BACKGROUND:Although patients with chronic pain show behavioral signs of impaired endogenous pain modulation, responsible cerebral networks have yet to be anatomically delineated. We used diffusion tensor imaging (DTI) to examine the white-matter alterations in patients with chronic pain compared with healthy subjects. We further measured thermal pain modulatory responses using the offset analgesia (OA) paradigm. We tested whether the white-matter indices be associated with psychophysical parameters reflecting morbidity and modulatory responses of pain in patients, and whether they could serve as diagnostic biomarkers of chronic pain. METHODS:Twenty-six patients with chronic pain and 18 age- and gender-matched healthy controls were enrolled. After completing psychophysical questionnaires, they underwent OA measurement and whole-brain DTI in a 3 Tesla magnetic resonance imaging scanner. Fractional anisotropy (FA) and radial diffusivity (RD) of the white-matter were computed and compared between the groups with tract-based spatial statistics using the FMRIB Software Library (FSL) software. Correlations were sought among white-matter indices, thermal pain responses, and psychophysical parameters. The white-matter indices and OA-related parameters were tested whether they distinguish patients from controls by receiver operating characteristic analysis. RESULTS:During OA, patients showed a shorter latency to the maximum (maximum visual analog scale [VAS] latency, 16.0 ± 3.7 vs 18.9 ± 3.1 second [mean ± standard deviation, SD]; P = .032) but a longer latency to the minimum pain (OA latency, 15.6 ± 3.5 vs 11.1 ± 4.2 seconds; P = .004) than controls. They showed a smaller mean FA (0.44 ± 0.12 vs 0.45 ± 0.11; P = .012) and a larger mean RD of the global white-matter (0.00057 ± 0.00002 vs 0.00056 ± 0.00002; P = .038) than controls, at specific areas including the corpus callosum, anterior thalamic radiation, and forceps major. FA of the splenium of the corpus callosum was associated with maximum VAS latency (r = 0.493) and OA latency (r = -0.552). The Pain Catastrophizing Scale scores showed strong negative correlations with FA across those specific areas (r = -0.405). Those latencies during OA and white-matter metrics distinguished patients from controls ( P < .05). CONCLUSIONS:Patients with chronic pain showed dysfunction of the white matter concerned with interhemispheric communication of sensorimotor information as well as descending corticothalamic modulation of pain in association with affective morbidity and altered temporal dynamics of pain perception. We suggest that an impaired interhemispheric modulation of pain, through the corpus callosum, might be a novel cerebral mechanism in chronification of pain.

Detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) post-curative intent treatment is predictive of recurrence in NSCLC. Due to biological challenges with low ctDNA shed in early-stage disease and potential to detect non-tumor derived alterations in plasma (e.g. CHIP), most ctDNA MRD assays require a priori knowledge of genomic alterations from tumor tissue to achieve high sensitivity and specificity. Prior data from tumor-informed assays indicate ctDNA detection correlates with histologic subtype and lower sensitivity for lung adenocarcinomas compared to lung squamous cell carcinomas have been reported (Abbosh et al., 2017).

Pain remains a purely subjective experience that cannot be measured in an objective manner. Such difficulty in diagnosing pain facilitated neuroimaging research endeavours to find cerebral biomarkers of pain perception1Peyron R. Laurent B. Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000).Neurophysiol Clin. 2000; 30: 263-288Crossref PubMed Scopus (1767) Google Scholar and various aspects of chronic pain including prognosis2Baliki M.N. Petre B. Torbey S. et al.Corticostriatal functional connectivity predicts transition to chronic back pain.Nat Neurosci. 2012; 15: 1117-1119Crossref PubMed Scopus (674) Google Scholar and chronicity.3Hashmi J.A. Baliki M.N. Huang L. et al.Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits.Brain. 2013; 136: 2751-2768Crossref PubMed Scopus (447) Google Scholar, 4Ikeda E. Li T. Kobinata H. Zhang S. Kurata J. Anterior insular volume decrease is associated with dysfunction of the reward system in patients with chronic pain.Eur J Pain. 2018; 22: 1170-1179Crossref PubMed Scopus (15) Google Scholar Current neuroimaging modalities mostly utilise MRI: stimulus- or task-evoked functional MRI (fMRI), resting-state fMRI (RS-fMRI), diffusion-weighted imaging, and high-resolution anatomical imaging. We can analyse both functional and anatomical information from these various modalities of MRI. Among all these modalities, RS-fMRI has increasingly been used by many neuroimaging scientists.5Birn R.M. The role of physiological noise in resting-state functional connectivity.Neuroimage. 2012; 62: 864-870Crossref PubMed Scopus (249) Google Scholar Briefly, it is obtained while a subject in a scanner keeps calm, in a ‘resting’ condition, without any stimuli or tasks for several minutes in the same imaging sequence with conventional fMRI based on blood oxygenation level-dependent (BOLD) contrast. A specific slow-range BOLD signal spectrum at 0.01-0.08 Hz is determined by statistical analysis, which was previously discarded as meaningless signal drift during analysis of conventional fMRI.5Birn R.M. The role of physiological noise in resting-state functional connectivity.Neuroimage. 2012; 62: 864-870Crossref PubMed Scopus (249) Google Scholar Temporal synchrony of such slow waves has been analysed to evaluate functional connectivity between remote brain areas5Birn R.M. The role of physiological noise in resting-state functional connectivity.Neuroimage. 2012; 62: 864-870Crossref PubMed Scopus (249) Google Scholar: the more synchronous in slow waves, the more ‘connected’ in neuronal activity. Whole brain networks have been classified into several major functional networks.6Raichle M.E. Snyder A.Z. A default mode of brain function: a brief history of an evolving idea.Neuroimage. 2007; 37 (discussion 97–9): 1083-1090Crossref PubMed Scopus (1653) Google Scholar For example, the default mode network, where cerebral blood flow (CBF) tends to decrease under specific stimuli or tasks,7Raichle M.E. MacLeod A.M. Snyder A.Z. Powers W.J. Gusnard D.A. Shulman G.L. A default mode of brain function.Proc Natl Acad Sci U S A. 2001; 98: 676-682Crossref PubMed Scopus (9040) Google Scholar was found connected with remote cortical areas using this approach.8Greicius M.D. Krasnow B. Reiss A.L. Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis.Proc Natl Acad Sci U S A. 2003; 100: 253-258Crossref PubMed Scopus (4879) Google Scholar Could there be any further biological meaning in the slow waves of BOLD signals? Faster spectra of BOLD signals arise from neuronal activity-dependent, phasic fluctuations of CBF in specific brain regions.9Ogawa S. Tank D.W. Menon R. et al.Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging.Proc Natl Acad Sci U S A. 1992; 89: 5951-5955Crossref PubMed Scopus (2838) Google Scholar Could slower spectra also have associations with tonic neuronal activity? Some recent research using RS-fMRI suggests so,10Pelled G. Goelman G. Different physiological MRI noise between cortical layers.Magn Reson Med. 2004; 52: 913-916Crossref PubMed Scopus (39) Google Scholar although sufficient evidence has yet to be obtained supporting such associations. Amplitude of low-frequency fluctuations (ALFF) is one such example of indices derived from slow wave analysis of RS-fMRI data.11Zang Y.F. He Y. Zhu C.Z. et al.Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI.Brain Dev. 2007; 29: 83-91Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Zhang and colleagues12Zhang B.L. Jung M.Y. Tu Y.H. et al.Identifying brain regions associated with the neuropathology of chronic low back pain: a resting-state amplitude of low-frequency fluctuation study.Br J Anaesth. 2019; 123: e303-e311Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar opted to use ALFF to search for neuropathological fingerprints in chronic low back pain (cLBP) subjects. They performed RS-MRI in 90 cLBP subjects, before and after a pain-exacerbating manoeuvre, and in 74 healthy control subjects. They found that cLBP subjects showed larger ALFF in specific brain areas compared with control subjects, and that ALFF was modulated in other areas depending on the pain intensity in cLBP patients. Those areas included some common pain-related areas such as the cingulate, sensorimotor, insular, and prefrontal cortices. They also studied the discriminatory potency of ALFF by a machine learning algorithm in a separate cohort of 36 subjects. They further explored morphometric alterations from anatomical data and showed increased cortical volume at the rostral anterior cingulate cortex (ACC) in cLBP subjects. The authors are to be congratulated for tackling a poorly defined index, managing a large amount of data from up to 200 subjects, and confirming its discriminatory power by machine learning analysis to validate its use as a potential biomarker of chronic pain. I would like to suggest a few caveats in interpretation of current results based on earlier neuroimaging studies of pain. Strictly speaking, a biological basis of fMRI signals is an alteration of T2*-weighted MRI signal intensity that follows CBF changes associated with increased or decreased neuronal activity with a haemodynamic delay of several seconds.13Kurata J. Functional magnetic resonance imaging explained for pain research and medicine.Reg Anesth Pain Med. 2002; 27: 68-71PubMed Google Scholar In contrast to conventional fMRI studies targeting phasic signal changes concomitant with a specific stimulus or task, RS-fMRI studies are performed to calculate non-specific signal fluctuations exclusively in very slow frequency spectra that might be free from any specific neuronal activities. Indeed, a significant shortcoming of RS-fMRI is a lack of specificity, which allows no assumptions on brain regional activity changes. ALFF was developed to cover this shortcoming. ALFF is an index expressing an averaged square root of power spectra across 0.01–0.08 Hz from fast Fourier-transformed RS-fMRI data at a given voxel.11Zang Y.F. He Y. Zhu C.Z. et al.Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI.Brain Dev. 2007; 29: 83-91Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar From only the RS-fMRI data, it gives every voxel a standardised parameter reflecting an averaged amplitude of the slow wave spectra. It is not at all an evoked signal activity, as is usually expected in a traditional BOLD-fMRI study, but merely a spontaneous fluctuation of BOLD signals under total absence of stimuli or tasks. Its physiological significance remains undetermined. To date, there have been no studies to clearly indicate its relevance to known physiological phenomena, such as CBF, electrical activity, and synaptic input. ALFF remains too indirect a measure to represent brain activity in a quantified manner, in contrast to evoked BOLD signals validated with electrophysiological measurements.14Logothetis N.K. Pauls J. Augath M. Trinath T. Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal.Nature. 2001; 412: 150-157Crossref PubMed Scopus (4695) Google Scholar An original paper using ALFF not only claimed its possible relevance to regional spontaneous neuronal activity, but also disclosed its controversial nature.11Zang Y.F. He Y. Zhu C.Z. et al.Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI.Brain Dev. 2007; 29: 83-91Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Thus the distribution pattern of high ALFF brain areas overlapped with those with abundant major vasculature and cisterns potentially causing false positive signals. Validation of ALFF with some electrophysiological measures should be mandatory to establish this index as a marker for regional neuronal activity. Studies of ALFF15Yuan R. Di X. Kim E.H. Barik S. Rypma B. Biswal B.B. Regional homogeneity of resting-state fMRI contributes to both neurovascular and task activation variations.Magn Reson Imaging. 2013; 31: 1492-1500Crossref PubMed Scopus (66) Google Scholar, 16Zou Q. Wu C.W. Stein E.A. Zang Y. Yang Y. Static and dynamic characteristics of cerebral blood flow during the resting state.Neuroimage. 