term
Intelligenzquotient, his term for a scoring method for intelligence tests he advocated in a 1912
book.When current IQ tests are developed, the median raw score of the norming sample is defined
as IQ 100 and scores each standard deviation (SD) up or down are defined as 15 IQ points greater
or less,although this was not always so historically. By this definition, approximately two-thirds of
the population scores between IQ 85 and IQ 115. About 5 percent of the population scores above
125, and 5 percent below 75.
IQ scores have been shown to be associated with such factors as morbidity and mortality, parental
social status, and, to a substantial degree, biological parental IQ. While the heritability of IQ has
been investigated for nearly a century, there is still debate about the significance of heritability
estimates and the mechanisms of inheritance.
IQ scores are used for educational placement, assessment of intellectual disability, and evaluating
job applicants. Even when students improve their scores on standardized tests, they don't always
improve their cognitive abilities, such as memory, attention and speed. In research contexts they
have been studied as predictors of job performance, and income. They are also used to study
distributions of psychometric intelligence in populations and the correlations between it and other
variables.
Raw scores on IQ tests for many populations have been rising at an average rate that scales to three
IQ points per decade since the early 20th century, a phenomenon called the Flynn effect.
Investigation of different patterns of increases in subtest scores can also inform current research on
human intelligence.
TYPES OF INTELLIGENCE TEST:-
• Individual tests
• Group tests
• Verbal tests
• Non verbal tests
• Performance tests
• Culture –Fair tests
19. 17
COMMONLY USED INTELLIGENCE TEST:-
The Gesell Developmental Schedules
It shows the approximate developmental level in months that the child has attained in each of four
major areas of behavior
1 Motor
2 Adaptive
3 Language
4 Personal-social
Vineland Social Maturity Scale
Items are scored after interviewing someone well acquainted with the subject. A social age is then
obtained this is divided by chronological age, yielding a social quotient (SQ)
Abilities assessed
1 Communication
2 Self help eating
3 Self help dressing
4 Occupation
5 Socialization
6 Locomotion
7 Self help general
8 Self direction
20. 18
Binet kamath Test of Intelligence.
( Dr. V.V. Kamath 1934))
• Indian adaptation of Stanford- Binet intelligence test
• Test items organized under different age levels
• Final output is Mental age which is converted to ratio IQ IQ = (MA / CA) x100
• Mental age levels: 3 years to 22 years
• English, Kannada and Marathi Version
Abilities Assessed
1. Language
2. Meaningful Memory
3. Non-meaningful Memory
4. Conceptual Thinking
5. Verbal Reasoning
6. Non-verbal Reasoning
7. Numerical Reasoning
8. social intelligence
• Primarily based on verbal material
Wechsler’s Adult Performance Intelligence Scale (WAPIS)
• ( Dr. Prabha Ramalingaswamy)
• Indian adaptation of Performance subtests of Wechsler’s Adult Intelligence Scale (WAIS)
• Age range: 15 years to 45 years
• Minimum 5 years f education is necessary
• 5 Subtests: Picture completion; Digit Symbol coding; Block Design, Picture arrangement
and Object assembly
• Primarily based on performance
21. 19
Each sub test assess different abilities
Picture completion Ability to perceive details
Digit symbol Visual perception speed
and accuracy
Block design Spatial perception visual
and abstract process and
problem solving
picture arrangement social relation, visual
perception and analysis
Object assembly synthesis visual –motor
integration
Bhatia Battery of Performance Tests of Intelligence Dr. C.M. Bhatia (1934)
• Consists of 5 subtests:
Koh’s Block Design; Alexander’s Pass Along Test; Pattern Drawing Test; Immediate
Memory Test; Picture Construction Test
• Age range: 11 years to 16 years
• For both literates and illiterates
• To assess syntheses and analysis ability
• Can’t be used to assess the degree of mental retardation.
Raven’s Progressive Matrices:
• Developed by J.C. Raven
• Standard Progressive Matrices (1938)
• Ability to gradually develop a systematic method of reasoning by working on the problems
• Age Range: 11 - 65 years
• 5 sets of problems with 12 problems in each
• Within the set and among the sets difficulty level gradually increases
• To assess “g factors” of intelligences, logical reasoning and planning.
• Colored Progressive Matrices (CPM) for children
• Advanced Progressive Matrices(APM)for above average adolescent and adults
22. 20
• Also used as a test of General Intellectual capacity
• Not used for assessment of people having a possibility of Mental retardation.
Culture Fair Tests.
Test bias or differential item functioning
Differential item functioning (DIF) or sometimes referred to as measurement bias is a phenomenon
when participants from different groups (ex gender, race, disability) with the same latent abilities
give different answer to specific questions on the same IQ test.
DIF analysis measures such specific items on a test alongside measuring participants latent abilities
on other similar questions. A consistent different group response to a specific question among
similar type of questions can indicate an effect of DIF. It does not count as differential item
functioning if both groups have equally valid of chance of giving different responses to the same
questions. Such bias can be a result of culture, educational level and other factors that are
independent of group traits. DIF is only considered if test-takers from different groups with the same
underlying latent ability level have a different chance of giving specific responses.Such questions
are usually removed in order to make the test equally fair for both groups. Common techniques for
analyzing DIF are item response theory (IRT) based methods, Mantel-Haenszel, and logistic
regression.
Reliability and validity
Psychometricians generally regard IQ tests as having high statistical reliability. A high reliability
implies that – although test-takers may have varying scores when taking the same test on differing
occasions, and although they may have varying scores when taking different IQ tests at the same
age – the scores generally agree with one another and across time. Like all statistical quantities, any
particular estimate of IQ has an associated standard error that measures uncertainty about the
estimate. For modern tests, the standard error of measurement is about three points. Clinical
psychologists generally regard IQ scores as having sufficient statistical validity for many clinical
purposes.
55. 53
Q: Functions of limbic system
1) Olfaction: Limbic structures are closely related to olfactory cortex and have a role in processing
olfactory sensation. Amygdala is involved in the emotional response to smell while, entorhinal cortex is
concerned with olfactory memories.
2) Appetite and eating behaviour:
Amygdala plays a role in food choice and emotional modulation of food intake. The lateral nucleus of the
hypothalamus is the centre for control of feeding, whereas the ventromedial nucleus functions as the
satiety centre.
3) Sleep and dream:
Functional brain imaging like PET and fMRI have shown that the limbic system is one of the most active
brain areas during the process of dreaming. Limbic system probably interweaves unconscious primal
emotions with our conscious thoughts and perceptions and thereby ties together emotions and memories
during REM sleep to form content of dreams.
Suprachiasmatic nucleus of hypothalamus is the circadian rhythm generator,controlling sleep-wake cycle.
The ventrolateral preoptic nucleus of the hypothalamus sends projections which are inhibitory in nature to
the centres responsible for arousal,such as- Histaminergic tuberomammillary(TMN); Serotonergic dorsal
and medial raphe nucleiNoradrenergic locus ceruleus; Cholinergic basal forebrain ; Pedunculopontine
thalamic nucleus(PPT) and lateral dorsal thalamic nucleus(LDT). Through these inhibitory
projections(gabargic and galaninergic)VLPO functions as ‘sleep switch’,promoting sleep Lateral
hypothalamic area(LHA)contains orexinergic neurones that promote wakefulness.These neurones inhibit
sleep promoting VLPO and the REM sleep promoting neurones in PPT-LDT’,also increase the firing of the
locus ceruleus,dorsal raphe and TMN and in a way act as a finger pressing the flip-flop switch into
wakefulness position.Absence of these neurones causes narcolepsy.
4) Fear:
fear responses are produced by stimulation of hypothalamus and amygdala and abolished when amygdala
are destroyed. Amygdala is involved in fear learning.Imaging studies show that seeing fearful faces
activates left amygdala.
5) Rage and placidity:
Rage responses are produced,1)by minor stimuli when neo-cortex is removed.2)destruction of
ventromedial nuclei and septal nuclei with intact cerebral cortex 3)stimulation of LHA extending back to
central gray matter of midbrain produces rage.
Placidity :bilateral removal of amygdala causes placidity. However, if VMN of hypothalamus is destroyed
after destruction of amygdala,placidity generated is converte to rage.
56. 54
6) Sexual behaviour: medial preoptic area of hypothalamus(MPOA) and medial amygdala(MeA) are
impotant for male sexual behaviour.They receive genitosensory input from spinal cord through the central
tegmental field.Suprafascicular nucleus seems to be especially important for stimuli related to ejaculation.
MPOA sends efferents to the paraventricular nucleus of hypothalamus(PVN),VTA,nucleus
paragigantocellularis,and other autonomic and somatosensory areas.
Parvocellular part of PVN contain oxytocinergic and vasopressinergic projections to lumbosacral
cord.Penile erection occurs on stimulation of oxytocinergic neurons by dopamine and its agonists,
excitatory amino acid(NMDA), or oxytocin itself or by electrical stimulation.
Whereas inhibition of these neurons by GABA and its agonists or opoid peptides and opiate like
drugs,inhibits sexual response.
Some glutamatergic inputs to MPOA are from MeA and BNST (bed nucl. Of stria terminalis),increases
dopamine and facilitates sexual activity. Extracelluar glutamate in MPOA increases during copulation and
ejaculation,which facilitates these activities.
7) Addiction and motivation: Reward circuit underlying addictive behaviour includes amygdala and nucleus
accumbens. The amygdala plays a central role in cue-related relapse.Relapse associated with
cues,stress,and a single dose of a drug of abuse results in release of excitatory neurotransmitters in brain
areas like hippocampus and amygdala.
