
==== Front
Neuropsychopharmacology
Neuropsychopharmacology
Neuropsychopharmacology
0893-133X
1740-634X
Springer International Publishing Cham

38918578
1906
10.1038/s41386-024-01906-2
Article
Ketamine reduces the neural distinction between self- and other-produced affective touch: a randomized double-blind placebo-controlled study
http://orcid.org/0000-0003-2177-7380
Kaldewaij Reinoud reinoud.kaldewaij@liu.se

12
Salamone Paula C. 1
Enmalm Adam 1
Östman Lars 1
Pietrzak Michal 1
Karlsson Hanna 1
Löfberg Andreas 1
Gauffin Emelie 1
Samuelsson Martin 1
Gustavson Sarah 1
http://orcid.org/0000-0003-1758-2206
Capusan Andrea J. 1
http://orcid.org/0000-0002-6319-1786
Olausson Håkan 12
Heilig Markus 12
http://orcid.org/0000-0003-2803-3069
Boehme Rebecca 12
1 https://ror.org/05ynxx418 grid.5640.7 0000 0001 2162 9922 Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden
2 https://ror.org/05ynxx418 grid.5640.7 0000 0001 2162 9922 Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
25 6 2024
25 6 2024
10 2024
49 11 17671774
19 1 2024
7 6 2024
14 6 2024
© The Author(s) 2024, corrected publication 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
A coherent sense of self is crucial for social functioning and mental health. The N-methyl-D-aspartate antagonist ketamine induces short-term dissociative experiences and has therefore been used to model an altered state of self-perception. This randomized double-blind placebo-controlled cross-over study investigated the mechanisms for ketamine’s effects on the bodily sense of self in the context of affective touch. Thirty healthy participants (15 females/15 males, age 19–39) received intravenous ketamine or placebo while performing self-touch and receiving touch by someone else during functional MRI – a previously established neural measure of tactile self-other-differentiation. Afterwards, tactile detection thresholds during self- and other-touch were assessed, as well as dissociative states, interoceptive awareness, and social touch attitudes. Compared to placebo, ketamine administration elicited dissociation and reduced neural activity associated with self-other-differentiation in the right temporoparietal cortex, which was most pronounced during other-touch. This reduction correlated with ketamine-induced reductions in interoceptive awareness. The temporoparietal cortex showed higher connectivity to somatosensory cortex and insula during other- compared to self-touch. This difference was augmented by ketamine, and correlated with dissociation strength for somatosensory cortex. These results demonstrate that disrupting the self-experience through ketamine administration affects neural activity associated with self-other-differentiation in a region involved in touch perception and social cognition, especially with regard to social touch by someone else. This process may be driven by ketamine-induced effects on top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. These findings provide further evidence for the intricate relationship of the bodily self with the tactile sense.

Subject terms

Sensorimotor processing
Perception
Social neuroscience
Human behaviour
https://doi.org/10.13039/501100003246 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) 019.211SG.005 Kaldewaij Reinoud https://doi.org/10.13039/501100004359 Vetenskapsrådet (Swedish Research Council) 2019-01873 Boehme Rebecca issue-copyright-statement© American College of Neuropsychopharmacology 2024
==== Body
pmcIntroduction

Our sense of self is crucial for our well-being and social interactions. Self-related disturbances can be found in several psychiatric conditions, including schizophrenia [1]. Ketamine offers a pharmacological model for an altered state of self-perception as it induces short-term dissociative experiences. Here, we investigated the effects of ketamine on self-other-distinction and its neural underpinnings in the context of affective touch, using functional MRI and psychophysical measures.

The profound and multifaceted experience of selfhood is widely considered to be anchored in bodily self-awareness [2]. A coherent bodily self relies on the multimodal integration of sensory information, including interoceptive and proprioceptive signals from within our body [3, 4]. The sense of touch plays a crucial role in forming and maintaining this bodily self [5]. From early life on, touch enables us to experience bodily self-boundaries [6]. These experiences are often social in nature and involve affective touch, for example when a baby perceives caressing touch from a parent [7]. Affective touch, which is typically slow in speed and perceived as pleasant, typically involves C-tactile (CT) afferents peripherally [8] and affect-related cortical areas such as the insula centrally [9]. Interestingly, the insula is known to be involved in processing interoceptive signals, i.e. sensations from within our own body [10]. Following these observations, the CT-system has been suggested to be concerned with the establishment and maintenance of the bodily self [11]. Cortical processing of CT-mediated signals seems to differentiate between self- and non-self- generated sensations, further supporting the notion of a critical role for the social other in maintaining a functional bodily self: Activation across a broad range of regions involved in somatosensation and socio-affective processing is attenuated during self-produced touch compared to affective touch from others [12]. This raises the question: does the somatosensory system play a role in self-related dysfunctions?

Disturbances related to the sense of self can be found across several psychiatric disorders, e.g. in schizophrenia, dissociative disorders, and anorexia [13], and “Perceptions and understanding of self” has been included as a transdiagnostic Research Domain Criteria dimension [14, 15]. Such disturbances severely impact well-being and mental health: self-disorders correlate with impaired social functioning and suicidality [16]. Self-related dysfunctions are rarely addressed in currently available therapies, and they often persist even when other symptoms improve. This might be in part due to the complexity of self-related dysfunction and its co-occurrence with other symptoms.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is a dissociative anesthetic drug, clinically used in anesthesia and in lower doses in the treatment of depression [17, 18] and chronic pain [19, 20]. It has been suggested as a pharmacological model of self-related functional alterations, since it produces a state that resembles aspects of endogenous psychoses [21–23]. For example, ketamine administration in healthy individuals is associated with an aberrant experience of agency [24] and increased illusory body ownership [25]. If a coherent sense of self and bodily self-other-distinction are intertwined, a reduced self-other-distinction is expected in the dissociated state elicited by ketamine. However, it remains unknown if ketamine administration alters tactile self-other-distinction, and if so, through which neural mechanisms.

In this randomized double-blind placebo-controlled within-subject study, participants received intravenous ketamine during functional MRI, while experiencing self- or other-produced affective touch on the forearm (Fig. 1). Affective touch is operationalized as slow and gentle touch which is generally perceived as pleasant [26]. Moreover, dissociative states were assessed, and a psychophysical task was employed to determine tactile detection thresholds during self- and other-touch. Our preregistered hypotheses were that ketamine reduces the distinction of self- and non-self-generated touch, based on the known dissociative effects of ketamine at a subanesthetic dose [21]. Specifically, we hypothesized that differences in neural signatures of self-touch and other-touch [12] are smaller under ketamine than under placebo, as we have previously shown that regions involved in somatosensation and socio-affective processing differentiate between other-touch and self-touch [12]. We now predicted that these regions would differentiate less during the ketamine session when participants are expected to have dissociative experiences. Moreover, we predicted that tactile detection thresholds during self-touch are lower under ketamine, in line with notions of reduced attenuation of self-produced sensations in self-disorders [27, 28]. We further expected these changes to relate to measures of interoception and attitudes towards social touch, i.e. to alterations in how intra- and inter-subjective signals are experienced.Fig. 1 Experiment overview.

A Timeline of the drug administration sessions. CADSS clinician administered dissociative state scale. Self-report STQ, MAIA, and AQ questionnaires. B Self-other-touch paradigm [12]. The position of the touched arm (red) and object (yellow) during the MRI session.

