Brain Imaging of Pain

The brain is the principal processor of internal and external sensory experiences including pain. Pain is a multidimensional experience influenced by complex interactions among multiple processes including nociception (the afferent neural activity transmitting sensory information about noxious stimuli), cognitive appraisals (expectation, attention), and emotional aspects (affect)

Investigation of the neural correlates of ongoing pain states using quantitative perfusion arterial spin labelling

At present, there are few clinically effective pain therapies available to treat chronic pain. One reason is due to a lack of understanding about how pain emerges in the brain. Excitingly, an emerging body of work suggests that the perfusion imaging technique, arterial spin labelling (ASL), is particularly well-suited to investigate this issue. The primary aim of this thesis is to develop and optimise a quantitative perfusion imaging approach to investigate the neural correlates of both experimental and pathological tonic pain. In Chapter 2, we explore different methods of inducing ongoing pain in healthy subjects. Results from this study show that mechanically induced pain is well suited for use in ASL FMRI experiments. In Chapter 3, we compare currently available ASL FMRI approaches for investigating tonic states, using a range of sensory paradigms. Results from these experiments support the use of an optimised version of Continuous ASL (CASL) FMRI to obtain whole-brain perfusion. Additionally, we discuss our decision to proceed with the newly acquired pseudo-continuous ASL (pCASL); a novel ASL technique that benefits from maximal signal-to-noise (SNR) across a whole-brain volume. In Chapter 4 we implement the pCASL FMRI approach to image the neural correlates of ongoing experimental pain. Results from the investigation of parametrically modulated ongoing mechanical pain show robust pain-related activation of key pain related regions that are monotonically active with an increase in stimulus intensity. Additionally, data from this experiment shows the presence of complex perfusion dynamics relative to pain worthy of further study. In Chapter 5, we optimised the pCASL sequence to obtain absolute perfusion changes across the whole-brain volume, using multi-inversion times, so that we could investigate the perfusion dynamics observed in Chapter 4. Results show that absolute perfusion changes during tonic pain are considerably less than for regions recruited during a non- pain task. Additionally, dynamic perfusion changes show complex stimulus responses across all active regions regardless of stimulus type. We conclude that while the technique is well suited to quantify absolute perfusion, the mechanisms underlying the dynamic changes in CBF (neuronal signal, neurovascular coupling) need further study. Finally, in Chapter 6, we implement the absolute perfusion approach developed in Chaper 5 to interrogate the neural correlates of the genetic pain disease, Erythromelalgia, and pleasurable relief. The results of this study show pain-related activation (and relief-induced reduction) of key pain-related regions. We conclude from these results that the ASL technique developed over the course of this thesis can be used to study a range of pain pathologies.Taken together, the results of this thesis document the development of a powerful perfusion imaging technique capable of quantifying absolute perfusion changes across a whole-brain volume. The data presented here from investigations of both experimental and pathological pain states supports the use of this technique in future tonic pain studies, as well as other neuroscience applications. We are confident that implementation of this imaging approach will provide integral insight into the mechanisms of ongoing pain states; and further the development of novel efficacious pain treatment options.</p

Imaging clinically relevant pain states using arterial spin labeling

Arterial Spin Labeling (ASL) is a perfusion-based functional magnetic resonance imaging technique that uses water in arterial blood as a freely diffusible tracer to measure regional cerebral blood flow (rCBF) noninvasively. To date its application to the study of pain has been relatively limited. Yet, ASL possesses key features that make it uniquely positioned to study pain in certain paradigms. For instance, ASL is sensitive to very slowly fluctuating brain signals (in the order of minutes or longer). This characteristic makes ASL particularly suitable to the evaluation of brain mechanisms of tonic experimental, post-surgical and ongoing/or continuously varying pain in chronic or acute pain conditions (whereas BOLD fMRI is better suited to detect brain responses to short-lasting or phasic/evoked pain). Unlike positron emission tomography or other perfusion techniques, ASL allows the estimation of rCBF without requiring the administration of radioligands or contrast agents. Thus, ASL is well suited for within-subject longitudinal designs (e.g., to study evolution of pain states over time, or of treatment effects in clinical trials). ASL is also highly versatile, allowing for novel paradigms exploring a flexible array of pain states, plus it can be used to simultaneously estimate not only pain-related alterations in perfusion but also functional connectivity. In conclusion, ASL can be successfully applied in pain paradigms that would be either challenging or impossible to implement using other techniques. Particularly when used in concert with other neuroimaging techniques, ASL can be a powerful tool in the pain imager's toolbox

The dorsal posterior insula subserves a fundamental role in human pain

Several brain regions have been implicated in human painful experiences, but none have been proven to be specific to pain. We exploited arterial spin-labeling quantitative perfusion imaging and a newly developed procedure to identify a specific role for the dorsal posterior insula (dpIns) in pain. Tract tracing studies in animals identify a similar region as fundamental to nociception, which suggests the dpIns is its human homolog and, as such, a potential therapeutic target

Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling.