2009; 48: 515-524Crossref PubMed Scopus (158) Google Scholar clearly showed that it is relevant to a variance in neurovascular coupling among neighbouring voxels such as regional homogeneity (ReHo), another parameter derived from RS-fMRI data. That is, ALFF changes should not be correlated with pain-related neuronal activity itself, but rather with regional homogeneity in the extent of neurovascular coupling response as a basis for conventional BOLD signals. ALFF should therefore be interpreted as partly associated with the extent of neurovascular reactivity reserve—that is a higher ALFF in a brain region might lead to a higher BOLD amplitude only when the neurones therein are physiologically activated. Therefore, a high ALFF value of a specific region means that this region might potentially show a high BOLD amplitude by electrical activation, but not that this region shows a high neuronal activity in the resting state. We have no direct evidence for association between ALFF and neuronal activation. A high ALFF in a specific region only implies that it might be associated with high CBF or BOLD signals when local neurones are electrically activated. ALFF is not a sign of present, steady-state CBF/BOLD signals. ALFF values were associated with the size of breath holding-associated CBF or BOLD signal changes.15Yuan R. Di X. Kim E.H. Barik S. Rypma B. Biswal B.B. Regional homogeneity of resting-state fMRI contributes to both neurovascular and task activation variations.Magn Reson Imaging. 2013; 31: 1492-1500Crossref PubMed Scopus (66) Google Scholar In contrast, there has been no evidence to support relevance of ALFF to neuronal activation (or CBF increase) under specific stimulus or task conditions. It is regrettable that the present study included only RS-fMRI, but no other modalities to examine CBF or BOLD signal changes induced by pain exacerbation itself. Any evident ‘neuropathology of cLBP’ or associations between ALFF and CBF (or BOLD) signals were not shown. Relevance should be sought between ALFF and pain-related CBF or BOLD signals in the same experiment, as the authors mentioned in the limitation section. A machine learning algorithm was successfully used to discriminate cerebral activation patterns among physical and social pain.17Wager T.D. Atlas L.Y. Lindquist M.A. Roy M. Woo C.W. Kross E. An fMRI-based neurologic signature of physical pain.N Engl J Med. 2013; 368: 1388-1397Crossref PubMed Scopus (956) Google Scholar The authors attempted to apply the same methodology for ALFF maps to detect the most significant differences between patients and controls. The authors developed discriminatory regressors from the first cohort using a machine learning algorithm, and validated them on a separate cohort with or without cLBP. They found that the paracentral lobule and supplementary motor area (PCL/SMA) survived the validation cohort, and suggested its potential in classifying cLBP.12Zhang B.L. Jung M.Y. Tu Y.H. et al.Identifying brain regions associated with the neuropathology of chronic low back pain: a resting-state amplitude of low-frequency fluctuation study.Br J Anaesth. 2019; 123: e303-e311Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Those areas appeared compatible with the bilateral primary sensorimotor areas, which showed increased grey matter volume and enhanced connectivity between hemispheres in chronic pain patients in an earlier study.18Li T. Zhang S. Kurata J. Suppressed descending pain modulatory and enhanced sensorimotor networks in patients with chronic low back pain.J Anesth. 2018; Google Scholar Such localisation of an ALFF abnormality might imply its possible pathophysiological relevance in this specific region. Further relevance should be sought between ALFF at the PCL/SMA and various psychophysical parameters of cLBP. The ACC has been recognised for its significant roles in affective/cognitive dimensions of pain and pain modulation. The authors showed increased cortical volume, but not thickness or surface area, in the left ACC in cLBP subjects.12Zhang B.L. Jung M.Y. Tu Y.H. et al.Identifying brain regions associated with the neuropathology of chronic low back pain: a resting-state amplitude of low-frequency fluctuation study.Br J Anaesth. 2019; 123: e303-e311Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar However, the exact location of ACC volume increase was not specified. The ACC is a large structure spanning from the subgenual anterior cingulate to the midcingulate cortex. They showed average cortical volume of the left ACC to be significantly larger in cLBP subjects than in controls. Why did they restrict morphometric analysis to the ACC? Earlier whole brain, voxel-based morphometry studies showed decreased cortical volumes at the midcingulate,4Ikeda E. Li T. Kobinata H. Zhang S. Kurata J. Anterior insular volume decrease is associated with dysfunction of the reward system in patients with chronic pain.Eur J Pain. 2018; 22: 1170-1179Crossref PubMed Scopus (15) Google Scholar dorsolateral prefrontal cortices,18 19 and medial thalamus19Apkarian A.V. Sosa Y. Sonty S. et al.Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.J Neurosci. 2004; 24: 10410-10415Crossref PubMed Scopus (1049) Google Scholar in chronic pain patients. I would encourage the authors to reanalyse whole brain anatomical data and examine these other areas for morphometric changes. An increase in ACC volume in cLBP might be a novel finding that warrants further investigation, suggesting enhanced activity of this region contributing to chronicity of pain. Possible association with altered ALFF/BOLD signals, functional connectivity, and behavioural parameters should be sought. The current study by Zhang and colleagues12Zhang B.L. Jung M.Y. Tu Y.H. et al.Identifying brain regions associated with the neuropathology of chronic low back pain: a resting-state amplitude of low-frequency fluctuation study.Br J Anaesth. 2019; 123: e303-e311Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar provides a unique piece to complete a very complicated puzzle of functional and anatomical signatures of chronic pain in the human brain. Such efforts might eventually enable objective diagnosis of chronic pain by neuroimaging, which is of critical importance both clinically and experimentally in developing new therapies.20Wanigasekera V. Wartolowska K. Huggins J.P. et al.Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging.Br J Anaesth. 2018; 120: 299-307Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar The authors declare that they have no conflicts of interest. Grant-in-Aid for Scientific Research (#18K08849) from Japan Society for the Promotion of Science.

Although cerebral structural and functional changes were uncovered by neuroimaging in patients with chronic low back pain (CLBP), their associations remain to be clarified. We co-analyzed anatomical and functional magnetic resonance imaging data in those patients and tested whether cortical gray matter volume changes are associated with altered pain modulatory networks underlying chronification of pain.

