Chapter 016, Hypothalamus
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Corresponding right limb functions are normal. He has difficulty standing, and the limited walking he is able to accomplish is associated with a broad-based gait. His voice sounds hoarse. He is able to extend his tongue along the midline. On further examination, the patient also is noted to have mild ptosis on the left. His pupils were reactive to light, but his left pupil was smaller than the right. Finally, the left side of his face feels dry and warm to touch. The bright dorsolateral region in part A is the site of an infarction.
Answer the following questions on the basis of your reading of this chapter and prior chapters on sensory and motor functions of the dorsolateral medulla. Occlusion of which artery would infarct the medullary region shown on the MRI?
Indicate the particular nucleus or tract that, after damage by infarction, produces: The site of lesion corresponds to the distribution of the posterior inferior cerebellar artery. The territory supplied by this artery receives little collateral circulation see Chapter 3. This means that blood flow from a functioning neighboring artery does not take over, as in many regions of the brain.
Remaining areas of the medulla at this level are supplied by small, direct branches from the vertebral artery. The lesion produced a classical sign. Ipsilateral loss of facial pain and temperature sensation is due to interruption of the spinal trigeminal tract, as well as part of the spinal trigeminal nucleus caudal nucleus. Contralateral loss of pain and temperature sensation on the neck, limbs, and trunk is due to interruption of the anterolateral system, which decussates in the spinal cord Figure 15—1C.
This pattern was considered in This div only appears when the trigger link is hovered over. Otherwise it is hidden from view. About MyAccess If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus. Sign in via OpenAthens. Early studies in SIDS infants used immunohistochemistry, enzyme activities, and tissue binding, with a focus on the catecholamines; these are summarized in Table Our studies examined very different neuronal activities.
The orexin peptides were discovered by two groups in 28 , 35 , and it was demonstrated that if they were injected into the lateral ventricles or near specific arousal regions such as the locus coeruleus of the pons, they led to increased wakefulness and marked suppression of rapid eye movement REM sleep 28 , 36 , Narcolepsy is caused by loss of orexin neurons in humans; it is associated with severe sleepiness and intrusion of fragments of REM sleep into wakefulness, including dream-like hallucinations and sudden bouts of loss of muscle tone cataplexy , brought on by emotion.
The orexin system is also dysregulated in other, less specific neurodegenerative disorders 38 , It was known that narcolepsy was associated with brain lesions in the pre-optic area of the anterior hypothalamus before the neurotransmitter was identified We accessed human brain tissue from the Coroner and from the NSW Tissue Resource Centre, University of Sydney Sydney, New South Wales, Australia in order to evaluate changes in the normal distribution of orexin with ageing, within the tuberal hypothalamus. While the cause of the loss is speculative, it could result in sleep dysregulation in normal ageing, since the loss of orexin neurons is known to cause this effect in other medical disorders Is orexin also abnormal in SIDS?
While in piglets we could correlate such changes with exposure to intermittent hypoxia, we found no correlations with risk factors in the infants. For infants, risk exposures were identified from questionnaire information collected at the death scene investigation or were documented in relationship to the location and circumstances of death, including prone sleeping position and cigarette smoke exposure.
Our laboratory studies the brain of newborn piglets exposed to various experimental paradigms in parallel with our studies of human infant brain tissue. The animal studies model exposure to SIDS risk factors, allow comparison to control subjects, and therefore add to the understanding of our findings in SIDS infants see below.
The two experimental paradigms used are of intermittent hypercapnic hypoxia IHH and nicotine exposure Nic: The piglet models therefore explore mechanisms that may underlie the neuropathological lesions in SIDS infants by studying brain changes secondary to noxious insults, rather than underlying vulnerabilities such as genetic defects. In the framework of the Triple Risk Hypothesis for SIDS 42 , one can postulate how noxious exposures cause brain changes, or one can postulate that they may cause secondary vulnerabilities.
From a neuropathological perspective, our focus within these piglet models was predominantly of the medulla. Studying various neurotransmitter and growth factor systems provided a way to decipher mechanisms responsible for our findings of increased apoptosis in the medulla of these models We found that the dorsal motor nucleus of the vagus DMNV within the medulla repeatedly showed changes for the markers studied, indicating a strong vagal effect of these exposures The markers we have studied include apoptosis, the cholinergic and catecholaminergic systems, serotoninergic, and growth factors BDNF As the PVN of the hypothalamus is the only direct forebrain projection to the DMNV 31 , this provided us with additional rationale for expanding our studies to the hypothalamus.
