Pain perception during baroreceptor unloading by lower body negative pressure.

BACKGROUND: People with high blood pressure have reduced sensitivity to pain, known as blood pressure hypoalgesia. One proposed mechanism for this is altered baroreceptor sensitivity. In healthy volunteers, stimulating the carotid baroreceptors causes reduced sensitivity to acute pain; however, this effect may be confounded by a rise in blood pressure due to baroreflex stimulation. The present study tests whether baroreceptor unloading contributes to the physiological mechanism of blood pressure-related hypoalgesia. METHODS: In the present study, pain perception to thermal stimulation of the forearm was studied in 20 healthy volunteers during baroreceptor unloading by lower body negative pressure (LBNP) at -5 and -20 mmHg. Blood pressure and heart rate were measured continuously throughout. To address issues relating to stimulation order, the sequence of LBNP stimulation was counterbalanced across participants. RESULTS: Increased heart rate was observed at a LBNP of -20 mmHg, but not -5 mmHg, but neither stimulus had an effect on blood pressure. There was no change in warm or cold sensory detection thresholds, heat or cold pain thresholds nor perceived pain from a 30s long thermal heat stimulus during LBNP. CONCLUSION: Therefore, baroreceptor unloading with maintained systemic blood pressure did not alter pain perception. The current study does not support the hypothesis that an altered baroreflex may underlie the physiological mechanism of blood pressure-related hypoalgesia. SIGNIFICANCE: This work provides evidence that, when measured in normotensive healthy young adults, the baroreflex response to simulated hypovolaemia did not lead to reduced pain sensitivity (known as blood pressure hypoalgesia).

A second-order and slice-specific linear shimming technique to improve spinal cord fMRI.

PURPOSE: To develop a second-order and slice-specific linear shimming technique and investigate its efficiency in the mitigation of signal loss and distortions, and the increase of temporal signal-to-noise ratio (tSNR) within the spinal cord during functional Magnetic Resonance Imaging (fMRI) of the human cervical spinal cord. METHODS: All scans were performed on a General Electric Discovery MR750 3 T scanner, using a head, neck and spine coil and a neurovascular array. To improve B0 homogeneity, a field map was acquired, and second-order shims (SOS) were optimized over manually defined regions of interest (ROIs). Signal loss from dephasing by susceptibility-induced gradients was reduced by optimizing slice-specific x-, y- and z-shims to maximize signal within the spinal cord. Spectral-spatial excitation pulses were used in both the slice-specific linear shimming calibration scan and fMRI acquisitions. The shimming technique's efficiency was initially tested on eight healthy volunteers by comparing tSNR between images acquired with the manufacturer's standard linear shimming and with our SOS and xyz-shimming technique. Subsequently, using an increased spatial resolution as needed for fMRI of the spinal cord, tSNR measurements were performed on resting-state fMRI images from 14 healthy participants. RESULTS: Spinal fMRI images acquired with only the standard linear shimming suffered from severe signal loss below the C5 vertebral level. The developed shimming technique compensated for this loss especially at levels C6 and C7, while tSNR was significantly higher at all vertebral levels with SOS and xyz-shimming than without it. CONCLUSION: A comprehensive shimming approach which includes the use of spectral-spatial excitation pulses along with both second-order and slice-specific linear shim optimization reduces regional signal loss and increases tSNR along the c-spine (C3-C7), improving the ability to record functional signals from the human spinal cord.

Task-related BOLD responses and resting-state functional connectivity during physiological clamping of end-tidal CO(2).

Carbon dioxide (CO(2)), a potent vasodilator, is known to have a significant impact on the blood-oxygen level dependent (BOLD) signal. With the growing interest in studying synchronized BOLD fluctuations during the resting state, the extent to which the apparent synchrony is due to variations in the end-tidal pressure of CO(2) (PETCO(2)) is an important consideration. CO(2)-related fluctuations in BOLD signal may also represent a potential confound when studying task-related responses, especially if breathing depth and rate are affected by the task. While previous studies of the above issues have explored retrospective correction of BOLD fluctuations related to arterial PCO(2), here we demonstrate an alternative approach based on physiological clamping of the arterial CO(2) level to a near-constant value. We present data comparing resting-state functional connectivity within the default-mode-network (DMN), as well as task-related BOLD responses, acquired in two conditions in each subject: 1) while subject's PETCO(2) was allowed to vary spontaneously; and 2) while controlling subject's PETCO(2) within a narrow range. Strong task-related responses and areas of maximal signal correlation in the DMN were not significantly altered by suppressing fluctuations in PETCO(2). Controlling PETCO(2) did, however, improve the performance of retrospective physiological noise correction techniques, allowing detection of additional regions of task-related response and resting-state connectivity in highly vascularized regions such as occipital cortex. While these results serve to further rule out systemic physiological fluctuations as a significant source of apparent resting-state network connectivity, they also demonstrate that fluctuations in arterial CO(2) are one of the factors limiting sensitivity in task-based and resting-state fMRI, particularly in regions of high vascular density. This must be considered when comparing subject groups who might exhibit differences in respiratory physiology or breathing patterns.

BOLD signal responses to controlled hypercapnia in human spinal cord.