One feels a disproportionately large decrease of pain sensation on a slight decrease of thermal pain stimulus. Such phenomenon is termed offset analgesia and considered mediated by endogenous analgesic mechanisms. Offset analgesia was found attenuated in patients with neuropathic pain. We further found that such attenuation occurred in a more heterogeneous population of patients with chronic pain. By functional magnetic resonance imaging, we also found negative blood oxygenation level-dependent signals at those areas concerned with descending pain modulatory and reward systems during offset analgesia in the same cohort of patients. We propose that dysfunction of those systems, as revealed by attenuation of offset analgesia, might well be part of neural mechanisms of pain chronification.

Chronification of pain is associated with both anatomical and functional alterations of the brain. Alteration in regional grey matter volume might potentially be associated with modified activity of specific brain networks. In this cross‐sectional, observational study, we sought to identify brain regions with grey matter volume changes in patients with chronic pain and to reveal its significance by analysing alteration in functional connectivity from those regions. We further explored relevance of such alterations with psychometrics of chronic pain.

Inadvertently, the Fig. 7 was published incorrectly in the original publication of the article. The correct figure should be as below.

Background Offset analgesia is a disproportionate decrease of pain perception following a slight decrease of noxious thermal stimulus and attenuated in patients with neuropathic pain. We examined offset analgesia in patients with heterogeneous chronic pain disorders and used functional magnetic resonance imaging to explore modification of cerebral analgesic responses in comparison with healthy controls. Results We recruited seventeen patients with chronic pain and seventeen age-, sex-matched healthy controls. We gave a noxious thermal stimulation paradigm including offset analgesia and control stimuli on the left volar forearm, while we obtained a real-time continuous pain rating and a whole-brain functional magnetic resonance imaging. Baseline, first plateau (5 s), increment (5 s), and second plateau (20 s) temperatures of offset analgesia stimulus were set at 32°C, 46°C, 47°C, and 46°C, respectively. Control stimulus included 30-s 46°C stimulus or only the first 10 s of offset analgesia stimulus. We evaluated magnitude of offset analgesia, analyzed cerebral activation by thermal stimulation, and further compared offset analgesia-related activation between the groups. Magnitude of offset analgesia was larger in controls than in patients (median: 28.9% (interquartile range: 11.0–56.0%) vs. 19.0% (4.2–48.7%), p = 0.047). During the second plateau, controls showed a larger blood oxygenation level-dependent activation than patients at the putamen, anterior cingulate, dorsolateral prefrontal cortices, nucleus accumbens, brainstem, and medial prefrontal cortex ( p < 0.05), which are known to mediate either of descending pain modulation or reward responses. Offset analgesia-related activity at the anterior cingulate cortex was negatively correlated with neuropathic component of pain in patients with chronic pain ( p = 0.004). Conclusions Attenuation of offset analgesia was associated with suppressed activation of the descending pain modulatory and reward systems in patients with chronic pain, at least in the studied cohort. The present findings might implicate both behavioral and cerebral plastic alterations contributing to chronification of pain. Clinical trial registry: The Japanese clinical trials registry (UMIN-CTR, No. UMIN000011253; http://www.umin.ac.jp/ctr /)

Abstract Offset analgesia (OA) represents a disproportionately large decrease of pain perception after a brief, temporary increment of thermal pain stimulus and was reported attenuated in patients with neuropathic pain. We examined whether OA depends on the increment duration before offset, and whether individual features of OA distinguish patients with chronic pain and healthy controls. We used a Peltier-type thermal stimulator and OA paradigms including 5-, 10-, or 15-s duration of 1°C-increment (T2) over 45°C. We first examined OA response, on the left volar forearm, at 3 different T2's in 40 healthy volunteers, and OA and constant stimulus responses in 12 patients with chronic pain and 12 matched healthy controls. We measured magnitude of OA ([INCREMENT]OA) and maximum visual analogue scale (VAS) latency (time to peak VAS) during constant stimulus for each individual. Pain perception kinetics were compared with analysis of variance and sought for correlations with psychophysical parameters with a significance threshold at P < 0.05. In healthy controls, longer T2 at 10 or 15 seconds resulted in larger [INCREMENT]OA compared with T2 at 5 seconds (P = 0.04). In patients, [INCREMENT]OA was significantly smaller than controls at T2 = 5 or 10 seconds (P < 0.05) but grew comparable at T2 = 15 seconds with controls. Maximum VAS latency was longer in patients than in controls and negatively correlated with [INCREMENT]OA in patients. An OA index ([INCREMENT]OA/[maximum VAS latency]) proved diagnostic of chronic pain with an area under the receiver operating characteristic curve at 0.897. Patients with chronic pain showed impairment of OA and reduced temporal sharpening of pain perception, which might imply possible disturbance of the endogenous pain modulatory system.

STUDY DESIGN:A cross-sectional study.OBJECTIVE:The aim of this study was to evaluate activity of the nucleus accumbens (NAc) in response to lumbar mechanical stimulation in patients with chronic low back pain (cLBP) using functional magnetic resonance imaging (fMRI).SUMMARY OF BACKGROUND DATA:Although a modified activity of the NAc was characterized in cLBP patients, its pathological significance has yet to be determined. We hypothesized that NAc activation in response to pain might differ depending on the extent of psychiatric problems, which might be associated with the affective/motivational background of chronic pain.METHODS:Twenty-one patients with cLBP (four men, 17 women) were recruited. Subjects were divided into two groups on the basis of scores on the patient version of the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) scores: ≥17 (High Score, HiS group) and <17 (non-High Score, non-HiS group). Each subject was placed in the prone position on a 3-Tesla magnetic resonance imaging (MRI) scanner and stimulated by mechanical stimulation on the left lower back. Three blocks of 30-second pain stimulus calibrated at either 3 or 5 on an 11-grade numerical rating scale (NRS) were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. Functional images were analyzed using a multisubject general linear model with Bonferroni multiple comparisons.RESULTS:Subjects in the HiS group had more intense daily pain and lower quality of life than those in the non-HiS group (P < 0.05). Catastrophic thinking in relation to pain experience did not differ between the groups. Activation at the NAc was smaller in the HiS group than in the non-HiS group (P < 0.001).CONCLUSION:The presence of psychiatric problems was associated with attenuated activity of the NAc in cLBP patients. Dysfunction of the NAc might potentially be involved in the affective/motivational factors in the chronification of LBP.LEVEL OF EVIDENCE:N/A.

