Brain-based measures of nociception during general anesthesia with remifentanil: A randomized controlled trial.

BACKGROUND: Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation. METHODS AND FINDINGS: We investigated the effects of continuous remifentanil on cortical hemodynamics during cardiac ablation under anesthesia. In a randomized, double-blinded, placebo (PL)-controlled trial, we examined 32 pediatric patients (mean age of 15.8 years,16 females) undergoing catheter ablation for cardiac arrhythmias at the Cardiology Department of Boston Children's Hospital from October 2016 to March 2020; 9 received 0.9% NaCl, 12 received low-dose (LD) remifentanil (0.25 mcg/kg/min), and 11 received high-dose (HD) remifentanil (0.5 mcg/kg/min). The hemodynamic changes of primary somatosensory and prefrontal cortices were recorded during surgery using a continuous wave fNIRS system. The primary outcome measures were the changes in oxyhemoglobin concentration (NadirHbO, i.e., lowest oxyhemoglobin concentration and PeakHbO, i.e., peak change and area under the curve) of medial frontopolar cortex (mFPC), lateral prefrontal cortex (lPFC) and primary somatosensory cortex (S1) to ablation in PL versus remifentanil groups. Secondary measures included the fNIRS response to an auditory control condition. The data analysis was performed on an intention-to-treat (ITT) basis. Remifentanil group (dosage subgroups combined) was compared with PL, and a post hoc analysis was performed to identify dose effects. There were no adverse events. The groups were comparable in age, sex, and number of ablations. Results comparing remifentanil versus PL show that PL group exhibit greater NadirHbO in inferior mFPC (mean difference (MD) = 1.229, 95% confidence interval [CI] = 0.334, 2.124, p < 0.001) and superior mFPC (MD = 1.206, 95% CI = 0.303, 2.109, p = 0.001) and greater PeakHbO in inferior mFPC (MD = -1.138, 95% CI = -2.062, -0.214, p = 0.002) and superior mFPC (MD = -0.999, 95% CI = -1.961, -0.036, p = 0.008) in response to ablation. S1 activation from ablation was greatest in PL, then LD, and HD groups, but failed to reach significance, whereas lPFC activation to ablation was similar in all groups. Ablation versus auditory stimuli resulted in higher PeakHbO in inferior mFPC (MD = 0.053, 95% CI = 0.004, 0.101, p = 0.004) and superior mFPC (MD = 0.052, 95% CI = 0.013, 0.091, p < 0.001) and higher NadirHbO in posterior superior S1 (Pos. SS1; MD = -0.342, 95% CI = -0.680, -0.004, p = 0.007) during ablation of all patients. Remifentanil group had smaller NadirHbO in inferior mFPC (MD = 0.098, 95% CI = 0.009, 0.130, p = 0.003) and superior mFPC (MD = 0.096, 95% CI = 0.008, 0.116, p = 0.003) and smaller PeakHbO in superior mFPC (MD = -0.092, 95% CI = -0.680, -0.004, p = 0.007) during both the stimuli. Study limitations were small sample size, motion from surgery, indirect measure of nociception, and shallow penetration depth of fNIRS only allowing access to superficial cortical layers. CONCLUSIONS: We observed cortical activity related to nociception during cardiac ablation under general anesthesia with remifentanil. It highlights the potential of fNIRS to provide an objective pain measure in unconscious patients, where cortical-based measures may be more accurate than current evaluation methods. Future research may expand on this application to produce a real-time indication of pain that will aid clinicians in providing immediate and adequate pain treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02703090.

Rhythmic Change of Cortical Hemodynamic Signals Associated with Ongoing Nociception in Awake and Anesthetized Individuals: An Exploratory Functional Near Infrared Spectroscopy Study.

BACKGROUND: Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain. METHODS: Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block. RESULTS: A reduction of the total fractional power in both groups-specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex-was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34). CONCLUSIONS: These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia.

Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

Focused ultrasound induced opening of the blood-brain barrier disrupts inter-hemispheric resting state functional connectivity in the rat brain.

