Correlation of prefrontal activity measured by near-infrared spectroscopy (NIRS) with mood, BDNF genotype and serum BDNF level in healthy individuals

Daisuke Matsuzawa, Kotaro Takeda, Hiroyuki Ohtsuka, Jun Takasugi, Takashi Watanabe, Junko Maeda, Saeka Nagakubo, Chihiro Sutoh, Ichiro Shimoyama, Ken Nakazawa, Eiji Shimizu

Clinical Research Center, National Hospital Organization Murayama Medical Center, Tokyo, Japan.
Department of Cognitive Behavior Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Section for Human Neurophysiology, Frontier Medical Engineering, Chiba University, Chiba, Japan.

DOI: 10.4236/ojpsych.2012.23025                

Abstract

Depression has been known to reduce the prefrontal activity associated with the execution of certain cognitive tasks, although whether a temporarily depressed or anxious mood in healthy individuals affects the prefrontal blood oxygen level during cognitive tasks is unknown. Combining the measurement of prefrontal activity with near-infrared spectroscopy (NIRS) and the two cognitive tasks, namely the letter version of the verbal fluency test (VFT-l) and the Stroop test, we measured the effect of a depressed or anxious mood and gender on the changes in the prefrontal oxygenated hemoglobin (Oxy-Hb) levels during those cognitive tests in healthy individuals. Depressed mood or anxious mood was assessed by the Hospital Anxiety and Depression Scale (HADS). Thereby we aimed to explore the possibility of NIRS measurement for detecting the early subclinical manifestation of major depression. Moreover, we examined the possible relationships between prefrontal activation and the functional Val66Met polymorphisms of the brain derived neurotropic factor (BDNF) gene and serum BDNF level. As a result, the increased prefrontal Oxy-Hb levels during cognitive tasks were significantly correlated with the severity of depressed mood in males. The course of the prefrontal Oxy-Hb increase was different depending on the cognitive tasks, i.e., the VFT-l or the Stroop test, in both genders. Correlations of BDNF genotype and serum BDNF level with the prefrontal Oxy-Hb levels during those cognitive tasks were negative. Our results suggest that the early subclinical manifestation of depressed mood in males might be detected by the NIRS measurement, which is not correlated with the individual properties of BDNF.

Keywords

Near-Infrared Spectroscopy (NIRS); Depression; Anxiety; Brain Derived Neurotropic Factor (BDNF)

1. INTRODUCTION

Depression is a common psychiatric disease and results in considerable social-economic burdens due to loss of productivity [1-3]. Thus, the prevention of depression with early detection and intervention is critically important for those exposed to chronic stress because of its potential to induce depression in some individuals [4,5].

Near-infrared spectroscopy (NIRS) is a non-invasive method of measuring the relative change in the concentrations of oxygenated and deoxygenated hemoglobin (Δ [Oxy-Hb]) and Δ [DeOxy-Hb], respectively), which are closely correlated to the neural activity of the brain [6]. Using this technique, altered prefrontal activation has been reported in various psychiatric diseases such as schizophrenia, major depression, bipolar disorder and anxiety disorder [7]. In the case of major depression, a reduced increase of the dorsolateral prefrontal Oxy-Hb level compared to healthy controls during the letter version of the Verbal Fluency Test (VFT-l-l) as determined by the measurement of NIRS has been reported repeatedly [8-10]. However, it has not been clarified whether a temporarily depressed or anxious mood in healthy individuals affects the frontal blood oxygen level during cognitive tasks. Given that one of the main symptoms of major depression is depressive mood, it is a matter of concern whether prefrontal activations could be affected by such a mood. In addition, several lines of evidence have shown that there exist gender differences in the prevalence, comorbidity, and symptom presentation pattern in major depression [11], thus, early manifestations of the disease might be different between the genders, and these differences might be observed in the altered prefrontal activation measured by NIRS.

Brain derived neurotrophic factor (BDNF), the most abundant neurotrophic factor in the human brain, plays important roles in the survival, development, and proliferation of the central and peripheral neurons [12,13]. A functional polymorphism of the BDNF gene, an amino acid substitution of a valine for a methionine at codon 66 (Val66Met) as a single nucleotide polymorphism (SNP), has been suggested to be associated with the performance of episodic memory in schizophrenia patients [14] as well as healthy control subjects [14,15], and with the performance of prefrontal cognitive tasks in bipolar disorder [16]. In addition, accumulating evidence suggests that serum BDNF level, which likely reflects brain BDNF level, is altered in mood disorders such as depression. Serum BDNF level has been reported to be associated with depression severity [17] and has been observed to be increased after antidepressant treatment in depressed patients [18-20]. One of the personally traits, neuroticism in the NEO-five factor inventory (NEO-FFI), which is considered to be a marker of depression, appeared to have a negative correlation with serum BDNF level in healthy humans [21]. Taken together, these findings suggest that prefrontal activation is potentially correlated with each individual’s BDNF profile, but to date no NIRS study has been conducted to assess this potential correlation.

