Quantitative Analysis of Arterial Spin Labeling FMRI Data Using a General Linear Model

Arterial spin labeling techniques can yield quantitative measures of perfusion by fitting a kinetic model to difference images (tagged-control). Because of the noisy nature of the difference images investigators typically average a large number of tagged versus control difference measurements over long periods of time. This averaging requires that the perfusion signal be at a steady state and not at the transitions between active and baseline states in order to quantitatively estimate activation induced perfusion. This can be an impediment for functional magnetic resonance imaging task experiments. In this work, we introduce a general linear model (GLM) that specifies Blood Oxygenation Level Dependent (BOLD) effects and arterial spin labeling modulation effects and translate them into meaningful, quantitative measures of perfusion by using standard tracer kinetic models. We show that there is a strong association between the perfusion values using our GLM method and the traditional subtraction method, but that our GLM method is more robust to noise

B 0 field inhomogeneity considerations in pseudo‐continuous arterial spin labeling (pCASL): effects on tagging efficiency and correction strategy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89456/1/nbm1675.pd

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

Optimized simultaneous ASL and BOLD functional imaging of the whole brain

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106990/1/jmri24273.pd

A primer on functional magnetic resonance imaging

Abstract In this manuscript, basic principles of functional magnetic resonance imaging (fMRI) are reviewed. In the first section, two intrinsic mechanisms of magnetic resonance image contrast related to the longitudinal and transverse components of relaxing spins and their relaxation rates, T 1 and T 2 , are described. In the second section, the biophysical mechanisms that alter the apparent transverse relaxation time, T * 2 , in blood oxygenation level dependent (BOLD) studies and the creation of BOLD activation maps are discussed. The physiological complexity of the BOLD signal is emphasized. In the third section, arterial spin labeling (ASL) measures of cerebral blood flow are presented. Arterial spin labeling inverts or saturates the magnetization of flowing spins to measure the rate of delivery of blood to capillaries. In the fourth section, calibrated fMRI, which uses BOLD and ASL to infer alterations of oxygen utilization during behavioral activation, is reviewed. The discussion concludes with challenges confronting studies of individual cases. Keywords Functional magnetic resonance imaging . Perfusion magnetic resonance imaging . Regional blood flow . Cerebral oxygen metabolism G. G. Brown ( ) Psychology Service (MC 116B), VA San Diego Healthcare System, 3350 La Jolla Village Drive

Detection power, temporal response, and spatial resolution of IRON fMRI in awake, behaving monkeys at 3 Tesla

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2007."September 2006."Includes bibliographical references.The main goal of this thesis was to systematically characterize the detection sensitivity, temporal response, and spatial resolution of IRON contrast for fMRI within the awake, behaving monkey. Understanding these issues provides insights into the physiology of the functional response to local changes in brain activity, enables researchers to optimize experimental designs, and delineates the advantages and limitations of neuroimaging within this important animal model. The injection of the iron oxide contrast agent (MION) provided a 9-fold increase in efficiency for block designs relatively to BOLD contrast. Because the hemodynamic response function acts as a low-pass filter on neural activation to attenuate the size of differential responses to alternate stimuli, this factor dropped to approximately 2 for rapidly presented stimuli. Detection efficiency for event-related stimulus designs for BOLD and IRON contrasts could be optimized using random or semi-random distributions for interstimulus intervals. Small increases in predictability could be traded for large gains in efficiency, particularly for the IRON method. A general linear model was successfully employed to describe IRON and BOLD impulse response functions. Both responses were accurately described by a bimodal exponential model with similar time constants, a fast (4.5 sec) and a slow (13.5 sec).(cont.) The slow response comprised 80% of IRON signal, and was responsible for the BOLD post-stimulus undershoot. It likely encompasses changes in post-arteriole blood volume. Optimized IRON activation maps do not show activation in draining veins or draining tissue, in contrast with BOLD contrast. To examine what happens at the level of small vessels and capillaries, we used point-image stimuli to measure IRON and BOLD point spread functions (PSF) in V1. We estimated an IRON PSF no larger than approximately 0.4 mm, and a BOLD PSF with twice the size. Severe image distortions arising from monkey's body motion outside of the field of view currently limit the achievable spatial resolution. Preliminary data suggests multi-shot EPI with navigators may be useful in improving image stability at higher resolution for IRON fMRI, which can employ short echo times to minimize phase variations, while achieving maximum efficiency by increasing the MION dose.by Francisca Maria Pais Horta Leite.Ph.D

