Original Article

Yonago Acta medica 2016;59:15–23

Residual Symptoms Were Differentially Associated with Brain Function in
Remitted Patients with Major Depressive Disorders
Mieko Masai, Shenghong Pu, Katsutoshi Yokoyama, Hiroshi Matsumura, Takehiko Yamanashi, Masashi Itakura,
Takuya Sugie, Akihiko Miura, Izumi Nagata, Masaaki Iwata and Koichi Kaneko

Division of Neuropsychiatry, Department of Brain and Neuroscience, School of Medicine, Tottori University Faculty of Medicine,
Yonago 683-8503, Japan

ABSTRACT“Positive affect”, showed significantly negative correlations with the mean [oxy-Hb] changes mainly in the left
hemisphere, whereas “Interpersonal problems” factor
showed a significantly positive correlation with the sizeof NIRS activation predominantly in right prefrontal regions.
Conclusion Our results indicate that remitted patientswith MDD possibly have residual symptoms which aremost likely to impair their social functioning and thatthese symptoms are differentially associated with brain
function measured with NIRS.

BackgroundThe desirable goals of the treatment ofmajor depressive disorder (MDD) are considered bothto achieve symptom remission and to help the patients
be restored to their premorbid levels of functioning. Remission has often been defined clinically as a thresholdusing standardized scales. Such a definition, however,allows several residual symptoms to be present in theremitted state. The aim of this study was to examine therelationship between the levels of residual symptoms
and social functioning and also the relationship between
residual symptoms and brain function.
Methods The subjects were 21 patients with MDD in
remission, defined operationally using clinician-rated
17-item Hamilton Depression Scale. Depressive symptoms and social functioning were self-assessed with theJapanese versions of the Center for Epidemiologic Studies Depression Scale (CES-D) and the Social Adaptation Self-evaluation Scale (SASS), respectively. Brainfunction was measured by the changes in concentrationof oxy-hemoglobin ([oxy-Hb]) in the prefrontal andtemporal cortices during verbal fluency task using nearinfrared spectroscopy (NIRS).
Results The mean CES-D total score was 18.0, s =13.2, indicating that they have on average mild depression. Scores of CES-D total and those of its four factors
showed a significantly negative correlation with the
SASS total score. Among the four factors, “Interpersonal problems” factor showed the strongest correlation
with it. CES-D total score and those of its three factors,“Depressed affect”, “Somatic and retarded activity” andKey words

major depressive disorder; near-infrared
spectroscopy; prefrontal cortex; remission; residual
symptoms

Major depressive disorder (MDD) is one of the serious
health problems worldwide. From a currently prevailingview, MDD is assumed to be of a chronic or recurrent
nature with many patients encountering enormous difficulty in achieving full remission.1 These properties
may prevent them from returning to premorbid functioning levels.2 The desirable goals of its treatment thus areboth to achieve symptom remission and to fully recoversocial functioning. To date, remission has been operationalized, however, in clinical trials as a cut-off scoreusing standardized rating scale. Specifically, a score of
7 or less on the 17-item Hamilton Depression Rating
Scale (HAM-D17) typically designates remission.3 In
large prospective study, 28% of the participants achieved
remission after initial treatment4 with lower rates for
those requiring subsequent treatment.5 As regards longterm outcome, patients in remission at follow-up entry
were shown to be less likely to relapse than those not inremission.5
Although achieving remission is thus a highly recommended goal of the treatment of MDD in order forthe patients to return to normal functioning, the serious
problem is that patients who are in remission defined
operationally do not necessarily achieve full recovery.6
As such definitions do not require that patients be completely asymptomatic, they may have a varying degree

Corresponding author: Koichi Kaneko, MD, PhD
kaneko@med.tottori-u.ac.jp
Received 2015 December 7
Accepted 2015 December 17
Abbreviations: CES-D, Center for Epidemiologic Studies Depression Scale; “D”, group with depression; DLPFC, dorsolateralprefrontal cortex; DMN, default mode network; GAF, Global Assessment of Functioning; HAM-D17, 17-item Hamilton Depression
Rating Scale; MDD, major depressive disorder; MINI, the MiniInternational Neuropsychiatric Interview; “ND”, group without depression; NIRS, near-infrared spectroscopy; PFC, prefrontal cortex;[oxy-Hb], concentration of oxy-hemoglobin; SASS, Social Adaptation Self-evaluation Scale; VFT, verbal fluency task

