by Ben Best
This installment is something of a digression in my "systematic" attempt to investigate the anatomical basis of mind. Here I investigate in detail a single component of the "Limbic System": the amygdala. The basis of this investigation is a book of scientific papers entitled THE AMYGDALA, Edited by John P. Aggleton (Wiley-Liss, 1992). Almost all of my material is drawn from this book.
My motivation for this detailed study is the claim by
that there exists in the brain a "self-circuit" that is the seat of
feeling, and that this brain center is probably below the cerebrum
because self&feeling are attributes of all animals.
If were to attempt to rationalize his thesis, I
would locate the "self-circuit" in the orbitofrontal cortex. But Robert
specifically excludes residence in the cerebrum. What about the "Limbic
System", so often identified as the locus of emotion in the brain?
The problem with the "Limbic
System" is that is an abstraction,
not an anatomical referent. It
includes several areas in the
cerebrum (cingulate gyrus, orbito-
frontal cortex, parahippocampus) as
well as a number of sub-cerebral
structures such as portions of the
thalamus & hypothalamus, the nucleus
accumbens (in the basal ganglia), the
septal nuclei and the amygdala. If a
"self-circuit" exists through all
these structures, it is not highly
localized. The "circuit of Papez"
has already been discredited
(see The Hippocampus).
The nucleus accumbens & septal nuclei both serve the function
of "pleasure centers": cocaine reputedly
produces euphoria by enhancing dopamine
action in the nucleus accumbens, and the
septal nuclei produces such pleasure when
electrically stimulated that laboratory
animals will ardently press levers to
stimulate those nuclei. If there is
a subcortical structure which is central
to the Limbic System, it is
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The amygdala in a human is not much bigger than an almond (the Greek root word). At the base of the brain, the elevation of the parahippocampus at the uncus is due to the amygdala, which lies beneath it. The amygdala is really three collections of nuclei. The largest (and best differentiated) portion of the amygdaloid complex is the basolateral nuclear group [BL], consisting of the lateral nucleus, the multi-faceted basal nucleus and the accessory basal nucleus. The other major portion consists of the centromedial group [Ce-M], consisting of the central nucleus and the medial nucleus. The Ce-M group is connected through a strand of fibers (the stria terminalis) — traveling alongside the tail of the caudate nucleus) to an area by the hypothalamus known as the bed nucleus of the stria terminalis [BST]. Cell types in the BST are identical to those in the Ce-M, causing the BST to be included in the definition of the "extended amygdala". The BST lies in the basal forebrain (substantia innominata), which also contains the nucleus accumbens, the basal nucleus of Meynert and the ventral portions of the putamen and globus pallidus (which are basal ganglia). The smallest portion of the amygdaloid complex is the cortical nucleus, also known as the olfactory amygdala because the primary input to the cortical nuclear group is from the olfactory bulb and olfactory cortex. (The naming and groupings of nuclei in the amygdala is far from standard, which can make the literature on the subject unnecessarily difficult to understand. Some authors group the cortical and centromedial nuclei together as the cortiomedial amygdala.)
The major cell classes in the basolateral nucleus are spiny-pyramidal & spine-sparse stellate neurons, closely resembling those found in the cerebrum, with the pyramidal cells predominating. If cell-type is regarded as the basis of functionality, then the basolateral nuclei could be regarded as a functional extension of the cerebral cortex. There seems to be a continuum of cell morphologies between the pyramidal and stellate cells (as in the cortex).
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Two major bundles of fibers connect the amygdala with other areas of
the brain: the stria terminalis and the ventral amygdalofugal pathway.
The centromedial amygdala projects through the stria terminalis primarily
to the hypothalamus and through the ventral amygdalofugal tract to the
brain stem, where it can influence hormonal and somatomotor aspects of
behavior & emotional states (eg, eating, drinking & sex). Projections
from the lateral and central amygdala go to the lateral hypothalamus
through the ventral amygdalofugal pathway. The functioning of the basolateral
amygdala is more like the cerebral cortex — with which it is closely in
communication. The basolateral amygdala has direct connections (shown in
the figure as bidirectional arrows) with many cerebral areas so that it can
receive and modulate sensory and polysensory processing. The strongest
connections are with the insular cortex, orbital cortex and the medial wall
of the frontal lobe. These connections (like cortical pyramidal connections)
use glutamate and/or aspartate as the neurotransmitter. Like the cerebrum,
the basolateral nuclei project to the striatum (caudate nucleus, putamen
and nucleus accumbens of the basal ganglia) and receives direct cholinergic
(ie, acetylcholine neurotransmitter) input from the basal nucleus of Meynert.
The basolateral group also projects to the mediodorsal thalamus (which
projects to the prefrontal cortex).
