RESUMEN
Neural-vascular coupling (NVC) is the process by which oxygen and nutrients are delivered to metabolically active neurons by blood vessels. Murine models of NVC disruption have revealed its critical role in healthy neural function. We hypothesized that, in humans, aging exerts detrimental effects upon the integrity of the neural-glial-vascular system that underlies NVC. To test this hypothesis, calibrated functional magnetic resonance imaging (cfMRI) was used to characterize age-related changes in cerebral blood flow (CBF) and oxygen metabolism during visual cortex stimulation. Thirty-three younger and 27 older participants underwent cfMRI scanning during both an attention-controlled visual stimulation task and a hypercapnia paradigm used to calibrate the blood-oxygen-level-dependent signal. Measurement of stimulus-evoked blood flow and oxygen metabolism permitted calculation of the NVC ratio to assess the integrity of neural-vascular communication. Consistent with our hypothesis, we observed monotonic NVC ratio increases with increasing visual stimulation frequency in younger adults but not in older adults. Age-related changes in stimulus-evoked cerebrovascular and neurometabolic signal could not fully explain this disruption; increases in stimulus-evoked neurometabolic activity elicited corresponding increases in stimulus-evoked CBF in younger but not in older adults. These results implicate age-related, demand-dependent failures of the neural-glial-vascular structures that comprise the NVC system.
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Acoplamiento Neurovascular , Humanos , Animales , Ratones , Anciano , Acoplamiento Neurovascular/fisiología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Circulación Cerebrovascular/fisiología , Imagen por Resonancia Magnética/métodos , Envejecimiento/fisiología , OxígenoRESUMEN
Facial recognition ability declines in adult aging, but the neural basis for this decline remains unknown. Cortical areas involved in face recognition exhibit lower dopamine (DA) receptor availability and lower blood-oxygen-level-dependent (BOLD) signal during task performance with advancing adult age. We hypothesized that changes in the relationship between these two neural systems are related to age differences in face-recognition ability. To test this hypothesis, we leveraged positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to measure D1 receptor binding potential (BPND) and BOLD signal during face-recognition performance. Twenty younger and 20 older participants performed a face-recognition task during fMRI scanning. Face recognition accuracy was lower in older than in younger adults, as were D1 BPND and BOLD signal across the brain. Using linear regression, significant relationships between DA and BOLD were found in both age-groups in face-processing regions. Interestingly, although the relationship was positive in younger adults, it was negative in older adults (i.e., as D1 BPND decreased, BOLD signal increased). Ratios of BOLD:D1 BPND were calculated and relationships to face-recognition performance were tested. Multiple linear regression revealed a significant Groupâ¯×â¯BOLD:D1 BPND Ratio interaction. These results suggest that, in the healthy system, synchrony between neurotransmitter (DA) and hemodynamic (BOLD) systems optimizes the level of BOLD activation evoked for a given DA input (i.e., the gain parameter of the DA input-neural activation function), facilitating task performance. In the aged system, however, desynchronization between these brain systems would reduce the gain parameter of this function, adversely impacting task performance and contributing to reduced face recognition in older adults.
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Envejecimiento/fisiología , Reconocimiento Facial/fisiología , Neuroimagen Funcional , Desempeño Psicomotor/fisiología , Receptores de Dopamina D1/metabolismo , Lóbulo Temporal/fisiología , Adulto , Factores de Edad , Anciano , Envejecimiento/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/metabolismo , Adulto JovenRESUMEN
Behavioral studies investigating fundamental cognitive abilities provide evidence that processing speed accounts for large proportions of performance variability between individuals. Processing speed decline is a hallmark feature of the cognitive disruption observed in healthy aging and in demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica, and Wilson's disease. Despite the wealth of evidence suggesting a central role for processing speed in cognitive decline, the neural mechanisms of this fundamental ability remain unknown. Intact neurovascular coupling, acute localized blood flow increases following neural activity, is essential for optimal neural function. We hypothesized that efficient coupling forms the neural basis of processing speed. Because MS features neural-glial-vascular system disruption, we used it as a model to test this hypothesis. To assess the integrity of the coupling system, we measured blood-oxygen-level-dependent (BOLD) signal in healthy controls (HCs) and MS patients using a 3T MRI scanner while they viewed radial checkerboards that flickered periodically at 8 âHz. To assess processing speed and cognitive function, we administered a battery of neuropsychological tests. While MS patients exhibited reduced ΔBOLD with reductions in processing speed, no such relationships were observed in HCs. To further investigate the mechanisms that underlie ΔBOLD-processing speed relationships, we assessed the physiologic components that constitute ΔBOLD signal (i.e., cerebral blood flow, ΔCBF; cerebral metabolic rate of oxygen, ΔCMRO2; neurovascular coupling ratio) in speed-preserved and -impaired MS patients. While ΔCBF and ΔCMRO2 showed no group-differences, the neurovascular coupling ratio was significantly reduced in speed-impaired MS patients compared to speed-preserved MS patients. Together, these results suggest that neurovascular uncoupling might underlie cognitive slowing in MS and might be the central pathogenic mechanism governing processing speed decline.
