Functional Imaging of Autonomic Regulation: Methods and Key Findings.

Central nervous system processing of autonomic function involves a network of regions throughout the brain which can be visualized and measured with neuroimaging techniques, notably functional magnetic resonance imaging (fMRI). The development of fMRI procedures has both confirmed and extended earlier findings from animal models, and human stroke and lesion studies. Assessments with fMRI can elucidate interactions between different central sites in regulating normal autonomic patterning, and demonstrate how disturbed systems can interact to produce aberrant regulation during autonomic challenges. Understanding autonomic dysfunction in various illnesses reveals mechanisms that potentially lead to interventions in the impairments. The objectives here are to: (1) describe the fMRI neuroimaging methodology for assessment of autonomic neural control, (2) outline the widespread, lateralized distribution of function in autonomic sites in the normal brain which includes structures from the neocortex through the medulla and cerebellum, (3) illustrate the importance of the time course of neural changes when coordinating responses, and how those patterns are impacted in conditions of sleep-disordered breathing, and (4) highlight opportunities for future research studies with emerging methodologies. Methodological considerations specific to autonomic testing include timing of challenges relative to the underlying fMRI signal, spatial resolution sufficient to identify autonomic brainstem nuclei, blood pressure, and blood oxygenation influences on the fMRI signal, and the sustained timing, often measured in minutes of challenge periods and recovery. Key findings include the lateralized nature of autonomic organization, which is reminiscent of asymmetric motor, sensory, and language pathways. Testing brain function during autonomic challenges demonstrate closely-integrated timing of responses in connected brain areas during autonomic challenges, and the involvement with brain regions mediating postural and motoric actions, including respiration, and cardiac output. The study of pathological processes associated with autonomic disruption shows susceptibilities of different brain structures to altered timing of neural function, notably in sleep disordered breathing, such as obstructive sleep apnea and congenital central hypoventilation syndrome. The cerebellum, in particular, serves coordination roles for vestibular stimuli and blood pressure changes, and shows both injury and substantially altered timing of responses to pressor challenges in sleep-disordered breathing conditions. The insights into central autonomic processing provided by neuroimaging have assisted understanding of such regulation, and may lead to new treatment options for conditions with disrupted autonomic function

Modeling of dynamic cerebrovascular reactivity to spontaneous and externally induced CO2 fluctuations in the human brain using BOLD-fMRI

In this work, we investigate the regional characteristics of the dynamic interactions between arterial CO2 and BOLD (dynamic cerebrovascular reactivity - dCVR) during normal breathing and hypercapnic, externally induced step CO2 challenges. To obtain dCVR curves at each voxel, we use a custom set of basis functions based on the Laguerre and gamma basis sets. This allows us to obtain robust dCVR estimates both in larger regions of interest (ROIs), as well as in individual voxels. We also implement classification schemes to identify brain regions with similar dCVR characteristics. Our results reveal considerable variability of dCVR across different brain regions, as well as during different experimental conditions (normal breathing and hypercapnic challenges), suggesting a differential response of cerebral vasculature to spontaneous CO2 fluctuations and larger, externally induced CO2 changes that are possibly associated with the underlying differences in mean arterial CO2 levels. The clustering results suggest that anatomically distinct brain regions are characterized by different dCVR curves that in some cases do not exhibit the standard, positive valued curves that have been previously reported. They also reveal a consistent set of dCVR cluster shapes for resting and forcing conditions, which exhibit different distribution patterns across brain voxels

Cerebral metabolic changes during visuomotor adaptation assessed using quantitative fMRI

The brain retains a lifelong ability to adapt through learning and in response to injury or disease-related damage, a process known as functional neuroplasticity. The neural energetics underlying functional brain plasticity have not been thoroughly investigated experimentally in the healthy human brain. A better understanding of the blood flow and metabolic changes that accompany motor skill acquisition, and which facilitate plasticity, is needed before subsequent translation to treatment interventions for recovery of function in disease. The aim of the current study was to characterize cerebral blood flow (CBF) and oxygen consumption (relative CMRO2) responses, using calibrated fMRI conducted in 20 healthy participants, during performance of a serial reaction time task which induces rapid motor adaptation. Regions of interest (ROIs) were defined from areas showing task-induced BOLD and CBF responses that decreased over time. BOLD, CBF and relative CMRO2 responses were calculated for each block of the task. Motor and somatosensory cortices and the cerebellum showed statistically significant positive responses to the task compared to baseline, but with decreasing amplitudes of BOLD, CBF, and CMRO2 response as the task progressed. In the cerebellum, there was a sustained positive BOLD response in the absence of a significant CMRO2 increase from baseline, for all but the first task blocks. This suggests that the brain may continue to elevate the supply energy even after CMRO2 has returned to near baseline levels. Relying on BOLD fMRI data alone in studies of plasticity may not reveal the nature of underlying metabolic responses and their changes over time. Calibrated fMRI approaches may offer a more complete picture of the energetic changes supporting plasticity and learning

Separating vascular and neuronal effects of age on fMRI BOLD signals.

