Catherine E. Warnaby

Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients.

OBJECTIVE The groin pain experienced by patients with hip osteoarthritis (OA) is often accompanied by areas of referred pain and changes in skin sensitivity. We aimed to identify the supraspinal influences that underlie these clinical manifestations that we consider indicative of possible central sensitization. METHODS Twenty patients with hip OA awaiting joint replacement and displaying signs of referred pain were recruited into the study, together with age-matched controls. All subjects completed pain psychology questionnaires and underwent quantitative sensory testing (QST) in their area of referred pain. Twelve of 20 patients and their age- and sex-matched controls underwent functional magnetic resonance imaging (MRI) while the areas of referred pain were stimulated using cold stimuli (12 degrees C) and punctate stimuli (256 mN). The remaining 8 of 20 patients underwent punctate stimulation only. RESULTS Patients were found to have significantly lower threshold perception to punctate stimuli and were hyperalgesic to the noxious punctate stimulus in their areas of referred pain. Functional brain imaging illustrated significantly greater activation in the brainstem of OA patients in response to punctate stimulation of their referred pain areas compared with healthy controls, and the magnitude of this activation positively correlated with the extent of neuropathic-like elements to the patients pain, as indicated by the PainDETECT score. DISCUSSION Using psychophysical (QST) and brain imaging methods (functional MRI), we have identified increased activity with the periaqueductal grey matter associated with stimulation of the skin in referred pain areas of patients with hip OA. This offers a central target for analgesia aimed at improving the treatment of this largely peripheral disease.

Dysmenorrhoea is associated with central changes in otherwise healthy women.

&NA; Patients with chronic pain conditions demonstrate altered central processing of experimental noxious stimuli, dysfunction of the hypothalamic–pituitary–adrenal axis, and reduced quality of life. Dysmenorrhoea is not considered a chronic pain condition, but is associated with enhanced behavioural responses to experimental noxious stimuli. We used behavioural measures, functional magnetic resonance imaging, and serum steroid hormone levels to investigate the response to experimental thermal stimuli in otherwise healthy women, with and without dysmenorrhoea. Women with dysmenorrhoea reported increased pain to noxious stimulation of the arm and abdomen throughout the menstrual cycle; no menstrual cycle effect was observed in either group. During menstruation, deactivation of brain regions in response to noxious stimulation was observed in control women but not in women with dysmenorrhoea. Without background pain (ie, in nonmenstrual phases), activity in the entorhinal cortex appeared to mediate the increased responses in women with dysmenorrhoea. Mean cortisol was significantly lower in women with dysmenorrhoea and was negatively correlated with the duration of the symptom. Additionally, women with dysmenorrhoea reported significantly lower physical but not mental quality of life. Thus, many features of chronic pain conditions are also seen in women with dysmenorrhoea: specifically a reduction in quality of life, suppression of the hypothalamic–pituitary–adrenal axis, and alterations in the central processing of experimental noxious stimuli. These alterations persist when there is no background pain and occur in response to stimuli at a site distant from that of the clinical pain. These findings indicate the potential importance of early and adequate treatment of dysmenorrhoea. In common with chronic pain patients, women with dysmenorrhoea demonstrate altered central processing of noxious stimuli and reduced serum cortisol and quality of life.

Slow-Wave Activity Saturation and Thalamocortical Isolation During Propofol Anesthesia in Humans

