Phantom limb pain after unilateral arm amputation is ... - zora.uzh

Zurich Open Repository andArchiveUniversity of ZurichMain LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.ch

Year: 2022

Phantom limb pain after unilateral arm amputation is associated withdecreased heat pain thresholds in the face

Fuchs, Xaver ; Diers, Martin ; Trojan, Jörg ; Kirsch, Pinar ; Milde, Christopher ; Bekrater-Bodmann,Robin ; Rance, Mariela ; Foell, Jens ; Andoh, Jamila ; Becker, Susanne ; Flor, Herta

Abstract: BACKGROUND The mechanisms underlying chronic phantom limb pain (PLP) are complexand insufficiently understood. Altered sensory thresholds are often associated with chronic pain butquantitative sensory testing (QST) in PLP has so far been inconclusive due to large methodologicalvariation between studies and small sample sizes. METHODS In this study, we applied QST in 37unilateral upper-limb amputees (23 with and 14 without PLP) and 19 healthy controls. We assessed heatpain (HPT), pressure pain, warmth detection and two-point discrimination thresholds at the residuallimb, a homologous point and the thenar of the intact limb as well as both corners of the mouth.RESULTS We did not find significant differences in any of the thresholds between the groups. However,PLP intensity was negatively associated with HPT at all measured body sites except for the residuallimb, indicating lower pain thresholds with higher PLP levels. Correlations between HPT and PLPwere strongest in the contralateral face (r = -0.65, p < 0.001). Facial HPT were specifically associatedwith PLP, independent of residual limb pain (RLP) and various other covariates. HPT at the residuallimb, however, were significantly associated with RLP, but not with PLP. CONCLUSION We concludethat the association between PLP and, especially facial, HPT could be related to central mechanisms.SIGNIFICANCE Phantom limb pain (PLP) is still poorly understood. We show that PLP intensity isassociated with lower heat pain thresholds, especially in the face. This finding could be related to centralnervous changes in PLP.

DOI: https://doi.org/10.1002/ejp.1842

Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-212435Journal ArticlePublished Version

The following work is licensed under a Creative Commons: Attribution-NonCommercial 4.0 International(CC BY-NC 4.0) License.

Originally published at:Fuchs, Xaver; Diers, Martin; Trojan, Jörg; Kirsch, Pinar; Milde, Christopher; Bekrater-Bodmann, Robin;Rance, Mariela; Foell, Jens; Andoh, Jamila; Becker, Susanne; Flor, Herta (2022). Phantom limb painafter unilateral arm amputation is associated with decreased heat pain thresholds in the face. EuropeanJournal of Pain, 26(1):114-132.

DOI: https://doi.org/10.1002/ejp.1842

2

114 | Eur J Pain. 2022;26:114–132.wileyonlinelibrary.com/journal/ejp

DOI: 10.1002/ejp.1842

O R I G I N A L A R T I C L E

Phantom limb pain after unilateral arm amputation is associated

with decreased heat pain thresholds in the face

Xaver Fuchs1,2 | Martin Diers1,3 | Jörg Trojan1 | Pinar Kirsch1 | Christopher Milde1,4 | Robin Bekrater- Bodmann1 | Mariela Rance1,5 | Jens Foell1,6 | Jamila Andoh1,7 | Susanne Becker1,8 | Herta Flor1

1Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim,

Germany

2Biopsychology and Cognitive Neuroscience, Faculty of Psychology and Sports Science, Bielefeld University, Bielefeld, Germany

3Department of Psychosomatic Medicine and Psychotherapy, LWL University Hospital, Ruhr University Bochum, Bochum, Germany

4Department of Psychology, University of Koblenz- Landau, Landau, Germany

5Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA

6Department of Psychology, Florida State University, Tallahassee, Florida, USA

7Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Heidelberg,

Germany

8Integrative Spinal Research, Research Chiropractic, Balgrist University Hospital, University of Zurich, Zurich, Switzerland

This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium,

provided the original work is properly cited and is not used for commercial purposes.

© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®

Correspondence

Xaver Fuchs, Institute of Cognitive and

Clinical Neuroscience, Central Institute of

Mental Health, Medical Faculty Mannheim,

J5, 68159 Mannheim, Germany.

Email: [email protected]

Funding information

Deutsche Forschungsgemeinschaft, Grant/

Award Number: SFB1158/B07; European

Research Council, Grant/Award Number:

FP7/2007– 2013/230249

Abstract

Background: The mechanisms underlying chronic phantom limb pain (PLP) are

complex and insufficiently understood. Altered sensory thresholds are often associ-

ated with chronic pain but quantitative sensory testing (QST) in PLP has so far been

inconclusive due to large methodological variation between studies and small sample

sizes.

Methods: In this study, we applied QST in 37 unilateral upper- limb amputees (23

with and 14 without PLP) and 19 healthy controls. We assessed heat pain (HPT),

pressure pain, warmth detection and two- point discrimination thresholds at the re-

sidual limb, a homologous point and the thenar of the intact limb as well as both

corners of the mouth.

Results: We did not find significant differences in any of the thresholds between the

groups. However, PLP intensity was negatively associated with HPT at all measured

body sites except for the residual limb, indicating lower pain thresholds with higher

PLP levels. Correlations between HPT and PLP were strongest in the contralateral

face (r = −0.65, p < 0.001). Facial HPT were specifically associated with PLP, inde-

pendent of residual limb pain (RLP) and various other covariates. HPT at the residual

limb, however, were significantly associated with RLP, but not with PLP.

| 115FUCHS ET AL.

1 | INTRODUCTION

Phantom limb pain (PLP)— pain perceived in an absent limb or

portions of an absent limb— is a common consequence of limb

amputation and occurs in about 50%– 80% (Nikolajsen, 2013)

of all amputees. Both peripheral and central mechanisms are

involved in chronic PLP (Flor & Fuchs, 2017; Flor et al., 2006;

Ramachandran & Hirstein, 1998). However, their exact roles

and impact are under debate. Peripheral factors relate to no-

ciceptive input stemming from the residual limb and can in-

volve peripheral sensitization, spontaneous discharges from

the residual limb due to involuntary movement or physiolog-

ical arousal (Sherman et al., 1989), neuromas (Devor, 1991;

Fried et al., 1991; Wiffen et al., 2006), or activity generated

in dorsal root ganglia (Vaso et al., 2014). Central sensitiza-

tion can develop as a consequence of long- term peripheral

nociceptive input and is mediated by spinal cord neurons

(Latremoliere & Woolf, 2009; Woolf & Salter, 2000) or the

brain (Woolf, 2014). In the brain, PLP has been associated

with maladaptive reorganization of body maps in the primary

somatosensory (S1) (Flor et al., 1995) and primary motor

cortex (Lotze et al., 2001) as well as preserved function of

the section of S1 that formerly represented the missing limb

(Kikkert et al., 2018; Makin, Scholz, et al., 2013).

Increased sensitivity to painful stimuli encompasses both

peripheral and central mechanisms (Woolf & Salter, 2000)

and is commonly assessed psychophysically by quanti-

tative sensory testing (QST; Magerl et al., 2010; Maier

et al., 2010; Rolke et al., 2006). Although QST has previ-

ously been applied in amputees, the results are mixed and

do not support an association with PLP. Some previous stud-

ies reported enhanced tactile (Haber, 1955; D. Katz, 1921;

Teuber et al., 1949; Wilson et al., 1962), thermal (Engkvist

et al., 1985; Wahren, 1990) or pressure pain sensitivity

(Cronholm, 1951; Korin et al., 1963; Vase et al., 2011) of

the residual limb compared to a homologous site on the in-

tact limb but did not relate these findings to PLP. The studies

that examined the relationship of tactile and pain sensitivity

to PLP mostly found no significant relationship with tac-

tile sensitivity (Grüsser et al., 2001; Hunter et al., 2005;

Katz, 1992; Li et al., 2015), heat pain (Flor et al., 1998;

Harden et al., 2010; Hunter et al., 2005; Li et al., 2015) or

cold perception (Harden et al., 2010). One study reported hy-

peralgesia for electrical painful stimulation on the intact limb

in amputees with but not without PLP, suggesting central

sensitization (Li et al., 2015).

Hence, findings of previous studies do not suggest that there

is an association of PLP and thresholds for non- painful stimuli

and are inconsistent with respect to the question whether PLP is

associated with pain thresholds. However, inconsistencies and

negative findings might be partly related to small sample sizes

and heterogeneity of the samples (e.g. lower- vs. upper- limb

amputations) and large heterogeneity in the applied assessment

methods and tested body sites. In particular, comparisons relat-

ing the residual to the intact limb might be problematic for vari-

ous reasons. First, it is difficult to standardize measures taken at

the residual limb due to variations in levels of amputation and

scar tissue. Second, QST of the residual limb may be related to

residual limb pain (RLP) rather than PLP. Third, testing only

the residual limb and a homologous contralateral site cannot

determine whether altered pain thresholds are also present at re-

mote sites, for instance at the thenar or the mouth. The face and

the missing upper limb have adjacent representations in sensory

and motor areas of the brain and the mouth might therefore have

altered sensitivity related to cortical reorganization.

As central sensitization might also play a role in PLP, the

present study tested whether PLP is accompanied by changes

in sensitivity to painful and non- painful stimuli applied at sev-

eral standardized body sites. The aims were (a) to investigate

whether there are changes in sensory thresholds, which are as-

sociated with the presence and/or the intensity of PLP, (b) to

test whether potential changes are restricted to the residual limb,

which could involve peripheral mechanisms, and/or whether

changes are also present in other areas of the body, which could

point to central mechanisms and finally, in order to test the

specificity to PLP, we sought to (c) take into account associa-

tions with other variables, which are potentially related to sen-

sitization and brain changes, especially RLP (Kern et al., 2009).

2 | METHODS

2.1 | Participants

Thirty- seven unilateral upper- limb amputees and 19 healthy

controls (HCs) took part in this study. We employed QST and

the assessment of phantom phenomena and chronic pain. The

sample was recruited from a nationwide database on which

Conclusion: We conclude that the association between PLP and, especially facial,

HPT could be related to central mechanisms.

Significance: Phantom limb pain (PLP) is still poorly understood. We show that PLP

intensity is associated with lower heat pain thresholds, especially in the face. This

finding could be related to central nervous changes in PLP.

116 | FUCHS ET AL.

we had previously reported (Bekrater- Bodmann, Schredl,

et al., 2015). The participants were selected from the data-

base and contacted directly. The criteria for selection were

unilateral arm amputation and eligibility for magnetic reso-

nance imaging testing (used in another study). We recruited

amputees with and without PLP and attempted to achieve

comparable distributions of age, sex and side of amputation

between the groups. The study was approved by the Ethics

Commission II of the Medical Faculty Mannheim, Heidelberg

University. The amputees were divided into two groups— one

with PLP (PLP; N = 23) and one without PLP (non- PLP;

N = 14). Grouping was based on the Phantom Pain Severity

subscale of the German version of the West Haven- Yale

Multidimensional Pain Inventory (MPI; Flor et al., ,1990,

1995; Kerns et al., 1985) adapted for separate assessments of

PLP and RLP. The MPI is a 22- item questionnaire that uses a

7- point numeric rating scale for each item ranging from 0 to 6.

The Pain Severity subscale is calculated as the average value

of three items assessing (a) the intensity of momentary pain,

(b) the average pain during the last week and (c) the inten-

sity of pain- related suffering. Amputees with a Pain Severity

score of 0 were assigned to the non- PLP group and all other

amputees to the PLP group. The HC were matched for age,

sex and stimulation sites with amputees from both groups.

Sample and demographic details are provided in Table 1.