The pathway of motivated behaviour involves the prefrontal cortex,VTA,amygdala,especially basolateral
and extended amygdala,nucleus accumbens core and the ventral pallidum.This pathway is involved in the
motivation to take drugs of abuse(drug seeking) and the compulsive nature of drug taking.
8) Memory:
Emotional memory:Emotion has powerful infuence in learning and memory.Amygdala, in conjunction with
prefrontal cortex and medial temporal lobe,is involved in consolidation and retrievalof emotional
memories. Amygdala,prefrontal cortex and hippocampus are also involved in acquisition, extinction,and
recovery of fears to cues and context.
Hippocampus is critical for long-term declarative memory(episodic) storage.
Medial temporal lobe memory system: the components include the hippocampus and adjacent cortex,the
parahippocampal regions, and entorhinal and perirhinal regions.This memory system is involved in the
storage of new memories.
Diencephalic memory system:consists of hypothalamus,mammillary body and the dorsomedial nucleus of
thalamus.This circuit is important for the storage of recent memory;a dysfunction of this circuit results in
Korsakoff’s syndrome.
9) Social Cognition:
Social cognition refers to thought processes involved in understanding and dealing with other people.Social
cognition involves regions that mediate face perception;emotional processing;theory of mind;self
reference and working memory.Together the functioning of these regions would support the complex
behaviours necessary for social interactions.Limbic strucures involved are the cingulate gyrus and
amygdala.
57. 55
CLINICAL IMPLICATION:
Epilepsy:
TLE isthe most common epilepsy in adults and is most often caused by hippocampal sclerosis. Hippocampal
sclerosis with additional involvement of the amygdala and parahippocampal gyrus is termed mesial
temporal sclerosis.
CA1-is the region,most vulnerable to hypoxia
CA4 has immediate vulnerability to insults
CA3 is only slightly vulnerable;CA2is the most resistant and well preserved sector. MTS is not limited to the
medial temporal lobe,instead,represents a limbic system disorder.
Limbic Encephalitis:-
It is a paraneoplastic syndrome, that has been reported with carcinoma o f the lung, breast,and some other
primaries.
Mechanism of the disease is not known,but it manifests as encephalitis that primarily involves the
hippocampus,amygdala,cingulate gyrus,insula and OFC.
Dementia:-
Afflicted pts develop subacute onset of memory loss, dementia,involuntary movements and ataxia.
Degenerative changes in the limbic system likely have a role in the genesis of neurodegenerative
disease,particularly Pick’s disease and Alzheimer’s disease.Marked atrophy is found in the limbic
system,most notably in the dentate gyrus and hippocampus.
In Alzheimer’s disease,senile plaques and neurofibrillary tangles are dispersed throughout the cerebral
cortex and basal ganglia,but the hippocampus and amygdala are often severely involved.
Anxiety Disorder:
Different types of anxiety have two core features in common,1)anxiety/fear symptoms which is controlled
by a circuit,in which amygdala plays a central role.2)worry- controlled by CSTC loop.
Amygdala has reciprocal connections with a wide range of brain regions,which help amygdala to integrate
both sensory and cognitive informations and then use that information to trigger(or not) a fear response.
Symptoms of anxiety produced by amygdala through its reciprocal connections as noted below :
PFC,OFC and ACC: regulate affect or feeling
PGA(periacquiductal grey area): regulate motor responses like fright,flight or freezing.
Hypothalamus control endocrine responses, activation of HPA axis and increased cortisol level.
Parabrachial nucleus: control breathing output.
Locus ceruleus :Autonomic output of fear by NE.
Amygdala is also influenced by other brain stem nuclei such as 5HT
GABA,glutamate,CRF/HPA,NE and voltage -gated ion channels.
58. 56
Amygdala is also activated by traumatic memories stored in hippocampus to produce fear response,called
‘re-experiencing’in case of PTSD.
Amygdala is also responsible for fear conditioning and fear extinction.
Affective Disorder :-
Studies have shown variation in the volumes of the frontal lobes, basal ganglia,amygdala, and hippocampus
in affective disorders.
Functional studies have revealed decreased prefrontal and anterior cingulate activity
The anterior cingulate is the centre for integration of attentional and emotional output and helps effortful
control of emotional arousal.
Recent researchers have posited that spectrum of affective and cognitive symptomatology represents
dysfunction within a single extended network- the anterior limbic network,which includes PFC and
subcortical structures such as the thalamus, the striatum and amygdala.
The dysfunction in this system is suggested in bipolar disorder,but its role in depression is unclear.
Schizophrenia:-
Studies have shown reduced limbic volumes in schizophrenia .The Papez circuit is probably involved.The
evidence for this is
• 1)the distortion of cortical neuronal organization of layer II of ERC,
• 2)decreased size of the hippocampus,and
• 3)the reduced number of GABAergic cells in the cingulate and anterior thalamus,with resultant
glutamatergic excitotoxicity.
The other circuit involved is the basolateral circuit which mediates the social cognition deficits in
schizophrenia.
ADHD :
Limbic structures have been implicated in the genesis of ADHD.
The enlarged hippocampus in children and adolescents with ADHD may represent a compensatory
response to the presence of disturbances in the perception of time, temporal processing and stimulus-
seeking associated with ADHD.
Disrupted connection between the amygdala and OFC may contribute to behavioural disinhibition.
Autism:
Autism and Asperger’s syndrome involve the disproportionate impairment in specific aspect of social
cognition.
59. 57
Limbic structures involved include cingulate gyrus and amygdala which mediate cognitive and affective
processing.The basolateral circuit integral for social cognition is disrupted in ASD.
CONCLUSION:
The limbic system plays a pivotal role in behaviour. The intricate neuroanatomy of limbic system with its
diverse circuits may explain some of the manifestations of neuropsychiatric disorders. Relentless research
has identified the role of amygdala in various anxiety disorders and emotional memory. The monitoring
role of anterior cingulate,the trisynaptic hippocampal circuitry underlying cognitive functioning, and the
significance of hypothalamus in various neurovegetative functions suggest the integral role of the limbic
system in understanding human behaviour and its aberrations.
.
60. 58
Q: Melatonin
Refer Synopsis 11th
edition pages
67;88,89,90;535;542;554;798;991-992;1051.....
& the pdf document assimilated....
Many biological effects of melatonin are produced through activation of melatonin
receptors, while others are due to its role as a pervasive and powerful antioxidant,
with a particular role in the protection of nuclear and mitochondrial DNA. The full
effects of long-term exogenous supplementation in humans have not yet been
ascertained. Melatonin is categorized by the US Food and Drug Administration
(FDA) as a dietary supplement, not a drug.
Melatonin in Mammals
Melatonin, produced in the pineal gland which is outside of the blood–brain barrier,
acts as an endocrine hormone since it is released into the blood. Melatonin can
61. 59
suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals
that have a breeding season when daylight hours are long. The reproduction of long-
day breeders is repressed by melatonin and the reproduction of short-day breeders is
stimulated by melatonin. During the night, melatonin regulates leptin, lowering its
levels. Light/dark information reaches the suprachiasmatic nuclei (SCN) from retinal
photosensitive ganglion cells, which are intrinsically photosensitive photoreceptor
cells that are distinct from those involved in the primary (at least, from one point of
view) image formation function of the eye (that is the rods and cones of the retina).
These cells represent approximately 2% of all retinal ganglion cells in humans and
express the photopigment melanopsin. Melanopsin, often confused with melatonin
because of its similar name, is structurally unrelated to the hormone. It is a
conventional 7-transmembrane opsin protein with the usual vitamin A-like cis-retinal
cofactor having a peak absorption at 484 nm, in the blue light part of the visible
spectrum. The photoperiod cue created by blue light (from a blue image of the sky)
entrains a circadian rhythm, and thus governs resultant production of specific "dark"-
and "light"-induced neural and endocrine signals that regulate behavioral and
physiological circadian rhythms associated with melatonin. Melatonin is secreted in
darkness in both day-active (diurnal) and night-active (nocturnal) animals.
Melatonin in Humans
Circadian rhythm
In humans, melatonin is produced by the pineal gland, a small endocrine gland
located in the center of the brain but outside the blood–brain barrier. The melatonin
signal forms part of the system that regulates the sleep–wake cycle by chemically
causing drowsiness and lowering the body temperature, but it is the central nervous
system (specifically the suprachiasmatic nuclei, or SCN) that controls the daily cycle
in most components of the paracrine and endocrine systems rather than the melatonin
signal (as was once postulated).
Infants' melatonin levels become regular in about the third month after birth, with the
highest levels measured between midnight and 08:00 (8 AM).
In humans, 90% of melatonin is cleared in a single passage through the liver, a small
amount is excreted in urine, and a small amount is found in saliva. Human melatonin
production decreases as a person ages. It is believed that as children become
teenagers, the nightly schedule of melatonin release is delayed, leading to later
sleeping and waking times.
Light dependence
62. 60
Production of melatonin by the pineal gland is inhibited by light to the retina and
permitted by darkness. Its onset each evening is called the dim-light melatonin onset
(DLMO). It is principally blue light, around 460 to 480 nm, that suppresses melatonin,
proportional to the light intensity and length of exposure. Until recent history, humans
in temperate climates were exposed to few hours of (blue) daylight in the winter; their
fires gave predominantly yellow light. The incandescent light bulb widely used in the
twentieth century produced relatively little blue light. Wearing glasses that block blue
light in the hours before bedtime may decrease melatonin loss. Kayumov et al.
showed that light containing only wavelengths greater than 530 nm does not suppress
melatonin in bright-light conditions. Use of blue-blocking goggles the last hours
before bedtime has also been advised for people who need to adjust to an earlier
bedtime, as melatonin promotes sleepiness. When used several hours before sleep
according to the phase response curve for melatonin in humans, small amounts (0.3
mg) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset
and morning awakening.