15

M. Masai et al.

of residual symptoms. Many clinical studies have shownthat the presence of residual symptoms is a strong predictor of relapse.7–9 Moreover, their presence may prevent even remitted patients from functioning normally.
In addition to common symptoms such as low mood andloss of interest, patients with MDD often have as residual symptoms interpersonal difficulties as well, which areusually not used for the diagnosis10 but may neverthelessseriously hinder social functioning as well. The interpersonal problems have a pivotal role in the perpetuation ofdepressive symptoms11 with the efficacy of interpersonal
therapy for MDD providing indirect evidence for its rolein the maintenance of depression.12
In addition to adversely affected mood, MDD isalso characterized by impaired cognition.13 Neuropsychological dysfunction contributes to poor functional
outcome14: e.g., verbal fluency deficits were found to
predict poor functioning. In previous study, we founda positive relationship between the verbal fluency task
(VFT)-related hemodynamic responses in the prefrontal
regions of MDD patients measured with near-infrared
spectroscopy (NIRS) and levels of social functioning.15
In addition, impaired cognition has been demonstrated
irrespective of their current mood even in first-episodepatients.16 These cognitive deficits are thus most likely
to persist into the remitted state, and might compromise
their social functioning possibly in association with residual symptoms.
We should then address the critical issues of characterizing the clinical and pathophysiological nature of theresidual symptoms, which are likely involved in the impaired functioning in a certain portion of remitted MDD
patients. Little is known, however, about the relationshipin remitted state of MDD between brain dysfunction andresidual symptoms. In this pilot cross-sectional study, as
the first approach to characterizing the possible relationship of residual symptoms with brain function and social
functioning, we performed NIRS measurements during
VFT period in MDD patients in operationally defined
remission using clinician-assessed HAM-D17.7 Self-report depressive symptoms were also examined with theJapanese version of the Center for Epidemiologic Studies Depression Scale (CES-D),17 which is assumed to be
the only instrument that assesses interpersonal aspects
besides common symptoms. When using VFT as a task,
NIRS is approved for application in clinical practice forassisting differential diagnosis of depression in Japanbecause attenuated VFT-related prefrontal activationin depressed MDD patients is a consistent finding.15, 18
It is therefore well established that VFT-related NIRS
signals are a useful tool for evaluating the pathophysiological aspects of MDD. We hypothesized that, even in

remitted MDD patients, certain residual symptoms areassociated with impaired psychosocial functioning, andthat impaired brain activity in the prefrontal or temporal
cortical regions underlies these residual symptoms.
SUBJECTS AND METHODS
Subjects (Table 1)

Twenty-one euthymic patients with MDD (7 males, 14
females) were enrolled in the study after they provided awritten informed consent. All the patients were recruitedfrom among the outpatients at Tottori University Hospital. They had been diagnosed with MDD during theirclinical course based on the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition19 using theMini-International Neuropsychiatric Interview (MINI).20
They were also demonstrated at study initiation to havebeen in the state of remission for at least one month, defined as a score of seven or less on the HAM-D173 evaluated by two trained psychiatrists. None of the subjects
had clinical evidence of other central nervous systemdisorders based on history and medical examination. Patients with previous head trauma, stroke, electroconvulsive therapy, and current or previous history of substanceabuse were excluded from the study. All the participants
were right-handed by the criterion on the Edinburgh
Inventory Index21 and were native speakers of Japanese.
The study was approved by the Ethics Committee of
Tottori University Faculty of Medicine and the investigation was carried out in accordance with the latest versionof the Declaration of Helsinki.
Clinical Assessment

Prior to NIRS measurement, all the participants selfassessed depression symptom with the Japanese version of the CES-D scale.17 This scale consists of twentyquestions which measure depressive symptomatology
during the past week. Respondents rate the frequency ofoccurrence of each symptom on a 4-point Likert scale (0:less than 1 day; 1: last for 1–2 days; 2: last for 3–4 days;and 3: last for 5–7 days). The scores for each item can besummed to give a total score ranging from 0 to 60 withhigher scores indicating more severe depression. Basedon the total score, patients can be categorized as having mild depression (score 16 to 26) or major depression(score 27 to 60). The CES-D has been shown to consistof four factors, namely “Depressed affect”, “Positive affect”, “Somatic and retarded activity” and “Interpersonal
problems”.22
All the subjects also self-assessed the Japanese versionof social functioning with the Social Adaptation Self-Evaluation Scale (SASS), which is a 21-item scale developed
for the evaluation of patients’ social functioning by Bosc
16