There were no statistically significant differences between

the three groups (PLP, non- PLP and HC) in the distribution of

sex [ratio male/female: PLP, 20/3; non- PLP, 12/2; HC, 16/3;

χ2(2, N = 56) = 0.06, p = 0.97] and age (mean ± standard devi-

ation [SD, years]: PLP, 51.3 ± 12.3; non- PLP, 53.1 ± 10.6;

HC, 51.6 ± 11.7; F(2, 53) = 0.10, p = 0.90). The PLP group and

the non- PLP group did not significantly differ in their level of

amputation (mean ± SD [% arm length]: PLP, 32.0 ± 18.8;

non- PLP, 40.2 ± 23.9; t(22.7) = −1.10, p = 0.28) or side of

amputation [χ2(1, N = 37) = 0.53, p = 0.47]. None of the ampu-

tees was amputated at an age below 5 years and the groups

did not differ significantly with respect to age of amputation

(mean ± SD, range [years]: PLP, 27.1 ± 12.5, 13– 55; non- PLP,

19.8 ± 11.5, 5– 45; t(29.5) = 1.80, p = 0.08). All amputees were

in a later stage after amputation with at minimum 3 years pass-

ing between amputation and sensory testing and the groups

did not differ significantly with respect to that (mean ± SD,

range [years]: PLP, 24.1 ± 11.4, 9– 58; non- PLP, 33.3 ± 15.6,

3– 55; t(29.5) = 1.84, p = 0.08). All amputees were right- handed

before amputation and so were all of the HC, according to the

Edinburgh Handedness Inventory (Oldfield, 1971).

2.2 | Body sites

Sensory testing was performed at five body sites. Amputees

were tested at the thenar of their intact hand, both corners of the

mouth, the residual limb and at a homologous site on the intact

arm. The sites at the corners of the mouth were symmetric and

located laterally of the lips on the hairy skin of the cheeks.

The test site at the residual limb was located 5 cm from the

distal end of the limb (Grüsser et al., 2001; Hunter et al., 2005)

and outside of scar tissue. Both sites on the arms were marked

using cosmetic colour and a photo was taken for documenta-

tion. The sites on the arms used in the HC were anatomically

homologous to the ones used in the matched amputees.

Body sites for sensory testing were selected based on the

following rationale: the residual limb was tested as the body

site directly affected by the amputation with a homologous site

on the intact arm as a control site. The corners of the mouth

were tested because they are remote from the amputation site

and clearly outside the area of potential nerve damage. In addi-

tion, the face is a relevant area with regards to central changes,

as the hand and the face are represented at adjacent sites

within the cortical body map in S1. Previous studies showed

that an expansion (in terms of functional S1 reorganization) of

the mouth area in the hemisphere contralateral to the amputa-

tion into the neighbouring former hand area is positively cor-

related with PLP (Flor et al., 1995; Lotze et al., 2001; MacIver

et al., 2008). It is, however, unclear whether cortical reorgani-

zation is reflected in altered sensitivity to stimuli presented at

the corners of the mouth. Additionally, we tested the thenar of

the existing hand, as sensory changes at the thenar might indi-

cate altered interhemispheric connectivity in the brain as the

cortical representation of the existing hand is functionally (van

den Heuvel & Hulshoff Pol, 2009) and structurally (Bonzano

et al., 2008) coupled to the corresponding area in the contra-

lateral hemisphere. Another reason for including the thenar is

that it is a standard site for QST (Rolke et al., 2006).

2.3 | Sensory testing

Measures were chosen to detect increased or decreased sen-

sitivity to noxious or non- noxious thermal or mechanical

stimuli. In total, we assessed four different measures: two

pain thresholds— heat pain threshold (HPT) and pressure pain

threshold (PPT)— and two detection thresholds— warmth de-

tection threshold (WDT) and tactile two- point discrimination

thresholds (2PDT). This allowed us to separate the effects

related to the nociceptive system from other somatosensory

modalities. The protocol used here adhered to the standards of

the German Research Network on Neuropathic Pain (DFNS)

but did not use the complete protocol. Thermal QST was se-

lected for comparability with several previous QST studies

with amputees (Flor et al., 1998; Harden et al., 2010; Hunter

et al., 2005; Li et al., 2015) and because it allows assessment of

both detection and pain thresholds using the same stimulus type

(temperature). Tactile 2PDT were selected because body sites

with larger S1 representation usually have smaller 2PDT and

the measure is sensitive to detect changes in S1 representation

| 117FUCHS ET AL.

TA

BL

E 1

D

escr

ipti

on o

f th

e st

udy s

ample

IDT

yp

eG

rou

pM

atc

hin

gS

exA

ge

EH

I

score

a

Lvl.

of

stim

. (%

)b

Age

at

am

p.

Tim

e

sin

ce a

mp

.

Sid

e of

am

p.c

Cau

se o

f

am

p.d

Ph

an

tom

lim

bT

eles

cop

eP

rost

hes

is

PL

P

inte

nsi

tye

RL

P

inte

nsi

tye

A01

Am

pute

eP

LP

None

M57

100.0

15

27

30

Rig

ht

Tra

um

aY

esY

esN

one

0.7

1.0

A02

Am

pute

eP

LP

HC

12

M48

75.0

70

18

30

Lef

tT

raum

aY

esY

esC

osm

etic

3.0

3.0

A03

Am

pute

eP

LP

HC

01

M69

57.1

45

45

24

Lef

tT

raum

aY

esY

esM

yo- e

l.3.3

2.7

A04

Am

pute

eP

LP

HC

06

M42

84.6

35

23

19

Rig

ht

Tra

um

aY

esY

esM

yo- e

l.0.7

1.7

A05

Am

pute

eP

LP

HC

02

M50

72.7

20

21

29

Rig

ht

Tra

um

aY

esY

esC

osm

etic

4.0

0.3

A06

Am

pute

eP

LP

HC

09

M52

84.6

042

10

Rig

ht

Tra

um

aY

esN

oC

osm

etic

2.3

0.0

A0

7A

mpute

eP

LP

HC

08

M64

66.7

055

9L

eft

Tum

or

Yes

Yes

None

2.0

0.0

A08

Am

pute

eP

LP

None

M62

100.0

15

43

19

Rig

ht

Tra

um

aY

esY

esN

one

2.3

2.0

A09

Am

pute

eP

LP

None

M39

80.0

35

15

24

Lef

tT

raum

aY

esN

oN

one

0.3

0.0

A1

0A

mpute

eP

LP

HC

15

M37

50.0

50

13

24

Lef

tT

raum

aY

esY

esC

osm

etic

0.3

0.0

A11

Am

pute

eP

LP

None

M30

75.0

25

19

11

Rig

ht

Tra

um

aY

esY

esN

one

2.0

2.0

A12

Am

pute

eP

LP

None

M67

83.3

45

38

29

Lef

tT

raum

aY

esN

oC

osm

etic

1.7

4.7

A13

Am

pute

eP

LP

HC

14

M54

84.6

21

42

12

Rig

ht

Tra

um

aY

esY

esN

one

1.7

1.3

A14

Am

pute

eP

LP

None

M73

84.6

15

15

58

Rig

ht

Tra

um

aY

esN

oN

one

0.7

0.0

A1

5A

mpute

eP

LP

HC

13

M26

57.1

38

17

9R

ight

Tra

um

aY

esY

esN

one

2.3

2.0

A16

Am

pute

eP

LP

HC

04

M42

100.0

43

19

23

Lef

tT

raum

aY

esN

oN

one

1.0

1.7

A17

Am

pute

eP

LP

None

M54

46.7

15

14

40

Rig

ht

Tra

um

aY

esY

esN

one

0.7

1.0

A1

8A

mpute

eP

LP

None

M63

75.0

30

40

23

Rig

ht

Tra

um

aY

esY

esM

yo- e

l.1.7

1.0

A19

Am

pute

eP

LP

None

M52

69.2

50

16

36

Rig

ht

Tra

um

aY

esN

oM

anual

1.3

2.0

A20

Am

pute

eP

LP

None

M48

76.5

30

18

30

Rig

ht

Tra

um

aY

esY

esN

one

4.3

3.0

A2

1A

mpute

eP

LP

HC

19

F40

100.0

45

25

15

Lef

tO

ther

Yes

Yes

None

2.7

0.0

A22

Am

pute

eP

LP

HC

17

F58

100.0

25

37

21

Lef

tT

raum

aY

esY

esN

one

2.3

0.7

A23

Am

pute

eP

LP

None

F53

66.7

70

23

30

Rig

ht

Tra

um

aY

esN

oN

one

3.7

2.7

A24

Am

pute

enon- P

LP

None

M59

84.6

20

10

49

Rig

ht

Tra

um

aN

oN

oM

yo- e

l.0.0

0.0

A25

Am

pute

enon- P

LP

HC

05

M67

90.0

62

19

48

Rig

ht

Tra

um

aY

esY

esM

yo- e

l.0.0

0.0

A26

Am

pute

enon- P

LP

HC

07

M54

100.0

72

23

31

Rig

ht

Tra

um

aY

esN

oN

one

0.0

0.0

A27

Am

pute

enon- P

LP

None

M24

83.3

45

618

Lef

tT

raum

aN

oN

oM

yo- e

l.0.0

A28

Am

pute

enon- P

LP

None

M60

57.1

60

555

Lef

tT

raum

aN

ono

None

0.0

0.0

A29

Am

pute

enon- P

LP

HC

11

M62

71.4

10

10

52

Lef

tT

raum

aN

oN

oN

one

0.0

0.0

A30

Am

pute

enon- P

LP

HC

10

M47

60.0

022

25

Lef

tT

raum

aY

esN

oN

one

0.0

0.0

A31

Am

pute

enon- P

LP

None

M48

70.0

62

45

3R

ight

Tra

um

aN

oN

oN

one

0.0

0.0

(Conti

nues

)

118 | FUCHS ET AL.

IDT

yp

eG

rou

pM

atc

hin

gS

exA

ge

EH

I

score

a

Lvl.

of

stim

. (%

)b

Age

at

am

p.

Tim

e

sin

ce a

mp

.

