There are several aspects of touch. In addition to a well-defined discriminative role, touch has an affective dimension of fundamental importance to physical, emotional and social well-being, both developmentally and throughout life (McGlone et al., 2014). C-tactile afferents, a subclass of unmyelinated low threshold mechanosensitive C-fibers innervating human hairy skin, are strongly implicated as the neurobiological substrate subserving the affective and rewarding properties of touch (McGlone et al., 2014).

C-tactile afferents have slow conduction velocities (~1 m s⁻¹) which, along with other neurophysiological properties such as fatigue to repeated stimulation, makes them poorly suited for tactile discrimination (Vallbo et al., 1999; Olausson et al., 2010; McGlone et al., 2014). Instead, microneurography and psychophysical investigations indicate that C-tactile afferents preferentially respond to tactile velocities and forces typical of a gentle caress (Löken et al., 2009; Ackerley et al., 2014a) with peak firing rates that positively correlate with perceived touch pleasantness (Löken et al., 2009).

In keeping with a role in signalling the affective aspects of touch, selective C-tactile stimulation activates contralateral posterior insula cortex (Olausson et al., 2002; Olausson et al., 2008), a region considered a gateway for sensory systems to emotional cortical areas (Craig, 2008), but not somatosensory areas S1 and S2 (Olausson et al., 2002; Olausson et al., 2008). In addition, patients with ischemic stroke affecting the posterior contralateral opercular-insular cortex demonstrate impairments in the perception of C-tactile optimal touch (Kirsch et al., 2019). Likewise, posterior insula activation is not modulated by C-tactile optimal stimulation in individuals with congenital C-fiber denervation (Morrison et al., 2011). C-tactile-mediated affective touch pathways are, therefore, proposed to diverge from the Aβ low threshold mechanoreceptor afferent dorsal column/medial-lemniscal discriminative touch stream and form a distinct coding channel projecting primarily to emotional rather than classical somatosensory cortical regions (Craig, 2002; Morrison et al., 2010; McGlone et al., 2014).

The major somatosensory input into primate dorsal posterior insular cortex arise from the posterior ventral medial nucleus of thalamus (Craig et al., 1994; Craig and Zhang, 2006). Spinal inputs to this thalamic relay derive, almost exclusively, from projection cells in dorsal horn lamina I via the spinothalamic tract (Craig and Zhang, 2006). The central terminals of C-low threshold mechanosensitive receptor (C-LTMR) afferents, the animal equivalent of C-tactile afferents, arborise in laminae II/IIIi of the spinal cord dorsal horn (Light and Perl, 1979; Sugiura, 1996; Li et al., 2011; Abraira and Ginty, 2013; Larsson and Broman, 2019). Lamina II cells activated by C-LTMR afferents arborise in lamina I (Lu and Perl, 2005; Maxwell et al., 2007; Lu et al., 2013) where they can contact projection neurons (Lu et al., 2013).

Thus, the ‘dual pathway’ model of discriminative and emotional touch predicts that signals arising from C-tactile activation diverge from dorsal column-bound Aβ inputs to ascend alongside other small-diameter primary afferent modalities in the lamina I spinothalamic pathway. Accordingly, disruption of the spinothalamic tract, which lies within the anterolateral funiculus of the spinal cord, would, in addition to causing contralateral deficits in classical spinothalamic modalities of pain, temperature and itch, be predicted to induce alterations in affective but not discriminative touch domains. To test this prediction the effects of targeted spinothalamic tract ablation on discriminative and affective touch were investigated in patients undergoing anterolateral cordotomy to treat refractory unilateral cancer-related pain.

Assessment of noxious and innocuous temperature, itch and noxious mechanical sensation as well as discriminative and affective aspects of touch were performed on the pain-affected and unaffected sides in 19 patients undergoing anterolateral cordotomy. All sensory testing was performed on hairy skin of the dorsal forearm distant to the sites of clinical pain. No patient had pre-existing neurological deficits in the area of testing. The cordotomy was performed percutaneously at cervical level C1/C2 on the side contralateral to clinical pain. A cordotomy electrode was inserted under X-ray guidance in to the anterolateral funiculus of the spinal cord (Figure 1a and b). Lesioning was performed using a radiofrequency current to produce heat-induced lesions targeting the spinothalamic tract (for clinical and procedural-related information see Materials and methods and Supplementary file 1). The pre-test, post-test design resulted in four conditions; pre-cordotomy pain-affected, pre-cordotomy control, post-cordotomy pain-affected and post-cordotomy control.