Materials and methods

The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Swedish Ethical Review Authority (2020-06515) and the Swedish Medical Products Agency. The study protocol is registered in clinical trials database EudraCT (2020-004487-25). The analysis plan was preregistered on the Open Science Framework before unblinding (https://osf.io/grud4).

Participants

After a pre-screening during the initial phone contact, 34 potential participants were screened, of whom 31 were included. One participant dropped out during the second MRI session (visit 4), due to nausea. A total of 30 healthy participants (15 females, 15 males, mean age: 24.8 years, age range 19–39) completed the study. This sample size was preregistered and based on a power calculation for a two-phase cross-over comparison with 80% power to detect an effect size of Cohen’s D ≥ 0.6 at alpha = 0.05, i.e., a medium—large effect size. Exclusion criteria included: any clinically significant medical condition, any current clinically significant psychiatric problems including any diagnosis of alcohol or substance use disorder, history of psychotic experiences, familial history (first and second degree relatives) of psychosis or alcohol use disorder, known hypersensitivity to ketamine, use of central nervous system active medications, inability to provide a negative drug screen test, pregnancy or breastfeeding, and contraindications for MRI. Participants received 1500 Swedish kronor (approximately $150) as reimbursement. All participants provided written consent before study participation.

Procedure

The study had a within-subject, cross-over, double-blind, randomized placebo-controlled design. The study consisted of four sessions: (1) a screening visit; (2) a baseline visit including informed consent, questionnaires (social touch questionnaire (STQ) [29], autism spectrum quotient (AQ) [30], multidimensional assessment of interoceptive awareness (MAIA) [31]), and a heartbeat detection task; and two (3 & 4) ketamine/placebo administration sessions including functional MRI (self-other-touch task), interview of dissociative experiences (Clinician-Administered Dissociative States Scale (CADSS), psychophysics (tactile threshold task), and the aforementioned questionnaires. Participants were randomized 1:1 to one of two groups which received ketamine (Ketamin Abcur 10 mg/ml, dosage 0.5 mg/kg body weight during a 40 min i.v. infusion without bolus) on either the first or second MRI session. During the other MRI session, participants received placebo (standard saline infusion). The fMRI task started approximately 20 min after the start of infusion to ensure that robust ketamine plasma concentrations were achieved. Randomization was stratified by gender. To optimize blinding, participants were informed that they may receive placebo or ketamine in any or both sessions, and that the dosage may differ between sessions. They also received basic information about the potential side-effects of ketamine, including dissociative symptoms. See supplement for a detailed description of each session and the analysis of questionnaire data.

Experimental tasks

Self-other-touch paradigm

Participants performed our previously established self-other-touch paradigm (Fig. 1) [12, 32]. The task has a randomized block design and consists of three different conditions: stroking of the own left forearm (self-touch), being stroked by the experimenter (other-touch) or stroking a pillow (object-touch). To allow for stroking movements within the scanner, the left forearm was placed on the participant’s belly. For the object-touch condition, a small, sand-filled, rectangular pillow with a soft, skin-like surface was placed right above the left forearm. Participants were instructed to stroke gently, as they would touch someone they like, with their right hand. They received textual instructions regarding the upcoming block on a screen viewed through MR-compatible goggles (VisuaStim Digital; Resonance Technologies). The instructions were presented in Swedish for 3 s: “Active, please stroke your arm”; “Active, please stroke the object”; “Passive, your arm will be stroked by the experimenter.” When the text turned from white to green, the participant was stimulated or had to perform the stimulation for as long as the text was on the screen (12 s). During this condition the experimenter mimicked the motion and touched area of the participants as closely as possible. Each of the three conditions occurred 10 times and consisted of stimulation for 12 s followed by 12 s rest, resulting in a total duration of 13.5 min (Fig. 1). The female experimenter performing the strokes stood next to the scanner bore and received auditory cues on the timing of the other-touch condition via headphones. Participants met this experimenter beforehand and the same experimenter performed the touch in both sessions if logistically feasible, which was the case for 80% of the participants.

Touch threshold task

A previously described procedure for the touch threshold task was followed [12], using von-Frey monofilaments (Bioseb) of increasing thickness and the same three different touch conditions as during the MRI session. See supplement for a full description of the procedure and the analysis.

Functional MRI analysis

See supplement for a detailed description of the MRI acquisition protocol and preprocessing steps. Statistical analyses were performed using the general linear model approach (SPM12). At the first-level (single-subject level), regressors of interest were the blocks of stimulation (self-touch, other-touch, and object-touch). Regressors of no interest were added for the cue phase (separately for each block) and arm movements after each active block (self-touch and object-touch; duration: 1 sec), when subjects put their arm back into a resting position. To account for movement associated variance, realignment parameters and their first temporal derivates were included as regressors of no interest, as well as a regressor censoring scans with more than 1 mm scan-to-scan movement. Contrast maps were generated for the other-touch vs. self-touch condition, as well as the self-touch vs. object-touch condition. Movement-corrected contrast maps were generated by contrasting other-touch vs. [self-touch minus object-touch].

At the second-level, a paired samples t-test was used to quantify ketamine vs. placebo effects on other-touch vs. (movement-controlled) self-touch contrast maps. For whole-brain analyses, results were corrected for multiple comparisons using the family-wise error (FWE) correction based on Gaussian random field theory at the voxel-level (as implemented in SPM and shown to be valid [33]). In addition, within four a-priori (and preregistered) regions of interest (anatomically defined), a small volume correction (SVC) was used: right posterior superior temporal gyrus, right insula, right anterior cingulate cortex, and right postcentral gyrus (functionally known as primary somatosensory cortex). Given strong evidence for involvement of the thalamus and the posterior cingulate in dissociation [34–37] exploratory (non-preregistered) analyses also assessed activation differences in these regions.

Initial analyses of a treatment (ketamine vs. placebo) effect on activation differences for self vs. other touch revealed significant voxels showing reduced activation in the cerebellum (See supplement). Control analyses showed the same effect of ketamine on activation differences for object-touch vs. other-touch, indicating that the cerebellar activation differences related to the arm movements (inherent to the self-touch and object-touch conditions), rather than touch sensations. We anticipated this issue in our preregistered analysis plan, so we used a movement-controlled analysis in the remainder of our analysis, in line with previous work [32]. For this analysis, object-touch contrast maps were subtracted from the self-touch contrast maps. Crucially, control analyses showed that ketamine did not modulate differences between self- and object-touch (paired-sample t-test on self-object contrast maps for ketamine vs. placebo, in both directions; no significant voxels on the whole-brain FWE-corrected level).

See supplement for a description of the follow-up generalized psycho-physiological interaction (gPPI) analysis [38].

Results

Ketamine induced a dissociative state

Participants indicated a significantly higher dissociative state after receiving ketamine compared to placebo (range increase 1–39 points, t(29) = 9.81, p < 0.001, Cohen’s d = 1.79, Fig. 2). See Figure S2 for difference scores on individual items and distribution across participants.Fig. 2 Ketamine administration induced a dissociative state.

Dissociative states determined by a clinical interview (clinician administered dissociative state scale, CADSS) were higher for all participants during the ketamine session compared to the placebo session.