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Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Esclerosis Múltiple/fisiopatología , Acoplamiento Neurovascular/fisiología , Tiempo de Reacción/fisiología , Percepción Visual/fisiología , Adulto , Encéfalo/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Estimulación Luminosa/métodosRESUMEN
BACKGROUND: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. OBJECTIVE: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. METHODS: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. RESULTS: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects' reaction time and predicted reaction time after controlling for disease processes. CONCLUSION: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS.
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Circulación Cerebrovascular , Esclerosis Múltiple , Encéfalo , Cognición , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagenRESUMEN
Functional magnetic resonance imaging (fMRI) has been used to infer age-differences in neural activity from the hemodynamic response function (HRF) that characterizes the blood-oxygen-level-dependent (BOLD) signal over time. BOLD literature in healthy aging lacks consensus in age-related HRF changes, the nature of those changes, and their implications for measurement of age differences in brain function. Between-study discrepancies could be due to small sample sizes, analysis techniques, and/or physiologic mechanisms. We hypothesize that, with large sample sizes and minimal analysis assumptions, age-related changes in HRF parameters could reflect alterations in one or more components of the neural-vascular coupling system. To assess HRF changes in healthy aging, we analyzed the large population-derived dataset from the Cambridge Center for Aging and Neuroscience (CamCAN) study (Shafto et al., 2014). During scanning, 74 younger (18-30 years of age) and 173 older participants (54-74 years of age) viewed two checkerboards to the left and right of a central fixation point, simultaneously heard a binaural tone, and responded via right index finger button-press. To assess differences in the shape of the HRF between younger and older groups, HRFs were estimated using FMRIB's Linear Optimal Basis Sets (FLOBS) to minimize a priori shape assumptions. Group mean HRFs were different between younger and older groups in auditory, visual, and motor cortices. Specifically, we observed increased time-to-peak and decreased peak amplitude in older compared to younger adults in auditory, visual, and motor cortices. Changes in the shape and timing of the HRF in healthy aging, in the absence of performance differences, support our hypothesis of age-related changes in the neural-vascular coupling system beyond neural activity alone. More precise interpretations of HRF age-differences can be formulated once these physiologic factors are disentangled and measured separately.
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Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Envejecimiento Saludable/fisiología , Hemodinámica/fisiología , Adulto , Anciano , Circulación Cerebrovascular/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Acoplamiento Neurovascular/fisiología , Adulto JovenRESUMEN
The hemodynamic response function (HRF), a model of brain blood-flow changes in response to neural activity, reflects communication between neurons and the vasculature that supplies these neurons in part by means of glial cell intermediaries (e.g., astrocytes). Intact neural-vascular communication might play a central role in optimal cognitive performance. This hypothesis can be tested by comparing healthy individuals to those with known white-matter damage and impaired performance, as seen in Multiple Sclerosis (MS). Glial cell intermediaries facilitate the ability of neurons to adequately convey metabolic needs to cerebral vasculature for sufficient oxygen and nutrient perfusion. In this study, we isolated measurements of the HRF that could quantify the extent to which white-matter affects neural-vascular coupling and cognitive performance. HRFs were modeled from multiple brain regions during multiple cognitive tasks using piecewise cubic spline functions, an approach that minimized assumptions regarding HRF shape that may not be valid for diseased populations, and were characterized using two shape metrics (peak amplitude and time-to-peak). Peak amplitude was reduced, and time-to-peak was longer, in MS patients relative to healthy controls. Faster time-to-peak was predicted by faster reaction time, suggesting an important role for vasodilatory speed in the physiology underlying processing speed. These results support the hypothesis that intact neural-glial-vascular communication underlies optimal neural and cognitive functioning.