Multimodal Investigation of Peripheral and Central Nervous System Pain Mechanisms in Burning Mouth Syndrome (BMS) Using Magnetic Resonance Imaging and Psychometry (MRIBMS)

Background The International Classification of Orofacial Pain (ICOP) has defined burning mouth syndrome (BMS-ICOP) as an intraoral burning or dysaesthetic sensation that reoccurs daily for more than two hours per day and more than three months without evidence of causative lesions upon clinical examination and investigation. The burning mouth symptoms can be caused by primary and secondary BMS. Primary BMS is idiopathic BMS or true BMS, while secondary BMS, also known as burning mouth disorder (BMD), is attributed to local factors or systemic conditions. The prevalence of BMS in women was significantly higher than in men and mainly occurred at the post-menopausal age between 50 and 80 years. This intense, continuous, spontaneous pain severely affects the patient’s oral function, health, and psychology, with high reported rates of anxiety and depression. The pathophysiology of primary BMS as defined by ICOP (BMS-ICOP) remains uncertain, and with no standardised treatment protocol, treatment outcomes are further complicated. Over the years, there have been reports of altered cerebral activities in various levels of the neuraxis in patients with BMS-ICOP, which implies that BMS pain has a central nervous system component. AimThis thesis aimed to characterise patients’ cerebral responses associated with chronic trigeminal pain following administration of two topical peripheral-acting analgesics, clonazepam mouthwash (CMW) and dental local anaesthetic (LA), and the difference between treatment responders and non-responders. Attenuating or escalating pain in response to peripheral medications will allow in-depth phenotyping of patients with BMS-ICOP and facilitate tailored medicine. This thesis also studied and described the characteristics of patients with BMS-ICOP and the psychological impact of BMS-ICOP.MethodsThis prospective, open-label study was conducted at King’s College Dental Institute and Clinical Research Facilities, King’s College London. In the first visit, 26 participants diagnosed with BMS-ICOP were clinically screened and psychologically assessed using psychometric questionnaires. Functional magnetic resonance imaging (fMRI) and pulsed-continuous arterial spin labelling (pCASL) imaging techniques were employed to provide quantitative measurements of the resting-state functional connectivity (FC) and regional cerebral blood flow (rCBF), respectively, that related to changes in the brain activity. Participants underwent a series of fMRI and pCASL scans and rated their pain intensity using the numerical rating scale (NRS, 0-10) and visual analogue scale (VAS, 0-100) before and after the administration of CMW and LA. A subgroup of 15 BMS-ICOP patients with burning pain across the tongue was selected from the initial 26 BMS-ICOP patients to receive LA intervention. In addition to it, patients’ grey matter volume (GMV) was quantified using voxel-based morphometry (VBM) analysis. Here, we performed seed-based FC and pCASL analysis of the regions of interest (ROIs), including the left hippocampus, ventromedial prefrontal cortex (vmPFC), left amygdala, thalamus, right anterior insula (RAI), and periaqueductal grey matter (PAG); given reports of perturbed functioning changes in this region in chronic pain. Treatment responders were defined as reporting 50% or greater pain reduction from baseline following analgesic administration. ResultsOverall, the cohort of patients had daily recurring and continuously hot burning pain, with a mean NRS intensity rating of 5.15, progressively worsening during the day.Although experiencing a high pain level, most patients had a low tendency to catastrophise the threat value of pain or pain-related thoughts and did not exhibit depression, anxiety, or somatic symptom disorders. When comparing the pain and control sites, more than 90% of patients showed no chairside qualitative sensory deficit to touch and two-point discrimination. Meanwhile, 42% and 20% of patients had pin-prick and thermal sensitivity changes, respectively. This similarity was also reflected in the quantitative mechanical detection threshold assessment, where