Functional MRI of the spinal cord is challenging due to the small cross section of the cord and high level of physiological noise. Though blood oxygenation level-dependent (BOLD) contrast has been used to study specific responses of the spinal cord to various stimuli, it has not been demonstrated using a controlled stimulus. In this paper, we use hypercapnic manipulation to study the sensitivity and specificity of functional MRI in the human cervical spinal cord. Simultaneous MR imaging in the brain and spinal cord was performed for direct comparison with the brain, in which responses to hypercapnia have been more extensively characterized. Original contributions include: (i) prospectively controlled hypercapnic changes in end-tidal PCO(2), (ii) simultaneous recording of BOLD responses in the brain and spinal cord, and (iii) generation of statistical maps of BOLD responses throughout the brain and spinal cord, taking into account physiological noise sources. Results showed significant responses in all subjects both in the brain and the spinal cord. In anatomically-defined regions of interest, mean percent changes were 0.6% in the spinal cord and 1% in the brain. Analysis of residual variance demonstrated significantly larger contribution of physiological noise in the spinal cord (P<0.005). To obtain more reliable results from fMRI in the spinal cord, it will be necessary to improve sensitivity through the use of highly parallelized coil arrays and better modeling of physiological noise. Finely, we believe that the use of controlled global stimuli, such as hypercapnia, will help assess the effectiveness of new acquisition techniques.

Simultaneous recording of laser-evoked brain potentials and continuous, high-field functional magnetic resonance imaging in humans.

Simultaneous recording of event-related electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) responses has the potential to provide information on how the human brain reacts to an external stimulus with unique spatial and temporal resolution. However, in most studies combining the two techniques, the acquisition of functional MR images has been interleaved with the recording of evoked potentials. In this study we investigated the feasibility of recording pain-related evoked potentials during continuous and simultaneous collection of blood oxygen level-dependent (BOLD) functional MR images at 3 T. Brain potentials were elicited by selective stimulation of cutaneous Adelta and C nociceptors using brief radiant laser pulses (laser-evoked potentials, LEPs). MR-induced artifacts on EEG data were removed using a novel algorithm. Latencies, amplitudes, and scalp distribution of LEPs recorded during fMRI were not significantly different from those recorded in a control session outside of the MR scanner using the same equipment and experimental design. Stability tests confirmed that MR-image quality was not impaired by the evoked potential recording, beyond signal loss related to magnetic susceptibility differences local to the electrodes. fMRI results were consistent with our previous studies of brain activity in response to nociceptive stimulation. These results demonstrate the feasibility of recording reliable pain-related LEPs and fMRI responses simultaneously. Because LEPs collected during fMRI and those collected in a control session show remarkable similarity, for many experimental designs the integration of LEP and fMRI data collected in separate, single-modality acquisitions may be appropriate. Truly simultaneous recording of LEPs and fMRI is still desirable in specific experimental conditions, such as single-trial, learning, and pharmacological studies.

Somatotopic organisation of the human insula to painful heat studied with high resolution functional imaging.

Pain perception is a multidimensional phenomenon, derived from sensory, affective, cognitive-evaluative and homeostatic information. Neuroimaging studies of pain perception have investigated the role of primary somatosensory cortex (SI); however, they have typically failed to demonstrate the expected somatotopy. An alternative network for the sensory component of pain has been proposed, involving a temperature and pain-specific nucleus of the thalamus (VMpo) and its projections to dorsal posterior insula (dpIns). According to this hypothesis, projections to the insula should be arranged somatotopically. In order to test for the presence of somatotopy in the operculo-insular brain region, we delivered moderately painful thermal stimuli to the right face, hand and foot in 14 healthy subjects and recorded brain responses using high resolution functional magnetic resonance imaging at 3 T. For each subject, the thermode temperature was adjusted to produce pain ratings of 5 to 6 out of 10, which corresponded to average temperatures for the face, hand and foot of 49.6, 48.5 and 48.5 degrees C, respectively. Examination of mixed effects group activation maps suggested a pain-related somatotopy in the contralateral posterior insula and putamen. Construction of frequency maps revealed that face activation within the posterior insula was anterior to both hand and foot, whilst foot activation was located medially in the circular sulcus. Single subject analysis demonstrated that only coordinates for dpIns activation were significantly dependent on stimulus location (Hotelling's Trace, P = 0.012). Coordinates for face (paired t test, P = 0.004) and hand (P < 0.001) activity were more lateral than those for foot, whilst face activation was anterior to the foot (P = 0.037). Based on single subject analyses, the average standard space (MNI) coordinates for face, hand and foot activity were (-40,-16,11), (-40,-19,14) and (-35,-21,11) respectively.

A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging.

Animal studies have established a role for the brainstem reticular formation, in particular the rostral ventromedial medulla (RVM), in the development and maintenance of central sensitisation and its clinical manifestation, secondary hyperalgesia. Similar evidence in humans is lacking, as neuroimaging studies have mainly focused on cortical changes. To fully characterise the supraspinal contributions to central sensitisation in humans, we used whole-brain functional magnetic resonance imaging at 3T, to record brain responses to punctate mechanical stimulation in an area of secondary hyperalgesia. We used the heat/capsaicin sensitisation model to induce secondary hyperalgesia on the right lower leg in 12 healthy volunteers. A paired t-test was used to compare activation maps obtained during punctate stimulation of the secondary hyperalgesia area and those recorded during control punctate stimulation (same body site, untreated skin, separate session). The following areas showed significantly increased activation (Z>2.3, corrected P<0.01) during hyperalgesia: contralateral brainstem, cerebellum, bilateral thalamus, contralateral primary and secondary somatosensory cortices, bilateral posterior insula, anterior and posterior cingulate cortices, right middle frontal gyrus and right parietal association cortex. Brainstem activation was localised to two distinct areas of the midbrain reticular formation, in regions consistent with the location of nucleus cuneiformis (NCF) and rostral superior colliculi/periaqueductal gray (SC/PAG). The PAG and the NCF are the major sources of input to the RVM, and therefore in an ideal position to modulate its output. These results suggest that structures in the mesencephalic reticular formation, possibly the NCF and PAG, are involved in central sensitisation in humans.