Figure 1

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As expected, anterolateral cordotomy induced clear-cut contralateral deficits in canonical spinothalamic modalities: there was striking amelioration of clinical pain (Supplementary file 1); perceptual thresholds for innocuous temperature and thermal pain were markedly elevated (Related-Samples Wilcoxon Signed Rank Test all p<0.0005) (Figure 1c and d and Supplementary file 2a) and in the majority of patients thermal sensibility was abolished; Cowhage-induced itch was abolished (Supplementary file 2a). In contrast tactile acuity and graphesthesia were unchanged (Supplementary file 2a). These findings, therefore, confirm marked cordotomy-induced disruption of lamina I spinothalamic pathways.

The pleasant aspects of touch were evaluated using structured psychophysical assessments based on characteristic C-tactile stimulus-response properties. C-tactile afferents respond optimally to gentle skin stroking and display peak firing rates to stroking stimuli delivered with velocities of ~3 cm s⁻¹ (Löken et al., 2009; Ackerley et al., 2014a). The resulting inverted U-shaped relationship of the neural response to brushing velocity is, critically, matched by subjective ratings of touch pleasantness (Löken et al., 2009; Ackerley et al., 2014a). Correspondingly, pre-cordotomy visual analogue scale (VAS) ratings for touch pleasantness to gentle brushing stimuli were greater to stroking at 3 cm s⁻¹ than at 0.3 and 30 cm s⁻¹ (Figure 2a - d). However, cordotomy did not affect ratings for touch pleasantness (Figure 2a- d and Supplementary file 2b). Regression analysis of brush velocity and VAS scores for all four conditions showed that a negative quadratic regressor provided a better fit than a linear regressor (F test, p=0.001–0.003). The negative quadratic term, β₂, and extracted Y-intercept values for individual patients, which provide measures of the degree of the inverted U-shape and overall perceived touch pleasantness across all velocities respectively, were not significantly altered by cordotomy (Figure 2d-f and Supplementary Table 3). For individual patients a negative quadratic regressor provided a better fit than a linear regressor (F test, p=0.05 or less) for 14/19 (pre-cordotomy pain affected, pre-cordotomy control) and 13/19 (post-cordotomy pain affected and post-cordotomy control) patients.

Figure 2

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Ratings of touch intensity, which show a close correlation with A-β low threshold mechanoreceptor afferent firing rates, increased with increasing brushing velocity as expected (Figure 3a-c) (Löken et al., 2009). This pattern was present in all conditions, however, VAS touch intensity across all velocities was significantly lower following cordotomy in the pain-affected side (Figure 3a-b and Supplementary file 2b). Ratings for both touch pleasantness and intensity on the control side (i.e. ipsilateral to the cordotomy lesion) were unaffected by anterolateral cordotomy. Therefore, counter to our prediction that spinothalamic tract lesioning would reduce the pleasant properties of touch, we found instead that touch intensity – a generally accepted discriminative function - was reduced.

Figure 3

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We also used the Touch Perception Task (Guest et al., 2011; Ackerley et al., 2014b) to measure any changes in touch hedonics. In the Touch Perception Task ratings for sensory/discriminative and affective/emotional descriptors are provided in response to specific tactile events. Relative to hairy skin, gentle stroking of skin lacking C-tactile innervation (e.g. palmar glabrous skin) results in lower ratings for positive emotionally relevant terms (e.g. calming and comfortable) (Ackerley et al., 2014b; McGlone et al., 2012). Here, a stroking stimulus was applied at C-tactile optimal velocity (3 cm s⁻¹) using a force-controlled (0.22 N) device attached to which was a material typically perceived as either pleasant (fake fur) or unpleasant (sandpaper). Mean ratings for individual sensory/discriminative and affective/emotional descriptor terms are shown in Figure 4a. Using principle component analysis to reduce the number of variables, four sensory/discriminative factors; termed ‘texture’, ‘pile’, ‘slip’ and ‘heat’; and three affective emotional factors; termed ‘positive’, ‘arousal’ and ‘negative’; were extracted from the data sets (see Materials and methods). Each of these factor terms are variably contributed to by the descriptors allowing for computation of an overall weighted factor score. The changes in weighted score for the factor terms between the pre-cordotomy and post-cordotomy states are shown in Figure 4b-g. Prior to cordotomy, stroking with fur resulted in high mean descriptor ratings and weighted factor scores for positive emotional terms, as well as discriminative terms relating to surface pile (e.g. fluffy, soft) (Figure 4a). However, these were all unaffected by cordotomy, further supporting the finding that following spinothalamic tract disruption the emotional descriptive profile for soft stroking of hairy skin does not shift towards that seen with stimulation of skin lacking C-tactile innervation (Figure 4a-g) (McGlone et al., 2012). In contrast, for stimulation with sandpaper, which is an unpleasant stimulus, lesioning significantly attenuated roughness perception (Figure 4a-b) and, concomitantly, shifted the affective valance of tactile sensation from negative to positive (Figure 4a,f and g). Ratings for both sensory and emotional descriptor terms were unaffected on the control side (Figure 4a-g).