Residual symptoms in remitted depression

et al.23; the reliability and validity of the Japanese version have been confirmed.24 Levels of social functioning
were also objectively evaluated with Global Assessmentof Functioning (GAF) scale by a trained psychiatrist.

using the “integral mode”; the pre-task baseline wasdetermined as the mean over a 10-s period prior to the
VFT period, and the post-task baseline as the mean overthe last 5 s of the post-task period.

Activation task

Statistical analysis

The task procedure in this study was similar to that of
Takizawa et al.25 The changes in concentration of oxyhemoglobin ([oxy-Hb]) were measured during VFT (letter version). Each subject sat on a comfortable chair andwas instructed to minimize movement during the NIRS
measurements so as to avoid artifacts. The activation
task included a 30-s pre-task baseline, a 60-s VFT and a
70-s post-task baseline. For the two baseline periods, thesubjects repeat the five Japanese vowels (“a”, “i”, “u”, “e”,“o”) aloud. The subtraction method (task minus pre- andpost-task baseline) minimized the vocalization effects
during VFT. During VFT period, they were instructed
to generate as many Japanese words beginning with adesignated syllable as possible. The three sets of initialsyllables (A; /to/, /se/, /o/, B; /a/, /ki/, /ha/, C; /na/, /i/, /ta/) were presented in counterbalanced order among the
subjects and each syllable changed every 20 s during the
60-s task. The total number of correct words generated
was adopted as a measure of performance.

When making a comparison of SASS total score between the two groups of differing CES-D total score(0–15, the group without depression, termed as “ND”
vs. 16–60, the group with depression, termed as “D”),
Student’s t-test was performed. Additionally, we investigated the relationships between these clinical or psychosocial variables using Spearman’s ρ because the scoresof CES-D total and individual factors did not show normal distribution.
We then tested the relationships between the clinicalvariables and the mean [oxy-Hb] change during the VFT
period for each channel. The clinical and psychosocial
variables assessed were as follows: HAM-D17, CESD, SASS and GAF. As regards CES-D, each score of its
four factors were tested for its correlation with the meantask-related [oxy-Hb] change as well as the total score.
We investigated these relationships using Spearman’s ρ
as well.
All the statistical analyses were performed using
SPSS 21.0 software. A P value of < 0.05 was considered
statistically significant. The multiplicity of the correlation analyses including NIRS data from 52 channels was
not corrected, and the results should therefore be taken
as exploratory.

NIRS measurements

The 52-channel NIRS machine (ETG-4000; Hitachi
Medical, Tokyo, Japan) measures relative changes in[oxy-Hb] and concentration of deoxy-hemoglobin using two wavelengths (695 and 830 nm) of infrared lightbased on the modified Lambert-Beer law. In this continuous-wave NIRS system, these [Hb] values include a
differential pathlength factor; therefore, the unit of NIRS
measurement is mM·mm. The distance between pairsof source detector probes was set at 3.0 cm and eachmeasuring area between them was defined as ‘channel’.
It is considered that the machine measures the surface
regions of the cerebral cortex.26 The probes of the NIRS
machine were placed on a subject’s fronto-temporal region with the mid column of the probe located over Fpz,
and the lowest probes are located along the T3–Fp1–
Fpz–Fp2–T4 line in accordance with the international
10/20 system used in electroencephalography. Their arrangement enabled the measurement of concentration ofhemoglobin values from bilateral prefrontal and superior
temporal cortical surface regions. The correspondence
between the NIRS channels and the measurement points
on the cerebral cortex was confirmed by the previous
study that performed simultaneous recording of NIRS
and functional magnetic resonance imaging.27 The sampling rate was 0.1 s. The obtained data were analyzed

