Journal of Affective Disorders 176 (2015) 78–86

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Research report

Association between longitudinal changes in prefrontal hemodynamic responses and social adaptation in patients with bipolar disorder and major depressive disorder Toshiyuki Ohtani a,c,n, Yukika Nishimura a,b,d, Katsuyoshi Takahashi b, Reina Ikeda-Sugita b, Naohiro Okada a,b,d, Yuji Okazaki b,e a

Department of Clinical Laboratory, Tokyo Metropolitan Matsuzawa Hospital, Setagaya-ku, Tokyo 156-0057, Japan Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Setagaya-ku, Tokyo 156-0057, Japan Safety and Health Organization, Chiba University, Chiba 263-8522, Japan d Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan e Michino-o Hospital, Nagasaki 852-8055, Japan b c

art ic l e i nf o

a b s t r a c t

Article history: Received 9 January 2015 Accepted 15 January 2015 Available online 22 January 2015

Background: Patients with affective disorders exhibit changes in regional brain function and show abnormal social adaptation. However, to our knowledge, no near-infrared spectroscopy (NIRS) study has examined the relationship between these two phenomena longitudinally. This study examined the region-specific functional abnormality associated with bipolar disorder (BD) and major depressive disorder (MDD), and the association between particular longitudinal changes in regional activation and social adaptation. Methods: We evaluated frontotemporal functioning during a verbal fluency test (VFT) for patients with BD (N¼18), those with MDD (N ¼10), and healthy controls (HCs; N ¼14) using NIRS. NIRS measurements and the Social Adaptation Self-evaluation Scale (SASS) were administered twice with an interval of approximately 6 months. Results: The BD and MDD groups showed lesser activation than the HCs in the bilateral ventro-lateral prefrontal cortex and the anterior part of the temporal cortex (VLPFC/aTC). Longitudinal changes in SASS scores were positively associated with the extent of change in left VLPFC/aTC activation in the BD group and with right VLPFC/aTC activation in the MDD group. Limitations: Our small sample size limited statistical power, and the effect of medication and multiple comparisons cannot be excluded, although these effects were considered in the interpretation of the present results. Conclusion: Longitudinal increases of VLPFC/aTC activation were associated with improvement in social adaptation in patients with BD and those with MDD. NIRS measurement could be a useful tool for objective evaluation of changes in social adaptation in BD and MDD. & 2015 Elsevier B.V. All rights reserved.

Keywords: Near-infrared spectroscopy Bipolar disorder Major depressive disorder Executive function Social adaptation

1. Introduction Improving social functioning and quality of life are primary goals of clinical treatment. Cognitive function can be a major determinant of social functioning in patients with various psychiatric disorders (Pu et al., 2013). Cross-sectional studies have shown that patients with bipolar disorder (BD) typically exhibit deficits in executive function (Ancín et al., 2013; Martino et al., 2013). These deficits have been shown to improve with reductions

n Correspondence to: Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan. Tel./fax: þ81 43 290 2216. E-mail address: [email protected] (T. Ohtani).

http://dx.doi.org/10.1016/j.jad.2015.01.042 0165-0327/& 2015 Elsevier B.V. All rights reserved.

in symptom severity (Torres et al., 2014). Similarly, patients with major depressive disorder (MDD) also typically exhibit deficits in executive function (McIntyre et al., 2013; Schmid and Hammar, 2013). However, the results of longitudinal studies on cognitive functioning and MDD symptom severity have been inconsistent. Douglas and Porter (2009) suggested that verbal fluency is sensitive to the clinical state of patients with MDD. In contrast, Schmid and Hammar (2013) reported that patients with MDD exhibit prolonged poor performance in executive function, including semantic fluency, despite reductions in symptom severity. Previous functional neuroimaging studies have suggested that in BD, the deficits in executive function are related to abnormal activation of the frontal and temporal regions (Altshuler and Townsend, 2012; Cerullo et al., 2014), and the same applies to

