Psychiatry Research 275 (2019) 86–93

Contents lists available at ScienceDirect

Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Effects of music therapy on major depressive disorder: A study of prefrontal T

hemodynamic functions using fNIRS☆
Kun Fenga,b,1, Chen-Yu Shenb,1, Xiang-Yun Mac, Gui-Fang Chena, Ming-Lu Zhangd, Bo Xub,
⁎ ⁎
Xiao-Min Liub, Jing-Jing Sunb,e, Xiao-Qian Zhanga,b, Po-Zi Liub,1, , Ya Jud,1,
a
School of Clinical Medicine, Tsinghua University, Beijing, China
b
YuQuan Hospital, Tsinghua University, Beijing, 10000 China
c
Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), National Clinical
Research Center for Mental Disorders, Beijing, China
d
Bruce Copen Laboratories (Since 1947) GmbH & Co. KG Meisenweg 19a 82152 Krailling, Germany
e
Shanxi Medical University, Taiyuan, China

A R T I C LE I N FO A B S T R A C T

Keywords: Major depressive disorder (MDD) is a recurrent, chronic mental illness. While music therapy has been estab-
Major depressive disorder lished as an effective treatment for MDD patients, the effects of this therapy on brain function remain unclear.
Music therapy This research employed near-infrared spectroscopy (NIRS) to explore the effects of music therapy on brain
Near-infrared spectroscopy activity in mild or moderate MDD patients and to illustrate the potential mechanism of music therapy. Methods:
NIRS
Fifteen MDD patients and fifteen healthy controls (HC) underwent neuropsychological evaluations and NIRS
Prefrontal cortex
Verbal fluency task
measurements. All participants were treated with continuous music therapy for 10 days. Subsequently, all in-
Two-way mixed ANOVA dividuals were evaluated with neuropsychological assessments and NIRS measurements again. Results: The
verbal fluency task (VFT) performances of the participants yielded significantly higher scores after music therapy
in terms of vegetables, four-footed animals and fruit blocks. After the music treatment, the NIRS data showed
that the mean active oxy-Hb values of channels 21, 23, 19, and 41 were significantly increased in both the MDD
and HC groups. The MDD group showed significant activation in the dorsolateral prefrontal cortex (DLPFC),
orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (VMPFC) after music therapy. The results indicate
that music therapy could improve the brain function of MDD patients.

1. Introduction for MDD. (“Depression in adults: recognition and management,” 2016;

Gartlehner et al., 2008; McAllister-Williams et al., 2015). There are two
Major depressive disorder (MDD) is a common, chronic and re- types of therapeutic options for MDD: psychopharmacology and psy-
current psychiatric disease: 6% of adults worldwide suffer from MDD chotherapy (Gelenberg, 2010). Although drug therapy is the most
annually (Browne et al., 2011). MDD is characterized by depressed commonly prescribed primary treatment for MDD, fewer than 50% of
mood, decreased interest, anhedonia, and diminished social function patients respond to antidepressant treatment (ADT) (Rush et al., 2014);
(Association, 2013) . The main impairments of MDD are in cognitive moreover, approximately 20% of patients are unable to adhere to ADT
and social function(Boschloo et al., 2014; der Wee et al., 2011; due to the severe adverse drug reactions (Xing et al., 2011). More than
Hardeveld et al., 2013), which is more severe than that in other chronic 60% of patients have at least one adverse event during ADT that often
diseases (Kessler et al., 2003). The more severe the depressive symp- leads to withdrawal (Gartlehner et al., 2016). One meta-analysis illu-
toms, the worse the psychosocial function (Judd et al., 2000). Due to strated that the effect of ADT in mild or moderate depression is com-
the high prevalence and recurrence rate of this disorder, MDD is be- parable to that of a placebo (Fawcett et al., 2010). Therefore, psy-
coming a major contributor to the global disease burden. chotherapy is an alternative choice for MDD patients who are
Therefore, it is essential to improve the effectiveness of treatment noncompliant with antidepressants.

☆
The name of the registry: Chinese Clinical Trial Registry (ChiCTR) website: www.chictr.org.cn The registration number: ChiCTR1800017297.
⁎
Corresponding authors.
E-mail addresses: liupozi@mail.tsinghua.edu.cn (P.-Z. Liu), juya.china@gmail.com (Y. Ju).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.psychres.2019.03.015
Received 29 November 2018; Received in revised form 8 March 2019; Accepted 9 March 2019
Available online 10 March 2019
0165-1781/ © 2019 Published by Elsevier B.V.
K. Feng, et al. Psychiatry Research 275 (2019) 86–93

Fig. 1. New music therapy technique: the ‘S’ sequence. This sequence begins with a moderate speed and then consists of reductions in musical tempo, musical
instrument size, frequencies and volume to achieve a state of relaxation. After achieving relaxation, the patients reach the phase of vitality.