Animals in the Nic group showed increased expression of OxR1 and OxR2 which was both receptor- and region-specific. For OxR2, however, the combined exposure resulted in even greater increases A follow-up quantitative evaluation of OxA and OxB expression examined the cumulative effects of IHH exposure in the tuberal hypothalamus This progressive decrease in both OxA and OxB indicated that chronic IHH exposure induces progressively greater changes in orexin neuropeptide expression in the hypothalamus. The reduction seen after four days of IHH exposure would be expected to disrupt sleep regulation Three methods were used to examine the possible mechanisms for the reduction in orexin in SIDS infants.
Interestingly, Nic exposure was associated with both increased expression of OxA and OxB and an increase in the number of orexin neurons in the central tuberal hypothalamus. As with our first study in piglets, IHH exposure was associated with reduced expression of OxA and OxB in the hypothalamus and pons, although this occurred without changes in neuronal numbers. Combined exposure to Nic and IHH did not prevent the nicotine-induced increases. Our protein studies have been confined to the brainstem so far, rather than the hypothalamus, but they remain relevant to the exploration of mechanisms for the hypothalamic abnormalities.
A methodological hurdle was working with formalin fixed tissue, since this is the preferred method for tissue preservation from SIDS autopsies However, proteomic studies have now identified peptides and thereby protein abnormalities in SIDS infants compared to controls. For this technique, only small group numbers are used six in each group , but differences were identified, affecting proteins involved with molecular function, cellular component organization, biological processes, cellular components, and cytoskeletal protein classes Interestingly, when we examined these exact three markers in the hypothalamus of the SIDS infants, we found their expression not to differ when compared to the non-SIDS controls 48 Table This indicates that the mechanisms at play within the SIDS brain may be region-dependent.
Our investigation of increased apoptosis and altered UPR in the hypothalamus of our SIDS cohort compared to control cases showed that decreased orexin levels in SIDS infants matched the decrease of dynorphin No differences were found for the markers of apoptosis, so this ruled out a loss of orexin cells due to activation of cell death pathways. Since accumulation of pPERK was also found in areas of the pons locus coeruleus and dorsal raphe , the finding could both indicate a common pathway for loss of protein expression and be responsible for the reduction in other neurotransmitters, such as 5-HT and noradrenaline, which have also been found found in SIDS in these regions.
As the orexins are essential for promoting wakefulness and arousal, they are an excellent candidate pathway for study. The orexinergic neurons are responsible for maintaining wakefulness, and project to almost every brain region involved in the regulation of wakefulness However, hypothalamic neurotransmitters other than the orexins are involved in the arousal response, particularly PrRP Prolactin releasing peptide , creating evidence for hierarchy, redundancy, and feedback in the sleep-regulatory system 50 , Thus, further investigation of the hypothalamus in SIDS is warranted in order to add to our already-known findings of the abnormalities reported to date, as summarized in Table While it seems unlikely that a single transmitter defect would lead to failure of the arousal system, orexin is unique in that a deficiency is associated with the human disease narcolepsy.
Alternatively, identification of several individual abnormalities may reveal a pattern of defects, or clues to a more generalized process. The abnormal process in SIDS infants may occur throughout the entire brain or throughout a particular system s , such as the arousal pathways, of the brain.
This wider view is important to consider, given the strong evidence for an abnormality in the serotoninergic system of SIDS infants, the role of serotonin in the arousal pathways, and the close inter-relationships between the serotonin and orexin systems The amount of orexin found in infants was consistent for different groups, both across our studies and in the literature. This applies to both immunoreactivity and neuronal numbers. In addition to comparison with controls, methods to account for whether loss of orexin is due to loss of orexin neurons, or to loss of the transmitter alone, include comparison with other cell types, or evaluation of co-localized transmitters 53 , The fairly steady decline in neuron numbers and neuron density with increasing age required that we study groups of infants and children 47 in contrast to other authors who focused on adult disease Several groups have studied the number of orexin neurons in the hypothalamus, although most report cell numbers using stereological techniques, which we were not able to undertake due to the limits of the tissue available.source
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However, use of control cases, including adults, allowed us to make appropriate comparisons with the number of cells per section 55 , 56 and cell density 57 , where these have been reported. These findings could also indicate involvement of other neurotransmitters released by the same cells 53 , although this has not yet been studied in SIDS cases.