Focused ultrasound (FUS) is a technology capable of delivering therapeutic levels of energy through the intact skull to a tightly localized brain region. Combining the FUS pressure wave with intravenously injected microbubbles creates forces on blood vessel walls that open the blood-brain barrier (BBB). This noninvasive and localized opening of the BBB allows for targeted delivery of pharmacological agents into the brain for use in therapeutic development. It is possible to use FUS power levels such that the BBB is opened without damaging local tissues. However, open questions remain related to the effects that FUS-induced BBB opening has on brain function including local physiology and vascular hemodynamics. We evaluated the effects that FUS-induced BBB opening has on resting state functional magnetic resonance imaging (rs-fMRI) metrics. Data from rs-fMRI was acquired in rats that underwent sham FUS BBB vs. FUS BBB opening targeted to the right primary somatosensory cortex hindlimb region (S1HL). FUS BBB opening reduced the functional connectivity between the right S1HL and other sensorimotor regions, including statistically significant reduction of connectivity to the homologous region in the left hemisphere (left S1HL). The effect was observed in all three metrics analyzed: functional connectivity between anatomically defined regions, whole brain voxel-wise correlation maps based on anatomical seeds, and spatial patterns from independent component analysis. Connectivity metrics for other regions where the BBB was not perturbed were not affected. While it is not clear whether the effect is vascular or neuronal in origin, these results suggest that even safe levels of FUS BBB opening have an effect on the physiological processes that drive the signals measured by BOLD fMRI. As such these effects must be accounted for when carrying out studies using fMRI to evaluate the effects of pharmacological agents delivered via FUS-induced BBB opening.

Increased Amplitude of Thalamocortical Low-Frequency Oscillations in Patients with Migraine.

UNLABELLED: For many years, neurobiological theories have emphasized the importance of neuronal oscillations in the emergence of brain function. At the same time, clinical studies have shown that disturbances or irregularities in brain rhythms may relate to various common neurological conditions, including migraine. Increasing evidence suggests that the CNS plays a fundamental role in the predisposition to develop different forms of headache. Here, we present human imaging data that strongly support the presence of abnormal low-frequency oscillations (LFOs) in thalamocortical networks of patients in the interictal phase of migraine. Our results show that the main source of arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus. In addition, spontaneous LFOs in the thalamus were selectively associated with the headache attack frequency, meaning that the varying amplitude of dysrhythmia could predispose patients to recurrent attacks. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability. We further speculate that the intrinsic dynamics of thalamocortical network oscillations are crucial for early sensory processing and therefore could underlie important pathophysiological processes involved in multisensory integration. SIGNIFICANCE STATEMENT: In many cases, migraine attacks are thought to begin centrally. A major obstacle to studying intrinsic brain activity has been the identification of the precise anatomical structures and functional networks that are involved in migraine. Here, we present imaging data that strongly support the presence of abnormal low-frequency oscillations in thalamocortical networks of patients in the interictal phase of migraine. This arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus and was selectively associated with headache attack frequency. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability and higher-level processes involved in multisensory integration.

In child and adult migraineurs the somatosensory cortex stands out again: An arterial spin labeling investigation.

Over the past decade, human brain imaging investigations have reported altered regional cerebral blood flow (rCBF) in the interictal phase of migraine. However, there have been conflicting findings across different investigations, making the use of perfusion imaging in migraine pathophysiology more difficult to define. These inconsistencies may reflect technical constraints with traditional perfusion imaging methods such as single-photon emission computed tomography and positron emission tomography. Comparatively, pseudocontinuous arterial spin labeling (pCASL) is a recently developed magnetic resonance imaging technique that is noninvasive and offers superior spatial resolution and increased sensitivity. Using pCASL, we have previously shown increased rCBF within the primary somatosensory cortex (S1) in adult migraineurs, where blood flow was positively associated with migraine frequency. Whether these observations are present in pediatric and young adult populations remains unknown. This is an important question given the age-related variants of migraine prevalence, symptomology, and treatments. In this investigation, we used pCASL to quantitatively compare and contrast blood flow within S1 in pediatric and young adult migraineurs as compared with healthy controls. In migraine patients, we found significant resting rCBF increases within bilateral S1 as compared with healthy controls. Furthermore, within the right S1, we report a positive correlation between blood flow value with migraine attack frequency and cutaneous allodynia symptom profile. Our results reveal that pediatric and young adult migraineurs exhibit analogous rCBF changes with adult migraineurs, further supporting the possibility that these alterations within S1 are a consequence of repeated migraine attacks. Hum Brain Mapp 38:4078-4087, 2017. © 2017 Wiley Periodicals, Inc.