Many caregivers provide nonverbal expressive therapies, such as diagnostic criteria for MDD based on the Diagnostic and Statistical
music therapy, dancemovement therapy, art therapy and drama Manual of Mental Disorders-Fifth Edition (DSM-V). Fifteen healthy
therapy, which may serve as effective means of communication for controls (HC) were recruited from the local community and matched to
patients (Castillo-Pérez et al., 2010; Fachner et al., 2011). In recent the MDD patients in terms of age, gender, level of education and right-
clinical studies, researchers suggested that music therapy could alle- handedness.
viate the symptoms of depression and increase positive emotional ex- Notably, patients with the following psychiatric disorders were ex-
periences (Gold et al., 2009). Another prospective controlled clinical cluded: mental retardation, dementia, autism spectrum disorders,
trial also supported this finding. Brandes (Brandes et al., 2010) found schizophrenia and bipolar disorders. Participants with chronic sub-
that music therapy could reduce the symptoms of depression and en- stance abuse and neurological diseases related to cognitive function
hance treatment compliance. Another meta-analysis revealed that were also excluded.
music therapy helped to relieve symptoms and improve quality of life
(Van Assche et al., 2015). Thus, music therapy has been demonstrated 2.2. Design
as a new option for MDD patients.
Music is an effective emotion inducer that is often used as a coping The thirty subjects were all right-handed, and all attended the entire
strategy to adjust one's emotional state in depression (Aalbers et al., 10-day therapy session, with zero dropouts. The depressed patients and
2017; Zatorre and McGill, 2005). Music therapy is a noninvasive in- HC group all underwent the neuropsychological evaluations and NIRS
tervention with the advantages of good tolerance, high feasibility, and measurements before and after 10 days of continuous music therapy
low drop-out rates for MDD patients (Van Assche et al., 2015). A survey intervention.
demonstrated that 82% of depressive patients agreed that listening to
music is an effective treatment measure (Holzinger et al., 2012).
No obvious side effects have been found to be associated with music 2.3. Music therapy
therapy to date. A neuroimaging study investigated the effects of music
therapy on the normal brain (Raglio et al., 2016) and suggested that There are two fundamental methods of music therapy: (1) ‘creative’,
many brain areas involved in memory and autobiographical processes wherein subjects compose music or songs with their voices or musical
are activated during music therapy. instruments; and (2) ‘receptive’, wherein subjects listen to music.
NIRS is a noninvasive, real-time neuroimaging technique because of Receptive relaxation music therapy is often used to treat anxiety, de-
its high-frequency time resolution compared with other neuroimaging pression and cognitive impairment (Guétin et al., 2005). Our clinical
tools, such as MRI, that can detect changes in oxygenated and deox- practice has shown that S-sequence can relieve symptoms in patients
ygenated hemoglobin (oxy-Hb and deoxy-Hb, respectively) concentra- with mild to moderate depression. A meta-analysis of relaxation indu-
tions triggered by nervous activity (Ferrari and Quaresima, 2012). cing music shows that music-induced emotions affect one's cognitive
According to the mechanism of neurovascular coupling, regional cere- ability (Westermann et al., 1996).
bral blood flow (rCBF) increases with neuronal activity in areas of In this study, the second method was used for all subjects. Only
cortical activation. The ultimate consequence is the activation of brain original music was used for the treatment, and the music design ori-
areas, accompanied by functional hyperemia, which ensures an ade- ginated from the original ‘S’ sequence (Fig. 1) designed by Bruce Copen
quate energy supply (Boas et al., 2004). Therefore, NIRS is a promising Laboratories (SINCE 1947). Every session included 60 min of music
technique for evaluating cortical functional changes in real time. listening, which was divided into several stages and gradually pro-
The aim of this study was to compare the NIRS differences before gressed. According to the ‘S’ sequence, each patient felt relaxed and
and after music therapy. This research provides a foundation for music peaceful.
therapy and will improve the usage of music therapy in clinical prac- The following steps were included in the ‘S’ sequence: in step 1, the
tice. music was synchronized with the emotional state; in steps 2–3, the
melodies occurred gradually and the tempo slowed down, both of
which helped the patient's body become progressively relaxed; in step
2. Materials and methods 4, the patient's body became deeply relaxed; in step 5, the melodic lines
gradually increased upward; in step 6, the musical elements increased,
2.1. Subjects synchronizing the body and emotion with the music once again; and in
step 7, positive emotions were stimulated, effectively improving the
This study was a nonrandomized clinical controlled trial (CCT) that psychological state of emotion. The entirety of the musical ‘S’ sequence
was approved by the Ethics Committee of Yuquan Hospital. The re- was designed by Bruce Copen Laboratories (SINCE 1947).
cruitment and experimental procedures were conducted from March During each of the ten treatment sessions, the participants laid
2017 to February 2019. Fifteen patients with moderate MDD were re- down in the music therapy room with patches over their eyes so that
cruited from the Psychiatry Department of Yuquan Hospital as subjects, they felt relaxed. They listened to music through earphones.
all of whom were untreated at the first onset of depression and met the Before the 1st therapy session, the selection process involved