RESULTS
Demographic and clinical data of patients in remission

Table 1 summarizes demographic characteristics andclinician-rated severity (HAM-D17) of depressive symptom in the remitted MDD patients. Only patients with
HAM-D17 score of 7 or less for more than one month
were eligible for the present study.
Residual depressive symptoms and social functioning

Table 2 summarizes self-report severity of depression
symptom (CES-D), self- and clinician-rated social functioning, SASS and GAF, respectively and task performance on the VFT. In MDD patients who were operationally classified as being in the state of remission, themean CES-D total score was 18.0, s = 13.2, indicatingthat the self-report severity of residual symptoms in thissample were yet in the range of mild depression on average. The numbers of the participants classified into each17

M. Masai et al.
Table 1. Clinical and demographic characteristics ofthe remitted patients with MDD

Table 3. Correlational analyses between severity ofdepression and social functioning

Remitted MDD
patients (n = 21)
Age (years old)

59.4 ± 12.0 (32–81)

Gender (male/female)

7/14

Education (years)

12.3 ± 2.1 (9–16)

Estimated premorbid IQ

101.9 ± 15.0 (73–120)

HAM-D17 total score

2.8 ± 2.5 (0–7)

Severity of depressive symptoms Social functioning

Medication
Imipramine equivalent dose (mg/day)

85.7 ± 71.5 (0–300)

SASS

GAF

CES-D total–0.57*–0.42

Depressed affect–0.54**–0.45*

Somatic and retarded activity–0.63***–0.25

Interpersonal problems–0.65***–0.70****

Positive affect–0.51*–0.50*

HAM-D17 total–0.45*–0.54*

Values are expressed as Spearman’s ρ.
*P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001.
CES-D, Center for Epidemiologic Studies Depression Scale; GAF,
Global Assessment of Functioning; HAM-D17, 17-item Hamilton
Depression Rating Scale; SASS, Social Adaptation Self-Evaluation Scale.

Values are expressed as mean ± s (range).
HAM-D17, 17-item Hamilton Depression Rating Scale; IQ, intelligence quotient; MDD, major depressive disorder.

Table 2. Self-assessed residual symptoms, social
functioning and task performance
Remitted MDD
patients (n = 21)
CES-D total

18.0 ± 13.2 (0–47)

Depressed affect

4.4 ± 5.2 (0–17)

Somatic and retarded activity

4.8 ± 4.6 (0–14)

Interpersonal problems

1.0 ± 1.6 (0–6)

Positive affect

7.8 ± 3.7 (0–12)

SASS

34.1 ± 10.1 (18–56)

GAF

80.3 ± 9.8 (61–100)

VFT performance (words generated)

12.3 ± 4.0 (5–18)

GAF scores of the two groups were of similar levels(“ND”, mean 83.3, s = 7.5 vs. “D”, mean 76.2, s = 11.5,
P = 0.13).
Levels of self-assessed residual symptoms were correlated with those of SASS (Table 3): Scores of the CESD total and of any of its individual factors showed a significant negative correlation with the SASS total score.
Among these factors, “Interpersonal problems” factor
showed the strongest correlation with the SASS total
score. In contrast, CES-D total score merely indicateda trend towards a correlation with clinician-rated GAF
score (r = –0.42, P = 0.06). Of its four factors, levelsof three factors were significantly negatively correlatedwith the GAF score with “Interpersonal problems” factor again showing the strongest association (Table 3).
HAM-D17 total score was also significantly correlatedwith either scale for social functioning, although withmuch smaller significance compared with most individual factors of CES-D (Table 3).

Values are expressed as mean ± s (range).
CES-D, The Center for Epidemiologic Studies Depression Scale;
GAF, Global Assessment of Functioning; MDD, major depressive
disorder; SASS, Social Adaptation Self-Evaluation Scale; VFT,
verbal fluency task.

of the two categories of mood state were as follows: i)twelve in “ND” (range of CES-D total score, 0–15) andii) nine in “D” (16–60). Any combination of two factors
within CES-D scale showed a significant, positive correlation between one another (r = 0.45 to 0.88, P = 0.00001
to 0.02).

