Low putamen activity associated with poor reward sensitivity in childhood chronic fatigue syndrome.

Motivational signals influence a wide variety of cognitive processes and components of behavioral performance. Cognitive dysfunction in patients with childhood chronic fatigue syndrome (CCFS) may be closely associated with a low motivation to learn induced by impaired neural reward processing. However, the extent to which reward processing is impaired in CCFS patients is unclear. The aim of the present functional magnetic resonance imaging (fMRI) study was to determine whether brain activity in regions related to reward sensitivity is impaired in CCFS patients. fMRI data were collected from 13 CCFS patients (mean age, 13.6 ± 1.0 years) and 13 healthy children and adolescents (HCA) (mean age, 13.7 ± 1.3 years) performing a monetary reward task. Neural activity in high- and low-monetary-reward conditions was compared between CCFS and HCA groups. Severity of fatigue and the reward obtained from learning in daily life were evaluated by questionnaires. Activity of the putamen was lower in the CCFS group than in the HCA group in the low-reward condition, but not in the high-reward condition. Activity of the putamen in the low-reward condition in CCFS patients was negatively and positively correlated with severity of fatigue and the reward from learning in daily life, respectively. We previously revealed that motivation to learn was correlated with striatal activity, particularly the neural activity in the putamen. This suggests that in CCFS patients low putamen activity, associated with altered dopaminergic function, decreases reward sensitivity and lowers motivation to learn.

Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome.

The ability to divide one's attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging. Patients exhibited a much larger area of activation, recruiting additional frontal areas. The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension. In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively. Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.

Temporal organization of rest defined by actigraphy data in healthy and childhood chronic fatigue syndrome children.

BACKGROUND: Accumulating evidence has shown a universality in the temporal organization of activity and rest among animals ranging from mammals to insects. Previous reports in both humans and mice showed that rest bout durations followed long-tailed (i.e., power-law) distributions, whereas activity bouts followed exponential distributions. We confirmed similar results in the fruit fly, Drosophila melanogaster. Conversely, another report showed that the awakening bout durations, which were defined by polysomnography in bed, followed power-law distributions, while sleeping periods, which may correspond to rest, followed exponential distributions. This apparent discrepancy has been left to be resolved. METHODS: Actigraphy data from healthy and disordered children were analyzed separately for two periods: time out of bed (UP period) and time in bed (DOWN period). RESULTS: When data over a period of 24 h were analyzed as a whole, rest bouts showed a power law distribution as previously reported. However, when UP and DOWN period data were analyzed separately, neither showed power law properties. Using a newly developed strict method, only 30% of individuals satisfied the power law criteria, even when the 24 h data were analyzed. The human results were in contrast to the Drosophila results, which revealed clear power-law distributions for both day time and night time rest through the use of a strict method. In addition, we analyzed the actigraphy data from patients with childhood type chronic fatigue syndrome (CCFS), and found that they showed differences from healthy controls when their UP and DOWN data were analyzed separately. CONCLUSIONS: These results suggested that the DOWN sleep, the bout distribution of which showed exponential properties, contributes to the production of long-tail distributions in human rest periods. We propose that separate analysis of UP and DOWN period data is important for understanding the temporal organization of activity.

No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents.

BACKGROUND: Identification of gene × environment interactions (G × E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin-regulating genes. METHODS: This study was designed to ascertain the G × E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother's history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients' depression symptoms. RESULTS: Binary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression. CONCLUSIONS: To assess G × E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects.

Cognitive dysfunction and mental fatigue in childhood chronic fatigue syndrome--a 6-month follow-up study.

OBJECTIVES: Cognitive function was investigated in patients with childhood type chronic fatigue syndrome (CCFS) using the modified advanced trail making test (mATMT). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Effort-reward imbalance for learning is associated with fatigue in school children.

We examined relationships among fatigue, sleep quality, and effort-reward imbalance for learning in school children. We developed an effort-reward for learning scale in school students and examined its reliability and validity. Self-administered surveys, including the effort reward for leaning scale and fatigue scale, were completed by 1,023 elementary school students (grades 4-6) and 1,361 junior high school students (grades 7-9) at the end of 2006. Effort-reward imbalance for learning was associated with a high incidence of fatigue and sleep problems in elementary and junior high school students of both genders. A good relationship with family was associated with a low fatigue score in junior high school boys, and a good relationship with friends was associated with a low fatigue score in junior high school girls by multiple regression analysis. Fatigue score was associated with effort-reward imbalance and fatigue and quality of sleep in schoolchildren. Fatigue may lead to a decline in school performance, negative health outcomes, or refusal to attend school. These results suggest that it is desirable to consider social support, quality of sleep, and effort-reward imbalance when managing fatigue in school children.

Temperament and character as predictors of fatigue-induced symptoms among school children in Japan: a 1-year follow-up study.