In subjects treated with an anesthetic, saturation of slow-wave activity in the EEG indicates the onset of thalamocortical isolation from the external world. Can You Hear Me Now? What actually happens in your brain when you lose awareness of what is going on around you? Clinicians would like to know so they can monitor awareness in the operating room without requiring the person to respond to a sound or a touch. Ní Mhuircheartaigh and colleagues have found a signal in the EEG (electrical brain waves recorded from outside the head) that may reflect this transition. The authors gave the drug propofol to 16 individuals and monitored their EEGs. In each patient, as the drug concentrations in their system rose, the amplitude of electrical waves of a certain frequency (slow-wave activity) grew. Eventually, the slow-wave amplitude reached a plateau and, even though drug concentrations continued to increase, the amplitude stayed at this plateau value. To test whether the transition to the plateau represented the point at which the subjects lost awareness, they performed simultaneous functional magnetic resonance imaging and sensory stimulation. The beginning of the plateau coincided with the point at which sensory signals no longer reached the thalamocortical portion of the brain, rendering it an “island” of activity. Unexpectedly, other brain regions still responded to stimuli, including posterior parietal and prefrontal cortices. Although more studies of slow-wave activity and its relation to perceptual awareness are needed, the transition of slow-wave activity to saturation is a potential individualized index of sensory isolation that may prove useful in the operating room. The altered state of consciousness produced by general anesthetics is associated with a variety of changes in the brain’s electrical activity. Under hyperpolarizing influences such as anesthetic drugs, cortical neurons oscillate at ~1 Hz, which is measurable as slow waves in the electroencephalogram (EEG). We have administered propofol anesthesia to 16 subjects and found that, after they had lost behavioral responsiveness (response to standard sensory stimuli), each individual’s EEG slow-wave activity (SWA) rose to saturation and then remained constant despite increasing drug concentrations. We then simultaneously collected functional magnetic resonance imaging and EEG data in 12 of these subjects during propofol administration and sensory stimulation. During the transition to SWA saturation, the thalamocortical system became isolated from sensory stimuli, whereas internal thalamocortical exchange persisted. Rather, an alternative and more fundamental cortical network (which includes the precuneus) responded to all sensory stimulation. We conclude that SWA saturation is a potential individualized indicator of perception loss that could prove useful for monitoring depth of anesthesia and studying altered states of consciousness.

Brain imaging reveals that engagement of descending inhibitory pain pathways in healthy women in a low endogenous estradiol state varies with testosterone

Summary Activity in key regions of the descending pain inhibitory system varies with testosterone in women in both a natural and induced low endogenous estradiol state. Abstract The combined oral contraceptive pill (COCP) has been implicated in the development of a number of chronic pain conditions. Modern COCP formulations produce a low endogenous estradiol, low progesterone environment similar to the early follicular phase of the natural menstrual cycle, with a variable effect on serum androgen levels. We used behavioural measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli in healthy women, in both a natural and COCP‐induced low endogenous estradiol state, to investigate whether alterations in central pain processing may underlie these observations in COCP users. Although COCP users overall did not require lower temperatures to obtain a fixed pain intensity, alterations in the brain response to these stimuli were observed. In a subgroup of COCP users with significantly reduced serum testosterone, however, lower temperatures were required. Region‐of‐interest analysis revealed that within key regions of the descending pain inhibitory system, activity in response to noxious stimulation varied with serum testosterone levels in both groups of women. Of particular interest, in COCP users, activity in the rostral ventromedial medulla increased with increasing testosterone and in those women with low testosterone, was significantly reduced compared to controls. These findings suggest that, in a low endogenous estradiol state, testosterone may be a key factor in modulating pain sensitivity via descending pathways. Specifically, failure to engage descending inhibition at the level of the rostral ventromedial medulla may be responsible for the reduction in temperature required by COCP users with low circulating testosterone.