Cognitive task-related changes in [oxy-Hb] changes

The mean VFT-related [oxy-Hb] changes averaged
across 11 channels in the prefrontal region was 0.03, s =0.06 (in mM·mm) in the remitted MDD patients group(n = 21). Those values averaged across 10 channels eachin the left and right temporal regions were 0.07, s = 0.10
and 0.08, s = 0.10, respectively.
The mean VFT-related [oxy-Hb] changes in theprefrontal region were roughly comparable when classifying the subjects into two subgroups, “ND” and “D”,
whereas those in the bilateral temporal regions showed

Relationships between severity of residual symptoms and degrees of psychosocial impairment(Table 3)

When subdividing the participants into the two subgroups based on the CES-D total score, that is, “ND”
(0–15) and “D” (16–60), SASS total score was significantly higher in “ND” than in “D” (“ND”, mean 40.5, s= 7.7 vs. “D”, mean 30.4, s = 8.6, P < 0.05). In contrast,
18

Residual symptoms in remitted depression

a trend to be larger in “ND” than in “D” : i) prefrontal
region; “ND”, mean 0.03, s = 0.05 vs. “D”, mean 0.02, s= 0.06, P = 0.92, ii) right temporal region; “ND”, mean
0.11, s = 0.10 vs. “D”, mean 0.05, s = 0.09, P = 0.14, iii)
left temporal region, “ND”, mean 0.11, s = 0.09 vs. “D”,
mean 0.03, s = 0.08, P = 0.06.

pressed affect” in three channels (Fig. 1A and 1C; ch31,
ch41 and ch52; r = –0.53 to –0.48; P = 0.01 to 0.03);“Somatic and retarded activity” in five channels (ch31,
ch34, ch41, ch44 and ch52; r = –0.60 to –0.44; P = 0.01
to 0.05). In contrast, “Interpersonal problems” showed
a positive correlation with the NIRS activation in fivechannels located in the bilateral prefrontal regions (Figs.
1A and 1B; ch14, ch17, ch35, ch36 and ch47; r = 0.49
to 0.55; P = 0.01 to 0.02). Among the channels whose
hemodynamic responses were likely affected by medication, only ch36 was related to the severity of residual
symptoms with the responses there being positively
associated exclusively with “Interpersonal problems”
factor. Medication dose, however, did not show any correlation with the levels of this factor at all (r = 0.10, P =0.66), excluding the possibility that medication mediatedthe close association between the brain activation andthe symptom severity.
The distribution pattern of the NIRS channels correlated with the symptom severity indicated differential
associations of distinct self-assessed residual symptoms

Relationship between VFT-related [oxy-Hb] changes and demographic and clinical variables.

In remitted patients, the mean task-related [oxy-Hb]changes were not significantly correlated with any ofdemographic variables except for a negative correlation
with imipramine-equivalent doses in four channels:
ch15, ch25, ch36 and ch48. The hemodynamic responses
were not correlated with clinician-rated HAM-D total
scores either except for single channel 33 (ch33). On
the other hand, scores of CES-D total and its two factors showed significantly negative correlations with the
responses at multiple channels mainly in the left hemisphere: CES-D total in two channels (ch41 and ch52; r= –0.50 and –0.45, respectively; P = 0.03 to 0.04); “De-Fig. 1. Relationship between the amount of VFT-related [oxy-Hb] changes and severity of self-report residual symptoms in remitted
patients with MDD. A: The brain regions depicted in yellow and green correspond to the NIRS channels that exhibited a significant
positive correlation (Spearman’s rank-order correlation; P < 0.05) between the degrees of NIRS activation and scores of “Interpersonal
problems” (yellow) and “Depressed affect”, respectively, factors of CES-D. B: Representative scatter diagram at channel 47 (right orbitofrontal and frontopolar cortical regions; Spearman’s rank correlation; r = 0.53 and P = 0.017). C: Representative scatter diagram at channel 52 (left superior and middle temporal cortical regions; Spearman’s rank correlation; r = –0.50 and P = 0.020). The location of NIRS
channels were estimated and labeled anatomically in the standard brain space in accordance with Sato et al.27
CES-D, Center for Epidemiologic Studies Depression Scale; MDD, major depressive disorder; NIRS, near-infrared spectroscopy; [oxyHb], concentration of oxy-hemoglobin; VFT, verbal fluency task.