Within the amygdala itself, connections primarily begin in the basolateral division and terminate in the centromedial division. Projections in the opposite direction are much weaker. It is the lateral nucleus that receives most of the sensory information arriving at the amygdala from the cerebrum. The lateral nucleus receives highly processed visual (recognition) information from the TE region of the temporal cortex. This information is projected into the magnocellular basal nucleus of the amygdala, which returns project- ions to every level of the visual information-processing hierarchy of the temporal & occipital cortex. Recordings of individual neurons in the amygdala have found neurons that respond specifically to auditory, taste, smell or somatosensory as well as visual stimuli, but the visual neurons are the most plentiful. Some amygdala neurons respond primarily to faces.
In general, the lateral portion of the amygdala is regarded as inhibitory & reflective of the external environment, whereas the medial amygdala is regarded as facilitatory & reflective of the internal environment. Stimulation of the basolateral amygdala reduces feeding behavior, whereas stimulation of the corticomedial amygdala increases food intake. Stimulation of the basolateral nuclear group results in arousal and attention. Amygdala outputs tend to originate in the central nucleus, the most peptide-rich region of the brain, and are carried by peptide-containing fibers in the stria terminalis & ventral amygdalofugal pathway.
There are many more projections from the amygdala to the hippocampus than in the opposite direction. The strongest projection is from the lateral nucleus to the entorhinal cortex (ie, the cortical area from which the hippocampus receives most sensory input). Secondary projections arise primarily from the parvicellular division of the basal nucleus, which receives most of the return connections (from the CA1/subiculum border zone and the entorhinal cortex).
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Monkeys without amygdalas have difficulty learning to associate a light-signal with an electric shock — and also have difficulty associating a neutral stimulus with a food reward. It has been suggested that the amygdala functions to associate sensation with reward or punishment. Amphetamine injections to the ventral striatum enhance the effects of a conditioned reinforcing stimulus only if the amygdala is intact.
Neurons in the lateral, basal and central nuclei of primate amygdalas have been found to respond to visual stimuli associated with a food reward. But when the reward was changed to an aversive food (saline) the response of these neurons did not change — in contrast to neurons in the orbitofrontal cortex and basal forebrain which show a rapid reversal in response to a positive reinforcement becoming a negative one. This implies that the amygdala neuron response corresponds to whether a stimulus has reward/punishment significance (and merits attention), rather than associating the stimulus with a reward or punishment.
Signals from the thalamus, co-ordinated with signals from the visual cortex, evidently allow the amygdala to assist in focusing attention in response to fear [SCIENCE 300:568-569 (2003)]. Fearful images — notably other humans with fearful facial expressions — apparently increase attention, arousal and cortical processing through amygdala mediation.
LTP (Long-Term Potentiation) can occur in amygdala brain slices. The basal nucleus has high levels of NMDA receptors. Infusion of NMDA antagonists into the amygdala blocks the acquisition, but not the expression, of conditioned fear. However, infusion of NMDA has no effect on the acquisition of conditioned taste aversion. Lesions or electrical stimulation of the amygdala impair aversion taste learning without affecting maze learning (which is dependent on the hippocampus). Conversely, lesions or electrical stimulation of the hippocampus impairs maze learning, but not taste aversion learning. Human patients with amygdala lesions show impaired immediate visual recognition, while visual memory is normal.
Like the hippocampus, the amygdala is rich in receptors for cortisol (hydrocortisone, ie, stress hormone). While prolonged stress (prolonged cortisol exposure) impairs LTP in the hippocampus, the same stresses facilitate LTP in the amygdala [NEUROCHEMICAL RESEARCH 28(1):1735-1742 (2003)].
Both the hippocampus and the amygdala (particularly the lateral nucleus) contain high concentrations of receptors for the benzodiazepine anti-anxiety drugs. Microinjections of benzodiazepines into the amygdala reduces fear & anxiety, but this effect is not seen upon microinjection into the hippocampus. Humans with amygdala lesions show a decrease in "emotional tension". It has been postulated that benzodiazepines may act on the lateral nucleus to prevent the linkage of emotional significance to sensory stimuli — prior to conscious processing. The basolateral amygdala has been demonstrated to mediate anxiety in mice [NATURE; Tye,KM; 471:358-362 (2011)]. An 8-week Mindfulness-Based Stress Reduction program for individuals with high psychological stress showed decreases in right basolateral amygdala gray matter density correlated with the perceived reduction in stress [SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE; Holzel,B; 5(1):11-17 (2010)].
Electrical stimulation of the amygdala increases plasma levels of corticosterone — and human subjects nearly always report experiencing fear. Lesions to the cortical and centromedial nuclei markedly reduce the fear-response of wild rats to a cat.
Both the amygdala and the hippocampus contain many receptors for neurotransmitters. The central nucleus of the amygdala is the most strongly modulated: by dopamine, norepinephrine, epinephrine and serotonin. The basal nuclei receive moderately high inputs of dopamine, norepinephrine and serotonin.