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K. Feng, et al. Psychiatry Research 275 (2019) 86–93

Fig. 3. Fourteen pairs of probes comprised 45 channels. Red and blue numbers
represent emission and detector probes, respectively. (For interpretation of the
references to color in this figure legend, the reader is referred to the web ver-
Fig. 2. VFT task design sion of this article.)
Note: Four-block (vegetables, family applications, four-footed animals, and
fruits) semantic category versions of the VFT included a 15 s pre-task baseline, a
30 s VFT, and a 15 s post-task baseline.
Abbreviation: VFT, verbal fluency task.

identifying the instruments and types of music that each patient liked. A
questionnaire was administered before the music therapy to understand
the music preferences of each patient to make the appropriate choices
for treatment. Each session lasted 60 min, at a rate of one session per
day. The entire process lasted 10 days.

2.4. Activation task

A semantic category version of the verbal fluency task (VFT) was

utilized as the activation task. The VFT task contains four blocks,
namely, vegetables, domestic applications, four-legged animals, and
fruits. Each block was composed of 3 periods, namely, a 15-s pre-task
baseline, a 30-s task, and a 15-s post-task baseline (Fig. 2). The parti-
cipants were asked to verbally describe as many words as possible
pertaining to a certain semantic category, with all categories believed
to be equivalent in stimulating the prefrontal cortex. The number of
correct words generated during the task was evaluated as cognitive
performance.

2.5. Assessments Fig. 4. Channel layout of the NIRS cap over the prefrontal cortex. Relative
position of the near-infrared spectroscopy (NIRS) channels and the PFC.
All subjects were interviewed by two experienced psychiatrists ac-
cording to the Structured Clinical Interview for DSM Disorders. The square tests. Student's t-test was used to analyze differences in age and
Hamilton Depression Rating Scale (HDRS, 24 items; Hamilton, 1960) education level between the HC group and the MDD group at baseline.
and the Hamilton Anxiety Rating Scale (HAMA, 17 items; Hamilton, Regarding the NIRS data, the mean oxy-Hb increase was calculated
1956) were completed by the participants to determine the severity of as the difference between the mean oxy-Hb during the task and that
depression and anxiety, respectively. Questionnaires developed by our during the pretask period. The mean oxy-Hb changes were calculated
group were used to collect demographic information. by subtracting the mean relative concentration of oxy-Hb in the pretask
period from the mean oxy-Hb in the task period.
2.6. NIRS measurements We used a two-way mixed ANOVA with different groups (MDD
group vs. HC group) as the between-subject factor and time (pre vs.
Hemodynamic responses in the prefrontal cortex (PFC) were mea- post) as the within-subject factor to analyze the effect of the music
sured using a 45-channel near-infrared spectroscopy system (FOIRE- therapy intervention on the oxy-Hb values. The two-way mixed ANOVA
3000, Shimadzu, Kyoto, Japan), with a sampling frequency of 5 Hz. included a 2 (time point: pre- and post-music therapy) × 2 (group:
Based on the modified Beer-Lambert Law, relative concentrations of MDD group and HC group) design. Oxy-Hb was selected as the analysis
oxy-hemoglobin (oxy-Hb), deoxy-Hb and total-Hb were recorded index because of its reliability in demonstrating changes in rCBF (Kono
during the task, which consisted of a 15-s pre-task baseline, a 30-s VFT, et al., 2007; Singh and Dan, 2006). The Statistical Package for Social
and a 15-s post-task baseline. Forty-five logic channels were established Sciences version 22.0 for Windows (SPSS, IBM Corporation, Armonk,
by 14 emission probes and 14 detector probes (Fig. 3), with one NY, USA) was used for the analyses.
emission probe and detector probe consisting of a logic channel. In
accordance with the International 10–20 System of electro-
encephalogram electrode placement, the lowest probes were positioned 3. Results
along the Fp1–Fp2 line (Fig. 4) (Hori et al., 2008).
3.1. Demographic and clinical data
2.7. Statistical analysis
The demographic data and clinical characteristics of the participants
The demographic and clinical data were compared by t-tests or chi- are presented in Table 1. There were no significant differences in