Background: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal cardiovascular disease if left untreated. In patients with IPAH with psychiatric illness or other complications, careful attention is required when administering medical therapies that may affect their hemodynamics. Patients suffering from IPAH who undergo anesthesia and surgery have a high mortality and morbidity rate. We describe the treatment of intractable psychiatric symptoms with electroconvulsive therapy (ECT) in a patient with IPAH.Case presentation: A 23-year-old woman with IPAH and type I diabetes mellitus (DM) presented with malignant catatonia. Her heart function was classified as New York Heart Association (NYHA) class III. She required a rapid cure and ECT due to various psychiatric symptoms resistant to conventional medications. Pulmonary hypertensive (PH) crisis is the most concerning complication that can be induced by the sympathetic stimulation of ECT. To avoid PH crisis, we administered oxygen using a laryngeal mask and administered remifentanil for anesthesia. We also prepared standby nitric oxide for possible PH crisis, although it was ultimately not needed. With 14 ECT sessions, her malignant catatonia was ameliorated without physical complications.Conclusion: ECT is an acceptable option for the treatment of medication-refractory psychiatric disturbances in patients with IPAH, provided careful management is assured to prevent or address complications.

Before the inception of commercial depth-of-anaesthesia monitors using electrophysiological parameters from the brain, such as processed electroencephalography (EEG) and evoked potentials, we used to evaluate the balance between anaesthesia and surgical stress using multimodal information derived from several physiological monitors, including the electrocardiogram (ECG), indirect or direct blood pressure, pulse oximetry, body temperature, peripheral nerve stimulation, as well as pharmacokinetic assumptions. In addition, we used our own senses to see the colour of the skin and the blood; to touch the body and feel its temperature and whether it was sweating, and to assess peripheral circulation; to assess the pupils for anaesthetic/narcotic effects; and even to talk to a patient to determine response by body movement and postoperative recall 1, 2. Although a major part of this evaluation is based on scientific logic, the rest rather belongs to some kind of ‘art’. Put another way, such art might be rephrased as ‘fuzzy logic’ 3, which enables clinical decision-making using a mixture of positive, negative, and grey-zone signs of various physiological phenomena. Even in the present era of high-tech, computer-intensive EEG monitoring, we are still routinely required to make such decisions by integrating heterogeneous information during our clinical practice. Such an art remains indispensable in modern anaesthetic management, where multiple drugs are often administered to attempt to attain a balanced anaesthetic state, consisting of unconsciousness (or amnesia), antinociception, immobility, suppression of the stress response, and preserved homeostasis. Part of the art of managing general anaesthesia or sedation may be easily explained, but some may not, and cannot even be documented in any detail: clinicians can therefore be said to be using their ‘sixth sense’. As practitioners, we usually estimate the balance of anaesthesia ourselves, and titrate anaesthetic agents and related drugs routinely, often without using objective, validated parameters from a modern EEG-based depth-of-anaesthesia monitor. This sixth sense tries to make the most of the multimodal information displayed by various monitors, mostly circulatory, respiratory, and other autonomic variables. The apparent absence of stress-related autonomic and escape-like motor responses to surgical stimulus makes us assume that an anaesthetised patient should probably be unconscious and pain-free. However, such experience-based decisions, and even an EEG monitor, cannot ever exclude possible ‘dysanaesthesia’, i.e. preserved responsiveness under apparently sufficient surgical anaesthesia and amnesia 4. Both the sixth sense and EEG remain imperfect in titrating anaesthesia. In this issue of Anaesthesia, Kenwrite et al. 5 try to put some evidence-based shape to the sixth sense. They programmed a computer to memorise unique patterns among several kinds of processed physiological parameters from the heart, lungs, skin, and the peripheral pulses during the awake and anaesthetised state. Then the computer, using a kind of newly developed ‘machine-learning’ algorithm, succeeded in distinguishing between the awake and the anaesthetised state, and between propofol and sevoflurane anaesthesia, with high precision (above 90%). Specifically, they recruited 27 surgical patients and gave either propofol (n = 12; targeted plasma concentration at 3 μg.ml−1) or sevoflurane (n = 15; end-tidal concentration 2%) to patients who were breathing spontaneously. Before and during anaesthesia, they recorded 1) ECG R-peaks, 2) chest cage movement, 3) temperatures at the right hand and the right foot, 4) skin conductivity at the right thumb, and 5) the pressure-generated pulse wave at the right index finger, using a custom-made monitoring device at a high sampling rate of 1200 Hz. They subsequently dissected each rhythm into multiple ‘wavelets’ and calculated power distribution across different frequency ranges. They further analysed patterns of interaction among different modalities by examining phase synchronisation of wavelets. The wavelets showed unique patterns of power spectrum and synchronisation among different modalities, such as the cardiac and respiratory rhythms, depending on the three states: wakefulness, propofol- and sevoflurane-anaesthesia. Such information from wavelet analysis was used to define the unique ‘fingerprint’ of each state using a ‘distance-based classification technique’ 5. The question that needs to be asked is: what would such fingerprints mean from a physiological point of view? As we already know, the heart and lungs are functionally inseparable. During spontaneous breathing, inspiration and expiration cause rhythmic changes in the preload of the heart, which in turn affects the cardiac output and rhythm by a centrally mediated autonomic reflex by way of afferents from the carotid sinus baroreceptor and efferent autonomic innervations of the heart. As such, all the different systems, including circulatory, respiratory, and autonomic systems, interact or cross-talk with each other in an inseparable way. Part of such interaction could potentially be estimated by analysing wavelets across various frequency ranges 6, 7. General anaesthesia might potentially affect such inseparable relationships in a certain way that our senses, or even the sixth sense, cannot even notice. Can the