Person:

Borsook, David

Evaluation of pain-induced changes in functional connectivity was performed in pediatric complex regional pain syndrome (CRPS) patients. High field functional magnetic resonance imaging was done in the symptomatic painful state and at follow up in the asymptomatic pain free/recovered state. Two types of connectivity alterations were defined: (1) Transient increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb vs. unaffected limb in the CRPS state, but with normalized connectivity patterns in the recovered state; and (2) Persistent increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb as compared to the unaffected limb that persisted also in the recovered state (recovered affected limb versus recovered unaffected limb). The data support the notion that even after symptomatic recovery, alterations in brain systems persist, particularly in amygdala and basal ganglia systems. Connectivity analysis may provide a measure of temporal normalization of different circuits/regions when evaluating therapeutic interventions for this condition. The results add emphasis to the importance of early recognition and management in improving outcome of pediatric CRPS.

The cornea has been a focus of animal electrophysiological research for decades, but little is known regarding its cortical representation in the human brain. This study attempts to localize the somatotopic representation of the cornea to painful stimuli in human primary somatosensory cortex using functional magnetic resonance imaging (fMRI). In this case study, a subject was imaged at 3T while bright light was presented in a block-design, which either produced pain and blinking (during photophobia) or blinking alone (after recovery from photophobia). Pain and blinking produced precisely localized activations in primary somatosensory cortex and primary motor cortex. These results indicate that noxious stimulation of the cornea can produce somatotopic activation in primary somatosensory cortex. This finding opens future avenues of research to evaluate the relationship between corneal pain and central brain mechanisms relating to the development of chronic pain conditions, such as dry eye-like symptoms.

Dynamic thalamic regulation of sensory signals allows the cortex to adjust better to rapidly changing behavioral, physiological and environmental demands. To fulfill this role, thalamic neurons must themselves be subjected to constantly changing modulatory inputs that originate in multiple neurochemical pathways involved in autonomic, affective and cognitive functions. Our overall goal is to define an anatomical framework for conceptualizing how a ‘decision’ is made on whether a trigeminovascular thalamic neuron fires, for how long, and at what frequency. To begin answering this question, we determine which neuropeptides/neurotransmitters are in a position to modulate thalamic trigeminovascular neurons. Using a combination of in-vivo single-unit recording, juxtacellular labeling with tetramethylrhodamine dextran (TMR) and in-vitro immunohistochemistry, we found that thalamic trigeminovascular neurons were surrounded by high density of axons containing biomarkers of glutamate, GABA, dopamine and serotonin; moderate density of axons containing noradrenaline and histamine; low density of axons containing orexin and melanin concentrating hormone (MCH); but not axons containing CGRP, serotonin 1D receptor, oxytocin or vasopressin. In the context of migraine, the findings suggest that the transmission of headache-related nociceptive signals from the thalamus to the cortex may be modulated by opposing forces (i.e., facilitatory, inhibitory) that are governed by continuous adjustments needed to keep physiological, behavioral, cognitive and emotional homeostasis.

The purpose of this study was to use functional near-infrared spectroscopy (fNIRS) to examine patterns of both activation and deactivation that occur in the frontal lobe in response to noxious stimuli. The frontal lobe was selected because it has been shown to be activated by noxious stimuli in functional magnetic resonance imaging studies. The brain region is located behind the forehead which is devoid of hair, providing a relative ease of placement for fNIRS probes on this area of the head. Based on functional magnetic resonance imaging studies showing blood-oxygenation-level dependent changes in the frontal lobes, we evaluated functional near-infrared spectroscopy measures in response to two levels of electrical pain in awake, healthy human subjects (n = 10; male = 10). Each subject underwent two recording sessions separated by a 30-minute resting period. Data collected from 7 subjects were analyzed, containing a total of 38/36 low/high intensity pain stimuli for the first recording session and 27/31 pain stimuli for the second session. Our results show that there is a robust and significant deactivation in sections of the frontal cortices. Further development and definition of the specificity and sensitivity of the approach may provide an objective measure of nociceptive activity in the brain that can be easily applied in the surgical setting.

Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI) in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg) preceded by either saline (Sal-Nalb) or naloxone 0.4 mg (Nalox-Nalb). Blood oxygen level-dependent (BOLD) activation maps followed by contrast and connectivity analyses revealed marked differences. Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen). Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity.

The hypothalamus has been implicated in migraine based on the manifestation of autonomic symptoms with the disease, as well as neuroimaging evidence of hypothalamic activation during attacks. Our objective was to determine functional connectivity (FC) changes between the hypothalamus and the rest of the brain in migraine patients vs. control subjects. This study uses fMRI (functional magnetic resonance imaging) to acquire resting state scans in 12 interictal migraine patients and 12 healthy matched controls. Hypothalamic connectivity seeds were anatomically defined based on high-resolution structural scans, and FC was assessed in the resting state scans. Migraine patients had increased hypothalamic FC with a number of brain regions involved in regulation of autonomic functions, including the locus coeruleus, caudate, parahippocampal gyrus, cerebellum, and the temporal pole. Stronger functional connections between the hypothalamus and brain areas that regulate sympathetic and parasympathetic functions may explain some of the hypothalamic-mediated autonomic symptoms that accompany or precede migraine attacks.