Stimulus Site and Modality Dependence of Functional Activity within the Human Spinal Cord

Chronic pain is thought to arise because of maladaptive changes occurring within the peripheral nervous system and CNS. The transition from acute to chronic pain is known to involve the spinal cord (Woolf and Salter, 2000). Therefore, to investigate altered human spinal cord function and translate results obtained from other species, a noninvasive neuroimaging technique is desirable. We have investigated the functional response in the cervical spinal cord of 18 healthy human subjects (aged 22–40 years) to noxious thermal and non-noxious tactile stimulation of the left and right forearms. Physiological noise, which is a significant source of signal variability in the spinal cord, was accounted for in the general linear model. Group analysis, performed using a mixed-effects model, revealed distinct regions of activity that were dependent on both the side and the type of stimulation. In particular, thermal stimulation on the medial aspect of the wrist produced activity within the C6/C5 segment ipsilateral to the side of stimulation. Similar to data recorded in animals (Fitzgerald, 1982), painful thermal stimuli produced increased ipsilateral and decreased contralateral blood flow, which may reflect, respectively, excitatory and inhibitory processes. Nonpainful punctate stimulation of the thenar eminence provoked more diffuse activity but was still ipsilateral to the side of stimulation. These results present the first noninvasive evidence for a lateralized response to noxious and non-noxious stimuli in the human spinal cord. The development of these techniques opens the path to understanding, at a subject-specific level, central sensitization processes that contribute to chronic pain states.

Investigation of Slow-wave Activity Saturation during Surgical Anesthesia Reveals a Signature of Neural Inertia in Humans.

Background: Previously, we showed experimentally that saturation of slow-wave activity provides a potentially individualized neurophysiologic endpoint for perception loss during anesthesia. Furthermore, it is clear that induction and emergence from anesthesia are not symmetrically reversible processes. The observed hysteresis is potentially underpinned by a neural inertia mechanism as proposed in animal studies. Methods: In an advanced secondary analysis of 393 individual electroencephalographic data sets, we used slow-wave activity dose-response relationships to parameterize slow-wave activity saturation during induction and emergence from surgical anesthesia. We determined whether neural inertia exists in humans by comparing slow-wave activity dose responses on induction and emergence. Results: Slow-wave activity saturation occurs for different anesthetics and when opioids and muscle relaxants are used during surgery. There was wide interpatient variability in the hypnotic concentrations required to achieve slow-wave activity saturation. Age negatively correlated with power at slow-wave activity saturation. On emergence, we observed abrupt decreases in slow-wave activity dose responses coincident with recovery of behavioral responsiveness in ~33% individuals. These patients are more likely to have lower power at slow-wave activity saturation, be older, and suffer from short-term confusion on emergence. Conclusions: Slow-wave activity saturation during surgical anesthesia implies that large variability in dosing is required to achieve a targeted potential loss of perception in individual patients. A signature for neural inertia in humans is the maintenance of slow-wave activity even in the presence of very-low hypnotic concentrations during emergence from anesthesia.

Anesthesia-induced Suppression of Human Dorsal Anterior Insula Responsivity at Loss of Volitional Behavioral Response.

Background:It has been postulated that a small cortical region could be responsible for the loss of behavioral responsiveness (LOBR) during general anesthesia. The authors hypothesize that any brain region demonstrating reduced activation to multisensory external stimuli around LOBR represents a key cortical gate underlying this transition. Furthermore, the authors hypothesize that this localized suppression is associated with breakdown in frontoparietal communication. Methods:During both simultaneous electroencephalography and functional magnetic resonance imaging (FMRI) and electroencephalography data acquisition, 15 healthy volunteers experienced an ultraslow induction with propofol anesthesia while a paradigm of multisensory stimulation (i.e., auditory tones, words, and noxious pain stimuli) was presented. The authors performed separate analyses to identify changes in (1) stimulus-evoked activity, (2) functional connectivity, and (3) frontoparietal synchrony associated with LOBR. Results:By using an FMRI conjunction analysis, the authors demonstrated that stimulus-evoked activity was suppressed in the right dorsal anterior insula cortex (dAIC) to all sensory modalities around LOBR. Furthermore, the authors found that the dAIC had reduced functional connectivity with the frontoparietal regions, specifically the dorsolateral prefrontal cortex and inferior parietal lobule, after LOBR. Finally, reductions in the electroencephalography power synchrony between electrodes located in these frontoparietal regions were observed in the same subjects after LOBR. Conclusions:The authors conclude that the dAIC is a potential cortical gate responsible for LOBR. Suppression of dAIC activity around LOBR was associated with disruption in the frontoparietal networks that was measurable using both electroencephalography synchrony and FMRI connectivity analyses.