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MDD (Monks et al., 2004; Pu et al., 2008; Kikuchi et al., 2012). More specifically, the lateral prefrontal cortex, which contains the dorsolateral (DLPFC) and ventrolateral prefrontal cortices (VLPFC), is responsible for coordinating appropriate executive function (Robbins, 1998). Multi-channel near-infrared spectroscopy (NIRS) can detect spatiotemporal functioning near the brain's surface non-invasively (Strangman et al., 2002a; Boas et al., 2004) without the habituation effects associated with repeated measurements (Kono et al., 2007; Schecklmann et al., 2008; Kakimoto et al., 2009). NIRS measures concentration of oxygenated ([oxyHb]) and deoxygenated hemoglobin ([deoxyHb]) in micro-blood vessels and estimates brain activation as an increase of [oxyHb] (Strangman et al., 2002a, 2002b). NIRS has been used to assess brain function in many psychiatric disorders (Suto et al., 2004; Kameyama et al., 2006). Previous studies examining patients with BD have reported divergent results: hypofrontality during the verbal fluency test (VFT) or working memory tasks (Matsuo et al., 2007; Schecklmann et al., 2011), and hyperfrontality during the VFT (Kubota et al., 2009). On the other hand, studies using NIRS to examine brain activity in patients with MDD have consistently reported hypoactivity during the VFT (Noda et al., 2012; Pu et al., 2012a, 2012b; Liu et al., 2014) and working memory tasks (Pu et al., 2012a, 2012b), compared to HCs. The divergence in results of studies of patients with BD might be caused by the mental state of the subject. Most NIRS studies have been conducted in patients with depression or euthymic individuals (Matsuo et al., 2007; Schecklmann et al., 2011; Kubota et al., 2009; Kameyama et al., 2006; Matsubara et al., 2013), or combined patients with different mental states (Kubota et al., 2009). Our group has focused on the hypomanic state of patients with BD, and has found significantly more left DLPFC activation in patients with hypomania than those in patients with depression. Follow-up measurements in patient with hypomanic BD revealed that prefrontal activation decreased with the disappearance of hypomanic symptoms (Nishimura et al., 2014). This showed the effect of mood states on prefrontal activation cross-sectionally and longitudinally in patients with BD. Of note, in many NIRS studies, probes have been arranged to measure functional activities in the bilateral prefrontal cortex (i.e., dorsolateral [Brodmann areas (BAs) 9 and 46], ventrolateral [BAs 44, 45, and 47] and frontopolar [BA 10] regions) and the superior and middle temporal cortical surface regions. This method has been corroborated by a multi-individual study of anatomical craniocerebral correction via the international 10–20 system (Tsuzuki et al., 2007). However, retest reliability was unsatisfactory at the single-individual and single-channel levels, and studies of repeated NIRS measurements have only demonstrated acceptable reliability at the group and cluster levels (Schecklmann et al., 2008). Thus, in the present study, we performed an analysis of NIRS signals at the group and cluster levels. The Social Adaptation Self-evaluation Scale (SASS) is a self-rating questionnaire for assessing social functioning. The reliability and validity of the Japanese version of the SASS have been confirmed (Goto et al., 2005). Reduced activation in the prefrontal and temporal regions during cognitive tasks has been associated with the lower SASS scores in patients with late onset major depression (Pu et al., 2012a, 2012b). To our knowledge, no NIRS study has examined the association between this regional brain activation and social functioning assessed by SASS in patients with BD. We hypothesized that the deficits in executive function that affect social functioning can be detected by reduced activation in the prefrontal and temporal regions during cognitive tasks using NIRS, and such abnormally low levels activation can change over time, reflecting improvement in social functioning, including social adaptation in patients with BD and MDD. In the present study, we analyzed regional activation associated with cognitive tasks in three frontal brain regions of interest (ROIs) defined by

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Takizawa et al. (2014). Furthermore, we examined the correlation between longitudinal changes of activation in those regions that show abnormal activation compared to HCs and the longitudinal change in SASS scores for the patients with BD and MDD. The aim of the present study was to test our hypothesis and examine whether NIRS can be a biomarker of longitudinal changes in social functioning. This study is, to our knowledge, the first longitudinal NIRS study examining the association between regional brain activation and social functioning in patients with BD and MDD.