We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Na(v)1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject

Optimization and reliability of multiple postlabeling delay pseudo-continuous arterial spin labeling during rest and stimulus-induced functional task activation

Arterial spin labeling (ASL) sequences that incorporate multiple postlabeling delay (PLD) times allow estimation of when arterial blood signal arrives within a region of interest. Sequences that account for such variability may improve the reliability of ASL and therefore make the technique well suited for future clinical and experimental investigations of cerebral perfusion. This study assessed the within- and between-session reproducibility of an optimized pseudo-continuous ASL (pCASL) functional magnetic resonance imaging (FMRI) sequence that incorporates multiple postlabeling delays (multi-PLD pCASL). Healthy subjects underwent four identical scans separated by 30 minutes, 1 week, and 1 month using multi-PLD pCASL to image absolute perfusion (cerebral blood flow (CBF) and arterial arrival time (AAT)) during both rest and a visual-cued motor task. We show good test-retest reliability, with strong consistency across subjects and sessions during rest (inter-session within-subject coefficient of variation: gray matter (GM) CBF = 6.44%; GM AAT = 2.20%). We also report high sensitivity and reproducibility during the functional task, where we show robust task-related decreases in AAT corresponding with regions of increased CBF. Importantly, these results give insight into optimal PLD selection for future investigations using single-PLD ASL to image different brain regions, and highlight the necessity of multi-PLD ASL when imaging perfusion in the whole brain

A systematic study of the sensitivity of partial volume correction methods for the quantification of perfusion from pseudo-continuous arterial spin labeling MRI

Arterial spin labeling (ASL) MRI is a non-invasive technique for the quantification of cerebral perfusion, and pseudo-continuous arterial spin labeling (PCASL) has been recommended as the standard implementation by a recent consensus of the community. Due to the low spatial resolution of ASL images, perfusion quantification is biased by partial volume effects. Consequently, several partial volume correction (PVEc) methods have been developed to reduce the bias in gray matter (GM) perfusion quantification. The efficacy of these methods relies on both the quality of the ASL data and the accuracy of partial volume estimates. Here we systematically investigate the sensitivity of different PVEc methods to variability in both the ASL data and partial volume estimates using simulated PCASL data and in vivo PCASL data from a reproducibility study. We examined the PVEc methods in two ways: the ability to preserve spatial details and the accuracy of GM perfusion estimation. Judging by the root-mean-square error (RMSE) between simulated and estimated GM CBF, the spatially regularized method was superior in preserving spatial details compared to the linear regression method (RMSE of 1.2 vs 5.1 in simulation of GM CBF with short scale spatial variations). The linear regression method was generally less sensitive than the spatially regularized method to noise in data and errors in the partial volume estimates (RMSE 6.3 vs 23.4 for SNR=5 simulated data), but this could be attributed to the greater smoothing introduced by the method. Analysis of a healthy cohort dataset indicates that PVEc, using either method, improves the repeatability of perfusion quantification (within-subject coefficient of variation reduced by 5% after PVEc)

Calibration of arterial spin labeling data — potential pitfalls in post‐processing

Purpose: To assess the impact of the different post‐processing options in the calibration of arterial spin labeling (ASL) data on perfusion quantification and its reproducibility.Theory and Methods: Absolute quantification of perfusion measurements is one of the promises of ASL techniques. However, it is highly dependent on a calibration procedure that involves a complex processing pipeline for which no standardized procedure has been fully established. In this work, we systematically compare the main ASL calibration methods as well as various post‐processing calibration options, using 2 data sets acquired with the most common sequences, pulsed ASL and pseudo‐continuous ASL.Results: Significant and sometimes large discrepancies in ASL perfusion quantification were obtained when using different post‐processing calibration options. Nevertheless, when using a set of theoretically based and carefully chosen options, only small differences were observed for both reference tissue and voxelwise methods. The voxelwise and white matter reference tissue methods were less sensitive to post‐processing options than the cerebrospinal fluid reference tissue method. However, white matter reference tissue calibration also produced poorer reproducibility results. Moreover, it may also not be an appropriate reference in case of white matter pathology.Conclusion: Poor post‐processing calibration options can lead to large errors in perfusion quantification, and a complete description of the calibration procedure should therefore be reported in ASL studies. Overall, our results further support the voxelwise calibration method proposed by the ASL white paper, particularly given the advantage of being relatively simple to implement and intrinsically correcting for the coil sensitivity profile