Sid

e of

am

p.c

Cau

se o

f

am

p.d

Ph

an

tom

lim

bT

eles

cop

eP

rost

hes

is

PL

P

inte

nsi

tye

RL

P

inte

nsi

tye

A32

Am

pute

enon- P

LP

HC

03

M65

69.2

52

15

50

Rig

ht

Tra

um

aY

esY

esC

osm

etic

0.0

0.0

A33

Am

pute

enon- P

LP

None

M51

83.3

10

23

28

Lef

tT

raum

aN

oN

oC

osm

etic

0.0

0.0

A34

Am

pute

enon- P

LP

HC

16

M56

100.0

65

38

18

Rig

ht

Tra

um

aN

oN

oC

osm

etic

0.0

0.0

A35

Am

pute

enon- P

LP

None

M47

100.0

25

15

32

Lef

tT

um

or

Yes

Yes

Myo- e

l.0.0

0.0

A36

Am

pute

enon- P

LP

HC

18

F52

100.0

50

18

34

Lef

tT

raum

aN

oN

oM

yo- e

l.0.0

3.0

A37

Am

pute

enon- P

LP

None

F51

86.7

30

28

23

Lef

tT

raum

aY

esY

esN

one

0.0

0.7

HC

01

Contr

ol

HC

A03

M71

100.0

45

Lef

t

HC

02

Contr

ol

HC

A05

M50

61.3

20

Rig

ht

HC

03

Contr

ol

HC

A32

M64

100.0

52

Rig

ht

HC

04

Contr

ol

HC

A16

M41

70.4

43

Lef

t

HC

05

Contr

ol

HC

A25

M67

88.6

62

Rig

ht

HC

06

Contr

ol

HC

A04

M44

75.0

35

Rig

ht

HC

07

Contr

ol

HC

A26

M54

73.9

72

Rig

ht

HC

08

Contr

ol

HC

A07

M64

93.3

0L

eft

HC

09

Contr

ol

HC

A06

M53

88.9

0R

ight

HC

10

Contr

ol

HC

A30

M47

51.7

0L

eft

HC

11

Contr

ol

HC

A29

M63

89.5

10

Lef

t

HC

12

Contr

ol

HC

A02

M47

63.6

70

Lef

t

HC

13

Contr

ol

HC

A15

M25

53.8

38

Rig

ht

HC

14

Contr

ol

HC

A13

M51

65.2

21

Rig

ht

HC

15

Contr

ol

HC

A10

M35

89.5

50

Lef

t

HC

16

Contr

ol

HC

A34

M55

71.4

65

Rig

ht

HC

17

Contr

ol

HC

A22

F58

100.0

25

Lef

t

HC

18

Contr

ol

HC

A36

F53

31.2

50

Lef

t

HC

19

Contr

ol

HC

A21

F39

82.9

45

Lef

t

Abbre

via

tions:

EH

I, E

din

burg

h h

anded

nes

s in

ven

tory

; H

C, hea

lthy c

ontr

ol;

myo- e

l., m

yoel

ectr

ic p

rost

hes

is;

non- P

LP

, w

ithout

phan

tom

lim

b p

ain;

PL

P, phan

tom

lim

b p

ain;

RL

P, re

sidual

lim

b p

ain.

a A v

alue

of

100 i

n t

he

EH

I in

dic

ates

the

stro

nges

t deg

ree

of

right-

han

ded

nes

s, a

val

ue

of

−100 i

ndic

ates

the

stro

nges

t deg

ree

of

left

- han

ded

nes

s.bL

evel

of

stim

ula

tion w

as d

efin

ed a

s th

e posi

tion o

f m

easu

rem

ents

at

the

arm

rel

ativ

e to

the

length

of

the

(inta

ct)

arm

, m

easu

red f

rom

the

caput

hum

eri

to t

he

tip o

f th

e th

ird d

igit

. In

the

ampute

es, th

is p

osi

tion w

as d

efin

ed b

y t

he

length

of

the

resi

dual

lim

b. H

om

olo

gous

site

s w

ere

mea

sure

d i

n t

he

mat

ched

HC

.c S

ide

of

amputa

tion i

n t

he

HC

(in

bra

cket

s) r

efer

s to

the

side

of

amputa

tion o

f th

e m

atch

ed a

mpute

e.dT

he

cate

gory

‘oth

er’

cause

s of

amputa

tion s

ubsu

mes

unknow

n c

ause

s not

fall

ing i

nto

the

cate

gori

es t

raum

atic

, in

jury

, dysp

lasi

a, i

nfe

ctio

n, tu

mour

or

vas

cula

r dis

ease

.e P

ain s

ever

ity s

ubsc

ale

of

the

MP

I ad

apte

d f

or

PL

P a

nd R

LP

, re

spec

tivel

y. V

alues

ran

ge

from

0 (

low

est

sever

ity)

to 6

(hig

hes

t se

ver

ity).

TA

BL

E 1

(C

onti

nued

)

| 119FUCHS ET AL.

(Dinse, 2003; Muret et al., 2016). PPTs were selected to assess

an additional pain threshold referring to mechanical stimuli.

The procedures for HPT, WDT and PPT were based on the

study protocol developed by the DFNS (Rolke et al., 2006)

and were carried out by experimenters trained in QST.

2.3.1 | Thermal thresholds

Warmth detection thresholds and HPT were measured using

a Medoc ATS thermode (3 x 3 cm surface) included in

the Medoc Pathway system (PATHWAY Pain & Sensory

Evaluation System, Medoc Ltd. Advanced Medical System).

Stimuli were applied with a baseline temperature of 32 ℃

and a rising rate of 1.5 ℃/s (ascending method of limits)

(Bekrater- Bodmann, Chung, et al., 2015). The maximum

temperature of the system was set to 52 ℃ to avoid skin

injuries.

Because amputees, when tested at the thenar, could not

respond with button presses, all responses for all body sites

and groups, including the ones in the HC, were given verbally

to ensure comparability between sites and groups. The as-

sessment of WDT and HPT only differed with respect to the

instructions (‘say “stop” as soon as you feel that the tempera-

ture is getting warmer’ for WDT and ‘say “stop” when the

temperature just becomes painful’ for HPT). When partici-

pants said ‘stop’, the experimenter immediately terminated

the ascending stimulus and the thermode returned to the

baseline temperature at a rate of 8 ℃/s. The participants were

asked to keep their eyes closed throughout the test.

When assessing WDT and HPT in the face, the thermode

was attached to the skin with adhesive tape and the participant

was additionally asked to gently press the index finger against

the thermode to ensure good contact with the skin. In each

series, we conducted five consecutive trials. The first trial of

each series was presented to familiarize participants with the

test and the remaining four stimuli were averaged to calculate

the threshold (Bekrater- Bodmann, Chung, et al., 2015).

2.3.2 | Pressure pain thresholds

Pressure pain threshold were measured using a Medoc

Algomed (Medoc Ltd. Advanced Medical System) comput-

erized pressure algometer (surface of 1 cm2). Four consecu-

tive stimuli were applied using a rate of 50 kPa/s (ascending

method of limits) (Rolke et al., 2006). The participants were

instructed to say ‘stop’ when the pressure started to feel pain-

ful. Four consecutive stimuli were applied; the first stimulus

was excluded and the remaining three were averaged for cal-

culation of the pain threshold. When testing at the corners of

the mouth, the participants clenched the teeth to ensure that

the tested tissue was pushed against the teeth when applying

the pressure algometer. The experimenter gently stabilized

the participant's head using the hand not applying the algom-

eter. This prevented the participant from compensating the

pressure using the neck muscles, avoiding discomfort.

2.3.3 | Two- point discrimination thresholds

Two- point discrimination threshold were measured using a

set of 28 calibrated compasses (Rotring “Centro”; Rotring)

ranging in size from 1 to 82 mm in steps of 3 mm. The tips

of the compasses were exchanged with blunt rods in order to

induce a light touch. Stimuli were applied by placing the com-

pass perpendicularly onto the skin from above. The skin was

touched briefly (1– 2 s) while the participants kept their eyes

closed. We used a simple adaptive staircase (‘up- down’) pro-

cedure (Dixon & Mood, 1948; Levitt, 1971), stopping after

seven reversals. The first reversal point was excluded and the

following six were averaged to calculate the absolute (50%)

threshold. To avoid biases in the estimation of the thresholds

that can be introduced when the starting point is far away

from the threshold, we used different compass sizes as start-

ing points, depending on the body site: 25 mm for the corners

of the mouth where the threshold was expected to be lower

than on the arms (Mancini et al., 2014; Weinstein, 1968) and

46 mm for the arms. 2PDT at the arms were always meas-

ured in proximal- to- distal direction while the participant sat

in a chair. 2PDT at the corners of the mouth were measured

parallel to the inferior- to- superior axis while the participant

was lying on a bench to facilitate applying the stimuli per-

pendicularly from above. Beforehand, the protocol had been

evaluated in a pilot study, testing the dorsal forearms of 10

participants. The procedure showed good within- session reli-

ability (Pearson's r = 0.81). The data of this pilot are provided

in Supplementary Material (Figure S5). 2PDT were measured

in a subsample of 27 amputees (19 in the PLP and 8 in the

non- PLP group) and all HC and at all body sites except for

the thenar.

2.4 | Specificity for PLP

To test whether associations between PLP and sensory

thresholds were specific to PLP and not mediated by other

correlates of PLP or related brain plasticity, we performed

additional analyses to control their potential influence.

Especially, RLP is correlated with PLP (Kern et al., 2009)

and can therefore confound interpretations if not statistically

controlled. Apart from RLP, we also ruled out confound-

ers and the results of these analyses are reported in detail

in Supplementary Material: (a) use of prostheses (Dietrich

et al., 2012; Lotze et al., 1999), (b) telescoping (Flor

et al., 2006; Grüsser et al., 2001), (c) compensation in daily

120 | FUCHS ET AL.

activities by the existing hand (Makin, Cramer, et al., 2013),

(d) level of the amputation and (e) time since amputation.

2.5 | Statistical analyses

2.5.1 | Data inspection and outliers

Because large variation was observed in the sensory data (see

the boxplots in Figure 2 in the Section 3), we performed a sys-

tematic analysis for the presence and the influence of outliers

which is included in Supplementary Material. Despite the pres-

ence of some outliers, the results were not strongly influenced,

and the conclusions remain identical for statistical analyses

with and without outliers. Therefore, no data were removed for

the analyses presented in the article. Supplementary Material

includes a reanalysis of the data after removal of outliers.

2.5.2 | Transformation of sensory data

In accordance with the recommendations given by Rolke

et al. (2006), we transformed WDT and PPT logarithmically

prior to the statistical analyses using a log- transformation.

WDT were coded as deviation from the baseline, with the

baseline temperature of 32℃ subtracted from the thresholds,

prior to the log- transformation.

2.5.3 | Statistical models for comparisons between groups and body sites

To compare thresholds between the groups and body sites, we

fitted a (repeated measures) linear mixed model (LMM) for

each sensory measure using group (PLP, non- PLP and HC) as

a between- subject fixed factor and body site (arm ipsilateral,

arm contralateral, corner of the mouth ipsilateral, corner of the

mouth contralateral and thenar contralateral to the amputation)

as a within- subject fixed factor. All models included partici-

pants as a random intercept effect. LMMs are a flexible and ro-

bust alternative to repeated measures analyses of variance and

permit simultaneous analysis of discrete grouping variables,

repeated factors and continuous covariates, providing a frame-

work for both factorial and regression- type analyses (Pinheiro

& Bates, 2000). To test whether differences between groups

depended on the body site (or vice versa), we also included the

interaction between group and body site in the models.

The coding of body site (‘ipsilateral’ and ‘contralat-

eral’) in the HC was defined by the side of amputation of

the matched (yoked) amputee. For example, if an HC was

matched to a right- sided amputee, his or her right corner of

the mouth was coded as ipsilateral. Note that in the amputees,

‘ipsilateral arm’ refers to the residual limb. This allowed a

balanced mixture of right- and left- side body parts of the HCs

within the categories.

Significant effects were followed up by pairwise post-

hoc comparisons to test which mean values differed signifi-

cantly. To avoid alpha error inflation, post- hoc test p- values

were corrected using the false discovery rate (Benjamini &

Hochberg, 1995).

2.5.4 | Associations between sensory thresholds and PLP

To test the association between the sensory thresholds and

PLP intensity, we correlated each sensory threshold in the

PLP group with the Phantom Pain Severity score from the

MPI using Pearson correlations.

Next, to test whether PLP intensity was associated with a

combination of sensory thresholds and to account for the inter-

correlation of sensory variables, we performed a stepwise mul-

tiple regression analysis. We predicted PLP intensity in the PLP

group by a combination of HPT, PPT and WDT at all body sites

and determined the best- fitting model using stepwise elimina-

tion of regression terms (based on Akaike's information criterion

[AIC], as implemented in R’s stepwise function). As missing

values are a problem for multiple regression approaches, we im-

puted missing data with the mean values prior to the analyses

(1 value [0.8%] for HPT and PPT, respectively). As 2PDT were

only measured in a subset of the participants, this would have

resulted in an imputation of 18% of the values. Therefore, we

excluded 2PDT from the multiple regression analyses.

