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Although we may be able to detect and quantify cell death antibiotics for dogs diarrhea buy 500 mg panmycin, axon dysfunction antibiotics on birth control discount panmycin 250 mg on-line, or neurodegenerative changes virus 3 game online cheap panmycin 500mg without prescription, given the barely conceivable degree of biological diversity due to cellby-cell variation in post-concussive change antimicrobial prophylaxis buy cheap panmycin 500 mg on line, where should one mark the threshold between brain injury versus brain non-injury Candidly antimicrobial soap brands buy panmycin, it may take another generation of work and thought before we have a good answer antibiotic cement spacer buy discount panmycin on-line. When the patient returns complaining of headache, vertigo, and inability to think clearly and to concentrate, the doctor. On the Risk Factor Called History of Pre-Morbid Neuropsychiatric Problems As displayed in Table 7. Indeed, most lay people would make the same prediction, since common sense suggests that a person with a behavioral problem at time A is more likely to have a problem at time B. The question of interest is not whether preinjury psychiatric/behavioral problems are a risk factor for occurrence or persistence of post-injury problems, but what this means. To the confirmed skeptic, the data demonstrate that hitting the brain does not cause neurobehavioral distress lasting more than a month or two, because no biological harm could possibly last that long, so persistent complaints must be attributed to pre-morbid fragility, imagination, or feigning. First, the rhetoric used to make the argument that concussion does not cause lasting harm often rests on fidelity to two errors: (1) unfamiliarity with the data on persistent brain damage; and (2) the Cartesian dogma of the separateness of mind and brain. With the evolution of theories of hysteria at the turn of the 20th century, it was common for psychologists to distinguish purportedly psychological versus organic causes of illness. In fact, "most physicians practiced neurology and psychiatry as a combined specialty in the 1930s" [520]. Those sad events provoked the migration of many psychoanalytically oriented psychiatrists to the United States. As a result of pressure for a unique professional identity, the two disciplines split. As Grinker explained in 1959 [521]: "that decision was based on realistic recognition that neuropsychiatry has become separated into neurology and psychiatry as distinct clinical specialties. Thus, the indefensible Cartesian mind/brain dichotomy became concretized in separate medical guilds. That divisive division helps explain the perspective of 20thcentury opinions about post-concussive behavioral problems. Most of the early papers reporting the statistical association between pre-morbid behavior problems and post-concussive symptoms employ the terms "psychological" and "organic" in the semantic usage of 1900. The reader sees the conceptual error: since psychological constructs are labels for brain states and traits, there is no biological basis for this mind/brain differentiation. If a previously depressed person suffers a concussion and remains symptomatic for years, that is a brain problem. That non-specific and unconfirmed reportage about pre-injury status was coded in the variable: "presence or absence of psychiatric history. This kind of variable lumping may prevent statistical detection of important associations. According to the observations of athletic trainers, 127 subjects were subsequently concussed. As the first authentic prospective study of its kind, these findings possibly support the hypothesis that pre-morbid perceived physical distress is associated with postconcussion symptoms. The justifiable conclusion: boys who are willing to express feelings about their bodies before a concussion are willing to express feelings about their bodies after a concussion. Third, a plurality of 20th-century papers on this subject discuss post-traumatic symptoms as if they were universal. That is, investigators have correctly noted that, three months after a concussion or a limb fracture, the number of complaints is about the same. This factual observation is then used to support a logical error: some investigators concluded that the psychological impact of trauma itself, not physical brain change, must therefore explain prolonged post-concussive problems. That argument would be worthy of consideration if all traumatic injuries were followed by the same symptoms. Indeed, there will be considerable overlap between the symptoms listed by the survivor of an accident with a broken leg or a shaken brain; the signs of traumatic stress (anguished or blank facial expressions, sweat, tremor, agitation, distraction) have surely been recognizable to adult hominids since bipedalism. But brain injury has unique effects not expected in other trauma, such as double vision, dizziness, impaired new learning with preserved declarative memory, slowed thinking, and imbalance. The main point is simple: the relationship between pre-morbid behavioral traits and brain injury is different from the relationship between pre-morbid