Ketamine was associated with reduced neural distinction of self- versus other-generated touch sensations

Stronger activation for other-touch compared to self-touch during the placebo session was found in right postcentral gyrus (S1) and bilateral posterior superior temporal gyrus (pSTG)/parietal operculum, among other regions, replicating previous findings [12]. See Fig. 3A and table S1. During the ketamine session, a similar pattern was found, i.e. higher S1 and bilateral pSTG activation for other- vs. self-touch (Fig. 3B and table S2).Fig. 3 Ketamine administration was associated with a reduced distinction of self- versus other-generated touch sensations at the neural level.

A, B Activation differences for other- vs. self-touch under placebo A and ketamine B. C Ketamine reduces self-other-differentiation in the right temporoparietal cortex. Negative values indicate a ketamine-related reduction. D Mean beta-values for the different treatment and touch conditions, extracted from the cluster of voxels for display purpose, showing the significant interaction depicted in C. All statistical maps displayed according to the neurological convention, thresholded at p < 0.001 uncorrected for display purpose. Axial cut-through slices are at level Z = 18 according to the MNI system.

Comparing ketamine and placebo directly revealed that the difference in right temporo-parietal cortex (rTPC) activation for other- vs. self-produced affective touch was reduced when participants received ketamine (interaction between treatment (placebo vs. ketamine) and condition (other-touch vs. self-touch): pFWE(whole brain) = 0.012, MNIxyz = 58,−32,22; Fig. 3C; see Fig. 3D for an illustration of the nature of the interaction). The peak of this interaction effect was located on the border between the parietal operculum (or S2), pSTG, and supramarginal gyrus (SMG), and the expanded dorsally towards the anterior temporoparietal junction and ventromedially towards the posterior insula. This interaction effect overlapped with two preregistered volumes of interest: the STG (SVC pFWE < 0.001, MNIxyz = 58,−32,22) and the border of S1 (SVC pFWE = 0.032, MNIxyz = 62,−16,22). No suprathreshold voxels were found in the right ACC and right insula. Additional analyses for each condition separately (see Supplement Table S3) revealed a significant reduction in activation in the TPC under ketamine for other-touch, but not for self-touch or object-touch. See supplement for an exploratory task-based functional connectivity analysis using the rTPC as a seed region.

In sum, during ketamine administration, the neural distinction between self- and other-produced affective touch was preserved but attenuated in the right temporoparietal cortex, rendering the neural signal during other-touch more similar to the neural signal during self-touch (Fig. 3C, D). Hereafter, this interaction effect is referred to as “reduction in temporoparietal distinction”.

Ketamine did not affect tactile detection thresholds during self- and other-generated touch

Participants showed increased touch thresholds for stimulation with von Frey filaments administered simultaneously with both the self- and other-touch condition compared to baseline in the placebo condition (Fig. S4). No evidence was found for the hypothesized reduction in tactile detection thresholds during self-touch under ketamine (t(28) = 0.97, p = 0.34), indicating that a sub-anesthetic dose of ketamine did not significantly affect basic sensing of tactile stimuli. See supplement for further analyses.

Ketamine was associated with alterations in social touch attitudes and interoceptive awareness

Social touch (STQ) scores were lower after ketamine compared to placebo, indicating a relative increase in social touch seeking (or decrease in social touch avoidance) during the ketamine session (t(29) = −2.14, p = 0.041, Cohen’s d = 0.39). Total interoceptive awareness (MAIA) scores did not differ between ketamine and placebo sessions (t(29) = −0.087, p = 0.93). See supplement of an analysis of MAIA-subscales. Session differences for total MAIA-scores (∆-MAIA) and STQ-scores (∆-STQ) were inversely correlated (r = −0.41, p = 0.024), indicating that increases in interoceptive awareness accompanied increases in social touch seeking.

Ketamine-induced changes in reported experiences related to changes in neural markers of self-other-distinction

An exploratory analysis assessed the relationships between ketamine-related changes in reported experiences and ketamine-related reductions in temporoparietal distinction. Reductions in temporoparietal distinction correlated with reductions in interoceptive awareness (∆-MAIA; r = 0.54, p = 0.002, Fig. 4A). ∆-MAIA was also associated with reductions in self-other-distinction in rInsula, rSTG, rACC, bilateral thalami and posterior cingulate cortex (see Table S6). In accordance with the negative relationship between ∆-MAIA and ∆-STQ described above, reduced temporoparietal distinction correlated negatively with increased social touch seeking tendencies (∆-STQ) (r = −0.39, p = 0.034). However, mediation analyses showed that this was an indirect relationship mediated by ∆-MAIA (indirect relationship: B = −0.15, bootstrapped CI [−0.35, −0.0033], p < 0.05, see Fig. 4B).Fig. 4 Ketamine-induced changes in experiences related to ketamine-induced changes in neural self-other-distinction.

A Reductions in self-other-distinction correlated with reductions in interoceptive awareness (∆-MAIA). Negative values indicate a ketamine-related reduction. B The relationship between ketamine-induced changes in temporoparietal self-other-distinction and social touch seeking (the inverse of touch-avoidance; ∆-STQ) was mediated by ketamine-induced changes in interoceptive awareness. *p < 0.05. C Ketamine-induced connectivity differences (other vs. self-touch) between the right temporoparietal cortex and right S1 correlated with ketamine-induced dissociative states. Y-value refers to MNI-coordinate of cut-through slice. Maps are thresholded at p < 0.001 uncorrected for display purpose. D Visualization of the relationship between dissociation and connectivity between the temporoparietal cortex and S1, for the ketamine session. Mean beta-values for the different touch conditions are extracted from the voxels depicted in C.

In an additional exploratory connectivity analysis, change in dissociation symptoms (∆-CADSS) was included as a regressor. ∆-CADSS correlated with the increase in ketamine-induced rTPC-rS1 connectivity during other- vs. self-touch (SVC pFWE = 0.034, MNIxyz = 26,−32,56, Fig. 4C, D), but not with rTPC-rIns and rTPC-rACC connectivity. See supplement for a similar analysis assessing the relationship between functional connectivity and ∆-MAIA.

Discussion

This study investigated the effects of ketamine on self-other-distinction in the context of affective touch. Since the bodily self is established and maintained through tactile inputs (among others), we hypothesized that changing the experience of the bodily self using a sub-anesthetic dose of ketamine known to evoke dissociative experiences would be accompanied with a change in touch processing. Using an established task that shows strong neural self-other-distinction of touch under normal conditions [12], we found that this distinction was reduced in the right temporoparietal cortex (rTPC) when people experienced a mild dissociative state. Activity in this region related to changes in interoceptive awareness and its connectivity with the right S1 correlated with dissociation.