2. Methods 2.1. Participants Participants included 18 patients with BD, 10 with MDD, and 14 healthy controls. Patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IVTR) (APA, 2000). Patients with BD and MDD were recruited from inpatient and outpatient units of Tokyo Metropolitan Matsuzawa Hospital. HCs were volunteers. All three groups were matched for gender, age, years of education, and estimated intelligence (IQ) (Table 1). Exclusion criteria were as follows: left-handedness, history of major physical illness, neurological disorder, substance use, alcohol abuse, and any loss of consciousness due to head injury. Participant IQ was estimated using the Japanese version of the National Adult Reading Test (JART) (Matsuoka et al., 2006). Social functioning of patients with BD and MDD was evaluated using the 21-item SASS (Bosc et al., 1997). Participants were asked to answer either item 1 or item 2, in accordance with their occupational status (item 1) or other types of primary activities such as housework (item 2), and then answer the other 20 items. Each item is scored from 0 to 3, corresponding to minimal and maximal social adjustment, with a total score range of 0–60. The reliability and validity of this Japanese version have been confirmed (Goto et al., 2005). Using principal component analysis, previous studies demonstrated that the 20 SASS items can be classified into three factors: interpersonal relations, interest and motivation, and selfperception (Goto et al., 2005). Of note, the interpersonal relations factor can be scored as the sum of the items: “family seeking behavior,” “family relationship quality,” “gregariousness,” “relationship seeking behavior,” “external relationship quality,” “external relationship appreciation,” “social attractiveness,” and “social compliance.” The interest and motivation factor can be scored as the sum of the items: “job interest or homework interest,” “work enjoyment,” “interest in hobbies,” “quality of spare time,” “community involvement,” “social inquisitiveness,” “intellectual interest,” and “control of surroundings.” In addition, to confirm the effect of overall symptom severity on brain function and social functioning, affective symptom severities were evaluated by welltrained psychiatrists (KT, TO, RI) using Japanese versions of the Hamilton Rating Scale for Depression (HAM-D) 17-item version (Hamilton, 1960) and Young Mania Rating Scale (YMRS; Young et al., 1978). The SASS, HAM-D, and YMRS were administered less than 1 week before each NIRS measurement. Patient medications are listed in Tables 1 and 2. Written informed consent was obtained from all participants prior to participation. This study was approved by the Research Ethics Committee of Tokyo Metropolitan Matsuzawa Hospital. 2.2. Activation task We used the letter version of the VFT of one block design model to measure the regional activation of the frontal and temporal brain regions. The cognitive activation task included a 30 s

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Table 1 Participant characteristics in the cross-sectional sample. BD

Gender ratio (m/f) Age (years) Estimated IQ Education (years) VFT performance (words) Duration of treatment (months) Medication Lithium (mg/day) VPA (mg/day) Clonazepam (mg/day) Lamotrigine (mg/day) Imipramine eq. dose (mg/day)c CP eq. dose (mg/day)d Diazepam eq. dose (mg/day)e

MDD

P-valuea

HC

Mean

SD

Mean

SD

Mean

SD

9/9 39.7 104.5 14.4 12.9 83.9b

9.0 7.9 1.5 3.7 68.3b

4/6 39.2 107.1 14.7 15.0 73.0

12.1 8.3 1.4 3.7 71.9

7/7 33.6 105.9 15.6 14.4 –

8.3 8.4 1.3 6.3 –

0.858 0.179 0.721 0.075 0.482 –

344.4 164.7 1.0 33.3 9.4 138.3 12.5

421.8 382.3 1.4 78.6 16.6 264.9 12.4

– 60.0 – 5.0 52.9 7.6 10.7

– 189.7 – 15.8 110.1 24.0 9.6

– – – – – – –

– – – – – – –

– – – – – – –

Abbreviation: BD ¼ bipolar disorder; MDD¼ major depressive disorder; HC ¼healthy control; SD¼ Standard Deviation; IQ¼ Intelligence Quotient; VFT¼ verbal fluency task; VPA ¼ Sodium Valproate; CP¼ chlorpromazine. a

P-value by one-way analysis of variance of clinical group: bipolar disorder, major depressive disorder, and healthy controls. Missing data for one patient. Antidepressant dosages were evaluated by imipramine equivalent dosage. d Antipsychotic dosages were evaluated by CP equivalent dosage. e Anxiolytic dosages were evaluated by diazepam equivalent dosage. b c

Table 2 Participant characteristics in longitudinal comparison. Bipolar disorder (N ¼18)

Baseline

6-month Follow-up

Mean SD

Mean

P-value

SD

HAM-D 12.6 6.1 10.0 YMRS 4.4 4.8 3.6 SASS total 28.9 8.2 31.2 Interpersonal relations 13.6 3.2 13.6 Interest and motivation 10.1 4.8 11.6 Self-perception 5.3 1.9 6.0 VFT performance 12.9 3.7 14.1 a CP eq. dose (mg/day, N ¼9) 138.3 264.9 185.6 Imipramine eq. doseb (mg/day, N ¼5c) 9.4 16.6 0 d e Diazepam eq. dose (mg/day, N ¼14 ) 12.5 12.4 9.7 Lithium (mg/day, N ¼ 9f) 344.4 421.8 266.7

6.4 6.3 7.0 2.8 4.3 1.7 4.7 314.1 0 8.3 363.0

0.102 0.615 0.204 0.935 0.252 0.138 0.158 0.187 0.029 0.398 0.393

Major depressive disorder (N ¼ 10) HAM-D YMRS SASS total Interpersonal relations Interest and motivation Self-perception VFT performance CP eq. dose a (mg/day, N ¼ 1) Imipramine eq. dose (mg/day, N ¼3) Diazepam eq. dose (mg/day, N ¼4) Lithium (mg/day, N ¼ 0)

