**E**ff**ects of Psychoactive Massage in Outpatients with Depressive Disorders: A Randomized Controlled Mixed-Methods Study**

**Michaela Maria Arnold 1,2,\*, Bruno Müller-Oerlinghausen 3, Norbert Hemrich <sup>2</sup> and Dominikus Bönsch 1,4**


Received: 9 August 2020; Accepted: 21 September 2020; Published: 26 September 2020

**Abstract:** The clinical picture of depressive disorders is characterized by a plethora of somatic symptoms, psychomotor retardation, and, particularly, anhedonia. The number of patients with residual symptoms or treatment resistance is high. Touch is the basic communication among humans and animals. Its application professionally in the form of, e.g., psychoactive massage therapy, has been shown in the past to reduce the somatic and mental symptoms of depression and anxiety. Here, we investigated the effects of a specially developed affect-regulating massage therapy (ARMT) vs. individual treatment with a standardized relaxation procedure, progressive muscle relaxation (PMR), in 57 outpatients with depression. Patients were given one ARMT or PMR session weekly over 4 weeks. Changes in somatic and cognitive symptoms were assessed by standard psychiatric instruments (Hamilton Depression Scale (HAMD) and the Bech–Rafaelsen–Melancholia–Scale (BRMS)) as well as a visual analogue scale. Furthermore, oral statements from all participants were obtained in semi-structured interviews. The findings show clear and statistically significant superiority of ARMT over PMR. The results might be interpreted within various models. The concept of interoception, as well as the principles of body psychotherapy and phenomenological aspects, offers cues for understanding the mechanisms involved. Within a neurobiological context, the significance of C-tactile afferents activated by special touch techniques and humoral changes such as increased oxytocin levels open additional ways of interpreting our findings.

**Keywords:** massage therapy; psychoactive massage; affect-regulating massage therapy; affective touch; depression; pain; interoception; C-tactile fibers; body psychotherapy

#### **1. Introduction**

Depressive disorders are among the most common mental diseases in the western world [1]. In addition to the personal suffering of those affected and their environment, the disease represents a significant challenge for society as a whole. Lifetime prevalence has been found to range between 16% and 20%. The World Health Organization (WHO) has declared that it will become the leading cause of global disease burden in the future [2]. The course of the disorder in most patients is episodic and is characterized by a lowered, depressed mood lasting for at least 2 weeks, vital and cognitive retardation, negative thoughts, and the core symptom of anhedonia inflicting nearly all

areas of normal life and making life dull and gray. Suicidal ideation and suicidal behavior occur frequently; 10–15% of patients with affective disorders who do not receive efficacious prophylactic long-term treatment (e.g., with lithium salts) will finally die from suicide. In addition, a plethora of somatic symptoms, including pain and physical fatigue affect quality of life, impair working function, increase healthcare utilization, worsen depression outcomes, and increase the risk of recurrence [3]. There is further evidence that depression is associated with substantially disturbed body awareness and desynchronization causing psychomotor retardation [4,5]. These aspects do not receive sufficient consideration if depression is simply called a "mood disorder" or "affective disorder" [6].

It is important to realize that the body ("Leib" in German language and philosophy) of a depressed individual is affected just as much as the mental state. Many facets of colloquial language illustrate the close connection of body and depression, e.g., talking about a person who is depressed or mortified, we may say "he/she is down in the mouth".

Although the diagnosis and treatment of depression has improved significantly in recent years, there are still deficits in the care and therapy of affected individuals. Optimal treatment success often cannot be achieved, so that in about 30% of cases residual symptoms can be observed. These include primarily, sleep disorders, chronic depressed and/or anxious mood, cognitive deficits, and somatic symptoms [7,8].

The main treatment modalities comprise different types of psychotherapy and/or treatment with antidepressants and other psychotropic agents. However, although prescriptions for antidepressants are rising from year to year in most European countries and in the US [9], their overall efficacy is far from satisfactory. In recent years critical voices based on meta-analyses and serious, independent studies have drawn the attention of a larger audience to the fact that in some patient cohorts the therapeutic efficacy of antidepressants was not found to be higher than that of placebo [10–12]. On the other side, increased awareness of patients, doctors, and the general public has been directed particularly to adverse reactions to these compounds, such as a worsened course of the illness, increased cardiovascular mortality, suicidal ideation, or persistent sexual disturbances even after withdrawal [13,14]. Furthermore, it also appears that the beneficial effects of psychotherapy on depression were overestimated in the past [15]. This might be the reason why patients with depression often seek help and relief from their symptoms with "alternative" or complementary therapies [16].

Treatment strategies such as body-oriented methods, including mindfulness-based approaches, have been discussed and explored recently, e.g., body psychotherapy for the management of chronic depression [17]. There is also sufficient evidence for the effectiveness of, e.g., physical training such as aerobic exercise for depression [18,19]. In addition, elements from yoga, tai chi, and qigong are increasingly being investigated and used to treat mental disorders, but evidence of their efficacy is preliminary [20,21].

Survey data suggest frequent utilization of massage therapy or other hands-on treatment among patients with depression [16]. Whether a passive treatment modality such as massage therapy would have a beneficial effect on symptoms of depression presents an intriguing question in view of the great number of patients with treatment-resistant depression [22] and the practical lack of side effects of most types of massage [23]. In medical practice, positive effects of massage therapy, such as relaxation or anxiety relief, and antidepressant effects have been observed. These clinical experiences are supported by a meta-analysis of available studies. On the basis of 10 randomized controlled trials (RCTs) comprising 249 participants, Moyer et al. (2004) found that treatment resulted in a lower post-treatment level of depression than in 73% of the control subjects. The authors considered this finding as persuasive evidence for an antidepressive effect in particular and concluded that the medium effect size equaled that of psychotherapy [24]. In addition, they also found strong evidence for reduced trait anxiety. An earlier meta-analysis by Peters (1999), however, had concluded that existing studies on the effectiveness of massage as a nursing intervention had only limited validity and that more rigorous research would be needed [25]. A meta-analysis of 17 RCTs was performed by Hou et al. in 2010, indicating significant effectiveness in the treatment vs. control groups in spite of only moderate quality of the included studies [26]. Baumgart et al. (2011) presented findings from a systematic survey of 22 carefully selected randomized studies published between 1996 and 2009, including seven studies on patients with depression, anxiety, or exhaustion/fatigue as the main diagnosis [27]. All seven studies, only two of them on hospitalized patients, showed a significant reduction in anxiety symptoms, and depression was significantly reduced in five studies. However, the authors also underlined that the heterogeneity of the diagnoses and the diversity of the controls and the assessment methods still limited valid general conclusions on the efficacy of massage therapy in the treatment of depression.

The website of the American Massage Therapy Association (www.amtamassage.org) clearly documents the still existing paucity of controlled studies in this area and the need for further studies recruiting patients with clinical depression. There is a great variety of massage methods, such as Swedish massage, Esalen massage, Thai massage, etc. [28–30]. Our research group has been concentrating for many years on studying the clinical effects of affective touch, also called soft or gentle touch or psychoactive massage, in patients and healthy volunteers. In a previous randomized controlled trial, the application of a specially developed one-hour psychoactive massage (Slow Stroke®Massage) showed antidepressive efficacy in hospitalized patients with depression [31]. Sufficient evidence could be provided that within the special setting of this study, gentle touch was the key element to produce the antidepressive/anxiolytic effect on the behavioral and somatic level. In the present study, we investigated the mental and subjective somatic effects of a special form of psychoactive massage, the affect-regulating massage therapy (ARMT) vs. progressive muscle relaxation (PMR) in outpatients with depression. (PMR has become an established relaxation method over the last decades and is already used regularly in the psychiatric and psychosomatic field [32,33]). A direct comparison of the effectiveness of psychoactive massage therapy and PMR in patients with depression has not been done so far. The present study, therefore, tested the following hypotheses:

**Hypothesis 1.** *It is expected that the application of ARMT will prove to be more e*ff*ective in positively influencing the behavioral and somatic dimensions related to depression than a standardized relaxation method such as PMR. This di*ff*erence will be reflected in the observer ratings using the assessment instruments described below*.

