In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer's disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE It has been known since the Ebers papyrus  in 1552 Fast-forwarding to the 20th century, several researchers in the late 1970s became aware of an intriguing link between a sick heart and the start of cognitive deterioration that often led to vascular dementia (VaD) [Research in the early 1990s additionally began to suggest that cardiovascular disease could also signal the start of Alzheimer's disease (AD), an assumption that, as will be seen below, has gained evidence-based support from more detailed studies published in the last decade. The suggested link between cardiovascular deficits as a risk to AD was important not only because it has now been generally accepted to be true but because it implied that other extracardiac vascular risk factors might also play a crucial role in the initiation of this dementia by possibly sharing common pathological pathways or markers common in AD. Moreover, the therapeutic implications of controlling such vascular risk factors to AD have become one of the most important inroads in the search to lower the rising prevalence of AD and VaD , 4. Cardiovascular disease comes in many forms, and its outcome is dependent on the patient's age, prior history, life style, primary prevention, genetics and pathological factors affecting structural, and hemodynamic function. Cardiovascular disease affects the heart vessels which affect the structural tissue of the heart and can be classified as coronary (the most common), valvular, cardiomyopathic, arrhythmic, congenital, and heart failure . Due to The original association between cardiac pathology and cognitive dysfunction described above as cardiogenic dementia was based on the high incidence of cardiac dysrhythmias seen in patients with dementia solely due to vascular causes . Thus, cAt the present time, brain hypoperfusion that develops from low cardiac output or hypotension has been shown to cause cognitive deficits in attention and memory , and morWhen hypotension is involved, its link to cognitive decline has been generally ignored in clinical practice. One reason for this attitude is the current dogma that low systemic blood pressure does not cause brain dysfunction because compensatory cerebral autoregulation prevents brain hypoperfusion from being activated . HoweverEvidence to support the concept linking cognitive function to cerebral perfusion also comes from studies showing that cerebral blood flow rises in healthy subjects following moderate exercise but cerebral perfusion may not increase if cardiac output is limited by cardiac pathology affecting, for example, heart rate from a dysrhythmia . These findings indicate that cerebral autoregulation does not reverse brain hypoperfusion when cardiac output is compromised by specific cardiac pathology. Normally, cerebral autoregulation maintains a constant blood flow to the brain between 50–150 mm Hg mean arterial pressure. The main function of cerebral autoregulation is to maintain cerebral perfusion pressure by signaling brain arterioles to dilate or constrict during changes in arterial blood pressure . CerebraStudies have reported that normal aging reduces CBF about 20% at age 60 as compared to age 20 –26, so a2, endothelin-1, and 20-hydroxyeicosatetraenoic acids (20-HETE). Curiously, pharmacologic inhibition of 20-HETE appears to impair cerebral autoregulation in vivo [If impaired cerebral autoregulation is indeed one of the culprits that contributes to cognitive failure in the elderly following chronically evolving vascular insults, a number of cerebral vasoactive molecules may be coconspirators in the development of AD, among them vasodilators such as endothelial nitric oxide, adenosine, prostacyclin, and epoxygenases that yield epoxyeicosatrienoic acids and vasoconstrictors such as thromboxane A in vivo . Another cyclic burden on the heart that generates reduced blood flow to the brain is the finding that cerebral hypoperfusion can impair cerebrovascular reactivity , 31, posOther vascular risk factors, such as chronic hypertension can shift the limits of autoregulation toward higher blood pressure levels . This adNot surprisingly, when dynamic cerebral autoregulation is impaired from unilateral carotid artery stenosis, carotid endarterectomy, or stenting can reverse the effects of the brain dysautoregulation . Recent Despite the obvious importance that connects some types of heart disease to cognitive impairment , it has The ultimate fallout from low cardiac output on the brain is that hemodynamic pump dysfunction in the older person can significantly lower blood flow to brain cells via cerebral hypoperfusion, thereby diminishing energy substrate supply needed for normal brain cell metabolism –50.4, and atrial fibrillation are more common in the elderly. These conditions are reported to contribute to cognitive dysfunction and decline affecting performance in executive functions, attention, learning, psychomotor speed, verbal fluency, mental alertness, and memory [4 genotype [Epidemiological findings indicate that a broad spectrum of cardiovascular risk factors, including heart failure, thrombotic events, hypertension, hypotension, homocysteine, hypercholesterolemia, C-reactive protein, coronary artery disease, valvular disease, heart failure, apoEd memory –60  . LVD proLow ejection fraction or low cardiac output in elderly patients with heart failure is reported to be associated with impairments of specific aspects of attention, specifically continuous vigilance and discriminability . Low carCardiac resynchronization therapy is a relatively recent intervention that has been shown to increase cardiac function in symptomatic heart failure resulting from systolic dysfunction. It does this essentially by improving cardiac hemodynamics, ventricular contractility, and stroke volume while reducing myocardial energy consumption . This teAge may be a determinant of potential cognitive dysfunction. When ejection fraction dropped below 30%, patients older than 63 years showed a significant decline in memory performance, specifically, verbal delayed recall and recognition as compared to those under 63 years who were able to maintain stable memory function or similar ejection fraction levels . AlthougAtrial fibrillation is a heart rhythm disorder (arrhythmia) usually involving a rapid heart rate. In the normal heart, the rate of ventricular contraction is the same as the rate of atrial contraction. In atrial fibrillation, however, the rate of ventricular contraction is less than the rate of atrial contraction. This condition can lead to a decrease in cardiac output diminishing the amount of blood pumped into the body by the ventricles because the atria are unable to fill the ventricles adequately due to their rapid rate of contraction and their absence of normal contractions. The risk of atrial fibrillation increases with age and is more common in males . Not surprisingly, studies have shown an association between atrial fibrillation and diminished cognitive function leading to AD in the absence of stroke, high blood pressure, and diabetes . The risAtrial fibrillation also appears to involve a significant conversion to dementia in nondemented subjects whether or not cognitive impairment was present . Many stFew studies have examined the effects of myocardial valve damage and its possible effect on cognitive function. Autopsy findings have reported significant aortic and mitral valve damage in AD subjects when compared to a nondemented control group . This asMitral valve prolapse and abundant senile plaques characteristic of AD were found at autopsy in the brains of elderly subjects who died from critical coronary artery disease but were not demented . This fiIt is tempting to speculate that left atrial dysfunction stemming from mitral valve damage can be a therapeutic target that is preventable either by surgical or pharmacologic approaches to lessen the risk of AD in such patients. More work should determine whether this speculation has any merit.According to the American Heart Association, some 60 million Americans have high blood pressure although about 70% of these show only mild hypertension. The incidence of hypertension in other countries such as China appears to be even higher due to their high salt intake. High blood pressure is estimated to affect 25% of the adult population in developed countries such as the USA and Canada. It is well established that high blood pressure can increase the risk of stroke and heart disease and decrease life expectancy. Many studies including the Framingham, the Kungsholmen, and the Honolulu-Asia Aging studies have implicated impaired cognitive function to hypertension in geriatric patients –81. It hThe mechanisms linking hypertension to Alzheimer's disease remain to be elucidated, but damage to brain endothelial cells and smooth muscle cells that control cerebral blood flow is suspected to be a culprit due to the pulsatile pressure changes on the cerebral microvasculature generated by chronic hypertension . These h40 in hypertensive patients may compromise cerebral perfusion by promoting vasoconstriction and/or cerebral angiopathy [When lacunar infarcts or accumulation of lesions in the white matter secondary to chronic hypertension lead to subsequent cognitive deterioration, it has been proposed that disconnection of cortico-subcortical pathways may be involved . Possiblgiopathy . What is still not clear is precisely how hypertension increases the incidence of AD, particularly in those not treated with antihypertensives . Also unRecent randomized controlled trials including SYST-EUR, PROGRESS, HOPE, MRC, SHEP, SCOPE, and HYVET-COG examined the impact of antihypertensive therapy with cognitive function as a secondary end point. Three studies found positive results using antihypertensive therapy in preventing cognitive decline and dementia while the other four  trials reported no significant differences between treated and untreated subjects . Since absence of evidence is not necessarily evidence of absence, a cautious conclusion can be advanced that the positive results of SYST-EUR, PROGRESS, and HOPE open the possibility of discovering target-specific cardiovascular therapies to lower AD and VaD prevalence by correcting the structural and physiological deficits encountered by a stressed heart.