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.This work is supported by the British Academy (PF160048), the Guarantors of Brain (G101149), the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400; and SUAG/046 G101400), European Union’s Horizon 2020 (732592) and the Cambridge NIHR Biomedical Research Centre

Multiparametric measurement of cerebral physiology using calibrated fMRI

The ultimate goal of calibrated fMRI is the quantitative imaging of oxygen metabolism (CMRO2), and this has been the focus of numerous methods and approaches. However, one underappreciated aspect of this quest is that in the drive to measure CMRO2, many other physiological parameters of interest are often acquired along the way. This can significantly increase the value of the dataset, providing greater information that is clinically relevant, or detail that can disambiguate the cause of signal variations. This can also be somewhat of a double-edged sword: calibrated fMRI experiments combine multiple parameters into a physiological model that requires multiple steps, thereby providing more opportunity for error propagation and increasing the noise and error of the final derived values. As with all measurements, there is a trade-off between imaging time, spatial resolution, coverage, and accuracy. In this review, we provide a brief overview of the benefits and pitfalls of extracting multiparametric measurements of cerebral physiology through calibrated fMRI experiments

Using physiological MRI to estimate dynamic cerebral autoregulation metrics: functional MRI feasibility study

Cerebral autoregulation is the homeostatic mechanism that maintains sufficient cerebral circulation despite changes in the perfusion pressure. Dynamic CA refers to the changes that occur in CBF within the first few seconds after an acute MAP change. Assessment of the CA impairment plays important role in the prognosis of many cerebrovascular diseases such as stroke, sub-arachnoid haemorrhage, as well as traumatic brain injury and neurodegenerative disorders. This thesis investigates the feasibility of using physiological MRI to estimate dynamic cerebral autoregulation (dCA) metrics. In particular, this thesis has an emphasis on measuring beat-to-beat arterial blood pressure inside the scanner to provide better understanding of the physiological aspects of dCA. Further, continuous blood pressure (BP) measures in response to different non invasive BP fluctuating methods are acquired to evaluate the reliability of these methods to induce response changes. Blood Oxygen Level Dependent (BOLD) fMRI method was used to estimate the expected variations of tissue oxygenation during induced dCA changes in healthy volunteers. The non invasive arterial blood pressure measurements were acquired using MR compatible arterial blood pressure monitoring device (NIBP-MRI/Caretaker; Biopac®). Further, sudden release of inflated thigh-cuffs (TCR) and inspiratory breath-hold (iBH) methods were used in the scanner to induce dynamic autoregulatory changes. These two methods were investigated in a pilot study, to evaluate the reliability prior to the MR study by comparing BP measurements obtained outside the scanner using non invasive methods. This pilot study included monitoring BP changes in response to four types of non invasive BP fluctuating methods. The reliability of NIBP/MRI Caretaker device was examined by comparing the BP response changes with the simultaneously acquired BP data from Finometer plethysmographic device. The cerebral autoregulation metrics were estimated by calculating the rate of regulation (RoR) following dynamic BP fluctuating events. Rate of regulation defines the rate at which the BOLD signal changes depending on MAP changes at a particular time. Further, the tissue specific regulation parameters were obtained for grey matter (GM), white matter (WM) and water shed areas (WS). The effect of iBH method on cerebral blood flow (CBF) and velocity (CBFV) was explored in a preliminary study by quantitative measures using time resolved 4D PC MRI angiography in two subjects. The mean arterial blood pressure (MAP) changes in response to TCR and iBH method were comparable. The fMRI data demonstrated BOLD signal amplitude change in response to the induced fast MAP changes. The GM and WS areas showed similar rates of regulation, and these were nominally higher than WM RoR in both TCR and iBH methods. Further, the 4D PC MRI data suggested 29% CBF-increase in response to 33% iBH in four minutes acquisition time. The acquired non invasive arterial BP measures concurrent with the BOLD signal amplitude response, allowed deriving the rate of regulation as a metric of dCA. It is not known whether this information is clinically relevant to gauge the haemodynamic risk association to cerebrovascular disease. However, BOLD signal change and CBF changes after iBH are confounded by the extent to which the CO2 gradually accumulate in response to iBH and causes an overshoot in the CBF response-change. In conclusion, the presented study indicates the feasibility of using physiological MRI to measure dCA in response to non-invasively induced MAP changes. Estimation of the dCA metrics could be improved by using advanced data fitting methods as well as controlling for physiological parameters such as PECO2