General anaesthesia as fragmentation of selfhood: insights from electroencephalography and neuroimaging

Abstract Selfhood is linked to brain processes that enable the experience of a person as a distinct entity, capable of agency. This framework naturally incorporates a continuum of both non‐conscious and conscious self‐related information processing, and includes a hierarchy of components, such as awareness of existence (core self), embodied self (sentience), executive self (agency/volition), and various other higher‐order cognitive processes. Consciousness relates to, but is not congruent, with selfhood; understanding the processes required for selfhood can explain the partial consciousness seen in anaesthesia. Functional‐brain‐imaging and electroencephalographic studies in sleep and general anaesthesia have shown differential effects of anaesthetic drugs on various specific self‐related functional brain networks. In particular, drug‐induced selective impairment of anterior insula function suggests there might be a crucial difference between anaesthesia and natural sleep when it comes to the salience network. With increasing concentrations of anaesthetics, it is not uncommon for patients to become depersonalised (i.e. to lose sentience and agency), but retain many higher‐order functions and a disembodied self‐awareness, until quite high concentrations are reached. In this respect, general anaesthesia differs significantly from physiological sleep, where it appears that loss of agency and sentience parallels, or lags behind, the decrease in self‐awareness. Interestingly, connectivity within the posterior brain regions is maintained even to quite high concentrations of anaesthetics, potentially representing a pathognomonic marker of the core self that possibly is involved in maintaining a reduced energy state of homeostasis.

Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage.

Objectives:Aneurysmal subarachnoid hemorrhage often leads to death and poor clinical outcome. Injury occurring during the first 72 hours is termed “early brain injury,” with disruption of the nitric oxide pathway playing an important pathophysiologic role in its development. Quantitative electroencephalographic variables, such as &agr;/&dgr; frequency ratio, are surrogate markers of cerebral ischemia. This study assessed the quantitative electroencephalographic response to a cerebral nitric oxide donor (intravenous sodium nitrite) to explore whether this correlates with the eventual development of delayed cerebral ischemia. Design:Unblinded pilot study testing response to drug intervention. Setting:Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom. Patients:Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41–69 yr]; 11 women). Interventions:IV sodium nitrite (10 &mgr;g/kg/min) for 1 hour. Measurements and Main Results:Continuous electroencephalographic recording for 2 hours. The alpha/delta frequency ratio was measured before and during IV sodium nitrite infusion. Seven of 14 patients developed delayed cerebral ischemia. There was a +30% to +118% (range) increase in the alpha/delta frequency ratio in patients who did not develop delayed cerebral ischemia (p < 0.0001) but an overall decrease in the alpha/delta frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to –31%) (p = 0.006, multivariate analysis accounting for major confounds). Conclusions:Administration of sodium nitrite after severe subarachnoid hemorrhage differentially influences quantitative electroencephalographic variables depending on the patient’s susceptibility to development of delayed cerebral ischemia. With further validation in a larger sample size, this response may be developed as a tool for risk stratification after aneurysmal subarachnoid hemorrhage.

Photothermal modeling of thulium fiber laser-tissue interactions

A one-dimensional finite difference model has been used to investigate the temperature distribution within thulium fibre laser-irradiated tissue. Temperature-time and temperature-depth profiles are presented for various laser stimulus parameters in the 2 micron region. These current calculations are aimed at determining theoretical temperature distributions in the application of relatively low power fibre lasers for thermal stimulation of cutaneous nerves in human pain processing. Theoretical skin surface temperatures are compared with those from thermal camera measurements during thulium fibre laser irradiation. The effectiveness of the thulium fibre laser for thermally stimulating cutaneous nerves is confirmed.