behavioral traits and non-specific trauma in two obvious ways: (1) unlike in the circumstances of other traumas. Recall Georgia, the 29year-old high school teacher and equestrienne discussed at the beginning of this chapter. In the 120 months prior to her concussion she was dysthymic for 29 months and depressed to the point of disability for 11 months. Arousal and stress would have provoked changes in neurotransmission involving amines and steroids, ions and receptors. It would have been no surprise if she expressed more pain and emotional upset than average after her fracture. One cannot argue with the view that pre-morbid emotional sensitivity tends to be associated with a higher likelihood of post-traumatic distress. But in addition to the commonplace changes in transmitters and hormones, she probably up- or down-regulated expression of about a thousand neuronal and glial genes. Just as in the case of a leg fracture, sensitive Georgia was at risk for a more prolonged recovery simply because acute stress is hard on a fragile brain. Abundant research supports this prediction, although it may require a decade or more to refine the technology to visualize these differences. In the meantime, it is a plausible hypothesis: when the brain of a neurobehaviorally atypical person is rattled by an abrupt external force in a traumatic event, the resulting brain changes represent a double hit (stress plus mechanical shaking) on already-atypical circuits. Note: this analysis is not to imply that pre-morbid depression has a particular uniform biological basis and therefore, for instance, depression-plus-concussion yields a predictable result. To say, "Georgia has a history of depression" means, "Georgia has had periods of subjective distress reflecting molecular happenings unique to her in all the world and far beyond our capacity to analyze. In brief summary: it seems very reasonable that some pre-morbid neuropsychiatric traits are risk factors and help to explain some of the variance in outcome. The fact that human distress tends to make a brain injury harder to bear would be predicted simply on the basis of the overlapping neurobiology, if it were not already obvious based on common sense. Another meta-analysis reported that women fared worse in two of eight high-quality studies but no sex difference was found in the other six studies [528]. At least one study reports that cognitive outcome was actually superior among women [529]. Teen girls and adult women are prone to post-concussive neuropsychiatric problems, especially depression. For these reasons, rather than assessing outcome by the number of complaints, the present author urges attention to quality of life. Sex differences seem to be larger or smaller in different age groups and between alternate mechanisms of injury. Is that because a single fix should not be expected to work for a heterogeneous problem Given the wealth of evidence of sex differences in response to concussion, it seems vital that clinical investigators consider that different treatments may be optimal for men and for women. However, that summary statement oversimplifies an increasingly intriguing biological story about sex and the brain. Our goal in this section is again to quest beyond the merely epidemiological association and explain why sex differences occur. In this case, a fine-grained analysis of epidemiology provides hints regarding the biological basis of the sex-related differences in outcome. Impartial clinicians have observed for centuries that women (1) have a higher incidence of emotional illnesses than men, and (2) have a higher incidence of emotional complications of other illnesses. A century ago many medical men would have confidently attributed feminine predisposition to emotional problems to innate weakness or to "hysteria. The emphasis on hysteria as the explanation for sex differences in certain mental disorders persisted well into the tawdry mid-20th-century era during which American psychiatry was distracted by psychodynamic thought. Sex is often listed in epidemiological reports about brain injury as a "demographic" trait. But sex should not be classified among traits such as zip code and household income; it is a biological trait unique to a subset of animals. Although most people realize without academic input that sex has profound implications for individual and group behavior among social species, it has recently become evident that sex and associated biological differences profoundly influence vulnerability to and resilience in the face of the same diseases [549, 553, 554]. Moreover, contrary to a 1960s political claim of perfect neurobiological equality, there are systematic sex differences in many aspects of brain structure and function. Before readers revolt, the author does not mean to resurrect the puerile biases of mid-20th-century North America. Sexual Dimorphism Among potential scientific explanations for different outcomes after a blow to the head, the most obvious question is whether male and female heads (and head contents) differ. To begin with, "the forehead of the skull is one of the human parts History the historical progress in explanation for sex-related difference in outcome from head trauma, or