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ABSTRACT: Neurocognitive impairment is a feature of childhood chronic fatigue syndrome (CCFS). Several studies have demonstrated reduced attention control in CCFS patients in switching and divided attention tasks. In students, the extent of deterioration in task performance depends on the level of fatigue. Poor performance in switching and divided attention is common in both fatigued students and CCFS patients. Additionally, attentional functions show dramatic development from childhood to adolescence, suggesting that abnormal development of switching and divided attention may be induced by chronic fatigue. The brain structures associated with attentional control are situated in the frontal and parietal cortices, which are the last to mature, suggesting that severe fatigue in CCFS patients and students may inhibit normal structural and functional development in these regions. A combination of treatment with cognitive behavioral therapy and antidepressant medication is effective to improve attentional control processing in CCFS patients. Studies identifying the features of neurocognitive impairment in CCFS have improved our current understanding of the neurophysiological mechanisms of CCFS.
Frontiers in physiology. 01/2013; 4:87.
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ABSTRACT: Background: Development of the ability to divide attention is of crucial importance in the transitional period from elementary to junior high school. The relationship between divided attention and the prevalence of fatigue or low academic motivation is observed in junior high school students. In order to clarify the factors underlying decreased ability to divide attention, we examined the relationships between divided attention, as assessed by the kana pick-out test, lifestyle factors, and academic and family conditions in junior high school students. Methods: The study group consisted of 158 healthy 1st-, 2nd-, and 3rd-grade level junior high school students. Each participant performed the kana pick-out test and questionnaires dealing with lifestyle factors (nocturnal sleeping hours on school days, breakfast, exercise, watching television, and spending time with family members), and academic and family conditions (good friendships at school and praise from family members when participants showed good academic performance). Results: On multiple regression analyses adjusted for grade and gender, scores on the kana pick-out test were positively associated with spending time with family members. In addition, the comprehension score of the kana pick-out test was positively associated with having breakfast every day and praise by family members. The score was negatively associated with watching television. Conclusion: The present findings suggest that the ability to divide attention is independently associated with good lifestyles and academic and family conditions in junior high school students.
Brain & development 08/2012; · 1.74 Impact Factor
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ABSTRACT: The kana pick-out test has been widely used in Japan to evaluate the ability to divide attention in both adult and pediatric patients. However, the neural substrates underlying the ability to divide attention using the kana pick-out test, which requires participants to pick out individual letters (vowels) in a story while also reading for comprehension, thus requiring simultaneous allocation of attention to both activities, are still unclear. Moreover, outside of the clinical area, neuroimaging studies focused on the mechanisms of divided attention during complex story comprehension are rare. Thus, the purpose of the present study, to clarify the neural substrates of kana pick-out test, improves our current understanding of the basic neural mechanisms of dual task performance in verbal memory function. We compared patterns of activation in the brain obtained during performance of the individual tasks of vowel identification and story comprehension, to levels of activation when participants performed the two tasks simultaneously during the kana pick-out test. We found that activations of the left dorsal inferior frontal gyrus and superior parietal lobule increase in functional connectivity to a greater extent during the dual task condition compared to the two single task conditions. In contrast, activations of the left fusiform gyrus and middle temporal gyrus, which are significantly involved in picking out letters and complex sentences during story comprehension, respectively, were reduced in the dual task condition compared to during the two single task conditions. These results suggest that increased activations of the dorsal inferior frontal gyrus and superior parietal lobule during dual task performance may be associated with the capacity for attentional resources, and reduced activations of the left fusiform gyrus and middle temporal gyrus may reflect the difficulty of concurrent processing of the two tasks. In addition, the increase in synchronization between the left dorsal inferior frontal gyrus and superior parietal lobule in the dual task condition may induce effective communication between these brain regions and contribute to more attentional processing than in the single task condition, due to greater and more complex demands on voluntary attentional resources.