OBJECTIVE: This 1-year follow-up study was performed to examine the association of temperament and character dimensions with new onset of fatigue-induced symptoms among school children in Japan, focusing on the transition from childhood to early adolescence. METHOD: This study prospectively reviewed data from 1512 school children from four elementary and four junior high schools in Japan. The survey was conducted in 2006 and 2007. Multivariate logistic regression analyses were performed to examine the association of psychological dimensions, assessed by the Junior Temperament and Character Inventory, with fatigue-induced symptoms. RESULTS: The correlation between temperament and character dimensions with new-onset of fatigue-induced symptoms differed as the students advanced into higher grades. In terms of physical symptoms in males, traits correlated with fatigue-induced symptoms included Novelty Seeking (headaches OR, 1.36; 95% CI, 1.07-1.73) or Reward Dependence (extreme tiredness OR, 1.84; 95% CI, 1.09-3.12; muscle weakness OR, 2.32; 95% CI, 1.28-4.20) during elementary school, whereas in females, Novelty Seeking was mainly associated with both physical (morning fatigue OR, 1.40; 95% CI, 1.10-1.77; headaches OR, 1.22; 95% CI, 1.04-1.43) and mental (mood changes OR, 1.30; 95% CI, 1.09-1.56) symptoms. Among ninth graders, more mental symptoms of fatigue were associated with Harm Avoidance (males, poor motivation OR, 1.20; 95% CI, 1.02-1.42; females, mood changes OR, 1.25; 95% CI, 1.06-1.49) and Self Directedness (males, poor motivation OR, 0.75; 95% CI, 0.59-0.96; females, difficulty thinking OR, 0.78; 95% CI, 0.62-0.98). CONCLUSION: Confirmation that the correlation between personality traits and fatigue-induced symptoms changes with grade at school has implications for screening susceptible children and adolescents and may help prevent the occurrence of such symptoms at an early stage.

Metabolic dysfunction and circadian rhythm abnormalities in adolescents with sleep disturbance.

BACKGROUND: Sleep disturbance attributable to circadian rhythm abnormalities frequently occurs in previously healthy children and adolescents who often complain of gastrointestinal discomfort after meals. METHODS: Glucose metabolism, autonomic function, and human clock gene expression in whole blood cells were investigated in 18 adolescent patients with circadian rhythm sleep disorder. RESULTS: Glucose tolerance was significantly lower in the patients than in normal controls: the mean sigma blood glucose level was significantly higher (P<0.05) and the insulinogenic index was significantly lower (P<0.05) in the patient group than in controls. Messenger ribonucleic acid level of hPer2 was significantly higher at 6:00 in the control subjects, but in only 3 of the 18 patients. Component analysis of cardiographic R-R interval revealed that high-frequency component peaks were suppressed significantly in the patient group compared to the controls (P<0.001). CONCLUSIONS: Metabolic and endocrine dysfunctions were identified in adolescents with sleep disturbance as decreased glucose tolerance and absence of human clock gene regulation in whole blood cells. Their brain dysfunction attributable to sleep disturbances might cause such peripheral autonomic imbalance and carbohydrate metabolic dysfunction.

Reliability and validity of the Japanese version of the Chalder Fatigue Scale among youth in Japan.

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.

Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder.

In recent years, circadian rhythm sleep disorders in humans have been increasing. Clinical features characteristic of this disorder are well known, but the specific causes remain unknown. However, various derangements of circadian expression of the clock gene are a probable cause of this disease. We have attempted to elucidate the relationship between the expression of the clock genes in whole blood cells and the clinical features characteristic of this disorder. In this study, we indicate the daily expression of clock genes period (Per) 1, 2, 3, Bmal1, and Clock in whole blood cells in 12 healthy male subjects. The peak phase of Per1, Per2, and Per3 appeared in the early morning, whereas that of Bmal1 and Clock appeared in the midnight hours. Furthermore, in one patient case with circadian rhythm sleep disorder, we observed variations of the peak phase in clock genes by treatments such as light therapy, exercise therapy, and medicinal therapy. This study suggested that the monitoring of human clock genes in whole blood cells, which may be functionally important for the molecular control of the circadian pacemaker as well as in suprachiasmatic nucleus, might be useful to evaluate internal synchronization.

Case study: differences in human Per2 gene expression, body temperature, cortisol, and melatonin parameters in remission and hypersomnia in a patient with recurrent hypersomnia.

Recurrent hypersomnia is characterized by recurring episodes of hypersomnia of 18 h or more per day lasting from several days to several weeks. We report the case of a 17-year-old male subject with recurrent hypersomnia who displayed change in the 24 h expression of the hPer2 gene in whole red and white blood cells as well as markers [deep body temperature (DBT) and cortisol] of the circadian time structure during an episode of hypersomnia compared to remission. The patient was studied for the temporal characteristics of hPer2 gene, DBT, cortisol, and melatonin expression during a single 24 h span during an episode of hypersomnia and again during a single 24 h span in the following remission. The approximation of a 24 h cosine curve to the time series data revealed circadian rhythmicity (P < 0.05) only in DBT in the two stages of the disease with differences in amplitude and acrophase. Cortisol circadian rhythmicity was detected during remission, but not during hypersomnia. Statistically significant differences were detected by ANOVA between the remission and active disease stages in the 24 h mean level of hPer2 gene expression (P < 0.05), cortisol (P < 0.05), and DBT (P < 0.05). The findings of this case study suggest the expression of hPer2 gene and alterations in circadian time structure might play an important role in the pathogenesis of recurrent hypersomnia, although additional study is required.