Pain is a complex multidimensional sensation that includes sensory, affective, cognitive, and motor aspects. With the development and refinement of new imaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), cortical and subcortical structures were found to be involved in pain transmission (1,2). It became evident that not a single pain center but, rather, a matrix of supraspinal central nervous system regions account for pain processing. Within this brain network, a regional specialization of function has been shown. Sensory aspects of pain are processed by the lateral pain system (lateral thalamic nuclei, S1, S2), while the affective dimension is encoded in the medial pain system (medial thalamic nuclei, anterior cingulate cortex [ACC]) (3).
Functional imaging methods also provide a noninvasive means to study changes in brain activation (fMRI, H215O-PET), metabolism (FDG-PET), or receptor occupancy (ligand-PET) in response to pharmacological interventions. Various drugs have been shown not only to attenuate the sensation of experimental pain but also to change central activation patterns in a specific way. For instance, fentanyl infusion significantly augmented pain-related relative cerebral blood flow (rCBF) increases in the prefrontal cortex and supplementary motor area (4). In an fMRI study, remifentanil infusion has been shown to most significantly modulate pain processing in the contralateral insula (5). The selective serotonin reuptake inhibitor fluvoxamine, administered over 7 days, reduced pain-induced activations in the ACC, insula, S2, lentiform nucleus, and cerebellum (6).
Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been used in clinical medicine for more than 30 yr. At the NMDA receptor site, ketamine reduces the excitatory effect of glutamate. Although the NMDA blockade is believed to mainly determine the analgesic properties of ketamine, the drug also interacts with opioidergic, σ, as well as cholinergic, noradrenergic, dopaminergic, and serotoninergic receptors.
Electrophysiological studies have suggested that during ketamine anesthesia sensory input may reach primary cortical areas but that processing in associated areas may be depressed (7,8). The condition of the patient resembles a state of catalepsy, evoked by inhibition of the coordination between neocortical-thalamic and limbic-reticular brain structures. According to psychological changes and clinical phenomena during this state (e.g., analgesia, separation of personality and environment, maintenance of consciousness), this unique type of anesthesia was termed “dissociative anesthesia” (9).
The effects of racemic ketamine on rCBF have been investigated by two H215O-PET studies. The results showed that ketamine induced the most profound dose-dependent increases in rCBF in the ACC, frontal cortex, and insula (10). Holcomb et al. (11) reported a monophasic pattern of rCBF alteration with pronounced increases in the ACC and frontal cortex and decreases in the cerebellum only.
FMRI was used in an attempt to document the effects of ketamine on the blood oxygen level-dependent (BOLD) signal during an experimental pain setting. Rogers et al. (12) revealed a decrease in the activation of the cerebral pain network by combining a high intensity pain stimulus with subanesthetic, but relatively high doses of the less potent racemic ketamine.
Ketamine is currently available as racemic and S-(+)-isomer, with the isomer thought to have stronger analgesic potency and a preferable side effect profile concerning psychomimetic properties. Less intense psychomimetic adverse effects improve the interpretability of analgesic effects during neuroimaging techniques. No information from functional imaging studies is available about the impact of S-(+)-ketamine on pain modulation, especially its pharmacodynamic effects on brain regions suspected to be involved in pain unpleasantness and pain intensity.
This study was designed to investigate the dose-dependent differential modulation effects of S-(+)-ketamine on a functional whole brain level by fMRI. We expected attenuation of the subjective pain experience and concomitantly of cerebral pain activation by S-(+)-ketamine in a dose-dependent manner. As ketamine has been shown to predominantly affect pain unpleasantness (13), we hypothesized greater alterations in the medial pain system with respect to the lateral.
Twelve right-handed male volunteers without any history of neurological, psychiatric, or internal medical disease participated in the study. Their age ranged from 23 to 36 yr, with a mean (±sd) age of 27 ± 4.6 yr. All participants fasted at least 3 h before the study, received detailed information about the experimental heat pain stimulation procedure, and were informed about the application of different IV drugs (including ketamine) in 4 sessions on 1 day. Subjects were blinded as to the order of administration of the drugs. All volunteers were free to withdraw from the study at any time and gave written informed consent. The study protocol was approved by the local ethics committee and the study was conducted in accordance with the declaration of Helsinki.