Neuropsychologia 05/2012; 50(8):1998-2009. · 3.64 Impact Factor
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ABSTRACT: Fatigue is a common complaint in modern society. As photosensitivity is associated with fatigue, this study aimed to clarify the relationship between neural response to visual stimuli and fatigue using a 160-channel whole-head-type magnetoencephalographic system. Twelve healthy male volunteers were enrolled. Participants were randomly assigned to two groups in a single-blinded, crossover fashion to perform acute fatigue-inducing mental task sessions, i.e., 0-back or 2-back test for 30 min. Visual evoked magnetic field (VEF) intensities were evaluated by standardized low-resolution brain electromagnetic tomography modified for a quantifiable method. VEF consisted of two phases, and although acute fatigue did not alter the VEF intensities and the intensities before the acute fatigue-inducing mental task sessions were not correlated with the Chalder's Fatigue Scale scores in either of the two phases, the intensities after the 0-back test trials for 30 min in Phase 1 and those after the 2-back test trials in Phase 2 were significantly correlated with the fatigue scale scores. The daily level of fatigue was related to VEF intensity after the acute mental fatigue loads. Our findings provide new perspectives to evaluate our daily level of fatigue as well as to clarify the neural mechanisms underlying it.
Brain research 04/2012; 1457:44-50. · 2.46 Impact Factor
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Shigeyuki Yamamoto,
Yasuomi Ouchi,
Daisaku Nakatsuka,
Tsuyoshi Tahara, Kei Mizuno,
Seiki Tajima,
Hirotaka Onoe,
Etsuji Yoshikawa,
Hideo Tsukada,
Masao Iwase,
Kouzi Yamaguti,
Hirohiko Kuratsune,
Yasuyoshi Watanabe
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ABSTRACT: Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(-)] autoantibodies.
Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[(11)C]methyl-3-piperidyl benzilate [(11)C](+)3-MPB for the mAChR binding and N-[(11)C]methyl-4-piperidyl acetate [(11)C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [(11)C](+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower [(11)C](+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the [(11)C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups.
The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.
PLoS ONE 01/2012; 7(12):e51515. · 4.09 Impact Factor
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ABSTRACT: Fatigue is a common complaint among elementary and junior high school students, and is known to be associated with reduced academic performance. Recently, we demonstrated that fatigue was correlated with decreased cognitive function in these students. However, no studies have identified cognitive predictors of fatigue. Therefore, we attempted to determine independent cognitive predictors of fatigue in these students.
We performed a prospective cohort study. One hundred and forty-two elementary and junior high school students without fatigue participated. They completed a variety of paper-and-pencil tests, including list learning and list recall tests, kana pick-out test, semantic fluency test, figure copying test, digit span forward test, and symbol digit modalities test. The participants also completed computerized cognitive tests (tasks A to E on the modified advanced trail making test). These cognitive tests were used to evaluate motor- and information-processing speed, immediate and delayed memory function, auditory and visual attention, divided and switching attention, retrieval of learned material, and spatial construction. One year after the tests, a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) was administered to all the participants.
After the follow-up period, we confirmed 40 cases of fatigue among 118 students. In multivariate logistic regression analyses adjusted for grades and gender, poorer performance on visual information-processing speed and attention tasks was associated with increased risk of fatigue.
Reduced visual information-processing speed and poor attention are independent predictors of fatigue in elementary and junior high school students.
Behavioral and Brain Functions 06/2011; 7:20. · 2.13 Impact Factor
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ABSTRACT: Fatigue is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance, we attempted to determine whether cognitive functions were associated with the prevalence of fatigue.
Participants were 148 elementary school students from 4th- to 6th-grades and 152 junior high school students from 7th- to 9th-grades. Participants completed a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) and paper-and-pencil and computerized cognitive tests which could evaluate the abilities of motor processing, immediate, delayed and working memory, selective, divided and alternative attention, retrieve learned material, and spatial construction.
We found that in multivariate logistic regression analyses adjusted for grade and gender, slow motor processing was positively correlated with the prevalence of fatigue in the elementary school students and decreases in working memory and divided and alternative attention processing were positively correlated with the prevalence of fatigue in the junior high school students.
The grade-dependent development of cognitive function influences the severity of fatigue in elementary and junior high school students.