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Table 1 block, meaning that the vegetables block performances were improved
Demographic data of MDD patients and controls (mean ± SD). after music therapy in all participants (Table 2). The interaction be-
Demographics Patients Healthy controls MDD vs. HC tween Group and Time point was not significant [F(1,28) = 0.789,
MDD (n-15) HC (n = 15) t/χ2 p p = 0.382, ηp2 = 0.027].
Task 2 (family applications block): The results revealed no sig-
Gender (female/male) 8/7 9/6 0.136 0.713a
nificant difference in the main effect of Group, main effect of Time
Age (years) 30.93 ± 13.47 30.87 ± 10.11 0.154 0.879b
Education (years) 13.8 ± 1.821 14.80 ± 1.014 −1.858 0.077b
point, or the interaction between Group and Time point between the
Marital status (married/ 6/9 8/7 0.536 0.464a normal control group and MDD group.
unmarried) Task 3 (four-footed animals block): The results showed no sig-
nificant difference in the main effect of Group and the interaction be-
MDD: major depressive disorder group; HC: healthy controls.
a
tween Group and Time point in the normal control group and MDD
chi-square test;.
b group. The main effect of Time point was significant [F(1,28) = 21.831,
t-test (p value).
p < 0.001, ηp2 = 0.438] in terms of the four-footed animals block,
meaning that the performances on this task were improved after music
gender, age, marital status, or education level between the MDD and HC
therapy in all participants (Table 2).
groups (all p-values > 0.05).
Task 4 (fruits block): The results were similar to those for Task 1.
The main effect of Group was significant [F(1,28) = 12.328, p = 0.002,
3.2. Clinical data and VFT task performance of participants before and
ηp2 = 0.306] in terms of the fruits block, meaning that the perfor-
after therapy
mances on the VFT task (fruits block) in the MDD group were lower
than those in the HC group. The main effect of Time point was also
3.2.1. Clinical data
significant [F(1,28) = 8.599, p = 0.007, ηp2 = 0.235], meaning that the
The HDRS was employed to assess the severity of depression in the
performances in the fruits block were improved after music therapy in
MDD patients and HC group. A 2 (group: MDD group, HC group) * 2
all participants (Table 2). The interaction between Group and Time
(time point: pretherapy, posttherapy) two-way mixed ANOVA was
point was not significant [F(1,28) = 1.777, p = 0.193, ηp2 = 0.060].
conducted to examine the effect of music therapy on participants. The
results showed that the main effect of Group was significant [F
(1,28) = 151.782, p < 0.001, ηp2 = 0.844], meaning that HDRS scores 3.3. NIRS data analysis
in the MDD group were higher than those in the HC group. The main
effect of Time point was significant [F(1,28) = 218.273, p = 0.002, A 2 (Group: MDD group, HC group) * 2 (Time point: pretherapy,
ηp2 = 0.886], meaning that HDRS scores decreased after music therapy posttherapy) two-way mixed ANOVA was applied to examine the mean
in all participants (see Table 2). The interaction between Group and [oxy-Hb] changes in participants.
Time point was significant [F(1,28) = 153.719, p < 0.001,
ηp2 = 0.846]. Simple effect analyses revealed that HDRS scores in the
3.3.1. The main effect of time point
MDD group were significantly reduced at the post-therapy assessment
The results showed that the main effect of Time point was sig-
compared with the pre-therapy time point (p < 0.001), while the HC
nificant in channel 21 [F(1,28) = 7.254, p = 0.012, ηp2 = 0.206],
group did not show significant differences between the two time points
channel 23 [F(1,28) = 7.633, p = 0.010, ηp2 = 0.214], channel 41 [F
(p = 0.104); according to the simple effect analysis of treatment time,
(1,28) = 7.464, p = 0.011, ηp2 = 0.210], channel 44 [F(1,28) = 4.318,
the results showed that the HDRS scores in the MDD group were sig-
p = 0.047, ηp2 = 0.134], and channel 19 [F(1,28) = 5.054, p = 0.033,
nificantly higher than those in the HC group not only at the pre-therapy
ηp2 = 0.153] (Fig. 5), indicating that the mean active oxy-Hb values in
time point but also at the post-therapy time point (p < 0.001).
the above channels were increased after music therapy in the partici-
pants.
3.2.2. VFT task performance
During the VFT task, the numbers of words generated by the MDD
and HC groups are summarized in Table 2. A 2 (Group: MDD group, HC 3.3.2. The main effect of group
group) * 2 (Time point: pre-therapy, post-therapy) two-way mixed The results showed that the main effect of Group was significant in
ANOVA was conducted to examine the performance of subjects on the channel 20 [F(1,28) = 5.996, p = 0.021, ηp2 = 0.176], channel 35 [F
VFT task. (1,28) = 4.260, p = 0.048, ηp2 = 0.132], channel 36 [F(1,28) = 5.693,
Task 1 (vegetables block): The results showed that the main effect of p = 0.024, ηp2 = 0.169], and channel 41 [F(1,28) = 7.104, p = 0.013,
Group was significant [F(1,28) = 13.769, p = 0.001, ηp2 = 0.330] in ηp2 = 0.202] (Fig. 6), indicating that the mean active oxy-Hb values in
terms of the vegetables block, meaning the performances on the VFT the MDD group were lower than those in the HC group. Channel 23
task (vegetables block) in the MDD group were lower than those in the showed a marginal significant change [F(1,28) = 3.948, p = 0.057,
HC group. The main effect of Time point was also significant [F ηp2 = 0.124], which also indicated that the mean active oxy-Hb value
(1,28) = 12.620, p = 0.001, ηp2 = 0.311] in terms of the vegetables in the MDD group was lower than that in the HC group.

