The Effects of Subcortical Lesions
By: Kristen Matthews
The subcortex consists of diverse sets of nuclei
responsible for various behaviors. Lesions to this area
result in a wide range of behavior changes. These changes
are dependent on various factors including the location,
severity, and onset among others. As research will show,
the subcortex is hardly isolated within the cortex. Its
connections are vast and necessary for normal functioning
throughout the brain.
Many studies have emphasized the association between
subcortical lesions and cortical functioning. This
relationship is exemplified in patients with vascular
dementia (VaD), a disease caused by:
cerebrovascular pathologic changes that affect the
cerebral cortex, subcortical white matter tracts,
subcortical nuclei (particularly the basal ganglia
and thalamus), or a combination of these regions.
The majority of patients with VaD have lesions that
involve subcortical structures (Sultzer, Mahler,
Cummings, Van Gorp, Hinkin, 1995).
This particular study examined the relationship of these
lesions to the cognitive deficits experienced and the
metabolic rate of the cortex using positron emission
tomography (PET).
Patients with VaD with no cortical lesions, but with
subcortical lesions of varied severity were assessed
using the Neurobehavioral Rating Scale (NRS). NRS
"measures the severity of cognitive deficits, psychiatric
symptoms and behavioral disturbances...(Sultzer et al,
1995)." Magnetic Resonance Imaging (MRI) was used to
assess subcortical features and PET images were used to
asses cortical metabolic rates. The relationship between
these evaluations were used to determine whether
metabolic deficits of the frontal cortex occurs with
lesions to the subcortex and whether "...neuropsychiatric
symptoms are associated with the extent of subcortical
lesions (Sultzer et al, 1995)."
The results of this study confirm a relationship
between changes in the subcortex and cortical
functioning, but question limitations and variability of
that relationship. In cases of damage to subcortical
nuclei in only one hemisphere, impairment of the
metabolic rate occurred in the ipsilateral cortex.
Furthermore, the exact location of the damage determined
the area of hypometabolism
in the cortex. Lesions to the basal ganglia and the
thalamus revealed itself in changes to the ipsilateral
frontal cortex. Similarly, anterior periventricular
hyperintensities (PVH) also appear to affect the
ipsilateral frontal cortex. However, bilateral PVH's
around the lateral ventricles seemed related to
abnormalities throughout the cortex. VaD is most often
associated with the basal ganglia and thalamus with
hypometabolism in the frontal cortex. The severity of
lesions in these and other areas also correlates with the
extent of cognitive impairment (Sultzer et al, 1995).
Although further research is necessary for a more
comprehensive explanation, this study exemplifies how
damage to a particular area can impair function in areas
that are anatomically distant to the damaged site.
Conversely to this, Morys, Narkiewicz and Wisniewski
(1993) examined the effect of cortical damage on the
subcortical region of the claustrum. The purpose of this
study was to verify that there are extensive
connections' between the claustrum and areas throughout
the cerebral cortex. The claustrum was observed in
patients with severe gyral scarring in various places on
the cortex. Deterioration of different parts of the
cortex seemed to lead to pathological changes in specific
parts of the claustrum depending on the location of
cortical damage. Lesions to the frontal cortex had effect
on the anterior part of the claustrum, while lesions to
parietal and occipital areas seemed to have caused neural
degeneration in the central and posterior regions of the
claustrum. The result of these two previous studies
emphasize the interdependent relationship between the
subcortex and other cortical areas.
In relation to this, a case study is cited in which
a seemingly healthy man acquired a bilateral lesion to
his globus pallidus from an unknown cause (Strub, 1989).
No other area of the brain revealed any damage.
Curiously, the man's change in behavior as a result of
this lesion reflects that of symptoms identical to
frontal lobe syndrome. "He has given up his hobbies and
fails to make timely decisions in his work. He knows what
actions are required of him in his business, yet he
procrastinates and leaves details unattended (Strub,
1989)." It has been recognized that that these symptoms
do appear from lesions elsewhere than the frontal cortex.
For example, lesions that damage pathways between the
frontal and limbic regions have been observed. However,
it is proposed that the globus pallidus is too remote for
this to be the case. One explanation offered suggests
that frontal lobe syndrome is not only due to damage of
the frontal lobe. The syndrome may be a set of behavior
changes whose source may be lesions in various of regions
in the brain. The second explanation offered suggests
that frontal syndrome may be due to damage of brain
structures interconnected with the frontal lobe, as well
as damage to the frontal lobe and its direct pathways.
This case study exemplifies the different structures of
the brain that may share functions once attributed to one
area. An interdependent network of systems may be
necessary for these functions to occur.
Similar behavior changes were noted in a patient
with bilateral lesions to the globus pallidus, nucleus
accumbens, septal gray matter, and the nucleus of the
diagonal band of broca. These changes included an
increase in apathy and withdrawal, a loss of initiative,
and impaired memory. His intelligence and verbal fluency
remained unaffected (Cummings, 1993).
Carbon monoxide poisoning was responsible for
bilateral globus pallidus lesions in three patients. All
experienced a reduction in spontaneous activities and
initiative, and an inability to conceive new thoughts.
Functions remaining unimpaired were language, reasoning,
and an intact mental control of memory (Cummings, 1993).