The effects of ketamine on the bodily self are of special interest as ketamine has been suggested as a model for certain aspects of schizophrenia [21, 23]. Ketamine has also shown efficacy as a treatment, especially for depression [17, 18, 39] and pain [19, 20]. However, the antidepressant effects of ketamine appear to be unrelated to the dissociative experience during ketamine administration [40, 41] and might depend on distinct underlying mechanisms [42]. The same has been suggested for the use of ketamine to manage pain [43], (but also see [44]). Our study used ketamine specifically to induce an acute altered state of self, therefore the results will be discussed mainly with a focus on their relation to the sense of self and alteration of it as seen e.g. in psychosis. Similar to other psychedelic drugs, ketamine induces an altered state of consciousness, but its effect on disembodiment is more pronounced compared to, for example, psilocybin [45]. Ketamine is a non-competitive NMDA receptor antagonist, and its pharmacological effects include disruptions of glutamatergic and dopaminergic systems [22]. Glutamatergic signaling occurs mainly via NMDA receptors at descending (top-down) connections [46]. NMDA receptor blockade leads to a reduction of top-down signaling, i.e. reduces constraints on inferences about the causes of sensory inputs [47]. Reduced (or aberrant) top-down inference will render the processing of predictable and unpredictable stimuli more similar [47]. This process was illustrated by a recent study showing that ketamine reduced activation during surprising tactile stimuli in the mouse S1 and S2 [48]. The S2 is homologous to our locus of decreased activation during the ketamine session. In the case of psychosis, it is also suggested that top-down modulation is affected [49, 50]: Predictive coding accounts assign a central role to decreased precision of prior expectations in psychosis, potentially due to increased volatility estimates [51]. These alterations in predictive coding are thought to result in aberrant associative learning and, in the long term, the formation of delusions [22, 23].

Naturally, predictive coding plays a crucial role in the distinction of self- vs. other-generated sensations, including touch. Touch perceived from others is intrinsically more unpredictable than self-generated touch [52, 53]. Consequently, the processing of self-produced sensations is attenuated and perceived as less intense than other-generated sensations. An illustration of this phenomenon is that we do not perceive self-touch as ticklish [53–55]. In the placebo condition of the current study, the stark difference in predictability of other- vs. self-generated touch was reflected in stronger activation during other-touch, a replication of our previous studies [12, 32]. In accordance with the proposed mechanism of ketamine described here, this difference in activation was reduced during the ketamine session, rendering the neural signal closer to that of self-generated touch. This suggests that the difference in predictability of other- and self-touch was reduced because of decreased top-down signaling and less constrained inferences about the causes of sensory input under ketamine.

Our results provide new information regarding two open issues in predictive coding accounts of NMDA receptor functioning in psychosis: (1) the model is opaque about the level on which the predictive coding deficits occur. We showed that ketamine affected an intermediate processing area. (2) It is unclear if the predictive processing deficits vary between sensory domains [50]. We found effects on at least two sensory (sub)domains, social touch and interoception. These are relevant for both self-experience and social interactions, which are severely impacted in psychotic experiences.

The reduction in self-other-distinction under ketamine was specific for a region in the right temporoparietal cortex, on the border of the parietal operculum, posterior superior temporal gyrus (STG), and supramarginal gyrus (SMG). The parietal operculum is the anatomical site of the secondary somatosensory cortex (S2) [56] and is consistently involved in tactile self-other-distinction [12, 53, 55]. The S2 is one of the main output regions of the primary sensory cortex (S1), and is involved in a broad range of somatosensory functions, including (affective) body perception [57]. Lesion studies suggest that the S2 (together with the insula) is critical for the conscious perception of touch [58]. Both the posterior STG and SMG are consistently involved in social cognition [59]. This appears to be in line with their location, in between a unimodal processing area, S1, and a transmodal/abstract area, the temporoparietal junction (TPJ) [59, 60]. The TPJ plays a role in cognitive self-other-distinction, whereas affective self-other-distinction involves the SMG [61]. Taken together, ketamine affected tactile processing in an intermediate processing area located between the S1, responsible for processing the primary tactile input, and higher-order processing areas, including (1) the insula, which plays an important role in the conscious perception of touch and its integration with interoceptive information from the body [10], and (2) the TPJ, involved in social cognition [59]. Underlining this central role in touch processing, rTPC showed in our study an increased task-based connectivity to the right S1, right insula, and the thalamus during other-touch. rTPC-rS1 connectivity strength was positively correlated to dissociation symptoms under ketamine. These findings fit with previous reports that link (thalamic) hyperconnectivity with both ketamine and dissociation symptoms [34, 35, 62]. This is thought to reflect an overabundance of sensory information [35] and disruptions in the integration thereof [63]. The fact that ketamine induced increased connectivity with the rTPC but reduced its activation may be a result of a lack of specificity (or precision) of the incoming sensory signal.

The effect of ketamine on neural self-other-distinction paralleled a shift in interoceptive awareness, which was in turn associated with social touch seeking. Understanding others involves the engagement of brain and bodily functions primarily used to assess our own state [61]. However, for this mechanism to work adequately, it is important that we are able to distinguish ourselves from others [61]. Here, we show that blunted interoception is associated with blunted neural self-other-distinction, in line with the notion that our internal model of ourselves is highly dependent on interoceptive processing [3]. This relationship is also in line with the suggestion that the C-tactile-system is concerned with the establishment and maintenance of the bodily self [11] and the consistently reported involvement of the insula in both social touch perception and interoception [9, 10]. Increased touch seeking might be interpreted as a direct reaction to perceiving the own body and its boundaries less clearly under ketamine, in line with the proposed role of social touch in strengthening (and re-establishing) these bodily self-boundaries.

Ketamine significantly reduced activation in the cerebellum during self- vs. other- and object- vs. other-touch, indicating a potential effect of ketamine on the neural processes underlying action generation. This interpretation is corroborated by additional analyses showing reduced cerebellar activation during ketamine for both object- and self-touch separately. However, no evidence was found within this sample for a specific effect of self-oriented action (i.e. self- vs. object-touch). We did not have any measurement of touch parameters during the MRI scan, therefore, we cannot evaluate changes in the touching performance. However, even if the touching during self- and object-touch condition would have differed slightly between sessions, it probably would not have altered our main finding on the sensory aspects of self-other distinction, because the ketamine-related rTPC activity differences were strongest in the other-touch condition, which lacks an action generation component.

In contrast to the effects of ketamine on the neural level, we did not find any significant differences between tactile detection thresholds for self- and other-touch during the ketamine and placebo sessions. This could indicate that a subanesthetic dose of ketamine does not affect basic tactile discrimination in general, which fits with the fact that the neural effects did not occur in the primary somatosensory area. However, the results should be interpreted with caution, as we did not replicate earlier findings on differential thresholds during self-touch and other-touch in the placebo condition, suggesting that our manipulation was not completely successful. Moreover, the tactile detection thresholds were assessed approximately 15 min after administration ended, so the ketamine effects may already have been wearing off.

Participants in the current study had an accurate intuition about whether they had received ketamine during a session or not—a common challenge in placebo-controlled psychedelic studies. Although there is no obvious mechanism by which this awareness may have influenced our main result, it would be valuable to compare our results with other psychoactive drugs. Another limitation of the current study is that it did not evaluate the phenomenology of the actual touch, for example by evaluating differences in subjective experiences like perceived intensity of pleasantness. While of interest, such a measure was not implemented due to methodological concerns, i.e. the risk of drawing or altering the attention to the touch, inducing expectations about the task’s purpose, and altering touching behavior during the task. Our results may also have been influenced by potential differences in the subjective experience of touch from a relative stranger (i.e. the experimenter). Furthermore, no baseline dissociation scores were collected, but the low CADSS scores during the placebo session suggest low baseline scores (as one would expect the placebo effect to increase not decrease a baseline level of dissociation). The absence of plasma measurements of ketamine and its metabolites is another limitation. Such measurements would have been difficult to acquire in the MR setting and could have interfered with the touch task, but would have been valuable for evaluating individual differences in the pharmacokinetics/dynamics.