Figure 4

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The development of a velocity-tuned preference to slow touch is dependent on the activity of small diameter afferents, presumably C-tactile fibers. Patients who have congenital C-fiber denervation, but normal A-β fiber function, lack the inverted U-shaped relationship between stroking velocity and pleasantness (Morrison et al., 2011; Macefield et al., 2014). Instead, their rating patterns indicate a reliance on A-β low threshold mechanosensitive receptor afferent inputs. If there were a dedicated lamina I spinothalamic coding channel responsible for the perception of affective aspects of touch one would expect post-cordotomy affective touch metrics to shift towards those seen in patients with congenital C-fiber denervation. However, here we have shown that, unlike the unambiguous absence of the perceptions of temperature, itch and pain following anterolateral cordotomy, judgments about touch pleasantness, including that predicated on distinctive velocity tuned C-tactile responses, were unaltered. This unexpected finding poses an intriguing question about the functional neuroanatomy of hedonic touch. How, and in what form, might C-tactile afferents impart their emotionally salient activity on the higher central nervous system?

Slow, stroking stimuli targeting C-LTMR afferents do elicit velocity tuned responses in lamina I projection neurons in rats (Andrew, 2010). These projection neurons are, however, wide dynamic range and also respond to noxious stimuli (Andrew, 2010). Furthermore, C-LTMR terminals in dorsal horn lamina IIi that connect to lamina I projection neurons (Lu and Perl, 2003; Maxwell et al., 2007; Lu et al., 2013) do so via an interneuronal relay subject to complex regulation (Larsson and Broman, 2019). Other recent evidence suggests that rodent C-LTMR afferents access the dorsal column pathway (Abraira et al., 2017) via the interneuronal rich dorsal horn zone spanning lamina II_iv through lamina V that receives synapses from myelinated and unmyelinated low threshold mechanosensitive receptor subtypes (Li et al., 2011; Abraira and Ginty, 2013; Abraira et al., 2017). Integrated outputs from this recipient zone target the indirect, post-synaptic dorsal column pathway (Abraira et al., 2017). C-LTMR terminals in the dorsal horn paradoxically, given the poor spatial resolution of C-tactile-mediated touch (Olausson et al., 2002; McGlone et al., 2014; Olausson et al., 2007), show precise somatotopic arrangement with little overlap (Kuehn et al., 2019). This suggests that C-LTMR afferents, rather than signalling directly, shape the processing of hairy skin A-β subtypes in ‘somatotopically relevant’ manner (Kuehn et al., 2019).

Unlike in individuals with congenital small afferent fiber deficits, the integrative processing and shaping between C-Tactile and A-β low threshold mechanoreceptor afferents in neurodevelopmentally intact individuals, whether within the dorsal horn, subcortical regions or distributed cortical regions, will have been present over a lifetime. Whilst the emerging realization of the complexity of processing of tactile information at the earliest central nervous system relay (Abraira et al., 2017) suggests a more complex explanation it is conceivable that the cordotomy patients may have learned to associate certain tactile velocities with touch pleasantness and thus rely purely on ascending A-β low threshold mechanoreceptor afferent inputs when making judgements about the affective/emotional properties of touch. In either case the current findings indicate in individuals with a neurodevelopmentally normal somatosensory system that fibers ascending outside the anterolateral funiculus, most likely within the dorsal columns, provide sufficient information to conserve judgements about touch pleasantness.