We performed a pilot study (n = 6) to define a ketamine dose (which was then used as maximal dose) with minimal psychomimetic properties but reproducible analgesic effects. Ketamine doses used in the pilot study based on manufacturer's recommendation (product monograph), a literature search, previous clinical research (8,14,15), and our own clinical experience. Considering all factors, we found 0.15 mg · kg−1 · h−1 S-(+)-ketamine to be the ideal maximal infusion rate that best met our above-mentioned criteria.
The study was conceptualized as a block design of 4 successive fMRI sessions using an identical pain stimulation protocol in all sessions (Fig. 1). The subjects remained in the scanner continuously between sessions 1 and 4. In the first session, participants received placebo infusion (0.9% saline—referred to as condition ‘P'). In the other 3 sessions, they received 3 increasing doses of ketamine (0.05 [“K1”], 0.1 [“K2”], 0.15 mg · kg−1 · h−1 [“K3”] with an infusion pump). A period of 30 min between sessions was used to acquire an anatomical brain scan and to ensure equilibration of the ketamine dose. While remaining in the scanner, the volunteers were asked to rate the intensity and unpleasantness of pain stimulation after each of the 4 experimental sessions on a numerical rating scale (NRS) ranging from 0 to 100 (0 = no pain, 100 = maximal pain) (Fig. 1). At the end of the last scanning session, the NRS results were crosschecked by interrogating the participants about their subjective awareness of a difference concerning the pain sensation during the four conditions. Thereby, the subjects were asked to group the sessions in order from the most painful to the least painful session. These results were then compared to the pain ratings obtained directly after each session.
The stimulation protocol consisted of a series of heat pulses with 4 non-noxious (3°C below the individual pain threshold) and 4 noxious (1°C above the individual pain threshold) stimuli. Volunteers received noxious and non-noxious stimuli in an alternating order (Fig. 1). Stimuli were applied to the right volar forearm with a 30 × 30 mm thermode using the MEDOC TSA-2001 thermal stimulator system (Medoc, Ramat-Yishai, Israel).
The individual pain threshold was assessed using a step protocol, in which the temperature from baseline (35°C) increased at a rate of 4°C/s to the next temperature step, which was maintained for 40 s. Individually, this protocol was applied and repeated with 0.5°C increments to the next temperature step until reaching a temperature giving rise to a moderate pain sensation (NRS rating between 40/100 and 60/100) was reached. This individual temperature was then used for all fMRI scans. Subjects were blinded as to the applied temperature of the thermode.
To avoid thermal skin damage, noxious heat stimuli undulated with a frequency of 0.5 Hz and an amplitude of 1°C starting from the individual pain threshold (16). The non-noxious heat stimuli also undulated with the identical frequency and amplitude starting 3°C below the individual pain threshold. Between the experimental stimuli a 20-s neutral stimulus of 35°C was used to determine basal neuronal activity. The thermode temperature was also maintained constantly at 35°C between the fMRI sessions.
Electrocardiogram and arterial oxygen saturation (Sao2) were measured and continuously recorded, and noninvasive arterial blood pressure measurements were performed at 5-min intervals using a MRI-suitable monitoring device (Datex-Ohmeda S/5 MRI Shield Compact Anesthesia Monitor; Datex-Ohmeda® Helsinki, Finland).
The degree of alteration in consciousness was measured using the German version of the 5D-ABZ-questionnaire (17) directly before the scanning and again immediately after the last experimental session (Fig. 1). This questionnaire is a modified version of the original APZ rating scale including the so called “BETA” questionnaire and covers 5 dimensions (factors) comprising 94 items altogether. Each item is answered on a visual analog scale (0–100). Briefly, the first dimension, “oceanic boundlessness” (OSE, 27 items), measures derealization and depersonalization. The second dimension, “visionary restructuralization” (VUS, 18 items), includes illusions, (pseudo-) hallucinations, synesthesias, and altered experience of meaning. The third subscale, “anxious ego-dissolution” (AIA, 21 items), measures thought disorder, delusions, and loss of control over body and thought associated with arousal and anxiety. The fourth factor evaluates “auditive alteration” (AVE, 16 items) and the fifth measures the dimension “vigilance reduction” (VIR, 12 items). The reliability and validity of these scales have been proven to be satisfactory and a tested version of these scales is available in German (17).