Table 2
Clinical data and VFT task performance of MDD patients and controls (mean ± SD).
Condition MDD-pre music therapy MDD-post music therapy HC-pre music therapy HC-post music therapy

a a a
HDRS 24.73 ± 4.862 12.53 ± 5.097 4.07 ± 0.884 3.00 ± 0.845a
HAMA 17.13 ± 2.774a 6.60 ± 4.239a 3.67 ± 1.676a 2.73 ± 1.223a
VFT-Vegetables 8.33 ± 2.024a 9.67 ± 2.350a 11.73 ± 2.187a 12.53 ± 3.114a
VFT-Family applications 8.87 ± 1.922a 9.60 ± 1.639a 10.33 ± 2.526a 10.53 ± 2.666a
VFT-Four-footed animals 9.13 ± 1.995a 11.67 ± 2.944a 11.47 ± 3.044a 12.53 ± 2.900a
VFT-Fruit 9.0 ± 1.309a 10.07 ± 1.907a 12.00 ± 2.699a 12.40 ± 2.558a

MDD: major depressive disorder; HC: healthy controls; NIRS: near-infrared spectroscopy; VFT: verbal fluency task; HDRS: 24-item Hamilton Depression Rating Scale;
HAMA: Hamilton Anxiety Rating Scale.
a
: Two-way mixed ANOVA.

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K. Feng, et al. Psychiatry Research 275 (2019) 86–93

in the MDD group was significantly lower than that in the HC group at
the pre-therapy time point (p = 0.007), but no significant change was
found at the post-therapy time point between the MDD and HC groups
(p = 0.390).
Simple effect analyses revealed that the mean active oxy-Hb value in
channel 23 was significantly increased at the post-therapy assessment
compared with the pre-therapy time point (p = 0.002), while the HC
group did not show any significant difference between the two time
points (p = 0.599). According to the simple effect analysis of treatment
time, the results demonstrated that the mean active oxy-Hb value in the
MDD group was significantly lower than that in the HC group at the
pretherapy time point (p = 0.024), but no significant change was found
at the posttherapy time point between the MDD group and the HC
group (p = 0.680).

4. Discussion

To the best of our knowledge, this study is the first to use NIRS to
investigate the effects of music therapy on oxy-Hb changes in the PFC of
MDD patients. It is also the first study to use the ‘S’ sequence technique
Fig. 5. The main effect of time: The figure shows that the mean oxy-Hb value in as the music therapy intervention for MDD patients.
the pre-group was significantly lower than that in the post-group during the Our results showed that the mean active oxy-Hb values of channels
VFT. Channels in dark colors show significantly lower oxy-Hb changes during 21, 23, 19, and 41 were significantly increased in the two groups after
the VFT in the pre-therapy group compared with the post-therapy group during music therapy. These results indicate that music therapy is effective in
the VFT (P < 0.05). The gray channel represents P > 0.05. improving brain function in both MDD patients and HC participants.
The most relevant cortexes include the dorsolateral prefrontal cortex
(DLPFC), orbitofrontal cortex (OFC) and ventromedial prefrontal cortex
(VMPFC). Altogether, these results indicate that music therapy could
change the hemodynamics of the left DLPFC, VMPFC and OFC.
The mean active oxy-Hb values of channel 23 and channel 41 in the
MDD group post-therapy were significantly increased compared with
the values in the MDD group pre-therapy, whereas there was no sig-
nificant difference between the HC-pre and HC-post groups. The in-
teraction effect showed no significant difference between MDD-post
and HC-post in channel 23 and channel 41. The results revealed that the
hypofunction of channel 23 and channel 41 in MDD patients was sig-
nificantly recovered in the VMPFC and right DLPFC.