β-blockers, calcium channel blockers, and diuretics significantly lowered the risk of AD [For starters, a recent large population-based study of persons 65 years and older in Cache, Utah, reported that the use of antihypertensive medication, including angiotensin-converting enzyme inhibitors, sk of AD . The gresk of AD . It is psk of AD  while losk of AD , aggregask of AD , and vassk of AD , conditisk of AD . β peptide synthesis, while upregulating BACE-2, the enzyme that cleaves amyloid precursor protein (APP), so that Aβ production cannot take place [High blood pressure is known to reduce cerebral blood flow but the mechanisms involved in this action remain unexplained . Since cke place . Hypotension is a common clinical condition that commonly affects elderly persons over age 70. The most common causes of hypotension are blood pressure anomalies, dehydration, bleeding, medications, genetics, and cardiac pathology, including carotid sinus and vasovagal syndromes. Low diastolic blood pressure is associated with an increased risk of AD in the elderly population, particularly among users of antihypertensive drugs. While the reason for this finding is not clear, undetected cerebral hypoperfusion could explain the pathogenic link of hypotension to cognitve decline and AD . In the Baltimore Longitudinal Study of Aging, both hypertension and hypotension have been shown to be associated with poorer performance on tests of executive function in older individuals and perceptuomotor speed and confrontation naming among persons not receiving antihypertensives medication . Although the collective evidence appears to support a strong relationship between hypertension and the development of AD or VaD , no defiFor example, a common office procedure that has received almost no clinical attention in relation to AD development may be cited. That procedure is “white coat hypertension” (WCH). WCH occurs when a transient and usually mild increase in blood pressure is observed in certain individuals when attending a doctors' office. WCH is not generally linked to target organ damage or prognosis from true normotensives . Although there is a controversy about whether WCH should be treated or not, many doctors assume mild blood pressure elevation needs to be treated, especially in the elderly. As a consequence, these individuals are given antihypertensives for the rest of their lives which can lower their blood pressure subnormally. It must be remembered that in the aging individual, diastolic hypotension can not only introduce cerebral hypoperfusion, but also the prospect of AD . The besThe other side of the coin is not treating moderate or high hypertension or preventing hypotension, and this choice can lead to cardiac and cerebrovascular complications and the threat of death. For these reasons, more studies are rapidly needed that can guide the practitioner in managing a patient with blood pressure anomalies.Heart failure is a condition in which the heart can not adequately pump enough blood to meet the body's needs. It is marked by weakness, tissue edema, and shortness of breath. The most common cause of heart failure occurs from stenosis of the coronary arteries which supply oxygen to the heart.Heart failure is often associated with other comorbid vascular risk factors for AD including ischemic heart disease, hypertension, and atrial fibrillation . Brain hAs blood flow pumped out of the heart slows down, returning venous blood to the heart backs up, causing tissue edema particularly in the lungs. Heart failure is the most common reason for hospitalization among older adults  and has A recent report by Alves and her colleagues  indicateCoronary artery disease (CAD) is the single leading cause of mortality in the United States, resulting in over 900,000 deaths annually. CAD is associated with a decreased blood supply to the heart, also known as ischemic heart disease. This happens when the arteries that supply blood to the heart muscle become hardened and narrowed due to a build-up of subintimal fatty deposits called plaques. These atheromatous plaques are made up of a chemical bouillabaisse that includes cholesterol, fatty compounds, inflammatory cells, calcium, and fibrin. Plaques are the basis of atherosclerosis in coronary, peripheral, or cerebral blood vessels. When a plaque suddenly ruptures, platelets aggregate around it inducing intraluminal thrombosis or increased narrowing of the vessel, a condition that can result in myocardial infarction or stroke. The use of platelet deaggregators such as aspirin and clopidogrel or cilostazol, a phosphodiesterase type 3 inhibitor that can widen vessel lumen to increase blood flow, has been used to prevent cognitive dysfunction after intraarterial plaque rupture. Stroke and CAD are known to reduce brain blood flow and potentially impair cognitive function, and both are reported to be vascular risk factor for AD , 109. The risk to AD could stem primarily from atherosclerotic coronary vessels that damage endothelial cells and lower the heart's pumping ability to optimally perfuse the brain. This thinking is supported by the presence of high levels of cholesterol, low density lipoprotein and triglycerides found in the blood of probable AD subjects . A number of studies are now in progress testing whether cholesterol homeostasis and lipoprotein disturbances using cholesterol-lowering statins can alter AD pathology. However, the results of these studies are inconclusive and controversial with regard to the potential neuroprotective effects of statins . Another4 allele may be at higher risk of cognitive decline because among other things, the presence of this gene predisposes to an increased risk of cardiovascular pathology [Carriers of the ApoEathology . 4 allele, a well-studied risk factor for AD, can increase the risk of coronary heart disease by approximately 40% [Aside from sharing many environmental risk factors for AD and for cardiovascular disease, there appears also to be an overlap between genetic risk factors for both conditions. For example, the ApoEtely 40% .4 varies considerably, one association found in the Baltimore Longitudinal Study of Aging was that carriers of this genotype but not noncarriers had greater decline in cerebral blood flow in nondemented older adults [Although the functional activity of ApoEr adults . This der adults . Aortic stiffening is associated with advanced aging and hypertension 116ribkin). There is also compelling data that links aortic stiffening in the elderly to cognitive dysfunction . Evidence indicates that cognitive impairment induced by damaged cerebral microcirculation can be induced by aortic stiffness [ribkin. TSince the aorta is normally more compliant (distensible) than the stiffer carotid arteries, it is believed to absorb the ventricular ejection and dampen pulsatile flow into the distal vasculature, a hemodynamic condition called the Windkessel effect . The WinHowever, during aging, hypertension, or atherosclerosis, there is a loss of elastin which provides elasticity to the aorta, markedly reducing aortic compliance with the net effect of increasing pulse pressure and systolic pressure (hypertension) and reducing wave reflection at the carotid arteries. This hemodynamic phenomenon is worsened in the presence of vascular risk factors  Figure .When this happens, exaggerated pulsatile flow or pulse wave velocity is transmitted to microvessels in the brain where white matter hyperintensities and damage to endothelial cells that participate in controlling cerebral blood flow may result . This paChronic brain hypoperfusion is not a disease but a sign that cerebral perfusion is functioning improperly. Cerebral blood flow is known to decline with aging and under normal circumstances in the absence of vascular disease will not result in significant cognitive loss . To apprThe vascular hypothesis of Alzheimer's disease (AD), which we proposed in 1993 , has bec4 genotype became risk factors to AD by virtue of their potential to lower blood flow to the brain. Since then, several dozen heterogenous vascular risk factors to AD have been reported in the literature [Following our vascular hypothesis proposal in 1993  we obserterature , 131–135But, if chronic brain hypoperfusion is initially involved in AD, how does cardiovascular disease become a risk factor for AD?We believe that cardiovascular disease and the risk factors that characterize it promote brain hypoperfusion in the aging individual by inducing cerebral hemodynamic deficits and reducing blood flow to the brain through various vasculopathic pathways  Figure . One likThis double burden on blood flow can readily lead to a neuronal energy crisis characterized by a cerebral hypometabolic state that can usher cognitive decline and dementia . crisis-dysfunction-death spectre begins in ischemic-sensitive zones such as the hippocampus and specific cortical areas [The neuronal energy crisis is typically followed by progressive neuronoglial dysfunction and eventual neuronal death. The al areas  and willal areas   of selective neuronal energy failure , 147. SuA more detailed description of this neuronal energy crisis inequity can be found in our previous publications , 152. cerebral hypoperfusion and cerebral ischemia, when they have been used interchangeably in the literature. To avoid this confusion, the term cerebral hypoperfusion should be used to describe the relatively slow pathologic process involving months or years when brain perfusion is not commensurate with neurometabolic demand. Conversely, cerebral ischemia should refer to the more rapid pathologic process involving hours or days of sudden blood flow reduction that is capable of killing or damaging brain cells in the epicenter of the ischemic lesion and often allows the formation of a penumbral region made up of undamaged but inactive or “idling” neurons [Finally, much confusion has been generated surrounding the terms  neurons . This deCan anything be done to slow down the total number of new AD cases expected in the next few decades? In our judgment –154 and Based on cross-sectional and longitudinal epidemiologic studies involving mostly elderly subjects, a variety of cardiovascular-related risk factors to AD have been reported. These include high serum lipid/cholesterol levels, high serum homocysteine, body-mass index, smoking, physical inactivity, unhealthy diet, hypertension, hypotension, and metabolic syndrome . ComorbiWhen any or several of these risk factors, are discovered during clinical examination, the physician should be suspicious of actual or impending structural heart damage. Structural heart damage may involve aortic or mitral valve thickening, chronic valvular regurgitation, left ventricular wall motion abnormalities, ventricular filling defects, and left ventricular hypertrophy. Structural heart damage can reduce cardiac output and ejection fraction (or cardiac index) thus directly affecting cerebral perfusion , 163. In Many of these cardiac risk factors, however, can be corrected or treated successfully if identified in time . For example, high blood pressure is a major risk factor for stroke and for heart failure and as we have noted, is also closely correlated with cognitive decline and dementia. Its treatment with anti-hypertensive drugs in the elderly has been shown to reduce cognitive decline and dementia  and to pThe heart-brain connection to memory function can be appreciated from experimental data on rodents. We reported that during exposure to chronic brain hypoperfusion in aged rats, vulnerable brain cells initially undergo a hypometabolic state that reduces memory function while neurons remain structurally intact . Even afWe have attempted to show in the present paper the association between chronic brain hypoperfusion and cardiovascular risk factors of AD in a crystallized fashion pointing out the major problems associated with cardiovascular pathology, cerebral hypoperfusion, and development of AD. Cerebral hypoperfusion following cardiovascular pathology during aging is a much neglected research topic in AD that deserves greater attention. It is crucial to note that cardiovascular risk is generally present prior to AD and that AD neurodegenerative lesions such as Abeta and NFTs are not essentially considered precursors or triggers of heart disease but may be more a manifestation of the neuronal energy crisis provoked by vascular risk factors to dementia. The findings lend support to the design of therapeutic targets aimed at preventing chronic brain hypoperfusion and its consequential neural hypometabolism prior to the onset of cognitive symptoms or neuropathology during normal aging. The therapeutic blueprint will largely depend on early detection of low cerebral blood flow in asymptomatic individuals who present cardiovascular risks factors associated with progressive cognitve decline.