from any trauma, has tracked 26 these writers reached their conclusion based on counting up studies that did and did not report sex differences from within a tiny and nonsystematically selected subset of the existing literature. For instance, they included a study as proof of no sex difference in outcomes that never addressed that question [530]. They included a study that judged post-concussive symptoms less than one month after injury [531]. They included a study the outcome of which was unrelated to health or well-being [532]. Most concerningly, they included a study that clearly reported that females had worse outcome ("Female athletes performed worse than male athletes on visual memory (mean, 65. Although skull thickness is not systematically different, a variety of geometric measures reliably distinguish male from female skulls [556]. An inescapable prediction is that if identical abrupt external forces visit identical skull loci in a man and a woman, their skulls will differently disperse that force to the brain. The differences reported below are those found in mature adult women, typically between age 18 and 59. As one might intuit, some evidence suggests a correlation between the density of sex hormone receptors and the regions exhibiting the greatest degree of sex-related difference [564, 565]. Remaining at the level of regional analysis (before considering chemical, microscopic, or molecular factors), some evidence suggests that emotional disorders differentially impact Table 7. This methodology also permits localization of critical cerebral "addresses" that function as hubs or nodes for information processing. However, only scans of males detected functional nodes in four regions: the left superior frontal gyrus, left lingual gyrus, left fusiform gyrus, and right inferior temporal gyrus. The data suggested greater connectivity between hemispheres among females but greater connectivity within hemispheres among males. The authors interpreted their data as follows: "The observations suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes. Still, taking the rhetoric with a grain of salt, these connectome studies support the hypothesis that males and females successfully accomplish survival-relevant information processing using different brain structures and functions. One: if a man begins with more white-matter fibers he may have more of a reserve in regard to axon damage. Men tend to have more neurons, higher neuronal density, and more synapses, even controlling for body size. Women tend to have significantly higher gray-matter density in the left frontal pole [561], perhaps higher neuronal densities in the granular cortical layers [564], and possibly larger neurons than men, especially in the left hemisphere [570]. Again, the observation that men tend to have large hippocampi with denser complements of neurons conceivably makes male brains more resilient in the face of partial hippocampal cell loss. Other evidence suggests a link between female stress vulnerability and a combination of steroid hormone and amine transmitter differences [574]. It is conceivable that female excess of post-concussive problems merely reflects a difference in stress reactivity. Given the location of the damage, one would suspect some alteration in their stress responsiveness.

In the light of such a flickering life expectancy 6 bacteria buy panmycin from india, it seems remarkable that some brain enhancements remained to blossom late bacteria 3d models discount panmycin 500 mg overnight delivery, such that wisdom and subjective well-being bloom well into the senium antibiotics for uti with least side effects purchase panmycin in india. The author guesses that selection played some little role in that happy phenomenon bacteriophage order panmycin 250mg amex. Phenotypes of time-passing-related brain change vary little in childhood but a lot in late adulthood antibiotic resistant strep throat purchase panmycin canada. Time-Passing-Related Life History Feature #2 There are many threats to mortality antibiotics for acne spots buy discount panmycin 250mg online, such as accidents, diseases, and innate factors eroding the integrity of biomolecules and cells. Although it is popular to refer to these accidental mortal threats as chance, random, or stochastic, that terminology is a perhaps misleading for two reasons. First, out of an infinite number of potential threats, only a few dominate the threat matrix because the environment confronts us with some threats more often than others. Second, because an interaction occurs between aging feature #1, the development-and-aging life history plan, and feature #2, exposure to accidents. Yet the degree to which selective pressures orchestrated the symphony varied greatly with the life stage. Begin with the typical biography of the Neolithic cave painter: a minority survived infancy. For the period of life from conception to full somatic "maturity" (about age 25), the life history plan was composed very much under the strict supervision of competition for survival and reproduction. For instance, the age of birth hovers around nine months; the age of menarche only varies between about age 9 and 15; the age of complete brain myelination (about age 24) corresponded with the average age of death (about 22). During the post-child-rearing part of life, less selection pressure exists to favor gene rescue tactics. Hence, the development-and-aging life history plan is deeply interwoven with the risk of accidental deterioration. The author is not sure how many gerontologists will embrace the idea that time-passing-related somatic change is rightly conceptualized as an integrated mammalian trait, a life history plan that capitalizes on the most fitness-promoting facets of gaining and losing functions. This impressionistic paradigm shift might some day be shown to be either a helpful alert to the coherently selected nature of brain life history plans or demonstrably inconsistent with some law of nature. This perspective is only offered because it overcomes the simplistic model of life histories according to which development proceeds until day X and aging begins on day X + 1. Although human cells share a genome, their biographies are astonishingly divergent. As counterintuitive and even repellent as it sounds, humans are possibly better conceptualized not as organisms but as mosaics of human cells collaborating with one another and with non-human cells,21 each one and each type following its own life trajectory. An instance of the apparent unitary purpose of development and aging: the acquisition of wisdom after about age 50 or 60 occurs despite the withering of gray matter, the culling of synapses, and a marked decline in the capacity for experience-dependent plasticity. One might be forgiven for suspecting that the human life history plan, including the normal biography of the brain, evolved in a meaningful, explainable way. Gene expression choreographs gains and losses such that brain state at each point serves life stage-related needs in an energy-efficient way. Combining the foregoing concepts with an evolutionary perspective might: (1) clarify the relationship between concussion and aging; (2) explain the heterogeneity of late effects; and (3) explain why it may take decades of further study before we know whether (or how often, or under what circumstances) a single concussion increases the risk of deleterious alteration of time-passing-related brain change or the occurrence of "dementia. All you saw were false color images estimating fractional anisotropy derived indirectly from bouncing radio waves and liberally interpreted as "white-matter integrity" in 78 regions of interest. The term gained favor among 20th-century neuropathologists and remains popular in peerreviewed publications, but is rarely linked with a specific, let alone validated, biological meaning. That raises an important question: when scholars discuss "neurodegenerative diseases" or investigate whether concussion provokes "neurodegenerative changes," are any of them discussing the same thing Technically inclined readers will want to know that those authors employed a tortoise (tolerably obsessive registration and tensor optimization indolent software ensemble) to conduct their analyses for them. Little evidence links that phenomenon to either loss of function or death of neurons. That may also be typical of the normal, healthy life history plan, for instance, in pregnancy. It cannot have a purely functional definition, since function varies within and between brains from before birth. One promising definition might be "a loss of neurons with deleterious consequences for fitness. Yet even that begs the question (in the formal sense of petitio principii) because it assumes the yet-to-be-proven hypothesis that changes that discommode an individual organism are always negative in the biological sense. Because evidence suggests that some degree of neuronal loss with the passing of time is normal and expected. For example, employing modern stereological techniques, Pakkenberg and Gundersen [81] reported that about 10% of cortical neurons are lost between the ages of 20 and 93 in both sexes. Yet (closing our eyes to the weakness of that assumption), in practical terms, how might one determine whether one neuron or 1 million neurons have been lost The best way would be to somehow label each neuron, count it, await a health event, and repeat the count, listing each neuron that went missing. Again, our ideals seem to have outpaced the empirical record: even the most vigorous brain bankers have yet to conduct such counts in each architectonically discrete cortical subregion in large post-mortem samples matched for age, sex, and other potentially confounding factors. As Juraska and Lowry summarized the state of the art: "To date, there do not appear to be any studies of cortical subregions that have combined stereological counting techniques with consideration of reference volume. If one does not know the age-adjusted average number of neurons in a specific brain area, or the number of neurons in that area before a patient suffered a change, or the number after that change, how might one claim that there was either loss or deleterious loss One sees some shrunken neurons, some pyknotic neurons, signs of suspected apoptosis. In motor neuron disease or spinal muscular atrophy, a micro-wasteland combined with a devastating clinical change