There is evidence for differences in the amygdala of males & females. The posterior medial amygdala is densely populated with estrogen and androgen receptors, and this area is about 20% larger in male rats than in females. Stimulation of the corticomedial amygdala may cause ovulation in the female, but cutting the stria terminalis abolishes this effect. Lesions to rat amygdalas which include the medial nucleus eliminates male libido, but not female libido. In humans, temporal lobe epilepsy has been associated with sexual arousal in women — and even orgasms — but there are no reported cases of this happening for men.
There may be species differences in amygdala function as well. Removal of the amygdala from female monkeys eliminate maternal behavior (resulting in infant neglect), but amygdalectomy actually increases the maternal behavior of female virgin rats (although this has been interpreted as reduced xenophobia or fear). Lesions to the amygdala of other primates disrupt social communication, but this does not occur in humans. The converse is true for lesions near Wernicke's area on the cerebral cortex — humans are rendered verbally incoherent, but social communication of other primates is unaffected. Inputs to the human amygdala tend to be much more cognitive, whereas for other primates the inputs are more sensory.
Sensory inputs to the amygdala mainly terminate in the lateral nucleus. Damage to the lateral nucleus interferes with Pavlovian fear conditioning associated with specific stimuli. If an animal has been given Pavlovian fear conditioning (eg, association of a sound with an electric shock) in a distinctive environment, placing the animal in that environment can also elicit fear (contextual conditioning). Projections from the CA1 & subiculum areas of the hippocampus to the basal nucleus & accessory basal nucleus mediate contextual conditioning. Damage to these nuclei interfere with contextual conditioning.
The central nucleus mediates expression of conditioned fear responses. The "defensive response" to a threatening stimulus consists of elevated heart rate (mediated by the lateral hypothalamus) and a "freeze state" (mediated by the central gray), both of which receive input from the central nucleus of the amygdala. Lesions to the lateral hypothalamus eliminate the effect on heart rate, but not the "freeze state", whereas lesions to the central gray have the opposite effect. Both responses can be evoked by amygdala stimulation. The bed nucleus of the stria terminalis mediates the release of pituitary-adrenal stress hormone (Corticotropin-Releasing Hormone, CRH) in response to fear. CRH causes the adrenal gland to release epinephrine & cortisol. Chronic stress causes cortisol-induced release of epinephrine from the locus coeruleus to the amygdala — creating a viscious cycle.
One experimenter cut the optic chiasm and forebrain commissures of monkeys after lesioning the amygdala on one side of the brain. These monkeys reacted in a wild fashion when shown threatening sights to the eye connected to the intact amygdala, but were tame when they viewed the same sights through the other eye.
A monkey will normally become excited at the sight of a banana, but becomes indifferent upon bilateral amygdalectomy. Food preferences based on visual appearance are eliminated. Nonetheless, animals show no change in the motivating power of food as a reward for work, even though the animals appear to be emotionally indifferent. It has been suggested that sensory input is given emotional & motivational significance by transmission to the amygdala.
Removal of both amygdalea from monkeys leads to tameness, loss of fear, "excessive" examination of objects (often with the mouth) and the eating of previously rejected foods. These symptoms are similar to those of the "Kluver-Bucy syndrome" produced in monkeys by removing the anterior temporal lobe (including the amygdala), except that the Kluver-Bucy monkeys also exhibit "hypersexuality". The amygdala seems to be responsible for a kind of "food xenophobia" because rats also more readily eat unknown substances if their amygdalae are damaged.
Brains of human schizophrenics show a significant reduction of the hippocampus and amygdala (especially the central and basolateral nuclei). PET scans show increased amygdala blood flow in depressed patients and in experimental subjects experiencing anticipatory anxiety prior to a mild shock.
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The results of experimental science can be somewhat unsatisfying when it contains many fragmentary bits of data which have no simple explanation. But this reflects our current state of knowledge about the amygdala.
The amygdala does seem to be closely associated with the feeling of fear, but removal of the amygdala seems to disinhibit feelings of lust and curiosity. Hunger and thirst are feelings centered more in the hypothalamus, whereas pure pleasure seems to be concentrated in the nucleus accumbens and the septal nuclei. Stimulation of the globus pallidus can produce an experience of joy. Interests qualify as feelings also, and are likely associated with the cingulate cortex. Guilt, anxiety and paranoia may be associated with the orbitofrontal cortex. Neurophysiology still has little to say about boredom, hope, jealousy, love and sadness, but it wouldn't surprise me if these emotions were found in different neural structures.
The amygdala itself is a highly complex collection of nuclei, so it could conceivably support different emotions in different areas — as it does appear to do in the case of fear & anger. Nonetheless, just as the processing of visual information has moved from the tectum in amphibians to the occipital lobe of species with a more developed cerebral cortex, emotional experience in humans may not have remained entirely sub-cerebral, as indicated by the right/left brain dichotomy and by the emotional effects of prefrontal lobotomy. The evidence indicates multiple centers of feeling in the brain, associated with various aspects of self (self-image, conscience, will, etc.). Locating all brain functions related to feeling & self in a single "circuit" not only entails the fallacy of the homunculus, it doesn't leave much for the rest of the brain to do.
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