Using physiological MRI to estimate dynamic cerebral autoregulation metrics: functional MRI feasibility study

Cerebral autoregulation is the homeostatic mechanism that maintains sufficient cerebral circulation despite changes in the perfusion pressure. Dynamic CA refers to the changes that occur in CBF within the first few seconds after an acute MAP change. Assessment of the CA impairment plays important role in the prognosis of many cerebrovascular diseases such as stroke, sub-arachnoid haemorrhage, as well as traumatic brain injury and neurodegenerative disorders. This thesis investigates the feasibility of using physiological MRI to estimate dynamic cerebral autoregulation (dCA) metrics. In particular, this thesis has an emphasis on measuring beat-to-beat arterial blood pressure inside the scanner to provide better understanding of the physiological aspects of dCA. Further, continuous blood pressure (BP) measures in response to different non invasive BP fluctuating methods are acquired to evaluate the reliability of these methods to induce response changes. Blood Oxygen Level Dependent (BOLD) fMRI method was used to estimate the expected variations of tissue oxygenation during induced dCA changes in healthy volunteers. The non invasive arterial blood pressure measurements were acquired using MR compatible arterial blood pressure monitoring device (NIBP-MRI/Caretaker; Biopac®). Further, sudden release of inflated thigh-cuffs (TCR) and inspiratory breath-hold (iBH) methods were used in the scanner to induce dynamic autoregulatory changes. These two methods were investigated in a pilot study, to evaluate the reliability prior to the MR study by comparing BP measurements obtained outside the scanner using non invasive methods. This pilot study included monitoring BP changes in response to four types of non invasive BP fluctuating methods. The reliability of NIBP/MRI Caretaker device was examined by comparing the BP response changes with the simultaneously acquired BP data from Finometer plethysmographic device. The cerebral autoregulation metrics were estimated by calculating the rate of regulation (RoR) following dynamic BP fluctuating events. Rate of regulation defines the rate at which the BOLD signal changes depending on MAP changes at a particular time. Further, the tissue specific regulation parameters were obtained for grey matter (GM), white matter (WM) and water shed areas (WS). The effect of iBH method on cerebral blood flow (CBF) and velocity (CBFV) was explored in a preliminary study by quantitative measures using time resolved 4D PC MRI angiography in two subjects. The mean arterial blood pressure (MAP) changes in response to TCR and iBH method were comparable. The fMRI data demonstrated BOLD signal amplitude change in response to the induced fast MAP changes. The GM and WS areas showed similar rates of regulation, and these were nominally higher than WM RoR in both TCR and iBH methods. Further, the 4D PC MRI data suggested 29% CBF-increase in response to 33% iBH in four minutes acquisition time. The acquired non invasive arterial BP measures concurrent with the BOLD signal amplitude response, allowed deriving the rate of regulation as a metric of dCA. It is not known whether this information is clinically relevant to gauge the haemodynamic risk association to cerebrovascular disease. However, BOLD signal change and CBF changes after iBH are confounded by the extent to which the CO2 gradually accumulate in response to iBH and causes an overshoot in the CBF response-change. In conclusion, the presented study indicates the feasibility of using physiological MRI to measure dCA in response to non-invasively induced MAP changes. Estimation of the dCA metrics could be improved by using advanced data fitting methods as well as controlling for physiological parameters such as PECO2

BOLD signal physiology: Models and applications

The BOLD contrast mechanism has a complex relationship with functional brain activity, oxygen metabolism, and neurovascular factors. Accurate interpretation of the BOLD signal for neuroscience and clinical applications necessitates a clear understanding of the sources of BOLD contrast and its relationship to underlying physiology. This review describes the physiological components that contribute to the BOLD signal and the steady-state calibrated BOLD models that enable quantification of functional changes with a separate challenge paradigm. The principles derived from these biophysical models are then used to interpret BOLD measurements in different neurological disorders in the presence of confounding vascular factors related to disease

Effects of normobaric hypoxia on the activation of motor and visual cortex areas in functional magnetic resonance imaging (fMRI)