Brain & development 06/2011; 33(6):470-9. · 1.74 Impact Factor
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ABSTRACT: When students proceed to junior high school from elementary school, rapid changes in the environment occur, which may cause various behavioral and emotional problems. However, the changes in cognitive functions during this transitional period have rarely been studied.
In 158 elementary school students from 4th- to 6th-grades and 159 junior high school students from 7th- to 9th-grades, we assessed various cognitive functions, including motor processing, spatial construction ability, semantic fluency, immediate memory, delayed memory, spatial and non-spatial working memory, and selective, alternative, and divided attention.
Our findings showed that performance on spatial and non-spatial working memory, alternative attention, divided attention, and semantic fluency tasks improved from elementary to junior high school. In particular, performance on alternative and divided attention tasks improved during the transitional period from elementary to junior high school.
Our finding suggests that development of alternative and divided attention is of crucial importance in the transitional period from elementary to junior high school.
Brain & development 05/2011; 33(5):412-20. · 1.74 Impact Factor
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ABSTRACT: Cognitive function was investigated in patients with childhood type chronic fatigue syndrome (CCFS) using the modified advanced trail making test (mATMT).
mATMT was performed on 19 patients with CCFS and 25 healthy controls of comparable age and sex. The effectiveness of combined treatment with cognitive behavioral therapy (CBT) and pharmacotherapy and its relationship to cognitive function was investigated by evaluation of Chalder's fatigue scale and behavior state before and after treatment for 6 consecutive months.
All three tasks (motor skill, selective and alternative attention, and spatial working memory) of the mATMT, especially the difference in reaction time of the alternative attention task, could discriminate CCFS patients from control subjects with 70.5% accuracy (P=0.007). CCFS patients showed significantly lower alternative attention and Chalder's fatigue score before treatment (P=0.037 and 0.002, respectively). A significant improvement in performance status scores was found during the 6 months follow-up period with combined treatment with CBT and medication (P<0.001). Improvement of their cognitive symptoms was significantly correlated with improvement of alternative attention (r=0.653, P=0.002).
Higher-order level cognitive dysfunction affects CCFS pathogenesis. Alternative attention performance evaluated by the mATMT may be used to monitor improvement in patients with CCFS. Combined treatment with CBT and medication may be effective to improve poor attention characteristics associated with CCFS.
Brain & development 04/2011; 33(10):832-41. · 1.74 Impact Factor
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ABSTRACT: Fatigue is a common symptom in both sick and healthy people. We examined autonomic nervous alterations associated with fatigue to clarify the mechanisms underlying fatigue.
The study group consisted of 19 healthy participants who performed a 2-back test for 30 min as a fatigue-inducing mental task session. Before and after the session, they completed the advanced trail making test (ATMT) for 30 min for mental fatigue evaluation, subjective scales to measure fatigue sensation, and underwent electrocardiography to allow assessment of autonomic nerve activities.
After the fatigue-inducing task, the total error counts on the ATMT tended to increase (P = 0.076); the ATMT for total trial counts (P = 0.001), the subjective level of fatigue (P < 0.001), and the % low-frequency power (%LF) (P = 0.035) increased significantly; and the % high-frequency power (%HF) decreased compared with before the fatigue-inducing task although this did not reach the statistical significance (P = 0.170). Although LF measured in absolute units did not change significantly before and after the fatigue-inducing task (P = 0.771), and HF measured in absolute units decreased after the task (P = 0.020). The %LF and LF/HF ratio were positively associated with the daily level of fatigue evaluated using Chalder's fatigue scale. In addition, %HF was negatively associated with the fatigue score.
Increased sympathetic activity and decreased parasympathetic activity may be characteristic features of both acute and daily levels of fatigue. Our findings provide new perspectives on the mechanisms underlying fatigue.
Behavioral and Brain Functions 01/2011; 7:46. · 2.13 Impact Factor
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ABSTRACT: Decrease in intrinsic motivation is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance by these students, we examined whether cognitive functions are related to the prevalence of decrease in intrinsic academic motivation.