is persuasive and tragic. But when slow, progressive neocortical neuron loss occurs along with mental changes that might have a dozen explanations, cause and effect is harder to argue. That brings us back around to the challenging issue of what is and is not normal, expected, inevitable species-specific timepassing-related brain change, given that good health means a brilliantly orchestrated symphony of gains and losses. And it requires acceptance of an indisputable biological idea that has yet to become popular in clinical medicine: death is not, by nature, bad. The fact that involutional somatic collapse and return to dust are irritating to some does not endow that phenomenon with organic negativity. Scholars more clever than the present author will have to mark the measuring stick. If that were an accurate story, one might claim a relatively straightforward association between aging and brain change. Second, the best guess about the average number of adult human neurons has recently been updated and downgraded. According to Herculano-Houzel [87], based on scaling up from confirmed counts in other primates, human adults have about 16 billion cortical neurons and about the same number of cerebellar neurons. In fact, students are often surprised to learn, "There appears to be a normal biological variation in the number of neocortical neurons by a factor of more than 2; this represents a variance of more than eight times the variance of human body height" [88]. However, it is self-evident that the suspected loss of neurons between age ten and 20 is not a biomarker for functional decline! Some evidence suggests a fitness advantage for this normal, healthy pregnancy-induced brain atrophy: it is perhaps associated with social bonding. The molecular changes underlying this atrophy are unknown at the time of this writing. His impression is that too little is presently known about the relationship between time-passing-related brain change and inclusive fitness to make the required judgments regarding goodness versus badness. For practical purposes, one might declare with confidence, "A theoretical boundary line exists between neuronal loss with the passing of time that does or does not negatively impact inclusive fitness. Amazingly, 50 years after the start of modern dementia research, our field lacks clarity on this fundamental question of definition. Pinel is also credited, by most historians of neurology, with the first medical use of the term "dementia. In fact, tracing the subsequent use of dementia in medicine reveals that an association with the elderly is a recent deviation from semantic convention, creating a misleading term of art. For more than a century, a typical adult case report described a 20-year-old woman with catatonic psychosis, or a 33-year-old man with general paralysis of the insane. The contemporary use of the term has been confined in three arbitrary ways and typically refers to (1) progressive (2) cognitive loss in (3) late life. Just as our French and German forebears would be baffled by the semantically deviant use of concussion to refer to the (1) head and (2) to something mild, so would they be flummoxed by our odd use of "dementia. One encounters competing definitions from the American Psychiatric Association [23], the American Psychological Association [107], the World Health Organization [108], and the European Dementia Consensus Network [109]. Multiple debates have delayed consensus: whether dementia should refer to a clinical state or to expected manifestation of a subset of pathological processes; whether it should be regarded as an all-or-none phenomenon, or something that passes through biologically meaningful stages, or something that progresses insidiously along a continuum from normal aging to decerebration; whether a specific cognitive domain. In his 2006 publication, Breitner [102] attempted to crystallize what he believes underlies the contemporary use of the term dementia, hoping to derive what he called an "implicit consensus. There is a global deficit in cognitive abilities, that is, in several domains of cognitive activity. Although the last are not a defining feature, they can complicate dementia, adding significantly to the burden or difficulty of its care. The deficit represents a state of decline from a previously established level of abilities. The cognitive deficits or associated features are of sufficient severity to impair accustomed social or occupational functions. The decline in cognition or functional abilities is not attributable to alteration in level of consciousness. It devalues the important and common phenomenon of disabling declines in emotional regulation. If the answer to any of these questions is "yes," a compelling reason exists to press for safe and effective interventions to mitigate these risks. Metabolic stress (perhaps persistent due to acquired network inefficiency) increasing oxidative injury [149, 163, 164] Readers who have bought a "Here is the cascade" model of concussion have been sold a bill of goods. But one cannot understand Guernica by staring at the flaring left nostril of the central horse. A worthy goal is to identify, amidst this multifactorial melee of biological