4.1. Hypofunction in the MDD group pre-therapy during the VFT

Previous neuroimaging studies have consistently reported hypo-

function in the DLPFC and the frontopolar cortex in MDD patients
during the VFT (Akashi et al., 2015; Murray et al., 2011; Golkar et al.,
2012). These studies helped researchers localize the dysfunction in
MDD to the orbital and frontal cortices. Some researchers found that
depressed individuals had decreased activity in the DLPFC, which made
it difficult for the patients to make plans and decisions and to mediate
Fig. 6. The main effect of group: The figure shows that the mean oxy-Hb value
social behavior (Ohtani et al., 2015; Hirano et al., 2017). Other studies
in the HC group was significantly higher than that in the MDD group during the
VFT. Channels in dark color show significantly lower oxy-Hb changes during
found that deactivation in the OFC of MDD patients was related to
the VFT in the MDD group compared with the HC group during the VFT emotion regulation, decision making and sensory integration (Noda
(P < 0.05). The gray channel represents P > 0.05. A marginal significant et al., 2012; Rolls and Grabenhorst, 2008). In addition, this deactivation
change was found in Channel 23. of the OFC impaired the related learning, emotional behaviors and
subjective experiences (Rolls, 2017) . Current imaging studies have
shown that the DLPFC and the lateral OFC are activated to contribute to
3.3.3. The interaction between group and time point
emotion regulation through reappraisal (Ochsner and Gross, 2005). The
The interaction between Group and Time point was significant
VMPFC is associated with emotional and autonomic processing
in channel 41 [F(1,28) = 6.428, p = 0.017, ηp2 = 0.187. Channel 23
(Zald et al., 2002); for example, patients with brain lesions in this area
showed a marginal significant change [F(1,28) = 4.040, p = 0.054,
have difficulty reacting to emotional stimuli (Damasio et al., 1990). The
ηp2 = 0.126]. The mean active oxy-Hb values in participants are shown
VMPFC is also related to social cognition, involving facial emotion re-
in Fig. 7.
cognition and internal reflection (Wolf et al., 2016). For MDD patients,
Simple effect analyses revealed that the mean active oxy-Hb value in
deactivation in the regions mentioned above would make it difficult for
channel 41 was significantly increased at the post-therapy assessment
these patients to estimate context-related emotion in response to stimuli
compared with the pre-therapy time point (p = 0.001), while the sig-
and to choose appropriate behaviors on the basis of those evaluations.
nificant differences between the two time points were not found in the
In the experiment involving the MDD group, our finding of hypofunc-
HC group (p = 0.890); according to the simple effect analysis of treat-
tion in the DLPFC, VMPFC and OFC was in accordance with those of
ment time, the results demonstrated that the mean active oxy-Hb value
previous studies. In our research, we sought to investigate whether

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Fig. 7. The mean oxy-hemoglobin (oxy-Hb) changes in the two channels across the groups. * p < 0.05,** p < 0.01.

music therapy is involved in the process of emotion regulation. The VMPFC is related to emotional control (Plewnia et al., 2015).
Another fMRI study showed thatmusic therapy is effective in normal
4.2. Effects of music therapy on MDD patients revealed by NIRS: activation brains and that the VMPFC was activated after music therapy
in the OFC, VMPFC and DLPFC (Raglio et al., 2016).
In this study, activation of the right DLPFC, VMPFC and OFC of
The findings showed that the DLPFC, VMPFC and OFC of MDD MDD patients was detected after music therapy. Our results implied
participants were significantly activated after music therapy. This result that music therapy could improve the ability of MDD patients to reg-
indicated that music therapy could change the hemodynamics of the ulate emotions and make decisions through activation of the VMPFC,
left DLPFC, VMPFC and OFC. In accordance with the neurovascular OFC and DLPFC. These findings may indicate that music therapy could
coupling mechanism (Phillips et al., 2015; Leithner and Royl, 2014), enhance emotion regulation by helping patients become sensitive to
the increase in the mean oxy-Hb value after music therapy implied that and recognize their emotions. When treatment strategies reduced ne-
the compensatory mechanisms in response to oxygen consumption were gative emotions, activation of the DLPFC, vmPFC and OFC increased
significantly recovered in the OFC, VMPFC and right DLPFC. (Ochsner and Gross, 2005). Regarding the OFC, this region is related to
Neuroimaging studies have shown that DLPFC is related to execu- the reward mechanism. Music therapy, as a pleasurable stimulus, could
tive function and cognitive function (Miller and Cohen, 2002), and the become involved in the reward system by activating the dopaminergic
imbalance of cortical activity in the DLPFC is related to cognitive im- system, including the OFC (Lepping et al., 2016).
pairment and affective disorder of depression. Researchers used tran- This research demonstrated that music therapy could activate the
scranial direct current stimulation (tDCS) to study the effects of DLPFC DLPFC and VMPFC to enhance positive emotions and cognitive func-
stimulation on cognitive function in MDD patients. The results showed tion. It was also shown that music therapy could activate the OFC to
that DLPFC stimulation could improve executive dysfunction in MDD improve the reward mechanism.
patients (Salehinejad et al., 2017). Mohammad reported that emotion
regulation was associated with cognitive control in MDD, which was 4.3. Other results
related to hypofunction in the DLPFC. Some researchers found that
emotion regulation and cognitive control were improved by activating Although the depressive symptoms of MDD patients were sig-
the left DLPFC in MDD patients. Similar results were found in other nificantly improved after music therapy, their HDRS scores were still
studies (Brunoni and Vanderhasselt, 2014). significantly higher than those in the HC group. In the HC group, no
The orbitofrontal cortex (OFC) is related to reward and emotional significant difference was found between pre-therapy and post-therapy.
value, which represents the value of target action. Subjective experi- These results indicate that 10 consecutive receptive listening music
ence of emotional stimulation can activate the orbital frontal lobe. treatments can significantly improve the symptoms of patients with
Consistent with this theory, low activation in the medial orbitofrontal mild to moderate depression but cannot completely eliminate the de-
cortex and high activation in the lateral orbitofrontal cortex have been pressive symptoms. A recent meta-analysis showed that music therapy
shown to be related to depression (Rolls, 2017). An fMRI study reported could relieve symptoms of depression and provide short-term beneficial
that music could enhance the feeling of affective images and showed effects in patients (Aalbers et al., 2017).
that many regions (VMPFC, OFC and other regions) in the brain acti-
vated by music therapy are involved in the emotion process 4.4. VFT performance
(Baumgartner et al., 2006). Some similar studies also demonstrated the
power of music in emotion regulation. These studies showed that music The VFT has been confirmed as a standard procedure that can be
listening elicited emotional experiences that are involved in reward, applied to study cognitive performance and language retrieval abilities
motivation and arousal, involving the OFC and prefrontal regions (Herrmann et al., 2003). This performance task has been widely used to
(Blood and Zatorre, 2002). In addition, an fMRI study indicated that study executive capability in depression, which has been purported to
music listening was involved in the reward process through cognitive be associated with cognitive impairment (Wolfe et al., 1987).
and emotion regulation and involved the OFC and temporoparietal The number of words generated by the HC group was significantly
junction (Li et al., 2015). greater than that generated by the MDD group within the categories of