The study group consisted of 134 elementary school students from 4th to 6th grades and 133 junior high school students from 7th to 9th grades. Participants completed a questionnaire on intrinsic academic motivation. They also performed paper-and-pencil and computerized cognitive tests to measure abilities in motor processing, spatial construction, semantic fluency, immediate memory, short-term memory, delayed memory, spatial working memory, and selective, alternative, and divided attention.
In multivariate logistic regression analyses adjusted for grade and gender, scores of none of the cognitive tests were correlated with the prevalence of decrease in intrinsic academic motivation in elementary school students. However, low digit span forward test score and score for comprehension of the story in the kana pick-out test were positively correlated with the prevalence of decrease in intrinsic academic motivation in junior high school students.
The present findings suggest that decrease in capacity for verbal memory is associated with the prevalence of decrease in intrinsic academic motivation among junior high school students.
Behavioral and Brain Functions 01/2011; 7:4. · 2.13 Impact Factor
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ABSTRACT: It is known that chronic fatigue is associated with sympathetic hyperactivity. However, the relationship between autonomic function and mental fatigue caused by a prolonged mental load in healthy humans is still unclear. Thus, in order to clarify the mechanisms underlying mental fatigue, we examined the association between mental fatigue and autonomic functions.
The study group comprised 10 healthy participants. To induce mental fatigue, participants performed mental tasks, which consisted of the advanced trail making test, kana pick-out test and mirror drawing test, for 8 hr, corresponding to a normal work day. Autonomic functions were measured by accelerated plethysmography before and after the fatigue-inducing mental tasks. As a control, the same participants completed an 8-hr relaxation session 4 weeks before the fatigue session.
After the 8-hr relaxation session, low-frequency component power (LF), high-frequency component power (HF) and low-frequency component power/high-frequency component power ratio (LF/HF ratio) were not changed from baseline. In contrast, after the fatigue session, the HF and LF/HF ratio were significantly changed from baseline; specifically, the HF was lower and LF/HF ratio was higher as compared to those after the relaxation session.
Sympathetic hyperactivity based on decreased parasympathetic activity is associated with mental fatigue induced by prolonged cognitive load.
Behavioral and Brain Functions 01/2011; 7:17. · 2.13 Impact Factor
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ABSTRACT: Among medical students, fatigue is a common complaint and is related to poor academic outcomes. Associations of scores on personality traits and fatigue in medical students were examined. A group of 125 healthy second-year medical students completed a questionnaire about fatigue, the Japanese version of the Chalder Fatigue Scale, and the Temperament and Character Inventory. On simple regression analyses, the Temperament and Character Inventory dimension of Harm Avoidance was positively associated with Fatigue scores and those on Self-directedness were negatively associated. Similarly, on multiple regression analyses adjusted for age and sex, scores on the Temperament and Character Inventory dimension of Harm Avoidance were positively associated with Fatigue scores, and those for Self-directedness were negatively associated. These correlations were evident even after adjustment for other Temperament and Character Inventory dimensions. The temperament dimension of Harm Avoidance and the character dimension of Self-directedness were both associated with Fatigue in medical students.
Psychological Reports 04/2010; 106(2):567-75. · 0.44 Impact Factor
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ABSTRACT: Bathing in hot water is very common in Japan; people bathe in order to clean their bodies and to recover from physical and mental fatigue. However, there have been few reports examining the effects of bathing on recovery from mental fatigue. The purpose of this study was to examine the effects of mild-stream bathing on recovery from mental fatigue.
During mild-stream bathing, a mild stream continuously passes from the sole to the calf, thigh, waist and back, thus providing a massage function. In a double-blinded, placebo-controlled, crossover experiment, 14 male healthy volunteers were randomized into normal bathing and mild-stream bathing experiments. After a fatigue-inducing mental task for 4 hours, subjects took a normal or mild-stream bath.
Heart rate was higher, muscle stiffness in the waist was lower and plasma cortisol levels tended to be lower after mild-stream bathing when compared to normal bathing. In addition, after mild-stream bathing, mental task performance, as assessed by reaction times on an advanced trail making test, was better than that after normal bathing.