Background: Intravenous infusion of calcitonin-gene-related-peptide (CGRP) provokes headache and migraine in humans. Mechanisms underlying CGRP-induced headache are not fully clarified and it is unknown to what extent CGRP modulates nociceptive processing in the brain. To elucidate this we recorded blood-oxygenation-level-dependent (BOLD) signals in the brain by functional MRI after infusion of CGRP in a double-blind placebo-controlled crossover study of 27 healthy volunteers. BOLD-signals were recorded in response to noxious heat stimuli in the V1-area of the trigeminal nerve. In addition, we measured BOLD-signals after injection of sumatriptan (5-HT1B/1D antagonist). Results: Brain activation to noxious heat stimuli following CGRP infusion compared to baseline resulted in increased BOLD-signal in insula and brainstem, and decreased BOLD-signal in the caudate nuclei, thalamus and cingulate cortex. Sumatriptan injection reversed these changes. Conclusion: The changes in BOLD-signals in the brain after CGRP infusion suggests that systemic CGRP modulates nociceptive transmission in the trigeminal pain pathways in response to noxious heat stimuli.

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder of unknown etiology. Although relatively common in children, how this condition affects brain structure and function in a pediatric population remains unclear. Here, we investigate brain changes in adolescents with IBS and healthy controls. Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution T1-weighted anatomical scan was acquired followed by a T2-weighted functional scan. We used a surface-based morphometric approach along with a seed-based resting-state functional connectivity (RS-FC) analysis to determine if groups differed in cortical thickness and whether areas showing structural differences also showed abnormal RS-FC patterns. Patients completed the Abdominal Pain Index and the GI Module of the Pediatric Quality of Life Inventory to assess abdominal pain severity and impact of GI symptoms on health-related quality of life (HRQOL). Disease duration and pain intensity were also assessed. Pediatric IBS patients, relative to controls, showed cortical thickening in the posterior cingulate (PCC), whereas cortical thinning in posterior parietal and prefrontal areas were found, including the dorsolateral prefrontal cortex (DLPFC). In patients, abdominal pain severity was related to cortical thickening in the intra-abdominal area of the primary somatosensory cortex (SI), whereas HRQOL was associated with insular cortical thinning. Disease severity measures correlated with cortical thickness in bilateral DLPFC and orbitofrontal cortex. Patients also showed reduced anti-correlations between PCC and DLPFC compared to controls, a finding that may reflect aberrant connectivity between default mode and cognitive control networks. We are the first to demonstrate concomitant structural and functional brain changes associated with abdominal pain severity, HRQOL related to GI-specific symptoms, and disease-specific measures in adolescents with IBS. It is possible such changes will be responsive to therapeutic intervention and may be useful as potential markers of disease progression or reversal.

Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1) receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis) were selected out of a larger (n = 120) randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis). These ten subjects were examined by positron emission tomography (PET) with the NK1-specific radioligand 11C-GR205171 before, and eight patients were followed up after treatment with graded exercise. Brain binding in the ten patients before treatment, reflecting NK1-receptor availability (NK1-RA), was compared to that of 18 healthy subjects and, longitudinally, to the eight of the original ten patients that agreed to a second PET examination after treatment. Before treatment, patients had significantly lower NK1-RA in the insula, vmPFC, postcentral gyrus, anterior cingulate, caudate, putamen, amygdala and the midbrain but not the thalamus and cerebellum, with the largest difference in the insula contralateral to the injured elbow. No significant correlations between brain NK1-RA and pain, functional severity, or peripheral NK1-RA in the affected limb were observed. In the eight patients examined after treatment, pain ratings decreased in everyone, but there were no significant changes in NK1-RA. These findings indicate a role for the substance P (SP) / NK1 receptor system in musculoskeletal pain and tissue healing. As neither clinical parameters nor successful treatment response was reflected in brain NK1-RA after treatment, this may reflect the diverse function of the SP/NK1 system in CNS and peripheral tissue, or a change too small or slow to capture over the three-month treatment.

The predictability of pain makes surgery an ideal model for the study of pain and the development of strategies for analgesia and reduction of perioperative pain. As functional near-infrared spectroscopy reproduces the known functional magnetic resonance imaging activations in response to a painful stimulus, we evaluated the feasibility of functional near-infrared spectroscopy to measure cortical responses to noxious stimulation during general anesthesia. A multichannel continuous wave near-infrared imager was used to measure somatosensory and frontal cortical activation in patients undergoing catheter ablation of arrhythmias under general anesthesia. Anesthetic technique was standardized and intraoperative NIRS signals recorded continuously with markers placed in the data set for the timing and duration of each cardiac ablation event. Frontal cortical signals only were suitable for analysis in five of eight patients studied (mean age 14 ± 1 years, weight 66.7 ± 17.6 kg, 2 males). Thirty ablative lesions were recorded for the five patients. Radiofrequency or cryoablation was temporally associated with a hemodynamic response function in the frontal cortex characterized by a significant decrease in oxyhemoglobin concentration (paired t-test, p<0.05) with the nadir occurring in the period 4 to 6 seconds after application of the ablative lesion. Cortical signals produced by catheter ablation of arrhythmias in patients under general anesthesia mirrored those seen with noxious stimulation in awake, healthy volunteers, during sedation for colonoscopy, and functional Magnetic Resonance Imaging activations in response to pain. This study demonstrates the feasibility and potential utility of functional near-infrared spectroscopy as an objective measure of cortical activation under general anesthesia.