Studies of deaf individuals who are users of signed languages have provided profound insight into the neural representation of human language. Case studies of deaf signers who have incurred left- and right-hemisphere damage have shown that left-hemisphere resources are a necessary component of sign language processing. These data suggest that, despite frank differences in the input and output modality of language, core left perisylvian regions universally serve linguistic function. Neuroimaging studies of deaf signers have generally provided support for this claim. However, more fine-tuned studies of linguistic processing in deaf signers are beginning to show evidence of important differences in the representation of signed and spoken languages. In this paper, we provide a critical review of this literature and present compelling evidence for language-specific cortical representations in deaf signers. These data lend support to the claim that the neural representation of language may show substantive cross-linguistic differences. We discuss the theoretical implications of these findings with respect to an emerging understanding of the neurobiology of language. Case studies of deaf signing individuals with acquired brain damage and neuroimaging studies of healthy deaf subjects provide evidence for the importance of left-hemisphere systems in the mediation of signed languages. Deaf signers, like hearing speakers, exhibit language disturbances when left-hemisphere cortical regions are damaged and appear to be remarkably spared following right-hemisphere lesions that may nonetheless disrupt non-linguistic visual-spatial functions  represent “core-linguistic functions,” which are somehow more elemental in status, while everything else , are simply “extra-linguistic functions.” More recently we can observe a re-characterization of the neural representation of speech which claims the left temporal-lobe exhibits more domain-specific mechanisms, while the right-hemisphere exhibits domain-general mechanisms , prepositional meaning, locative relations, and speaker viewpoint in ways that may not have direct parallels in spoken languages. For example, certain classes of sign forms have been described as depictive. That is, some verbs have, in addition to their usual function as verbs, the ability to depict the event they encode Liddell, . As descIn a similar fashion, spatial prepositional relations between objects such as “on, above, under,” etc., can be conveyed via the depiction of the physical relation itself rather than encoded by a discrete lexical item. For example, an ASL translation of the English sentence “The pen rests on a book” may, in part, involve the use of the two hands whereby one hand configuration with an outstretched finger (representing the pen) is placed on the back of a flat open hand (representing the book). This configuration encodes the spatial meaning “on” but without the need for a conventional lexical preposition corresponding to “on.”Many signed languages express locative relationships and events in this manner and have discrete inventories of highly productive grammatical forms, typically referred to as classifiers or classifier predicates, which participate in these depictive constructions. While the use of these forms constitutes a major contrastive linguistic function in signed languages , precentral sulcus, superior, and middle temporal cortical regions, posterior superior temporal sulcus, angular gyrus, and supramarginal gyrus  relative to control sentences. This N400 response was broadly distributed over posterior regions in a pattern widely consistent with studies of semantic violations in aural-oral languages. Syntactic violations elicited an anterior negativity followed by a widely distributed P600; however, compelling differences in the distribution of this early negativity were noted. Reversed verb-agreement violations elicited an early anterior negativity (140–200 ms) that was largest over the lateral sites of the left-hemisphere, i.e., a Left Anterior Negativity similar to what has been found in studies of syntactic violations in spoken languages  simply reflect general visual-spatial resources that are required for processing of perceived human movements. Because sign languages require the registration of such visual-spatial information, and right-hemisphere parietal regions normally participate in these functions, it stands to reason that we may observe activation of these regions during sign processing and deficits in processing when these general-purpose regions are damaged. Under this view, we don’t observe activations for spoken languages as such requirements for the registration of human movements are not required.A second logical possibility is that the right-hemisphere involvement does reflect linguistic processing; however, this processing is not specific to signed languages. It is simply the case that we have yet to systematically identify the proper grammatical constructions in spoken languages that trigger the involvement of this region. For example, perhaps there are languages with complex case-marking systems which require registration of the spatial-temporal ordering of morphemes for determining subject and object relationships; or, perhaps, appreciation of specific spatial-preposition constructions whose processing dynamics have yet to be fully explored.A third possibility is that the right-hemisphere activation reflects general visual-spatial processes and is used in the perception of human movements that underlie both sign and speech. As discussed above, this account has been evoked to explain the lateral temporal activation seen during the processing of audio-visual speech and signed language, but fails to account for the right posterior-parietal activations reported in Newman et al. . We consSigners with left-hemisphere posterior lesions evidence fluent sign aphasia with associated comprehension deficits. There is, however, controversy in regards to anatomical regions that may give rise to comprehension problems in spoken and signed languages. In an effort to examine the role of the temporal lobe in ASL comprehension deficits, Hickok et al.  comparedIt is noteworthy that the cases described by Chiarello et al.  and PoizSign language breakdown following left-hemisphere damage is not haphazard, but affects independently motivated linguistic categories . This observation provides support for viewing aphasia as a unique and specific cognitive deficit rather than as a subtype of a more general motor or symbolic deficit. An example of the systematicity of paraphasic errors across signed and spoken languages can be found in Corina . These iAn unusual case of sign paraphasia that does not have a clear mapping to patterns observed in spoken language is reported by Hickok et al. . A life-In summary, we have considered three specific instances where data from users of signed languages suggests that competencies in sign language use may require participation of neural resources not typically encountered for the processing of spoken language. First, we examined the mounting evidence that the right-hemisphere parietal regions may be required for some aspects of sign comprehension, especially in the context of specialized syntax, as well as in the appreciation of classifier forms. We then considered evidence for the claim that left posterior temporal regions are necessary for sign comprehension. While research shows that left temporal regions do impact sign language comprehension, we noted that research to date has not properly excluded the contributions of left parietal regions in sign language comprehension impairment, thus undermining the claims for isomorphic functions of left temporal lobes in the mediation of all human languages, spoken or signed. Finally, we briefly recounted the unusual presentation of linguistic impairment in case of signer R. S., whose language errors are limited to linguistic productions of two-handed ASL signs, here again providing evidence that specialized neural resources are required to implement articulatory demands of a signed language such as ASL.There are important theoretical issues raised by these data. Principally, the data suggests a conflict between an amodal account of language processing, in which one considers brain areas responsible for language to be independent of language modality, versus a modality-influenced view of language, whereby one acknowledges that there may be properties required for the execution and understanding of language forms that vary as a function of linguistic form and structure. As stated previously, language researchers are increasingly cognizant of the fact that the neural organization reflects the intimate coupling between language perception and production. In the present case, we have considered the differences and similarities between the neural processing of spoken and signed languages. Some scientists will likely conclude that this represents an extreme situation with a tendency to outright dismiss the validity of the comparisons. However, if we acknowledge that both signed and spoken languages are true manifestations of the capacity for human language, one must consider the possibility that specialized and language-specific neural mechanisms may be required for competency. Generally, researchers tend to avoid this latter position as it leads toward the proverbially slippery slope. If we acknowledge language-specific neural specialization, might we further expect to see cases of language specificity across the diverse forms of spoken languages? The broader point is whether aphasic deficits should be solely defined as those that have clear homologies to the left-hemisphere maladies that are evidenced in spoken languages, or whether the existence of signed languages will force us to reconsider the conception of linguistic deficits such as aphasia and open the possibility that there may be multiple ways in which the human brain may manifest linguistic abilities.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Prognosis of peripheral artery disease (PAD), especially critical limb ischemia, is very poor despite the development of endovascular therapy and bypass surgery. Many patients result in leg amputation and, therefore, vascular regenerative therapy is expected in this field. Gene therapy using vascular endothelial growth factor is the first step of vascular regenerative therapy, but did not confirm effectiveness in a large-scale randomized comparative study. Based on animal experiments, bone marrow mononuclear cells (MNCs), peripheral blood MNCs were used as the cell source for regenerative therapy. Those cells were confirmed to be effective to decrease rest pain and ulcer size, but its effect was not fully satisfied. Mesenchymal stem cells (MSCs) are expected as an effective cell source for vascular regeneration and clinical studies are ongoing, because the cells are able to differentiate into various cell types and produce a significant amount of vascular growth factors. Of vascular regeneration therapy, peripheral MNCs and bone marrow MNCs were recognized as advanced medical technology but do not attain to the standard therapy. However, clinical use of MSCs have already started, and induced pluripotent stem cells are surely promising tool for vascular regeneration therapy although further basic studies are required for clinical application.  