change, modifiable risk factors for bad outcome. However, before searching for those modifiable mechanisms by which trauma may influence later-life function, an epidemiological question of profound human importance needs to be resolved. If a large and representative sample of the human population had ever been assessed, using identical and valid criteria, reliably applied, for the diagnosis of concussion and so-called dementia, one might hope to learn something about the association. Due to (1) the inconsistent lumping of brain and/or behavior changes into the artificial dichotomies such as mild versus not mild, dementia versus not dementia, as well as (2) the commonplace misrepresentation of cases as pure types. It is tempting to trust that two laboratories judged the presence, absence, or degree of dementia comparably. The weight of uncertainty regarding what was actually wrong with each subject in this pile of disappointing literature is, for the purposes of scientific inference, unbearable. In the 20th century, some doctors adopted the habit of classifying patients into two categories, demented or not. The present author wishes to credit an old colleague, John Morris, for his important insistence that dementia is not a categorical but a dimensional concept that varies both in the ways in which it manifests and the degree to which it influences life. That tool rescues dementia from abstraction and provides earthly tethers for behavior. A total of 811,622 Swedish male conscripts were followed for a median period of 33 years. No significant differences were found between persons with and without such brain injuries in any feature assessed. In essence, they came to opposite 26 For instance, in the domain of home and hobbies, the clinician determines whether the patient is fairly described as having "mild but definite impairment of function at home; more difficult chores abandoned; more complicated hobbies and interests abandoned. As the present chapter strives to emphasize, the essential question of whether concussions have late effects lies helpless, tied to the railroad tracks of nosology. And, in fact, one cannot predict whether the detour is worthwhile until more is known about the spectrum of time-passing-related brain change. But, according to memos written by Alzheimer and others, the brain exhibited gross atrophy and arteriosclerosis of the large vessels. Thus, the obvious and indisputable diagnosis in this case was cerebrovascular disease. Due to curiosity and the then-recently-adopted but naive faith in the meaning of little things, Alzheimer also made thin slices, stained some slices with a few concoctions provided by his colleague, Nissl, and peered at the slices through a stack of lenses. Alzheimer suspected neuronal loss (a phenomenon that remains tough to confirm, since it is impractical (and illegal) to count all the neurons before and after an insult) and he saw some peculiar blobs and swirls. Although there was endothelial proliferation (typical of cerebrovascular disease), infiltration of the vessels was absent (atypical for cerebrovascular disease).

The author only digresses to mention this drama because it so perfectly parallels the recent course of the concussion debate virus zona cheap panmycin online amex. The analogy of the melee remains heuristically helpful: just as a blow to the head triggers a battle between pro- versus anti-apoptotic gene expression antimicrobial gel buy discount panmycin, and pro- and antiinflammatory activity antibiotics for dogs after dog bite buy 500 mg panmycin with amex, there seems to be a battle pitting apoptosis against neurogenesis antibiotic resistance nursing implications order panmycin 500 mg free shipping. That battle may determine whether the outcome will be a net gain or a net loss in brain cells [137] oral antibiotics for acne while pregnant order panmycin cheap online. In 1997 antibiotics for acne during pregnancy discount panmycin amex, Scott and Hansen [138] became among the first to show this in the laboratory. Many of these studies reported local proliferation of new neurons and focal incorporation of those neurons into functional circuits of the hippocampus. That may be pertinent, since FoxJ1 triggers the differentiation of stem cells in the subventricular zone to be differentiated into astrocytes, oligodendrocytes, and neurons. Critically, it has been shown that new neurons are associated with both incorporation into circuits and functional improvement [149, 154]. Not to put too fine a point on a study that requires replication, neurogenesis seems to help fix concussed brains. This handful of findings is so inconsistent that one begs leave to defer an answer for a few months. It was compiled with a view toward the future, for the benefit of clinical researchers looking for a project and perhaps even for pharmaceutical entrepreneurs. F: Traumatic brain injury mice had increased cell migration away from the subgranular zone on the injured hemisphere compared with sham mice. Since our goal is, at least, to do no harm, it is also important to know what factors depress or inhibit posttraumatic neurogenesis. Readers will be familiar with the pejorative implications of the phrase "reactive