**Hypothesis 2.** *It is expected that a stronger e*ff*ect in favor of ARMT will also be seen in patients' self-assessments. Significant results are expected in the pre-post di*ff*erences of at least half of the items tested on a specially developed visual analogue scale*.

#### **2. Materials and Methods**

#### *2.1. Study Design*

The study was designed as a two-arm, monocentric, randomized controlled intervention study with a fixed number of cases. Every patient in the intervention group received four weekly treatments by means of a standardized massage technique (ARMT). Patients in the control group received four applications of PMR over the same time period. Before starting and immediately after completing the study, patients were assessed by an external rater blinded to the specific treatments the patients had been assigned to. A visual analogue scale was used for self-assessment, which was filled in by the patients before and after each treatment. The study center was the outpatient clinic of the vocational school for massage at the University Hospital of Würzburg (Würzburg, Germany), directed by N. Hemrich.

#### *2.2. Instruments for Assessing Mental and Somatic Symptoms*

#### 2.2.1. HAMD

The Hamilton Depression Scale (HAMD) was used as the external assessment instrument [34,35]. A total of 17 items concerning the depressive symptoms of the previous seven days are checked. Each item is scored from 0 to 4. The severity of the depression is classified as follows [36]: 0–8 points:

no depression or clinically unremarkable or remitted; 9–16 points: mild depression; 17–24 points: moderate depression and ≥25 points: severe depression.

#### 2.2.2. BRMS

The Bech–Rafaelsen Melancholia Scale (BRMS) was used as a further questionnaire for external assessment at multiple time points [37]. It comprises a total of 11 items, which refer to the depressive symptoms of the previous three days. Each item is scored between 0 and 4. The interrater reliability of the German version has been found to be *r* = 0.80 and higher [38]; it has also generally been found to be *r* = 0.80 and higher. The severity of depression is classified according to the sum of all scores as follows: 0–5 points: no depression; 6–14 points: mild depression; 15–25 points: moderate depression and 26–44 points: severe depression.

#### 2.2.3. VAS

A specially designed 100 mm visual analogue scale (VAS) was used for subjective assessment of depressive symptoms consisting of 8 items for self-assessment of the current mood [39]. It was completed by the patients immediately before and after each intervention in order to document changes that occurred during the intervention. Only the symptom of sleep disorder could not be recorded due to the given time frame. In addition, patients could write down free-form personal comments. The following items, indicating the negative poles (zero points) of the scale, were assessed:


2.2.4. Assessment on Clinical Interview

The initial examination included an assessment of the patient's general history as well as a detailed disease-focused interview. After the end of the treatment series, a final consultation was held. During this semi-structured interview, the patient's subjective experiences and attitudes toward the study were questioned and documented. All interviews were conducted by the principal investigator (first author) and recorded in writing.

#### *2.3. Conducting the Study*

#### 2.3.1. Sample Size Calculation

The study by Müller-Oerlinghausen et al. served as the basis for the sample size calculation [31,40]. The mean values and mean differences between pre- and post-assessments and the standard deviation could be derived with regard to VAS. Differences of about 20 scale points with a standard deviation of

25 had been described for several VAS variables. Against this empirical background and assuming a significance level of 5% for two-sided tests, we calculated an optimal sample size of 58.75 cases, which was rounded up to 60. No potential attrition rate was taken into consideration.

#### 2.3.2. Ethical Approval

The study was approved by the Ethics Committee of the Medical Faculty of the Julius Maximilian University of Würzburg. Performance of the study, including informed consent of the patients, followed the Declaration of Helsinki.

#### 2.3.3. Recruitment and Randomization

The patients were recruited in cooperating psychiatric or psychotherapeutic practices in Würzburg. Advertisements were placed in the press and leaflets were distributed at the University Hospital ofWürzburg.

Inclusion criteria were as follows:


Exclusion criteria:


The first contact of potential study participants was usually made by phone or email. Suitability for participation in the study was checked on the basis of the inclusion and exclusion criteria. If there was agreement, the patient's written consent to participate in the study was then obtained. Within two months, 60 patients were recruited. Randomization took place in the order of admission to the study. A randomization list was used, which was based on numbers from the random number generator of the SPSS® statistical program package. After being notified of the randomization result, three participants in the control group terminated their participation in the study prematurely because they did not agree with the assigned group. This resulted in 30 participants in the intervention group and 27 participants in the control group. The initial rating was carried out by an external observer blinded with regard to the randomization result. The threshold for inclusion in the study was set before as 9 points on the HAMD 17 and 6 points on the BRMS. No financial or other compensation was offered to the study participants. The process is shown in Figure 1.

#### *2.4. Description of Interventions (ARMT and PMR)*

#### 2.4.1. Massage Group (ARMT)

The study was performed in cooperation with the vocational school for massage at the University Hospital of Würzburg. A working group was formed consisting of nine masseurs under training, the principal of the vocational school, and the principal investigator/first author, who is also a certified massage therapist. Through intensive training and communication, a standardized treatment procedure was developed, which was carried out by all therapists equally. Techniques for psychoactive massage described in the literature, e.g., Slow Stroke© Massage [28,31], were taken as the matrix for developing our own massage technique, described in detail below. (To get an idea of these special touch techniques ref. also to some video material under www.bruno-mueller-oerlinghausen.de or www.affective-touch.com).

**Figure 1.** Recruitment and randomization.

Any massage session lasted 60 min including rest. It took place in a quiet room. A constant room temperature of at least 25 ◦C was ensured. The massage oil was preheated to 35 ◦C. Massage always began with the undressed patient in a supine position. The genital area was covered by a towel. At the beginning, the preheated massage oil was distributed on the ventral body surface to the abdomen, legs, and arms to ensure continuous treatment without interruption. Afterwards, the therapist's hands rested on the palmar side of the patient's feet to achieve conscious contact. Subsequently, extensive whole-body strokes were performed. Both hands were used to massage from the legs over the flanks up to the arms and over the pelvis and legs, and back to the starting point. This was followed by treatment of the lower extremities with superficial, partially stretching strokes and soft kneading. The sequence was continued by strokes from the middle of the body cranially and caudally as a diagonal whole-body stroke. After classical abdominal, thoracic, and arm treatment, as well as symmetrical whole-body strokes, the patient changed to the prone position. The treatment then began analogous to the ventral side, starting from the heel bone and continuing over the legs, back, and arms. This was followed by a sequence of diagonal and symmetrical whole-body strokes and soft kneading of the dorsal body. Finally, to mark the end of the treatment, the hands rested on the plantar sides of the feet. The patient was then allowed to rest for another 10–15 min. During this time, he or she was covered with sheets and a woolen blanket. Overall, the treatment was carried out very calmly and evenly. Possible muscular tension was not addressed in order to not interrupt the massage flow by any painful perceptions. No conversations were held during the treatment and no background music was played. Care was taken to ensure that patients were always treated by the same therapist within a treatment series.

#### 2.4.2. Control Group (PMR)

In the control group, progressive muscle relaxation (PMR) according to Jacobson, a widely recognized relaxation method, was used [32,33]. In order to make the general conditions as equivalent as possible to those of the massage group, PMR was not performed in the group, but as an individual 45-min treatment. The instructions were given by the same therapists who were also active in the massage group. At the beginning of PMR, the patient was asked to get into in a comfortable supine position, using a massage table or gymnastics mat as a base. Care was taken to ensure a comfortable position through appropriate room temperature and the use of pillows and blankets. The patient was then individually guided through a PMR whole-body schedule. The standardized instructions were presented in a calm and pleasant tone. Afterwards, the patient could rest for 10–15 min. During the treatment, no conversations were held and no background music was played. Care was taken to ensure that the patients were always treated by the same therapist within one series.

#### *2.5. Accompanying Therapy*

Any existing therapy with psychotropic drugs and/or psychotherapy could be continued. Changes in this respect were documented at the end of the trial period.