computers do better than our art, the sixth sense, in estimating anaesthetic states by detection of such ‘dysrhythmias’? The fingerprints measured in this study included much more information than we could usually glean from standard monitors; that is, the extents of variability and synchronisation of the heart and respiratory rates. The cardiac rhythm has been known to show decreased variability during anaesthesia 8, as well as in cardiac disease and other critical illness 9. The authors found decreased variability in heart and respiratory rates, and skin conductivity changes during general anaesthesia compared with those during wakefulness. That is, general anaesthesia seems to have flattened the natural fluctuations commonly observed in the human vegetative system. Decreased variability might be a common signature belonging to the anaesthetised state, in contrast with wakefulness. In addition, general anaesthesia decreased the complexity or randomness of the interaction between the circulatory and respiratory systems usually observed under physiological conditions, i.e. increased cardiopulmonary synchronisation. Such changes in bodily rhythms might be regarded as ‘hidden dysrhythmias’ induced by general anaesthesia, which might potentially turn out to be a ‘biomarker’ of the anaesthetised state. The authors’ success in developing an algorithm to classify such unnoticed, multi-faceted fingerprints should be one pioneering example in developing an ideal depth-of-anaesthesia monitor in the future. This is amongst the first studies published that have attempted to adapt machine learning to develop an algorithm to estimate the anaesthetised state using multimodal information from the whole body, with the exception of the electrical activity of the brain. The question arises why the authors opted not to use an EEG as part of their algorithm? One reason may be that EEG monitors may not yet reliably provide parameters to indicate ‘depth of anaesthesia’, which should involve much more than the bivariate states of ‘conscious or unconscious’, or ‘probability of awareness’ 10. Another group in Germany have adopted a similar approach, but included the EEG. Schneider et al. 11 tried to establish a depth-of-anaesthesia monitor using multimodal information from the EEG and other standard physiological monitoring. They developed a computational algorithm using an ‘Adaptive Neuro Fuzzy Inference System’ for the computers to distinguish between various anaesthetic regimens and estimate depth of anaesthesia. They reported that their novel algorithm, named ‘Anaesthesia Multimodal Index of Consciousness’, differentiated multiple behavioural states of anaesthesia: wakefulness; unconsciousness; surgical anaesthesia; and deep anaesthesia characterised by burst suppression on the EEG. They also showed that this was more efficient than either standard or bispectral index monitoring. On the other hand, Kenwrite et al. 5 did not use either EEG or behavioural evaluation in their study. It is possible that they designed this to be a feasibility study to explore the possibility of evaluating anaesthesia using information from the body alone. In this sense, their study remains only preliminary. Real-life general anaesthesia utilises multiple drugs whose actions are balanced, including narcotic, local anaesthetic, neuromuscular blocking, and cardiovascular agents that potentially affect autonomic tone. Respiration is also frequently controlled by mechanical ventilation, which may totally mask its spontaneous trigger. Behavioural planes ranging from wakefulness to deep anaesthesia, calibrated with EEG analysis, should also result in various patterns of autonomic wavelets. In the future, as the authors are aware 5, the present algorithm should be tested and calibrated under numerous different conditions. All the data were derived from control awake and single anaesthetic agent conditions, which can only be comparable with sedation or hypnosis with opioid/regional analgesia but without neuromuscular blockade. Most actual anaesthetic regimens, however, are made up with a balanced mixture of several agents with different roles, i.e. hypnotics, analgesics, and immobilisers, and may often require controlled mechanical ventilation. Such anaesthesia in the real world would highly complicate the coherent interactions among the different systems of the body. The state of general anaesthesia does not necessarily implicate the binary states of consciousness or a linear measure of anaesthetic depth, but rather encompasses biologically heterogeneous conditions where multiple agents act on various receptors in multiple organs and systems of the body to a variable extent 12. The ‘discriminatory classification’ algorithm was developed from data recorded from 27 patients, and it was also validated on the same dataset 5. Therefore, it is not surprising that the authors demonstrated a high success rate. A separate validation study is required, performed on a different dataset from a different cohort of subjects/patients, who are administered multiple, different doses of anaesthetics. It would also be important to make it a double-blind study to both patients and the scientists analysing the data. No doubt, the authors might also want to test the dose-response and behaviour-response characteristics of the algorithm. The anaesthetised state should also be described using behavioural parameters as well as calculated effect-site or end-tidal concentrations of agents. Without such validation, the authors cannot conclude the true feasibility of the presented methodology. Such further studies for this pioneering work should be keenly awaited. The present study raises an important issue in the current era of EEG-weighted monitoring. Loss of consciousness or memory is no doubt a definite prerequisite of general anaesthesia. Although a general anaesthetic principally targets the brain, it affects all the other organ systems of the body. Modern balanced anaesthetic techniques mandate not only loss of consciousness but also protection of the patient's body and mind from surgical stress and its consequences, that are mediated through multiple bodily systems, including the nervous, circulatory, hormonal systems, cytokines, and even anaesthetics themselves. Therefore, it is entirely conceivable that we should indeed analyse and integrate multimodal information from the whole body, consisting of multiple organs and systems, to determine the most appropriate anaesthetised state for the best surgical outcome, and whole life after surgery, of patients. The present study by Kenwrite et al. 5 surely indicates there is a need for such an approach for the next generation of depth-of-anaesthesia monitors. The present work was supported by Grants-in-Aid for Scientific Research (no. 26460695 to J.K.), Japan. No conflicts of interest declared.