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M. Masai et al.

of MDD with task-related brain activation in the corticalregions: i) CES-D total, “Depressed affect” and “Somaticand retarded activity” factors predominantly in left temporal and ventrolateral prefrontal regions and ii) “Interpersonal problems” factor mainly in right dorsolateral,orbitofrontal and frontopolar prefrontal regions. There
was no overlap in the distribution of the correlated NIRS
channels between these two symptom groups.

be rightly interpreted to examine the aspect of interpersonal sensitivity28 or rejection sensitivity29 in depression.
Importantly, interpersonal life events have been shown
to predict persistence of depressive symptoms in MDD
patients.30 The present finding thus indicated the importance of evaluating this crucial aspect even in remitted patients when considering the likely impairment inpsychosocial functioning due to relationship problems,
although the items that tap into this aspect have not been
included in the common rating scale, and thus not beenroutinely examined in the clinical practices. However,it should also be borne in mind that rejection sensitivity
may be trait-dependent rather than state-dependent.
As regards the cross-sectional relationship between
the self-report residual symptoms (CES-D) and the [oxyHb] activation in the remitted MDD patients, NIRS
measurements during VFT task period revealed differential associations between the distinct residual symptoms of depression and brain activations in the frontotemporal cortical regions: scores of CES-D “Interpersonal problems” factor were positively correlated withthe extent of the activation predominantly in the rightprefrontal cortex (PFC), whereas those of “Somatic andretarded activity” and “Depressed affect” factors were
negatively correlated with it mainly in the left temporal
cortex. These distinct cortical distributions of the associated channels were such that there was not a partial
overlap in these channels between the two groups ofresidual symptoms. This apparent lack of overlap in the
distribution of the correlated channels suggests the possible involvements of distinct neural networks in the persistence of different class of residual symptoms into theremitted state. As the amount of mean task-related [oxyHb] changes in the remitted MDD patients in this study
was of a comparable level to that of patients in current
depression, which we previously examined in similar
research settings,15, 31, 32 the patients in this study may
well be considered to be associated with more attenuatedactivation than healthy population. These results, taken
together, suggest that, even in remitted patients, residual
symptoms are related to dysfunction of frontal and/or
temporal cortices, although causal relationship cannot
be determined due to the cross-sectional nature of thisstudy. As the physiological dysfunction in the PFC in
MDD patients with ongoing symptoms has been increasingly clarified by functional neuroimaging studies,33–35
our results suggest that such dysfunction persist into theremitted state. As for currently depressed patients, manycross-sectional studies, however, failed to find their association when generally assessing symptom severity
with total score of HAM-D17.15, 36, 37 By contrast, using
self-assessed CES-D scale and its four factors,22 theDISCUSSION
The present study showed that MDD patients presumed
to be in the state of symptom remission defined as ascore of seven or less on the clinician-rated HAMD17 nevertheless self-reported a mild level of residual
symptoms on the CES-D scale on average, and that theseverity of the residual symptoms was negatively correlated with levels of social functioning self-rated with
SASS. Moreover, VFT-related hemodynamic responses
measured with NIRS revealed differential associations
between the distinct residual symptoms and the hemodynamic responses in different brain regions. Specifically,scores of CES-D total and of its two factors, “Depressed
affect” and “Somatic and retarded activity”, were negatively correlated with the activation chiefly in the left
temporal regions, whereas the relationship was somewhat reverse for “Interpersonal problems”, that is, positive correlations in the multiple prefrontal subregions.
These findings indicate that residual symptoms may
compromise levels of social functioning even in a certain subpopulation of patients in operationally defined
remission, and that the residual symptoms were possibly
linked with dysfunctional task-related neuronal activation in the prefrontal and temporal cortical regions.
Although remission is commonly defined using cut-off score on a rating scale for depressive
symptoms,3,defining it this way has been shown to not
identify a relatively homogeneous group of patients as
for morbidity and functioning. Judd et al.8 have foundthat remitted MDD patients with residual symptoms
were at greater risk for relapse and had more severe psychosocial impairment than those without them. Participants of the present study were also found to be rightly
subdivided into two subgroups based on the CES-D total
score, which may be justified on the grounds of clear
negative correlation between residual symptoms and ofself-rated social functioning. Such associations were also
observed for any of the four factors of CES-D with “Interpersonal problems” factor exhibiting much stronger
association than the other factors representing common
depressive symptoms. “Interpersonal problems” factor
is made up of the two items, “people were unfriendly”
and “I felt that people dislike me”, both of which may
20Residual symptoms in remitted depression