More than 25 million people have peripheral arterial disease (PAD) in Europe and the United States –5 and itFor cardiovascular regenerative therapy, gene therapy for PAD using vascular endothelial growth factor (VEGF) started in 1996 in the United States . The effGene therapy of cancer is about 65% of those performed in the world; on the other hand, that of cardiovascular disease is about 9%, second-ranked. Adenovirus and retrovirus are major viral vectors; however, accidental death occurred in the United States after intracoronary delivery of adenovirus in 1999  and leukHepatocyte growth factor (HGF) is known to regulate proliferation and migration of vascular endothelial cells via c-met, its receptor. HGF was confirmed to have angiogenic activity similarly to VEGF and a small size clinical study for patients with PAD confirmed the efficacy and safety of HGF . Also inα-smooth muscle actin-positive vessels were observed in the FGF-2 group significantly more frequently and it was confirmed that mature and functional angiogenesis was established [Basic fibroblast growth factor (bFGF or FGF-2) is attracting attention similarly to VEGF and HGF or more. An animal study showed that local VEGF concentration after administration increased up to severalfold and caused adverse reactions including edema and hemorrhage without effective angiogenic activity; in contrast, FGF-2 caused no adverse reaction at high doses and had efficacy already at low doses. In histological examination, angiogenesis caused by vascular endothelial cell marker was similar between the two groups; however, significantly more ablished . On the ablished , 24. A sablished .+ cells in monocytes were separated as EPC fraction and administered locally to the muscle of CLI [Angiogenesis in adults was considered to be produced by proliferation and migration of adjacent existing microvascular endothelial cells. However, in 1997, it was found that EPCs differentiating into endothelial cells existed in monocytes of adult peripheral blood  and vasce of CLI . Long-tee of CLI .Bone marrow cells were confirmed to contain a plenty of EPCs and secrete abundant angiogenic factors VEGF and bFGF. Consequently, autologous bone marrow transplantation to limb skeletal muscles in limb ischemia model enhanced angiogenesis and significantly increased lower limb blood flow . Based oβ, which was the main cause of angiogenesis [Bone marrow MNCs have already been confirmed to be effective; however, the major issue of concern was the size of invasion to patients complicated with other cardiovascular disease who were frequently found in patients with CLI among patients with PAD. Consequently, MNCs were collected from peripheral blood without collecting bone marrow, administered to the ischemic limb, and confirmed to be effective . An angiogenesis . Peripheogenesis . In this+ cells into peripheral blood were injected into ischemic sites, and ischemic improvement was confirmed by thermography and plethysmography [+ cells, hemodialysis, Fontaine classification, male, and age were factors for overall survival and amputation-free survival [+ cell were factors for overall survival [In another study, collected peripheral blood mononuclear cells after intravenous administration of G-CSF inducing CD34mography . In a posurvival .in vitro study and the MSC group was considered to be resistant to ischemia more than the MNC group. In a randomized, double-blind, controlled trial in patients with diabetes and CLI [MSCs are included in not only bone marrow but also placenta, amnion, umbilical cord, and chorion and have been confirmed in vitro to differentiate into not only bone and cartilage but also myocardium and endothelial cells and inhibit cell death . Further and CLI , pain-fr and CLI  conducte and CLI  and the  and CLI . Rat fet+ cells differentiate into endothelial cells and mural cells in vitro and were implemented in angiogenesis [+ cells were transplanted to limb ischemia nude mouse model, blood flow in the chronic phase increased in comparison with that of the control group and Flk-1+ cells were observed directly in ischemic tissues. In addition, VEGF mRNA expression was increased. Consequently, it was suggested that administered cells were implemented in vasculogenesis in addition to paracrine effects of increased cytokine production [ESCs are cell line produced from the inner cell mass of the early embryo and have high proliferative capacity differentiate to all types of cells. It was confirmed that grafting of ES cell-derived EPCs in the body enhanced angiogenesis . Howeverogenesis . In a stoduction . StudiesNot only cells to administer but also development of transplantation procedures is very important issues to furthermore improve therapeutic efficacy. In conventional cell administration method, local administration, transfection efficiency, and surviving rate of grafted cells in ischemic area are low; consequently, cells are disappeared within several days. Cell viability should be improved to release more cytokines secreted from transplanted cells as long as possible. Extremely low differentiation rate of transplanted cells to endothelial cells and vessels is also important issue to improve.Studies of vascular regeneration therapy started around 1990 and studies of myocardial regeneration have been also conducted. Of vascular regeneration therapy, some including peripheral MNCs and bone marrow MNCs were approved as advanced medical technology but do not attain to the standard therapy.However, MSCs that are contained in many organs including bone marrow attract massive attention as a new type regenerative medicine including future banking due to potent cytokine production capacity and low antigenicity. On the other hand, iPSCs are surely promising tool for vascular regeneration therapy although far from clinical application; therefore, further basic studies are required for clinical application.


Although astrocytes are increasingly recognized as important modulators of neuronal excitability and information transfer at the synapse, whether these cells regulate neuronal network activity has only recently started to be investigated. In this article, we highlight the role of astrocytes in the modulation of circuit function with particular focus on sleep-related rhythmogenesis. We discuss recent data showing that these glial cells regulate slow oscillations, a specific thalamocortical activity that characterizes non-REM sleep, and sleep-associated behaviors. Based on these findings, we predict that our understanding of the genesis and tuning of thalamocortical rhythms will necessarily go through an integrated view of brain circuits in which non-neuronal cells can play important neuromodulatory roles.


In this study, we compared resting state connectivity between 49 psychotic patients with chronic AVH and 49 matched controls using the rIFG and the lSTG as seed regions, to identify functional brain systems underlying the predisposition to hallucinate. The right parahippocampal gyrus showed increased connectivity with the rIFG in patients as compared to controls. Reduced connectivity with the rIFG in patients was found for the right dorsolateral prefrontal cortex. Reduced connectivity with the lSTG in patients was identified in the left frontal operculum as well as the parietal opercular area. Connectivity between the lSTG and the left hippocampus was also reduced in patients and showed a negative correlation with the severity of hallucinations. Concluding, we found aberrant connectivity between the seed regions and medial temporal lobe structures which have a prominent role in memory retrieval. Moreover, we found decreased connectivity between language-related areas, indicating aberrant integration in this system potentially including corollary discharge mechanisms.Auditory verbal hallucinations (AVH) are not only among the most common but also one of the most distressing symptoms of schizophrenia. Despite elaborate research, the underlying brain mechanisms are as yet elusive. Functional MRI studies have associated the experience of AVH with activation of bilateral language-related areas, in particular the right inferior frontal gyrus (rIFG) and the left superior temporal gyrus (lSTG). While these findings helped to understand the neural underpinnings of hearing voices, they provide little information about possible brain mechanisms that predispose a person to experience AVH, i.e. the  Insight into aberrations of neuronal networks underlying such vulnerability, in turn, may be particularly relevant for guiding the development and evaluation of treatment strategies.Auditory verbal hallucinations (AVH) are among the most common and distressing symptoms of schizophrenia and also affect persons with affective psychosis and some  personality disorders. While AVH are thus a highly prevalent feature of psychiatric illnesses, their underlying brain mechanisms remain elusive. Models proposed for their pathophysiology include the misattribution of inner speech It could be hypothesized that a predisposition to AVH may be instantiated by aberrant connectivity between inferior frontal and temporo-parietal areas leading to a misattribution of inner speech Alternatively, deviant connectivity between speech-related areas and the medial temporal lobe could give rise to spontaneous verbal memory recollection Either of these hypothesized dysconnectivities may become evident in the absence of external tasks, given that the latter may override the endogenous dynamics of AVH. Therefore, aberrations in functional coupling that may predispose a person to hearing voices may become evident by examining resting state connectivity data. Resting state fMRI connectivity measures low-frequency fluctuations in the cerebral haemodynamics (around 0.01–0.1 Hz). Recently, attention has been focused on the possible origins of these slow variations. Various investigations suggested that these signal variations are of neuronal origin and characterize the neuronal baseline activity of the human brain in the absence of externally stimulated neuronal activity.Resting state connectivity can be assessed by using Regions of Interest (ROIs); areas that are thought to play a major role in the trait