Parkinson's disease, a neurological disorder
affecting the motor system, finds its roots in and around
the basal ganglia(Thompson, 1993). The major symptoms of
this disease are: tremors, usually when the limb is at
rest; muscle ridgity; slowness of movement; and having
difficulties in initiating movements, such as sitting
down or getting up (Carlson, 1994).
In a normally functioning brain, the pars compacta
of the substantia nigra sends dopamine releasing neurons
containing information regarding motion control to the
striatum, which includes the putamen and caudate nucleus.
Next, neurons using acetylcholine (Ach) from the striatum
branch into the cortex for final processing of motor
movements. Parkinson's disease is a result of the
dopamine releasing neurons degenerating. This disrupts
the motion control information from reaching the striatum
which causes an overabundant release of Ach into the
cortex. Although these cells naturally die with age,
Parkinson's disease increases this process by 70 percent
(Youdim and Riederer, 1997). Why this process occurs is
still unclear. Suggestions include environmental toxins,
abnormal metabolism, unknown infections (Carlson, 1994),
or a genetic defect involving chromosome 4 (Youdim and
Riederer, 1997).
Huntington's Chorea (HC) is another disease related
to the degeneration of subcortical nuclei and motor
control. HC is characterized by involuntary jerky
movements of the arms and legs. Neuropsychological
features include problems with attention, concentration,
organization, and planning. Cognitive abilities decline
as the disease progresses (Brandt and Bylsma, 1993). The
cause of this disease seems to be a "degeneration of the
caudate nucleus and putamen, especially of GABAergic and
(Ach) neurons (Carlson, 1993)." It is likely that
glutamate may have a toxic effect' on these cells "by
prolonged excessive excitation of neurons that ultimately
result in cell death (Brandt and Bylsma, 1993)."
The caudate nucleus and putamen seem to be the
center of control for slow, smooth movements (Carlson,
1993). Damage to these areas cause muscle excitation or
contraction, such as in Huntington's Chorea.
Other behavioral consequences have been cited due to
lesions in the caudate nucleus. A review done by Jeffrey
L. Cummings (1993) found impairment to dorsal areas of
the caudate nucleus lead to such behaviors as confusion
and lack of interest, while a ventral caudate lesion lead
to euphoria, inhibition and inappropriate behavior. Both
areas resulted in attention, memory, and executive
function deficits. Furthermore, neuroacanthocytosis, also
a disorder affecting the caudate nucleus, resulted in
behaviors including an impaired intellect and personality
changes, similar to those of frontal lobe syndrome.
Neuropsychiatric disorders have also been linked to
deficiencies in circuits between frontal and subcortical
regions (Cummings, 1993). Lesions of the caudate nucleus
and dorsolateral prefrontal cortex have been observed as
being precursors for depression. PET images show a
decreased glucose metabolism in these areas in patients
with idiopathic unipolar depression (Cummings, 1993).
Diseases of the caudate nucleus, and damage to the
thalamus or medial orbitofrontal cortex seem to be
involved with manic behavior. Furthermore, obsessive
compulsive behavior is found to accompany diseases that
damage the caudate nucleus and putamen, such as
Huntington's disease (Cummings, 1993).
The subcortex is composed of networks within
networks, operating as a unit with the entire cortex. As
research has shown, behavior changes from the result of
lesions vary extensively. Localization of functions seems
to be not entirely as applicable as it was once thought.
WORKS CITED
Brandt, J., Bylsma, F. The Dementia of Huntington's
Disease. In R.W. Parks, R.F. Zec and R.S. Wilson (Eds.),
NEUROPSYCHOLOGY OF ALZHEIMER'S DISEASE AND OTHER
DEMENTIAS. Oxford University Press. 1993.
Carlson, Neil R. PHYSIOLOGY OF BEHAVIOR, 5TH ED. Boston:
Allyn and Bacon, 1994.
Cummings, Jeffrey L. (1993). Frontal-Subcortical
Circuits and Human Behavior. ARCHIVES OF NEUROLOGY, 50,
873-879.
Morys, J., Narkiewicz, O., Wisniewski, H. (1993).
Neuronal Loss In the Human Claustrum Following Ulegyria.
BRAIN RESEARCH, 616, 176-180.
Strub, Richard. (1988). Frontal Lobe Syndrome In a
Patient With Bilateral Globus Pallidus Lesions. ARCHIVES
OF NEUROLOGY, 46, 1024-1027.
Sultzer, D.L., Mahler, M.E., Cummings, J.L., Van Gorp,
W.G., Hinkin, C.H. (1995). Cortical Abnormalities
associated With Subcortical Lesions in Vascular Dementia:
Clinical and positron emission tomographic findings.
ARCHIVES OF NEUROLOGY, 52, 773-780.
Thompson, Richard F. THE BRAIN: A NEUROSCIENCE PRIMER,
2ND ED. New York: W.H. Freeman and Company, 1993.
Youdim, M.B.H., Riederer, P. (1997). Understanding
Parkinson's Disease. SCIENTIFIC AMERICAN, 276, 52-59.
Hypothalamic obesity by Jude Stromberg
Compared to the organism as a whole, the
hypothalamus has an incredibly high function per size
ratio. Encompassed within it's designated 1 cubic cm of
area is the homeostatic regulatory systems for the entire
organism (Holmes, 1993). The hypothalamus, connected via
nerve fibers to the cerebral cortex, thalamus, and other
parts of the brain stem, receives input from these
locations allowing it to regulate many visceral
activities as it serves as a link between the nervous and
endocrine system.