Antioxidant
Besides its function as synchronizer of the biological clock, melatonin was found to
be a powerful free-radical scavenger and wide-spectrum antioxidant in 1993. In many
less complex life forms, this is its only known function. Melatonin is an antioxidant
that can easily cross cell membranes and the blood–brain barrier. This antioxidant is
a direct scavenger of radical oxygen and nitrogen species including: OH, O2−, and
NO. Melatonin works with other antioxidants to improve the overall effectiveness
from each antioxidant.
Immune system
While it is known that melatonin interacts with the immune system, the details of
those interactions are unclear. There have been few trials designed to judge the
effectiveness of melatonin in disease treatment. Most existing data are based on small,
incomplete clinical trials. Any positive immunological effect is thought to be the
result of melatonin acting on highaffinity receptors (MT1 and MT2) expressed in
immunocompetent cells. In preclinical studies, melatonin may enhance cytokine
production, and by doing this counteract acquired immunodeficiences. Some studies
also suggest that melatonin might be useful fighting infectious disease including viral,
such as HIV, and bacterial infections, and potentially in the treatment of cancer.
Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-
2) production and to the expression of IL-2 receptor. This suggests that melatonin is
involved in the clonal expansion of antigenstimulated human T lymphocytes. In
rheumatoid arthritis patients, melatonin production has been found increased when
compared to agematched healthy controls. Although it has not yet been clearly
demonstrated whether melatonin increases non-specific immunity with resulting
63. 61
contraindication in autoimmune diseases, an increase in the production of IL-2 and
IL-1 was noted in cultured splenocytes.
Dreaming
Some supplemental melatonin users report an increase in vivid dreaming. Extremely
high doses of melatonin (50 mg) dramatically increased REM sleep time and dream
activity in people both with and without narcolepsy.
It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs
emulate melatonin activity in the awakened state and that both act on the same areas
of the brain.
Autism
Some individuals with autism spectrum disorders (ASD) may have lower than
normal levels of melatonin. A 2008 study found that unaffected parents of
individuals with ASD also have lower melatonin levels, and that the deficits were
associated with low activity of the ASMT gene, which encodes the last enzyme of
melatonin synthesis.
ROLES
In the biological clock
Nobel Prize winner Julius Axelrod performed many experiments
that elucidated the role of melatonin and the pineal gland in
regulating sleep-wake cycles (circadian rhythms)
Normally, the production of melatonin by the pineal gland is
inhibited by light and permitted by darkness. For this reason
melatonin has been called "the hormone of darkness". The
secretion of melatonin peaks in the middle of the night, and
gradually falls during the second half of the night.
As an antioxidant
Melatonin is a powerful antioxidant that can easily cross cell
membranes and the blood-brain barrier. Melatonin, once oxidized,
cannot be reduced to its former state because it forms several stable
64. 62
end-products upon reacting with free radicals. Therefore, it has been
referred to as a terminal (or suicidal) antioxidant.
In animal models, melatonin prevents the damage to DNA by some
carcinogens, stopping the mechanism by which they cause cancer.
The antioxidant activity of melatonin may reduce damage caused by
some types of Parkinson's disease, may play a role in preventing
cardiac arrhythmia and may increase longevity.
In immune system
Melatonin is an immunoregulator that enhances T cell production.
When taken in conjunction with calcium, it is a very potent
immunostimulator of the T cell response. Due to these
immunoregulatory effects, it is used as an adjuvant in many clinical
protocols.
Increased immune system activity may aggravate autoimmune
disorders.
In dreaming
Many melatonin users have reported an increase in the vividness or
frequency of dreams. High doses of melatonin (50mg) dramatically
increased REM sleep time and dream activity in both
narcoleptics and normal people.
It is interesting to note that many psychotropic drugs, such as LSD
and cocaine, increase melatonin synthesis. Hallucinogenic drugs
increase melatonin activity.
65. 63
Medical applications
1. Treatment of circadian rhythm sleep disorders, such as jet lag and
delayed sleep phase syndrome.
2. Studied for the treatment of cancer, immune disorders,
cardiovascular diseases, depression, seasonal affective disorder
(SAD), and sexual dysfunction. A study by Alfred J. Lewy and
other researchers found that it may ameliorate SAD and circadian
misalignment.
3. Basic research indicates that melatonin may play a significant role
in modulating the effects of drugs of abuse such as cocaine.
4. Learning, Memory and Alzheimers: Melatonin can alter
electrophysiological processes associated with memory, such as
long-term potentiation (LTP). Melatonin prevent the
hyperphosphorylation of the tau protein so formation of
neurofibrillary tangles, a pathological feature seen in Alzheimer's
disease. Thus, melatonin may be effective for treating Alzheimer's
Disease.
5. Preventative treatment for migraines and cluster headaches.
6. Other: Studies are going on for treatment of various forms of
cancer, HIV, and other
Adverse effects
Melatonin appears to cause very few side-effects in the short term, up to three
months, when healthy people take it at low doses. A systematic review in 2006 looked
specifically at efficacy and safety in two categories of melatonin usage: first, for sleep
disturbances that are secondary to other diagnoses and, second, for sleep disorders
such as jet lag and shift work that accompany sleep restriction. The study concluded
that "There is no evidence that melatonin is effective in treating secondary sleep
disorders or sleep disorders accompanying sleep restriction, such as jet lag and
shiftwork disorder. There is evidence that melatonin is safe with short term use". A
similar analysis by the same team a year earlier on the efficacy and safety of
exogenous melatonin in the management of primary sleep disorders found that:
66. 64
"There is evidence to suggest that melatonin is safe with short-term use (3 months or
less)." Unwanted effects in some people may include nausea, next-day grogginess,
irritability, reduced blood flow and hypothermia.
While no large, long-term studies that might reveal side-effects have been conducted,
there do exist case reports about patients having taken melatonin for months.
Melatonin can cause somnolence (drowsiness), and, therefore, caution should be
shown when driving, operating machinery, etc. In individuals with auto-immune
disorders, there is conflicting evidence whether melatonin supplementation may
either ameliorate or exacerbate symptoms due to immunomodulation. Individuals
experiencing orthostatic intolerance, a cardiovascular condition that results in
reduced blood pressure and blood flow to the brain when a person stands, may
experience a worsening of symptoms when taking melatonin supplements, a study at
Penn State College of Medicine's Milton S. Hershey Medical Center suggests.
Melatonin can exacerbate symptoms by reducing nerve activity in those experiencing
the condition, the study found. Melatonin has been found to lower FSH levels. Effects
of the hormone on human reproduction remain unclear, although it was with some
effect tried as a contraceptive in the 1990s. Melatonin was thought to have a very low
maternal toxicity in rats. Recent studies have found results which suggested that it is
toxic to photoreceptor cells in rats' retinas when used in combination with large
amounts of sunlight and increases the incidence of tumours in white mice.
77. 75
Q: MEMORY – TYPES & CORRELATES
Types of memory:
1. On the basis of time
a) Ultra short:
Refers to a process measured in milliseconds which may, for
instance, be related to the decay of the photopigments in the
retina's rods and cones.
Of two types iconic and echoic depending on sensory modality,
with visual and auditory modality respectively.
b) Short term:
Refers to the active on-line holding and manipulation of
information and includes the preparation of stored information for
retrieval.
Can have 7±2 items.
The time ranges from seconds to few minutes.
Situated in parietal and DLPFC.
c) Long term:
Refers to information which is stored off-line for periods which
extend from minutes to decades.
Short-term or working memory appears to rely on sensorial or
surface encoding, while long-term memory seems to be more
dependent on semantic (or deep) encoding.
PS: The learning of word lists helps to distinguish short-term from long-term
memory. When recalling items from a list of 12 words, for example, subjects tend to
retrieve a disproportionally higher number of words that were presented at the
beginning and end of the list. The greater recall of initial items is known as the
primacy effect and reflects processes related to long-term memory, whereas the
greater recall of late items is known as the recency effect and is more closely related
to short-term memory.
2. On the basis of contents
a) Explicit/ declarative
a. Episodic
78. 76
Episodic memory refers to specific events in one's biography.
These events are embedded in time and place.
Selectively impaired in mainly in right frontotemporla region
b. Semantic/factual
Deals with factual information.
Some authors believe episodic memory to be part of semantic
memory.
Episodic memory is actively rememberd, semantic memory is
only known.
Mainly impaired in damage to left frontotemporal region.
b) Implicit / Nondeclarative:
Memory which is independent from conscious recollection; memory
is inferred indirectly through a faster or better performance on certain
tasks.
a. Priming
Defined as a process of information recognition in the absence
of conscious reflection.
Refers to the influence that a previously perceived stimulus has
on future performance.
In perceptual priming the stimuli are of an identical sensory
structure at all phases of presentation, while in conceptual
priming they only belong to the same category, or concept.
In priming tests, the stimuli are not required to be learned
actively.
b. Procedural memory/Perceptual, motor and strategic skills
Learning of perceptuomotor skills, and the acquisition of rules
and sequences.
c. Conditioning
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IMPORTANT TERMS RELATED TO MEMORY
ENGRAM: Hypothetical memory trace
ECPHORY: refers to the process wherein retrieval cues interact with stored
information so that an image or a representation of the desired information
becomes activated.
FORGETTING: The loss of information available for explicit recall or
recognition. Usually processes of decay are assumed to exist
FREE RECALL: Voluntary recall of learned information without external help or
cuing.
CUED RECALL: Recall with the help of superficial (first letter) or deep (category
of word) cues
RECOGNITION: Identification of the previously presented stimulus in a list
containing a large number of similar stimuli
AMNESIA: Originally, the term meant a complete, "global" loss of memory. In
recent times the term is frequently also used to indicate fractionated memory
impairments
ANTEROGRADE AMNESIA: The inability to acquire new information for long-
term storage and retrieval.