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vegetables and fruits. A major discrepancy was shown between the efficacy. Psychother. Psychosom. 79, 321–322. https://doi.org/10.1159/000319529.
post-therapy and pre-therapy groups in three categories, with the ex- Browne, M.O., Mora, M.E.M., Alonso, J., Levinson, D., Iwata, N., Andrade, L.H., Posada-
Villa, J., Kostyuchenko, S., Hwang, I., Demyttenaere, K., Lépine, J.-P., Bromet, E.,
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was illustrated by Task 2, the average number of words collected post- de Graaf, R., Sampson, N.A., Kessler, R.C., Hu, C., 2011. Cross-national epidemiology
therapy was greater than that pre-therapy. Thus, these findings sug- of DSM-IV major depressive episode. BMC Med. 9. https://doi.org/10.1186/1741-
7015-9-90.
gested that a performance improvement in cognitive capacity accom- Brunoni, A.R., Vanderhasselt, M.A., 2014. Working memory improvement with non-in-
panied music therapy. vasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review and
The underlying mechanism of this finding has not been clearly de- meta-analysis. Brain Cogn. 86, 1–9. https://doi.org/10.1016/j.bandc.2014.01.008.
Castillo-Pérez, S., Gómez-Pérez, V., Velasco, M.C., Pérez-Campos, E., Mayoral, M.A.,
monstrated. Music therapy has been confirmed to be beneficial for 2010. Effects of music therapy on depression compared with psychotherapy. Arts
emotion regulation, including depression, in which cognitive impair- Psychother. 37, 387–390. https://doi.org/10.1016/j.aip.2010.07.001.
ment is a prominent symptom. Along with remission of depressive Damasio, A.R., Tranel, D., Damasio, H., 1990. Individuals with sociopathic behavior
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mood, cognitive performance also exhibited improvement.
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Picazio's research suggested music listening in combination with Depression in adults: recognition and management [WWW Document], 2016. Natl. Inst.
transcranial cerebellar Direct Current Stimulation (tcDCS) can improve Heal. Care Excell.
cognitive functions (Petrosini et al., 2015). Furthermore, based on the der Wee, N.van, Beekman, A.T.F., Lamers, F., Cuijpers, P., der Meer, K.van, Ormel, J., de
Jong, P.J., Penninx, B.W.J.H., van Dyck, R., Verhaak, P., Nolen, W.A., Spinhoven, P.,
study of Fiveash, language and music may share common syntactic Hoogendijk, W.J., van Marwijk, H.W.J., Zitman, F.G., de Graaf, R., Laurant, M.G.H.,
processing resources, which can give an explanation of this result Smit, J.H., 2011. Two-year course of depressive and anxiety disorders: results from
(Fiveash et al., 2018). However, one study illustrated that music lis- the Netherlands Study of Depression and Anxiety (NESDA). J. Affect. Disord. 133,
76–85. https://doi.org/10.1016/j.jad.2011.03.027.
tening(without cerebellar continuous theta burst stimulation) did not Fachner, J., Gold, C., Tervaniemi, M., Ala-Ruona, E., Vanhala, M., Erkkilä, J., Punkanen,
influence cognitive performance (Oliveri et al., 2013). M., Pöntiö, I., 2011. Individual music therapy for depression: randomised controlled
trial. Br. J. Psychiatry 199, 132–139. https://doi.org/10.1192/bjp.bp.110.085431.
Fawcett, J., Fournier, J.C., Amsterdam, J.D., Dimidjian, S., Shelton, R.C., Hollon, S.D.,
4.5. Limitations DeRubeis, R.J., 2010. Antidepressant drug effects and depression severity. JAMA