Conclusion

This study demonstrated that pharmacologically manipulating the experience of the bodily self is accompanied by a change in neural processing of affective touch. During ketamine administration, self-other-distinction was reduced in a region associated with touch perception and social cognition. This process may be driven by a ketamine-induced reduction in top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. Our findings provide further evidence for the intricate relationship of the bodily self with social touch.

Supplementary information

Supplemental material

Table S4

Table S5

CONSORT Flow Diagram

Supplementary information

The online version contains supplementary material available at 10.1038/s41386-024-01906-2.

Acknowledgements

The authors thank all participants for their willingness to participate in this study, L. Severin for her help in participant recruitment, and L. Severin, S. Boda, L. Medling for their support in data collection.

Author contributions

Conceptualization, RB; Formal Analysis, RK, RB, and PCS; Investigation, AE, PCS, RK, LÖ, MP, AJC, HK, AL, EG, MS, and SG; Writing—Original Draft RK, RB, PCS, and AE; Writing—Review & Editing, RB, HO, MH, AJC and RK; Visualization, RK; Supervision, RB.

Funding

Open access funding provided by Linköping University. This research was supported by a Svenska Vetenskapsrådet (VR) grant (2019-01873) and Åke Wiberg Stiftelse grant (M19-0369) awarded to RB, and an NWO-Rubicon grant (019.211SG.005) awarded to RK.

Data availability

Unthresholded activation maps are available at NeuroVault, https://identifiers.org/neurovault.collection:17403. The rest of the datasets generated during and analysed during the current study are not publicly available due restrictions from the local ethical committee, but are available from the corresponding author on reasonable request.

Competing interests

MH has received research funding or consulting fees in the past 5 years from Aelis Farma, Brainsway Technologies, Camurus, Indivior, Janssen, Molteni, Nordic Drugs and Pfizer, and he is an Associate Editor of Neuropsychopharmacology. AJC has received consultancy and speakers’ fees from Indivior, Camurus, Nordic Drugs and DNE Pharma all outside the scope of this work. All remaining authors have no competing interests.

The original online version of this article was revised: due to a typesetting mistake, the funding information was incomplete. The Funding section has been corrected from “Open access funding provided by Linköping University” to “Open access funding provided by Linköping University. This research was supported by a Svenska Vetenskapsrådet (VR) grant (2019-01873) and Åke Wiberg Stiftelse grant (M19-0369) awarded to RB, and an NWO-Rubicon grant (019.211SG.005) awarded to RK.”

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

7/22/2024

A Correction to this paper has been published: 10.1038/s41386-024-01916-0
==== Refs
References