RETROGRADE AMNESIA: The inability to retrieve information that had been
stored prior to the onset of the amnesia.
AMNESIC SYNDROME: Global memory loss in explicit (declarative, episodic)
domains.
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THE ANATOMICAL SUBSTRATES OF MEMORY
Memory is not controlled by a single center in the brain but, instead, by a
distributed network.
IMPLICIT MEMORY:
With the exception of fear conditioning, which has been related to the
amygdale implicit learning is mediated by nonlimbic structures. These may be
neocortical or may be found in the cerebellum and the basal ganglia.
Visual priming: processed by peristriate unimodal sensory cortex along with
heteromodal association areas of the temporal and parietal cortex.
Procedural memory: may be processed predominantly within regions of the
cerebellum and the basal ganglia, perhaps with the additional participation of
dorsolateral frontal cortex.
The fear conditioning is processed in amygdale which is part of the limbic
system.
SHORT TERM (WORKING) MEMORY:
Role of DLPFC in association with ventral portions of PFC.
Patients with circumscribed predominantly parietal lesions also show
impairment in implicit memory.
In summary, short-term (or working) memory is a predominantly attentional
function under the control of a fronto-parietal network whereas long-term
explicit (or episodic) memory is under the control of a limbic network.
EPISODIC MEMORY:
Hebbe proposed that newly acquired information reverberates in a neural
circuit before being transferred into long-term storage. Such circuits for
encoding and consolidating information include regions of the limbic system,
especially the hippocampo-entorhinal complex, as their critical components.
There are two interacting circuits within the limbic system: the Papez circuit,
centered around the hippocampus, and the basolateral limbic circuit
(amygdaloid circuit).
The amygdaloid circuit is more closely related to emotional processing but is
also relevant for encoding the emotional valence of experiences. It includes the
amygdala, the mediodorsal thalamic nucleus, and associated paralimbic
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regions such as the paraolfactory gyrus of the subcallosal region, the temporal
pole, the insula, the orbitofrontal cortex, and interconnecting fibers such as the
ventral amygdalofugal pathway, ant. Thalamic peduncle and diagonal band.
B/L damage of limbic system especially of papez circuit leads to severe
memory impairment.
Hippocampal entorhinal complex and limbic nuclei of thalamus are most
important. B/L damage to these areas lead to inability to form new stable
memories which are accessible to recall.
The selective damage to B/L amygdala leads to loss of preferential coding of
emotionally laden memories vs. neutral items and emotional coloring of the
memories.
The basal forebrain areas including medial septal region, diagonal band of
Broca and basal nucleus of myenert are important for long term memory. In
patients with lesion with these sites have less severe and enduring memory
impairment in comparison to entorhinal cortex or diencephalic damage. But
the personality changes and confabulation are more prominent.
Damage to fibre pathways of limbic system e.g. Fornix can lead to anterograde
amnesia.
The patients with medial temporal diencephalic damage also have higher
chance of confabulation and less insight.
ENCODING AND CONSOLIDATION:
The encoding mainly takes place through limbic system.
The evidence by some case reports have shown that there may be quite different
biological substrates for initial encoding into episodic (explicit) memory and
the subsequent consolidation/ retention of the information.
The biological substrates of consolidation remain to be elucidated.
STORAGE OF INFORMATION:
The tremendous volume of information that needs to be acquired during a
lifetime becomes accommodated within distributed cerebral cortical networks.
The memories are stored through changes in synaptic morphology, protein
synthesis, and gene expression. Though the information is far from conclusive.
The most frequently formulated proposal is that information is stored
throughout association cortex but that the limbic system has a critical role in
binding this information during storage and perhaps also retrieval.
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RETRIEVAL OF INFORMATION:
Strong and very consistent activation of left prefrontal cortical structures
during the encoding and of right prefrontal cortex during the retrieval process.
Patients with prefrontal damage have significant impairment in free recall, but
no impairment in cued and recognition tasks.
Retrograde amnesia refers to the inability to retrieve information that had been
stored prior to the onset of the amnesia-causing lesion (or event). The term is
used in at least two ways: For one it refers to information which is no longer
accessible because it is permanently lost. This may for instance be the case in
patients with Alzheimer's disease. Secondly, the term refers to an inability to
(explicitly) retrieve stored information which nevertheless may still exist in the
brain.
The patients with retrograde amnesia also have anterograde amnesia if the
lesion is in the limbic system mainly medial diencephalic or temporal damage.
But some cases have shown development of pure retrograde amnesia without
anterograde amnesia.
Inferolateral frontal and temporopolar regions are important for retrieval
Left: retrieving stored general knowledge (semantic memories)
Right: episodic autobiographical information.
The prefrontal contribution in this process of ecphory may involve the willed
initiation and mobilization of the relevant networks, the selection of
information among competing alternatives, and possibly the postretrieval
monitoring processes. The temporopolar regions, through their limbic
connections, may coordinate access to engrams encoded within association
cortices. As was shown by several studies, selective damage to either the
prefrontal or the temporal component of this network is insufficient to cause
permanent disruption of the retrieval process. Enduring and severe retrograde
amnesia usually requires bilateral damage to both components.
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Q: NEUROBIOLOGY OF MEMORY
•Memory is the ability to maintain previously learned information within an internal storage
system so that it may be accessed and used at a later time
• Memory is the glue that binds our mental life.
•Memory is also of clinical interest because disorders of memory and complaints about memory
are common in neurological and psychiatric illness.
THREE-STAGE PROCESS: (Squire 1987)
•encoding (or the acquisition of information),
•storage (or the retention of information over time)
•retrieval (or accessing information previously encoded)
TYPES OF MEMORY
•Declarative (explicit)- Intentional retrieval of the past which can be either facts(semantic)or
historic events from our lives(episodic). It is available for conscious recollection.
•non- declarative (implicit) memory- describes the process of learning a skill or making
association.
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STAGE OF RETENTION:-
CELLULAR MECHANISM
•The Canadian psychologist Donald O. Hebb proposed in 1949 that some changes must take place
between two neurons for memories to develop.
•When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part
in firing it, some growth process or metabolic change takes place in one or both cells such that A's
efficacy, as one of the cells firing B is increased.
•Hebb's Postulate and can be more easily stated as: neurons that fire together, wire together
•In 1960 Eric R. kandel and his colleagues used a radical reductionist strategy to study learning
and memory
•Selected Aplysia (giant marine snail) for 3 important reasons
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LONG TERM POTENTIATION
•LTP serves as a candidate mechanism for mammalian long-term memory.
•LTP has 2 phases-
•Early phase- is produced by a single train of stimuli, lasts only 1 to 3 hours and does not require
new protein synthesis. It involves covalent modification of preexisting proteins that lead to the
strengthening of preexisting connections
•Late phase- repeated trains of electrical stimuli produce a late phase of LTP. It persists for at least
a day and is associated with protein synthesis and synaptogenesis.
•The induction of LTP is known to be mediated postsynaptically and to involve activation of the
N-methyl-D-aspartate (NMDA) receptor, which permits the influx of calcium into the
postsynaptic cell.
•LTP is maintained by an increase in the number of α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionate (AMPA; non-NMDA) receptors in the postsynaptic cell and also possibly by
increased transmitter release.
LTP serves as a physiological substrate of memory:
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1)established quickly and then lasts for a long time
2)It is associative, in that it depends on the co-occurrence of presynaptic activity and postsynaptic
depolarization
3)It occurs only at potentiated synapses, not all synapses terminating on the postsynaptic cell
4)LTP occurs prominently in the hippocampus, a structure that is important for memory.
PROTEIN SYNTHESIS
•Synthesis of new protein is seen in long term memory.
NEUROPLASTICITY
•Some memories last an entire lifetime.
•These long-term memories persist despite surgical anaesthesia, epileptic seizures, and drug abuse
•Protein molecules are not stable enough to survive these insults
•long-term memories must be the result of more stable formations such as structural changes.
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SYNAPSE SPECIFICITY
NEUROGENESIS
Another mechanism that could explain the development of stable memories which can last a
human lifespan.
•Recently, Leuner et al, teaching rats to anticipate a puff of air, looked at learning and
neurogenesis. They found that those animals that showed a better performance with the task also
had more new neurons surviving several days after the instruction. In other words, the greater the
mastery of the skill, the greater the number of newly developing neurons that survived.
ORGANIZATION
•Bayley et al. examined eight patients with damage to their medial temporal lobes. All patients
had problems storing new memories. Then they studied their ability to recall remote
autobiographic memories. Only the three patients who also had significant additional damage to
the neocortex showed impairment with remote memories.
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SYSTEM CONSOLIDATION
There is evidence that memories undergo continuing remodelling even weeks and months after
they are formed. This process is called system consolidation. Researchers have found remodelling
of memories (system reconsolidation) within layers of the cortex. They found that total Fos(a
marker of gene activation) activity was the same at days 1 and 30. However, the location of
activity within the layers of the parietal cortex changed from days 1 to 30
Recent memory activates neurons in layers V and VI. Memory after 30 days, in comparison,
shows greater activity in layers II and III.
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HIPPOCAMPUS
FRONTAL LOBE
•the frontal lobes are fundamentally important for declarative memory
•Patients with frontal lesions have poor memory for the context in which information was
acquired, they have difficulty in unaided recall, and they may even have some mild difficulty on
tests of item recognition.