#### *2.6. Statistical Evaluation*

Absolute and relative frequencies, as well as mean and standard deviation, were used to present personal data such as age, gender, marital status, etc. All data collected manually by the questionnaire were first transferred to an Excel spreadsheet. Data were then analyzed using IBM SPSS Statistics (version 25). Since normal distribution of the parameters could not be assumed, the Mann–Whitney U-test, a nonparametric test, was chosen to calculate statistical significance. The level of statistical significance was set as *p* < 0.05 (two-sided). Pearson's correlation coefficient r was calculated for estimation of effect size.

#### **3. Results**

#### *3.1. Description of Sample*

#### 3.1.1. Sociodemographic Data

The ARMT group consisted of 30 participants. The mean age was 45.2 years; the youngest patient was 24, the oldest, 60 years old; 76.7% were female. About half of the participants were married or in a stable partnership (53.3%). The majority of participants (76.7%) had an intermediate or high school diploma and had qualified employment.

The PMR group consisted of 27 participants. The mean age was 45.0 years; the youngest patient was 19, the oldest, 64 years old; 81.5% of were female. About half of the participants were married or living in a stable partnership (55.6%). Almost all participants (96.3%) had an intermediate or high school diploma and had qualified employment; in this respect they were somewhat different from the subjects of the ARMT group. The sociodemographic data is shown in Table 1.


**Table 1.** Sociodemographic variables of the two patient groups.

ARMT = affect regulating massage therapy; PMR = progressive muscle relaxation; M = Mean; SD = Standard Deviation.

#### 3.1.2. Depression-Related Data

In the ARMT group, the severity of depression was rated as moderately severe, corresponding to 18.2 points on average on the HAMD at the beginning of the study. Assessment by means of the BRMS (mean value 16.1 points) also confirmed moderately severe depression. Psychopharmacological treatment as mono- or combination therapy was reported by 56.7% of the participants. There was no change in dosage for 83.3% of the patients over the duration of the study. About half (53.33%) of the participants were under psychotherapeutic treatment during participation in the study.

In the PMR group, the severity of depression rated by means of the HAMD averaged 19.2 points at the beginning of the study, also indicating a moderately severe depressive episode. The BRMS scores suggested an identical classification, with an average of 17.4 points. Psychopharmacological treatment as mono or combination therapy accounted for 55.5% of the participants. There was no change in dosage for 85.2% of the participants during participation in the study. Almost half (48.2%) of the participants were under psychotherapeutic treatment during the study.

#### *3.2. E*ff*ects of ARMT and PMR Assessed by HAMD and BRMS*

The averaged differences between the HAMD assessment at time *T*A, before the first treatment, and time *T*B, after the fourth treatment, were calculated. The reduction in symptom burden over 4 weeks was significantly more pronounced in the ARMT group than in the control group (*p* = 0.034, *r* = 0.28). The results are shown in Figure 2.

**Figure 2.** Summed up Hamilton Depression Scale (HAMD) scores in ARMT and PMR groups before (*T*A) and after (*T*B) completing the full series of treatments (mean ± SEM).

Focusing on individual items of the HAMD, changes in the following items proved to be highly statistically significant with a moderate effect size:


Although statistical significance was not reached, we consider the numerical change of item five (sleep disorders) to be particularly noteworthy (*p* = 0.059, *r* = 0.25). The course of the BRMS scores is depicted in Figure 3. The reduction in symptom burden during 4 weeks was significantly more pronounced in the massage group than in the control group (*p* = 0.04, *r* = 0.27). Focusing on individual items, the difference of the following single BRMS dimensions over time proved to be statistically significant:


**Figure 3.** Summed up Bech–Rafaelsen Melancholia Scale (BRMS) scores in ARMT and PMR groups before (*T*A) and after (*T*B) completing the full series of treatments (mean ± SEM).

Although statistical significance was not achieved, special attention might be given to the change in item one, motor activity (*p* = 0.063, *r* = 0.25).

In summary, the findings so far are in accordance with Hypothesis 1 (see above).

#### *3.3. Results of Participant's Self-Assessment (VAS)*

For each VAS item (one to eight), the pre-post differences related to each treatment session were averaged over time points *T*1–*T*4. Figure 4 shows that the treatment effects were markedly and significantly more pronounced in the ARMT group as compared to the PMR group. Statistical significance of this difference existed for six of the eight items. (Descriptions of single items can be found in Section 2.2.3).

**Figure 4.** Averaged differences (± SD) of individual pre-/post-treatment visual analogue scale (VAS) values over total study period (*T*1–*T*4).

Please note that a value of 100 on, e.g., VAS 1 ("tension") would signify that the proband felt completely relaxed. (A score of 100 is always the positive pole and zero the negative pole of each VAS item.) In detail, the following individual VAS items show (highly) significant changes in favor of the massage treatment, i.e., greater pre-post differences of particularly those variables closely associated with depression:

VAS 1: Stress/tension (*p* = 0.035, *r* = 0.28)

VAS 2: Hopelessness (*p* = 0.032, *r* = 0.28)

VAS 3: Internal unrest (*p* = 0.009, *r* = 0.35)

VAS 4: Pain sensations (*p* = 0.003, *r* = 0.39)

VAS 5: Psychomotor retardation (*p* = 0.012, *r* = 0.33)

VAS 8: Unpleasant physical sensations (*p* = 0.011, *r* = 0.34)

A moderate effect size was observed for most of the changes. The pre-post differences in VAS 6 (tendency to brood/negative thoughts, *p* = 0.075, *r* = 0.24) and VAS 7 (lack of drive, *p* = 0.070, *r* = 0.24) were not different between the two treatment groups. To illustrate the therapeutic process, Figure 5, as an example, presents the time course of VAS 5, psychomotor retardation (pre- and post-treatment scores) over the four treatment sessions. Obviously, the treatment effects are more marked in the ARMT group.

**Figure 5.** Time course of VAS 5 (psychomotor retardation) scores over time points *T*1–*T*4 in ARMT vs. PMR groups. Arithmetic means before and after treatment (right and left columns, respectively). Note: A score of 100 signifies that the proband agrees fully with the statement "My body feels light and mobile".

Consequently, Hypothesis 2 could be confirmed, i.e., it is expected that a stronger effect will also be seen in the patients' self-assessment. Significant results are assumed in at least half of the VAS items.

#### *3.4. Statements of Study Participants in Clinical Interviews*

The statistical results are underlined by the personal statements of the study participants. Particularly frequent positive comments were made by patients assigned to the massage group:


As points of criticism, some patients mentioned a feeling of coldness and a sense of shame about taking off their clothes before the massage.

Additionally, patients in the control group described positive effects of PMR:


The lack of background music was occasionally mentioned as a point of criticism. Patients in both groups indicated that they had particularly benefited from the morning sessions. The early treatment appointment significantly reduced the burden of a matutinal depressive mood and had a positive effect for the rest of the day. Some participants also experienced a continuous increase in the perceived positive effects during the course of the study. As a point of criticism, study participants from both groups mentioned particular unfavorable external conditions, such as noise from the adjacent construction site.

#### **4. Discussion**

As outlined above, somatic symptoms such as psychomotor retardation, sleep disorders, or general fatigue are prominent features of the clinical picture of depression. Thomas Fuchs perceives depression as a physical illness existing not only against the background of functional disorders of the entire organism, such as dysregulation of the hormone system and biorhythmics, metabolic and immunological changes. Rather, as a phenomenologist, he describes a disorder of the basic physical constitution that presents itself as a "corporisation of the body" (ref. [41] the contrasting significance of "corpse" and "body" in English). Like an objectification, the patient experiences himself distanced from his body-self and no longer "at home in his body", as the sociologist Hartmut Rosa illustrates it in general terms. The depressed person does not feel "comfortable in his skin", where the skin in Rosa's terminology constitutes an organ of resonance [42]. This disturbed bodily feeling manifests itself in different regions, such as tightness in the chest, heaviness of the limbs, or chronic fatigue. The body loses drive and spontaneity. Everything feels heavy. This is also reflected in the subject's exchange with the environment: breathing is flattened, facial expressions are reduced, libido is often tuned down. The "feeling of numbness" overshadows every perception, so that even crying is no longer possible. It is not mourning that is felt, but the feeling of emptiness and lifelessness that is expressed primarily in the body. "Being a body is replaced by having a body" [43]. Would it not be possible that the cognitive and emotional characteristics of depression are secondary reactions to the perception of the primary bodily changes [44,45]?