5.0 3.4 5.1 2.3 3.7 1.0 3.2 31.6 47.9 6.4 –

0.121 0.169 0.775 0.656 0.861 0.509 1.000 0.858 0.467 0.077 NA

14.8 1.2 28.7 12.3 10.2 6.2 15.4 7.6 52.9 10.7 –

8.9 1.9 7.1 2.7 4.0 1.9 3.7 24.0 110.1 9.6 –

10.1 2.7 28.2 12.0 10.4 5.8 15.4 10.0 23.0 3.5 –

Clonazepam, Carbamazepine, Sodium Valproate (No 3). Abbreviation: HAM-D¼Hamilton Rating Scale-Revised, 17-items version; YMRS ¼ Young Mania Rating Scale; VFT¼ verbal fluency task; CP¼ chlorpromazine. a

Antipsychotic dosages were evaluated by CP equivalent dosage. Antidepressant dosages were evaluated by imipramine equivalent dosage. c N¼ 0 at 6-month follow-up. d Anxiolytic dosages were evaluated by diazepam equivalent dosage. e N ¼ 13 at 6-month follow-up. f N ¼7 at 6-month follow-up. b

pre-task baseline, 60 s VFT, and a 70 s post-task baseline (Kameyama et al., 2004; Suto et al., 2004; Takizawa et al., 2008; Koike et al., 2011). Participants were instructed to generate as many Japanese words beginning with a designated syllable as possible during the 60 s task phase, with the initial syllable

changing every 20 s. The number of correct words generated during the VFT was used to measure performance. During preand post-task baseline assessments, participants consecutively repeated the five Japanese vowels (/a/, /i/, /u/, /e/, /o/) aloud. Participants were asked to stay seated, keep their eyes open, and minimize movement during measurements to avoid artifacts. 2.3. NIRS measurement We used a 52-channel NIRS machine (ETG-4000, Hitachi Medical Corporation, Tokyo, Japan) to measure relative changes of [oxyHb] and [deoxyHb] using two wavelengths (695 and 830 nm) of infrared light on the basis of the modified Beer Lambert law (Yamashita et al., 1996). The distance between pairs of emitter and detector probes was set at 3.0 cm, and each measuring area between pairs of emitter and detector probes was defined as a “channel.” The NIRS machine measures the region at 2–3 cm depth from the scalp, which is approximately the surface of the cerebral cortex (Toronov et al., 2001; Okada and Delpy, 2003). Probes were placed on participants' prefrontal and temporal regions. The lowest probes were positioned along the T4-Fpz-T3 line according to the International 10/20 system. This arrangement measured hemoglobin levels from the bilateral prefrontal cortical areas (e.g., DLPFC, VLPFC), frontopolar cortex (FPC), and anterior portion of the superior and middle temporal cortices (aTC) based on anatomical craniocerebral correction via the International 10/20 system (Okamoto et al., 2004). The correspondence between NIRS channels and cerebral cortex measurement points are presented based on the virtual registration method (Tsuzuki et al., 2007). The temporal resolution of the NIRS signal was 0.1 s. In order to remove any short-term motion artifacts, we used a moving average window of 5 s for analyses. In addition, we applied an automated method for rejecting artifacts focused on 3 kinds of noise (high frequency, low frequency, and no signal) and bodymovement (Takizawa et al., 2008). In order to examine task-related activation, data were analyzed using the “Integral Mode” of the ETG-4000 machine. Linear trend fitting was performed for data obtained between the two baselines phases. The pre- and post-task baselines were defined as the mean

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Fig. 1. Channel positions on the brain surface. The left figure shows the left side view and the right figure shows the right side view of the brain surface. Left region 2 consists of the left 10 yellow channels and is located approximately on the left ventrolateral prefrontal cortex (VLPFC) and anterior part of the temporal cortex (aTC) region. Right region 2 consists of the right 10 yellow channels and is located approximately on the right VLPFC and aTC region. Region 1 consists of the center 11 gray channels and is located approximately on VLPFC and frontal pole region.