A contralateral reduction in ratings for the intensity of stroking touch across all velocities was seen following anterolateral cordotomy although monofilament tactile detection thresholds were not affected. It is unlikely that these effects relate to a selective loss of ascending C-tactile inputs. There is evidence that C-tactile afferents contribute to the relative preservation of monofilament tactile detection in A-β denervated individuals and under conditions of A-fiber blockade (Cole et al., 2006; Nagi et al., 2015). However, their mean firing rates, unlike those of A-beta afferent LTMRs, do not correlate with the touch intensity ratings that increase in parallel stroking velocity (Löken et al., 2009; Ackerley et al., 2014a). Although the precise mechanisms underlying the reduction in the perceived intensity of stroking touch following cordotomy are unclear they too may relate to the distributed signalling of tactile information across multiple ascending pathways.

The current findings support such an integrative model of hedonic touch also for human hairy skin. They are, in fact, incompatible with a segregated model of touch where emotional and discriminative elements are signaled in anatomically discrete second order pathways. Indeed, the contralateral attenuations of texture perception and touch intensity seen post-cordotomy indicate that, for hairy skin, tactile information quintessentially regarded as discriminative and dependent on A-β activity (Saal and Bensmaia, 2014; Manfredi et al., 2014; Lieber et al., 2017), also partly relays in crossed pathways ascending the anterolateral funiculus.

All data generated or analysed during this study are either included in the manuscript and supporting files or available on Open Science Framework (https://osf.io/g8vyk/).

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Acceptance summary:

This is an important piece of work, elegant in its simplicity and match of the methods to the question. Now we know that C-fiber mediated pleasurable touch requires a pathway outside of the STT.

Decision letter after peer review:

Thank you for submitting your article "Spinal signaling of C-fiber mediated pleasant touch in humans" for consideration by eLife. Your article has been reviewed by three peer reviewers, including Peggy Mason as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by Christian Büchel as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: David A Mahns (Reviewer #2); Martin Schmelz (Reviewer #3).

All reviewers agree that this work is important and compelling. The changes suggested can all be addressed through revising the writing.

Please address the issues raised by reviewer 3; viz the roles of Ab learning and of a decrease in pain allowing for pleasantness.

Reviewer #1:

This is a clear and important demonstration that C-fibers underlying pleasant touch perception do not travel exclusively or even predominantly in the STT. The experiment is delightfully simple as in straightforward. Results are clear. Conclusions are warranted.

"touch intensity – a generally accepted discriminative function – was reduced," but only on pain affected side. This is not a critical point but warrants at least a mention of "we can’t explain this" or "we speculate that…."

I did not understand Figure 4B-G. Are these different factors that each depend on a group of words relevant to the term listed in the figure? This is a short paper and the authors have plenty of room to expand. I suggest taking a sentence or two to bring the reader along.

Reviewer #2:

This article addresses a simple question in somatosensory physiology, which ascending spinal pathways relay information about pleasant touch in patients undergoing an anterolateral cordotomy. The authors have used patients scheduled for cordotomy to test whether the perception of pleasant touch evoked by gentle brushing, a stimulus presumed to be preferential for C-tactile fibres, is abolished by sectioning the contralateral tract at the C1-2 level of the spinal cord. Prior to sectioning patients felt spontaneous / ongoing pain in thoracic, lumbar and sacral innervation territories whereas itch, touch, pain and thermal sensibility were normal at the test site in the forearm. Following cordotomy, there was an amelioration of clinical pain, while itch and touch (mechanical)-evoked pain were abolished, cold sensation / cold pain detection thresholds were fell and warm detection/ heat pain threshold rose. In contrast the pleasantness ratings were unaffected by chordotomy and retained an inverted U tuning frequently ascribed to response profile of C-tactile fibres and pleasant touch.

Overall the article is clear and concise and raises a key question, is information about pleasant touch relayed in dedicated pathways or distributed across multiple ascending pathways. The results clearly demonstrate that, in contrast to the prevailing narrative in the field of affective touch, that it is indeed the latter – the authors are commended for presenting an alternative view that will drive a deeper investigation of this field. Consequently, the results are clear novel and should be published as soon as possible.

Reviewer #3:

In this study patients undergoing antero-lateral cordotomy were investigated prospectively concerning the expected reduction of small fiber mediated function as compared to expectedly unchanged A-β function. In particular low threshold mechanosensitive C-fibers (C-touch) were studied. The main result is given by the unchanged pleasantness ratings after cordotomy contrasting the basically abolished other small fiber functions such as pain and itch. Moreover, touch intensity ratings were reduced indicating reduced processing of A-β information.