under investigation, or without the predefinition of ROIs as in an independent component analysis (ICA). In this paper, we used the first approach as there is good evidence for the essential contribution of certain well-defined areas in AVH. In contrast, the data-driven ICA approach may also pick up other differences in resting state between the groups that may not be related to hallucinations given that lack of focus on a specific system. In this study we aim to investigate the vulnerability to experience AVH in patients who have experienced AVH.A recent meta-analysis indicated consistent activation of the right inferior frontal gyrus (rIFG) and the left superior temporal gyrus (lSTG) during the experience of AVH Forty-nine patients with psychosis, as diagnosed according to DSM-IV criteria by an independent psychiatrist using the “Comprehensive Assessment of Symptoms and History (CASH)” Resting state scans of eight minutes duration (600 blood-oxygenation-level-dependent (BOLD) fMRI images) were obtained on a Philips Achieva 3 T MRI scanner using the following parameter: 40  slices, TR/TE 21.75/32.4 ms, flip angle 10°, FOV 224×256×160, matrix 64×64×40, voxel-size 4 mm isotropic. . This scan sequence achieves full brain coverage within 609 ms by combining a 3D-PRESTO pulse sequence with parallel imaging (SENSE) in two directions, using a commercial 8-channel SENSE headcoil The resting state scans were first corrected for head movement by affine registration using a two pass procedure. The mean PRESTO image for each subject was then spatially normalized to the MNI single subject template Voxel time courses were extracted for all voxels within a 5 mm sphere around the centre of the particular clusters that were located in the grey matter of the individual subject.Variance explained by the following nuisance variables was removed from the time series to reduce spurious correlations positive coupling across both groups (main effect) in conjunction with a reduced coupling in patients or significant negative coupling across both groups (main effect) in conjunction with enhanced coupling in patients as compared to controls indicating enhanced and reduced coupling. For all analyses, results were regarded as significant if they passed p<0.05, cluster-level FDR-corrected for multiple comparisons. Anatomical localizations were obtained using the SPM Anatomy Toolbox For each subject we computed linear (Pearson) correlation coefficients between the time series of the seeds and any other grey matter voxel, which were then transformed into Fisher's Z-scores. Group analysis was then performed on these by an analysis of variance (ANOVA) across subjects using appropriate non-sphericity correction. In the ANOVA, both the main effect of functional connectivity as well as the group-difference between patients and controls were modelled for each seed. Inference on this random-effects analysis was then sought using linear contrasts. First, main effects of connectivity (across both groups) were calculated for both seeds and a conjunction analysis was performed on these to reveal regions showing significant coupling. Subsequently, functional connectivity maps of rIFG and lSTG were assessed for significant differences between patients and controls using unilateral T-tests. These differences in connectivity were evaluated by testing for either significant To test whether the observed differences between patients and controls were additionally related to psychopathology, we extracted individual functional connectivity between the seeds and the peak voxels of the clusters showing significant differences. We then performed a Spearman rank-correlation between these and the individual scores on the “Hallucinatory behaviour” (P3) PANSS item to test for significant (p<0.05) associations. In a second follow-up analysis we divided the patients into those who actually experienced hallucinations during the scan and those who did not. Subsequently, we computed a one-way ANOVA between the groups on the individual functional connectivity scores between the seed and the peak of a significant cluster.All participants stayed awake during the resting state scan. Thirty-one out of the 49 patients reported the experience of hallucinations during the resting state scan. None of the controls experienced hallucinations during the scan.The analysis of the main effects for both seeds across both groups is provided in The right parahippocampal gyrus showed significantly increased connectivity with the rIFG  in the pReduced connectivity with the rIFG in the patients was found for the right dorsolateral prefrontal cortex (DLPFC) just anterior to and slightly encroaching cytoarchitectonically defined Area 45 .Two regions showed significantly (whole-brain corrected) reduced connectivity to the lSTG in patients . The firIn order to assess state-effects of AVH on functional connectivity with our seed regions, we performed a follow-up analysis for those regions that showed disturbed connectivity in the overall group of trait carriers  which assessed differences between controls, trait and state/trait-groups, i.e. individuals with acute AVH during scanning. For this purpose, we divided the patients into one group who hallucinated during the resting state scan, and those who did not. This analysis revealed that the reduction in connectivity between the lSTG and the left hippocampus was significantly stronger in those patients who hallucinated during scanning . That isWe compared resting state functional connectivity of 49 psychotic patients experiencing chronic auditory verbal hallucinations (AVH) to 49 healthy controls. Analysis was seeded from the left superior temporal gyrus (lSTG) and the right inferior frontal gyrus (rIFG) as these areas are consistently activated during the state of AVH To differentiate between trait and state aspects of AVH we divided the patient group into those who acutely hallucinated during scanning and those who did not. Here, only coupling of the lSTG with the left temporo-parietal operculum and hippocampus was more strongly decreased in the patients who actually hallucinated, indicating that these deviations may result from a combination of state and trait characteristics. Increased connectivity between the rIFG and the parahippocampus was equally strong in both patient groups.Our analysis revealed disturbed interactions between both seeds and medial temporal lobe (MTL) structures, including increased connectivity between the rIFG and the right parahippocampal gyrus. This observation resonates strongly with a previous symptom capture study which revealed that cortical activations during AVH were preceded by significant signal changes in the parahippocampal gryus Secondly, decreased connectivity in the patient group between the lSTG and the left frontal operculum was observed. We also found decreased connectivity between the rIFG and the right DLPFC. These findings may reflect decreased integration between areas mainly associated with the generation (rIFG) and interpretation (lSTG) of language, suggesting misattribution of inner speech as a potential pathomechanism. Furthermore, these regions are often found active during acute hallucinations Seeding from Wernicke's area (in close vicinity to our lSTG seed), Hoffman and colleagues A limitation of this study is the absence of a patient group without the trait to hallucinate. However, to our opinion, all patients with schizophrenia have a predisposition to hallucinate given their psychotic liability. The fact that a small proportion of schizophrenia patients have not experienced hallucinations may reflect adequate pharmacotherapy, rather than an absence of the trait.The current approach of assessing functional connectivity of regions that have previously been implicated in the pathophysiology of hallucinations allowed for a model-based assessment of dysfunctional circuitry in patients suffering from AVH. This may represent a considerable advantage in terms of functional specificity as compared to purely data-driven approaches such as ICA, as ICA would also identify other differences between the groups unrelated to AVH. In turn, however, analyses based on a-priori information evidently have low sensitivity to aberrations in non-probed circuits.The removal of noise from resting-state fMRI data as part of the preprocessing has been criticized because this process can introduce artificial anti-correlations It must also be acknowledged, that the observed differences may not be absolutely specific to hallucinations, as patients and controls also differed in variables such as the presence of other psychotic symptoms, negative symptoms and medication status. While all these factors may have influenced connectivity patterns, the specific, localized aberrations of connectivity with areas activated during AVH should point to a pathophysiological contribution. This is in particular the case for those connections showing a significant state effect or an association with the severity of hallucinations as assessed with the PANSS rating.In sum, we found two clear deviations in resting state connectivity in the patients with chronic AVH as compared to the controls. The first was aberrant connectivity between the seed regions that are active during AVH and MTL structures which have a prominent role in memory retrieval. The second deviation was decreased connectivity between language-related areas in the neocortex.Aberrations between neocortical association areas and MTL structures may underlie a liability to experience hallucinations in general. In turn, reduced connectivity within the neocortical language network may indicate deficits in corollary discharge mechanisms as another potentially important pathophysiological mechanism for hallucination in the language domain specifically.Supplementary Material S1The analysis of the main effects for both seeds across both groups. The analysis of the main effects for both seeds across both groups demonstrated significant positive coupling between both seed regions with (in particular the left) inferior frontal lobes and anterior insula, dorso-lateral prefrontal cortex, inferior parietal lobules, right anterior temporal lobe and the posterior medial frontal cortex. In turn, both regions were significantly anti-correlated with anterior and posterior cingulated regions, the precuneus, right posterior inferior parietal lobule, bilateral inferior temporal lobe and right cerebellum. Positive coupling, i.e., functional connectivity, with the seeds is shown in green, negative coupling in red. Significantly decreased connectivity with the seeds in patients is superimposed on the main effect in cyan, significantly increased connectivity in patients is superimposed on the main effect in yellow below .(TIF)Click here for additional data file.