Among the many functions of the hypothalamus are
regulation of heart rate, blood pressure, body
temperature, water and electrolyte balance, body weight,
hunger, reproduction, and circadian rhythms. Many of
these mechanisms, such as temperature regulation, can be
traced to specific anatomical locations. Others,
however, such as hunger and thirst, are not so readily
pinpointed. Since the early 1800's, the hypothalamus
has been inexorably linked to feeding. Observers noted
that hypothalamic tumors can produce hyperphagia, and
consequently, obesity in humans. Early studies suggested
that the hypothalamus contained two "feeding centers",
the ventromedial hypothalamus (VMH) satiety center and
the lateral hypothalamus (LH) feeding center.
Hetherington and Ranson (1940) discovered that
hyperphagia (excessive eating) and obesity could be
elicited via a bilateral lesion to the VMH. For obvious
reasons rats have been the bulk of the experimental
population for hypothalamic lesions. VMH hyperphagia
exists in two phases. The dynamic phase is characterized
by excessive eating and weight gain that begins as soon
as the subject regains consciousness after the operation. Food
consumption plateaus as the rat reaches a stable
level of obesity. The static stage is distinguished by
maintenance of this desirable weight. If weight loss is
induced by food deprivation, the dynamic phase will begin
until the desired weight is attained again. If the
subject is force fed and gains additional weight,
cessation of eating will occur until excess weight is
lost (Pinel, 1993).
Anand and Brobeck (1951) discovered that bilateral
lesions to the lateral hypothalamus will produce aphagia
(cessation of eating). Even VHM hyperphagic rats have
been shown to be susceptible to this phenomena. Adipose
(cessation of drinking) is also observed with LH lesions.
Given these findings, the dominating theory behind
eating 30 years ago suggested that the VHM satiety center
and the LH feeding center cooperated via a negative
feedback condition. Both centers received information
from various blood glucose and body fat chemoreceptors,
noted deviations from setpoints and elicited the
necessary behaviors to stabilize the situation. This
dual set-point theory served as a catalyst, laying the
foundation for vast amounts of research into the
biopsychology of eating behaviors.
Today, the dual set point theory has all but
disappeared. New evidence suggests that the primary role
of the hypothalamus is the regulation of energy
metabolism, not the regulation of eating, as the dual set
point theory would have us believe. VMH lesions
produce hyperphagia and consequently the organism becomes
obese. Originally, the obesity was believed to result
from over eating, but current research shows the opposite
is true. The obesity causes the over eating. VMH
lesions elevate the level of lipogenesis (production of
fat) and inhibits lypolysis (breakdown and release of fat
into the blood). The hyperphagia results from the need
for the organism to maintain an adequate, constant amount
of immediate energy (blood glucose). Normally this is
not a problem, but VMH lesioned subjects convert this
resource into fat so efficiently that blood glucose
levels are chronically low so they must eat constantly to
provide immediate energy. VMH lesioned rats exhibit
hyperinsulemia (elevated insulin levels) which is
responsible for this rapid absorption of glucose and its
conversion to fat. Also, when given the same amount of
food as non lesioned rats, VMH lesioned rats still gain
more weight (Pinel, 1993). All of this suggests that the
VMH controls metabolism, not eating.
The lateral hypothalamus and it's role as the
"feeding center" has also been heavily scrutinized.
Lesions of the LH disrupt the neurofiber pathways of the
dopaminergic nigro striatal bundle and cause aphagia.
Severing this bundle outside of the LH also produces
aphagia. This suggests that the LH is only involved in
feeding and is not the center. Also, the LH is an
ill-defined area encompassing many nuclei and several
large tracts, so consistent application of the lesion is
hard to control creating further pessimism (Rolls, 1994).
Electrical stimulation of the LH can induce eating.
However, drinking, temperature change, and sexual
activity are also elicited indicating that the LH
motivated multiple behaviors. Also, the LH isn't the
sole anatomical area that can induce one to eat. The
amygdala, hippocampus, thalamus, and frontal cortex all
motivate feeding when stimulated. All of this
information combined disprove the LH "feeding center"
theory (Pinel, 1993).
Several peptides have been implicated in this
scenario as well, notably leptin and neuropeptide Y.
Leptin is a recently discovered hormone that is
responsible for weight control. As fat stores get
bigger, so does the concentration of leptin, stimulating
the brain to stop eating and increase activity.
Conversely, weight loss and decreased leptin levels
stimulate an increase in eating. The leptin receptor
gene has been determined to exist exclusively in the
hypothalamus, again establishing the hypothalamus' role
in obesity and indicating potential problems should a
lesion occur (Gura, 1997).
Neuropeptide Y (NPY), a peptide long identified with
obesity, is controlled by leptin, as it suppresses NPY
production. NPY has consistently been found in elevated
concentrations in the hypothalamus of obese Zucker rats
(Beck et al, 1990). This elevated concentration has been
correlated with increased periods of feeding and
increased amounts of food during these periods. Rats
with elevated NPY also display increased central nervous
system levels of NPY causing increased amounts of insulin
to be released. This leads to hyperinsulemic conditions
and, consequently, lipogenesis. Beck et al (March, 1990)
also showed that fasting will increase the concentrations
of NPY, presumably to elicit an increased feeding
response.