1. Gallagher S Philosophical conceptions of the self: Implications for cognitive science Trends Cogn Sci 2000 4 14 21 10.1016/S1364-6613(99)01417-5 10637618
Gallagher S. Philosophical conceptions of the self: Implications for cognitive science. Trends Cogn Sci. 2000;4:14–21.10637618 10.1016/S1364-6613(99)01417-5
2. Blanke O Multisensory brain mechanisms of bodily self-consciousness Nat Rev Neurosci 2012 13 556 71 10.1038/nrn3292 22805909
Blanke O. Multisensory brain mechanisms of bodily self-consciousness. Nat Rev Neurosci. 2012;13:556–71.22805909 10.1038/nrn3292
3. Seth AK Tsakiris M Being a beast machine: the somatic basis of selfhood Trends Cogn Sci 2018 22 969 81 10.1016/j.tics.2018.08.008 30224233
Seth AK, Tsakiris M. Being a beast machine: the somatic basis of selfhood. Trends Cogn Sci. 2018;22:969–81.30224233 10.1016/j.tics.2018.08.008
4. Craig AD How do you feel–now? The anterior insula and human awareness Nat Rev Neurosci 2009 10 59 10.1038/nrn2555 19096369
Craig AD. How do you feel–now? The anterior insula and human awareness. Nat Rev Neurosci. 2009;10:59.19096369 10.1038/nrn2555
5. Serino A Haggard P Touch and the body Neurosci Biobehav Rev 2010 34 224 36 10.1016/j.neubiorev.2009.04.004 19376156
Serino A, Haggard P. Touch and the body. Neurosci Biobehav Rev. 2010;34:224–36.19376156 10.1016/j.neubiorev.2009.04.004
6. Ciaunica A Constant A Preissl H Fotopoulou K The first prior: from co-embodiment to co-homeostasis in early life Conscious Cogn 2021 91 103117 10.1016/j.concog.2021.103117 33872985
Ciaunica A, Constant A, Preissl H, Fotopoulou K. The first prior: from co-embodiment to co-homeostasis in early life. Conscious Cogn. 2021;91:103117.33872985 10.1016/j.concog.2021.103117
7. Tuulari JJ Scheinin NM Lehtola S Merisaari H Saunavaara J Parkkola R Neural correlates of gentle skin stroking in early infancy Dev Cogn Neurosci 2019 35 36 41 10.1016/j.dcn.2017.10.004 29241822
Tuulari JJ, Scheinin NM, Lehtola S, Merisaari H, Saunavaara J, Parkkola R, et al. Neural correlates of gentle skin stroking in early infancy. Dev Cogn Neurosci. 2019;35:36–41.29241822 10.1016/j.dcn.2017.10.004
8. Löken LS Wessberg J Morrison I McGlone F Olausson H Coding of pleasant touch by unmyelinated afferents in humans Nat Neurosci 2009 12 547 8 10.1038/nn.2312 19363489
Löken LS, Wessberg J, Morrison I, McGlone F, Olausson H. Coding of pleasant touch by unmyelinated afferents in humans. Nat Neurosci. 2009;12:547–8.19363489 10.1038/nn.2312
9. Morrison I Löken LS Olausson H The skin as a social organ Exp Brain Res 2010 204 305 14 10.1007/s00221-009-2007-y 19771420
Morrison I, Löken LS, Olausson H. The skin as a social organ. Exp Brain Res. 2010;204:305–14.19771420 10.1007/s00221-009-2007-y
10. Craig AD How do you feel? Interoception: the sense of the physiological condition of the body Nat Rev Neurosci 2002 3 655 66 10.1038/nrn894 12154366
Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3:655–66.12154366 10.1038/nrn894
11. McGlone F Wessberg J Olausson H Discriminative and affective touch: sensing and feeling Neuron 2014 82 737 55 10.1016/j.neuron.2014.05.001 24853935
McGlone F, Wessberg J, Olausson H. Discriminative and affective touch: sensing and feeling. Neuron. 2014;82:737–55.24853935 10.1016/j.neuron.2014.05.001
12. Boehme R Hauser S Gerling GJ Heilig M Olausson H Distinction of self-produced touch and social touch at cortical and spinal cord levels Proc Natl Acad Sci USA 2019 116 2290 9 10.1073/pnas.1816278116 30670645
Boehme R, Hauser S, Gerling GJ, Heilig M, Olausson H. Distinction of self-produced touch and social touch at cortical and spinal cord levels. Proc Natl Acad Sci USA. 2019;116:2290–9.30670645 10.1073/pnas.1816278116
13. Northoff G, Heinzel A. The self in philosophy, neuroscience and psychiatry: an epistemic approach. Self Neurosci Psychiatry. 2003:40–55.
14. Insel TR The NIMH research domain criteria (RDoC) project: precision medicine for psychiatry Phys Rev B 2014 171 395 7
Insel TR. The NIMH research domain criteria (RDoC) project: precision medicine for psychiatry. Phys Rev B. 2014;171:395–7.
15. Sui J Gu X Self as object: emerging trends in self research Trends Neurosci 2017 40 643 53 10.1016/j.tins.2017.09.002 28988827
Sui J, Gu X. Self as object: emerging trends in self research. Trends Neurosci. 2017;40:643–53.28988827 10.1016/j.tins.2017.09.002
16. Henriksen MG Raballo A Nordgaard J Self-disorders and psychopathology: a systematic review Lancet Psychiatry 2021 8 1001 12 10.1016/S2215-0366(21)00097-3 34688345
Henriksen MG, Raballo A, Nordgaard J. Self-disorders and psychopathology: a systematic review. Lancet Psychiatry. 2021;8:1001–12.34688345 10.1016/S2215-0366(21)00097-3
17. Zarate CA Singh JB Carlson PJ Brutsche NE Ameli R Luckenbaugh DA A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression Arch Gen Psychiatry 2006 63 856 64 10.1001/archpsyc.63.8.856 16894061
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.16894061 10.1001/archpsyc.63.8.856
18. Popova V Daly EJ Trivedi M Cooper K Lane R Lim P Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study Am J Psychiatry 2019 176 428 38 10.1176/appi.ajp.2019.19020172 31109201
Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176:428–38.31109201 10.1176/appi.ajp.2019.19020172
19. Niesters M Martini C Dahan A Ketamine for chronic pain: risks and benefits Br J Clin Pharm 2014 77 357 67 10.1111/bcp.12094
Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharm. 2014;77:357–67.10.1111/bcp.12094
20. Rogachov A Bhatia A Cheng JC Bosma RL Kim JA Osborne NR Plasticity in the dynamic pain connectome associated with ketamine-induced neuropathic pain relief Pain 2019 160 1670 9 10.1097/j.pain.0000000000001545 30839433
Rogachov A, Bhatia A, Cheng JC, Bosma RL, Kim JA, Osborne NR, et al. Plasticity in the dynamic pain connectome associated with ketamine-induced neuropathic pain relief. Pain. 2019;160:1670–9.30839433 10.1097/j.pain.0000000000001545
21. Krystal JH Karper LP Seibyl JP Freeman GK Delaney R Bremner JD Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans psychotomimetic, perceptual, cognitive, and neuroendocrine responses Arch Gen Psychiatry 1994 51 199 214 10.1001/archpsyc.1994.03950030035004 8122957
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214.8122957 10.1001/archpsyc.1994.03950030035004
22. Corlett PR Honey GD Fletcher PC From prediction error to psychosis: Ketamine as a pharmacological model of delusions J Psychopharmacol 2007 21 238 52 10.1177/0269881107077716 17591652
Corlett PR, Honey GD, Fletcher PC. From prediction error to psychosis: Ketamine as a pharmacological model of delusions. J Psychopharmacol. 2007;21:238–52.17591652 10.1177/0269881107077716
23. Corlett PR Honey GD Fletcher PC Prediction error, ketamine and psychosis: An updated model J Psychopharmacol 2016 30 1145 55 10.1177/0269881116650087 27226342
Corlett PR, Honey GD, Fletcher PC. Prediction error, ketamine and psychosis: An updated model. J Psychopharmacol. 2016;30:1145–55.27226342 10.1177/0269881116650087
24. Moore JW Turner DC Corlett PR Arana FS Morgan HL Absalom AR Ketamine administration in healthy volunteers reproduces aberrant agency experiences associated with schizophrenia Cogn Neuropsychiatry 2011 16 364 81 10.1080/13546805.2010.546074 21302161
Moore JW, Turner DC, Corlett PR, Arana FS, Morgan HL, Absalom AR, et al. Ketamine administration in healthy volunteers reproduces aberrant agency experiences associated with schizophrenia. Cogn Neuropsychiatry. 2011;16:364–81.21302161 10.1080/13546805.2010.546074