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Q: The bedside assessment of memory
1. Patients should be alert, attentive, cooperative, motivated, and neither anxious nor
depressed, and have intact perceptual processing systems or the assessment of memory is
meaningless. Thus, clinical assessment of memory may, paradoxically, first involve
assessment of possible comorbid deficits such as aphasia, alexia, visuoperceptual
impairments, apraxia, and inattention.
2. These cognitive deficits are more apparent than memory deficits and may complicate
memory assessment, as discussed above.
3. For patients who are initially lethargic or confused, it is best to wait until attention
improves before reaching any definite conclusion about memory.
4. Attention can be assessed with so-called mental control tasks: reciting the months of the
year backwards, spelling words backwards or doing serial subtractions.
5. Digit span forwards and backwards has the added benefit of determining the patient’s
list span, so subsequent memory tests such as serial list learning tasks can be modified
accordingly, if necessary.
6. Once adequate attention, language, and perceptual functions have been demonstrated,
memory can be evaluated.
7. For some patients with low probability of memory deficits, the coherence and detail of
the history provided by the patient may be sufficient testing.
8. There is one verbal memory task that can be very informative along many dimensions:
supraspan serial word list learning tasks, usually 9_10 words, from which the examiner
can extract a learning curve, delayed recall, and a recognition score.
1. Patients with executive deficits alone may have inefficient learning (a flat curve) or
a tendency to repeat items within single presentations, but little loss of items after
delay and good recognition.
2. Patients with true amnesia may have variable, even good, learning curves, but poor
recall and recognition.
9. Utilizing a list-learning task of this sort can be awkward at the bedside and requires that
the examiner be prepared with a list and a second list for recognition foils.
10. A more universally practical bedside test of memory is telling the patient a coherent story
with just three or four salient features, followed by a brief probe to be certain that the
details have been noted, then probed again after a delay for uncued recall.
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11. Bedside tests, although useful, have a limited sensitivity.
12. Visual and spatial memories are rarely tested at the bedside.
13. Copying and then, after a delay, reproducing abstract drawings is a reasonable assessment
of visual memory.
14. Observing the placement of a few objects in specific spatial relationships to each other and
then, after delay, describing or drawing the relationship of the objects is a reasonable
assessment of spatial memory.
SEMANTIC MEMORY
15. Semantic memory can be measured by questioning knowledge of historical facts. This is
certainly dependent on educational level, but this difficulty can be circumvented by asking
questions for well know historical facts.
16. NAME AND ADDRESS TEST - This is a good alternative test for verbal memory as it is short
and incorporates both verbal working memory and verbal episodic memory.
1. "I would like you to remember a name and address, listen carefully as I can only say
it once: Peter Black, 32 Long Street, Albany. Can you repeat that?"
2. Score 1 mark for each of the five components.
3. "Now try to remember this as I will ask for it again in a while."
4. If the patient has errors on repetition then repeat the phrase up to three times.
5. Allow 5 minutes to pass while distracting the patient.
6. A good distraction technique used
7. "Repeat the name and address that you learned earlier." Score 1 mark for each
component correctly recalled.
8. The test can be further expanded by using cues.
17. Component of working memory Method
Phonological loop Forward digit span
Word span
Phonological store Phonological similarity effect
Articulatory rehearsal mechanism Word length effect
Visuospatial sketchpad:
– spatial component Corsi Block Tapping Test
– visual component Pattern recall
Central executive Backwards digit span
Computation span
Sentence span
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1. Formal neuropsychological testing remains frequently warranted, especially in case of
memory complaint (by the patient or informant), when bedside test is impaired or when
the lesion concerns a region known to impair memory such as mediotemporal, thalamic,
genu of the internal capsule, basal forebrain, and frontal regions.
2. The standard neuropsychological tests of memory are valid, reliable, and standardized over
a very wide age range.
3. The tests can specify memory loss in all dimensions _ short-term versus long-term,
anterograde and retrograde, modality-specific, etc. _ much better than casual bedside
testing.
4. Memory tests provide valuable information on the pattern of episodic memory deficit:
5. True amnesia is characterized by poor recognition with poor benefit, if any, from cuing and
greater loss of items on delayed recall.
6. Conversely, executive deficits impair learning (as shown by a flat curve) and free recall
whereas cued recall is typically good as recognition (except for the possible presence of
false recognition);
7. Severity of memory loss, severity and prognosis of medical/vascular condition, time since
onset, comorbid neurological and medical diagnoses, age, and likely discharge setting are
all factors that influence the decision to obtain neuropsychological testing.
8. Clinicians should also recall that patients with attentional or executive impairments (e.g.
frontal or thalamic strokes) and patients with mild language deficits may appear more
memory impaired on standard tests than they actually are in real life.
The clock-drawing task
The clock-drawing task is a simple means to detect executive dysfunction, because the task
involves planning, sequencing, and abstract reasoning.
Of the many ways, most prefer the method of Nolan and Mohs (1994) for routine use.
The subject is presented with a blank page and asked to draw the face of a clock and to
place the numbers in the correct positions.
After drawing a circle and placing the numbers, the subject is asked to draw the hands so
they indicate the time as 20 minutes after 8.
Scoring is as follows: 1 point for drawing a closed circle, 1 point for placing numbers
correctly, 1 point for including all correct numbers, and 1 point for placing the hands in the
correct positions.
There is no cutoff score, but any score below 4 raises the suspicion of executive
impairment.
Distortions due to tremor are disregarded.
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Q: MMSE
The Mini-Mental State Examination (MMSE; Folstein et al. 1975), administered
directly to the patient, is the most widely used brief cognitive assessment tool.
It requires 10–15 minutes to administer.
It tests - orientation, attention, concentration, recent memory, naming, repetition,
comprehension, ideomotor praxis, constructional praxis, and the ability to construct a
sentence.
A perfect score is 30 points.
As a rule of thumb, patients with mild dementia tend to score from 20 to 24, moderate from
11 to 19 and severe from 0 to 10.
The MMSE is confounded by premorbid intelligence and education.
The originators indicate a score of 23 or below by someone with a high school education is
suggestive of dementia.
A cut-off score of 18 or below is suggested for those with an VIII-grade education or less.
A population-based study showed - The median score was 29 for unscreened individuals
with at least 9 years of schooling, 26 for those with 5–8 years of schooling, and 22 for those
with 0–4 years of education.
The same study showed an inverse relationship between age and test score, with a median
of 29 for those age 18–24 years and a median of 25 for those age 80 years or older.
The MMSE is not a sensitive test; it does not examine executive function and frequently
does not detect impairment in highly educated persons.
However, its brevity and the minimal training required for its administration make it
especially useful in conjunction with the clock-drawing task as a general screening of
cognitive impairment and for following the progression of cognitive disorders.
The MMSE is protected by copyright and must be ordered from Psychological Assessment
Resources.
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Q: MENTAL AGE
Mental age is a concept in relation to intelligence, expressed as the age at which
a child is performing intellectually. The mental age of the child that is tested is the same
as the average age at which normal children achieve a particular score.
However, a mental age result on an intelligence test does not mean that children function
at their "mental age level" in all aspects of life. For instance, a gifted six-year-old child can
still in some ways function as a three-year-old child.
Mental age was once considered a controversial concept.
History
Early Theories
During much of the nineteenth century, theories of intelligence focused on measuring the
size of human skulls.Anthropologist well known for their attempts in correlating cranial size
and capacity with intellectual potential are Samuel Morton and Paul Broca
The modern theories of intelligence began to emerge along with experimental psychology.
This is when much of psychology was moving from philosophical to more biology and
medical science basis. In 1890, James Cattell published what some consider the first
"mental test". Cattell was more focused on heredity rather than environment. This spurs
much of the debate about the nature of intelligence.
Mental age was first defined by the French psychologist Alfred Binet, who introduced the
intelligence test in 1905, with the assistance of Theodore Simon. Binet's experiments on
French schoolchildren laid the framework for future experiments into the mind throughout
the Twentieth Century. He created an experiment that was designed as a test to be
completed quickly and was taken by various ages of children. As was expected, the older
children performed better on these tests. However, the younger children who had
exceeded the average of their peers were said to have a higher "mental age" and those
who performed below average were deemed to have a lower mental age. Binet's theories
suggested that while mental age was a useful indicator, it was by no means permanently
affixed and individual growth or decline could be attributed to changes in teaching methods
and experiences.
Henry Herbert Goddard was the first psychologist to bring Binet's test to the United
States.Goddard was amongst one of the many psychologists in the 1910s that believed
intelligence was a fixed quantity. While Binet believed this wasn't the case, the majority of
those in the U.S believed it was hereditary.
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Modern Theories
The limitations of the Stanford-Binet caused David Wechsler to publish the Wechsler Adult
Intelligence Scale (WAIS) in 1955. These two tests were split into two different ones for
children. The WAIS-IV is the known current publication of the test for adults. The reason
for this test was to score the individual and compare it to others of the same age group
rather than to score by chronological age and mental age. The fixed average is 100 and
the normal range is between 85 and 115. This is a standard currently used and is used in
the Stanford-Binet test as well
Mental age and IQ
Originally, the differences between mental age and chronological age were used to
compute the intelligence quotient, or IQ. This was computed using the ratio method, with
the following formula: mental age/chronological age 100 = IQ.
No matter what the child's chronological age, if the mental age is the same as the
chronological age, then the IQ will equal 100.
An IQ of 100 thus indicates a child of average intellectual development. For a gifted child,
the mental age is above the chronological age; for a developmentally retarded child, the
mental age is below the chronological age.
Modern intelligence tests, including the current Stanford-Binet test, no longer compute
scores using the IQ formula. Instead, intelligence tests give a score that reflects how far
the person's performance deviates from the average performance of others who are the
same age, arbitrarily defined as an average score of 100.