In a separate study, Beck et al (July, 1990)
suggested that since NPY is a pancreatic polypepetide
found in both rats and humans, then Zucker obese rats can
effectively posed as models for human obesity. Again
they indicated that elevated levels of NPY are
consistently found in the paraventricular nucleus, the
arcuate nucleus, and other areas of the hypothalamus in
obese and hyperphagic rats. Since NPY is a strong
initiator of feeding, they suggested a possible treatment
for obesity could be found in inhibiting NPY. If drugs
could be created that bound specifically with NPY
receptors, they would act as inhibitors by irreversibly
binding to the NPY receptors, rendering them useless, and
thus inhibiting the entire system from functioning.
Presumably, drugs that would bind to leptin receptors
would have the same beneficial effect.
This represents one of the most reasonable cures for
hypothalamic obesity. Research of this design has been
hard to come by because human subjects are few and far
between. Often, by the time invasive research can be
done, the lesion state is far too advanced to pinpoint
the exact location and effect. Given this, rats have
again served as the bulk of the experimental population.
Extrapolation of rat findings to human populations is not
an absolute, but it does provide researchers with a
considerable knowledge base to work with.
Several other potential cures have surfaced in the
literature. Drugs such as fluoxetine and fenfluramine
enhance serotenergic function, eliciting appetite
suppressing effects. The serotenergic system enhances
the sensation of satiety via the serotonin sensitive
medial, ventromedial, and paraventricular hypothalamus.
Fluoxetine and fenfluramine inhibit reuptake of
serotonin, effectively increasing the concentration of
serotonin in the sensitive areas eliciting it's appetite
suppressing effect.
However, Jordan et al (1996) found that giving
fluoxetine and fenfluramine to a 36 year old male with
hypothalamic obesity had no effect. The subject's lesion
resulted from a glioma of the optic chiasm. Secondary
hypothalamic tumor invasion and suprastellar radiation
were the identified causes of his hypothalamic obesity.
The authors suggested that the tumor damaged the
serotonin sensitive hypothalamic nuclei, thereby negating
any effect by the drugs.
Another very interesting potential cure was offered
by Fukagawa et al (1996). Lean fetal ventromedial
hypothalamic tissue was introduced into the third
ventricle of obese Zucker rats. As previously mentioned,
Zucker rats exhibit hypoactivity, hyperphagia,
hyperlipidemia, hyperinsulemia, and increased fat
deposition. Similar effects are seen in VMH lesioned
rats. Due to difficulties in obtaining adequate human
subjects, both Zucker and VMH lesioned rats have been
considered adequate models for human obesity. The
study found that transplantation of lean fetal
hypothalamic tissue into the ventricles of obese Zucker
rats partially corrected the abnormalities. The study
clearly stated that the benefits were specific for
hypothalamus tissue only. Transplantation of frontal
tissue failed to elicit any response. The authors
suggested that the reduced hyperphagia may be a direct
result of the partial restoration of the function of the
hypothalamus by the fetal tissue. Neuropeptide Y levels
in the VMH, PVN, and the arcuate nucleus dropped in the
transplanted rats indicating the fetal tissue may have
helped restore the leptin-NPY system.
Adrenal gland hypertrophy decreased in the
transplanted rats, suggesting the fetal tissue may help
restore the damaged hypothalamic-pituitary-adrenal axis
function. Finally, the study suggested that the fetal
tissue may have restores the neuronal systems of the
hypothalamus, allowing improved communication by the
hypothalamus via its humoral and synaptic mechanisms.
Also, they proposed that glial or other interstitial
components of the fetal tissue may have provided a
"missing component" in the rats.
BIBLIOGRAPHY
Anand, B. and Brobeck, J. Localization of a "Feeding
Center" in the Hypothalamus of the Rat. Proceedings
of the Society of Experimental Biology and Medicine.
Vol. 77. pp. 149-172. 1940.
Beck, B., Burlet, A., Nicolas, J., Burlet, C.
Hypothalamic Neuropeptide Y (NPY) in Obese Zucker
Rats: Implications in Feeding and Sexual Behaviors.
Physiology and Behavior. Vol. 47(3). pp. 449-453.
Beck, B., Burlet, A., Nicolas, J., Burlet, C.
Hyperphagia in Obesity is Associated with a Central
Peptidergic Dysregulation in Rats. Journal of
Nutrition. Vol. 120(7). pp. 806-811. July, 1990.
Fukagawa, K., Knight, D., Price, H., Sakata, T., Tso, P.
Transplantation of Lean Fetal Hypothalamus Restores
Hypothalamic Function in Zucker Obese Rats. American
Journal of Physiology. Vol. 271 (Regulator Integrative
Comparative Physiology). pp. R55-R63.
Gura, T. Obesity Sheds Its Secrets. Science. Vol. 275.
pp. 751-753. February 7, 1997.
Hetherington, A., and Ranson, S. Hypothalamic Lesions and
Adiposity in the Rat. Anatomical Record. Vol. 78.
pp. 149-172. 1940.
Holes, O. Human Neuropsychology: A Student Text. New
York: Chapman and Hall Medical. 1993.