25. Morgan HL Turner DC Corlett PR Absalom AR Adapa R Arana FS Exploring the impact of ketamine on the experience of illusory body ownership Biol Psychiatry 2010 69 35 41 10.1016/j.biopsych.2010.07.032 20947068
Morgan HL, Turner DC, Corlett PR, Absalom AR, Adapa R, Arana FS, et al. Exploring the impact of ketamine on the experience of illusory body ownership. Biol Psychiatry. 2010;69:35–41.20947068 10.1016/j.biopsych.2010.07.032
26. Croy I Bierling A Sailer U Ackerley R Individual variability of pleasantness ratings to stroking touch over different velocities Neuroscience 2021 464 33 43 10.1016/j.neuroscience.2020.03.030 32224227
Croy I, Bierling A, Sailer U, Ackerley R. Individual variability of pleasantness ratings to stroking touch over different velocities. Neuroscience. 2021;464:33–43.32224227 10.1016/j.neuroscience.2020.03.030
27. Blakemore SJ Smith J Steel R Johnstone EC The perception of self-produced sensory stimuli in patients with auditory hallucinations and passivity experiences: evidence for a breakdown in self-monitoring Psychol Med 2000 30 1131 9 10.1017/S0033291799002676 12027049
Blakemore SJ, Smith J, Steel R, Johnstone EC. The perception of self-produced sensory stimuli in patients with auditory hallucinations and passivity experiences: evidence for a breakdown in self-monitoring. Psychol Med. 2000;30:1131–9.12027049 10.1017/S0033291799002676
28. Lemaitre AL Luyat M Lafargue G Individuals with pronounced schizotypal traits are particularly successful in tickling themselves Conscious Cogn 2016 41 64 71 10.1016/j.concog.2016.02.005 26891191
Lemaitre AL, Luyat M, Lafargue G. Individuals with pronounced schizotypal traits are particularly successful in tickling themselves. Conscious Cogn. 2016;41:64–71.26891191 10.1016/j.concog.2016.02.005
29. Wilhelm FH Kochar AS Roth WT Gross JJ Social anxiety and response to touch: incongruence between self-evaluative and physiological reactions Biol Psychol 2001 58 181 202 10.1016/S0301-0511(01)00113-2 11698114
Wilhelm FH, Kochar AS, Roth WT, Gross JJ. Social anxiety and response to touch: incongruence between self-evaluative and physiological reactions. Biol Psychol. 2001;58:181–202.11698114 10.1016/S0301-0511(01)00113-2
30. Baron-cohen S Wheelwright S Skinner R Martin J Clubley E The autism-spectrum quotient (AQ): evidence from asperger syndrome/high-functioning autism, males and females, scientists and mathematicians J Autism Dev Disord 2001 31 5 17 10.1023/A:1005653411471 11439754
Baron-cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord. 2001;31:5–17.11439754 10.1023/A:1005653411471
31. Mehling WE, Price C, Daubenmier JJ, Acree M, Bartmess E, Stewart A. The Multidimensional Assessment of Interoceptive Awareness (MAIA). 2012;7.
32. Frost-Karlsson M Capusan AJ Perini I Olausson H Zetterqvist M Gustafsson PA Neural processing of self-touch and other-touch in anorexia nervosa and autism spectrum condition NeuroImage Clin 2022 36 103264 10.1016/j.nicl.2022.103264 36451367
Frost-Karlsson M, Capusan AJ, Perini I, Olausson H, Zetterqvist M, Gustafsson PA, et al. Neural processing of self-touch and other-touch in anorexia nervosa and autism spectrum condition. NeuroImage Clin. 2022;36:103264.36451367 10.1016/j.nicl.2022.103264
33. Eklund A Nichols TE Knutsson H Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates Proc Natl Acad Sci USA 2016 113 7900 5 10.1073/pnas.1602413113 27357684
Eklund A, Nichols TE, Knutsson H. Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci USA. 2016;113:7900–5.27357684 10.1073/pnas.1602413113
34. Onofrj M Russo M Delli Pizzi S De Gregorio D Inserra A Gobbi G The central role of the Thalamus in psychosis, lessons from neurodegenerative diseases and psychedelics Transl Psychiatry 2023 13 384 10.1038/s41398-023-02691-0 38092757
Onofrj M, Russo M, Delli Pizzi S, De Gregorio D, Inserra A, Gobbi G, et al. The central role of the Thalamus in psychosis, lessons from neurodegenerative diseases and psychedelics. Transl Psychiatry. 2023;13:384.38092757 10.1038/s41398-023-02691-0
35. Abram SV Roach BJ Fryer SL Calhoun VD Preda A van Erp TGM Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia Mol Psychiatry 2022 27 2448 56 10.1038/s41380-022-01502-0 35422467
Abram SV, Roach BJ, Fryer SL, Calhoun VD, Preda A, van Erp TGM, et al. Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia. Mol Psychiatry. 2022;27:2448–56.35422467 10.1038/s41380-022-01502-0
36. Vesuna S Kauvar IV Richman E Gore F Oskotsky T Sava-Segal C Deep posteromedial cortical rhythm in dissociation Nature 2020 586 87 94 10.1038/s41586-020-2731-9 32939091
Vesuna S, Kauvar IV, Richman E, Gore F, Oskotsky T, Sava-Segal C, et al. Deep posteromedial cortical rhythm in dissociation. Nature. 2020;586:87–94.32939091 10.1038/s41586-020-2731-9
37. Parvizi J Braga RM Kucyi A Veit MJ Pinheiro-Chagas P Perry C Altered sense of self during seizures in the posteromedial cortex Proc Natl Acad Sci USA 2021 118 1 9 10.1073/pnas.2100522118
Parvizi J, Braga RM, Kucyi A, Veit MJ, Pinheiro-Chagas P, Perry C, et al. Altered sense of self during seizures in the posteromedial cortex. Proc Natl Acad Sci USA. 2021;118:1–9.10.1073/pnas.2100522118
38. McLaren DG Ries ML Xu G Johnson SC A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches Neuroimage 2012 61 1277 86 10.1016/j.neuroimage.2012.03.068 22484411
McLaren DG, Ries ML, Xu G, Johnson SC. A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches. Neuroimage. 2012;61:1277–86.22484411 10.1016/j.neuroimage.2012.03.068
39. Krystal JH Abdallah CG Sanacora G Charney DS Duman RS Ketamine: a paradigm shift for depression research and treatment Neuron 2019 101 774 8 10.1016/j.neuron.2019.02.005 30844397
Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: a paradigm shift for depression research and treatment. Neuron. 2019;101:774–8.30844397 10.1016/j.neuron.2019.02.005
40. Ballard ED Zarate CA The role of dissociation in ketamine’s antidepressant effects Nat Commun 2020 11 6431 10.1038/s41467-020-20190-4 33353946
Ballard ED, Zarate CA. The role of dissociation in ketamine’s antidepressant effects. Nat Commun. 2020;11:6431.33353946 10.1038/s41467-020-20190-4
41. Mathai DS Nayak SM Yaden DB Garcia-Romeu A Reconsidering “dissociation” as a predictor of antidepressant efficacy for esketamine Psychopharmacol (Berl) 2023 240 827 36 10.1007/s00213-023-06324-8
Mathai DS, Nayak SM, Yaden DB, Garcia-Romeu A. Reconsidering “dissociation” as a predictor of antidepressant efficacy for esketamine. Psychopharmacol (Berl). 2023;240:827–36.10.1007/s00213-023-06324-8
42. Tian F Lewis LD Zhou DW Balanza GA Paulk AC Zelmann R Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology Nat Commun 2023 14 12 18 36596811
Tian F, Lewis LD, Zhou DW, Balanza GA, Paulk AC, Zelmann R, et al. Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology. Nat Commun. 2023;14:12–18.36596811
43. Gitlin J Chamadia S Locascio JJ Ethridge BR Pedemonte JC Hahm EY Dissociative and analgesic properties of ketamine are independent Anesthesiology 2020 133 1021 8 10.1097/ALN.0000000000003529 32898213
Gitlin J, Chamadia S, Locascio JJ, Ethridge BR, Pedemonte JC, Hahm EY, et al. Dissociative and analgesic properties of ketamine are independent. Anesthesiology. 2020;133:1021–8.32898213 10.1097/ALN.0000000000003529
44. Olofsen E Kamp J Henthorn TK van Velzen M Niesters M Sarton E Ketamine psychedelic and antinociceptive effects are connected Anesthesiology 2022 136 792 801 10.1097/ALN.0000000000004176 35188952
Olofsen E, Kamp J, Henthorn TK, van Velzen M, Niesters M, Sarton E, et al. Ketamine psychedelic and antinociceptive effects are connected. Anesthesiology. 2022;136:792–801.35188952 10.1097/ALN.0000000000004176