astrocytosis. Scholars now ask whether newborn astrocytes are beneficial or detrimental [187, 188]. The answer is not clear and may depend very much on the genomic milieu into which these cells are thrust. Early reports, however, suggest that many neural stem cells become glia after brain injury, and that this is a salubrious event [186]. However, indirect neuroimaging tactics are already available that should soon enable investigators to visualize human neurogenesis in vivo. First, evidence suggests that the density of neural precursor cells in rodent hippocampus is detectable as a spectroscopic metabolite peak resonating at 1. If these techniques are validated and optimized, they may soon unleash a vital new research enterprise. Investigators will finally be able to monitor the natural history of spontaneous human post-concussive neurogenesis. More clinically important, they will be able to conduct randomized controlled trials of the many agents already shown to enhance 175 176 Part I: What is a Concussion For example, stains have been found to enhance visualization of biologically interesting features. As a result of such advances, judgments about the health or sickness of brain cells, neurons, and glia, have changed, changed, and changed again. Given this iterative progress, when can we say the microscope has showed us the truth We are forced to admit that optical microscopic assessment can never be definitive, since: 1. They sacrificed the animals after three days and examined the brains with several dyes. If they had stopped with crystal violet, one would sigh with relief and infer that concussion does not kill neurons: "Staining with crystal violet showed that cortical tissue was generally intact without dramatic lesions. Hence, whatever the microscope gazer announces in 1720 or 2020 must be taken with a grain of salt. In 2050, when we will have in vivo neuroimaging technology capable of video monitoring real-time neuronal function at the sub-molecular level, gorgeous still-deaths such as those published since Micrographia [193] may be relegated to history. In fact, the authors discovered that the region in which these degenerative-but-not-fatal changes occurred was 10. Source: Gao and Chen, 2011 [194] by permission of Oxford University Press What Experimental Studies With Non-Human Animals Reveal Readers, rejoice! Having squeezed the last drop out of the rock of caveats, having explained why the animal data fail to answer many questions, it seems about time to impartially review that data. If you only have a dead cell stain, you may be seeing the tip of the iceberg of concussion-induced brain change. Given that different stains yield different answers about cell loss, the most earnest neuropathologist working with the wrong box of paints might be excused for failing to see and acknowledge the dire effects of "mild" concussions. In essence, the scores of peer-reviewed scientific articles reporting "intact" brains after concussion may simply be telling the same misleading story as the old reports based on conventional neuropsychological tests: "Using insensitive methods, we found nothing. When a laboratory reports, "we did not see any changes," some might be tempted to interpret that as, "there was no brain damage. That discovery helps explain the subject of our worries: longterm, disabling post-concussive neurobehavioral change. When an abrupt external force is visited upon a head, if that force shakes the brain, and if that shaking is sufficient to trigger clinically meaningful change, certain events seem to occur with awful reliability. As Giza and Hovda described in 2001 [195], a molecular "cascade" commences as excitatory neurotransmitters bind to post-synaptic receptors, permitting excessive calcium to deluge the interior of brain cells. Simultaneously, brain-defense-or-repair mechanisms we have just begun to appreciate go to work. The popular phrase neurometabolic cascade of concussion, therefore, is a partial descriptor. The actual suite of events might more accurately (if less pithily) be called abrupt external force-related neuronal/glial change altering the molecular genetics and metabolic operations of cells, and brain metabolism, and axoplasmic integrity, and inflammatory and immune processes, and vascular function, and activation of protein aggregation akin to neurodegeneration. The author speculates that our professions will continue to offer gainful employment for several years. As Giza and Hovda [195] put it, "Each wave of gene expression and subsequent protein synthesis may, in turn, trigger secondary and tertiary waves of molecular change in the brain, both as a direct response to damage and to effect repair of injured neural systems" (p. For example, as previously mentioned, among the roughly 1000 genes known to be up- or down-regulated in the minutes after concussion, some tend to increase cell death, other to decrease it. On a longer time scale: release of dangerous reactive oxygen species by the limping mitochondria is countered by native antioxidants. Moreover, evidence exists that when one struggling little neuron is unidirectionally connected to another, deafferentation spreads dysfunction from the first cell to its target