Hartmut Rosa tries to separate the depressive experience from grief: "Grief is an element of a relationship to the world that is, on the whole, quite resonant. [ ... ] Depression, on the other hand, is characterized by the fact that there are no more tears: the relationship to the world can no longer be liquefied, it is petrified" [42]. The patient feels unable to counteract this weighing feeling of heaviness, and this fundamental phenomenon might induce speculation on a potential bridge to the concept of "learned helplessness" [46].

Against this background, it seems a rational approach to use body-oriented therapies in the treatment of depression. Our findings indicate antidepressive, anxiolytic, and analgesic effects, which were significantly more pronounced among the participants in the massage therapy group as compared to those in the PRM group. How can these remarkable therapeutic effects of a professional, empathetic, affective touch technique be explained? We shall discuss some options on various explanatory levels.

One of the most obvious effects of massage therapy, according to the patients' self-assessment, is the pronounced psychomotor relaxation, which is also reflected in the reduction in inner restlessness. However, it was not only general tension that was released by the treatment. Rather, feelings of hopelessness and inner restlessness were also significantly reduced. The therapeutic touch technique also had a positive effect on the existing obsessive brooding tendency. In the final open talks with the patients, we often heard statements such as that the massage finally allowed the individual to "turn off my thoughts" or "to break loose". One patient made a written comment after the third massage session: "Never before did I experience such a deep relaxation. None of the usual relaxing (mind–body) exercises had this strong effect".

However, even if this feeling of relaxation is a significant part of the overall effect, there must be other factors involved, otherwise the superiority of massage over a standardized relaxation method would hardly make sense. In modern theories of depression, the concept of interoception has been given increasing attention [47,48]. Interoception, i.e., the perception of the processes of the body's interior, distinguishes between proprioception (perception of body position and movement in space) and visceroception (perception of the inner organs' activity). In contrast to exteroception, the signals making up interoception are sent from the entire inner milieu of the individual to the brain. Interoception can likewise be understood as a skill that can be trained through regular practice (e.g., in mindfulness methods), thus contributing to a more conscious body perception and better emotional self-regulation.

In order to explain the effects of the body-oriented interventions examined in this study, we may refer to this concept. The external conditions per se that were more or less concordant in both groups provided a framework for increased body perception. A calm atmosphere without distractions was created to enable the patients to experience consciously their bodily condition, in the sense of an "inner view". The special feature of affective touch is the calm, mindful approach enabling patients to consciously experience their body. This procedure can thus be described as an intensive training of interoception. The patients' oral statements underline this assumption.

Recently a hypothesis was put forward that the antidepressive effect of affective touch can be explained by a normalization of disturbed interoception [49]. Another special factor that could explain the significant superiority of affect-regulating massage based on its basic element, affective touch, is the factor of touch itself. A gentle, empathetic touch is generally experienced as pleasant. It can soothe feelings of social exclusion and facilitate interpersonal binding [50,51]. The neurophysiological correlates of this type of touch have been intensively investigated during the last two decades. The specific feeling of well-being that humans and hairy mammals experience with this type of touch is based neurophysiologically on the activation of so-called C-actile afferents. In particular, Swedish researchers were able to show that a neuronal network of slowly conducting, non-myelinated C-fibers reacts to special receptors of the hairy skin (located, e.g., on the back of the hand, but not on the palm). For these receptors, gentle, slow, and rhythmic touch at a speed of about 3 cm/sec is the appropriate stimulus, projected directly and predominantly into the insular area. The stimulation of such C tactile fibers seems to have as its only "purpose" creating a feeling of well-being [52]. This might also have evolutionary biological significance, e.g., by promoting the feeling of kinship within a group. Other afferent projections via A-beta or A-alpha fibers as well as signals from mechanoreceptors in the hairy skin most likely will also contribute to the overall interoceptive signaling taking place in various limbic structures.

Switching to the level of experience and behavior, it should be kept in mind that touch is the basal medium of communication among humans and animals [53,54]. Against the background of anhedonia, described as the most common feature of depressive experience and behavior, our findings are in some way "paradoxical". How can patients with depression feel and express bodily and verbally affective touch as a positive experience? Obviously empathic, professional touch can slip into this basic communication disorder, i.e., can enter the disturbed emotional world of the patient. It fits into this concept that participants in the massage group often expressed feelings of having been "accepted" in the final talks with the first author. The following English translation of a patient's original final statement might help us in understanding some essentials of the therapeutic process:

"I cried a lot the first time. For the first time I was able to feel my legs and my feet. Tears of joy during the treatment. From the second session onwards, even better with a warming pad. Meeting of the hands on my belly—very touching. I never experienced such a loving touch before. With further treatments I was loosening up completely. Already during the second session I perceived more than the first time. Even my hands were treated! Because of the depression I couldn't allow touching me otherwise.... My shell has become softer, my heart is opened. The massage therapist was totally super gentle, helped me to become a "whole person" again".

Even though the patient quoted above was in all probability not familiar with the work of Wilhelm Reich [55], in her description she nevertheless takes up an essential aspect that plays an important role in modern body psychotherapy [56]. In Reichian terminology, one can speak of an armoring of the emotions [55], which can be influenced, if not eliminated, by massage therapy. According to our observations, patients often are taken by surprise that after a massage session their body feels "less heavy". A trusting therapist–patient relationship in the field of physiotherapy seems to be just as important as is already recognized in psychotherapy. The therapeutic relationship thrives on appropriate empathy and the right balance between affectionate empathy and professional demarcation. In contrast to psychotherapy, however, in the physiotherapeutic context it is specifically the body of the patient that is perceived and accepted and thus enters into resonance with the therapist. This leads to new, possibly corrective (body) experiences, which can be of decisive importance for the therapeutic process. To quote the clinical psychologist C.A. Moyer from his meta-analysis of studies on the effects of massage therapy in depression: "The finding that massage therapy has an effect on trait anxiety and depression that is similar in magnitude to what would be expected to result from psychotherapy suggests the possibility that these different treatments may be more similar than previously considered" [24].

However, coming back to the mechanism involved, a decisive difference exists in healing touch: according to Changaris, we offer the patient direct affect-regulating "bottom-up" therapy in contrast or addition to the "top-down" technique of cognitive psychotherapy [57]. Finally, humoral effects such as increased oxytocin levels and reduced cortisol, e.g., in saliva might add to the interpretation of the antidepressive effects of psychoactive massage within a neurobiological context [58,59]. Oxytocin has been attributed with significant effects on social interaction, as well as feelings of trust and connectedness [60]. Thus, it does not seem unlikely that depressive patients suffering from social withdrawal and isolation could profit from increased oxytocin release, possibly facilitating contact and communication [61]. Additionally, the analgesic effects of massage therapy might be related to increased oxytocin release [62]. Tiffany Field [58], against the background of various experimental studies, has often emphasized the importance of markedly reduced cortisol levels in urine or saliva of various diagnostic groups of depressed or stressed patients having been given massage therapy. The strong relaxing effect observed also in our patients might well be related to this hormonal change. Tiffany Field, however, has often argued that the lowered cortisol levels are related to increased vagal activity [63].

#### *4.1. Strengths of the Study*

#### 4.1.1. Control Group

It was already pointed out that the choice of an adequate control group, besides the impossibility of blinding, is one of the biggest methodical problems in developing a meaningful design in massage studies. Often the control conditions are chosen in such a way that only a standard therapy, waiting list, or general relaxation (quiet sitting/lying, relaxing music or movies) is used. In our study, a more adequate procedure was chosen instead, which led to the most equal conditions possible for all study participants, with the essential difference that therapeutic touch occurred only in the massage group. This allowed us to strengthen the evidence that it is not a bunch of mostly unknown unspecific effects such as personal devotion, but the affective touch as such that is responsible for the greater effectiveness of massage therapy. "Adequate control conditions" signifies that participants in both the massage and control groups always received individual treatments. PMR is typically performed as group therapy. It can be assumed that performing PMR as an individual treatment increased its effectiveness. In other words, we selected a rather conservative approach, which resulted in moderate effect sizes. Use of a "placebo" control would most likely produce much greater effect sizes. In addition, an identical group of therapists were involved in both groups in order to avoid distorting personal influence. Furthermore, the same premises were used for both the massage and control groups. All treatments took place in comparable periods within four months and in a constant environment.