Emergency medicine (EM) is a growing specialty in Colombia with five residency programs in the country. EM leadership is interested in incorporating point-of-care (POC) ultrasound into a standardized national EM residency curriculum. This study is a nationwide survey of Colombian EM residents designed to explore the current state of POC ultrasound use within EM residencies and examine specific barriers preventing its expansion.We conducted a mix-methodology study of all available current EM residents in the five EM residencies in Colombia. The quantitative survey assessed previous ultrasound experience, current use of various applications, desire for further training, and perceived barriers to expanded use. Focus group discussions (FGDs) were conducted with current EM residents to gather additional qualitative insight into their practice patterns and perceived barriers to clinician-performed ultrasound.Sixty-nine EM residents completed the quantitative survey, a response rate of 85% of all current EM residents in Colombia; 52% of resident respondents had previously used ultrasound during their training. Of these, 58% indicated that they had performed <10 scans and 17% reported >40 scans. The most frequently used applications indicated by respondents were trauma, obstetrics, and procedures including vascular access. A quarter indicated they had previously received some ultrasound training, but almost all expressed an interest in learning more. Significant barriers included lack of trained teachers (indicated by 78% of respondents), absence of machines (57%), and limited time (41%). In FGDs, the barriers identified were inter-specialty conflicts over the control of ultrasonography, both institutionally and nationally, and program-specific curriculum decisions to include POC ultrasound.While currently limited in their access, EM residents in Colombia have a strong interest in integrating POC ultrasound into their training. Current barriers to expanded use include traditional barriers such as a lack of equipment seen in many developing countries, as well as inter-specialty conflicts typical of developed countries. Further collaboration is underway to help overcome these obstacles and integrate POC ultrasound into Colombian EM residency training. Emergency medicine (EM) has grown as a specialty in Colombia over the past two decades as increasing attention is paid to developing a robust healthcare system capable of meeting the changing needs of Colombia’s population. As the Point-of-care (POC) ultrasound is an innovative bedside diagnostic tool that is transforming clinical care both in Colombia and globally. Numerous studies have shown its value and safety for improving emergency care in a broad variety of applications when performed by EPs-15. TherDespite the lack of such accreditation and guidance in their country, Colombian EM residency programs and emergency departments have begun to incorporate POC ultrasound into their education, training, and clinical practice to varying degrees. However, even in some of Colombia’s most advanced urban university-based hospitals, limited resources are still a reality. Nevertheless, Colombian EM residency leadership and medical directors have expressed interest in formally integrating POC ultrasound education and training into a unified EM residency curriculum and using it as a diagnostic adjunct in the clinical setting.We hypothesized that implementation of training programs in POC ultrasound in Colombian residencies faces many of the challenges experienced in both well-developed and developing healthcare systems. In this study, we explore current POC ultrasound exposure, use and interest in further training among EPs in Colombia’s EM residencies, and perceived barriers to expanding POC ultrasound education and clinical use. We conducted the first nationwide POC ultrasound needs assessment survey among all EM residency programs in Colombia and held focus group sessions with residents with the goal of understanding and describing its role as an emerging diagnostic modality in Colombian EM training programs.This study is a mixed methodology cross-sectional design using a quantitative survey and qualitative focus group discussions (FGDs). The survey was conducted at the five EM residency programs in Colombia, three in Bogota in March 2012 and two in Medellin in March 2013. In collaboration with representatives from these programs and from ACEM, we conducted site visits to the three Bogota programs  and to the two Medellin programs (Universidad de Antioquia and Universidad CES).Our target population was all current EM residents in all residency programs in Colombia, totaling 81 at the time of this study. Survey distribution and FGD sessions were primarily conducted during residency educational conference days to maximize resident availability and participation. All available EM residents were invited to participate in the study, and prior to inclusion in the survey and FGDs, the nature and objectives of the study were explained to respondents. Participation was entirely voluntary, nonetheless, no one on site declined to participate. Residents who were not available on the day of the site visit were contacted by email within 2 weeks and invited to voluntarily complete the survey.All respondents completed an anonymous self-administered quantitative ultrasound needs-assessment survey. This tool was developed and deployed previously by co-author PCH for similar work in other developing countries, and was translated into Spanish for this study. It contains 24 items and requires approximately 15 minutes to complete. In addition to basic demographics, the tool includes items in the following domains relating to POC ultrasound: current practice patterns, integration into workflow, extent of prior exposure, desire for training, and barriers to use.FGDs were also conducted at each of the five programs with all available residents, averaging approximately 8–10 respondents at each location. Sessions were facilitated by study co-authors fluent in Spanish according to an open-ended script and covered similar domains as listed above under the qualitative survey. The goal of these sessions was to develop a better understanding of the current and potential role of POC ultrasound in EM residency training by exploring current practice patterns. These sessions lasted approximately an hour and were conducted in a private location convenient to the respondents. The FGD facilitators kept careful thematic notes during the sessions to capture qualitative data that would provide programmatic context to the survey. Program administrators were not present during these sessions in order to encourage open discussion among residents. Three additional meetings were conducted with EM faculty and recent residency graduates working in several Bogota and Medellin hospitals in order to gain a historical and broader programmatic and clinical perspective on these issues from practicing EPs. This additional cohort of non-resident EPs did not complete the quantitative survey.Quantitative data entry and descriptive statistical analysis was conducted using Excel . Qualitative data was analyzed using a simplified grounded theory approach in which specific themes were identified. Due to the minimally invasive nature of this study, no perceived risk to participants, and no direct patient involvement, ethical approval for this study was waived by the Partners Healthcare Institutional Review Board.The quantitative survey was completed by 69 Colombian EM residents. Significantly, this represents 85% of all current EM residents 69/81) in Colombia. Respondents were distributed across all five-residency programs reflecting the underlying differences in residency size within these programs and evenly between all years of residency. Characteristics of EM resident respondents are summarized in Table  in ColomOverall, there was limited exposure to POC ultrasound among Colombian EM residents. Only 52% of EM residents had previously used an ultrasound machine during their training. Of those who had performed any scans, 20 (56%) indicated that they had performed fewer than ten scans during their training. All respondents indicated a desire to learn more about POC ultrasound, with 87% percent expressing a ‘high’ level of interest.Respondents were asked to select their most frequent uses for POC ultrasound from a list of 14 common applications. Within the group of 36 EM residents with prior ultrasound experience, a total of 138 items were selected with a mean of 3.6 selected per respondent. The three most commonly indicated applications were trauma , obstetrics (12%), and procedures including vascular access (11%). Figure The most important themes that emerged from analysis of the FGDs were identification of program-specific barriers to use. Respondents indicated that inter-specialty conflict and misunderstanding, such as with radiology or cardiology, both within their institution and nationally, hindered their department’s ability to fully implement ultrasound training and programs. Several respondents highlighted this barrier through reference to a Colombian national law which restricts the use of ultrasonography to radiologists, unless ultrasound is incorporated into residency training, thereby hindering expanded training efforts and adoption by already practicing EPs. AdditioThis is the first nationwide assessment of training and use of POC ultrasound among Colombian EM residents. With a very high response rate from the five EM residency programs in Colombia, we conclude that the majority of residents feel POC ultrasound should be a more important component of their training as EPs. Despite the significant interest, there is limited exposure to POC ultrasound among EM residents with only half of them having previously used an ultrasound machine during their training. Furthermore, at the time of our survey no residency program had a formal ultrasound curriculum in place. We note a wide disparity between residents both within and between residency programs. Within individual programs there were only 2–3 residents reporting a high level of prior exposure to POC ultrasound whereas the majority reported having completed very few, if any, prior scans. This may be due, in part, to an early adopter effect after the introduction of this new technology. It is important that these early adopters are identified as champions for the future expansion of POC ultrasound. Unfortunately, this disparity and the paucity of prior scanning experience also highlight the overall lack of exposure within Colombian EM residencies to this core competency.We report that the most commonly used POC ultrasound applications by current Colombian EM residents are trauma, obstetrics, and procedures including vascular access. The emergence of these specific applications as the most frequent is consistent with the typical emergent cases presenting to large urban centers and mirrors applications most frequently used in developed nations. This may also follow the patterns seen in the US around patient safety, particularly as it relates to established standard of care of using ultrasound for the placement of central venous catheters. Likewise, the less frequently used applications that we report also reflect international trends. They are likely less frequently used by beginners because their medical indications are less common and their technique is more difficult without specific training.Several important barriers to the expansion of POC ultrasound in Colombia were identified during this study, both during the quantitative and qualitative portions. As noted above, over 75% of respondents indicated a lack of adequately trained educators as a significant barrier. This may be expected given the relative infancy of POC ultrasound within the EM community in Colombia. This highlights the lack of a standardized training curriculum within EM residency programs that would in turn produce adequately trained clinical faculty who are comfortable teaching POC ultrasound. A second important barrier selected by respondents was the general lack of ultrasound machines in residency staffed emergency departments. The absence of a functioning and modern ultrasound machine negates the ability of the residency to train its residents in its use. More interesting, however, is an analysis of the likely reasons for this underinvestment which mirror similar issues experienced in both developing and developed healthcare systems. Many of the residents and faculty explained that a lack of funding in this area is a result of the generally poor quality of the national healthcare system and overall lack of resources, which represents a typical developing county barrier. Many also highlighted a lack of political will to obtain ultrasound machines or to support EM POC ultrasound use at all due to competing financial and professional interests from other specialties both institutionally and nationally. Specifically, respondents noted difficulties in overcoming resistance from the radiology community both within hospitals and nationally, often citing a perceived financial and professional threat if EPs were to begin using ultrasound more regularly. The national law restricting diagnostic ultrasound use to radiologists, noted above, creates an obstacle for those interested in expanding training and adoption by EPs. However, an exception to this law, which allows EPs to become credentialed in POC ultrasound only as part of their formal residency curriculum, creates a further incentive to strengthen this aspect of EM training. Advocacy and national regulatory change will be required to eventually allow mechanisms for practicing non-resident EPs to become credentialed in ultrasound use.Additional important identified barriers include lack of time and curriculum decisions within specific programs. Limited time was cited as the third major perceived barrier to POC ultrasound in the quantitative survey. This is consistent with the reality that most EM providers working in busy urban settings will often state that the multiple competing interests for their time prevents them from regularly using an ultrasound machine even if available. During the FGDs, many respondents indicated that their program’s specific decision-making regarding the implementation of POC ultrasound training was also a barrier, with several programs investing less heavily than others in equipment, teaching resources, and time for training. Finally, and equally important, only one EM resident noted a lack of interest as a perceived barrier to POC ultrasound. This reinforces the fact that Colombian EPs remain interested in POC ultrasound and is optimistic for the future of POC ultrasound in Colombia.These findings have significant implications for EM training and POC ultrasound use in Colombia. In order to integrate POC ultrasound competency into broader Colombian EM training standards, an initial focus should be on securing adequate ultrasound equipment and increasing the latitude for their regular use in residency programs. There are several programs that have begun to make such a commitment and have identified specific faculty champions in order to expand access for residents. Future collaborative work will continue to address the need to establish a national consensus that POC ultrasound has become standard of care in EM. This process will eventually result in more consistent training and skills acquisition among graduating EPs. Specific strategies will also need to be developed to expand POC ultrasound training beyond current EM residents to include fellowship training and continuing medical education on ultrasound for currently practicing EPs. Finally, future research will be important to show the benefits of POC ultrasound for patients. For example, many respondents highlighted that the lack of POC ultrasound in the emergency department has a negative impact on patient care due to the significant delays associated with the requirement to call a radiologist to perform even basic studies such as emergent abdominal sonography in trauma or ultrasound-guided central venous access. Studies assessing the impact of POC ultrasound training and regular use in the Colombian context, replicating many similar studies completed in the US and elsewhere during the last several decades, will allow Colombian EPs to advocate, institutionally and nationally, for adequate equipment and formalized training programs.This study has several limitations that are important to note. First, we used a survey tool initially designed for use in lower-income countries rather than middle-income context. We attempted to mitigate this through paying particular attention to Colombian-specific themes in the FGDs. Second, we limited our analysis to EM residency programs, which are located in urban university-based hospitals distinct from both the many relatively resource-rich private hospitals across the country as well as the relatively resource-poor, mostly rural, national healthcare system. We do not, therefore, make conclusions about the state of POC ultrasound use in Colombia in general, but limit our analysis and conclusions to residency training programs. The scope of this investigation was also limited to residents’ self-reported use of ultrasound and does not include direct measurements of use or any assessment of patient outcomes. Finally, this is a cross-sectional study of EM residencies that does not allow for a view of the changing patterns of ultrasound use over time, and was completed in the context of a dynamic situation in which programs have already begun to expand training opportunities and purchase new equipment as they increasingly appreciate the value of this diagnostic tool, partly prompted by the discussions generated through this and similar ongoing international collaborative work.The specialty of EM is expanding rapidly in Colombia and is beginning to make use of new tools such as POC ultrasound to address many of the health care challenges posed by Colombia’s situation as both a middle-income, yet still developing, country. In this study, we present the first nationwide assessment of training and use of POC ultrasound among Colombian EM residents. We demonstrate significant interest in expanding the use of this diagnostic tool within this population; however, we also highlight several barriers that remain and limit its expansion. Further collaboration is underway to determine how best to assist in the integration of POC ultrasound into the ongoing development of EM curricula and residency training.ACEM: Asociación Colombiana de Especialistas en Urgencias y Emergencias; EM: Emergency medicine; EPs: Emergency physicians; FGDs: Focus group discussions; POC: Point-of-care; US: United States.The authors declare that they have no competing interests.PH and CA designed the study and survey; PH, CA, DB, AG, CW, BN, MR, YM, LV, AO, and CV participated in data collection; PH, CA, DB, AG, DS, and MF contributed to the statistical analysis; PH, CA, DB, AG, and CW wrote the manuscript. All authors reviewed and approved the manuscript.