However, in the piglets we also examined effects on the orexin receptors. Animal models of narcolepsy are attributable to a defect in the gene for the orexin receptor, while studies in human subjects with narcolepsy have implicated the distribution of the orexin receptors and axons with the disease process 57 , This does not detract from the application of previous findings to discussion of the relevance to sudden infant death where it is postulated that neurodevelopment of the control of respiration creates a vulnerable profile in early development.
The complexity of the hypothalamic pathways, including internal cross-talk, makes it easy to correlate our recent studies with the earlier findings in SIDS infants — for example, the finding of reduced cholinergic synthetic enzymes and the knowledge that hypothalamic neurons involved in energy balance have a cholinergic phenotype Reduced serotonin content in the hypothalamus could link to low levels of serotonin expression in the brainstem neurons that project to this area It seems likely that as our understanding of these neurotransmitter pathways evolve, so, too, will our ability to link the many abnormalities found.
Other hypothalamic transmitter-receptor systems may also be worthy of future exploration, including the RFamide peptide family peptides possessing an Arg-Phe-NH2 motif at their C-terminus , which exerts important neuroendocrine, behavioral, sensory, and autonomic functions This system has orexinergic activity, which in humans is associated with regulation of food intake and energy homeostasis; but it has also been linked to activity and sleep in other species This same transmitter-receptor system has other roles which are potentially as diverse as pituitary hormone secretion, steroidogenesis, bone formation, nociceptive transmission, and arterial blood pressure The hypothalamus is a hub of neuronal control that oversees many vital functions and receives input from, and has projections to, large areas of the brain, as well as having direct interaction with the bloodstream Recently available techniques for study promise to continue to elucidate various locations and functions of neurons Wide-ranging possibilities are likely to exist for future research, first by exploring systems such as these other transmitters within the hypothalamus, but also by utilizing newer research methods, including the data-mining approaches that first led to the identification of some of these peptides themselves.
Ongoing research will help refine the insights obtained from our studies to date, with clarification of their importance to the unexpected death of these infants. To view a copy of this licence, visit http: This licence allows for the copying, distribution, display and performance of this work for non-commercial purposes providing the work is clearly attributed to the copyright holders. Address all inquiries to the Director at the above address. Turn recording back on. National Center for Biotechnology Information , U.
University of Adelaide Press ; May. Introduction Since deaths attributed to sudden infant death syndrome SIDS occur during sleep, failure to arouse in a stressful situation comprises one component in the proposed mechanism of death. Structure and Function of the Hypothalamus The hypothalamus is an integrative center for vital functions that lies above the superior, anterior aspect of the third ventricle, and below the thalamus. Hypothalamic peptides and neurotransmitters Hypothalamic peptide markers, identifying either the neurotransmitter or its receptor s , can be used to identify function.
Early Neuropathological Studies of the Hypothalamus in SIDS The studies by Ozand and Tildon 13 and Sparks and Hunsaker 2 were performed using homogenates of the hypothalamus, so they did not differentiate amongst the different hypothalamic regions. Human studies Early studies in SIDS infants used immunohistochemistry, enzyme activities, and tissue binding, with a focus on the catecholamines; these are summarized in Table Models exploring SIDS risk factors Our laboratory studies the brain of newborn piglets exposed to various experimental paradigms in parallel with our studies of human infant brain tissue.
Mechanisms Three methods were used to examine the possible mechanisms for the reduction in orexin in SIDS infants. Conclusions The hypothalamus is a hub of neuronal control that oversees many vital functions and receives input from, and has projections to, large areas of the brain, as well as having direct interaction with the bloodstream Development of the neuroendocrine hypothalamus. Sudden infant death syndrome: Altered aminergic-cholinergic synaptic markers in hypothalamus.
Development of the human hypothalamus.
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