The 9th International Symposium on Memory and Awareness in Anesthesia (MAA9) was held in Tokyo, Japan on June 20–23, 2014, attracting over 70 delegates from around the world. It was chaired by Jiro Kurata, from the Tokyo Medical and Dental University, and was jointly sponsored by the British Journal of Anaesthesia to support research activities in the fields of awareness during anaesthesia, neurobiological mechanisms of general anaesthesia, consciousness, and memory. This topic complements the recently published National Audit Project NAP5 survey of accidental awareness under general anaesthesia conducted in the UK in 2012 and published in the British Journal of Anaesthesia last year.1Pandit JJ Andrade J Bogod DG et al.5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.Br J Anaesth. 2014; 113: 549-559Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 2Cook TM Andrade J Bogod DG et al.5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent, and medicolegal issues.Br J Anaesth. 2014; 113: 560-574Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 3Pandit JJ Andrade J Bogod DG et al.5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: protocol, methods, and analysis of data.Br J Anaesth. 2014; 113: 540-548Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar The present British Journal of Anaesthesia special issue on Memory and Awareness in Anaesthesia was planned by Hugh Hemmings, a co-organizer of MAA9, to present the most current findings and views on topics from selected presentations during the meeting, in addition to submissions in response to an open call for papers. All the MAA9 abstracts are also included in this special on-line-only issue. Details of the MAA9 programme can be found at the conference website (http://maa9.umin.jp/). The scope of previous MAA symposia has ranged from the neuroscience of anaesthetic action, memory, and consciousness to the clinical aspects of awareness during anaesthesia. The MAA9 followed this tradition, while emphasizing the clinical aspects: epidemiology, diagnosis, prevention, and treatment of intraoperative awareness, with a conference slogan of 'Minding the Mind of Subconscious Self'. Although anaesthesiology has devoted tremendous efforts to studies of anaesthetic pharmacology and the mechanisms of anaesthetic-induced unconsciousness, which can be approached in a relatively direct manner through behavioural analyses, it has paid much less attention to subconscious processes of mind. At least part of memory is formed in the subconscious domain of mind,4Veselis RA Memory formation during anaesthesia: plausibility of a neurophysiological basis.Br J Anaesth. 2015; 115: i13-i19Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar and for this reason could be resistant to clinical ranges of general anaesthetics aimed to produce elimination of conscious behaviour. The MAA9 was programmed to propose that anaesthesiology should now approach the next stage, the care for the subconscious mind. Detection of intraoperative awareness during anaesthesia has historically been a major focus of research and technology development in anaesthesiology. Currently, there are several kinds of anaesthetic depth monitors, in addition to real-time or simulated monitors of anaesthetic concentrations, available in most operating theatres. Behaviour-based standardization of mathematically processed EEG, cortical evoked potentials, or both has attempted to turn 'probability of awareness' into an anaesthetic depth index, or a 'vital sign for consciousness'. In recent years, such indices for anaesthetic depth have been tested for efficacy in detecting intraoperative awareness compared with anaesthetic concentration monitors, which is summarized in the review by Mashour,5Mashour GA Avidan MS Intraoperative awareness: controversies and non-controversies.Br J Anaesth. 2015; 115: i20-i26Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar along with some of the controversial and established aspects of intraoperative awareness. Despite such efforts, titrated administration of anaesthetics, using either an anaesthetic depth or a concentration monitor, has not been successful in decreasing the incidence of intraoperative awareness with recall. No single reliable anaesthetic technique or monitor is yet available to eliminate awareness with recall during general anaesthesia. A significant concern is the increasing reliance on EEG-based monitors of anaesthetic depth to titrate administration of anaesthetic agents. Some of the issues with using processed indices of the EEG rather than the raw waveform are addressed in the review by Hagihira,6Hagihira S Changes in the electroencephalogram during anaesthesia and their physiological basis.Br J Anaesth. 2015; 115: i27-i31Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar along with editorial commentary by Veselis.7Veselis RA What about β? Relationship between pain and EEG spindles during anaesthesia.Br J Anaesth. 2015; 115: i3-i5Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Purdon and colleagues8Purdon PL Pavone KJ Akeju O et al.The aging brain: Age-dependent changes in the electroencephalogram during propofol and sevoflurane general anaesthesia.Br J Anaesth. 2015; 115: i46-i57Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar report profound age-dependent changes in the EEG that also have important implications for depth-of-anaesthesia monitors relying on processed EEG signals. Greater sensitivity to anaesthetics evident in the increased susceptibility to burst suppression in the elderly7Veselis RA What about β? Relationship between pain and EEG spindles during anaesthesia.Br J Anaesth. 2015; 115: i3-i5Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar is supported by animal studies that demonstrate delayed emergence and increased sensitivity to anaesthetics in old rats.9Chemali JJ Kenny JD Olutola O et al.Ageing delays emergence from general anaesthesia in rats by increasing anaesthetic sensitivity in the brain.Br J Anaesth. 2015; 115: i58-i65Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar This is highlighted in an editorial by Hudson and Proekt.10Hudson AE Proekt A Some heightened sensitivity.Br J Anaesth. 2015; 115: i5-i8Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Age-dependent changes in the EEG response to anaesthesia also occur in children, as demonstrated for sevoflurane by Akeju and colleagues;11Akeju O Pavone KJ Thum JA et al.Age-dependency of sevoflurane-induced electroencephalogram dynamics in children.Br J Anaesth. 2015; 115: i66-i76Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar this phenomenon has implications for EEG-based monitors of anaesthetic depth in both the young and the elderly. The impact of the unique pharmacological profile of ketamine on its EEG signature is described in a study by Pal and colleagues,12Pal D Hambrecht-Wiedbusch VS Silverstein BH Mashour GA Electroencephalographic coherence and cortical acetylcholine during ketamine-induced unconsciousness.Br J Anaesth. 