Biomarkers, designs, and interpretations of resting-state fMRI in translational pharmacological research: A review of state-of-the-Art, challenges, and opportunities for studying brain chemistry.

A decade of research and development in resting-state functional MRI (RSfMRI) has opened new translational and clinical research frontiers. This review aims to bridge between technical and clinical researchers who seek reliable neuroimaging biomarkers for studying drug interactions with the brain. About 85 pharma-RSfMRI studies using BOLD signal (75% of all) or arterial spin labeling (ASL) were surveyed to investigate the acute effects of psychoactive drugs. Experimental designs and objectives include drug fingerprinting dose-response evaluation, biomarker validation and calibration, and translational studies. Common biomarkers in these studies include functional connectivity, graph metrics, cerebral blood flow and the amplitude and spectrum of BOLD fluctuations. Overall, RSfMRI-derived biomarkers seem to be sensitive to spatiotemporal dynamics of drug interactions with the brain. However, drugs cause both central and peripheral effects, thus exacerbate difficulties related to biological confounds, structured noise from motion and physiological confounds, as well as modeling and inference testing. Currently, these issues are not well explored, and heterogeneities in experimental design, data acquisition and preprocessing make comparative or meta-analysis of existing reports impossible. A unifying collaborative framework for data-sharing and data-mining is thus necessary for investigating the commonalities and differences in biomarker sensitivity and specificity, and establishing guidelines. Multimodal datasets including sham-placebo or active control sessions and repeated measurements of various psychometric, physiological, metabolic and neuroimaging phenotypes are essential for pharmacokinetic/pharmacodynamic modeling and interpretation of the findings. We provide a list of basic minimum and advanced options that can be considered in design and analyses of future pharma-RSfMRI studies. Hum Brain Mapp 38:2276-2325, 2017. © 2017 Wiley Periodicals, Inc.

A new electronic diary tool for mapping and tracking spatial and temporal head pain patterns in migraine.

AIM: We present an electronic tool for collecting data on the patterns of migraine headache onset and progression. METHODS: A digitized map consisting of 44 color-coded segments was defined based on previous reports of migraine pain and the distribution of nerves in the face, head and neck. The map was overlaid on a schematic map of the face, head and neck nerves. Thirty-six patients (N = 36, 28 female/eight male), who met ICDH-II criteria for episodic migraine and had headaches for at least three years, identified all regions where pain typically started and how pain spread and subsequently progressed. RESULTS: Consistent with previous findings, throbbing was the most prevalent quality of migraine pain, always present in 70% of patients surveyed. For the 70% of the patients with throbbing pain, the temple was the onset site of throbbing pain, with no significant difference in the laterality of onset site (58.3% on the right vs. 55.6% on the left hemisphere). The tool was able to capture patterns of pain distribution for throbbing and pressure headache pain and also may be used to assess the change in the pattern of the pain distribution as the disease progresses. DISCUSSION: The pain map survey may be a useful tool for recording and tracking the temporal pattern of migraine onset both for clinical and research purposes. The tool could be used to create maps of pain locations on a large population scale and thus will be a very useful tool in correlating the temporal nature of headache symptoms with potential mechanisms of disease evolution.

Migraine Mistakes: Error Awareness.