#### 4.1.2. Study Participants

Relatively few studies on the efficacy of massage therapy have been conducted so far in patients with mental illness. The present study provides further evidence of the positive effects of massage therapy in depression. In selecting the study participants, we focused on patients with mild to moderate depression whose clinical picture and disease severity reflected a broad section of the general population. In this way we were able to create largely realistic conditions as they are encountered daily in practices of both GPs and psychiatrists, but also physiotherapists.

#### 4.1.3. Assessments

Standardized and widely used psychiatric scales for assessing and quantifying depressive symptoms were employed in validated German translation.

#### 4.1.4. Conducting the Study

In both groups, care was taken to ensure the consistency of therapists in individual treatment series. In addition to reducing variance, this also served to maximize the effects, as other studies have shown the importance of therapist consistency [64]. Furthermore, all therapists were equally prepared for the study owing to intensive training. This ensured a standardized and comparable execution of individual therapies.

#### *4.2. Limitation*

One important criterion for the quality of studies contributing to the bulk of evidence-based medicine, besides randomization and active control, is the blinding of study participants and directly involved investigators. For obvious methodological reasons, this requirement could not be met in the present study, as in many comparable studies. However, according to a recent meta-analysis, the absolute postulate of blinding when carrying out a sound study might be somewhat questioned in the future [65]. Furthermore, the self-assessment questionnaires (before and after each treatment) were handed out to the patients by the treating therapists themselves. In retrospect, the critical question came up as to whether this circumstance may have led to distortion. One may speculate whether it would have been important for some patients to leave a positive impression or not to "disappoint" the therapist by filling out a questionnaire in a neutral or negative way. However, since the same questionnaire handling was used in both groups, this possible bias was not further discussed, which might have caused a greater overall effect, but probably did not distort the difference between the two groups

#### *4.3. Outlook*

Due to the limited effectiveness of the currently available and widely used treatments in depression, it seems reasonable to expand the therapeutic spectrum for inpatients and outpatients with body-oriented procedures. In this context, affect-regulating or comparable psychoactive massage therapies represent a noteworthy opportunity to open up new access routes for acute treatment. They can be used as low-threshold offerings in the outpatient setting in order to achieve a rapid antidepressive effect. Their use in an inpatient setting is also conceivable according to the findings of a previous controlled study [31]. Very good adherence can be expected, as the present study was also able to prove. Body-oriented therapeutic approaches should be given higher value within the spectrum of antidepressive treatments. They also deserve a special place beside much propagated mind–body techniques [66,67]. A severely depressed patient will often be unable to participate in special psychological training sessions aimed at stress reduction.

#### **5. Conclusions**

This randomized controlled intervention study examined the psychophysical effects of body-oriented treatment methods on patients suffering from mild to moderate depression in an outpatient setting. We tested the hypothesis that a one-hour massage based on a special gentle touch technique (affect regulating massage therapy = ARMT) is superior in its positive effects to a relaxation method that has long been established in the clinical field, progressive muscle relaxation according to Jacobson. Our results confirm this assumption. In both the observer ratings and self-assessments of patients using a visual analogue scale, statistically significant superiority of massage therapy was shown. When focusing on individual dimensions of the HAMD, the superior effects were particularly evident in the items "depressive mood" and "general somatic symptoms". Assessment using the BRMS showed statistically significant superiority of massage therapy particularly in the items "emotional retardation" and "sleep disorders". As for the sleep disorders so often encountered in patients with depression, it should be noted that massage had a positive effect, especially on difficulty remaining asleep, while difficulty getting to sleep responded better to PMR. This observation also coincides with the free-form statements of some study participants who used the PMR technique outside of the study, independently as an aid to fall asleep. Especially in the self-assessment (VAS) of patients, massage therapy proved to be superior. This became obvious for the vast majority of items questioned. When inspecting the pre-post differences of individual VAS items, the stronger impact of massage therapy on the dimensions stress/tension, internal unrest, unpleasant physical sensation, psychomotor retardation, and hopelessness is particularly impressive. Changes were also marked for pain sensations. Overall, we were able to document the doubtless superiority of ARMT for core symptoms of depressive experience and behavior.

**Author Contributions:** M.M.A.: conceptualization, investigation, writing—review and editing; B.M.-O.: methodology, supervision, writing—original draft; N.H.: resources; D.B.: supervision. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding. The publication is supported by the "open access program" of Julius-Maximilians-Universität, Wuerzburg, Germany.

**Acknowledgments:** Thanks are due to Ulrich Stefenelli for his advice and help in statistical matters and to Michael Eggart for methodical input. Thanks are also due the Karl and Veronica Carstens Foundation (Essen, Germany) for scientific advice during M.M.A.'s work on her doctoral thesis.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

### *Article* **Anhedonia to Gentle Touch in Fibromyalgia: Normal Sensory Processing but Abnormal Evaluation**

**Rebecca Boehme 1,2,\*, Helene van Ettinger-Veenstra 2,3, Håkan Olausson 1,2,4, Björn Gerdle 2,3 and Saad S. Nagi 1,4**


Received: 30 March 2020; Accepted: 14 May 2020; Published: 18 May 2020

**Abstract:** Social touch is important for interpersonal interaction. Gentle touch and slow brushing are typically perceived as pleasant, the degree of pleasantness is linked to the activity of the C-tactile (CT) fibers, a class of unmyelinated nerves in the skin. The inability to experience pleasure in general is called anhedonia, a common phenomenon in the chronic pain condition fibromyalgia. Here, we studied the perception and cortical processing of gentle touch in a well-characterized cohort of fibromyalgia. Patients and controls participated in functional brain imaging while receiving tactile stimuli (brushing) on the forearm. They were asked to provide ratings of pleasantness of the tactile stimulus and ongoing pain. We found high distress, pain catastrophizing, and insomnia, and a low perceived state of health in fibromyalgia. Further, patients rated both slow (CT-optimal) and fast (CT-suboptimal) brushing as less pleasant than healthy participants. While there was no difference in brain activity during touch, patients showed deactivation in the right posterior insula (contralateral to the stimulated arm) during pleasantness rating and activation during pain rating. The opposite pattern was observed in healthy participants. Voxel-based morphometry analysis revealed reduced grey matter density in patients, in the bilateral hippocampus and anterior insula. Our results suggest anhedonia to gentle touch in fibromyalgia with intact early-stage sensory processing but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in fibromyalgia.

**Keywords:** touch; pain; C-tactile afferents; fibromyalgia; anhedonia; fMRI; posterior insula

#### **1. Introduction**

Fibromyalgia (FM) is a common, debilitating chronic pain condition. According to the American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia [1], the cardinal features comprise widespread pain and hypersensitivity, i.e., pain evoked by non-painful stimuli and exaggerated pain to painful stimuli. FM includes a myriad of other symptoms, including fatigue, sleep, and affective disturbances (e.g., anxiety and depression). The prevalence of FM is higher among females [2].

Social touch is important for human behavior and communication between individuals [3]. Pleasantness (or pleasure) associated with skin-to-skin contact is linked to a class of nerves in the skin, called C-tactile (CT) fibers. This is of considerable interest for questions about physical and social well-being and the interoceptive system [3]. CTs exhibit a unique 'inverted U-shaped' response pattern

to brushing velocities, with slow brushing (1–10 cm/s, 'CT-optimal') producing a robust discharge—a stimulus that is perceived as pleasant and preferred by participants over fast brushing [4]. CTs have also been implicated in pain processing either directly or indirectly, as an allodynic substrate itself or through malfunctioning of this network [5,6].