45. Vollenweider FX Kometer M The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders Nat Rev Neurosci 2010 11 642 51 10.1038/nrn2884 20717121
Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Nat Rev Neurosci. 2010;11:642–51.20717121 10.1038/nrn2884
46. Self MW Kooijmans RN Supèr H Lamme VA Roelfsema PR Different glutamate receptors convey feedforward and recurrent processing in macaque V1 Proc Natl Acad Sci USA 2012 109 11031 6 10.1073/pnas.1119527109 22615394
Self MW, Kooijmans RN, Supèr H, Lamme VA, Roelfsema PR. Different glutamate receptors convey feedforward and recurrent processing in macaque V1. Proc Natl Acad Sci USA. 2012;109:11031–6.22615394 10.1073/pnas.1119527109
47. Weber LA Diaconescu AO Mathys C Schmidt A Kometer M Vollenweider F Ketamine affects prediction errors about statistical regularities: a computational single-trial analysis of the mismatch negativity J Neurosci 2020 40 5658 68 10.1523/JNEUROSCI.3069-19.2020 32561673
Weber LA, Diaconescu AO, Mathys C, Schmidt A, Kometer M, Vollenweider F, et al. Ketamine affects prediction errors about statistical regularities: a computational single-trial analysis of the mismatch negativity. J Neurosci. 2020;40:5658–68.32561673 10.1523/JNEUROSCI.3069-19.2020
48. English G Ghasemi Nejad N Sommerfelt M Yanik MF von der Behrens W Bayesian surprise shapes neural responses in somatosensory cortical circuits Cell Rep. 2023 42 112009 10.1016/j.celrep.2023.112009 36701237
English G, Ghasemi Nejad N, Sommerfelt M, Yanik MF, von der Behrens W. Bayesian surprise shapes neural responses in somatosensory cortical circuits. Cell Rep. 2023;42:112009.36701237 10.1016/j.celrep.2023.112009
49. Adams RA Stephan KE Brown HR Frith CD Friston KJ The computational anatomy of psychosis Front Psychiatry 2013 4 47 10.3389/fpsyt.2013.00047 23750138
Adams RA, Stephan KE, Brown HR, Frith CD, Friston KJ. The computational anatomy of psychosis. Front Psychiatry. 2013;4:47.23750138 10.3389/fpsyt.2013.00047
50. Sterzer P Adams RA Fletcher P Frith C Lawrie SM Muckli L The predictive coding account of psychosis Biol Psychiatry 2018 84 634 43 10.1016/j.biopsych.2018.05.015 30007575
Sterzer P, Adams RA, Fletcher P, Frith C, Lawrie SM, Muckli L, et al. The predictive coding account of psychosis. Biol Psychiatry. 2018;84:634–43.30007575 10.1016/j.biopsych.2018.05.015
51. Deserno L Boehme R Mathys C Katthagen T Kaminski J Stephan KE Volatility estimates increase choice switching and relate to prefrontal activity in Schizophrenia Biol Psychiatry Cogn Neurosci Neuroimaging 2020 5 173 83 31937449
Deserno L, Boehme R, Mathys C, Katthagen T, Kaminski J, Stephan KE, et al. Volatility estimates increase choice switching and relate to prefrontal activity in Schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020;5:173–83.31937449
52. Von Helmholtz H. Handbuch der physiologischen Optik: mit 213 in den Text eingedruckten Holzschnitten und 11 Tafeln. 9. Voss; 1867.
53. Blakemore SJ Wolpert DM Frith CD Central cancellation of self-produced tickle sensation Nat Neurosci 1998 1 635 40 10.1038/2870 10196573
Blakemore SJ, Wolpert DM, Frith CD. Central cancellation of self-produced tickle sensation. Nat Neurosci. 1998;1:635–40.10196573 10.1038/2870
54. Weiskrantz L Elliott J Darlington C Preliminary observations on tickling oneself Nature 1971 230 598 9 10.1038/230598a0 4928671
Weiskrantz L, Elliott J, Darlington C. Preliminary observations on tickling oneself. Nature. 1971;230:598–9.4928671 10.1038/230598a0
55. Kilteni K Ehrsson HH Functional connectivity between the cerebellum and somatosensory areas implements the attenuation of self-generated touch J Neurosci 2020 40 894 906 10.1523/JNEUROSCI.1732-19.2019 31811029
Kilteni K, Ehrsson HH. Functional connectivity between the cerebellum and somatosensory areas implements the attenuation of self-generated touch. J Neurosci. 2020;40:894–906.31811029 10.1523/JNEUROSCI.1732-19.2019
56. Eickhoff SB Schleicher A Zilles K Amunts K The human parietal operculum. I. Cytoarchitectonic mapping of subdivisions Cereb Cortex 2006 16 254 67 10.1093/cercor/bhi105 15888607
Eickhoff SB, Schleicher A, Zilles K, Amunts K. The human parietal operculum. I. Cytoarchitectonic mapping of subdivisions. Cereb Cortex. 2006;16:254–67.15888607 10.1093/cercor/bhi105
57. De Haan EHF Dijkerman HC Somatosensation in the brain: a theoretical re-evaluation and a new model Trends Cogn Sci 2020 24 529 41 10.1016/j.tics.2020.04.003 32430229
De Haan EHF, Dijkerman HC. Somatosensation in the brain: a theoretical re-evaluation and a new model. Trends Cogn Sci. 2020;24:529–41.32430229 10.1016/j.tics.2020.04.003
58. Preusser S Thiel SD Rook C Roggenhofer E Kosatschek A Draganski B The perception of touch and the ventral somatosensory pathway Brain 2015 138 540 8 10.1093/brain/awu370 25541190
Preusser S, Thiel SD, Rook C, Roggenhofer E, Kosatschek A, Draganski B, et al. The perception of touch and the ventral somatosensory pathway. Brain. 2015;138:540–8.25541190 10.1093/brain/awu370
59. Schurz M Radua J Tholen MG Maliske L Margulies DS Mars RB Toward a hierarchical model of social cognition: A neuroimaging meta-analysis and integrative review of empathy and theory of mind Psychol Bull 2021 147 293 327 10.1037/bul0000303 33151703
Schurz M, Radua J, Tholen MG, Maliske L, Margulies DS, Mars RB, et al. Toward a hierarchical model of social cognition: A neuroimaging meta-analysis and integrative review of empathy and theory of mind. Psychol Bull. 2021;147:293–327.33151703 10.1037/bul0000303
60. Margulies DS Ghosh SS Goulas A Falkiewicz M Huntenburg JM Langs G Situating the default-mode network along a principal gradient of macroscale cortical organization Proc Natl Acad Sci USA 2016 113 12574 9 10.1073/pnas.1608282113 27791099
Margulies DS, Ghosh SS, Goulas A, Falkiewicz M, Huntenburg JM, Langs G, et al. Situating the default-mode network along a principal gradient of macroscale cortical organization. Proc Natl Acad Sci USA. 2016;113:12574–9.27791099 10.1073/pnas.1608282113
61. Lamm C Bukowski H Silani G From shared to distinct self-other representations in empathy: Evidence from neurotypical function and socio-cognitive disorders Philos Trans R Soc B Biol Sci 2016 371 20150083 10.1098/rstb.2015.0083
Lamm C, Bukowski H, Silani G. From shared to distinct self-other representations in empathy: Evidence from neurotypical function and socio-cognitive disorders. Philos Trans R Soc B Biol Sci. 2016;371:20150083.10.1098/rstb.2015.0083
62. Driesen NR McCarthy G Bhagwagar Z Bloch M Calhoun V D’Souza DC Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans Mol Psychiatry 2013 18 1199 204 10.1038/mp.2012.194 23337947
Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D’Souza DC, et al. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Mol Psychiatry. 2013;18:1199–204.23337947 10.1038/mp.2012.194
63. Sapienza J Bosia M Spangaro M Martini F Agostoni G Cuoco F Schizophrenia and psychedelic state: Dysconnection versus hyper-connection. A perspective on two different models of psychosis stemming from dysfunctional integration processes Mol Psychiatry 2023 28 59 67 10.1038/s41380-022-01721-5 35931756
Sapienza J, Bosia M, Spangaro M, Martini F, Agostoni G, Cuoco F, et al. Schizophrenia and psychedelic state: Dysconnection versus hyper-connection. A perspective on two different models of psychosis stemming from dysfunctional integration processes. Mol Psychiatry. 2023;28:59–67.35931756 10.1038/s41380-022-01721-5
