Functional Imaging of Autonomic Regulation: Methods and Key Findings

Abstract

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.

Keywords: SIDS; SUDEP; cerebellum; fMRI; insula; parasympathetic; sleep-disordered breathing; sympathetic.

Figure 1

Classical boxcar design for fMRI scanning; examples of rest/task timing for (A) classical visual or motor stimulus paradigms, (B) short autonomic challenges, and (C) long task/recovery duration autonomic challenges.

Figure 2

fMRI time series' global signal illustrating drift during a baseline (rest) period, with each timepoint representing the average signal intensity across the whole brain volume (scan). First fMRI scans are usually rejected due to time taken for the signal to stabilize (although modern sequences do this automatically; Data from single subject baseline of cold pressor in Macey et al., 2012).

Figure 3

Whole-brain and volume-of-interest analysis of fMRI signal during 2 min cold pressor in 31 healthy adolescents (age 15.0 ± 2.5, 14 female/17 male). Left: A whole-brain analysis of activations fitting a pre-determined pattern (boxcar, as in Figure 1C) highlights the sensory cortex and adjacent areas (pseudo-colored areas of significance overlaid onto anatomical background), but not right hippocampus. Right: Timetrend analysis of VOI based on pre-determined regions derived from the Automated Anatomical Labeling atlas (Tzourio-Mazoyer et al., 2002), highlighting significant activations (indicated by ^*) in both the sensory cortex and right hippocampal area (repeated measures ANOVA, P < 0.05) (Data from Valladares et al., 2006).

Figure 4

Brainstem involvement during autonomic challenges detected by fMRI. A “^*” symbol indicates a timepoint of significant signal increase relative to baseline, by repeated measures ANOVA at P < 0.05 (Data from Henderson et al., ; Harper et al., ; Henderson et al., 2003).

Figure 5

Foot cold pressor fMRI and heart rate responses in 29 healthy adolescents (16 male, age mean ± sd [range] = 15.3 ± 2.4 [10.1–19.0] years, 4 left handed). Analysis using SPM software with timepoint-by-timepoint modeling of significant responses (each point p < 0.05 t-test, all regions corrected at whole-model F-test level for multiple comparisons at p < 0.05 family-wise error). Heart rate calculated from pulse-oximetry signal. Regions of signal increases (warm colors) and decreases (cold colors) are overlaid on three sagittal (A–C) and one axial (D) slices at selected time-points during challenge (Data from Valladares et al., 2006).

Figure 6

Hand grip fMRI responses in 65 healthy controls (41 male, age mean ± sd [range] = 47.5 ± 8.8 [30.9–65.8] years, 11 left handed). The protocol consists of four 16 s challenges of 80% subjective maximal grip, 1 min apart. Analysis using SPM software with boxcar modeling of significant responses (p < 0.05 t-test, all regions corrected at whole-model F-test level for multiple comparisons at p < 0.05 family-wise error). Regions of signal increases (warm colors) and decreases (cold colors) are overlaid onto multiple views, illustrated the varied regions of response (Data from Harper et al., 2008).

Figure 7

Insular gyri organization during responses to Valsalva maneuver (simplification of findings in Macey et al., 2012). Left: gyral activation relative to posterior-most gyrus (posterior long gyrus; PLG) on the left side, with anterior-most gryi showing great activation over posterior areas. Right: greater activation in right over left insular cortex in anterior and posterior gyri (mid short gyrus [MSG], PLG). Differences are significant (P < 0.05; Data from Macey et al., 2012).

Figure 8

Valsalva fMRI responses in the right superior cerebellar cortex in 33 healthy controls (23 male, age mean ± sd [range] = 52.3 ± 7.7 years). Region-of-interest from which signal is extracted is overlaid in yellow on an anatomical background. The protocol consists of four 18 s challenges of 30 mmHg minimum expiratory pressure, 1 min apart. All subjects achieved this pressure for all four challenges. Red is mean and green error bars are SEM (Data from Ogren et al., 2012).

Figure 9

Global BOLD signal during an average of four Valsalva challenges averaged over 59 healthy subjects (18 s duration, target pressure 30 mmHg, starting at time 18 s). Mean of expiratory pressures in bottom graph. All subjects achieved target pressure for all four challenges. Blue overlays on average anatomical background indicate locations from which global BOLD signal was calculated (Data from Macey et al., 2014).