While unmyelinated nociceptors have been the focus of earlier studies on fibromyalgia [7], less is known about the role of their low-threshold counterparts, the CTs. We have previously shown a blunted affective distinction between slow CT-optimal and fast CT-suboptimal brushing in FM patients, compared to healthy participants [8], suggesting a reduced CT input or processing in FM.

CT-optimal touch produces robust activation of the posterior insula with a somatotopic organization similar to that reported for cutaneous and muscle pain in healthy participants [9,10]. FM patients show higher activity in the insular cortex in response to painful stimuli (5), and have higher levels of glutamate in the posterior insula, an excitatory neurotransmitter associated with clinical pain and mechanical hypersensitivity in FM [11].

In the current study, we hypothesized to find differences in neural processing in the insular cortex, in response to CT-optimal touch in FM. In a group of well-characterized FM patients, we used fMRI to examine the cortical responses to slow and fast brush stroking and compared with matched healthy controls. In parallel, ratings for touch pleasantness and ongoing pain were collected. Grey matter density was also measured.

#### **2. Materials and Methods**

#### *2.1. Participants*

Female patients with a clinical diagnosis of FM, ranging between 25–55 years old, were recruited through the Pain and Rehabilitation Center at the Linköping University Hospital. These patients were recruited as part of a broader characterization of FM. Age- and gender-matched healthy controls (HC) were recruited through advertisements at the Linköping University and the University Hospital, and in the local news media. The Linköping Regional Ethics Review Board approved the study (Dnr 2016/471-32) and written informed consent was obtained after participants had read the complete study description, in accordance with the Declaration of Helsinki.

On the first visit, all participants underwent a clinical examination. To confirm the patients' eligibility, the eighteen tender points according to the FM classification criteria of the American College of Rheumatology [1] were clinically examined by senior consultants in rheumatology or pain medicine. This was performed in both patients and HC. Revised criteria for FM were recently presented [12,13], but these were not available in the finished form when the current study was designed and ethical approval was sought. The clinical examination also included registration of systolic and diastolic blood pressures. Weight (kg) and height (m) were also registered; body mass index (BMI; kg/m2) was calculated as weight/height2. At the time-point of the clinical examination, the subjects answered a health questionnaire covering demographic data as well as pain and psychological characteristics.

Exclusion criteria were MRI-incompatibility (claustrophobia or metal in the body), pregnancy, difficulty understanding Swedish, metabolic disease, neurological disease or severe psychiatric conditions, malignancy, rheumatoid arthritis, unregulated thyroid disease, cardiovascular disease, or lung disease. Another exclusion criterion was the inability to refrain from analgesics, including NSAIDs and sleep medication, for 48 h prior to the fMRI visit (i.e., a 48-h pharmacological washout period). Participants in the HC group reported having no current pain.

Functional imaging data of good quality were obtained for 31 patients (mean age, 39.0 ± 11.4 years) and 29 matched controls (mean age 42.7 ± 10.1 years).

#### *2.2. Background Data*

Age and gender were registered. FM patients also reported the duration of their condition in years.

#### 2.2.1. Pain Intensity Aspects

A numeric rating scale (NRS) with anchor points 0 (denoting no pain) and 10 (denoting the worst imaginable pain) was used to capture the current pain (denoted by 'Pain Intensity Current') and the average pain intensity for the previous four weeks (denoted by 'Pain Intensity 4w').

#### 2.2.2. Psychological Distress

The Hospital Anxiety and Depression Scale (HADS) was used to measure symptoms of anxiety and depression. The validated Swedish translation of HADS was chosen to reflect aspects of psychological distress [14,15] and had good psychometric characteristics [15,16]. HADS contains seven items in each of the depression and anxiety subscales (HAD-Depression and HAD-Anxiety). Both subscale scores ranged from 0–21. A score of 7 or less on each subscale was considered normal, a score of 8 to 10 indicated a possible abnormality, and a score of 11 or more indicated a definite abnormality [15]. In the present study, a score ≥ 11 was considered as having severe anxiety and depression symptoms.

#### 2.2.3. Sleeping Problems

The Insomnia Severity Index (ISI) was used to quantify perceived insomnia severity. ISI captures the severity and impact of insomnia symptoms with good validity and internal consistency [17,18]. The seven items of ISI were rated on a five-point Likert scale (0–4). The scores of each item were added to calculate the total score of ISI (max = 28). The score could be divided into four categories–no insomnia (0–7), sub-threshold insomnia (8–14), moderate insomnia (15–21), and severe insomnia (22–28).

#### 2.2.4. Pain Catastrophizing Scale (PCS)

PCS measures three dimensions of catastrophizing—rumination, magnification, and helplessness [19,20]—based on 13 items with anchor points ranging from 0 (not at all) to 4 (all the time). The current study used the total PCS (PCS-total); 52 was the maximum score according to the original scale and a high score represented a worse outcome. This instrument had good internal consistency, test-retest reliability, and validity [21].

#### 2.2.5. Impact of the Pain Aspects

An NRS with anchor points 0 (denoted not at all) and 10 (denoted impossible to perform these activities) was used to capture to what extent the pain hindered daily activities (pain hindrance activities of daily living (ADL)), taking part in leisure activities including social and family activities (pain hindrance leisure), and working, including studies or homework (pain hindrance work). These items were only answered by the FM group.

#### 2.2.6. The European Quality of Life Instrument (EQ-5D)

EQ-5D captured a patient's perceived state of health [22–24]. The first part of the instrument captured five dimensions—mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In the present study, we used the second part of the instrument and measured the current day's health on a 100-point scale, a thermometer-like scale (EQ-VAS) with defined endpoints (high values indicated good health and low values indicated bad health).

#### 2.2.7. Pharmacological Treatments

Participants were asked to report their ongoing pharmacological treatments. Note that those included in the study were asked to refrain from analgesic use, including NSAIDs and sleep medication, for 48 h prior to the fMRI visit.

#### *2.3. Stimuli and Procedures*

#### 2.3.1. Task

Before entering the MRI scanner, participants were instructed that they will be brushed on the forearm and were shown the rating scales. They were also brushed once on the forearm. During MRI, participants were brushed on the left forearm at two different velocities—3 cm/s (CT-optimal) and 30 cm/s (CT-suboptimal). The brusher, who was trained in the delivery of these stimuli, stood next to the scanner bore and received auditory cues over headphones. A 9-cm long line with 3-cm increments, was marked on the left forearm to aid the brusher to maintain the correct speed. The task consisted of three runs of 6 min each. In between runs, the participants were asked if they were alright in the scanner and okay to continue with the next run. In total, there were 15 repetitions of slow and fast brushing blocks, each lasting 12 s. The intertrial interval (ITI) between blocks was 10 to 12 s. The order of brushing velocities was randomized. During ITIs, participants looked at a fixation cross. Three times per condition (slow or fast), following a 10 to 12-s ITI, a question appeared on the screen asking the participant to rate the pleasantness of the brushing ("How pleasant is the stimulus?") and if they felt any pain ("Do you feel any pain?"). We formulated the latter question in this specific way because we assumed it might be difficult for the FM group to disentangle ongoing pain and specific pain related to the stimulus. This rating was therefore to be understood as rating of any ongoing pain. Using a button box in their right hand, participants moved a cursor on a visual analog scale (VAS) between the endpoints "unpleasant–pleasant" or "no pain–intense pain" (in Swedish). During analysis, the cursor positions were converted to their numerical values, ranging from −10 to +10 for pleasantness and 0 to 20 for pain. The pain ratings were not specifically related to brush-evoked sensation but to the subjects' general pain level.

#### 2.3.2. MRI

Participants laid comfortably in a 3.0 Tesla Siemens scanner (Prisma, Siemens, Erlangen, Germany). Their left arm was placed on their belly and propped up by pillows. A 12-channel head coil was used to acquire 295 T2-weighted echo-planar images (EPI) per run, containing 48 multiband slices (TR = 1030 ms, TE = 30 ms, slice thickness = 3 mm, matrix size = 64 × 64, field of view = 488 × 488 mm, in-plane voxel resolution = 3 mm2, flip angle = 63◦). T1-weighted anatomical images were also acquired.