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Encéfalo/fisiopatología , Cognición/fisiología , Disfunción Cognitiva/fisiopatología , Hemodinámica/fisiología , Esclerosis Múltiple/fisiopatología , Acoplamiento Neurovascular/fisiología , Desempeño Psicomotor/fisiología , Adulto , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Femenino , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagenRESUMEN
INTRODUCTION: Medical education systems are trained to produce efficient, thorough clinicians. These programs provide limited training on personal finances. The current socioeconomic climate for medical trainees includes increasing education debt and stagnating reimbursement. We conducted a survey-based cross-sectional pilot study at an academic institution targeted at residents, fellows, and attendings of all medical specialties. Our aim was to understand baseline levels of financial literacy at different training and career stages, which can inform targeted interventions to improve this crucial aspect of physician well-being. METHODS: A survey was devised with the assistance of a certified financial planner. This survey was distributed at an academic institution targeting residents, fellows, and attendings. The survey was anonymous, and no identifying data were collected. Two reminders were sent to subjects to complete the survey. RESULTS: A total of 50 physicians completed the survey in 2021. There were eight responses from interns, 14 responses from residents (post-graduate year 2 or later), 14 responses from fellows, and nine responses from attendings. The majority of our respondents reported not having any particular financial education, and over 70% of respondents reported that their graduate education had not provided them with the tools needed for personal financial success. CONCLUSION: Financial education and financial literacy are important topics that need to be further incorporated into the medical education pathway. Physicians are not well equipped in this realm, and further training is necessary. This study provides pilot data that highlight important aspects of physician knowledge and practices in regard to finances.
RESUMEN
BACKGROUND: Most multiple sclerosis (MS) patients experience fatigue and cognitive decline but the underlying mechanisms remain unknown. Previous work has shown whole brain resting cerebral metabolic rate of oxygen (CMRO2) is associated with the extent of these symptoms. However, it is not known if the association between global CMRO2 and MS-related cognitive speed and fatigue can be localized to specific brain regions. Based upon previous research suggesting prefrontal involvement in MS-related changes in cognitive speed and fatigue, we hypothesized that oxygen metabolic changes within prefrontal cortex (PFC) might form the pathophysiologic basis of cognitive performance and fatigue in MS patients. OBJECTIVE: Investigate whether PFC ΔCMRO2 is associated with cognitive speed and fatigue in MS. METHODS: MS and healthy control (HC) participants were scanned using a dual--echo fMRI sequence and underwent a hypercapnia calibration experiment that permitted estimation of ΔCMRO2 while performing a scanner version of symbol-digit modalities task, a measure of information processing speed and utilized in the clinic as a reliable sentinel biomarker for global cognitive impairment in MS. Participants then completed the Modified Fatigue Impact Scale (MFIS) to measure fatigue. RESULTS: MS patients exhibited significant reductions in cognitive performance relative to HCs (p < 0.04). Prefrontal ΔCMRO2 explained significant variability (ΔR2 = 0.11) in cognitive speed, over and above disease and demographic variables, for the MS group only. Prefrontal ΔCMRO2 was not associated with fatigue across groups. ΔCMRO2 in visual and motor areas were not associated with cognitive performance or fatigue for either group. CONCLUSION: Prefrontal oxygen metabolism may be a sensitive measure of MS-related cognitive decline.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Cognición/fisiología , Encéfalo/diagnóstico por imagen , Fatiga/psicología , Oxígeno , Pruebas NeuropsicológicasRESUMEN
The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural-vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO2), and flow-metabolism coupling (ΔCBF/ΔCMRO2), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO2 increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow-metabolism coupling (ΔCBF/ΔCMRO2) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO2 in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO2 responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural-vascular coupling.