cells. Yet, gratifyingly, that deafferentation may be balanced by post-deafferentation denervation-induced axonal sprouting [196]. Yet it is probably erroneous to imagine this battle as shock and awe eventually followed by rally and counterattack. A more accurate view credits the remarkably quick reflexes of defensive biology: brain self-defense perhaps swings into action within a second after impact. For many dangerous changes that develop over the succeeding days and weeks, the brain has an answer. As mentioned in Chapters 1 and 2, animal experiments are the main source of this realization. In order to gain confidence that animal experiments mimic human concussion, one would want to see evidence that first, the same parts of the brain tend to be damaged in animals and humans and second, those are the very parts of the brain that help mediate post-concussive troubles such as memory and sadness. The ventromedial prefrontal cortex helps mediate self-control and social comportment. The hippocampus helps mediate acquisition and retrieval of memories for facts and events. Communication between these two relies on the excitatory neurotransmitter glutamate. No matter where one hits the little volunteer, certain brain parts take the brunt of the blow. Within the hippocampus, it seems that the dentate hilus is especially sensitive to force [205, 206]. Groat and Simmons crystalized this concept in 1950: "the concussive action is spatially discontinuous on a microscopic scale" [2, p. Second: are these brain parts also prone to damage in milder injury, such as the work-a-day concussion without prolonged coma Third: are these fragile brain parts in fact the very parts associated with the post-concussive neurobehavioral symptoms The reader may simply compare the list of fragile regions to the list of behaviorally critical regions. As noted above, the dentate hilus of the hippocampus is highly vulnerable to traumatic brain strain. It also plays a unique role in regulating the flow of information from the entorhinal cortex via the perforant pathway into the hippocampus. In consequence, depending on the relative degree of damage in these different zones of the hippocampus, one expects memory loss and/or emotional disinhibition. These deleterious regional effects are not only persistent but sometimes progressive: Smith et al. Periodic examination of the brain revealed pathological changes of progressive neurodegeneration and brain atrophy up to one year after the injuries. Similarly, ventricular expansion increased dramatically between three weeks and one year. Hence, we know that concussing a rodent head tends to deleteriously, lastingly, and perhaps progressively impact neurobehaviorally sensitive areas. In less-severe concussions, the almost inescapable hippocampal injuries may be more functional than structural, but that hardly lets the brain off the hook. The main problem may be years of ongoing abnormal activity of the remaining circuitry. Therefore, we assert that functional impairment may result from alterations in surviving neurons. More recent technical advances enable direct visualization of these functional changes. The subjects exhibited the expected disruption of hippocampal synaptic efficiency as well as cognitive impairment. The authors claim, however, that dietary treatment with branched-chain amino acids (direct precursors of temporal lobe glutamate synthesis) restored cognition. Readers may be less than satisfied by the declaration, "Trust me; these neurons are fragile. The author does not know the answer, but McCarthy [220] offered several reasons why these memory- and emotioncritical neurons are so vulnerable to concussion: 1. Axons from neurons in the entorhinal cortex project via the perforant pathway to synapse on dentate granular cells. Hippocampal pyramidal cells exhibit slower rebound in energy stores as compared with neocortical neurons. Glucocorticoid receptors make hippocampal neurons uniquely vulnerable to stress-induced saturation. Its cells are perhaps a little more resilient in the face of traumatic or ischemic threats. Of course, our ignorance outweighs our knowledge: are all the changes found after concussion in the hippocampus necessarily bad A concussion with a duration of less than one second can be thought of as provoking an hours- to months-long fight for the survival of hippocampal pyramidal cells. In this corner are the physical and chemical peculiarities of these neurons that give them something of a glass jaw. Evidence also exists that there is a direct relationship between this regionally selective brain damage and cognitive impairment. Prior to sacrifice at 25 days, the rats were tested for memory in a radial arm maze. Learning and memory were "profoundly impaired" at one week and still impaired at two weeks, although these deficits typically vanished after three weeks. Such studies confirm that learning and memory deficits, almost universally described by human survivors of concussion, are objectively verifiable in animal models. One animal model of depression is forced swimming, also known as the Porsolt test [227]: a rodent is confined to a narrow tube filled with water 6 cm deep.

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