present study indicated possible associations between
symptom severity and pathophysiological responses in aremitted MDD sample, although the distribution of correlated regions exhibited a rather complex pattern. The
temporal and ventrolateral cortical regions in the left
hemisphere associated negatively with the two factors,“Somatic and retarded activity” and “Depressed affect”,
topographically overlapped to some extent. This finding
suggests the possibility of shared pathophysiology ofthese two classes of residual symptoms. Similar associations were previously shown in these brain regions of
MDD patients with ongoing depression as for “Psychomotor retardation” item on the HAM-D scale.35 In thiscontext, it is noteworthy that a meta-analytic study by
Fitzgerald et al.38 demonstrated dysfunctional activity
at rest of superior and middle temporal gyri and ventrolateral cortex in MDD patients. This might support the
aforementioned idea of the persistence of pathophysiology underlying current depression into remitted state.
On the other hand, “Interpersonal problems” factor werepositively associated with the activation in wide regionsof the PFC including dorsolateral prefrontal cortex(DLPFC), frontopolar PFC and orbitofrontal PFC. Two
possible mechanisms are suggested to be involved in thisobservation. First, impaired DLPFC function may havea role for its inefficient activation. Recent studies suggestthat DLPFC-mediated cognitive control may pertain to
the regulation of negative emotion through reappraisal.39
Considering the coexistence of “Interpersonal problems”
and “Depressed affect” in certain remitted patients assuggested by a strong association between these symptoms, regulation of negative emotion, such as rejection
sensitivity, by the DLPFC was likely to just partiallywork despite its greater activation. Second, reduced deactivation of the prefrontal network functionally related
to social relationships may be associated with rejection
sensitivity. As rejection sensitivity is known to predict
increased depressive rumination,29 which is defined
as repetitive self-focused brooding, elevated scores of“Interpersonal problems” factor might reflect ongoingruminative thinking in certain MDD patients. Recently
it has been shown that the brain’s default mode network(DMN), whose normal activity is mostly correlated in
the resting state and suppressed by external task requirements,40 is closely involved in the pathophysiology ofdepressive rumination.41, 42 DMN consists mainly of
medial frontal structures, which appears to make it difficult for NIRS to directly measure its activity. Sasai etal.43 have demonstrated, however, that [oxy-Hb] changes
measured with NIRS in the ventral prefrontal region
partly reflect correlated activity of DMN. Attenuatedsuppression of DMN by VFT might thus partly con-tribute to the observed association. As the attenuation
is a possible predictor of relapse,44 symptoms resulting
from dysfunctional DMN might be of a clinical importance. Longitudinal studies are required to investigate
the predictability of outcome by symptoms representing
impaired social relationships in remitted MDD patients.
Finally, the current study has a number of limitations. First, the sample size of the present study was relatively small, which implies that our findings may not be
generalizable to the broader population. Second, we did
not make a direct comparison of the size of brain activation between our remitted MDD sample and those withcurrent depression. However, our previous findings oncurrently depressed patients indicate the comparable sizeof the activation for the two groups.15, 31, 32 Third, the effects of multiple comparison tests were not considered in
the correlation analyses, indicating that the findings areat best explorative. Finally, the cross-sectional design ofthis study was not intended to resolve the causal relationship between residual symptoms of depression and hemodynamic responses assessed with NIRS. This design
also prevented us from determining whether residual
symptoms, “Interpersonal problems” factor in particular,
are best recognized as trait or state dependent. Future
longitudinal studies of the relationships between changes
in NIRS data and those in residual symptoms should beundertaken to address these problems.
In conclusion, a subpopulation of MDD patients inremission operationally defined with a threshold using
HAM-D17 self-reported several residual symptoms ofdepression, the degrees of which were found to be positively correlated with the levels of self-assessed social
functioning. In addition these symptoms were suggested
to be differentially associated with dysfunction of cortical regions.
Acknowledgments: This study was supported by Intramural Research Grant for Tottori University Hospital. The authors thank all
the participants in this study. The authors also thank Dr. Yamada
T for critically reading the manuscript and the Hitachi Medical
Corporation for providing us with technical advice.
The authors declare no conflict of interest.

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