2.5.5 | Specificity of associations for PLP versus RLP intensity

To test whether the types of pain (PLP and RLP intensity)

are predicted differentially by the sensory thresholds, we

performed an LMM that resembled the multiple regression

model described in the previous paragraph but included both

PLP and RLP intensity as predicted values, coded by a factor

‘pain type’ that was included as a within- subject fixed fac-

tor. The model comprised all sensory thresholds as predic-

tors and all two- fold interactions between the pain type and

the sensory thresholds. A significant interaction between the

pain type and a sensory threshold variable indicates that the

prediction is significantly different (and therefore specific)

for PLP versus RLP intensity. As for the regression model,

we used a stepwise approach to determine the most appropri-

ate model based on AIC. The analysis included all amputees

showing either PLP or RLP values above zero. This was the

case for the 23 amputees from the PLP group and three cases

from the non- PLP group who reported RLP but no PLP; the

analysis therefore included 26 participants.

| 121FUCHS ET AL.

For another regression model aiming at ruling out

other confounding variables (described in Section 2.5), see

Supplementary Material.

2.5.6 | Software and data resources

All data and code to reproduce all statistical analyses and

figures reported in this article are publicly available online

in a repository hosted on the website of the Open Science

Framework and can be accessed via https://osf.io/v6hjy/

We used the R statistical software (R Core Team, 2014).

LMMs were performed using the “lme4” (Bates

et al., 2014) and the “lmerTest” (Kuznetsova et al., 2014)

packages for R. Degrees of freedom in the LMMs were

estimated using Satterthwaite's approximation as imple-

mented in the lmerTest (Kuznetsova et al., 2014) package.

Figures were created using the “ggplot2” package for R

(Wickham, 2009).

3 | RESULTS

3.1 | Effects related to the presence of PLP: differences between the groups and body sites

Results from the LMMs for all measures are shown in

Figure 1. Table 2 summarizes the coefficients for the full

models (including the factor group and body site, and the

group × body site interaction). Table 3 summarizes the re-

sults from post- hoc comparisons between the body sites.

3.1.1 | Heat pain thresholds

There was no significant main effect of group [F(2, 53) = 0.1,

p = 0.901] and no significant interaction between group and

body site [F(8, 211) = 0.65, p = 0.732]. The main effect of body

site was significant [F(4, 211) = 50.5, p < 0.001]. Post- hoc

comparisons (Table 3) showed that HPT were significantly

T A B L E 2 Results for main effects and interactions from linear

mixed models for heat pain thresholds, pressure pain thresholds,

warmth detection thresholds and two- point discrimination thresholds

including the factors group, body site and their interaction

Measure Term F

df (num./

denom.) p

HPT Group 0.10 2/52.9 0.906

Body site 51.77 4/211 <0 .001

Group × Body site 0.69 8/211 0.701

PPT Group 0.86 2/53 0.43

Body site 130.60 4/211 <0 .001

Group × Body site 1.91 8/211 0.061

WDT Group 2.88 2/53 0.065

Body site 88.91 4/212 <0 .001

Group × Body site 0.94 8/212 0.485

2PDT Group 1.43 2/44.2 0.25

Body site 304.21 3/128.5 <0 .001

Group × Body site 0.54 6/128 0.775

Abbreviations: 2PDT, two- point discrimination thresholds; HPT, heat pain

thresholds; PPT, pressure pain thresholds; WDT, warmth detection thresholds.

F I G U R E 1 Results of the linear mixed models comparing the thresholds for heat pain (HPT), pressure pain (PPT), warmth detection (WDT)

and two- point discrimination (2PDT) between the groups (amputees with phantom limb pain [PLP]: orange; amputees without phantom limb

pain [non- PLP]: blue; healthy controls [HC]: grey) and the body sites. The values represent estimated marginal means derived from the statistical

models with 95% confidence intervals shown as error bars. There were no significant differences between the groups in any of the pairwise

comparisons. The body sites differed significantly (see also section 3.1, Tables 2 and 3 for details)

122 | FUCHS ET AL.

lower at the ipsilateral arm compared to the contralateral arm

and also at both corners of the mouth compared to both arms

and the thenar. The corners of the mouth did not differ sig-

nificantly from each other, and the thenar did not differ sig-

nificantly from both arms.

3.1.2 | Pressure pain thresholds

For PPT, there was no significant effect of group [F(2, 53) =

0.86, p = 0.430] or group × body site [F(8, 211) = 1.91,

p = 0.061]. The factor body site was significant [F(4,

T A B L E 3 Results from post- hoc comparisons for the significant factor body site

Measure Contrast Estimate SE t ratio df p

HPT Arm contra– arm ipsi 1.19 0.448 2.65 211 0.012

Arm contra– mouth contra 4.55 0.447 10.20 211 <0 .001

Arm contra– mouth ipsi 4.57 0.447 10.23 211 <0 .001

Arm contra– thenar contra 0.28 0.447 0.63 211 0.587

Arm ipsi– mouth contra 3.37 0.448 7.51 211 <0 .001

Arm ipsi– mouth ipsi 3.38 0.448 7.54 211 <0.001

Arm ipsi– thenar contra −0.91 0.448 −2.02 211 0.055

Mouth contra– mouth ipsi 0.02 0.447 0.03 211 0.973

Mouth contra– thenar contra −4.27 0.447 −9.57 211 <0.001

Mouth ipsi– thenar contra −4.29 0.447 −9.60 211 <0.001

PPT Arm contra– arm ipsi 0.07 0.0250 2.68 211 0.009

Arm contra– mouth contra 0.31 0.0250 12.46 211 <0.001

Arm contra– mouth ipsi 0.33 0.0250 13.30 211 <0.001

Arm contra– thenar contra −0.14 0.0251 −5.40 211 <0.001

Arm ipsi– mouth contra 0.24 0.0250 9.77 211 <0.001


Arm ipsi– thenar contra −0.20 0.0251 −8.07 211 <0.001




WDT Arm contra– arm ipsi 0.04 0.0288 1.36 212 0.196



Arm contra– thenar contra 0.17 0.0288 5.94 212 <0.001



Arm ipsi– thenar contra 0.13 0.0288 4.58 212 <0.001




2PDT Arm contra– arm ipsi −0.08 0.213 −0.38 131 0.705






Note: Post- hoc tests followed linear mixed models for each of the sensory thresholds (HPT, PPT, WDT and 2PDT). Within each model, p values were adjusted for

multiple comparisons using false discovery rate.

Abbreviations: 2PDT, two- point discrimination thresholds; HPT, heat pain thresholds; PPT, pressure pain thresholds; SE, standard error; WDT, warmth detection

thresholds.

| 123FUCHS ET AL.

207) = 87.1, p < 0.001]. Post- hoc comparisons between body

sites revealed that all body sites differed significantly from

each other except for the homologous body parts at the corners

of the mouth, which did not differ significantly. At the arms,

PPT were significantly lower ipsilateral than contralateral.

3.1.3 | Warmth detection thresholds

No significant effect of group [F(2, 53) = 2.88, p = 0.065] and

group × body site was found [F(8, 212) = 0.94, p = 0.485]. The

factor body site was significant [F(4, 204) = 88.91, p < 0.001]. Post-

hoc comparisons revealed significant differences between all body

sites, except for the comparison between the corners of the mouth

and between both arms where the differences were not significant.

3.1.4 | Two- point discrimination thresholds

For 2PDT, there was no significant effect of group [F(2, 44) =

1.43, p = 0.25] or group × body site [F(6, 128) = 0.54,

p = 0.775]. Body site was significant [F(3, 129) = 304.21,

p < 0.001]. Post- hoc tests showed that thresholds were lower

at both corners of the mouth than at both arms. The homolo-

gous parts at the corners of the mouth and at the arms did not

differ significantly from each other.

3.2 | Effects related to the intensity of PLP: correlational analyses

3.2.1 | Correlations between PLP intensity and sensory thresholds

All correlations between the sensory thresholds in the

PLP group and the reported intensity of PLP are shown

in Figure 2. For HPT, the correlations were negative, in-

dicating that more intense PLP was associated with lower

HPT, and significant for the ipsilateral corner of the mouth

(r = −0.59, p = 0.003), the contralateral corner of the mouth

(r = −0.65, p < 0.001), the thenar (r = −0.64, p < 0.001)

and the contralateral arm (r = −0.45, p = 0.031). Only at

F I G U R E 2 Distributions of sensory thresholds and their correlations with the intensity of phantom limb pain (PLP) in the PLP group

(orange). The rows represent the thresholds, which were assessed: heat pain thresholds (HPT), pressure pain thresholds (PPT), warmth detection

thresholds (WDT) and two- point discrimination thresholds (2PDT). The columns represent the body sites: the arm ipsilateral to the amputation (in

amputees the residual limb, in healthy controls a matched site), the contralateral arm, the ipsilateral and the contralateral corner of the mouth, and

the contralateral thenar. Within each subplot, the scatter plots (on the left) show the data of the PLP group (orange) and the amputees without PLP

(non- PLP; blue) for the respective threshold and PLP intensity. For the PLP group, the result of a linear regression model is shown. The Pearson

correlation coefficients together with (two- sided) p- values are shown within the plots. The right side of each subplot shows the distribution of

the sensory thresholds as boxplots for the PLP group, the non- PLP group and healthy controls (HC; grey). The mean values for each group are

highlighted as a red point

124 | FUCHS ET AL.

the ipsilateral arm (residual limb), the correlation was not

significant (r = −0.33, p = 0.137). PPT were significantly

negatively correlated with PLP intensity at the contralateral

corner of the mouth (r = −0.48, p = 0.019) and at the ipsi-

lateral arm (r = −0.44, p = 0.036). However, the result for

the ipsilateral arm was no longer significant when outliers

were removed from the data (see Supplementary Material,

Table S3). At all other body sites, the correlations were nega-

tive but not significant (Figure 2). WDT and 2PDT were not

significantly correlated with PLP intensity at any of the body

sites (Figure 2).

Intra- individual differences between the homologous

areas at the arms and the corners of the mouth were not sig-

nificantly correlated with PLP intensity for any of the sen-

sory thresholds (all r > −0.32 and <0.37, all p > 0.07). All

correlations are shown Supplementary Material (Figure S1).

3.2.2 | Association of PLP intensity with a linear combination of all sensory thresholds

The stepwise multiple regression procedure removed 12 out

of the 15 sensory thresholds and resulted in a model in which

PLP intensity was predicted by a combination of three sen-

sory thresholds, which are listed in Table 4 (Model A). The

resulting model was statistically significant [F(9, 13) = 8.67,

p < 0.001; R2 = 0.57; R2adj = 0.51]. Two thresholds in this

model significantly predicted higher degrees of PLP in-

tensity: lower HPT [b = −0.21, t(19) = −4.74, p < 0.001]

and higher WDT at the contralateral corner of the mouth

[b = 2.96, t(19) = 2.96, p = 0.03] Note that HPT received

negative and WDT positive weights, indicating that higher

PLP intensity was associated with lower HPT and higher

WDT, which is shown in Figure 3.

Further multiple regression analyses (reported in

Supplementary Material, Table S5) confirmed that the asso-

ciations of PLP intensity with HPT and WDT at the corner

of the mouth were still present when a number of other po-

tentially relevant correlates of PLP were controlled for. This

shows that the relationship is robust and not mediated by any

of these variables.