#### 2.3.3. Analysis

Behavioral data were analyzed using SPSS (IBM Corp., Armonk, NY, USA). Ratings for slow and fast blocks were averaged. Ratings of the patient group were normally distributed; ratings of the control group were not due to a strong ceiling effect. Ratings were compared between conditions using paired t-test (FM) and Wilcoxon test (HC), and between groups, using Mann–Whitney U test. *p*-values < 0.05 were considered significant.

Functional MRI data were analyzed using statistical parametric mapping (SPM12, Wellcome Department of Imaging Neuroscience, London, UK; http://www.fil.ion.ucl.ac.uk/spm) in Matlab R2016a (The MathWorks, Natick, MA, USA). The following steps were performed—motion correction, co-registration of the mean EPI and the anatomical image, spatial normalization to the MNI T1 template, and segmentation of the T1 image, using the unified segmentation approach [25]. Normalization parameters were applied to all EPIs. All images were spatially smoothed with an isotropic Gaussian kernel of 6 mm full width, at half maximum. For statistical analysis of the BOLD response, the general linear model approach was used as implemented in SPM12. Using a block-design, the conditions (slow and fast) and the rating phase were convolved with the hemodynamic response function. Motion parameters were added as regressors of no interest. Family-wise-error (FWE) correction on the voxel level was used to correct for multiple comparisons on the whole-brain level and using small volume correction based on our a priori regions of interest (ROI). Based on previous studies [10,26], we were

specifically interested in posterior insula activations, therefore, a posterior insula mask was used for small volume corrections (SVC) [27].

#### 2.3.4. VBM

Voxel-based morphometry (VBM) was estimated using the VBM routine provided by the CAT12 toolbox (Gaser & Dahnke, Jena University Hospital, Departments of Psychiatry and Neurology) in SPM12. Total intracranial volume was included as a covariate. Groups were compared using a *t*-test at the whole brain level.

#### **3. Results**

#### *3.1. Clinical Characteristics*

The disease duration in the FM cohort was 4.4 years, on average, since diagnosis and as expected, they had a high number of tender points, i.e., at the group level, >16 out of 18. In HC, the tender points were scarcely found. FM patients had significantly higher blood pressure and BMI than HC. While HC reported no pain, both pain intensity measures (current and at 4 weeks) in FM patients were above 5 on the NRS. Distress, pain catastrophizing, and insomnia (HADS, PCS, and ISI) were significantly higher and overall health (EQ-VAS) was significantly lower in FM patients (Table 1).

**Table 1.** Age, pain characteristics, psychological variables, the impact of pain and health aspects in the fibromyalgia group (FM) and in the healthy controls (HC); mean and one standard deviation (SD).


BP = blood pressure; HADS = Hospital Anxiety and Depression Scale; PCS = Pain Catastrophizing Scale; ISI = Insomnia Severity Index; EQ-VAS = the health scale of EQ-5D (European Quality of Life instrument); w = weeks; NA = not applicable.

Four FM patients had more severe symptoms (≥11) according to the HADS-Depression subscale, compared to none in the HC. Corresponding figures for the HADS-Anxiety were eight patients in FM and none in HC. At least moderate insomnia (≥15) was found in 14 FM patients and in one HC.

Three FM patients and 26 HC did not use any pharmacological drugs. Those using medication among the FM cohort were often on several substances (range 1–5), including paracetamol (*n* = 19), antidepressant medication (selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor, *n* = 12), tricyclic antidepressants (*n* = 9), opioids (*n* = 7), vitamins (e.g., B12, *n* = 5), medication for high blood pressure (*n* = 3), proton-pump inhibitors (*n* = 3), gabapentin (*n* = 2), antihistamine (*n* = 2), and other medications (*n* = 9). HC reported sumatriptan (*n* = 1), tricyclic antidepressant (*n* = 1), methotrexate (*n* = 1), and metoprolol (*n* = 1). All participants refrained from analgesics including NSAIDs and sleep medication for 48 h prior to the fMRI visit (cf. Methods).

#### *3.2. Behavior*

HC rated slow and fast brushing as similarly pleasant (Figure 1, top panel). Within the FM patient group, slow brushing was rated as pleasant, while fast brushing was rated as unpleasant. Affective ratings to slow and fast brushing were lower in FM patients than HC. Pain was rated very low in HC, as expected (Figure 1, bottom panel). Notwithstanding, HC reported less pain to slow than to fast brushing. In FM, pain was also rated somewhat lower after slow than after fast brushing. As described in the Methods, the pain ratings were not specifically related to brush-evoked sensation but to the subjects' general pain level. In summary, the HC and FM groups differed in their ratings of touch pleasantness and ongoing pain. FM rated both slow and fast brushing as less pleasant than HC. In addition, pain ratings in FM were higher than HC.

**Figure 1.** Ratings of touch pleasantness and pain during fMRI. Top: HC rated slow and fast brushing as similarly pleasant on a VAS (mean slow = 8.2 ± 1.9, mean fast = 7.2 ± 3, Z = –1.6, *p* < 0.103). FM rated slow brushing as significantly more pleasant than fast (mean slow = 2.1 ± 3.7, mean fast = –0.9 ± 4.7, *t* = 4.9, *p* < 0.001). Groups differed in their ratings of the different conditions (Mann–Whitney U test, pleasantness ratings: slow Z = –5.7, *p* < 0.001, fast Z = –5.4, *p* < 0.001). Bottom: HC rated less pain after slow than after fast brushing on a VAS (mean slow = 0.33 ± 0.04, mean fast = 0.86 ± 1.53, Z = –2.4, *p* < 0.017). FM rated less pain after slow than after fast brushing (mean slow = 8.3 ± 4.7, mean fast = 9 ± 4.9, *t* = –2.7, *p* < 0.011). The groups differed in their ratings of the different conditions (Mann–Whitney U test, pain ratings: slow Z = –6.2, *p* < 0.001, fast Z = –5.9, *p* < 0.001). Note that the pain ratings were not specifically related to brush-evoked sensation but to the subjects´ general pain level.

#### *3.3. Functional Imaging*

Across all participants, we found a significantly stronger activation for slow compared to fast brushing in the right posterior insula (contralateral to the stimulated forearm) (Figure 2). There was no main effect of group and no difference between groups for separate slow or fast brushing.

**Figure 2.** More activation in the posterior insula during slow brushing compared to fast brushing. In all participants, [39–1920] *t* = 6.25, Z = 5.79, FWE corrected at the whole-brain level *p* < 0.05, color scale depicts *t*-values for the contrast slow > fast.

Since we found a difference in ratings between HC and FM, we also explored group differences during the rating period. Activation in posterior insula was related to whether the subjects were rating on the pleasantness or the pain scale (Figure 3A). While HC showed activation in this area during pleasantness ratings and deactivation during pain ratings, patients showed the opposite pattern, i.e., deactivation during pleasantness ratings and activation during pain ratings (Figure 3B).

**Figure 3. Insula activity di**ff**ers between FM patients and HC during rating period.** (**A**) Interaction group\*ratings type (pleasantness and pain). During the rating period, we found a group\*rating-type interaction in the posterior insula ([33–198], F = 22.67, Z = 4.39 p = 0.001 FWE, SVC for posterior insula), color scale depicts the F-values. (**B**) Beta values extracted from a 6 mm radius sphere around the peak of the interaction in the posterior insula [33–198].

#### *3.4. Voxel-Based Morphometry*

VBM analysis comparing HC and FM revealed reduced grey matter density in patients in the bilateral hippocampus and anterior insula. This difference was even stronger when including age as a covariate of no interest (Figure 4 and Table 2). There was no area where FM had a higher grey matter density than HC.

**Figure 4.** Reduced grey matter in FM. FM showed reduced grey matter density in bilateral insula and hippocampus ([35–19–1], *p* < 0.001, cluster size = 50), color scale depicts the *t*-values.


**Table 2.** Regions with reduced grey matter density in FM compared to HC. Age was included as covariate of no interest. *t*-test at the whole brain level, thresholded at *p* < 0.001 uncorrected.