Controversy
The Nature of Intelligence
Mental age as well as IQ have limitations. Binet did not believe these measures should be
used for a single, permanent and inborn level of intelligence. He stressed the limitation of
the test because intelligence overall is too broad to be represented by a single number. It
is influenced by many factors such as the individuals background and changes over time.
Throughout much of the 20th century many psychologists believed intelligence was fixed
and hereditary while others believed other factors would affect intelligence.
After World War I, the concept of intelligence as fixed, hereditary, and unchangeable
became the dominant theory within the experimental psychological community. By the mid-
1930s, there was no longer agreement among researchers on whether or not intelligence
was hereditary. There are still recurring debates about the influence of environment and
heredity upon an individual's intelligence and the intelligence intentional.
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MONOAMINE SYNTHESIS, STORAGE, AND DEGRADATION IN
GENERAL
Refer Synopsis 11th
edition chapter 1.4; pg 38....& fig 1.4-6 given below also
In addition to neuroanatomic similarities, monoamines are also synthesized, stored,
and degraded in similar ways (Fig. 1.4-6). Monoamines are synthesized within
neurons from common amino acid precursors (Fig. 1.4-6, step 1) and taken up into
synaptic vesicles by way of a vesicular monoamine transporter (Fig. 1.4-6, step 2).
On stimulation, vesicles within nerve terminals fuse with the presynaptic terminal and
release the neurotransmitter into the synaptic cleft (Fig. 1.4-6, step 3). Once released,
the monoamines interact with postsynaptic receptors to alter the function of
postsynaptic cells (Fig. 1.4-6, step 4), and they may also act on presynaptic
autoreceptors on the nerve terminal to suppress further release (Fig. 1.4-6, step 5). In
addition, released monoamines may be taken back up from the synaptic cleft into the
nerve terminal by plasma membrane transporter proteins (Fig. 1.4-6, step 6), a process
known as reuptake. Reuptake plays an important role in limiting the total magnitude
and temporal duration of monoamine signaling. Once monoamines are taken up, they
may be subject to enzymatic degradation (Fig. 1.4-6, step 7), or they may be protected
from degradation by uptake into vesicles.
FIGURE 1.4-6.....
100. 98
Catecholamines
The catecholamines are synthesized from the amino acid tyrosine, which is taken up
into the brain via an active transport mechanism (Fig.below ). Within
catecholaminergic neurons, tyrosine hydroxylase catalyzes the addition of a hydroxyl
group to the meta position of tyrosine, yielding L-dopa. This rate-limiting step in
catecholamine synthesis is subject to inhibition by high levels of catecholamines
(end-product inhibition). Because tyrosine hydroxylase is normally saturated with
substrate, manipulation of tyrosine levels does not readily affect the rate of
catecholamine synthesis. Once formed, L-dopa is rapidly converted to dopamine by
dopa decarboxylase, which is located in the
cytoplasm. It is now recognized that this enzyme acts not only on L-dopa but also on
all naturally occurring aromatic L-amino acids, including tryptophan, and thus it is
more properly termed aromatic amino acid decarboxylase. In noradrenergic and
adrenergic neurons. dopamine is actively transported into storage vesicles, where it
is oxidized by dopamine β-hydroxylase to form norepinephrine. In adrenergic
neurons and the adrenal medulla, norepinephrine is converted to epinephrine by
phenylethanolamine N-methyltransferase (PNMT), which is located within the
cytoplasmic compartment.
Two enzymes that play major roles in the degradation of catecholamines are
monoamine oxidase and catechol-O-methyltransferase (COMT). MAO is located on
the outer membrane of mitochondria, including those within the terminals of
adrenergic Obers, and oxidatively deaminates catecholamines to their corresponding
aldehydes. Two MAO isozymes with diPering substrate speciOcities have been
identiOed: MAOA, which preferentially deaminates serotonin and norepinephrine,
and MAO type B (MAOB), which deaminates dopamine, histamine, and a broad
spectrum of phenylethylamines. Neurons contain both MAO isoforms. The blockade
of monoamine catabolism by MAO inhibitors produces elevations in brain
monoamine levels. MAO is also found in peripheral tissues such as the
gastrointestinal tract and liver, where it prevents the accumulation of toxic amines.
For example, peripheral MAO degrades dietary tyramine, an amine that can displace
norepinephrine from sympathetic postganglionic nerve endings, producing
hypertension if tyramine is present in suQcient quantities. Thus patients treated with
MAO inhibitors are cautioned to avoid pickled and fermented foods that typically
have high levels of tyramine. Catechol-O-methyltransferase (COMT) is located in the
cytoplasm and is widely distributed throughout the brain and peripheral tissues,
although little to none is found in adrenergic neurons. It has a wide substrate
specificity, catalyzing the transfer of methyl groups from S-adenosyl methionine to
the m-hydroxyl group of most catechol compounds. The catecholamine metabolites
produced by these and other enzymes are frequently measured as indicators of the
activity of catecholaminergic systems. In humans, the predominant metabolites of
101. 99
dopamine and norepinephrine are homovanillic acid (HVA) and 3-methoxy-4-
hydroxyphenylglycol (MHPG), respectively.
Figure 1.4-8
102. 100
DOPAMINE (DA)
Dopamine is a phenethylamine naturally produced by the human body.
Discovered by Arvid Carlsson and Jils-Ake Hillarp at the Laboratory for Chemical
Pharmacology of the National Heart Institute of Sweden, in 1952. Arvid Carlsson won a
share of the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not
just a precursor of noradrenaline and adrenaline, but a neurotransmitter as well.
Biosynthesized in the body from tyrosine.
Dopamine is also a neurohormone released by the hypothalamus and inhibit the release
of prolactin.
Inactivation mechanism:
1) uptake via a specific transporter-- plays major role in inactivation
2) enzymatic breakdown; and
3) diffusion.
NOREPINEPHRINE
Norepinephrine is a catecholamine. It is released from the medulla of the adrenal glands as a
hormone into the blood, but it is also a neurotransmitter in the CNS and sympathetic nervous
system where it is released from noradrenergic neurons during synaptic transmission.
Major stress hormone related to fight-or-flight response, by directly increasing heart rate,
triggering the release of glucose from energy stores, and increasing skeletal muscle readiness.
Norepinephrine synthesized by the adrenal medulla from the amino acid tyrosine:
Steps of synthesis
– oxidation into dihydroxyphenylalanine (L-DOPA).
– decarboxylation into the neurotransmitter dopamine.
– β-oxidation into norepinephrine by dopamine beta hydroxylase.
Norepinephrine is produced from dopamine, with the help of the amino acids phenylalanine, lysine,
and methionine. Vitamins C and B6, magnesium, and manganese are important cofactors (refer
diagram above…..fig 1.4-8 )
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SEROTONIN
Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page. The name
"serotonin" is a misnomer.
Serotonin=> serum agent affecting vascular tone. This agent was later chemically
identified as 5-hydroxytryptamine (5-HT) by Rapport.
Serotonin is synthesized extensively in the human gastrointestinal tract (about 90%), and
the major storage place is platelets in the blood stream.
Synthesis and metabolism Synthesized directly from the
essential amino acid tryptophan, which must come from the diet, with the assistance of Vitamin
B6 and carbohydrates.
The CNS contains less than 2 percent of the serotonin in the body; peripheral
serotonin is located in platelets, mast cells, and enterochromaffin cells. More than 80
percent of all the serotonin in the body is found in the gastrointestinal system, where
it modulates motility and digestive functions. Platelet serotonin promotes aggregation
and clotting through a most unusual mechanism: The covalent linkage of serotonin
molecules to small GTP-binding proteins, which can then activate these proteins, is a
process termed “serotonylation.” Peripheral serotonin cannot cross the blood–brain
barrier, so serotonin is synthesized within the brain as well. Serotonin is synthesized
from the amino acid tryptophan, which is derived from the diet. The rate-limiting step
in serotonin synthesis is the hydroxylation of tryptophan
by the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan (4-HT (Fig. 1.4-
7). Two isoforms of tryptophan hydroxylase exist— one isoform is found mainly in
the periphery, whereas the second isoform is restricted to the CNS.
Under normal circumstances, tryptophan concentration is rate limiting in serotonin
synthesis. Therefore, much attention has focused on the factors that determine
tryptophan availability. Unlike serotonin, tryptophan is taken up into the brain by way
of a saturable active carrier mechanism. Because tryptophan competes with other
large neutral amino acids for transport, brain uptake of this amino acid is determined
both by the amount of circulating tryptophan and by the ratio of tryptophan to other
large neutral amino acids. This ratio may be elevated by carbohydrate intake, which
induces insulin release and the uptake of many large neutral amino acids into
peripheral tissues. Conversely, high-protein foods tend to be relatively low in
tryptophan, thus lowering this ratio. Moreover, the administration of specialized low
tryptophan diets produces significant declines in brain serotonin levels. After
tryptophan hydroxylation, 5-hydroxytryptophan is rapidly decarboxylated by
aromatic amino acid decarboxylase (an enzyme also involved in dopamine synthesis)
to form serotonin.The first step in the degradation of serotonin is mediated by
monoamine oxidase type A (MAOA), which oxidizes the amino group to form an
aldehyde. MAOA is located in mitochondrial membranes and is nonspeciOc in its
104. 102
substrate specificity; in addition to serotonin, it oxidizes norepinephrine. The
elevation of serotonin levels by MAO inhibitors (MAOIs) is believed to underlie the
antidepressant efficacy of these drugs. After oxidation by MAOA, the resulting
aldehyde is further oxidized to 5-hydroxyindoleacetic acid (5-
HIAA). Levels of 5-HIAA are often measured as a correlate of serotonergic system
activity, although the relationship of these levels to serotonergic neuronal activity
remains unclear.
