School Refusal and CFS:
In "School Refusal"/"School Phobia" many children experience "stomachache, headache or nausea." These are also the same symptoms experienced both in "Radio Wave Illness" and "Chronic Fatigue Syndrome."
Check out the following article, "Learning and Memorization Impairment in childhood chronic fatigue syndrome manifesting as school phobia in Japan." The author leaves his contact details at the end of the paper. I called him but he didn't want to talk to me and he didn't want to even consider EMR as a causal factor. Maybe if some of the well-known doctors, scientists, researchers, activists on this list gave him a call (or sent him an email), he would be more open to listening to them (instead of a person who previously had CFS, was able to clearly connect it to EMR, and was hence able to cure himself of it.)
Learning and memorization impairment in childhood chronic fatigue syndrome manifesting as school phobia in Japan
Teruhisa Miike*, Akemi Tomoda, Takako Jhodoi, Noritaka Iwatani, Hiroyo Mabe
Department of Child Development,
Faculty of Medical and Pharmaceutical Sciences,
Kumamoto University Graduate School,
1-1-1 Honjo, Kumamoto 860-8556, Kumamoto, Japan
Received 24 February 2003; received in revised form 11 September 2003; accepted 14 October 2003
Abstract
For the last 15 years, we have tried to understand the pathophysiology of childhood chronic fatigue syndrome (CCFS) in Japan. In this condition, two major symptoms are important: easy fatigability and disturbed learning and memorization. In CCFS patients we clinically evaluated autonomic nervous system function, circadian rhythm of hormonal secretion (melatonin, cortisol and 3-endorphin), core body temperature, and sleep–wake pattern. Most patients showed autonomic nervous system dysfunction and circadian rhythm disturbances, similar to those observed in jet lag. Radiological imaging studies (SPECT, Xe-CT, and MRS) revealed decreased blood flow in the frontal and thalamic areas, and accumulation of choline in the frontal lobe. We analyzed the relationship between the laboratory data and clinical symptoms in CCFS.
q 2004 Published by Elsevier B.V.
Keywords: Childhood chronic fatigue syndrome; Learning and memorization function; Circadian rhythm; Core body temperature; Melatonin; Magnetic resonance spectroscopy; Choline
1. Introduction
Recently, not only deterioration of scholastic ability but also life force itself has become a serious concern in children. A research group of the Ministry of Health and Welfare reported that pediatricians found symptoms of psychosomatic diseases in 5.8% of children older than 3 years of age at outpatient clinics throughout Japan on October 18, 1999; 20–70% of them complained of easy fatigability and/or a feeling of dullness [1]. These two symptoms, indicative of childhood type chronic fatigue syndrome (CCFS), had not been known to be the initial symptoms of school refusal. In this report we use the term CCFS, as a synonym for school refusal (school phobia). The Ministry of Education, Science, Sports and Culture reported that 2.8% of junior high school students suffered from school refusal or CCFS on August 9, 2002. In this condition, they exhibit easy fatigability, and impaired learning and memorization, which affect school social life seriously and even normal daily life. Once one has fallen into this condition, it will take several years for a complete recovery.
We anticipated that students not attending school suffered from CCFS; their symptoms would be similar to and as common as those of adult chronic fatigue syndrome (CFS) patients. We have tried to determine the medical and physiological backgrounds of the condition for more than 15 years. Consequently, we obtained various data that support dysfunction of the autonomic nervous system [2,3], dysregulation of the sleep–awake rhythm [2,4,5], dysregulation of deep body temperature [5,6], and disturbance of the hormonal secretion rhythm [2,4,5] in school refusal cases. Their daily life was similar to that in atypical chronic jet lag.