#### **4. Discussion**

In the current study, we found intact neural processing of positive affective touch in FM patients. However, slow soft brushing was reported as less pleasant by FM patients than healthy controls. We found that FM patients differed from HC during the rating of perceived pleasantness and pain. FM patients showed deactivation in the right posterior insula during the pleasantness rating and activation during the pain rating, the opposite pattern of what was observed in the HC.

#### *4.1. Behavior*

The pathophysiology of FM is not well-understood. Both peripheral and central nervous system alterations are involved in the development and maintenance of FM. Hence, alterations in the brain including neuroinflammation and activation of glial cells, nociception-driven amplification of neural signaling (central sensitization), opioidergic dysregulation, and impaired top-down modulation were found, as well as signs of systemic low-grade inflammation (e.g., regarding cytokine profile and inflammatory lipids) and nociceptor and muscle protein changes [28–40]. In an earlier psychophysical study in FM patients, we found that pleasantness ratings to brushing were normal, but the distinction between slow CT-optimal and fast CT-suboptimal brushing was diminished [8]. In the current study, we found that while the affective touch sensitivity (slow versus fast) was preserved, the pleasantness ratings were significantly lower in FM. Despite these differences which, in part at least, could be due to the heterogeneity of the condition [41], there is likely a disturbance in the affective touch system. To confirm whether this has a peripheral involvement would require electrophysiological recordings (microneurography) from CT afferents in FM patients.

The finding that HC did not rate the pleasantness of slow and fast brushing differently needs further consideration. Although average pleasantness ratings were descriptively higher for slow than for fast brushing, they were not statistically different. Previous studies have reported that people rate slow, CT-optimal brushing velocities as more pleasant than fast, CT-non-optimal brushing [3,26,42]. However, a recent study challenged the view of an inverted U-shaped curve for pleasantness ratings that peaks at the CT-optimal velocity, suggesting that the inverted U-shape can only be found as a group average [43]. Our sample might have contained healthy individuals who did not differentiate as much between a slow and fast touch. Another, possibly complementary explanation, might be

a ceiling effect. This might be driven by a number of factors; the MRI-scanner environment was loud, uncomfortable, and boring, so any positive stimulus might be evaluated as especially pleasant. In addition, the combination with a question on pain experience might drive an overly positive evaluation of the brushing stimuli.

#### *4.2. Functional Imaging*

We found differential processing during the evaluative period for the two groups and conditions. While HC showed activation in posterior insula during pleasantness evaluation and deactivation during pain evaluation, FM showed deactivation during pleasantness evaluation and activation during pain evaluation. This result should be considered preliminary as it was the result of an exploratory analysis. That the cluster of the interaction effect did not directly overlap with the main effect of slow versus fast touch was not surprising, since the evaluative processing of the current experience was a different, hierarchically higher processing, and might therefore have involved different clusters within the insula [44–48].

FM patients display hyper-sensitivity to a range of sensory stimuli [49], so it has been suggested that this might be a general hypersensitivity syndrome [50]. Our results suggest that FM patients do not exhibit hypersensitivity to pleasant touch at an early processing stage, as we found no difference in neural activation in the posterior insula. However, we found altered activation patterns during the evaluation of positive stimuli and reporting of current pain levels, suggesting dysfunctional evaluative processes. This was in line with other studies; for instance, a study in which FM patients were compared to subjects with masochistic behavior found an alteration in the late response to tactile stimulation in the primary somatosensory cortex, as measured by magnetoencephalography [51]. The amplitude of this cortical response was inversely correlated with pain catastrophizing. Dysfunctional evaluative processing of a pleasant stimulus might be associated with anhedonia in FM. FM patients are less efficient at modulating their pain perception through concomitant positive stimuli [52], however, we found a small but significant reduction in pain ratings after slow brushing (rated as pleasant by the patients). Pain catastrophizing affects pain sensitivity (i.e., pain thresholds for pressure, cold, or heat) as reported in various cohorts of patients with chronic pain [53,54]. However, correlations are moderate, and the pain sensitivity is not solely explained by psychological aspects. Moreover, catastrophizing is related to fear of pain but also these correlations are moderate [55–57].

#### *4.3. VBM*

Alterations in grey matter in many brain regions related to pain processing have been reported in several studies (for review see [58]). These include grey matter increases in the cerebellum and the striatum [59] and decreases in the brainstem, anterior and posterior cingulate cortices, prefrontal cortex, parahippocampal gyrus, and hippocampus [60,61]. For certain areas, interaction with age was also reported, e.g., increased grey matter in the insula of patients younger than 50 years [62]. In the current study, we found decreased grey matter density in FM, in the bilateral hippocampus and insula—a reduction that was more pronounced when age was included (as a covariate of no interest). However, we found no brain region where FM patients had higher grey matter density than HC.

The hippocampal grey matter is decreased in people suffering from stress [63] and post-traumatic stress disorder [64]. This is consistent with a high prevalence of early life stress and adverse events in FM [65,66]. In our FM cohort, we found high distress, pain catastrophizing and insomnia, and a low perceived state of health. The insula plays an important role in the perception of one's own body and sensations created within [48], specifically pain [67]. The anterior insula is involved in stratifying sensations into painful and non-painful [68]. The reduction in the anterior insular grey matter observed here might relate to alterations in the pain network in FM, as has been suggested previously [69].

#### *4.4. Limitations and Future Direction*

There are several limitations that need to be considered when interpreting our results. FM is a condition of highly varied symptoms and severity; therefore, patient samples tend to be heterogeneous. Larger and longitudinal studies are needed to distinguish subgroups within FM. Here, we focused on brushing for its affective attribute and link to C-tactile fibers, and questionnaires to capture the clinical characteristics, but we did not perform a detailed battery of quantitative somatosensory tests [70–72]; the combination of these could provide important insights into the peripheral nerve function, the role of top-down modulation, and the broader interplay between somatosensory and affective systems in aberrant pain states. To further disentangle perception and evaluation of sensory inputs, future studies could compare measures of hypersensitivity in the tactile domain with other sensory domains [73]. Physical activity is another important factor—while exercise leads to hypoalgesia in healthy individuals, it leads to hyperalgesia in patients with FM [74]. Further, FM patients have a heightened sensitivity to activity-related increases in pain [56]. Here, we simply asked patients to rate the extent to which pain affected their activities of daily living, leisure, and work. In future studies it would be interesting to explore this in detail using, for instance, the Sensitivity to Physical Activity (SPA) measures that are associated with clinical indices of pain hypersensitivity [75]. Another interesting future direction would be to focus on neurotransmitters such as glutamate, which is elevated in the insula in FM [11]. Glutamate could be tracked using biosensors [76] or could be measured in the brain using magnetic resonance spectroscopy [77], and these measures could then be related to behavioral and functional differences in FM patients.

Taken together, our results suggest intact early-stage sensory processing of positive tactile stimuli but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in FM.

**Author Contributions:** Conceptualization, B.G., H.O., and H.v.E.-V.; methodology, B.G., H.O., S.S.N.; software, R.B. and H.v.E.-V.; formal analysis, R.B.; investigation, S.S.N., R.B., and H.v.E.-V., B.G.; resources, B.G. and H.O.; data curation, R.B., S.S.N., H.v.E.-V., and B.G.; writing—original draft preparation, R.B.; writing—review and editing, R.B., S.S.N., H.O., and B.G.; visualization, R.B.; supervision, H.O. and B.G.; project administration, B.G.; funding acquisition, R.B., B.G., H.O., and S.S.N. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Research-ALF Region Östergötland awarded to H.O., S.S.N. (LIO-900631), and B.G. (LIO-700931) and the Swedish Research Council awarded to B.G. (2018-02470) and R.B. (2019-01873).

**Acknowledgments:** We would like to thank research nurse Eva-Britt Lind and research physiotherapist Ulrika Wentzel Olausson at the Pain and Rehabilitation Centre, University hospital, Linköping, for valuable help during the recruitment process and sample collection.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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#### *Article*