Figure 1.4-7...
MELATONIN
Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from
algae to humans, at levels that vary in a diurnal cycle.
Production
Produced by pinealocytes in the pineal gland and also by the retina, lens and GI tract.
Production of melatonin by the pineal gland is under the influence of the suprachiasmatic
nucleus of the hypothalamus (SCN) which receives information from retina about the daily
pattern of light and darkness.
105. 103
It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme
5-hydroxyindole-O-methyltransferase.
HISTAMINE
Histamine is a biogenic amine chemical involved in local immune responses as well as regulating
physiological function in the gut and acting as a neurotransmitter (Marieb, 2001). New evidence
also indicates that histamine plays a role in chemotaxis of white blood cells.
Synthesis, metabolism and clinical relevance
Synthesised from histidine.
Histamine released into the synapses is broken down by acetaldehyde dehydrogenase. It is
the deficiency of this enzyme that triggers an allergic reaction. Histamine is broken down
by histamine-N-methyltransferase and diamine oxidase, and is also possibly taken up by a
transporter.
Some forms of food poisoning are due to conversion of histidine into histamine in spoiled
food.
Most tissue histamine is found in granules in mast cells or basophils. Mast cells are
especially numerous at sites of potential injury - the nose, mouth, and feet; internal body
surfaces; and blood vessels.
Non-mast cell histamine is found in several tissues, including the brain, where it functions
as a neurotransmitter.
Synthesis and metabolism
106. 104
Transporters
A great deal of progress has been made in the molecular characterization of the
monoamine plasma membrane transporter proteins. These membrane proteins
mediate the reuptake of synaptically released monoamines into the presynaptic
terminal. This process also involves cotransport of Na+ and Cl− ions and is driven by
the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase.
Monoamine reuptake is an important mechanism for limiting the extent and duration
of activation of monoaminergic receptors. Reuptake is
also a primary mechanism for replenishing terminal monoamine neurotransmitter
stores. Moreover, transporters serve as molecular targets
for a number of antidepressant drugs, psychostimulants, and monoaminergic
neurotoxins. Whereas transporter molecules for serotonin (SERT), dopamine (DAT),
and norepinephrine (NET) have been well characterized, transporters selective for
histamine and epinephrine have not been demonstrated.
Among drugs of abuse, cocaine binds with high affinity to all three known
monoamine transporters, although the stimulant properties of the drug have been
attributed primarily to its blockade of DAT. This view has been recently supported
by the absence of cocaine-induced locomotor stimulation in a strain of mutant mice
engineered to lack this molecule. In fact, psychostimulants produce a paradoxical
locomotor suppression in these animals that has been attributed to their blockade of
the serotonin transporter. The rewarding
properties of cocaine have also been attributed primarily to dopamine transporter
inhibition, although other targets mediate these effects as well, since cocaine still has
rewarding effects in mice lacking the dopamine transporter. It appears that
serotonergic as well as dopaminergic mechanisms may be involved. Transporters may
also provide routes that allow neurotoxins to enter and damage monoaminergic
107. 105
neurons; examples include the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) and the serotonergic neurotoxin MDMA.
Vesicular Monoamine Transporter
In addition to the reuptake of monoamines into the presynaptic nerve terminal, a
second transport process serves to concentrate and store monoamines within synaptic
vesicles. The transport and storage of monoamines in vesicles may serve several
purposes:
(1) to enable the regulated release of transmitter under appropriate physiological
stimulation,
(2) to protect monoamines from degradation by MAO, and
(3)to protect neurons from the toxic effects of free radicals produced by the oxidation
of cytoplasmic monoamines.
In contrast with the plasma membrane transporters, a single type of vesicular
monoamine transporter is believed to mediate the uptake of monoamines into synaptic
vesicles within the brain. Consistent with this, blockade of this vesicular monoamine
transporter by the antihypertensive drug reserpine (Serpasil) has been found to deplete
brain levels of serotonin, norepinephrine, and dopamine and to increase the risk of
suicide and affective dysfunction.
108. 106
Q: NEUROHORMONES
Hormone Stimulated
1. Corticotropin-releasing hormone (CRH) Adrenocorticotropic hormone
(ACTH)
2. Thyrotropin-releasing hormone (TRH) Thyroid-stimulating hormone
(TSH)
3. Gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH)
Follicle-stimulating hormone (FSH)
4. Somatostatin (somatotropin release-inhibiting factor
[SRIF])
Growth hormone (GH)
5. Growth-hormone-releasing hormone (GHRH) GH
6. Oxytocin Prolactin
7. Arginine vasopressin (AVP) ACTH
Neurohormones: a neuronal secretory product of neuroendocrine transducer cells of
the hypothalamus. Chemical signals cause the release of these neurohormones from
the median eminence of the hypothalamus into the portal hypophyseal bloodstream
and coordinate their transport to the anterior pituitary to regulate the release of target
hormones. Pituitary hormones, in turn, act directly on target cells (e.g., ACTH on the
adrenal gland) or stimulate release of other hormones from peripheral endocrine
organs.
Hypothalamic-Pituitary-Adrenal Axis
CRH, ACTH, and cortisol levels all rise in response to a variety of physical
and psychic stresses and serve as prime factors in maintaining homeostasis and
developing adaptive responses to novel or challenging stimuli.
The hormonal response depends both on the characteristics of the stressor itself
and on how the individual assesses and is able to cope with it. Aside from
generalized effects on arousal, distinct effects on sensory processing, stimulus
habituation and sensitization, pain, sleep, and memory storage and retrieval
have been documented. In primates, social status can influence adrenocortical
profiles and, in turn, be affected by exogenously induced changes in hormone
concentration.
Pathological alterations in hypothalamic-pituitary-adrenal function have been
associated primarily with mood disorders, posttraumatic stress disorder, and
dementia of the Alzheimer's type, substance use disorders as well.
Disturbances of mood are found in more than 50 percent of patients with
Cushing's syndrome (characterized by elevated cortisol concentrations), with
psychosis or suicidal thought apparent in more than 10 percent of patients
studied. Cognitive impairments similar to those seen in major depressive
109. 107
disorder (principally in visual memory and higher cortical functions) are
common and relate to the severity of the hypercortisolemia and possible
reduction in hippocampal size.
In general, reduced cortisol levels normalize mood and mental status.
Conversely, in Addison's disease (characterized by adrenal insufficiency),
apathy, social withdrawal, impaired sleep, and decreased concentration
frequently accompany prominent fatigue. Replacement of glucocorticoid (but
not of electrolyte) resolves behavioral symptomatology. Similarly,
hypothalamic-pituitary-adrenal abnormalities are reversed in persons who are
treated successfully with antidepressant medications. Failure to normalize
hypothalamic-pituitary-adrenal abnormalities is a poor prognostic sign.
Alterations in hypothalamic-pituitary-adrenal function associated with
depression include elevated cortisol concentrations, failure to suppress cortisol
in response to dexamethasone, increased adrenal size and sensitivity to ACTH,
a blunted ACTH response to CRH, and, possibly, elevated CRH concentrations
in the brain.
Hypothalamic-Pituitary-Gonadal Axis
The gonadal hormones (progesterone, androstenedione, testosterone, estradiol,
and others) are steroids that are secreted principally by the ovary and testes,
but significant amounts of androgens arise from the adrenal cortex as well. The
prostate gland and adipose tissue, also involved in the synthesis and storage of
dihydrotestosterone, contribute to individual variance in sexual function and
behavior.
The timing and presence of gonadal hormones play a critical role in the
development of sexual dimorphisms in the brain. Developmentally, these
hormones direct the organization of many sexually dimorphic CNS structures
and functions, such as the size of the hypothalamic nuclei and corpus callosum,
neuronal density in the temporal cortex, the organization of language ability,
and responsivity in Broca's motor speech area.
Women with congenital adrenal hyperplasia, a deficiency of the enzyme 21-
hydroxylase, which leads to high exposure to adrenal androgens in prenatal and
postnatal life, in some studies, have been found to be more aggressive and
assertive and less interested in traditional female roles than control female
subjects.
110. 108
Testosterone
Testosterone is the primary androgenic steroid
Testosterone is associated with increased violence and aggression in animals
and in correlation studies in humans, but anecdotal reports of increased
aggression with testosterone treatment have not been substantiated in
investigations in humans.
In hypogonadal men, testosterone improves mood and decreases irritability.
Varying effects of anabolic-androgenic steroids on mood have been noted
anecdotally.
A prospective, placebo-controlled study of anabolic-androgenic steroid
administration in normal subjects reported positive mood symptoms, including
euphoria, increased energy, and sexual arousal, in addition to increases in the
negative mood symptoms of irritability, mood swings, violent feelings, anger,
and hostility.
Testosterone is important for sexual desire in both men and women. In males,
muscle mass and strength, sexual activity, desire, thoughts, and intensity of
sexual feelings depend on normal testosterone levels, but these functions are
not clearly augmented by supplemental testosterone in those with normal
androgen levels.
Adding small amounts of testosterone to normal hormonal replacement in
postmenopausal women has proved, however, to be as beneficial as its use in
hypogonadal men.
Dihydroepiandrosterone (DHEA),
Dihydroepiandrosterone (DHEA), an adrenal androgen, is the most abundant
circulating steroid. Its possible involvement in memory.
Several controlled trials of DHEA administration point to improved well-being
and functional status in both depressed and normal individuals. Its effects may
result from its transformation into estrogen or testosterone or from its
antiglucocorticoid activity.
Estrogen and Progesterone
Estrogens can influence neural activity in the hypothalamus and limbic system
directly through modulation of neuronal excitability.