Jordan, G., Roberts, M., Emsley, R. Serotonergic
Agents in the Treatment of Hypothalamic Obesity
Syndrome: A Case Report. International Journal of
Eating Disorders. Vol. 20(1). pp. 111-113. 1996.
Pinel, J. Biopsychology. Boston: Allyn and Bacon. 1993.
Rolls, E. Appetite: Neural and Behavioral Basis. New
York: Oxford University Press. 1994.
The role of the hypothalamus
in lesion induced obesity
by
Maria Chappa
The hypothalamus has many functions. It is connected
directly or indirectly to the central nervous system by
receiving and communication sensory information,
integrating it, and communicating it through a complex
system of electroresponsive, thermoresponsive and
chemoresponsive neurons specifically related to certain
parts of the brain. For example, initial sex behavior is
controlled in the neurons that are receptive to gonadal
and related hormones (Cross and Silver, 1966; Kawakami
and Sakuma, 1974), While body temperature change
similarly originates in the temperature sensitive neurons
and their associative circuits.(Nakayama et al.(1963).
Thirst and hunger, along with other functions, are
interspersed throughout the lateral hypothalamic area
(LHA) which as its name implies, lies lateral to the
ventomedial hypothalamus. Together, these two areas of
the hypothalamus play very important roles in the role of
initiating and terminating feeding behavior. It is
specifically these two areas, along with its
neuroanatomical, neurochemical and integrational aspects
that will be discussed here.
In 1942, Hetherington and Ranson discovered in their
research that lesions to the ventromedial hypothalamus
caused overeating and subsequent obesity. They found that
while destruction of the ventomedial hypothalamus (VMH)
produced obesity, lesions to the lateral hypothalamic
area (LHA) inhibited eating and drinking behavior.
Furthermore, the inverse occurred when these areas were
merely stimulated. Stimulation of the VMH produced
termination of eating, while the stimulation of the LHA
stimulated food intake. Many researchers concluded that
the effects of VMH lesions implicated a medial
hypothalamic "satiety" center that complemented a lateral
hypothalamic "hunger center". However, more recent
studies have shown that this is an oversimplified view
and that much more complex mechanisms are involved.
Elecrophysiological investigations at the single neuron
level reveal that a reciprocal activity between the two
areas that monitor hunger and satiety exist.
Simultaneous recordings of the discharges from the LHA
and VMH reveal that excitation of one is linked with the
inhibition of the other, indicating that during
feeding behavior one decreases while the other increases
in a simultaneous, reciprocal manner. Anatomically, the
neural processes of the LHA and VMH come in contact only
at points of common termination outside both areas, and
neither one sends axons directly into the antipodal
center. It is thought to be highly unlikely that this
reciprocity occurs through any direct connection, but
might be subserved at points of common termination in the
perifornical area of the hypothalamus. Looking at
studies of the resulting effects of lesions to the VMH
and LHA areas, provides us with a way of understanding
these complex mechanisms.
VMH lesions have been found to simultaneously disrupt
production and reception of satiety signals (Chhina et
al. 1971), while they cause disinihibition of the LHA.
This combination of effects increases consumption, and
results in obesity. It is hypothesized that when one is
full, muscle spindles send discharges through the vagus
nerve to increase VMH activity, (reducing food intake)
which in turn normally decreases LHA output. (remember
that stimulation of the LHA results in the increase of
food intake). It is further thought that glucose
sensitive units in the vagus nerve vary in response to
blood glucose concentration which may influence one or
both centers.
Gold and his colleagues (Gold 1973; Gold, Jones,
Sawchenko, and Kapatos) have shown that obesity is not
produced by damage to the hypothalamus, but through
disruption of the fibers connecting the paraventricular
nucleus with the brain stem region that control the
activity of the parasympathetic fibers of the vagus
nerve. It is interesting to note here that VMH lesions
accompanied by increased insulin, and increased gastric
acid secretion disturb the hormonal, metabolic, and
digestive functions. Many of these functions are
mediated by the vagus nerve, and it has been demonstrated
that VMH obesity can be alleviated by vagotomy (Powley
and Opsahl, 1974) which would would reduce abnormal
feedback to the control centers.
Although the mechanisms of hypothalamic obesity has been
traditionally attributed to the disinhibition of the
"feeding center" in the lateral hypothalamus after the
destruction of the "satiety center" in the ventromedial
hypothalamus, there has been a recent shift from a purely
neuroanatomical perspective toward a better neurochemical
understanding of the influence of neurotransmitters,
neuromodulators, and peripheral hormones on appetite
control. Two of the neurostransmitter systems that have
been implicated in hypothalamic obesity are the
noradrenergic and the serotonergic systems. The
noradrenergic system is believed to initiate eating at
certain stages of the circadian cycle, while the
serotonergic system promotes satiety and termination of
eating behaviors via the nuclei of the hypothalamus
(Leibowitz, Weiss,& Shor Posner, 1987,1988). Recently
there have been studies in which obesity was induced
through injections of certain drugs resulting in a
reduction or depletion of the serotonin
content,indicating possible destruction of the
serotonergic fiber system. Application of these drugs in
the lateral area of the anterior hypothalamus had the
reverse effect. The concentration of serotonin is
greater in the LHA than in other areas of the
hypothalamus, and generally inhibitory to LHA neurons.
The HLA when stimulated increases food intake, thus it
would appear that serotonin may participate in the
control of obesity, and that a deficency of serotonin
could lead to obesity.