In the present study, we examined the correlation of changes in the prefrontal Oxy-Hb levels measured by NIRS during cognitive tasks with depressed or anxious mood, gender, Val66Met polymorphisms of the BDNF gene and serum BDNF level in basically healthy individuals. Thereby we aimed to explore the possibility of using NIRS measurement to detect early subclinical manifestations of major depression or anxiety disorder.

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2. MATERIALS AND METHODS

2.1. Subjects and Blood Samples

The research was performed after the study was approved by the ethics committee of Chiba University Graduate School of Medicine and Chiba Prefectural College of Allied Medical Science. All of the subjects were the students of Chiba Prefectural College of Allied Medical Science. Subjects were well explained about the experiments, and written informed consent was obtained. Thirty eight healthy volunteers (female = 17, male = 20, mean age = 22.6 ± SD 3.7, range = 19 - 31) were enrolled in the NIRS study. None of them had past history of psychotic disorders of the DSM-IV axis I or II, neurological disorders, drug dependence, and any major physical illness. One female subject was excluded from the following analyses because of developing depression which needed medical service three months after the NIRS measurements. All except one male subject were righthanded. Whole blood samples for extracting DNA and serum samples for BDNF measurement were collected from 30 of those 37 subjects (female = 13, male = 17) between 11:00-12:00 AM and stored at −80˚C.

2.2. Assessment of Metal Status with HADS

Hospital Anxiety and Depression Scale (HADS) was used to assess subjects’ mental status. HADS is a selfreport screening scale that was developed to indicate the possible presence of anxiety and depression states in hospital and medical outpatient clinic settings. HADS consists of a seven-item anxiety subscale and a sevenitem depression subscale. Each item is scored on a four-point scale, giving maximum subscale scores of 21 for depression and anxiety, respectively. Cut-off scores were recommended as ≥8 for possible anxiety or depression in the original study [22]. Self-assessment of HADS was conducted blind to the experimenter of NIRS (H.O. and J.T.), BDNF measurement and genotyping (D.M.). In addition, analysis of HADS score was performed after all the other results were obtained in order to keep subjects’ mental status blind to those measurements. Some of them reached ≥8 in the scores of depression and anxiety subscales of HADS, but it was because the study was done right before the semester final examination, and none of them met the criteria of any mental illnesses in DSM-IV [23] when the NIRS measurement and blood collection were conducted. Thus, their mental statuses were assumed as healthy overall, even though temporal depressed or anxiety moods were existed.

2.3. NIRS Study

2.3.1. NIRS Recordings

NIRS recordings were performed using a multichannel optical topography system (FOIRE-3000, Shimadzu Co., Japan). Eleven light-emission and ten light-detection probes were arranged in a 3 × 7 rectangular lattice. Each recording channel consisted of one light-emission probe and one light-detection probe located 3 cm away from each other. A head shell that mounted the 21 probes for 32 recording channels was placed securely on the scalp overlying mainly the prefrontal area. The light-detection probe between channels No.3 and No.4 was located on Fz of the international 10 - 20 system (Figure 1(a)).

Figure 1. Probe setting and typical courses of the Oxyand DeOxy-Hb change during the tasks. (a) 21 probes for 32 recording channels were placed securely on the scalp overlying mainly the prefrontal area. The light-detection probe between channels No.3 and No.4 was located on Fz of the international 10 - 20 system. Eleven light-emission and ten light-detection probes were arranged in a 3 × 7 rectangular lattice. Each recording channel consisted of one light-emission probe and one light-detection probe located 3 cm away from each other; (b), (c) Typical courses of the Oxy-Hb (red line) and DeOxy-Hb (blue line) change during the two tasks, VFT-l (b) and Stroop test (c).

2.3.2. Cognitive Tasks for NIRS Recording

Prefrontal activities were recorded during the letter version of verbal fluency test (VFT-l) and Stroop tasks. For NIRS recording, each cognitive task was consisted of a 30 s pre-task baseline period, a 60 s task period, and a 60 s post-task baseline period. Instruction cues for each task were displayed on a 22-inch monitor connected to a laptop personal computer placed approximately 1 meter in front from the subject who was sitting on a comfortable chair.

The VFT-l was carried out according to the previous studies [10,24]. In briefly, during the task period, subjects were instructed to produce orally as many words that began with the cue as possible. During the task period, Three Japanese letters (/a/, /ka/, and /sa/) were presented on the display as cues in turn every 20 s. During the preand post-task baseline periods, the subjects were instructed to repeat the syllables /a/, /i/, /u/, /e/, and /o/.

To assess the Stroop effect [25], a list of color names (blue, yellow, red, and green, written in Japanese Kanji characters), which were printed in a color not denoted by the name, was presented during the task period, and a list of color dots (blue, yellow, red, and green) was presented during the preand post-task baseline periods. A set of 24 dots/words was presented consecutively on the display. The subjects were instructed to name the ink color in which the dots/words were presented as quickly as possible and explicitly not to read the words. The investigator recorded the number of correct and incorrect verbal responses.