3.2.3 | Specificity of associations of PLP and RLP intensities with sensory thresholds

Only two sensory thresholds remained in the resulting model

(Model B): HPT at the contralateral corner of the mouth and

HPT at the ipsilateral arm. Importantly, there were signifi-

cant interactions with type of pain (PLP vs. RLP intensity)

for both HPT at the contralateral corner of the mouth [F(1,

23) = 8.69, p < 0.001] and at the ipsilateral arm [F(1, 23) = 4.41,

p = 0.046]. The interactions are visualized in Figure 4. On

the ipsilateral arm, lower HPT was associated with higher

levels of RLP but not with PLP [b = −0.16, t(23) = −2.10,

p = 0.047]. On the contralateral corner of the mouth, how-

ever, lower HPT was specifically associated with more PLP

and not with RLP [b = 0.23, t(23) = 2.95, p = 0.007]. This

indicates that the two concurrent types of clinical pain, PLP

and RLP were differentially associated with sensory thresh-

olds: PLP was mainly associated with HPT in the face and

RLP with HPT at the residual limb.

Model Term b t df p

A (Intercept) 8.99 4.84 19 <0.001

HPT mouth contra −0.21 −4.75 19 <0.001

WDT arm ipsi 1.07 1.49 19 0.152

WDT mouth contra 2.96 2.38 19 0.028

B (Intercept) 9.54 3.33 42.6 0.002

Pain typea −2.48 −0.72 23.0 0.478

HPT arm ipsi 0.01 0.15 42.6 0.882

HPT mouth contra −0.19 −3.01 42.6 0.004

Pain type × HPT arm ipsi −0.16 −2.10 23.0 0.047

Pain type × HPT mouth contra 0.23 2.95 23.0 0.007

Note: The table lists regression terms that remained in the final model after iterative removal of terms not

significantly contributing to the model fit. (A) Statistical prediction of PLP by HPT, PPT and WDT measured

at all body sites. (B) Statistical prediction of both PLP and RLP by the same combination of thresholds like in

model A including the factor ‘pain type’ coding for PLP and RLP, respectively.

Abbreviations: HPT, heat pain thresholds; PLP, phantom limb pain intensity; PPT, pressure pain thresholds;

RLP, residual limb pain intensity; WDT, warmth detection thresholds.aThe baseline level was PLP, hence the regression coefficient codes the influence of RLP.

T A B L E 4 Results from stepwise

multiple regression and linear mixed models

| 125FUCHS ET AL.

4 | DISCUSSION

Based on research on other types of chronic pain and the find-

ings in cortical reorganization in PLP, we assumed that PLP

might be associated with lowered pain thresholds also at body

sites that are remote from the residual limb. Previous QST

studies in amputees have provided an inconclusive picture due

to inconsistencies in measures, small and heterogenous sam-

ples and a focus restricted to the residual limb. In this study,

we tested a relatively large and homogeneous sample of upper-

limb amputees. We investigated whether changes in pain and

detection thresholds assessed at different body sites correlate

with the presence and/or the perceived intensity of PLP.

Our most important finding is that the presence of PLP

(whether amputees reported PLP or not) was not related to

any sensory measure, whereas the perceived intensity of PLP

in amputees who reported PLP was clearly associated with

lower pain thresholds, especially in the face.

4.1 | No association between sensory thresholds and the presence of PLP

We tested for associations with the presence of PLP by com-

paring pain and perception thresholds measured in the PLP

group to those measured in the non- PLP group and in HC.

Surprisingly, there were no significant differences between

HPT and PPT at any of the measured body sites as a function

of the absence/presence of PLP. We also did not find any

evidence for an association between detection thresholds and

the presence of PLP. This negative finding was against our

primary hypothesis that the presence of PLP might be associ-

ated with pain perception.

4.2 | PLP intensity correlates with sensory thresholds

Contrary to the non- significant differences in sensory thresh-

olds between the groups, we found that higher PLP intensity

was associated with lower HPT at all body sites except for the

residual limb. Similar correlations were also found for PPT

although the relationships were numerically weaker and a ro-

bust significant correlation was only found at the contralateral

corner of the mouth. In contrast to the pain thresholds, detec-

tion thresholds for non- painful stimuli were not significantly

correlated with PLP intensity. However, when combining

pain and detection thresholds of all body sites to statistically

predict PLP intensity in multiple regression, we found a dif-

ferential relationship of PLP intensity with lowered HPT but

heightened WDT in the face. At the contralateral corner of

the mouth, the combination of HPT and WDT explained a

high proportion (of up to 51%) of the variance in PLP inten-

sity. This suggests that when PLP is present, its intensity is

strongly associated with decreased pain but increased warmth

detection thresholds in the face. Because the face is remote

from the residual limb, the observed patterns of sensory

thresholds are therefore not likely to have a peripheral origin.

It might strike as a surprise that PLP was differentially

associated with, on the one side, lower pain but, on the other

side, higher perception thresholds. However, it is well doc-

umented that chronic pain is associated with reduced preci-

sion in perception of non- painful stimuli (Catley et al., 2014;

Moseley, 2008; Moseley et al., 2012). Our results fit well

with the ‘imprecision hypothesis’ of chronic pain (Moseley

& Vlaeyen, 2015). This hypothesis posits that chronic pain

patients learn associations between multisensory events,

or bodily states, and painful events (e.g. during an injury).

Similar bodily states can later increase the likelihood to per-

ceive pain again due to classical conditioning. This learning

mechanism is enhanced when bodily states are less precisely

perceived.

F I G U R E 3 Results of a multiple regression model in which

the intensity of phantom limb pain (PLP intensity) in the group of

amputees with phantom limb pain was statistically predicted by

a linear combination of heat pain thresholds (HPT) and warmth

detection thresholds (WDT) at the corner of the mouth contralateral

to the amputation. The three- dimensional scatter plots show the data

together with a regression plane, representing the values predicted by

the multiple regression model. Higher PLP intensity was associated

with lower HPT and higher WDT. The proportion of variance in PLP

intensity explained by the model and the regression coefficients for

HPT and WDT (with statistical significance: *p < .05; ***p < .001)

are shown within the three- dimensional (3D) scatter plot

126 | FUCHS ET AL.

4.3 | Differences between body sites and their possible relationship to peripheral versus central processes

For all sensory measures, we found significant differences

between body sites. Many of the results were expected based

on prior research. For example, the corners of the mouth

showed lower thresholds than all other body sites in all sen-

sory measures. With respect to processes of PLP, compari-

sons between the homologous body sites at the corners of

the mouth and the arms are of particular interest. The com-

parison between the arms (i.e. between the residual limb and

its contralateral counterpart) can be indicative of peripheral

changes. Differences between the corners of the mouth could

be indicative of cortical changes in early sensory processing

areas such as S1. We found that HPT and PPT were signifi-

cantly lower at the residual limb compared to the intact limb,

which could be viewed as a sign of peripheral hyperalgesia.

However, this local hyperalgesia was observed in both the

PLP and in the non- PLP group. Moreover, the difference

between limbs was not significantly correlated with PLP

intensity. These findings do not suggest a close relation-

ship between PLP and pain thresholds at the residual limb.

We also revisited the hypothesis of increased tactile acuity

of the residual limb. Contrary to early studies (Haber, 1955;

D. Katz, 1921; Teuber et al., 1949; Wilson et al., 1962),

but in line with more recent ones (Flor et al., 1998; Grüsser

et al., 2001; Hunter et al., 2005), we did not find significantly

lower 2PDT at the residual limb. There were also no sig-

nificant differences between the limbs in WDT. Taken to-

gether, these results support the conclusion drawn by Hunter

et al. (2005) that sensory measures taken at the residual limb

do not in any simple way reflect phantom phenomena. Our

data further suggest that they are instead more strongly re-

lated to RLP.

Because cortical reorganization in S1 is both associated

with PLP (Flor et al., 1995) and with sensory changes in the

face of healthy subjects (Muret et al., 2016), sensory thresh-

olds might be altered in the mouth region of arm amputees.

We did not find significant differences between the groups at

the corners of the mouth and there were no significant intra-

individual differences between the corners of the mouth for

any of the thresholds. As discussed above, HPT and WDT

in the face correlated with PLP intensity in a multivariate

analysis. Because the face is remote from the residual limb,

this likely represents a centrally mediated effect. The fact that

facial pain thresholds were specifically associated with PLP

is in line with the notion that preamputation pain leads to the

formation of cortical pain memories via growth or broader

recruitment of nociceptive neurons in S1, resulting in an in-

creased range of stimuli eliciting pain (Flor, 2002; Vierck

et al., 2013; Yi & Zhang, 2011). It is possible that this process

also spreads to the neighbouring face area due to PLP- related

S1 reorganization. However, this association was present at

both sides of the face, whereas PLP- related S1 reorganization

of the face was found to be lateralized (Flor et al., 1995), that

is mainly affecting S1 contralateral to the amputation. If fa-

cial sensitivity closely paralleled cortical reorganization, the

sensory changes would be expected to be lateralized as well,

with changes primarily in the half of the face that is ipsilat-

eral to the amputation. From this view, it is surprising that

we found the strongest associations for the contralateral face.

However, associations were also present for the ipsilateral

F I G U R E 4 Results from a linear mixed model (LMM) testing statistical prediction of both phantom limb pain intensity (PLP) and residual

limb pain intensity (RLP) by a linear combination of heat pain thresholds (HPT) and warmth detection thresholds (WDT) at the corner of the

mouth contralateral to the amputation as well as by HPT at the ipsilateral arm (residual limb). The plots highlight the two statistically significant

interactions between the type of pain (PLP vs. RLP) and the sensory threshold predictor. The left panel shows that PLP— but not RLP— was

associated with lower HPT at the corner of the mouth; the right panel shows that RLP— but not PLP— was associated with lower HPT at the

residual limb. The lines represent regression parameters derived from the LMM. The points represent partial residuals (i.e., data corrected for the

influence of the not shown predictors)

| 127FUCHS ET AL.

face, as evident from the correlations. Due to the high degree

of intercorrelations between the thresholds, they are redun-

dant, and the ipsilateral face dropped in multiple regression

models. Second, it is possible that different generalization

mechanisms overlap and that changes might have affected

the ipsilateral face at an earlier and the entire face at a later

stage. Further studies are needed to investigate whether there

is a relationship between facial cortical reorganization in PLP

and changes in the facial thermal thresholds.

Most studies on cortical reorganization processes in am-

putees used tactile (e.g. Flor et al., 1995) or motor methods

(e.g. Lotze et al., 2001) to map the cortical reorganization

of the hand and the lips. As a tactile measure, this study as-

sessed 2PDT. There was no significant association between

PLP presence or intensity and facial 2PDT. Studies in healthy

participants have shown that peripheral input to the hand al-

ters its S1 reorganization and that this effect spreads to the

face, leading to altered facial 2PDT (Muret et al., 2016).

From this perspective, 2PDT might have been altered in the

amputation group. Other studies, however, suggest that 2PDT

is not closely related to S1 organization and rather reflects

processes outside of S1, for example in the inferior parietal

cortex (Akatsuka et al., 2008).

4.4 | Specificity of associations for PLP versus RLP and other chronic pain

Residual limb pain intensity should be carefully compared

with PLP, because as a frequent concomitant in chronic PLP,

it might be a driver of plastic changes in the nociceptive sys-

tem. We therefore compared the statistical association be-

tween PLP and RLP intensity with sensory thresholds. This

analysis showed that HPT at the contralateral corner of the

mouth specifically correlates with PLP whereas HPT at the

residual limb is specifically associated with RLP. In fact, the

residual limb was the only measured body site where HPT

was not significantly correlated with PLP. With respect to

the finding that it was mainly PLP, and not RLP, that was

associated with pain thresholds at areas of the body that were

remote from the residual limb, it can be assumed that it might

primarily be PLP that is associated with central factors of

pain enhancement, whereas RLP might rather be associated

with peripheral factors related to sensitivity of the residual

limb.