2015; 114: 979-989Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar who show that ketamine, like other general anaesthetics, suppresses high-frequency γ activity and promotes a breakdown in cortical coherence. Reasons for failure of general anaesthesia in suppressing memory and awareness could include technical problems or mishaps, such as an inadvertent discontinuation or a low concentration of general anaesthetic agent. Neuromuscular blocking agents, which are non-hypnotics, could also conceal conscious behaviour and affect reliability of EEG-based depth-of-anaesthesia monitors. These issues are highlighted in two studies by Thomsen and colleagues13Thomsen JL Nielsen CV Eskildsen KZ Demant MN Gätke MR Awareness during emergence from anaesthesia: significance of neuromuscular monitoring in patients with butyrylcholinesterase deficiency.Br J Anaesth. 2015; 115: i78-i88Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 14Thomsen JL Nielsen CV Palmqvist DF Gätke MR Premature awakening and underuse of neuromuscular monitoring in a registry of patients with butyrylcholinesterase deficiency.Br J Anaesth. 2015; 115: i89-i94Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar from a Danish registry of patients with documented butyrylcholinesterase (plasma cholinesterase) deficiency, showing that prolonged paralysis due to impaired elimination of esterase-dependent neuromuscular blockers (succinylcholine or mivacurium) markedly increased the likelihood of awareness during emergence from anaesthesia, particularly when neuromuscular function monitoring was not used. The importance of not withholding neuromuscular function monitoring when paralytic drugs are used during anaesthesia is highlighted in the editorial by Avidan and Stevens.15Avidan MS Stevens TW The diving bell and the butterfly.Br J Anaesth. 2015; 115: i8-i10Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar An important limitation of EEG-based depth-of-anaesthesia monitors is described by Schuller and colleagues16Schuller PJ Newell S Strickland PA Barry JJ Response of bispectral index to neuromuscular block in awake volunteers.Br J Anaesth. 2015; 115: i95-i103Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar in a fascinating study of volunteer anaesthetists who underwent intentional awake paralysis using the isolated forearm technique to show that the bispectral index monitor itself cannot always distinguish 'anaesthesia' from paralysis, the implications of which are highlighted in an editorial by Schneider and Pilge.17Schneider G Pilge S Restrict relaxants, be aware, and know the limitations of your depth of anaesthesia monitor.Br J Anaesth. 2015; 115: i11-i12Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Use of the isolated forearm technique as a monitor of depth of anaesthesia and as a research tool into mechanisms of anaesthesia is presented in a thought-provoking debate and review by Pandit and colleagues.18Pandit JJ Russell IF Wang M Interpretations of responses using the isolated forearm technique in general anaesthesia: a debate.Br J Anaesth. 2015; 115: i32-i45Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Not all known cases of intraoperative awareness with recall, however, can be explained by such 'logical' causes. Should we now question the ability of general anaesthetics to produce unconsciousness and amnesia reliably? Targeting only conscious behaviour might not necessarily provide reliable protection of patients from traumatic memory of physical or psychological injuries during surgery and anaesthesia. The mechanisms of memory formation are reviewed by Veselis,4Veselis RA Memory formation during anaesthesia: plausibility of a neurophysiological basis.Br J Anaesth. 2015; 115: i13-i19Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar while Pryor and colleagues19Pryor KO Root JC Mehta M et al.Effect of propofol on the medial temporal lobe emotional memory system: a functional magnetic resonance imaging study in human subjects.Br J Anaesth. 2015; 115: i104-i113Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar used functional magnetic resonance imaging to show that propofol suppresses emotional memory formation through a hippocampal mechanism. Implicit memory formation during anaesthesia remains understudied and poses a significant problem that could be relevant to post-traumatic stress disorder, and possibly, postoperative delirium and cognitive dysfunction. A report from the Anesthesia Awareness Registry of the American Society of Anesthesiologists indicates that explicit recall of intraoperative awareness can have significant negative psychological impact on patients, which suggests that a more systematic response and follow-up care are necessary.20Kent C Posner K Mashour G et al.Patient perspectives on intraoperative awareness with explicit recall: report from a North American anaesthesia awareness registry.Br J Anaesth. 2015; 115: i114-i121Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Amongst the irreplaceable roles of the MAA conferences has been, and hopefully will continue to be, an investigation into subconscious processing of information during anaesthesia. Now that we have abundant, if not sufficient, evidence for anaesthetic-induced unconsciousness, we should investigate further the science of subconsciousness. The next meeting, MAA10, will continue this conversation around the clinical and basic science of memory and awareness in anaesthesia, to be chaired by Professor Sinikka Münte in Helsinki, Finland in 2017. Until the details of MAA10 are officially announced, the MAA9 facebook page (http://www.facebook.com/maa9.jp/) will remain a source of information on the development of MAA10. Please leave a comment on this page if you have suggestions or would like to be included in the mailing list for MAA10. We sincerely hope that this special issue, marking the up-to-date knowledge and insights on memory and awareness in anaesthesia, will help to promote further scientific inquiries and technological development to eliminate the most dreadful complication of general anaesthesia: intraoperative awareness. Caring for the whole human existence, conscious and subconscious, should continue to be the core mission of anaesthesiology. Finally, we would like to thank all the authors of these excellent articles, all the attendees, support staff, and sponsors of the MAA9, and Oxford University Press for realizing this special issue. Wrote, edited, and approved the final version; contributed equally to the work: J.K. and H.C.H. J.K. is a member of the International Advisory Panel, Editorial Board of Anaesthesia and an Associate Editor of Journal of Anesthesia. H.C.H. is an Editor of the British Journal of Anaesthesia and an Editor of Anesthesiology. Grants-in-Aid for Scientific Research (no. 26460695 to J.K.), Japan; National Institutes of Health, Bethesda, MD, USA (H.C.H.).