Error awareness or detection is the conscious and subconscious processing to evaluate physiological signals that are different from a baseline or homeostatic level. Migraine is a unique neurological disorder in which there are repeated attacks interspersed by attack-free periods. These attacks are dynamic and multidimensional in the sense that sensory, affective, autonomic, and cognitive functions are altered and these changes evolve differently before (pre-ictal), during (ictal), and immediately after (post-ictal) an attack. Thus migraine serves as a model disease to understand how the brain monitors and react to the presence of errors.

Habenula functional resting-state connectivity in pediatric CRPS.

The habenula (Hb) is a small brain structure located in the posterior end of the medial dorsal thalamus and through medial (MHb) and lateral (LHb) Hb connections, it acts as a conduit of information between forebrain and brainstem structures. The role of the Hb in pain processing is well documented in animals and recently also in acute experimental pain in humans. However, its function remains unknown in chronic pain disorders. Here, we investigated Hb resting-state functional connectivity (rsFC) in patients with complex regional pain syndrome (CRPS) compared with healthy controls. Twelve pediatric patients with unilateral lower-extremity CRPS (9 females; 10-17 yr) and 12 age- and sex-matched healthy controls provided informed consent to participate in the study. In healthy controls, Hb functional connections largely overlapped with previously described anatomical connections in cortical, subcortical, and brainstem structures. Compared with controls, patients exhibited an overall Hb rsFC reduction with the rest of the brain and, specifically, with the anterior midcingulate cortex, dorsolateral prefrontal cortex, supplementary motor cortex, primary motor cortex, and premotor cortex. Our results suggest that Hb rsFC parallels anatomical Hb connections in the healthy state and that overall Hb rsFC is reduced in patients, particularly connections with forebrain areas. Patients' decreased Hb rsFC to brain regions implicated in motor, affective, cognitive, and pain inhibitory/modulatory processes may contribute to their symptomatology.

The human amygdala and pain: evidence from neuroimaging.

The amygdala, a small deep brain structure involved in behavioral processing through interactions with other brain regions, has garnered increased attention in recent years in relation to pain processing. As pain is a multidimensional experience that encompasses physical sensation, affect, and cognition, the amygdala is well suited to play a part in this process. Multiple neuroimaging studies of pain in humans have reported activation in the amygdala. Here, we summarize these studies by performing a coordinate-based meta-analysis within experimentally induced and clinical pain studies using an activation likelihood estimate analysis. The results are presented in relation to locations of peak activation within and outside of amygdala subregions. The majority of studies identified coordinates consistent with human amygdala cytoarchitecture indicating reproducibility in neuroanatomical labeling across labs, analysis methods, and imaging modalities. Differences were noted between healthy and clinical pain studies: in clinical pain studies, peak activation was located in the laterobasal region, suggestive of the cognitive-affective overlay present among individuals suffering from chronic pain; while the less understood superficial region of the amygdala was prominent among experimental pain studies. Taken together, these findings suggest several important directions for further research exploring the amygdala's role in pain processing.

Brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is a painful condition with approximately 50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures, and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety, and depression. The supraspinal mechanisms linked to these CRPS-related comorbidities remain poorly understood. METHODS: The authors used a previously characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n = 8 to 20 per group) observed in humans. The central hypothesis was that fracture/cast mice manifest changes in measures of thigmotaxis (indicative of anxiety) and working memory reflected in neuroplastic changes in amygdala, perirhinal cortex, and hippocampus. RESULTS: The authors demonstrate that nociceptive sensitization in these mice is accompanied by altered thigmotactic behaviors in the zero maze but not open field assay, and working memory dysfunction in novel object recognition and social memory but not in novel location recognition. Furthermore, the authors found evidence of structural changes and synaptic plasticity including changes in dendritic architecture and decreased levels of synaptophysin and brain-derived neurotrophic factor in specific brain regions. CONCLUSIONS: The study findings provide novel observations regarding behavioral changes and brain plasticity in a mouse model of CRPS. In addition to elucidating some of the supraspinal correlates of the syndrome, this work supports the potential use of therapeutic interventions that not only directly target sensory input and other peripheral mechanisms, but also attempt to ameliorate the broader pain experience by modifying its associated cognitive and emotional comorbidities.