values of the 10-s period just prior to the task and at the end of the 70-s post-task period, respectively. 2.4. Region of interest (ROI) Of our 52 NIRS channels, region 1 was defined as including channels 25–28, 36–38, and 46–49. The right side of region 2 was defined as channels 22–24, 32–35, and 43–45, and the left side of region 2 was defined as channels 29–31, 39–42, and 50–52 (Takizawa et al, 2014) (Fig. 1). The NIRS signal of region 1 consisted of the signals from channels located approximately in the frontopolar region and DLPFC (i.e., the superior and middle frontal gyrus). Region 2 consisted of signals from channels located approximately in the VLPFC and the aTC (Takizawa et al., 2014). 2.5. Statistical analysis Hemodynamic responses during the VFT in region 1 and left and right region 2 were assessed by the “integral value” (Takizawa et al., 2014) of [Hb] changes. The integral value reflects the size of the hemodynamic responses during the 60 s activation period. NIRS signals from each of the three representative regions (i.e. region 1, left and right region 2) were averaged separately for each type of [Hb] for each individual. All statistical analyses were performed using PASW Statistics 21.0 (SPSS Japan Inc., Tokyo, Japan). We especially focused on [oxyHb] changes, since [oxyHb] has a superior signal-to-noise ratio than [deoxyHb] (Huppert et al., 2006; Strangman et al., 2002a, 2002b). Furthermore, brain activation can be detected as an increase in [oxyHb] (Strangman et al., 2002a, 2002b), and increases in [oxyHb] were suggested to reflect task-related cortical activation more directly than decreases in [deoxyHb], as shown by a stronger correlation with blood-oxygenation level-dependent signal measured by fMRI (Strangman et al., 2002b). In the cross-sectional study, one-way analyses of variance (ANOVA) were performed among BD, MDD, and HC groups for age, years of education, estimated IQ, and VFT performance. Gender frequency between groups was compared with a χ2 test. In addition, independent t-tests were performed between BD and MDD groups for duration of illness, medication dosage (i.e., equivalent doses of imipramine and diazepam (Inagaki and Inada, 2006), chlorpromazine (Woods, 2003), and lithium), and HAM-D, YMRS, and SASS scores, including the interpersonal relations factor, the interest and motivation factor, the self-perception factor, and SASS total scores. Group differences in the integral value of [oxyHb] were first assessed using repeated-measures ANOVA, with clinical group (BD, MDD, and HC)

as a between-subject factor and the region (region 1, and left and right region 2) as a within-subject factor. For significant results, we further examined the integral value of [oxyHb] of each ROI using one-way ANOVAs, with post-hoc Tukey Honestly Significant Difference tests to evaluate which region showed group differences in ROI activation. Huynh–Feldt corrected degrees of freedom were used to correct for violations of sphericity. For those ROIs showing significant differences between BD and MDD groups compared to HCs, Pearson's correlation coefficients were calculated for the relationship between the integral value of [oxyHb] and SASS scores of the interpersonal relations factor, the interest and motivation factor, the self-perception factor, and the total SASS score. Furthermore, demographic characteristics (i.e., age, years of education, estimated IQ), VFT performance, medication dosage, HAM-D, and YMRS scores at baseline were analyzed for correlations with both the integral value of ROI [oxyHb] and SASS scores. The same correlation analyses were performed for the 6-month follow-up measurements. We performed these analyses to confirm any effects of these variables on the ROI activation or SASS scores. In the longitudinal comparison, the integral value of [oxyHb] changes, VFT task performance, and SASS total scores were compared between the first examination and the 6-month follow-up. We also compared total HAM-D and YMRS scores across time to assess any overall changes to symptom severity. Normality of scores was tested with Kolmogorov–Smirnov and Shapiro–Wilk tests. Normal data were analyzed with paired t-tests and nonnormal data were analyzed with Wilcoxon signed-rank tests. In addition, for those ROIs where patients with BD and MDD showed significant cross-sectional differences in the integral values of [oxyHb] from HC, we computed Pearson's correlation coefficients between change in the integral value of [oxyHb] and changes of the 3 factor scores or the total scores of SASS. In order to confirm the effect of the longitudinal change in the clinical symptoms (i.e., changes in HAM-D and YMRS scores), we also examined the relationships between these symptom changes and the changes in ROI activation or SASS scores. For all tests, the significance level was set at P o0.05.

3. Results 3.1. Cross-sectional study There were no significant group differences in age, gender, estimated IQ, education, and VFT performance at baseline (Table 1).

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Fig. 2. Waveforms of oxyHb concentration changes during the verbal fluency task. The upper figures show the overall average waveforms of the concentrations of oxygenated hemoglobin ([oxyHb]) changes during the verbal fluency task in patients with bipolar disorder (green), major depressive disorder (blue), and healthy controls (red). In the lower three figures, the right figure shows the average waveforms of [oxyHb] changes for the 10 channels in the right VLPFC/aTC region, the center figure shows that for the 11 channels in the frontal pole region, and the left figure shows that for the 10 channels in the left VLPFC/aTC region. Abbreviations: VLPFC: ventro-lateral prefrontal cortex, aTC: anterior part of temporal cortex.