The present results suggest that improved working memory processing, diminished waist muscle tone, and attenuated mental stress are induced by mild-stream bathing. Therefore, mild-stream bathing appears to be more effective for alleviating mental fatigue than normal bathing.
Medical science monitor: international medical journal of experimental and clinical research 01/2010; 16(1):CR8-14. · 1.70 Impact Factor
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Satoshi Nozaki,
Hiroshi Mizuma,
Masaaki Tanaka,
Guanghua Jin,
Tsuyoshi Tahara, Kei Mizuno,
Masanori Yamato,
Kaori Okuyama,
Asami Eguchi,
Kouji Akimoto,
Takahito Kitayoshi,
Noriko Mochizuki-Oda,
Yosky Kataoka,
Yasuyoshi Watanabe
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ABSTRACT: Impaired energy metabolism is considered a possible cause of fatigue. The thiamine derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is prescribed and is also an over-the-counter drug for the attenuation of fatigue. It is readily absorbed from the intestinal tract and converted into thiamine pyrophosphate (TPP), which plays an important role as a cofactor for enzymes of metabolic pathways involved in the production of adenosine triphosphate (ATP). We postulated that TTFD has an anti-fatigue effect by improving energy metabolism during physical-fatigue loading. Here, we initially used the forced swimming test to determine whether daily TTFD or thiamine for 5 days has anti-fatigue effects on weight-loaded rats. The swimming duration of TTFD-, but not of thiamine-treated rats, was significantly longer than that of control rats (P < .05). Based on these findings, we examined changes in the levels of thiamine and its phosphate esters in various organs and the effect of TTFD on ATP levels in skeletal muscle after forced swimming, to determine the cellular mechanisms of the anti-fatigue effect of TTFD. Daily TTFD resulted in a characteristic distribution of thiamine and its phosphate esters in rat skeletal muscle, liver, kidney, heart, brain, and plasma. Furthermore, daily TTFD attenuated the decrease in ATP content in the skeletal muscle caused by forced swimming with a weight load for a defined period (150 s). These results indicate that TTFD exerts anti-fatigue effects by improving energy metabolism during physical fatigue.
Nutrition research (New York, N.Y.) 12/2009; 29(12):867-72. · 1.20 Impact Factor
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ABSTRACT: Motivation is one of the most important psychological concepts in education and is related to academic outcomes in medical students. In this study, the relationships between personality traits and intrinsic academic motivation were examined in medical students.
The study group consisted of 119 Year 2 medical students at Osaka City University Graduate School of Medicine. They completed questionnaires dealing with intrinsic academic motivation (the Intrinsic Motivation Scale toward Learning) and personality (the Temperament and Character Inventory [TCI]).
On simple regression analyses, the TCI dimensions of persistence, self-directedness, co-operativeness and self-transcendence were positively associated with intrinsic academic motivation. On multiple regression analysis adjusted for age and gender, the TCI dimensions of persistence, self-directedness and self-transcendence were positively associated with intrinsic academic motivation.
The temperament dimension of persistence and the character dimensions of self-directedness and self-transcendence are associated with intrinsic academic motivation in medical students.
Medical Education 05/2009; 43(4):384-7. · 3.18 Impact Factor
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Hiroshi Mizuma,
Masaaki Tanaka,
Satoshi Nozaki, Kei Mizuno,
Tsuyoshi Tahara,
Suzuka Ataka,
Tomohiro Sugino,
Tomoko Shirai,
Yoshitaka Kajimoto,
Hirohiko Kuratsune,
Osami Kajimoto,
Yasuyoshi Watanabe
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ABSTRACT: This study compared the effects of placebo with a carotenoid compound, crocetin, as well as an antioxidant, ascorbic acid, on physical fatigue in humans. In this double-blind, placebo-controlled, 3-way crossover study, 14 Japanese healthy volunteers (7 men and 7 women) were randomized to oral administration of crocetin (15 mg), ascorbic acid (3,000 mg), or placebo for 8 days. Subjects performed workload tests on a bicycle ergometer at fixed workloads for 120 minutes at 2 times (a total of 240 minutes) as a fatigue-inducing physical task. During the physical task, subjects performed nonworkload tests at maximum velocity (MV) of 10 seconds at 30 minutes (30-minute test) after the start of the physical task and at 30 minutes before the end of the task (210-minute test). The change in MV from the 30- to the 210-minute test was significantly higher in men who received crocetin compared with men who received placebo (P < .05). This effect of crocetin was specific to males. Administration of ascorbic acid did not change in MV from the 30-minute to the 210-minute test on males or females. These results suggest that daily administration of crocetin may attenuate physical fatigue in men.