Patients with cervical spinal cord injury frequently need prolonged mechanical ventilation as a result of worsening pulmonary vital capacity due to paralysis of respiratory muscles, severe impairment of tracheobronchial secretions clearance and high incidence of respiratory complications like pneumonia or atelectasis. Patients with thoracic spinal cord injury may need mechanical ventilation due to associate injuries. For these reasons, tracheostomy is frequently performed in these patients, more frequently when the spinal cord injury is at cervical level.Percutaneous technique, performed in the ICU, should be considered the preferred procedure for performing elective tracheostomies in spinal cord injured patients. Tracheostomy should be implemented as soon as possible in SCI patients they require prolonged mechanical ventilation. Tracheostomy can be performed just after anterolateral cervical spine fixation surgery. Tracheostomy can be removed when no longer needed without major complications. It is estimated that approximately 40 new traumatic spinal cord injuries are produced annually per million population in the U. S. Approximately half of these patients suffer cervical spinal cord injury (SCI) Patients with cervical SCI frequently need prolonged mechanical ventilation as a result of worsening pulmonary vital capacity due to paralysis of respiratory muscles, severe impairment of tracheobronchial secretions clearance and high incidence of respiratory complications like pneumonia or atelectasis, th century. A tracheostomy is the formation of an artificial opening into the trachea between two adjacent rings of cartilage, with the aim of facilitate weaning from mechanical ventilation by decreasing anatomical dead space, prevention / treatment of retained tracheo-bronchial secretions or bypass upper airway obstruction.Tracheostomy is one of the oldest surgical procedures and was first successfully performed in the late 19Tracheostomy is a technique frequently performed on critically ill patients with respiratory failure who requiring prolonged mechanical ventilation. A retrospective nation-wide survey study reveal that the prevalence of tracheostomy was 10% in the ventilated patients under mechanical ventilation for more 24 hours. Most tracheostomies were performed during the 2nd week of ventilation. The frequency of tracheostomy varied widely according the hospitals (0–60 %) and was associated with the policy of hospitals to accept or refuse tracheostomized patients on their normal wards Tracheostomy have several advantages respect translaryngeal endotracheal intubation: its might improve the weaning period through decreases respiration work and facilitate weaning by reducing airway resistance and need for less sedation The most frequent causes of death in tracheostomy patients are obstruction and haemorrhage. A variety of complications resulting from tracheostomy placement have been described. Intra operative complications: Bleeding (in < 5% of tracheostomies), damage to adjacent structures: , laceration of the esophagus, and false passage; 2) Post procedural early complications: Wound infection, subcutaneous emphysema, tube obstruction by mucus or blood clots; 3) Post procedural late complications: Cuff leak, tracheomalacia, tube occlusion, tube dislodgement, tracheo-esophageal fistula, tracheo-innominate fistula and the more common tracheal stenosis, due to narrowing of the trachea by stenotic granular tissue The tracheostomy may be temporary or long term. A temporary tracheostomy tube will be inserted to maintain the patency of the airway and facilitate the weaning process due to the reduced airway resistance. This can be removed when the patient recovers. A temporary tracheostomy may become long term if the patient’s condition requires this. In non selected ICU-patients, tracheostomy allows earlier discharge of patients from the ICU, thus allowing better management of limited ICU resources Injury to cervical level of the spinal cord can lead to an impairment of the respiratory system by lung volumes decreases, changes in the breathing pattern and gas exchange alteration. As a result of the loss of diaphragmatic and/or intercostals muscle function, the higher and more complete the motor level of the injury, the respiratory system will become severely compromised following spinal cord injury (SCI). Interruption of the descending input from premotor neurons above the phrenic motoneurons located in the cervical spinal cord C3–C5 (phrenic nerve nucleus) results in immediate paralysis of the main inspiratory muscle, diaphragm. In C5 to C8 injury level there is paralysis of remaining inspiratory and expiratory muscles, which causes inefficient ventilation due to paradoxical respiration . This inefficiency contributes to the risk of respiratory muscle fatigue that causes reduction in vital capacity. There are also markedly impaired cough due to paralysis of expiratory muscles. Due to both factors are delayed insufficiency respiratory develops In the case of thoracic SCI injuries, respiratory failure will depend more on the associate injuries  or severe previous comorbidity , so considerations regarding tracheostomy implementation are those of the general critical patients The indications for tracheostomy in the spinal cord injured patients, as in other patients with respiratory failure, include failure in extubation, upper airway obstruction, airway access for tracheobronchial secretions removal, avoidance of serious oropharyngeal and laryngeal injury from prolonged translaryngeal intubation, and, specially, expected prolonged dependence on mechanical ventilation The main aim of rehabilitation program in cervical SCI patients is enhance the residual activity of debilitate diaphragm, the accessory respiratory muscles recruitment as far as possible, stabilizing the rib cage  for improving both inspiratory and expiratory function, and strength training expiratory muscle function In most cases this respiratory insufficiency is partially reversible duo to multiple factors, then the patient would weaning of mechanical ventilation after some time, more length the higher the level of the lesion. It is permanent if the level is above C4 sensory-motor and motor complete SCI (ASIA A + B) patients. In cases in which patients are unable to maintain adequate pulmonary ventilation, long-term mechanical ventilation support is indicated, and therefore the practice of tracheostomy An important clinical problem in SCI is weak cough, which causes retention of secretions during infections. As much as 50% of patients with a complete lesion of the cervical or thoracic spinal cord develop atelectasis or pneumonia within 30 days of the injury, with the peak incidence at 3–5 days After cervical SCI a great percentage of patients will require intubation and mechanical ventilation due to compromised respiratory function In a retrospective study of the 175 patients with acute tetraplegia, 72 were tracheotomised. The need for a tracheotomy could be predicted in 73.31% based on the neurological level, the ASIA impairment scale and severity of accompanying injuries. According to this, the authors recommend that in patients with acute tetraplegia, primary tracheotomy is indicated immediately in all patients on C1–C3 level with ASIA scale A/B, at an early stage in the patients with C4–C6 injury level with ASIA scale A/B and accompanying injuries/accompanying illnesses and there were accompanying injuries/accompanying illnesses and/or there was a complex cervical spine trauma requiring a combined operative procedure and/or ventilation for more than 10 days was required In summary, SCI can causes impairment of respiratory muscles function, reduced vital capacity, ineffective cough and reduction in lung and chest wall compliance. Severely affected individuals may require assisted ventilation, in most patients prolonged, or definitive in some cases. Late partial recovery can occurs spontaneously. The eventual weaning depends on the extent of spontaneous partial recovery of respiratory-muscle performance, time since injury, antecedents of chest injury, and others respiratory co-morbidities. Due to the need of prolonged mechanical ventilation, ineffective cough which need its frequent removal, and delay on recovery, the tracheostomy technique as a high prevalence in SCI persons.Tracheostomy is one of the traditional surgical procedures in ICU patients. In the last decades, percutaneous dilatational technique (PDT) has gained widespread acceptance as an alternative to surgical tracheostomy (ST). PDT is a less invasive bedside procedure. PDT was originally described by Ciaglia in 1985. In principle, the technique employs the use of serial dilators introduced into the trachea over a guide wire. Modifications to improve this technique have included design of special dilating forceps and use of a single-tapered dilator rather than multiplesized ones. Several commercial PDT kits are currently available, providing all of the necessary equipment for efficient and expedient application The development and rapid introduction of the PDT is due to it is technically easy to use, has a very low rate of complications it is minimally invasive, can be conducted with the neck in a neutral position Percutaneous tracheostomy was associated with a reduction in the incidence of clinically important wound infections but there was no clear difference in the incidence of clinically significant bleeding, major peri-procedural or long term complications, nevertheless few studies suggest a reduction in tracheal stenosis with PDT Addition of bronchoscopy guidance to PDT may lead to a lower risk for peri-procedural complications, so bronchoscopy can be recommended as a simple and safe technique with the potential to avoid complications such as fausse route and posterior tracheal wall lacerations Percutaneous dilatational tracheostomy, performed in the ICU, should be considered in this moment the procedure of choice for performing elective tracheostomies in critically ill adult patients both, general critical patients or SCI patients The prolonged intubation is the main risk factor for multiple complications. Local complications of translaryngeal intubation are more likely if tracheal intubation is continued for more than 2 weeks There has been a long debate on the optimal timing to place a tracheostomy in injured patients who require prolonged mechanical ventilation. The American College