3.2. Comparison of hemodynamic response across clinical groups

3.4. Longitudinal study

The overall mean [oxyHb] waveforms for the 52 channels and the 3 ROIs in each group are shown in Fig. 2. A repeated-measures ANOVA of the integral values of [oxyHb] with group (BD, MDD, or HC) as a between-subjects factor and ROI (region 1, left region 2, and right region 2) as a within-subjects factor revealed a significant main effect of group (F2,39 ¼16.70, Po 0.001), a significant main effect of ROI (F1.7,65.7 ¼ 15.06, P o0.001), and a significant interaction of ROI  group (F3.4,65.7 ¼17.66, P o0.001). The clinical group main effect was further analyzed using one-way ANOVAs of the integral value of [oxyHb], and significant group differences were found for left region 2 (F2,39 ¼ 15.69, P o0.001) and right region 2 (F2,39 ¼ 33.24, P o0.001). Tukey HSD tests revealed significantly smaller integral values of [oxyHb] in the BD versus the HC group (left region 2: P o0.001; right region 2: P o0.001), smaller integral values of [oxyHb] in the MDD versus the HC group (left region 2: P ¼0.001; right region 2: P o0.001), and an equal integral value of [oxyHb] in the BD and MDD groups (left region 2: P ¼0.84; right region 2: P ¼1.00).

The mean measurement interval was 5.7071.24 months (range¼ 3–9; BD: 5.9771.14 months, range¼ 3–9 months; MDD: 5.2071.32 months, range¼3–6 months). Changes in VFT performance, HAM-D, YMRS, and the 3 factor scores and total scores of SASS are shown in Table 2. Medication in the BD and MDD groups is also shown. No significant changes were found between the baseline examination and the 6-month follow-up for these variables and the integral values of ROI [oxyHb] changes in either the BD or MDD group.

3.3. Correlations between hemodynamic response and demographic characteristics, medication dosage, and social adaptation Since left and right region 2 showed abnormal hemodynamic responses in both the BD and MDD groups, correlation analyses were performed within each group to examine the relationship between the abnormal hemodynamic response and the following variables: age, education, estimated IQ, VFT performance, medication dosage, HAM-D, YMRS, and the 3 factor scores and total scores of the SASS. No significant correlations were found for any of these analyses.

3.5. Correlation between longitudinal changes in hemodynamic responses and changes in social adaptation Since both left and right region 2 showed abnormal hemodynamic responses in the BD and MDD groups compared with the HC group, within each clinical group we performed correlation analyses of the longitudinal change in the integral value of [oxyHb] in either the left or right region 2 and the longitudinal changes in the 3 factor scores and total scores of SASS. In the BD group, the integral value change in left region 2 was positively associated with the changes in interpersonal relations factor scores (R¼ 0.554, P¼ 0.017, N ¼18) and with the total score of SASS (R¼ 0.494, P ¼0.037, N ¼18) (Fig. 3). In the MDD group, right region 2 was positively associated with the changes in the interest and motivation factor (R¼0.691, P¼ 0.027, N ¼ 10) and total SASS score (R¼0.760, P¼ 0.011, N ¼10) (Fig. 3). 4. Discussion Both the BD and MDD groups showed reduced activation in the bilateral VLPFC/aTC (region 2 in the present study) during the VFT,

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Fig. 3. Correlations between longitudinal changes in the concentrations of oxygenated hemoglobin ([oxyHb]) of VLPFC/aTC and SASS scores. The X-axis indicates changes in the integral value of [oxyHb], and the Y-axis indicates changes in SASS scores. Left scatter plots show the association between changes in the integral value of [oxyHb] during the verbal fluency task (VFT) in the left VLPFC/aTC and changes in the interpersonal factor and total score of SASS in the bipolar disorder group. Right scatter plots show the association between changes in the integral value of [oxyHb] in the right VLPFC/aTC and the interest and motivation factor and total score of SASS in the major depressive disorder group. Abbreviations: VLPFC: ventro-lateral prefrontal cortex, aTC: anterior part of temporal cortex, SASS: social adaptation scale score.

which suggests hypofunctioning of this region in these patients. Although no association was found for the cross-sectional correlation analysis for patients with BD and MDD, the 6-month longitudinal increase in left VLPFC/aTC activation was positively associated with improved interpersonal relations (as indicated by SASS factor) and better overall social adaptation (total SASS score) for patients with BD. For patients with MDD, longitudinal increases in right VLPFC/aTC activation were positively associated with improved interest and motivation (SASS factor) and overall social adaptation (SASS total score). No significant association was found between demographic or clinical variables and activation in the bilateral VLPFC/aTC in either BD or MDD groups, suggesting that activation was independent of the effect of these variables. In the comparison of overall symptom severity and regional activation between baseline and 6-month follow-up, no significant longitudinal change was observed in either overall symptom severity or regional activation in either the BD or the MDD group. 4.1. Reduced VLPFC/aTC activation in patients with BD and MDD Previous studies have reported reduced activation during cognitive tasks in each of the left and right frontotemporal regions in BD (Blumberg et al., 2003; Townsend et al., 2012) and MDD (Pu et al., 2012a, 2012b; Noda et al., 2012), compared to HCs. The present results are partially consistent with these studies in that they show bilateral VLPFC/aTC hypoactivation during cognitive tasks. However, the present results show no significant hypoactivation in the FP region. Although patients with BD, MDD, and schizophrenia were grouped together in their study, Takizawa et al. (2014) reported in their Supplemental material that group differences could be observed between the mental health patients group and the healthy control group in the FP and bilateral VLPFC/ aTC activation, but that such differences were smaller in the FP