The cerebellum and addiction: insights gained from neuroimaging research.

Although cerebellar alterations have been consistently noted in the addiction literature, the pathophysiology of this link remains unclear. The cerebellum is commonly classified as a motor structure, but human functional neuroimaging along with clinical observations in cerebellar stroke patients and anatomical tract tracing in non-human primates suggests its involvement in cognitive and affective processing. A comprehensive literature search on the role of the cerebellum in addiction was performed. This review article (1) considers the potential role of the cerebellum in addiction; (2) summarizes the cerebellar structural alterations linked to addiction; (3) presents the functional neuroimaging evidence linking the cerebellum with addiction; and (4) proposes a model for addiction that underscores the role of the cerebellum. The data implicate the cerebellum as an intermediary between motor and reward, motivation and cognitive control systems, as all are relevant etiologic factors in addiction. Furthermore, consideration of these findings could contribute to deeper and more sophisticated insights into normal reward and motivational function. The goal of this review is to spread awareness of cerebellar involvement in addictive processes, and to suggest a preliminary model for its potential role.

BOLD responses in somatosensory cortices better reflect heat sensation than pain.

The discovery of cortical networks that participate in pain processing has led to the common generalization that blood oxygen level-dependent (BOLD) responses in these areas indicate the processing of pain. Physical stimuli have fundamental properties that elicit sensations distinguishable from pain, such as heat. We hypothesized that pain intensity coding may reflect the intensity coding of heat sensation during the presentation of thermal stimuli during fMRI. Six 3T fMRI heat scans were collected for 16 healthy subjects, corresponding to perceptual levels of "low innocuous heat," "moderate innocuous heat," "high innocuous heat," "low painful heat," "moderate painful heat," and "high painful heat" delivered by a contact thermode to the face. Subjects rated pain and heat intensity separately after each scan. A general linear model analysis detected different patterns of brain activation for the different phases of the biphasic response to heat. During high painful heat, the early phase was associated with significant anterior insula and anterior cingulate cortex activation. Persistent responses were detected in the right dorsolateral prefrontal cortex and inferior parietal lobule. Only the late phase showed significant correlations with perceptual ratings. Significant heat intensity correlated activation was identified in contralateral primary and secondary somatosensory cortices, motor cortex, and superior temporal lobe. These areas were significantly more related to heat ratings than pain. These results indicate that heat intensity is encoded by the somatosensory cortices, and that pain evaluation may either arise from multimodal evaluative processes, or is a distributed process.

Surgically induced neuropathic pain: understanding the perioperative process.

Nerve damage takes place during surgery. As a consequence, significant numbers (10%-40%) of patients experience chronic neuropathic pain termed surgically induced neuropathic pain (SNPP). The initiating surgery and nerve damage set off a cascade of events that includes both pain and an inflammatory response, resulting in "peripheral and central sensitization," with the latter resulting from repeated barrages of neural activity from nociceptors. In affected patients, these initial events produce chemical, structural, and functional changes in the peripheral and central nervous systems (CNS). The maladaptive changes in damaged nerves lead to peripheral manifestations of the neuropathic state-allodynia, sensory loss, shooting pains, etc, that can manifest long after the effects of the surgical injury have resolved. The CNS manifestations that occur are termed "centralization of pain" and affect sensory, emotional, and other (eg, cognitive) systems as well as contributing to some of the manifestations of the chronic pain syndrome (eg, depression). Currently there are no objective measures of nociception and pain in the perioperative period. As such, intermittent or continuous pain may take place during and after surgery. New technologies including direct measures of specific brain function of nociception and new insights into preoperative evaluation of patients including genetic predisposition, appear to provide initial opportunities for decreasing the burden of SNPP, until treatments with high efficacy and low adverse effects that either prevent or treat pain are discovered.

Parallel buprenorphine phMRI responses in conscious rodents and healthy human subjects.

Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial µ-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.

Pain response measured with arterial spin labeling.