There are similarities with other types of chronic pain. In

fibromyalgia, pain thresholds are lowered in a widespread

manner, both at so- called tender points and at other areas,

and PPT correlates negatively with clinical pain assess-

ments (Lautenbacher et al., 1994). Other studies reported

contralateral transfer of lowered PPT in complex regional

pain syndrome (CRPS), but not in arthritis patients (Palmer

et al., 2019), or in CRPS but not in a control group with other

chronic pain syndromes (Vatine et al., 1998). One study found

that transfer of lowered PPT to the forehead in CRPS was

more pronounced ipsilateral than contralateral to the affected

limb (Drummond & Finch, 2006). This finding is interesting

because it is in line with the idea that generalization might

be related to S1 reorganization, which is seen both in PLP

and CRPS (for a review see Di Pietro et al., 2013). Future

research could directly compare sensory processes in PLP,

CRPS and other chronic pain to advance the understanding of

specific processes in these chronic pain syndromes.

4.5 | Discrepancy between presence and intensity of PLP

Our results showed that, contrary to our hypothesis, lower

pain thresholds were not associated with having PLP. Lower

pain thresholds were observed in the PLP as well as in the

non- PLP group and were, as such, unspecific. However, for

those amputees who reported PLP, pain thresholds correlated

with PLP intensity. These two findings seem, at first glance,

almost incompatible. However, they might indicate that

lowered pain thresholds play a different role depending on

whether PLP is present or not. Such differential processing

of sensory information depending on the presence or absence

of pain is not unusual. In line with this, Davis et al. (2015)

suggested that the presence or absence of chronic pain is not

merely a quantitatively, but rather a qualitatively different

state. When, in their words, the ‘pain switch is turned on’,

pain- modulating factors might interact with each other in

a different way. As the presence of chronic pain is associ-

ated with changes in neural processing of sensory informa-

tion (Davis & Moayedi, 2013; Latremoliere & Woolf, 2009;

Woolf & Salter, 2000), memory, affective learning and emo-

tional processes (Flor & Turk, 2011), we propose that pain

thresholds might play a different role when PLP is present

compared to absent and influence its perceived intensity.

As another explanation, pain thresholds correlating

with PLP intensity, but not its presence per se, could also

be the end product of an etiological process. Central sen-

sitization resulting from long- term nociceptive input is a

potential explanation for the correlation between PLP in-

tensity and enhanced sensitivity to painful stimuli (Woolf

& Salter, 2000) and its generalization to remote areas of the

body (Le Bars, 2002) in participants with strong PLP. The

strong nociceptive input might decrease both pain thresh-

olds and lead to the formation of pain memories related to

PLP, resulting in an association between them. Yet, it is also

possible that participants who developed strong PLP already

had low pain thresholds before the amputation (Nikolajsen

et al., 2000). Low pain thresholds might have been present as

a preamputation trait, potentially promoting the emergence of

PLP. Preoperation pain sensitivity has been shown to predict

128 | FUCHS ET AL.

postoperative pain (Granot, 2009) and PLP early after ampu-

tation correlated positively with sensitivity to pain stimuli as-

sessed right before the amputation (Nikolajsen et al., 2000).

However, whether later- stage chronic pain is also associated

with pain sensitivity before injury is not known yet.

In one way or the other, sensory processes as such do not

seem to be able to explain why amputees develop chronic PLP

but it is possible that they interact with other factors. Factors

determining whether or not amputees develop chronic pain

are manifold (Flor, 2002) and altered pain processing might

be one among them (Flor et al., 2006; Nikolajsen et al., ,1997,

2000). Functional (Apkarian et al., 2013) and structural

(Mansour et al., 2013) brain connectivities have been shown

to predict the transition from acute to chronic back pain in

longitudinal studies. Although PLP patients might differ from

chronic back pain patients especially with respect to the role of

cognitive and emotional variables (Fuchs et al., 2015, 2018),

it should be clarified whether brain connectivity also predicts

chronic PLP and how this relates to sensory processing and

cortical reorganization. As these relevant questions need to be

addressed using a longitudinal design, the present study can,

by itself, not contribute to clarify these etiological questions.

Future studies should also investigate relationships be-

tween the decreased pain thresholds observed in this study

and other alterations of sensory processing that have been ob-

served in chronic pain. For example, diffuse noxious inhibi-

tory controls (DNIC) or conditioned pain modulation refer to

the fact that the response to a painful stimulus is reduced or

inhibited due to another concurrently applied painful stim-

ulus (Le Bars et al., 1979) and this process has been found

to be deficient in chronic pain (Lewis et al., 2012). In this

study, we only tested single painful stimuli but did not as-

sess pain inhibition as assessed in dual stimulation paradigms

testing DNIC. Sensitization and habituation to painful stim-

uli have been found to be altered in chronic pain (Kleinböhl

et al., 1999). In this study, habituation across HPT trials oc-

curred and reduced habituation correlated with PLP intensity,

which did, however, not explain the reduced pain thresholds

we have reported (see Supplementary Material, Figure S6).

Future research should use sensitization and habituation par-

adigms (e.g. Kleinböhl et al., 1999) to assess the role of these

variables in PLP.

4.6 | Limitations

There are some limitations for the present study. First, the

study is only based on psychophysical thresholds. While the

study design invites conclusions about underlying processes,

further studies using neuroimaging methods are needed

to further investigate whether the mechanisms at play are

peripheral or central. Second, the study relied on a cross-

sectional design and its findings are only correlational and

allow no direct conclusions about the etiology of PLP. Third,

the study was restricted to sensory mechanisms related to

the amputation and PLP and, in correlational analyses, RLP.

This leaves open how specific these findings are to PLP. This

could have been investigated by including another clinical

group with a pain condition other than PLP (e.g. chronic back

pain, CRPS, or fibromyalgia).

Another limitation arises from the choice of tested body

sites and used measures. In this study, even the remote sites,

such as the thenar of the contralateral limb, are connected

to the missing limb via interhemispheric connections. If

lowered pain thresholds more strongly generalize to body

parts with S1 representations adjacent to the hand than to

remote body parts, this suggests that generalization paral-

lels brain reorganization processes. For clarification of the

mechanisms of generalization, assessment of another, more

remote, site such as the contralateral foot would have been

informative. Furthermore, most studies on brain changes in

amputees are based on tactile or motor processes and the

present study used warmth detection as the primary detection

measure. The inclusion of mechanical detection thresholds

would have been advantageous but would have prolonged

the study protocol, which was not feasible in the context of

this study. Unfortunately, 2PDT, which have a close relation-

ship with S1 reorganization, were only available in a sub-

sample of the amputees, resulting in reduced testing power

for 2PDT and their exclusion from the multivariate analyses.

Hence, this study cannot answer some questions concerning

potential changes in tactile spatial acuity and its relationship

with PLP. The choice of body sites and the testing protocol

also diverged in some respects from the protocol proposed

by the DFNS (Rolke et al., 2006), which limits the compa-

rability of the results to other studies and to normative data

provided by the network (Magerl et al., 2010). For exam-

ple, the normative data for the face were assessed on the

cheeks for thermal thresholds and over the masseter muscle

for PPT, but we assessed them at the corners of the mouth

for theoretical reasons related to previous data on reorgani-

zation. Further, the DFNS protocol assessed thermal thresh-

olds on the hand dorsum while we used the thenar. While we

had theoretical reasons for using the corners of the mouth

instead of the cheeks, the thermal thresholds on the hand

could instead have been assessed on the dorsum of the hand

with the benefit of better comparability with the normative

data. Another deviation is that, for the thermal thresholds,

we used verbal responses and the experimenter pressed the

button as fast as possible. This procedure is not ideal be-

cause it creates a bias (overestimation) of the threshold due

to the reaction time of the experimenter. Second, the experi-

menter was not blinded concerning the group assignment of

the participants and could have been implicitly biased and

reacted slower (or faster) depending on the group assign-

ment of the participants, which could confound the data. The

| 129FUCHS ET AL.

experimenter tried best to always react as fast as possible

and to stay neutral. The finding of some results that were

contrary to our hypothesis suggests that this was successful.

In future studies, participants could use their feet to press the

response buttons, for example. In Supplementary Material,

we compared our thresholds with the DFNS normative data,

and we found that our WDT were inflated. This difference

could be related to the additional delay due to the experi-

menter's reaction time but should be interpreted with caution

due to the different body sites as mentioned above. Note that

these deviations are not problematic for the interpretation of

the present results because the protocol was identical for all

tested groups, but they limit the possibilities of comparison

with the normative data. This could be addressed in future

studies. For PPT at the thenar, where the protocols and body

site were identical, the thresholds match with the normative

data.

4.7 | Conclusions

In summary, our assessments of pain thresholds at different

body sites, remote from the residual limb, suggest that global

enhanced sensitivity to painful stimuli is related to the in-

tensity of PLP. The global pattern showed that amputees in

the PLP group with low levels of PLP were hypoalgesic and

those with strong PLP were hyperalgesic. For facial HPT, for

which the association with PLP was strongest, associations

were even stronger when WDT was also taken into account.

PLP was associated with decreased HPT but increased WDT

in the face. This pattern was specific to PLP. Pain thresholds

at the residual limb, however, were unrelated to PLP but spe-

cifically related to RLP.

Surprisingly, any differences in sensory thresholds be-

tween the groups were absent and so the mere presence of PLP

did not coincide with sensory thresholds at any body site. We

suggest that these global sensitivity changes reflect a central

aspect of sensory processing rather than peripheral mecha-

nisms, emphasizing the presence of ‘widespread hypersensi-

tivity’ which has already been suggested by Cronholm in 1951

(p. 119). Whether this phenomenon is related to plasticity pro-

cesses occurring after or to factors already present before am-

putation cannot be clarified based on the present data.

AUTHOR CONTRIBUTION

HF, MD and XF conceptualized and designed the study. XF

and PK collected the data. XF analyzed the data and drafted

the manuscript. All authors wrote and critically revised the

article and approved the final version.

ACKNOWLEDGEMENTS

This study was supported by a grant from the Deutsche

Forschungsgemeinschaft (SFB1158/B07) to HF and

JA and European Research Council Advanced grant

‘Phantom phenomena: A window to the mind and the brain'

(PHANTOMMIND, FP7/2007– 2013/230249) to HF. We

would also like to thank Astrid Wolf for help with recruit-

ment, Kristina Staudt and student assistants for their help

with data acquisition.

DATA AVAILABILITY STATEMENT

Data and code of this study are publicly available and can

be accessed via the Open Science Framework (https://osf.io/

v6hjy/).

REFERENCES

Akatsuka, K., Noguchi, Y., Harada, T., Sadato, N., & Kakigi, R. (2008).

Neural codes for somatosensory two- point discrimination in infe-

rior parietal lobule: An fMRI study. NeuroImage, 40(2), 852– 858.

https://doi.org/10.1016/j.neuro image.2007.12.013

Apkarian, A. V., Baliki, M. N., & Farmer, M. A. (2013). Predicting tran-

sition to chronic pain. Current Opinion in Neurology, 26(4), 360–

367. https://doi.org/10.1097/WCO.0b013 e3283 6336ad

Bates, D., Mächler, M., Bolker, B., & Walker, S. (2014). Fitting linear

mixed- effects models using lme4. ArXiv Preprint arXiv:1406.5823.