(P ¼0.05) compared to the VLPFC/aTC (P ¼0.02). Thus, we speculate that the reduction in activation in the FP is relatively small compared to VLPFC/aTC regions and that its significance might disappear when patients with BD and those with MDD are analyzed separately. Further NIRS studies examining the BD and MDD groups separately with larger sample sizes, analyzing the activation of ROIs including FP, and left and right VLPFC/aTC regions, are needed to confirm the present results. 4.2. Regional brain activation and social adaptation Longitudinal changes of the left DLPFC/aTC abnormal activation were associated with changes in interpersonal relations and overall social adaptation level in the BD group, while right DLPFC/aTC activation was associated with changes in interest and motivation and overall social adaptation level in the MDD group. However, no cross-sectional correlation between DLPFC/aTC activation and social adaptation was found for either BD or MDD groups. We discuss each of these findings in turn. Unlike healthy controls, patients with BD did not show activation in the inferior frontal and temporal regions during the theory of mind task that requires an essential skill for successful social interaction (Malhi et al., 2008). In addition, VLPFC has been suggested to play an important role in interpersonal conflicts (Hooker et al., 2010). Thus, we speculate that VLPFC and temporal activity might be associated with having a successful social interaction that may affect overall social adaptation in patients with BD. Our longitudinal results are consistent with this speculation. Activation in the FP and bilateral VLPFC/aTC regions has been associated with SASS total scores in patients with late-onset depression (Pu et al., 2012a, 2012b). Specifically, the VLPFC receives motivational and emotional information from orbitofrontal cortex and subcortical areas (Sakagami and Pan, 2007), and

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although participants in this previous study were healthy workers, their interest and motivation (SASS factor) were positively associated with activity in prefrontal regions (Pu et al., 2013). Thus, we speculate that activity in the prefrontal and temporal regions can be associated with interest and motivation (and therefore overall social adaptation) levels in patients with MDD. Our longitudinal results support this notion. In spite of the interesting findings of our longitudinal analyses, we found no association between prefrontal and temporal activation and the 3 factors or overall social adaptation levels in our cross-sectional analyses. To explain why such associations were only observed in longitudinal analyses, we speculate that the BD group included heterogeneous patients with various mood states. This may have affected the cross-sectional results by analyzing the regional activation or clinical characteristics in different states together. However, this effect of heterogeneity might be reduced or eliminated in longitudinal analyses. For the MDD group, null result in the cross-sectional analyses maybe explained by the characteristics of the patients. The present sample did not consist of patients with late-onset depression alone, and this might account for the divergence of results from the previous study (Pu et al., 2012a, 2012b). Taken together, when clinical groups consist of heterogeneous subjects, VLPFC/aTC activation may not reflect social adaptation levels at a single point in time, but longitudinal changes in regionspecific activation can still reflect changes in social adaptation level. Further studies considering the characteristics of the subjects may confirm the present results. 4.3. Laterality in the association between region specific activation and social adaptation Several previous studies have reported an association between regional activation and social functioning with laterality of the activated region. Activation in both the left DLPFC and left ACC was positively associated with global assessment of functioning (GAF) score in patients with BD (Yoshimura et al., 2014). GAF scores include the objective evaluation of both symptom severity and level of psychological, social, and occupational functioning. The present results are partially consistent with this previous study, showing the association between activation in left DLPFC and level of social functioning in patients with BD, although the tool for evaluating social function and study designs was different in the two studies. On the other hand, Noda et al. (2012) reported an association between right prefrontal and temporal activation and (a) level of work and activity, or (b) severity of psychomotor retardation in patients with MDD. Level of work and activity and severity of psychomotor retardation can directly or indirectly affect social functioning. Thus, although study designs differed, the present results may be consistent in that they show the association between right prefrontal and temporal activation and level of social functioning in patients with MDD.

measure longitudinal changes in brain activation in patients with psychiatric disorders. Taken together, longitudinal measurement with NIRS can detect changes in brain activation that may act as a biomarker of social functioning. The present 6-month follow-up study that showed an association between longitudinal change in regional activation and changes in social adaptation (without significant change in the clinical symptom severity) suggests that NIRS may indeed be an objective biological indicator of social adaptation.