303, 47. https://doi.org/10.1001/jama.2009.1943.
This study has some limitations. First, NIRS can only detect relative Ferrari, M., Quaresima, V., 2012. A brief review on the history of human functional near-
infrared spectroscopy (fNIRS) development and fields of application. Neuroimage 63,
concentrations of oxyhemoglobin and cannot provide absolute quanti- 921–935. https://doi.org/10.1016/j.neuroimage.2012.03.049.
tative results. Second, the S-curve technology used in this study was Fiveash, A., McArthur, G., Thompson, W.F., 2018. Syntactic and non-syntactic sources of
developed by the German music therapy system. Since the tracks are interference by music on language processing. Sci. Rep. 8 (1), 17918. https://doi.org/
10.1038/s41598-018-36076-x.
protected by copyright, other researchers need to obtain copyright
Gartlehner, G., Gaynes, B.N., Amick, H.R., Asher, G.N., Morgan, L.C., Coker-Schwimmer,
approval if they want to repeat our experiments. Finally, the sample E., Forneris, C., Boland, E., Lux, L.J., Gaylord, S., Bann, C., Pierl, C.B., Lohr, K.N.,
size of this study was not sufficient; therefore, additional large-scale 2016. Comparative benefits and harms of antidepressant, psychological, com-
cohort studies are necessary for further validation of the results. plementary, and exercise treatments for major depression: an evidence report for a
clinical practice guideline from the American College of Physicians. Ann. Intern. Med.
164, 331–341. https://doi.org/10.7326/M15-1813.
Author contributions Gartlehner, G., Thieda, P., Hansen, R.A., Gaynes, B.N., DeVeaugh-Geiss, A., Krebs, E.E.,
Lohr, K.N., 2008. Comparative risk for harms of second-generation antidepressants: a
systematic review and meta-analysis. Drug Saf 31, 851–865. https://doi.org/10.
Conceived and designed the experiments: K.F., C.Y.S., P.Z.L., and 2165/00002018-200831100-00004.
Y.J. Performed the experiments: K.F., X.Y.M., M.L.Z., and B.X.. Gelenberg, A.J., 2010. A review of current guidelines for depression treatment. J. Clin.
Analyzed the data: K.F. and G.F.C. Contributed reagents/materials/ Psychiatry 71, e15. https://doi.org/10.4088/jcp.9078tx1c.
Gold, C., Solli, H.P., Krüger, V., Lie, S.A., 2009. Dose-response relationship in music
analysis tools: X.M.L., X.Q.Z., and B.X. Wrote the manuscript: K.F. and therapy for people with serious mental disorders: systematic review and meta-ana-
C.Y.S. Operated the equipment: J.J.S. and X.J.R. Collected the data: lysis. Clin. Psychol. Rev. 29, 193–207. https://doi.org/10.1016/j.cpr.2009.01.001.
B.X. Golkar, A., Lonsdorf, T.B., Olsson, A., Lindstrom, K.M., Berrebi, J., Fransson, P., Schalling,
M., Ingvar, M., Öhman, A., 2012. Distinct contributions of the dorsolateral prefrontal
and orbitofrontal cortex during emotion regulation. PLoS One 7 (11), e48107.
Supplementary materials https://doi.org/10.1371/journal.pone.0048107.
Guétin, S., Coudeyre, E., Picot, M.C., Ginies, P., Graber-Duvernay, B., Ratsimba, D.,
Vanbiervliet, W., Blayac, J.P., Hérisson, C., 2005. Intérêt de la musicothérapie dans la
Supplementary material associated with this article can be found, in
prise en charge de la lombalgie chronique en milieu hospitalier (Étude contrô lée,
the online version, at doi:10.1016/j.psychres.2019.03.015. randomisée sur 65 patients). Ann. Readapt. Med. Phys. 48, 217–224. https://doi.org/
10.1016/j.annrmp.2005.02.003.
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