Bekrater- Bodmann, R., Chung, B. Y., Richter, I., Wicking, M., Foell,

J., Mancke, F., Schmahl, C., & Flor, H. (2015). Deficits in pain per-

ception in borderline personality disorder: Results from the thermal

grill illusion. Pain, 156(10), 2084– 2092. https://doi.org/10.1097/j.

pain.00000 00000 000275

Bekrater- Bodmann, R., Schredl, M., Diers, M., Reinhard, I., Foell, J.,

Trojan, J., Fuchs, X., & Flor, H. (2015). Post- amputation pain is asso-

ciated with the recall of an impaired body representation in dreams—

results from a nationwide survey on limb amputees. PLoS One,

10(3), e0119552. https://doi.org/10.1371/journ al.pone.0119552

Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery

rate: A practical and powerful approach to multiple testing. Journal

of the Royal Statistical Society. Series B (Methodological), 57(1),

289– 300. https://doi.org/10.2307/2346101

Bonzano, L., Tacchino, A., Roccatagliata, L., Abbruzzese, G., Mancardi,

G. L., & Bove, M. (2008). Callosal contributions to simultaneous

bimanual finger movements. The Journal of Neuroscience, 28(12),

3227– 3233. https://doi.org/10.1523/JNEUR OSCI.4076- 07.2008

Catley, M. J., O’Connell, N. E., Berryman, C., Ayhan, F. F., & Moseley,

G. L. (2014). Is tactile acuity altered in people with chronic pain? A

systematic review and meta- analysis. The Journal of Pain, 15(10),

985– 1000. https://doi.org/10.1016/j.jpain.2014.06.009

Cronholm, B. (1951). Phantom limbs in amputees; a study of changes

in the integration of centripetal impulses with special reference to

referred sensations. Acta Psychiatrica Et Neurologica Scandinavica

Supplementum, 72, 1– 310.

Davis, K. D., Kucyi, A., & Moayedi, M. (2015). The pain switch:

An “ouch” detector. Pain, 156(11), 2164– 2166. https://doi.

org/10.1097/j.pain.00000 00000 000303

Davis, K. D., & Moayedi, M. (2013). Central mechanisms of pain revealed

through functional and structural MRI. Journal of Neuroimmune

Pharmacology, 8(3), 518– 534. https://doi.org/10.1007/s1148

1- 012- 9386- 8

Devor, M. (1991). Neuropathic pain and injured nerve: Peripheral

mechanisms. British Medical Bulletin, 47(3), 619– 630. https://doi.

org/10.1093/oxfor djour nals.bmb.a072496

130 | FUCHS ET AL.

Di Pietro, F., McAuley, J. H., Parkitny, L., Lotze, M., Wand, B. M.,

Moseley, G. L., & Stanton, T. R. (2013). Primary somatosensory

cortex function in complex regional pain syndrome: A systematic

review and meta- analysis. The Journal of Pain, 14(10), 1001– 1018.

https://doi.org/10.1016/j.jpain.2013.04.001

Dietrich, C., Walter- Walsh, K., Preißler, S., Hofmann, G. O., Witte,

O. W., Miltner, W. H. R., & Weiss, T. (2012). Sensory feed-

back prosthesis reduces phantom limb pain: Proof of a principle.

Neuroscience Letters, 507(2), 97– 100. https://doi.org/10.1016/j.

neulet.2011.10.068

Dinse, H. R. (2003). Pharmacological modulation of perceptual learning

and associated cortical reorganization. Science, 301(5629), 91– 94.

https://doi.org/10.1126/scien ce.1085423

Dixon, W. J., & Mood, A. M. (1948). A method for obtaining and

analyzing sensitivity data. Journal of the American Statistical

Association, 43(241), 109– 126. https://doi.org/10.1080/01621

459.1948.10483254

Drummond, P. D., & Finch, P. M. (2006). Sensory changes in the fore-

head of patients with complex regional pain syndrome. Pain, 123(1–

2), 83– 89. https://doi.org/10.1016/j.pain.2006.02.013

Engkvist, O., Wahren, L. K., Wallin, G., Torebjrk, E., & Nystrm, B.

(1985). Effects of regional intravenous guanethidine block in post-

traumatic cold intolerance in hand amputees. Journal of Hand

Surgery (British and European Volume), 10(2), 145– 150. https://

doi.org/10.1016/0266- 7681(85)90003 - 8

Flor, H. (2002). Phantom- limb pain: Characteristics, causes, and treat-

ment. The Lancet Neurology, 1(3), 182– 189. https://doi.org/10.1016/

S1474 - 4422(02)00074 - 1

Flor, H., Elbert, T., Knecht, S., Wienbruch, C., Pantev, C., Birbaumers,

N., Larbig, W., & Taub, E. (1995). Phantom- limb pain as a percep-

tual correlate of cortical reorganization following arm amputation.

Nature, 375(6531), 482– 484. https://doi.org/10.1038/375482a0

Flor, H., Elbert, T., Mühlnickel, W., Pantev, C., Wienbruch, C., & Taub,

E. (1998). Cortical reorganization and phantom phenomena in

congenital and traumatic upper- extremity amputees. Experimental

Brain Research, 119(2), 205– 212. https://doi.org/10.1007/s0022

10050334

Flor, H., & Fuchs, X. (2017). Phantom limb pain. In Reference module in

neuroscience and biobehavioral psychology. Elsevier. https://www.

scien cedir ect.com/scien ce/artic le/pii/B9780 12809 32450 31436

Flor, H., Nikolajsen, L., & Jensen, T. S. (2006). Phantom limb pain: A

case of maladaptive CNS plasticity? Nature Reviews Neuroscience,

7(11), 873– 881. https://doi.org/10.1038/nrn1991

Flor, H., Rudy, T. E., Birbaumer, N., Streit, B., & Schugens, M. M.

(1990). Zur Anwendbarkeit des West Haven- Yale Multidimensional

Pain Inventory im deutschen Sprachraum [The applicability of the

West Haven- Yale multidimensional pain inventory in German-

speaking countries. Data on the reliability and validity of the MPI-

D.]. Der Schmerz, 4(2), 82– 87. https://doi.org/10.1007/BF025 27839

Flor, H., & Turk, D. C. (2011). Chronic pain: An integrated biobehav-

ioral approach (1 Pap/Cdr edition). IASP Press.

Fried, K., Govrin- Lippmann, R., Rosenthal, F., Ellisman, M. H., &

Devor, M. (1991). Ultrastructure of afferent axon endings in a

neuroma. Journal of Neurocytology, 20(8), 682– 701. https://doi.

org/10.1007/BF011 87069

Fuchs, X., Bekrater- Bodmann, R., & Flor, H. (2015). Phantom pain:

The role of maladaptive plasticity and emotional and cognitive vari-

ables. In G. Pickering & S. Gibson (Eds.), Pain, emotion and cog-

nition (pp. 189– 207). Springer International Publishing. https://doi.

org/10.1007/978- 3- 319- 12033 - 1_12

Fuchs, X., Flor, H., & Bekrater- Bodmann, R. (2018). Psychological

factors associated with phantom limb pain: A review of recent find-

ings. Pain Research and Management, 2018, 5080123. https://doi.

org/10.1155/2018/5080123

Granot, M. (2009). Can we predict persistent postoperative pain

by testing preoperative experimental pain? Current Opinion

in Anaesthesiology, 22(3), 425– 430. https://doi.org/10.1097/

ACO.0b013 e3283 2a40e1

Grüsser, S. M., Winter, C., Mühlnickel, W., Denke, C., Karl, A.,

Villringer, K., & Flor, H. (2001). The relationship of perceptual

phenomena and cortical reorganization in upper extremity ampu-

tees. Neuroscience, 102(2), 263– 272. https://doi.org/10.1016/S0306

- 4522(00)00491 - 7

Haber, W. B. (1955). Effects of loss of limb on sensory func-

tions. The Journal of Psychology, 40(1), 115– 123. https://doi.

org/10.1080/00223 980.1955.9712969

Harden, R. N., Gagnon, C. M., Khan, A., Wallach, G., & Zereshki,

A. (2010). Hypoesthesia in the distal residual limb of am-

putees. PM&R, 2(7), 607– 611. https://doi.org/10.1016/j.

pmrj.2010.03.033

Hunter, J. P., Katz, J., & Davis, K. D. (2005). Dissociation of phan-

tom limb phenomena from stump tactile spatial acuity and sensory

thresholds. Brain, 128(2), 308– 320. https://doi.org/10.1093/brain/

awh350

Katz, D. (1921). Zur Psychologie des Amputierten und seiner Prothese.

Barth.

Katz, J. (1992). Psychophysical correlates of phantom limb experience.

Journal of Neurology, Neurosurgery & Psychiatry, 55(9), 811– 821.

https://doi.org/10.1136/jnnp.55.9.811

Kern, U., Busch, V., Rockland, M., Kohl, M., & Birklein, F. (2009).

Prävalenz und Risikofaktoren von Phantomschmerzen und

Phantomwahrnehmungen in Deutschland [Prevalence and risk fac-

tors of phantom limb pain and phantom limb sensations in Germany.

A nationwide field survey]. Schmerz (Berlin, Germany), 23(5), 479–

488. https://doi.org/10.1007/s0048 2- 009- 0786- 5

Kerns, R. D., Turk, D. C., & Rudy, T. E. (1985). The West Haven- Yale

Multidimensional Pain Inventory (WHYMPI). Pain, 23(4), 345–

356. https://doi.org/10.1016/0304- 3959(85)90004 - 1

Kikkert, S., Johansen- Berg, H., Tracey, I., & Makin, T. R. (2018).

Reaffirming the link between chronic phantom limb pain and main-

tained missing hand representation. Cortex, 106, 174– 184. https://

doi.org/10.1016/j.cortex.2018.05.013

Kleinböhl, D., Hölzl, R., Möltner, A., Rommel, C., Weber, C., &

Osswald, P. M. (1999). Psychophysical measures of sensitization to

tonic heat discriminate chronic pain patients. Pain, 81(1), 35– 43.

https://doi.org/10.1016/S0304 - 3959(98)00266 - 8

Korin, H., Weiss, S. A., & Fishman, S. (1963). Pain sensitivity of am-

putation extremities. The Journal of Psychology, 55(2), 345– 355.

https://doi.org/10.1080/00223 980.1963.9916627

Kuznetsova, A., Brockhoff, P. B., & Christensen, R. H. B. (2014).

lmerTest: Tests for random and fixed effects for linear mixed effect

models (lmer objects of lme4 package). http://CRAN.R- proje ct.org/

packa ge=lmerTest

Latremoliere, A., & Woolf, C. J. (2009). Central sensitization: A gener-

ator of pain hypersensitivity by central neural plasticity. The Journal

of Pain, 10(9), 895– 926. https://doi.org/10.1016/j.jpain.2009.06.012

Lautenbacher, S., Rollman, G. B., & McCain, G. A. (1994).

Multi- method assessment of experimental and clinical pain

in patients with fibromyalgia. Pain, 59(1), 45– 53. https://doi.

org/10.1016/0304- 3959(94)90046 - 9

| 131FUCHS ET AL.

Le Bars, D. (2002). The whole body receptive field of dorsal horn multi-

receptive neurones. Brain Research. Brain Research Reviews, 40(1–

3), 29– 44. https://doi.org/10.1016/S0165 - 0173(02)00186 - 8

Le Bars, D., Dickenson, A. H., & Besson, J.- M. (1979). Diffuse nox-

ious inhibitory controls (DNIC). I. Effects on dorsal horn con-

vergent neurones in the rat. Pain, 6(3), 283– 304. https://doi.

org/10.1016/0304- 3959(79)90049 - 6

Levitt, H. (1971). Transformed up- down methods in psychoacous-

tics. The Journal of the Acoustical Society of America, 49(2),

Suppl2:467+.