MRI was performed on a 1.5 Tesla Siemens Symphony scanner equipped with Quantum gradients. The volunteers' heads were positioned comfortably inside a receive-only 2-channel birdcage head coil, supplied with ear plugs, heavily padded and secured with a strap across the forehead to minimize head motion. A high resolution 1-mm isotropic T1 weighted MPRage scan of the entire brain was obtained to provide anatomical information to superimpose functional activation maps. We used Echo Planar Imaging for the acquisition of the functional data. Acquisition parameters were: TR: 2510 ms; TE: 50 ms; flip angle: 90°; 220 time points; matrix: 64 × 64; FOV: 230 × 230 mm; 28 slices (whole brain); resulting voxel size: 3 × 3 × 5 mm.
Preprocessing and statistical analysis of the fMRI data were conducted with the Statistical Parametric Mapping software (SPM2; Wellcome Department of Imaging Neuroscience, London, UK) (18). fMRI data series were realigned and resliced with 4th degree B-spline interpolation to correct motion artifacts. Scans with sudden head movements of more than 2 mm were omitted. To enable intersubject analysis, the functional data were coregistered to the anatomical scan and transformed into a reference space according to the MNI template of SPM2 by normalization using trilinear interpolation (19). The resampled voxel volume of the normalized images was 3 × 3 × 3 mm. Subsequently, data were smoothed with an isotropic Gaussian kernel of 10 mm full-width at half maximum (FWHM) to reduce high-frequency noise and to account for anatomical variances. Condition-specific effects were estimated in SPM2 with the general linear model using a boxcar approach convolved with the hemodynamic response function. High-pass filtering removed the low frequency noise of the scanner. Statistical parametric maps of pain activation during placebo (P) and each ketamine dose (K1; K2; K3) were generated as t-contrasts for each subject individually (noxious versus baseline). Likewise, statistical parametric maps of the nonpainful heat activation during placebo and the 3 ketamine doses were generated (nonpainful heat versus baseline). The resulting contrast images were used to perform second-level analysis (random effects) with a one-sample Student's t-test (P < 0.05 FDR corrected for multiple comparisons).
Furthermore, ketamine dose response functions of the pain conditions respectively nonpainful heat conditions were created for each subject individually. We thereby evaluated decreases in brain activation resulting from increases in ketamine dose for the pain conditions (P>K1>K2>K3; contrast setting: 1.5 0.5 −0.5 −1.5) and for the nonpainful heat conditions (P>H1>H2>H3) (20). These contrasts were used for second level analysis, in which a region of interest (ROI) analysis was performed for the rostral ACC, midcingular ACC, thalamus, S1, S2, prefrontal cortex, inferior parietal cortex, insula, and amygdala. Here, predefined structural ROIs as defined by the marsbar ROI tool (21) were used. Results were corrected for multiple comparisons in all analyses (P < 0.05, Bonferroni corrected).
To distinguish brain structures affected by decreases in pain unpleasantness from those affected by pain intensity, we calculated weighted dose response functions. In these contrasts, either the intensity or unpleasantness ratings were incorporated. This was done by a regression analysis of the individual ratings (orthogonalized) multiplied with the contrast setting of each condition (ROI analysis with P < 0.05 Bonferroni corrected for multiple comparisons).
Systemic hemodynamic and respiratory values are presented in Table 1. Minor but significant (P < 0.05; Wilcoxon test) changes between the conditions were observed for diastolic and mean arterial blood pressure. Systolic blood pressure, heart rate, and oxygen saturation did not significantly change during the experimental conditions.
The applied average pain temperature was 44.9°C ± 0.3°C, whereas the applied temperature during the non-noxious heat condition was 41.9°C ± 0.3°C. The NRS pain ratings during the placebo condition (48.3/100 for pain unpleasantness and 54.2/100 for pain intensity) indicated a moderate pain magnitude.
Ketamine administration induced an almost linear reduction in pain NRS ratings (Fig. 2), with a highly significant decrease (from 48.3/100 during placebo to 21.7/100 during the highest ketamine dose; P < 0.001; Greenhouse-Geisser test) in pain unpleasantness during ketamine dose increase. The intensity ratings also decreased significantly (from 54.2/100 during placebo to 41.7/100 during the highest ketamine dose; P < 0.01) with increasing ketamine dose but to a lesser degree.
The crosschecking validated the results of the NRS ratings. No mismatch of the NRS ratings (being rated directly after each session) and the crosscheck at the end of the experiment was identified.
The volunteers answered the 5 dimensions of the ABZ questionnaire twice (before the placebo condition and after completion of the experiment).
Scores for the dimensions OSE, AIA, VUS, and VIR increased significantly (P < 0.05; Wilcoxon test) after administration of ketamine. A slight but nonsignificant (P = 0.11) increase was also noted for the AVE scores (Fig. 3).