The majority of functional MRI studies of pain processing in the brain use the blood oxygenation level-dependent (BOLD) imaging approach. However, the BOLD signal is complex as it depends on simultaneous changes in blood flow, vascular volume and oxygen metabolism. Arterial spin labeling (ASL) perfusion imaging is another imaging approach in which the magnetically labeled arterial water is used as an endogenous tracer that allows for direct measurement of cerebral blood flow. In this study, we assessed the pain response in the brain using a pulsed-continuous arterial spin labeling (pCASL) approach and a thermal stimulation paradigm. Using pCASL, response to noxious stimulation was detected in somatosensory cortex, anterior cingulate cortex, anterior insula, hippocampus, amygdala, thalamus and precuneus, consistent with the pain response activation patterns detected using the BOLD imaging approach. We suggest that pCASL is a reliable alternative for functional MRI pain studies in conditions in which blood flow, volume or oxygen extraction are altered or compromised.

Her versus his migraine: multiple sex differences in brain function and structure.

Migraine is twice as common in females as in males, but the mechanisms behind this difference are still poorly understood. We used high-field magnetic resonance imaging in male and female age-matched interictal (migraine free) migraineurs and matched healthy controls to determine alterations in brain structure. Female migraineurs had thicker posterior insula and precuneus cortices compared with male migraineurs and healthy controls of both sexes. Furthermore, evaluation of functional responses to heat within the migraine groups indicated concurrent functional differences in male and female migraineurs and a sex-specific pattern of functional connectivity of these two regions with the rest of the brain. The results support the notion of a 'sex phenotype' in migraine and indicate that brains are differentially affected by migraine in females compared with males. Furthermore, the results also support the notion that sex differences involve both brain structure as well as functional circuits, in that emotional circuitry compared with sensory processing appears involved to a greater degree in female than male migraineurs.

MRI assessment of cerebral perfusion in clinical trials.

Neurodegenerative mechanisms affect the brain through a variety of processes that are reflected as changes in brain structure and physiology. Although some biomarkers for these changes are well established, others are at different stages of development for use in clinical trials. One of the most challenging biomarkers to harmonize for clinical trials is cerebral blood flow (CBF). There are several magnetic resonance imaging (MRI) methods for quantifying CBF without the use of contrast agents, in particular arterial spin labeling (ASL) perfusion MRI, which has been increasingly applied in clinical trials. In this review, we present ASL MRI techniques, including strategies for implementation across multiple imaging centers, levels of confidence in assessing disease progression and treatment effects, and details of image analysis.

Aversion-related circuitry in the cerebellum: responses to noxious heat and unpleasant images.

The cerebellum is reliably activated during both acute and chronic pain conditions, but it is unclear whether the response to aversive painful stimuli can be generalized to other aversive stimuli. We hypothesized that cerebellar activation during pain reflects higher-level encoding of aversive stimuli. We used functional magnetic resonance imaging (fMRI) to compare cerebellar responses in 11 healthy volunteers to noxious heat (46 °C) applied to the hand and to the passive viewing of images selected from the International Affective Picture System. Aversive stimuli in the form of noxious heat and unpleasant pictures (unpleasant vs neutral) activated overlapping areas in the posterior cerebellum, specifically in hemispheric lobule VI, Crus I, and VIIb. Pleasant pictures (pleasant vs neutral) did not share the same pattern of activation as observed with the aversive stimuli. Cerebellar areas that showed functional overlap with both heat pain and unpleasant picture viewing were significantly inversely correlated with fMRI signals measured in limbic system structures, including the anterior hypothalamus, subgenual anterior cingulate cortex, and the parahippocampal gyrus. Heat-specific functional connectivity was detected in many regions including primary motor cortex, secondary somatosensory cortex, anterior insula, and the periaqueductal gray. The overlap between cerebellar lobuli reactive to noxious heat and passive viewing of unpleasant images suggest that the cerebellum may contain specific regions involved in encoding generalized aversive processing. The separate cortical networks suggest that noxious heat-evoked responses in the cerebellum can be divided into sensorimotor and emotional networks.