Nutrition research (New York, N.Y.) 04/2009; 29(3):145-50. · 1.20 Impact Factor
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ABSTRACT: Fatigue can be classified as physical or mental, depending on its cause. In physical fatigue, changes in the plasma levels of some amino acids have been reported. However, complex fatigue, which is experienced in daily life, is a combination of physical and mental fatigue. We aimed to identify changes in amino acid levels in the plasma, skeletal muscle, liver, and brain in an animal model of complex fatigue.
Rats were kept in a cage filled with water to a height of 2.2 cm for 5 d. Because rats showed a reduction of body weight when the model was developed, we also included a food-restricted group showing a similar profile in weight reduction as the water-immersed rats. A non-treated control group was also included.
Results indicated that levels of branched-chain amino acids (valine, leucine, and isoleucine) were increased in plasma (valine, leucine, and isoleucine; P < 0.01), skeletal muscle (valine, leucine, and isoleucine; P < 0.01), the liver (valine; P < 0.05), and brain (isoleucine; P < 0.05), whereas a reduction in other amino acid levels (total amino acids and glutamine in the plasma, skeletal muscle, and liver; and phenylalanine, tyrosine, arginine, and threonine in the brain; P < 0.01) was seen in animals with complex fatigue.
Complex fatigue may bring about systemic changes in amino acid metabolism in multiple organs.
Nutrition 02/2009; 25(5):597-607. · 3.03 Impact Factor
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ABSTRACT: Fatigue is a common symptom in modern society. In order to clarify the mechanisms underlying fatigue, we examined the association between central nervous system fatigue and autonomic nerve activity.
The study group consisted of 20 healthy subjects. They performed the 2-back test for 30 min to induce fatigue. Just before and after the fatigue-inducing session, they completed the advanced trail making test (ATMT) for 30 min as a fatigue-evaluating task session. In order to measure autonomic nerve activity, electrocardiograms were monitored continuously throughout the experiment.
After the fatigue-inducing task session, impaired task performance was demonstrated based on the total trial number and error counts of the ATMT. During the task session, although task performance as measured using the accuracy and the mean reaction time of the 2-back test was almost unchanged, electrocardiographic R-R wave interval analyses showed a decreased high-frequency component power and an increasing trend in the low-frequency component power/high-frequency component power ratio.
Decreased vagal nerve activity and increased sympathetic nerve activity are associated with central nervous system fatigue.
Life Sciences 01/2009; 84(7-8):235-9. · 2.53 Impact Factor
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ABSTRACT: In the present study, the reliability and construct validity of the Japanese version of the Chalder Fatigue Scale was evaluated as a measure of severity of fatigue among young students in Japan. A healthy group comprised 27 Grade 6 primary school students and 28 Grade 1 junior high school students. The severely fatigued group were hospital outpatients with childhood chronic fatigue syndrome (n = 21). Principal components analysis with varimax rotation identified 4 factors which accounted for 63.2% of the total variance, as in the original English version. Internal consistency (Cronbach coefficient alpha) was .73, and test-retest reliability measured using Spearman rank correlation coefficient was .55. Scale scores of the healthy subjects were lower than those of the patients with childhood chronic fatigue syndrome. The reliability (alpha) and construct validity of the Japanese version of the scale among healthy students in Japan were satisfactory for research studies among healthy school students.
Psychological Reports 01/2009; 103(3):682-90. · 0.44 Impact Factor