During placebo administration, pain-induced BOLD increases were found in regions known to be part of the pain processing network (thalamus, S2, ACC, insula, cerebellum, prefrontal cortex). With increasing ketamine dose, the number of brain regions activated by painful stimulation decreased. Statistical results of the functional imaging are summarized in Table 2. Figure 4 shows t-statistic maps of comparisons between baseline and pain stimulation in the different experimental conditions (placebo, 0.05, 0.1, 0.15 mg · kg−1 · h−1 ketamine).
Effect sizes from the dose response function analysis of the pain conditions are presented in Figure 5 (P>K1>K2>K3). A significant decrease of the BOLD signal for the condition P>K1>K2>K3 is evident in the S2 region and insula contralaterally and in the mid-ACC (ROI analysis with P < 0.05, Bonferroni corrected for multiple comparisons). No significant decreases were found for the other regions included in the ROI analysis. During the nonpainful heat conditions, no significant decrease in BOLD signal with increasing ketamine dose was observed (no significant results in ROI and whole brain analysis in P>H1>H2>H3).
In the weighted dose-response function analysis, which included the pain intensity ratings of the volunteers, we detected a significant attenuation of activation in the contralateral insula and S2 region (P < 0.05 Bonferroni corrected for multiple comparisons in ROI analysis).
The weighted dose-response function analysis with inclusion of the pain unpleasantness ratings showed variation of the BOLD signal in bilateral S2, contralateral insula, and mid-ACC (ROI analyses with P < 0.05 Bonferroni corrected for multiple comparisons for all regions).
We investigated subjective pain perception and cerebral pain processing during S-(+)-ketamine and placebo administration in healthy subjects by fMRI. Ketamine was given in three increasing doses, which were defined in a pilot study as being analgesic but not anesthetic and as having minor psychomimetic effects. During placebo infusion, pain ratings of intensity and unpleasantness indicated a moderately painful perception. The corresponding pain activation matrix was similar to the findings of previous functional brain imaging studies (2,3): significant activation was observed in the thalamus, insula, S2, prefrontal cortex, ACC, and cerebellum, depicting activation of the medial and lateral pain system. With increasing dosage of the NMDA antagonist, ketamine, the number of activated regions, as well as the subjective pain ratings, decreased (Table 2, Figs. 2 and 4). Ratings of pain intensity were less significantly affected than pain unpleasantness by an increase in ketamine dosage, indicating that ketamine has a stronger effect on the affective pain component. This finding is in accordance with a recent study, in which racemic ketamine significantly altered the unpleasantness of cutaneous pain stimulation but not the intensity (13).
In our study, ROI analysis of the dose-response functions of ketamine during pain stimulation revealed significant changes in the ACC and insula/S2 region bilaterally. The correlation of the dose-response functions with the unpleasantness ratings underlines the role of the ACC. This ACC modulation is not surprising considering the strong effect we observed on pain unpleasantness because rCBF, as an indicator of cerebral neuronal activity, has been reported to positively correlate with pain unpleasantness in the ACC (2). Moreover, hypnotic modulation of the affective reaction to pain-induced rCBF changes in the same region (22). Studies investigating affective responses to external stimuli other than pain also indicated a participation of the mid-ACC in the processing of emotions. Consistently, the mid-ACC was activated by facial expression of disgust, unpleasant musical dissonance, words with negative semantic content, unpleasant odors, and itching (23,24).
The second major finding of our study is a suppression of S2 and insula activity by ketamine. A similar attenuation of pain-induced activations in S2 has been induced by tranquilizing and hypnotic drugs, suggesting that this region plays a major role in the analgesic effects of general anesthesia (25). The S2 region is situated close to the perisylvian fissure and has long been known to participate in pain processing. Seizures originating in this region can be painful (26,27), and lesions of perisylvian cortex can cause alterations in pain perception (28–30). Based on electrophysiology and functional brain imaging, it has been hypothesized that the S2 cortex is involved in the detection and recognition of the noxious nature of painful stimuli (25,31).
Pain-related insular activity was also attenuated by increases in S-(+)-ketamine dose. Although this brain region is activated in most functional brain imaging studies on pain, its role in pain processing has not been definitely determined. It has been linked to the medial, as well as to the lateral, pain system (3). As it therefore seems to play an intermediate or integrating role between the medial and lateral pain systems, it is interesting that in our study the insula was affected by decreases in pain unpleasantness as well as by decreases in pain intensity.