of Chest Physicians Consensus Conference on Artificial Airways in Patients Receiving Mechanical Ventilation issued the recommendation that tracheostomy is preferred if the need for mechanical ventilation is anticipated to be greater than 21 days Many authors have evidenced that early tracheostomy placement is associated to a marked reduction in ICU stay and/or in the duration of MV in patients admitted to an ICU with medical illnesses, polytrauma and in surgical and neurosurgical patients Has been reported the incidence of pulmonary infections is reduced significantly following tracheotomy, and the rate of pulmonary infections increases with the duration of endotracheal intubation A meta-analysis has reported ET has no influence on mortality or pneumonia incidence in trauma patients Optimal timing to place tracheostomy in SCI, as well as in other critical illness, is still controversial for lack of evidence proving when it is more convenient to perform it In summary, early tracheotomy placement offers advantages in SCI patients they require prolonged mechanical ventilation, for shortening of mechanical ventilation, reducing ICU stay and probably decreases local late complications. Given of benefits suggested, we then recommend to implementing tracheostomy as soon as possible, preferable within the first week of ventilation.When a tracheostomy is performed after anterolateral cervical spine fixation surgery, the two incisions come into very close contact, which poses the potential risk of cross-contamination and therefore, of much-feared infection of the osteosynthetic wound. This is why, in daily clinical practice, there is a tendency to delay the procedure until the healing process following fixation surgery is completed or at a very prolonged translaryngeal intubation which could increase its complications In recent years the development of PDT, minimally invasive, with low rate of complications and can be implemented in the bedside at ICU with the neck in a neutral position, has permitted this technique to be practiced shortly behind anterolateral cervical fixation surgeryOwing to the difficulty of hyperextending the neck, the presence of a recent scar, as a result of anterolateral cervical spine fixation, and the great difficulty associated with reintubation after failed extubation, performing a tracheostomy is complicated Retrospective studies shown very low infection rates in early tracheostomy after cervical spinal stabilization by anterolateral approach without surgical wound dehiscence, which supports that this procedure is safe and effective Tracheotomy removal in patients who were weaned from prolonged mechanical ventilation can be considered if they are clinically stable, do not have psychiatric disorders, have adequate swallowing and are able to expectorate. The criteria for tracheotomy decannulation are stable arterial blood gases, absence of distress, haemodynamic stability, absence of fever or active infection, PaCO2 < 60 mmHg, absence of delirium or psychiatric disorder, normal endoscopic examination or revealing stenotic lesion occupying <30% of the airway, adequate swallowing and able to expectorate Many patients recovering from long-term mechanical ventilatory support may have normal airways but limited ventilatory reserve due to neuromuscular disease or underlying chronic obstructive pulmonary disease. These patients may benefit from “downsizing” of the tracheostomy stoma using progressively smaller cuff-less tracheostomy tubes with intermittent capping using stomal obturators Once successfully weaning, the tracheostomy remain patent until you consider that it will remain necessary aspirations of tracheobronchial secretions and the patient was capable of proper management. In this moment is possible to close the stoma, which is accomplished by removal of tracheal tube, the opening closed spontaneously. The wound spontaneously heals in less than 10 days in most cases. In our experience, the persistence of a tracheocutaneous fistula that needs surgical closure occurs in less than 5% of cases.


An increasing number of studies have relied on brain imaging to assess the effects of cognitive training in healthy aging populations and in persons with early Alzheimer’s disease or mild cognitive impairment (MCI). At the structural level, cognitive training in healthy aging individuals has been associated with increased brain volume, cortical thickness, and density and coherence of white matter tracts. At the functional level, task-related brain activation (using fMRI and PET) and fluorodeoxyglucose positron emission tomography (FDG-PET) were found to be sensitive to the effects of training. In persons with MCI, cognitive training increased brain metabolism and task-related brain activation, whereas healthy older adults showed patterns of increased and decreased activation. Further studies are required to generalize these findings to larger groups and to investigate more diverse training protocols. Research will also need to address important methodological issues regarding the use of biomarkers in cognitive aging, including reliability, clinical validity, and relevance to the pathophysiological process. Cognitive training is designed to restore, increase, or optimize capacities in persons suffering from cognitive impairment , 2••. MaA biomarker is a measurement used as an indicator of normal biological or disease processes. Biomarkers should meet the criteria of being a biologically plausible measure of the disease or condition and sharing a coherent relation with the disease progression and severity. For example, brain imaging allows for the measurement of structural and functional changes that are characteristic of Alzheimer’s disease (AD) and that correlate with disease progression and severity. Brain imaging measures are also modified by the normal aging process and are related to cognitive changes that occur with age. A biomarker also can be used as “surrogate marker.” Surrogate markers are used in therapeutic trials as clinically meaningful measures of the effect of a therapy , 10. SurNot all biological measures are appropriate biomarkers and similarly, not all biomarkers are appropriate surrogates of training efficacy. Biomarkers need to be sensitive to the disease and to correlate with progression and severity, and their biological relation with the disease must be at least partially understood. Surrogate markers are typically biomarkers of the disease, but they also need to be sensitive to change and reliable over time, and their mechanisms should be relevant to the therapeutic effect that they are expected to indicate. In this review, we will examine structural and functional brain imaging as potential surrogate markers for cognitive training effects. We will discuss studies that have used brain imaging as a marker of cognitive training effects in healthy aging and in MCI, the early stage of AD. We also will address some challenges, limitations, and implications of using brain imaging as biomarkers of cognitive training effects in aging populations.Structural brain imaging provides quantitative information on brain structure, including whole-brain volume, regional grey matter volumes, cortical thickness, and indicators of white matter integrity and microstructure. Brain imaging techniques have provided valuable information regarding the effects of aging on brain structure. Such studies have found that brain volume decreases with age and that those structural changes accelerate, with an annual decline of 0.35 % in older adults, compared to 0.12 % in young adults  and decreased activation patterns  or compensatory activation patterns. Compensatory patterns of activation refers to the process by which alternative or atypical brain regions compensate for reduced processing efficiency that occurs with age. Compensatory recruitment can involve the hemispheric homologues (see HAROLD model [hemispheric asymmetry reduction in older adults] proposed by Cabeza ) or anteFunctional brain imaging can thus qualify as a biomarker of aging and AD because it is sensitive to chronological age. It also reveals a characteristic pattern of impairment in those diagnosed with AD that changes with disease severity and progression. A few studies have used functional brain imaging as a biological surrogate of training efficacy in healthy aging populations and persons with MCI. In healthy aging, most studies reporting training-related changes in brain activation patterns have used memory training. Among the first studies to do so, Nyberg et al.  noted imTraining-induced changes in brain activity were also reported after attention control training using computer-based programs. Erickson et al.  conducteA few studies have used functional brain imaging as a biological surrogate of training efficacy in MCI, and those studies indicate that fMRI is sensitive to changes following cognitive training in this group of individuals. Belleville et al. •• found To our knowledge, only two studies have examined brain-related changes following executive training in MCI participants. Carlson et al.  randomlyPET can measure neural activity by recording the uptake of [18F]fluorodeoxyglucose (FDG). Reduced FDG-PET at rest may reveal early cerebrometabolic changes in AD and could represent a valid biomarker of neuronal injury in early AD and MCI , 45. A 6The present review of recent studies provides support for the use of structural and functional brain imaging as sensitive surrogate biomarkers for the effects of cognitive training . Relevance also can be determined by selecting biomarkers that reflect neuropathological processes underlying the disease, and in that case, it is important to fully understand the relationship between the surrogate marker and the pathophysiology of the condition of interest . Most stIn conclusion, this review supports the notion that brain-imaging techniques could be reliably used to assess training-related changes in brain structure and function in healthy older adults and patients with MCI or AD. However, future studies are needed to identify all the potential biomarkers and surrogate biomarkers of brain plasticity induced by cognitive training interventions. We believe that following a structured methodology that meets the prerequisites provided in the present review would effectively guide future research and help to increase the body of knowledge on brain changes associated with cognitive training in older adults.