Lewis, G. N., Rice, D. A., & McNair, P. J. (2012). Conditioned pain

modulation in populations with chronic pain: A systematic review

and meta- analysis. The Journal of Pain, 13(10), 936– 944. https://

doi.org/10.1016/j.jpain.2012.07.005

Li, S., Melton, D. H., & Li, S. (2015). Tactile, thermal, and electrical

thresholds in patients with and without phantom limb pain after

traumatic lower limb amputation. Journal of Pain Research, 8, 169–

174. https://doi.org/10.2147/JPR.S77412

Lotze, M., Flor, H., Grodd, W., Larbig, W., & Birbaumer, N. (2001).

Phantom movements and pain An fMRI study in upper limb am-

putees. Brain, 124(11), 2268– 2277. https://doi.org/10.1093/brain/

124.11.2268

Lotze, M., Grodd, W., Birbaumer, N., Erb, M., Huse, E., & Flor, H.

(1999). Does use of a myoelectric prosthesis prevent cortical reorga-

nization and phantom limb pain? Nature Neuroscience, 2(6), 501–

502. https://doi.org/10.1038/9145

MacIver, K., Lloyd, D. M., Kelly, S., Roberts, N., & Nurmikko, T.

(2008). Phantom limb pain, cortical reorganization and the thera-

peutic effect of mental imagery. Brain, 131(8), 2181– 2191. https://

doi.org/10.1093/brain/ awn124

Magerl, W., Krumova, E. K., Baron, R., Tölle, T., Treede, R.- D., &

Maier, C. (2010). Reference data for quantitative sensory testing

(QST): Refined stratification for age and a novel method for statis-

tical comparison of group data. Pain, 151(3), 598– 605. https://doi.

org/10.1016/j.pain.2010.07.026

Maier, C., Baron, R., Tölle, T. R., Binder, A., Birbaumer, N., Birklein,

F., Gierthmühlen, J., Flor, H., Geber, C., Huge, V., Krumova, E.

K., Landwehrmeyer, G. B., Magerl, W., Maihöfner, C., Richter,

H., Rolke, R., Scherens, A., Schwarz, A., Sommer, C., …

Treede, D.- R. (2010). Quantitative sensory testing in the German

Research Network on Neuropathic Pain (DFNS): Somatosensory

abnormalities in 1236 patients with different neuropathic pain

syndromes. Pain, 150(3), 439– 450. https://doi.org/10.1016/j.

pain.2010.05.002

Makin, T. R., Cramer, A. O., Scholz, J., Hahamy, A., Slater, D. H.,

Tracey, I., & Johansen- Berg, H. (2013). Deprivation- related and

use- dependent plasticity go hand in hand. Elife, 2, e01273. https://

doi.org/10.7554/eLife.01273

Makin, T. R., Scholz, J., Filippini, N., Henderson Slater, D., Tracey,

I., & Johansen- Berg, H. (2013). Phantom pain is associated with

preserved structure and function in the former hand area. Nature

Communications, 4, 1570. https://doi.org/10.1038/ncomm s2571

Mancini, F., Bauleo, A., Cole, J., Lui, F., Porro, C. A., Haggard, P.,

& Iannetti, G. D. (2014). Whole- body mapping of spatial acu-

ity for pain and touch: Mapping spatial acuity for pain. Annals of

Neurology, 75(6), 917– 924, https://doi.org/10.1002/ana.24179

Mansour, A. R., Baliki, M. N., Huang, L., Torbey, S., Herrmann, K. M.,

Schnitzer, T. J., & Apkarian, A. V. (2013). Brain white matter struc-

tural properties predict transition to chronic pain. Pain, 154(10),

2160– 2168. https://doi.org/10.1016/j.pain.2013.06.044

Moseley, G. L. (2008). I can’t find it! Distorted body image and tactile

dysfunction in patients with chronic back pain. Pain, 140(1), 239–

243. https://doi.org/10.1016/j.pain.2008.08.001

Moseley, G. L., Gallagher, L., & Gallace, A. (2012). Neglect- like tac-

tile dysfunction in chronic back pain. Neurology, 79(4), 327– 332.

https://doi.org/10.1212/WNL.0b013 e3182 60cba2

Moseley, G. L., & Vlaeyen, J. W. S. (2015). Beyond nociception: The

imprecision hypothesis of chronic pain. Pain, 156(1), 35– 38. https://

doi.org/10.1016/j.pain.00000 00000 000014

Muret, D., Daligault, S., Dinse, H. R., Delpuech, C., Mattout, J., Reilly,

K. T., & Farnè, A. (2016). Neuromagnetic correlates of adaptive

plasticity across the hand- face border in human primary somato-

sensory cortex. Journal of Neurophysiology, 115(4), 2095– 2104.

https://doi.org/10.1152/jn.00628.2015

Nikolajsen, L. (2013). Phantom limb. In S. B. McMahon, P. D. Wall, &

R. Melzack (Eds.), Wall and Melzack’s textbook of pain (6th ed., pp.

915– 925). Elsevier, Saunders.

Nikolajsen, L., Ilkjær, S., & Jensen, T. S. (2000). Relationship be-

tween mechanical sensitivity and postamputation pain: A prospec-

tive study. European Journal of Pain, 4(4), 327– 334. https://doi.

org/10.1053/eujp.2000.0194

Nikolajsen, L., Ilkjær, S., Krøner, K., Christensen, J. H., & Jensen, T.

S. (1997). The influence of preamputation pain on postamputa-

tion stump and phantom pain. Pain, 72(3), 393– 405. https://doi.

org/10.1016/S0304 - 3959(97)00061 - 4

Oldfield, R. C. (1971). The assessment and analysis of handedness: The

Edinburgh inventory. Neuropsychologia, 9(1), 97– 113. https://doi.

org/10.1016/0028- 3932(71)90067 - 4

Palmer, S., Bailey, J., Brown, C., Jones, A., & McCabe, C. S. (2019).

Sensory function and pain experience in arthritis, complex regional

pain syndrome, fibromyalgia syndrome, and pain- free volunteers:

A cross- sectional study. The Clinical Journal of Pain, 35(11), 894–

900. https://doi.org/10.1097/AJP.00000 00000 000751

Pinheiro, J. C., & Bates, D. M. (2000). Mixed- effects models in S and

S- PLUS. Springer Science & Business Media.

R Core Team (2014). R: A language and environment for statistical

computing. R Foundation for Statistical Computing. http://www.R-

proje ct.org/

Ramachandran, V. S., & Hirstein, W. (1998). The perception of phantom

limbs. The D. O. Hebb lecture. Brain, 121(9), 1603– 1630. https://

doi.org/10.1093/brain/ 121.9.1603

Rolke, R., Baron, R., Maier, C., Tölle, T. R., Treede, D. R., Beyer, A.,

Binder, A., Birbaumer, N., Birklein, F., Bötefür, I. C., Braune, S.,

Flor, H., Huge, V., Klug, R., Landwehrmeyer, G. B., Magerl, W.,

Maihöfner, C., Rolko, C., Schaub, C., … Wasserka, B. (2006).

Quantitative sensory testing in the German Research Network

on Neuropathic Pain (DFNS): Standardized protocol and refer-

ence values. Pain, 123(3), 231– 243. https://doi.org/10.1016/j.

pain.2006.01.041

Sherman, R. A., Arena, J. G., Sherman, C. J., & Ernst, J. L. (1989). The

mystery of phantom pain: Growing evidence for psychophysiologi-

cal mechanisms. Biofeedback and Self- Regulation, 14(4), 267– 280.

https://doi.org/10.1007/BF009 99118

Teuber, H.- L., Krieger, H., & Bender, M. (1949). Reorganization of

sensory function in amputation stumps: Two- point discrimination.

Federal Proceedings, 8:156.

van den Heuvel, M. P., & Hulshoff Pol, H. E. (2009). Specific somato-

topic organization of functional connections of the primary motor

network during resting state. Human Brain Mapping, 4(31), 631–

644. https://doi.org/10.1002/hbm.20893

132 | FUCHS ET AL.

Vase, L., Nikolajsen, L., Christensen, B., Egsgaard, L. L., Arendt-

Nielsen, L., Svensson, P., & Staehelin Jensen, T. (2011). Cognitive-

emotional sensitization contributes to wind- up- like pain in phantom

limb pain patients. Pain, 152(1), 157– 162. https://doi.org/10.1016/j.

pain.2010.10.013

Vaso, A., Adahan, H.- M., Gjika, A., Zahaj, S., Zhurda, T., Vyshka, G.,

& Devor, M. (2014). Peripheral nervous system origin of phan-

tom limb pain. Pain, 155(7), 1384– 1391. https://doi.org/10.1016/j.

pain.2014.04.018

Vatine, J.- J., Tsenter, J., & Nirel, R. (1998). Experimental pressure pain

in patients with complex regional pain syndrome, type I (reflex

sympathetic dystrophy). American Journal of Physical Medicine &

Rehabilitation, 77(5), 382– 387.

Vierck, C. J., Whitsel, B. L., Favorov, O. V., Brown, A. W., &

Tommerdahl, M. (2013). Role of primary somatosensory cortex in

the coding of pain. Pain, 154(3), 334– 344. https://doi.org/10.1016/j.

pain.2012.10.021

Wahren, L. K. (1990). Changes in thermal and mechanical pain thresholds

in hand amputees. A clinical and physiological long- term follow- up.

Pain, 42(3), 269– 277. https://doi.org/10.1016/0304- 3959(90)91139 - A

Weinstein, S. (1968). Intensive and extensive aspects of tactile sensitiv-

ity as a function of body part, sex, and laterality. In D. R. Kenshalo

(Ed.), The skin senses: Proceedings of the first International

Symposium on the Skin Senses, held at the Florida State University in

Tallahassee, Florida (pp. 195– 218). Charles C. Thomas Publishing.

Wickham, H. (2009). ggplot2: Elegant graphics for data analysis.

Springer Science & Business Media.

Wiffen, P., Meynadier, J., Dubois, M., Thurel, C., DeSmet, J., & Harden,

R. N. (2006). Chapter 4: Diagnostic and treatment issues in postam-

putation pain after landmine injury. Pain Medicine, 7(Suppl 2),

S209– S212. https://doi.org/10.1111/j.1526- 4637.2006.00234_6.x

Wilson, J. J., Wilson, B. C., & Swinyard, C. A. (1962). Two- point dis-

crimination in congenital amputees. Journal of Comparative and

Physiological Psychology, 55(4), 482– 485. https://doi.org/10.1037/

h0042122

Woolf, C. J. (2014). What to call the amplification of nociceptive

signals in the central nervous system that contribute to wide-

spread pain? Pain, 155(10), 1911– 1912. https://doi.org/10.1016/

j.pain.2014.07.021

Woolf, C. J., & Salter, M. W. (2000). Neuronal Plasticity: Increasing

the Gain in Pain. Science, 288(5472), 1765– 1768. https://doi.

org/10.1126/scien ce.288.5472.1765

Yi, M., & Zhang, H. (2011). Nociceptive memory in the brain: Cortical

mechanisms of chronic pain. The Journal of Neuroscience, 31(38),

13343– 13345. https://doi.org/10.1523/JNEUR OSCI.3279- 11.2011

SUPPORTING INFORMATION

Additional Supporting Information may be found online in

the Supporting Information section.

How to cite this article: Fuchs, X., Diers, M., Trojan,

J., Kirsch, P., Milde, C., Bekrater- Bodmann, R.,

Rance, M., Foell, J., Andoh, J., Becker, S., & Flor, H.

(2022). Phantom limb pain after unilateral arm

amputation is associated with decreased heat pain

thresholds in the face. European Journal of Pain, 26,

114– 132. https://doi.org/10.1002/ejp.1842

Phantom limb pain after unilateral arm amputation is ... - zora.uzh

Documents

Transcript of Phantom limb pain after unilateral arm amputation is ... - zora.uzh