Accordingly, evidence indicates that the antipsychotic effect of psychiatric
drugs can change over the menstrual cycle and that the risk of tardive
dyskinesia depends partly on estrogen concentrations.
111. 109
Several studies have suggested that gonadal steroids modulate spatial cognition
and verbal memory and are involved in impeding age-related neuronal
degeneration.
Increasing evidence also suggests that estrogen administration decreases the
risk and severity of dementia of the Alzheimer's type in postmenopausal
women.
Estrogen has mood-enhancing properties and can also increase sensitivity to
serotonin and imipramine, possibly by inhibiting monoamine oxidase.
In premenstrual dysphoric disorder, a constellation of symptoms resembling
major depressive disorder occurs in most menstrual cycles, appearing in the
luteal phase and disappearing within a few days of the onset of menses. No
definitive abnormalities in estrogen or progesterone levels have been
demonstrated in women with premenstrual dysphoric disorder, but decreased
serotonin uptake with premenstrual reductions in steroid levels has been
correlated with the severity of some symptoms.
Most psychological symptoms associated with the menopause are actually
reported during peri-menopause rather than after complete cessation of menses.
Although studies suggest no increased incidence of major depressive disorder,
reported symptoms include worry, fatigue, crying spells, mood swings,
diminished ability to cope, and diminished libido or intensity of orgasm.
Hormone replacement therapy (HRT) is effective in preventing osteoporosis
and reinstating energy, a sense of well-being, and libido; however, its use is
extremely controversial.
Hypothalamic-Pituitary-Thyroid Axis
Thyroid hormones are involved in the regulation of nearly every organ system,
particularly those integral to the metabolism of food and the regulation of
temperature, and are responsible for optimal development and function of all
body tissues. In addition to its prime endocrine function, TRH has direct effects
on neuronal excitability, behavior, and neurotransmitter regulation.
Thyroid disorders
Growth Hormone
GH is released in pulses throughout the day, but the pulses are closer together
during the first hours of sleep than at other times.
Growth hormone deficiencies interfere with growth and delay the onset of
puberty.
112. 110
Low GH levels can result from a stressful experience.
Administration of GH to individuals with GH deficiency benefits cognitive
function in addition to its more obvious somatic effects, but evidence indicates
poor psychosocial adaptation in adulthood for children who were treated for
GH deficiency.
A significant percentage of patients with major depressive disorder and
dysthymic disorder may have a GH deficiency.
A number of GH abnormalities have been noted in patients with anorexia
nervosa.
Secondary factors, such as weight loss, however, in both major depressive
disorder and eating disorders, may be responsible for alterations in endocrine
release.
Nonetheless, at least one study has reported that GHRH stimulates food
consumption in patients with anorexia nervosa and lowers food consumption
in patients with bulimia.
Oxytocin
Oxytocin, also a posterior pituitary hormone, is involved in osmoregulation,
the milk ejection reflex, food intake, and female maternal and sexual behaviors.
Oxytocin is theorized to be released during orgasm, more so in women than in
men, and is presumed to promote bonding between the sexes.
It has been used in autistic children experimentally in an attempt to increase
socialization.
Melatonin
Melatonin, a pineal hormone, is derived from the serotonin molecule and it
controls photoperiodically mediated endocrine events (particularly those of the
hypothalamic-pituitary-gonadal axis).
It also modulates immune function, mood, and reproductive performance and
is a potent antioxidant and free-radical scavenger.
Melatonin has a depressive effect on CNS excitability, is an analgesic, and has
seizure-inhibiting effects in animal studies.
Melatonin can be a useful therapeutic agent in the treatment of circadian phase
disorders such as jet lag.
113. 111
Intake of melatonin increases the speed of falling asleep, as well as its duration
and quality.
114. 112
Q: NEUROTRANSMITTERS
Definition:To classify as a neurotransmitter a molecule must have the following criteria:
a)It should be synthesized in a neurone,
b)It should be stored in the presynaptic neurone and released in physiologically significant amounts on
depolarization.
c)When the same molecule is given externally,its effects should mimic the actions of the molecule
d)there should be a mechanism to deactivate it once its action is over.
Classification:Neurotransmitters are classified according to their chemical structure:
1)Biogenic amines(catecholamines,histamine,serotonin):most well known but least frequent.
2)Amino acids(glycine,glutamate and GABA)
3)Peptides:least known but present on maximum neurones.Some of them are putative
neurotransmitters.
At least 4 other classes have been described incl. gases,nucleotides,eicosanoids and anandamide.
1)BIOGENIC AMINES:They are of two types:a)catecholamines;b)those formed from definite precursors.
A)CATECHOLAMINES:Formed from precursor tyrosine,tyrosine hydroxylase is the rate-limiting
enzyme.The steps upto formation of Dopamine occurs in axoplasm of adrenergic neurones,noradrenaline
is formed in granules of those neurones and adrenaline in adrenal medulla cells.
Release:contents of granules(CA,ATP,beta-hydroxylase) occurs by exocytosis.it is modulated by
presynaptic alpha-2 autoreceptors.
Uptake:Axonal-via active amine pump(inhibited by cocaine,desipramine and guanithedine)
Granular-via another amine pump which carries CA to granules(inhibited by reserpine)
Extraneuronal
Metabolism:Dopamine is metabolized by Monoamine oxidase and catechol-o-methyl-transferase.The
end products are VMA and other products.
DOPAMINERGIC SYSTEM
Dopaminergic tracts in CNS:There are three well-known tracts viz.the nigrostriatal,mesocortcal-
mesolimbic and tuberoinfubdibular.Besides this there is a small pathway in retina.
NIGROSTRIATAL:From SNPC to corpus striatum.D2 receptors here inhibit caudate nucleus which itself
dampens motor activity.So ultimately DA increases motor activity.
MESOLIMBIC-MESOCORTICAL:From Ventral tegmental area to different parts of cortex and limbic
system.
115. 113
TUBERO-INFUNDIBULAR:DA acts as prolactin inhibitory factor.
Metabolism:It is specifically metabolized by MAO-B.The main product is Homovanillic acid(HVA).
Receptors:Two groups-First,coupled with Gs protein[D1,5] and other one is coupled with Gi
protein[D2-4].D2 is present in caudate nucleus,D3 in nucleus accumbens and D4 in frontal lobe(also
found in heart & kidney).
DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA:Based on the observation that anti-dopaminergics(the
phenothiazines) are effective in schizophrenia & drugs that cause DA release (amphetamines)can
cause psychosis in non-schizophrenics.Dec. levels of urine HVA is found in responders to
antipsychotics
However there is room for 5-HT in this regard as the Serotonin Dopamine antagonists(SDA) have come
up.DA is also implicated in psychosis due to brain tumors and mania.
DOPAMINE has also role in affective disorders,levels may be low in depression and high in
mania.This is supported by the fact that Amphetamines have antidepressant action.Some studies
have shown low levels of DA metabolites in the depressed.
The D2 receptors of caudate nucleus suppress caudate activity i.e gating of motor acts.Decreased
D2 receptors thus decr. motor activity excessively resulting in bradykinesia.On other hand excess
D2 activity removes gating control and cause extraneous motor acts like tics & also gives rise to
intrusive thoughts as seen in OCD.OCD pts show inc. caudate DA-analog binding.
It has been observed that the potency of typical antipsychotics correlated with D2 receptor
antagonism as also the EPS.They were also effective in controlling positive symptoms because they
could block D2 receptors in mesolimbic pathway but not the negative symptoms as in the
mesocortical region the predominant neurotransmitter was 5-HT.The SDA which were more
selective for 5 HT2 were more useful in these regard.
Also studies have documented an inverse relation between D2 receptors and emotional
detachment(negativity).So typical antipsychotics which lower D2 levels may actually worsen the
negative symtoms instead of treating them
Cocaine addiction is much dependant on dopamine for its pleasure-giving effects.DA transporter is
necessary for its action.It has been seen that D1 receptors inhibit the desire for cocaine while D2
have opposite action.
Nicotine also acts via release of DA and glutamate.Nicotine analogues are under experimental
study to treat Parkinsonism and to reduce cognitive deficites due to Haloperidol.
NORADRENERGIC/ADRENERGIC SYSTEM
Noradrenergic tracts in CNS:The NA cell bodies are mostly located in locus cerulus of pons and
lateral tegmental area.The axons project to neocortex,all parts of limbic
system,thalamus,hypothalamus and to cerebellum,spinal cord.Limbic system & spinal cord gets
innervation from both groups while hypothalamus & brainstem gets innervated by lateral
tegmental area.Most of these are NA-ergic while a few adrenergic neurones are found in caudal
pons and medulla.
Metabolism:Formed from DA with help of DA β-hydroxylase.NA is converted in adrenal medulla
into Adrenaline by enzyme PNMT.Both these products are metabolised by MAO(mainly MAOA)and
COMT.
Receptors:Broadly of two types α, β . α receptor is of 2 types α1 and α2.α1 is of three subtypes
α1A,α1B and α1D.α2 receptor is of three types α2A,α2B and α2C.β receptor is three types:β1,β2
and β3. α1-receptors are associated with PIP-cascade,while otherα-receptors decrease cAMP and
β-receptors seem to stimulate formation of cAMP.β1 ,2 counteract α-receptor action and β-3
receptors regulate energy metabolism.
The BIOGENIC AMINE THEORY for mood disorders is developed based on the fact that the drugs
that inhibit reuptake of NA and 5-HT are useful in depression. Drugs that affect both or only NA or
only 5-HT are all effective. It is seen from animal models that an intact NA system is essential for
drugs that act on 5-HT system and vice versa.This shows the action of these systems is interlinked
but unfortunately the interrelationship and individual roles of these systems in pathophysiology is