Some recent supportive data of the serotonin theory
comes in the from of a case study of a man with
hypothalamic obesity. This 36 year old man who was
admitted for psychiatric assessment because of
inappropriate eating and social behaviors. Three years
prior he had received radiation therapy for a tumor in
the optic chiasm, resulting in a lesion. His weight
increased from 181 lbs. to 314 lbs. in three years.
Divorce, loss of employment, and deterioration of social
function had resulted. His assessment revealed no form
of psychosis. The main clinical features were severe
hyperphagia, disruption of the sleep cycle, and daytime
somnolence. Drug therapy consisting of the antibulimic
drug fluoxetine was administered at 20 mg daily for one
week, and at 60 mg daily thereafter for three months.
There was no change in his eating behavior during this
treatment period, and in fact gained 7 pounds. He
maintained the weight through a one week drug free
period, and subsequent six week period of drug therapy
consisting of 60 mg per day of fenfluramine. It was
concluded that neither fluoxetine nor fenfluramine
produced any effect on his eating behavior, or weight.
However, fluxoetine and fenfluramine are known to enhance
serotonergic function through their mediating effect on
the serotonin sensitive hypothalamic nuclei. Fenfluramine
acts centrally to produce increased release of serotonin
as well as inhibition of reuptake of serotonin. It was
concluded that the patient did not respond to the drug
therapy because of damage to the serotonin sensitive
hypothalamic nuclei. This case study supports the theory
that these drugs exert their appetite control action via
intact hypothalamic pathways (Jordaan, Robert,
Emsley;1995).
Hypothalamic obesity syndrome is only one type of
obesity, These studies however, aid us in the basic
understanding of the areas that may help us to
understand other types of obesity. In 1994,
identification of the obesity gene and its protein
product provided important support for the genetic
abnormality theory of obesity. The ob protein leptin, is
thought to act as a satiety signal in the brain. Because
of its properties resembling a hormone released by the
fatty tissues of our bodies that regulate appetite and
energy expenditure, and its reducing of plasma insulin
and glucose properties, leptin release is thought to be
stimulated by insulin, and appears to act on the
hypothalamus by inhibiting the release of the
neuropeptide Y. The data so far seems to suggest that
leptin acts as a hormone regulating body stores. High
levels of leptin decrease body fat, while low levels
increase body fat by decreasing or increasing appetite
and energy expenditure. This discovery of leptin
represents a remarkable breakthrough in the understanding
of the pathophysiology of obesity.
Research in the area of obesity continues in may
different areas such as behavior modification techniques,
metabolic properties,and genetic, anatomical, and
neurochemical areas. While the causes of obesity is
still a mystery, it is certain that through research of
these types, our knowledge is increased, allowing us to
come closer to specific mechanisms underlying obesity,
and develop therapies and treatments that will enable us
to deal effectively with it in the future.
REFERENCES
1.Cross and Silver (1966); Kawakami and Sakuma (1974),
Yamada (1975). Physiology of the hypothalamus vol.2:558.
2.Nakayama et al.(1963). Physiology of the hypothalamus
vol.2:558.
3.Hetherington and Ranson (1942). Dissociative analysis
o f ventromedial hypothalamic obesity syndrome.
American Physiological Society, 259:R829.
4. Chhina ET al.(1971). Physiology of the hypothalamus
vol 2:565.
5.Gold(1973); Gold, Jones, Sawchenko, and Kapatos (1977);
Physiology of Behavior:469
6.Leibowitz,Weiss and Shor Posner (1987,1988).
Serotonergic agents in the treatment of hypothalamic
obesity. International Journal of Eating Disorders, vol
20 ,no.1:111.
7. Jordaan,Roberts,Emsley; (1995) Serotonergic agents in
the treatment of hypothalamic obesity. International
Journal of Eating Disorders, vol 20 no. 1:111.
8.Rohner Jeanrenaud, Ph.D and Bernard Jeanrenaud,M.D.
(1996). Obesity, leptin and the brain, New England
Journal of Medicine, vol.334, no. 5:324.
Cerebellum function and disabling effects on behavior.
P. Reynolds
The cerebellum has introduced a fascinating amount of
change, adaptation, and evolution associated with human
behavior. From times of long ago, the cerebellum has not
only remained a key player in motor movement and
awareness, but has simultaneously continued to adapt and
evolve to physical and environmental change. This has
been recognized functionally in at least three ways. In
one dimension, the older cerebellum has shown this
through its transformation in aquatic vertebrates
(Eccles, 1977). The ventromedial pathways within the
cerebellum have integrated several sensory inputs which
allowed an aquatic organism to distinguish the
orientation of its body to the environment. It is through
adaptation to environment that a second dimension
involving these areas have made a significant appearance
in terrestrial beings. A modality effect was introduced,
in addition to orientation, which has helped support
posture and influence the control of coordination
involving fine, compound, movements (Carlson, 1994,
Northcutt et al.,1966). The cerebellum has changed to
include the development of a number of synaptic outputs
which are similarly constructed to that of the pyramidal
system of the cerebral cortex (Northcutt et al., 1966).