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Circulación Cerebrovascular/fisiología , Metabolismo Energético/fisiología , Esclerosis Múltiple/fisiopatología , Consumo de Oxígeno/fisiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangreRESUMEN
Multiple sclerosis (MS) diagnostic criteria are based upon clinical presentation and presence of white matter hyperintensities on two-dimensional magnetic resonance imaging (MRI) views. Such criteria, however, are prone to false-positive interpretations due to the presence of similar MRI findings in non-specific white matter disease (NSWMD) states such as migraine and microvascular disease. The coexistence of age-related changes has also been recognized in MS patients, and this comorbidity further poses a diagnostic challenge. In this study, we investigated the physiologic profiles within and around MS and NSWMD lesions and their ability to distinguish the two disease states. MS and NSWMD lesions were identified using three-dimensional (3D) T2-FLAIR images and segmented using geodesic active contouring. A dual-echo functional MRI sequence permitted near-simultaneous measurement of blood-oxygen-level-dependent signal (BOLD) and cerebral blood flow (CBF). BOLD and CBF were calculated within lesions and in 3D concentric layers surrounding each lesion. BOLD slope, an indicator of lesion metabolic capacity, was calculated as the change in BOLD from a lesion through its surrounding perimeters. We observed sequential BOLD signal reductions from the lesion towards the perimeters for MS, while no such decreases were observed for NSWMD lesions. BOLD slope was significantly lower in MS compared to NSWM lesions, suggesting decreased metabolic activity in MS lesions. Furthermore, BOLD signal within and around lesions significantly distinguished MS and NSWMD lesions. These results suggest that this technique shows promise for clinical utility in distinguishing NSWMD or MS disease states and identifying NSWMD lesions occurring in MS patients.
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Leucoencefalopatías , Esclerosis Múltiple , Sustancia Blanca , Circulación Cerebrovascular , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagenRESUMEN
Theories of neurocognitive aging rely heavily on functional magnetic resonance imaging (fMRI) to test hypotheses regarding the brain basis of age-differences in cognition. This technique is based on the blood-oxygen level dependent signal (BOLD) that arises from the coordinated neural-vascular coupling that leads to increased blood flow following an increase in neural activity. Here we review the literature and current controversies regarding the mechanisms by which blood flow and neural activity are coupled, and how they change in the aging process. This literature suggests that neural-vascular coupling is a complex of processes, involving dynamic signaling between neurons, glia, and blood vessels. Nearly every component of this process is affected in aging leading to changes in BOLD and pervasive age-related cognitive changes.
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Envejecimiento , Encéfalo/anatomía & histología , Acoplamiento Neurovascular , Envejecimiento/fisiología , Animales , Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Circulación Cerebrovascular/fisiología , Envejecimiento Cognitivo/fisiología , Humanos , Acoplamiento Neurovascular/fisiologíaRESUMEN
BACKGROUND AND PURPOSE: Multiple sclerosis (MS) clinical management is based upon lesion characterization from 2-dimensional (2D) magnetic resonance imaging (MRI) views. Such views fail to convey the lesion-phenotype (ie, shape and surface texture) complexity, underlying metabolic alterations, and remyelination potential. We utilized a 3-dimensional (3D) lesion phenotyping approach coupled with imaging to study physiologic profiles within and around MS lesions and their impacts on lesion phenotypes. METHODS: Lesions were identified in 3T T2 -FLAIR images and segmented using geodesic active contouring. A calibrated fMRI sequence permitted measurement of cerebral blood flow (CBF), blood-oxygen-level-dependent signal (BOLD), and cerebral metabolic rate of oxygen (CMRO2 ). These metrics were measured within lesions and surrounding tissue in concentric layers exact to the 3D-lesion shape. BOLD slope was calculated as BOLD changes from a lesion to its surrounding perimeters. White matter integrity was measured using diffusion kurtosis imaging. Associations between these metrics and 3D-lesion phenotypes were studied. RESULTS: One hundred nine lesions from 23 MS patients were analyzed. We identified a noninvasive biomarker, BOLD slope, to metabolically characterize lesions. Positive BOLD slope lesions were metabolically active with higher CMRO2 and CBF compared to negative BOLD slope or inactive lesions. Metabolically active lesions with more intact white matter integrity had more symmetrical shapes and more complex surface textures compared to inactive lesions with less intact white matter integrity. CONCLUSION: The association of lesion phenotypes with their metabolic signatures suggests the prospect for translation of such data to clinical management by providing information related to metabolic activity, lesion age, and risk for disease reactivation and self-repair. Our findings also provide a platform for disease surveillance and outcome quantification involving myelin repair therapeutics.