Aims: Hypoxia due to high altitude or otherwise altered fraction of inspired O2 affects cerebral mechanisms. Human brain function can be assessed indirectly via examination of local changes in haemodynamics in fMRI. The aim of this study was to examine if adaptation to normobaric hypoxia determines divergent activation in the brain regions supplied by the main cerebral arterial vessels. Methods: Visual and motor paradigms were used to shed light on the activation of different brain regions in fMRI under normobaric hypoxic conditions in 16 healthy male subjects. Hypoxia was produced by reducing the percentage of O2 in an inhaled gas mixture resulting in normobaric hypoxia with an FiO2 of 13 %. Participants had to complete a total of 3 MRI sessions to study different oxygen conditions: normoxia (FiO2 = 0.21, normal pressure), short-time (7 ± 1 min, FiO2 = 0.13, normal pressure), longtime hypoxia (8 h and 29 ± 24 min, FiO2 = 0.13, normal pressure). Each session lasted approximately 30 min, consisting of two fMRI runs (1 visual task, 1 motor task) which were pseudo-randomized between participants, followed by the structural sequence. Cerebral symptoms of AMS were assessed by means of the LLS and it was examined if symptomatic AMS has consequences on brain activation patterns measured as ∆S values. Results: Mean ∆S during normoxia was 2.43 ± 0.80 % due to motor stimulation, and 3.49 ± 1.41 % due to visual stimulation. During motor stimulation, the mean signal change due to short-time hypoxia was 0.55 ± 0.30 % and 0.82 ± 0,62 % due to longtime hypoxia. During visual stimulation, the mean signal change due to short-time hypoxia was 1.79 ± 0.69 %. Long-time hypoxia led to a mean signal change of 2.02 ± 1.18 %. Repeated ANOVA measures with factors task (motor, visual) and the hypoxic conditions (short-time hypoxia, long-time hypoxia) showed a main effect of task (F (1,15) = 52.10, p < 0.001), but no main effect of the hypoxic condition (F (1, 15) = 1.79, p = ns). Conclusions: Hypoxia led to diminished cerebral activation during motor and visual stimulation in spite of a preserved cerebral function. The oxygenation changes associated with brain activation seem more influential on the motor area, rather than the visual cortex. Therefore, the capability of the human brain to acclimatise to chronic hypoxic conditions may vary in the motor and the visual system.Ziele: Hypoxie aufgrund großer Höhe oder eines anderweitig veränderten Anteils von eingeatmetem O2-Gehalts beeinflusst zerebrale Mechanismen. Die menschliche Gehirnfunktion kann indirekt über den Nachweis lokaler hämodynamischer Veränderungen im fMRT bestimmt werden. Das Ziel dieser Studie war es, zu untersuchen, ob die Anpassung an normobare Hypoxie eine unterschiedliche Aktivierung in von den drei Hauptgefäßen versorgten Gehirnregionen erzeugt. Methoden: Bei 16 gesunden, männlichen Probanden wurden visuelle und motorische Testparadigmen angewendet, um die Aktivierung verschiedener Hirnregionen im fMRT unter normobaren, hypoxischen Bedingungen aufzuklären. Hypoxie wurde mit Hilfe eines sauerstoffreduzierten Gasgemischs (O2-Anteil 13%) erzeugt. Die Probanden mussten insgesamt 3 MRT-Sitzungen absolvieren, um verschiedene Sauerstoffzustände zu untersuchen: Normoxie (FiO2 = 0,21), Kurzzeithypoxie (7 ± 1 min Hypoxie, FiO2 = 0,13), Langzeithypoxie (8 h und 29 ± 24 min Hypoxie, FiO2 = 0,13). Jede Sitzung dauerte ca. 30 min und bestand aus je zwei fMRI-Durchgängen (1 visuelle Aufgabe, 1 motorische Aufgabe). Die zerebralen Symptome einer Höhenkrankheit wurden mittels des LLS bewertet und der Einfluss einer Höhenkrankheit auf die Gehirnaktivierungsmuster im fMRT untersucht. Resultate: Die mittlere BOLD-Signalveränderung während Normoxie betrug bei motorischer Stimulation 2,43 ± 0,80% und bei visueller Stimulation 3,49 ± 1,41%. Bei motorischer Stimulation betrug sie nach Kurzzeithypoxie 0,55 ± 0,30% und 0,82 ± 0,62% nach Langzeithypoxie. Bei visueller Stimulation betrug die mittlere Signaländerung aufgrund von Kurzzeithypoxie 1,79 ± 0,69 und aufgrund Langzeithypoxie 2,02 ± 1,18%. ANOVA-Messungen mit den Faktoren Aufgabe (motorisch, visuell) und hypoxische Bedingungen (Kurzzeithypoxie, Langzeithypoxie) zeigten einen Effekt der Aufgabe (F (1, 15) = 52.10, p <0.001), aber keinen Effekt der hypoxischen Bedingung (F (1, 15) = 1,79, p = ns) auf die BOLD Signalwertänderungen. Schlussfolgerungen: Hypoxie führte zu einer verminderten Hirnaktivität im fMRT bei motorischer und visueller Stimulation trotz erhaltener Hirnfunktion. Die mit der Gehirnaktivierung verbundenen Veränderungen der Oxygenierung scheinen eher Einfluss auf den motorischen Bereich als den visuellen Kortex zu haben. Die Adaptationsfähigkeit an chronische hypoxische Zustände scheint sich demzufolge zwischen dem motorischen und dem visuellen System zu unterscheiden