Our study assessed, for the first time, the effect of S-(+)-ketamine instead of racemic ketamine on cerebral sensory processing. In both animals and humans, S-(+)-ketamine has been shown to possess an approximately 4 times stronger analgesic effect than R-(-)-ketamine (32–35) and is therefore more potent than racemic ketamine as well. Moreover, in equianalgesic doses fewer psychic disturbances and less agitation than R-(-)-ketamine or the racemate are evoked (33,34,36). The favorable side effect profile, significant improvement in recovery, and reduced quantitative drug load of S-(+)-ketamine are the reasons for an increasing clinical application of S-(+)-ketamine. Moreover, the beneficial effects of minor psychomimetic adverse reactions results in more reliable subjective ratings.
Our results with S-(+)-ketamine-induced modulation in the ACC, insula, and S2 region are partly inconsistent with a previous fMRI study using racemic ketamine (12). Similar to our results, Rogers et al. (12) found general decreases in activation of the cerebral pain network resulting from ketamine administration. More specifically, modulation of pain-induced activity in the insula, thalamus, and the ACC was observed by Rogers et al. (ACC as trend only). As a consequence, the main mismatch between Rogers et al. and our study is the lack of significant thalamic modulation in our data set. Differences not only in the isomeric structure and dose of ketamine but also in the applied pain stimulus (moderate pain intensity in our study and strong pain intensity in the study of Rogers et al.) might have contributed to this mismatch.
In an fMRI study with pharmacological intervention, a generalized effect of the study drug on the cerebral vasculature and/or the coupling between neuronal and metabolic activity cannot be completely eliminated. However, racemic ketamine has been shown to affect brain activity focally rather than globally (12,37). Therefore, fMRI is a suitable tool to identify the analgesic impact of racemic ketamine on pain processing and to distinguish these phenomena from general anesthetic effects (12). In comparison to racemic ketamine, S-(+)-ketamine constitutes a pharmacological advance in terms of unspecific side effects. Hence the focal, instead of global, alterations by ketamine on cerebral hemodynamics should also apply for S-(+)-ketamine. Although we did not use a nonsensory control task, the lack of alterations in the cerebral processing of non-noxious heat supports the view of pain-specific effects by S-(+)-ketamine in our study. Moreover, none of the subjects we investigated showed any sign of anesthesia or subanesthesia. Although the sedation scores of the 5D-ABZ questionnaire clearly increased with ketamine application, the overall sedation can be considered as being mild in our study. Because of the characteristics of the questions and the use of a visual analog scale, the 5D-ABZ questionnaire detects very subtle changes in vigilance, leading to relatively large increases in the score. Other imaging studies published on ketamine using similar questionnaires for psychomimetic effects did not provide data for vigilance ratings. Direct comparisons with the literature are therefore not possible. However, the psychomimetic ratings were much higher in previous ketamine studies (38,39), suggesting that sedation was also considerably lower in our study cohort.
The mild degree of sedation we noted is inherent to the drug in analgesic doses and can, therefore, not be omitted by varying the study paradigm. However, we cannot completely exclude that a subtle change in vigilance may have contributed to the experimental results. Concerning the NRS ratings, none of the subjects had problems actively rating pain intensity and unpleasantness, and the rating results were confirmed by crosschecking, which supports the validity of the presented ratings.
We used a study design without randomization because randomization inevitably requires multiple scanning sessions per volunteer in studies with ketamine. Multiple scanning sessions would require a long inter-session time period, as in some cases ketamine analgesia may last for hours or even days after the acute psychotropic effects have subsided (35,40,41). In a previous fMRI study, we (42) investigated effects of serial heat pain stimulation on pain perception and processing and found no time-dependent effects as did Rogers et al. (12) in their study with serial heat stimulation. Finally, in one methodological study, Ibinson et al. (43) stated that there is no fMRI signal decay across pain sessions, if there is at least a 4-minute interval between sessions, which applies to our study.
S-(+)-ketamine attenuates the overall perception of painful stimuli by affecting the central processing of pain with differential effects on pain unpleasantness and pain intensity. A clearly pronounced effect on the affective component of pain was detected. This was reflected by a dose-dependent decrease in ACC activity. Pain processing in S2 and the insula was also affected in our fMRI study, which is in line with previous electrophysiological studies suggesting that sensory input is disrupted before reaching somatosensory association areas.
The authors thank Mary E. Spilker, PhD for her thoughtful comments on drafts of the manuscript.
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