The authors conclude that C-touch fiber function is not abolished by the antero-lateral cordotomy and therefore might rather follow the dorsal column pathway in human. Moreover, they propose an integrative model of touch in which c-touch fibers, albeit primarily involved in emotional aspects of touch, also contribute to touch discrimination by their spinal interaction with A-β input.

The beauty of this paper is investigating patients prospectively before a defined neurosurgical procedure to allow for conclusions on the effects on central pathway of the studied sensory qualities directly in humans. In particular, this approach allows to study the question whether or not the C-touch fibers are dependent on the spinothalamic tract. While the approach is straight forward some additional aspects need to be dealt with in the Discussion to strengthen the implications of unchanged pleasantness ratings after anterolateral chordotomy:

The authors suggest that unchanged velocity-tuned pleasantness ratings imply intact C-touch fibers as this function is abolished in patients with congenital C-fiber denervation. However, it is unclear to which extent live-long learning processes might be sufficient to link a certain touch velocity (as detected by the A-beta system) to pleasantness. Such a learning process might reduce the impact of actual sensory input from C-touch fibers.

Moreover, it is unclear to which extent abolished pain from the test sites affected pleasantness ratings.

It is unclear how many patients suffered from brush evoked allodynia before the operation. The observed reduction of touch intensity after chordotomy might be linked to possibly abolished allodynia or reduced ongoing nociceptive input.

The authors propose an integrative view in which C-touch fibers contribute to discriminative touch perception. It is not quite clear how they link this probably valid assumption to their results: reduced touch perception would not quite fit to such an interaction on the spinal level as this connection can be assumed to be unaffected by the chordotomy.

Reviewer #1:

This is a clear and important demonstration that C-fibers underlying pleasant touch perception do not travel exclusively or even predominantly in the STT. The experiment is delightfully simple as in straightforward. Results are clear. Conclusions are warranted.

"touch intensity – a generally accepted discriminative function – was reduced," but only on pain affected side. This is not a critical point but warrants at least a mention of "we can’t explain this" or "we speculate that…."

The following has been added to the Discussion:

“A contralateral reduction in ratings for the intensity of stroking touch across all velocities was seen following anterolateral cordotomy although monofilament tactile detection thresholds were not affected. […] Although the precise mechanisms underlying the reduction in the perceived intensity of stroking touch following cordotomy are unclear they too may relate to the distributed signalling of tactile information across multiple ascending pathways.”

I did not understand Figure 4B-G. Are these different factors that each depend on a group of words relevant to the term listed in the figure? This is a short paper and the authors have plenty of room to expand. I suggest taking a sentence or two to bring the reader along.

The following has been added:

“Ratings for individual descriptor terms and weighted scores for factors, extracted using principle component analysis (see Materials and methods), were calculated.”

Has been replaced by:

“Here, a stroking stimulus was applied at C-tactile optimal velocity (3 cm s^-1) using a force-controlled (0.22 N) device attached to which was a material typically perceived as either pleasant (fake fur) or unpleasant (sandpaper). […] The changes in weighted score for the factor terms between the pre-cordotomy and post-cordotomy states are shown in Figure 4B-G.”

Reviewer #3:

[…] The beauty of this paper is investigating patients prospectively before a defined neurosurgical procedure to allow for conclusions on the effects on central pathway of the studied sensory qualities directly in humans. In particular, this approach allows to study the question whether or not the C-touch fibers are dependent on the spinothalamic tract. While the approach is straight forward some additional aspects need to be dealt with in the Discussion to strengthen the implications of unchanged pleasantness ratings after anterolateral chordotomy:

The authors suggest that unchanged velocity-tuned pleasantness ratings imply intact C-touch fibers as this function is abolished in patients with congenital C-fiber denervation. However, it is unclear to which extent live-long learning processes might be sufficient to link a certain touch velocity (as detected by the A-beta system) to pleasantness. Such a learning process might reduce the impact of actual sensory input from C-touch fibers.