These pathways have also incorporated inputs from the
motor and association cortex and have worked to allow the
relay of impulses throughout the cortex also involving
learned motor reinforcement(Carlson, 1994). Although
these changes are not new to us as individuals, it was
obviously an evolutionary change. This change involves
adaptation and learning of movement. The cerebellum is
able to control and store control within a motor specific
domain which may designate, but keep differentiated,
different types of adaptation for the same body parts
(Thach, 1995). Whether different contexts or different
movements, the cerebellum is able to regulate and trigger
an appropriate and well practiced body response. The
cerebellum serves a wide range of inputs and outputs from
itself as well as to and from other areas in the brain.
Given this, it is almost necessary to assume the
cerebellum may be linked in a behavioral context to motor
response. Both response linkage (motor
movement/stimulus) and response composition
(stimulus/scenario) could then be achieved through
trial and error learning (Thach,1995).
The cerebellum ultimately receives sensory input and
regulates coordination of movement(internet 1). Classical
conditioning is dependent upon the cerebellum (Eccles,
1977). It is the strengthening of new neuronal pathways
from proposed stimulated brain areas in response to the
cerebellum, which will roughly help to explain this
theory. This theory has reflected the idea involving
trial and error physiological paired response and those
outputs which stretch into the neocortex. This
explanation may begin to help define the mechanisms
behind instrumental conditioning (Thach, 1995). The
cerebellum, as mentioned before, is involved in the
process by which complex motor tasks become automatic
(Ayres, 1975). This briefly introduces the theory of
automation through trial and error and error learning of
content response linkage. Theoretically, as learning of
motor response begins, the cerebellar cortex immediately
begins to acquire control of the motor task (Thach,
1995). The cerebellum will begin to "recognize" or
strengthen synapse between the area of context,(i.e.
language, tactile learning, speaking,) and each "piece"
of consciously initiated movement. After repeated tries,
the context will hypothetically be correctly linked to
the movement, in such that this context may trigger
similar movement for future context(Thach, 1995).
Although it may appear that the cerebellum is initiating
movement during learning of response linkage, this is
probably not true. When motor linkage is taking place,
the motor, premotor, and supplementary motor association
corticies are all fully active as execution of task
requires full participation from all of these
areas(Thach, 1995) This initiation will hold the same
synaptic activity level whether stimulated in the
cerebellum or prefrontal cortex, until such a complex
motor movement is fully automatic (Thach,1995). With
repeated trial and error learned linkage, the cerebellum
will come to control the execution of this connection
between motor and context response, with minimal and no
assistance for the cerebral cortex. This consequently
will allow the cerebral cortex to continue cognitive
processes as well as the ability to focus on other neo
cortical brain activity (Thach, 1995).
To divide the cerebellum into sub areas, may allow the
researcher to give a more concise example of how
information is received and distributed. These sub areas
are designated by the pathway in which they distribute
their axons. In the systems identified within the
cerebellum, the pathways are not only noted as having
outputs and inputs to and from this area, but as also
having inputs and outputs within it. This defines the
open and closed loop systems of the cerebellum (Eccles,
1977). The flocculonodular lobe of the cerebellum receive
inputs from two different vestibular systems and project
to the vestibular nucleus (Ayres, 1973). The midline area
receives auditory and visual stimulus from the tectum and
spinal cord and sends out axons to the fastigial nucleus
and motor nuclei in the reticular formation (Carlson,
1994) The fastigial nucleus receives input and follows by
making synapse back at the vestibular (Brooks, 1986).
This system maintains posture and balance under
gravitational force as well as having influence on
auditory and visual experience (Brooks, 1986). Although
the cerebellum receives every sensory modality, this is
only a small part of the overall input to the cerebellum
(Eccles et al., 1967). The third ventromedial pathway
makes up the rest of the cerebellum which includes input
from the motor and association cortex, as well as a small
amount of sensory information (Ayres, 1973). Synapse is
made through the pontine tegmental reticular nucleus, and
projects to interposed nuclei, the red nucleus and
through the lateral thalamic nucleus to the other motor
areas (Carlson, 1994). The behaviors include control of
hand and arm movements, integrates information and
modifies motor outputs, coordinates and times consistent
motion movements and response linkage pairing(Carlson,
1994).
This third ventromedial pathway reverberates automation
through trial and error within the cerebellum (Thach,
1995). When a new movement needs to be "learned or a
set movement needs to be adapted, the climbing fiber will
begin to fire (only once) immediately after an error
occurs and reliable time after time (Thach, 1995).
Although the usual firing rate of the climbing fibers are
irregular and in no particular relation to movement, they
will fire systematically in order to reduce the strength
of the Purkinje cells on those parallel fibers which are
active and causing inappropriate movement (Thach, 1995).
In other words, the climbing fibers responsibility is to
detect and correct errors in performance and reduce the
strength of parallel fiber/ Purkinje cell synapse(Thach,
1995). There is only one climbing fiber for every
Purkinje cell. The low frequency of firing is actively
equal to 1 HZ., and calls for these neurons to make up a
considerably large population (Eccles, 1977). By
stimulating the parallel fibers, the climbing fibers
short cut the neuronal route and cease the firing of the
Purkinje cell. Thus, they intercept and quickly stop the
incorrect message throughout the cerebral cortex. The
Purkinje cells connect output from inner and outer
regions of the cerebellum (Thach, 1995). It represents
the conditions and context in which the movement is to be
adapted and executed in the mossy fibers of the Purkinje
cells (Thach, 1995). The parallel fibers insure the
representation of context and combine the response or
motor movement by sending synapse to the Purkinje cells.