2.3.3. NIRS Data Analyses

Three near-infrared laser beams (wavelengths at 780, 805, and 830 nm) were emitted, and reflectance beams sampled at a 175-ms sampling interval were used to calculate Δ[Oxy-Hb] and Δ[DeOxy-Hb]. The linear trends of the continuous Δ[Oxy-Hb] and Δ[DeOxy-Hb] fluctuations were removed and smoothed with a five-point moving average. In the present study, we mainly report the Δ [Oxy-Hb] results because it may be the most sensitive parameter among hemodynamic responses [26]. Many previous NIRS studies calculated a z score in each recording channel for comparison among subjects or among recording channels [27-29], therefore, we also used the z score for comparison. In the present study, the z score was calculated in each recording channel as follows: the mean Δ[Oxy-Hb] value during the task period (30 - 60 s after task onset) versus that during a 30-s pre-task baseline period was divided by the standard deviation (SD) of Δ[Oxy-Hb] during the pre-task period. The signal processing was performed using MATLAB 7.5.0 (MathWorks, Natick, MA, USA). The significance level of Δ[Oxy-Hb] was set at z > 3.163, which reached the two-sided Bonferroni corrected significance level (p < −0.05). This calculation method for the significance level is similar to that used in previous NIRS studies [28, 29]. The mean z score of Δ[Oxy-Hb] over all channels was analyzed to measure the signal intensity, and the number of channels with a significant Δ[Oxy-Hb] was analyzed to measure the extent of cerebral activation. Typical courses of the change in Oxyand DeOxy-Hb during the two tasks, namely the VFT-l and the Stroop test, are shown in Figures 1(b) and (c), respectively.

2.4. Genotyping

The genomic DNA was extracted from peripheral leukocytes by standard procedures. Polymerase chain reaction (PCR) and the PCR-based restriction fragment length polymorphism (RFLP) assay were performed to genotype the DNA sequence variants of the BDNF gene as reported previously [30]. The primer sequences were forward: 5-GGTGAGAAGAGTGATGACCA-3 and reverse: 5-GCCAGCCAATTCTCTCTTTTT-3. The PCR products were digested at 37˚C with restriction enzyme PmaC I (Takara Shuzo Ltd., Kyoto, Japan), followed by 2% agarose gel-electrophoresis with ethidium bromide staining. After testing the Hardy-Weinberg equilibrium for genotype frequencies (Val/Val, Val/Met and Met/Met), subjects were divided by two groups, Val/Val and Met carrier (Val/Met and Met/Met) group.

2.5. Serum BDNF Measurements

Serum BDNF levels were measured using the BDNF Emax Immunoassay System kit (Promega, Madison, WI) according to the manufacturer’s instructions. Briefly, 96- well plates were coated with anti-BDNF monoclonal antibody and incubated at 4˚C for 18 hours. The plates were incubated in a blocking buffer for 1 hour at room temperature. The samples and BDNF standards were maintained at room temperature under conditions of shaking for 2 hours, followed by washing with the appropriate washing buffer. The plates were incubated with antihuman BDNF polyclonal antibody at room temperature for 2 hours, washed, and incubated with anti-IgY antibody conjugated to horseradish peroxidase for 1 hour at room temperature. The plates were incubated in peroxidase substrate and tetramethylbenzidine solution to produce a color reaction. The reaction was stopped with 1 mol/L hydrochloric acid, the absorbance at 450 nm was measured with an Emax automated microplate reader (Molecular Devices, Tokyo, Japan).

2.6. Statistical Analysis

All the calculations were performed with SPSS software (SPSS version 17.0J, Tokyo, Japan). Student’s t-test (two-tailed) was employed for each comparison of NIRS measurements and BDNF levels between the genders, and BDNF Val66Met genotypes. Spearman’s correlation coefficients were examined to identify the correlation of the intensity of the Oxy-Hb increase during the tasks with the genders, and with the serum BDNF level. The Hardy-Weinberg equilibrium for genotype frequencies was calculated using chi-square test. A value of p < 0.05 was used as the standard for statistical significance in all the analyses.

3. RESULTS

3.1. Scores of HADS and Cognitive Tasks between the Gender

The mean HADS scores and the cognitive task performance of males and females were summarized in Table 1. As is shown, none of the valuables was significantly different between the genders..

3.2. Gender Difference in the Prefrontal Activity

Table 2 shows the gender difference in the prefrontal activity. As shown, the mean z scores of Δ [Oxy-Hb] over all channels during the VFT-l were 6.52 ± 4.8 in males and 2.85 ± 2.1 in females. These results were significantly different between the genders (t = 2.95, p < 0.007). In addition, the mean number of channels with a significant increase in Δ [Oxy-Hb] during the VFT-l was significantly different between the genders, 19.1 ± 8.1 in

Conflicts of Interest

The authors declare no conflicts of interest.

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