there were no significant changes between the control and pain sites (p = 0.695, SE =0.06). We also did not observe any statistically significant correlation between behaviour changes and cerebral responses to pain (pre-intervention), such as anxiety (r=0.09, p=0.677, 95% CI= -0.31-0.46) and depression (r= -0.21, 95% CI= -0.55 – 0.2, p=0.314). ClonazepamRinsing with 2mg CMW for 10 minutes significantly reduced pain intensity across the participants. An acute 2mg dose was selected to provide an immediate state of pain relief effect, keeping in mind that the suggested maximum daily prescribed clonazepam dose for pain relief is 4mg/day. Patients experienced a mean pain intensity NRS score reduction of 2.67 (p<0.001), and 15 patients responded to treatment. The study found a correlation between patients’ brain GMV and resting-state FC and pain intensity before and after rinsing with CMW. These changes were seen in the brain regions responsible for pain-related cognitive and affective processing and descending pain modulation. We also demonstrated the effect of CMW, which caused a decrease in the FC in the L hippocampus and RAI ROIs. There were alterations in the FC (∆FC) following treatment that were associated with changes in pain levels, as seen in the L hippocampus and vmPFC ROIs. In attempting to predict treatment response towards clonazepam, we tested the baseline FC with changes in pain ratings, and we did not observe any significant correlation. In addition, patients with a minimum of 50% pain reduction following CMW had a lower baseline FC than non-responders in all six ROIs. Conversely, an increased FC was noted in responders between L hippocampus-brainstem/ cerebellum and vmPFC-primary motor/somatosensory cortices. Similarly, there was a reduction in post-mouthwash rCBF compared to pre-mouthwash rCBF. No significant changes were reported upon analysis of the baseline rCBF and changes in the rCBF (∆rCBF) along with pain intensity.Dental local anaesthesiaFollowing bilateral inferior alveolar nerve block, patients achieved greater pain intensity relief than CMW with a reduction of 3.73 NRS units (p<0.001, SD=1.91), with 13 patients responding to it, but two patients did not. At baseline, we also observed the FC presence between brain regions involved in cognitive and affective (emotion) pain processing and modulation, and these connectivities were associated with pain ratings and area size. Participants with a greater reduction in their pain intensity NRS (∆NRS) and VAS (∆VAS) scores after LA had weak baseline FC strength between L hippocampus-temporal lobe (p=0.024) and PAG–L amygdala (p=0.032), respectively. However, no significant association was found between the ∆FC with pain ratings and pain area size. Contrary to CMW’s pCASL analysis, no correlation was observed between LA group patients’ baseline rCBF and pain ratings and area size. However, further exploratory pCASL analysis (uncorrected initial threshold of p=0.005) showed a reduction in rCBF after LA administration in the cognitive (dorsolateral prefrontal cortex), primary motor cortex, and primary somatosensory cortex brain regions. When comparing the studies, differences in cerebral responses to pain are likely related to the context of expectancy effect and the differential in afferent nociceptive ascending trigeminothalamic inputs to the brain and descending pain inhibition modulation system.ConclusionOur cohort of patients with BMS-ICOP had a remarkable ability to engage in valued daily activities by having high pain acceptance behaviour and a low tendency to magnify the value of pain. Administration of topical peripheral analgesics during the ongoing experience of chronic pain modulated the brain’s resting state activities, such as FC and rCBF. Alterations in FC and rCBF between brain regions involved in chronic pain modulation may reflect ongoing BMS-ICOP pain symptomatology, possibly due to impaired central and/or peripheral nervous system function. Understanding the peripheral and central processes involved in BMS-ICOP pain and how analgesics alter them may provide preliminary insights into the mechanism of action of potential topical analgesics, which may be a valuable parameter in predicting treatment response and is fundamental to advancing pain medicine