(Thach, 1995).
The importance of explaining the components of the
cerebellum are easily understood in respect to predicting
what may happen if the cerebellum is damaged. A lesion
of the cerebellum may impair complex movements, cause
ataxia,(which cause difficulties in walking on a straight
line and difficulties in precise placement of the feet
(Dichgans & Diener, 1985), tremor, poor coordination, and
speech disorder (internet #2). Motor movement may be
selectively abolished dependent upon the damaged area
(Kirshner, 1986). The motor movements may also fall into
generalized categories such as loss of control of fine
movement, and degree of muscle coordination (Rose, 1973).
Lesions which occur in the cerebellum essentially can
have a lasting effect on any motor making part of the
body (Brooks, 1986). Cerebellum lesions however, seem
to most notably effect error detection and practice
related learning (Thach, 1995). Schweighofer et
al.,(1996), suggest that the role of the cerebellum is to
learn to compensate any error and lesions yield
considerable loss of adaptive capabilities. This is
shown in an inability or slowness in linking a novel
context to a motor pattern it should but does not
trigger. The movements will then be slow, irregular, and
require mental effort, as if newly learned (Thach, 1995).
These subjects will show little or no improvement
resulting from practice, and therefore their learning
curve will be "retarded" or flat (Brooks, 1986). Complex
muscle movements will be gross and irregular when
attempted (Brooks, 1986).
Lesions which occur in the lateral zone of the cerebellum
effect independent, quick and finite movements (Carlson,
1994). Impairment or error detection and practice
learning is also shown. There is an overall weakness and
decomposition of movement, in which movement will remain
simple and lack to be or become complex(Eccles, 1977).
This behavior, for example would impair simple
unconscious movement like throwing, kicking, typing and
so on. There is a inability for the cerebellum to
estimate when movement requires an excitatory or
inhibitory response in respect to timing (Brooks, 1986).
Within the intermediate zone, of the cerebellum, there is
also a disease which will cause a deficient in motor
timing but not perceptual estimates (Thach, 1995). A
lesion in this area may lead to limb rigidity, (Carlson,
1994). Posture and balance will be effected by a lesion
in the flocculonodular lobs or the vermis area (Carlson,
1994). Impairments of cognitive spatial operations,
found in Freidreich's ataxia have casually been related
to cerebellar pathology (Wallesch & Horn, 1990). In
addition, early loss of deep tendon reflexes and sensory
neuropathy may begin to develop (Wallesch & Horn, 1990).
Another disease, infantile onset of spinocerebellar
ataxia, includes symptoms such as ahtetosis epilepsy,
deafness, opthalmoplegia and optic atrophy and primary
hypogonadism in females (Koskinen et al, 1995). These
symptoms tend to be closely related to the severity of
disease onset and may include degeneration of the
Purkinje cells (Koskinen et al,1995).
The cerebellum has evolved in a similar pattern in
reference to the neocortex. It allows complex automatic
movement and adaptive pairing. The demonstration of its
complex inner workings, and cortex distribution of axonal
pathways, further allow the best demonstration of how
dependent an organism is on this system. Fortunately,
its structured to allow a graceful degradation when
deficit is introduced, and may sometimes allow an
individual to compensate for a disability in many ways.
References
Ayres, J. (1975) Sensory Integration and Learning
Disorders, California: Western Psychological
Association. pp 46-48,75-82.
Brooks, V. (1986). The Neuronal Basis of Motor Control,
New York: Oxford University Press. pp 271-289.
Carlson, N., (1994), Physiology of Behavior, Boston :
Allyn & Bacon pp. 245-49.
Darvesh, S. (1996), Subcortical dementia: a
neurobehavioral approach. Brain and Cognition, 31: 230-249.
Dichgans, J., & Diener, H. (1985), Cerebellar Functions
(ed. by Bloedel et al), Germany: Springer-Verlag. pp
127-147.
Eccles, J., (1977), The Understanding of the Brain, New
York: McGraw-Hill Book Company. pp. 121-146.
Eccles, J., Ito, M., Szenta-Gothal, J., (1967), The
Cerebellum as a Neuronal Machine, New York: Springer-Verlag New York Incorporated. pp. 156-176.
Kirshner, H. (1986), Behavioral Neurology: A Practical
Approach, New York: Churchill Livingstone. pp. 110-112
Koskinen, T., Valanne, L., Ketenon, L., Pihko, H.,
(1995), Infantile-onset spinocerebellar ataxia:MR and CT
findings. American Society of Neuroadiology, 16:1427-1433.
Northcutt, G., Williams, K., Barber, R., (1966), Atlas of
the Sheep Brain. Illinois: Atipes Publishing Company. pp
8-13.
Rose, S. (1974). The Conscious Brain. New York: Alfred
A. Knope. pp 41-49,312-314.
Schweighofer, N., Arbib, M., Dominey, P., (1996), A model
of the cerebellum in adaptive control of saccadic gain,
Biological Cybernetic, 75:19-28.
Thach, W., (1995) http://thachw@thalamus.wustl.edu.
Wallesch, C.& Horn, A., (1990) Long term effects of
cerebellar pathology on cognitive functions, Brain and
Cognition, 14:19-25.
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