5. Limitations First, NIRS measures only the surface regions of the brain, and thus we could not measure deep brain structures such as the limbic system. Second, the number of participants in our study was relatively small, and findings may not be generalizable to the broader population. Third, most patients took medication at the time of the NIRS measurement, although the association between the medication dosage and NIRS signal was not significant in the present study. We believe the effect of medication on the present results was negligible, but medication is an important factor requiring consideration when demonstrating executive dysfunction in mental disorders. Fourth, our BD and MDD groups might have been heterogeneous. Our analyses combined BD-I and BD-II in the BD group and melancholic and non-melancholic subtypes of depression in the MDD group. Previous studies have reported a difference between BD-I and BD-II in quality of life (Maina et al., 2007), cognitive function (Martinez-Aran et al., 2004), and brain metabolism (Li et al., 2012), as well as longitudinal differences between melancholic and non-melancholic subtypes of MDD in cognitive function (Withall et al., 2010). Thus, further follow-up studies with a larger number of participants that examine the subtypes of BD or MDD are required to confirm the validity of the present results. Finally, the statistical inflation of false-positive Type-I errors due to multiple comparisons could not be perfectly excluded from the present results, although we only focused on the activation of ROIs that showed abnormal activation in the cross-sectional comparison with healthy controls and the 3 factor and total scores on SASS in the longitudinal analysis, based on our hypotheses. As the observed association between longitudinal changes in VLPFC/aTC regional activation and SASS scores did not survive a Bonferroni correction, we acknowledge that the present results must be considered exploratory with regard to proving this association. However, we believe the present NIRS measurements of ROI activation confirm reduced activation in bilateral VLPFC/aTC during cognitive tasks, and provide candidates in prefrontal and temporal regions whose longitudinal change in activation might reflect social functioning. Further studies with larger sample sizes are required to more conclusively demonstrate the relationship between longitudinal changes in VLPFC/aTC activation and social functioning.

4.4. NIRS as a biomarker for the longitudinal evaluation of social adaptation 6. Conclusion For clinical populations, improving social functioning is one of the most important goals of treatment. In addition, it would be useful to detect longitudinal changes in social adaptation objectively and independently of changes in symptom severity or mood state. Using NIRS, prefrontal and temporal regional activation may act as a biomarker of social functioning cross-sectionally in patients with depression (Pu et al., 2012a, 2012b). Several NIRS studies have examined longitudinal changes in prefrontal activation caused by medication (Nishimura et al., 2014) or psychological treatment (Ohtani et al., 2009), suggesting that NIRS can

The present study found the hypoactivation of bilateral VLPFC/ aTC regions during executive tasks using NIRS in patients with BD and MDD. Longitudinally, for patients with BD or MDD, increases in VLPFC/aTC activation were associated with improvement in social adaptation. Thus, NIRS may be a useful clinical tool for the objective evaluation of longitudinal changes in social adaptation in patients with BD and MDD during treatment. Furthermore, the present results support the relationship between prefrontal and temporal activation and social functioning.

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Role of funding source This study was supported by the Ministry of Health, Labour, and Welfare (Health and Labour Science Research Grants for Comprehensive Research on Disability Health and Welfare, H23-seishin-ippan-002 to YN and TO); an Intramural Research Grant (23-10) for Neurological and Psychiatric Disorders of NCNP (to YN and TO); the Clinical Research Fund of Tokyo Metropolitan Government (H26080302) to KT; and a Grant-in-Aid for Young Scientists (B) (26860915) to YN. These sponsors had not had any role in the design of the present study; in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit this paper for publication.

Conflict of interest Yuji Okazaki of Tokyo Metropolitan Matsuzawa Hospital has potential conflicts of interest in the submitted work. Tokyo Metropolitan Matsuzawa Hospital has had an official contract with the Hitachi Group (Advanced Research Laboratory, Hitachi, Ltd., and The Research and Developmental Center, Hitachi Medical Corporation) for a collaborative study of the clinical application of NIRS in psychiatric disorders. For this study, the Hitachi Group provided a project grant (JPY 300,000 per year). All other authors have no relevant conflicts of interest.

Acknowledgments We appreciate the participants of the study, and the cooperation of the staff at Tokyo Metropolitan Matsuzawa Hospital. In addition, we gratefully acknowledge the support of the Health and Labour Science Research Grants for Comprehensive Research on Disability Health and Welfare (H23-seishin-ippan-002 (TO and YN)); an Intramural Research Grant (2310) for Neurological and Psychiatric Disorders of NCNP (TO and YN); the Clinical Research Fund of Tokyo Metropolitan Government (H26080302) (KT); and a Grantin-Aid for Young Scientists (B) (26860915) (YN).

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