The perception of touch will depend on the entirety of tactile afferent inputs. In a neurodevelopmentally intact somatosensory system there will almost certainly be considerable integration of A-β low threshold mechanosensitive receptor and C-tactile afferents at a number of anatomical levels. The authors agree that individuals may 'learn' to associate touch with a positive affective valence (engendered by C-tactile afferents inputs) with a particular velocity that could be signaled and detected by A-β low threshold mechanosensitive receptor fibres. However, this does not change the conclusion that with an intact somatosensory system fibres ascending outside the spinothalamic tract are sufficient to preserve the perception of touch pleasantness. The following has been added to the Discussion:

“Unlike in individuals with congenital small afferent fibre deficits, the integrative processing and shaping between C-Tactile and A-β low threshold mechanoreceptor afferents in neurodevelopmentally intact individuals, whether within the dorsal horn, subcortical regions or distributed cortical regions, will have been present over a lifetime. […] In either case the current findings indicate in individuals with a neurodevelopmentally normal somatosensory system that fibres ascending outside the anterolateral funiculus, most likely within the dorsal columns, provide sufficient information to conserve judgements about touch pleasantness.”

Moreover, it is unclear to which extent abolished pain from the test sites affected pleasantness ratings.

The patients had no pain at the test sites. This has been further emphasised in the

Methods

“No patient had pre-existing symptoms or signs of neurological impairment,

including pain, in the region of sensory testing.”

and Results

“All sensory testing was performed on hairy skin of the dorsal forearm distant to

the sites of clinical pain. No patient had pre-existing neurological deficits in the

area of testing.”

It is unclear how many patients suffered from brush evoked allodynia before the operation. The observed reduction of touch intensity after chordotomy might be linked to possibly abolished allodynia or reduced ongoing nociceptive input.

No patient had allodynia at the test site and indeed had ‘normal’ pleasantness ratings pre-cordotomy on both the painful and control sides (see Results). A single patient complained of allodynia on the chest wall which is distant from the test site (see Supplementary file 1).

The authors propose an integrative view in which C-touch fibers contribute to discriminative touch perception. It is not quite clear how they link this probably valid assumption to their results: reduced touch perception would not quite fit to such an interaction on the spinal level as this connection can be assumed to be unaffected by the chordotomy.

Rather than suggesting that C-tactile fibres contribute to tactile discrimination we are proposing that projection neurons in the anterolateral funiculus contribute to aspects of touch that are typically thought of as discriminative. Since the encoding of the intensity of an innocuous stroking cutaneous stimulus and the signaling of texture are thought to be A-β mediated this implies that A-β inputs gain access to ascending pathways in the anterolateral funiculus.

The following statement about touch intensity has been added to the Discussion:

“A contralateral reduction in ratings for the intensity of stroking touch across all velocities was seen following anterolateral cordotomy although monofilament tactile detection thresholds were not affected. […] Although the precise mechanisms underlying the reduction in the perceived intensity of stroking touch following cordotomy are unclear they too may relate to the distributed signalling of tactile information across multiple ascending pathways.”

Also, to reflect the findings that suggest projection neurons in the anterolateral funiculus contribute to aspects of touch that are typically thought of as discriminative the Discussion ends with the statement:

“Indeed, the contralateral attenuations of texture perception and touch intensity seen post-cordotomy indicate that, for hairy skin, tactile information quintessentially regarded as discriminative and dependent on A-β activity (Saal and Bensmaia, 2014; Manfredi et al., 2014; Lieber et al., 2017), also partly relays in crossed pathways ascending the anterolateral funiculus.”

Author details

1. Andrew G Marshall

   1. Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
   2. School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, United Kingdom
   3. Department of Pain Medicine, Walton Centre NHS Foundation Trust, Liverpool, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Methodology, Project administration

   For correspondence

   andrew.marshall@liverpool.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8273-7089

2. Manohar L Sharma

   Department of Pain Medicine, Walton Centre NHS Foundation Trust, Liverpool, United Kingdom

   Contribution

   Conceptualization, Resources, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Kate Marley

   Specialist Palliative Care Team, University Hospital Aintree, Liverpool, United Kingdom

   Contribution

   Investigation

   Competing interests

   No competing interests declared

4. Hakan Olausson

   1. Specialist Palliative Care Team, University Hospital Aintree, Liverpool, United Kingdom
   2. Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden
   3. Department of Clinical Neurophysiology, Linköping University Hospital, Linköping, Sweden

   Contribution

   Conceptualization, Supervision

   Competing interests

   No competing interests declared

5. Francis P McGlone

   1. School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, United Kingdom
   2. Institute of Psychology, Health and Society, University of Liverpool, Liverpool, United Kingdom

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Project administration

   Competing interests

   No competing interests declared

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