An oral glucose tolerance test (OGTT) and energy metabolism of lipids also were abnormal [7,8]. Some CCFS patients showed abnormally high titers of antinuclear antibodies (ANA), so-called anti-Sa-antibodies [9], suggesting an immunologic abnormality via the central nervous system. In addition, we observed decreased cerebral blood flow in both frontal and left thalamic areas on single photon emission computed tomography (SPECT) [10] and Xe-CT [11], and accumulation of choline in the frontal area in a magnetic resonance spectroscopy (MRS) study [12].
Based on these medical and physiological data, we concluded that deterioration of life force was a common phenomenon leading to dysfunction of learning and memory because of a decrease of adenosine triphosphate (ATP) and acetylcholine. These data also suggested that children experience strange fatigue with deteriorated psychosomatic activity, and that this condition is currently a common phenomenon in the world. We should pay more attention to the background of daily life in children living today. It has a strong influence on brain functions such as cognition, memory, and the will to learn. In this article we review briefly the results of our study.
2. Strange fatigue in children
A research group of the Ministry of Health and Welfare reported that the chief complaints of children considered to have psychosomatic diseases were easy fatigability and/or a feeling of dullness (16.4%), headache (10.7%), and abdominal pain (10.4%). In addition, 40–80% of them exhibited sleep disturbance such as difficulty in getting to sleep, difficulty in getting up in the morning, frequent awakening during sleep, and sleepiness during the day. The report suggested that this strange and spreading fatigue in children has sleep problems as a common background. Actually more than 80% of school refusal cases showed the sleep disorders mentioned above, with easy fatigability, and learning and memorization dysfunction, resulting in deterioration of school performance.
3. Circadian rhythm disturbances
The human biological rhythm comprises three circadian rhythms: (1) sleep–wake rhythm; (2) core body temperature rhythm; and (3) hormonal secretion rhythm.
3.1. Sleep–awake rhythm disturbance [1,3,4]
More than 80% of school refusal cases suffer from sleep disorders, with a tendency of day/night reversal, especially in the period immediately after termination of school social life. An overnight EEG study revealed a decrease in deep NREM sleep and delayed latency of REM sleep (Miike et al., unpublished data). Most of them need 10 hours’ sleep to remain awake for the rest of the daytime. These data suggest a deteriorated quality of night sleep. Even though sleep disorders are considered to begin in childhood, there have been no in depth studies on this problem.
3.2. Core (deep) body temperature rhythm (CBT or DBT) [5,6]
The three circadian rhythms mentioned above are closely related to each other. We examined the circadian CBT rhythm in CCFS cases using a special instrument developed by Terumo Company (Tokyo, Japan) [6]. The CBT rhythm was well-matched to the brain temperature rhythm. For this study 41 patients (24 males and 17 females) from 10 to 19 years of age (mean: 15.2 years) were referred to our clinic from 1993 to 1998. For normal age-matched controls, we recruited healthy school children as volunteers; six males and three females from 10 to 21 years (mean: 17.3 years). The results are summarized in Table 1. In the CCFS patients, the mesor of the circadian CBT rhythm was significantly higher than that in normal controls. In particular, the mean CBT at night and nadir were higher, and the nadir recorded on appearance was significantly delayed in the patients.
3.3. Hormonal secretion disorders [2,4,5]
Twenty-four-hour blood sampling was performed through an indwelling catheter in a forearm vein at 4-h intervals. Each blood sample was immediately centrifuged at 4 8C and stored at 280 8C until assays of melatonin, cortisol and b-endorphin. They were all abnormal; peak secretion time was delayed, and the amount of secretion was decreased. The area under the curve (AUC) of cortisol secretion was significantly smaller in the patients than in control subjects (167.3 ^ 46.3 vs. 202.8 ^ 28.4) (Fig. 1) [13]. Also, the peak shift of cortisol was significantly delayed in the patients than control subjects (9.11 ^ 4.25 am vs. 6.00 ^ 1.14 am; P 1⁄4 0:0278). These data suggested that circadian rhythms are deranged in CCFS patients, and indicate that the starting time of daily life is seriously delayed, because of delayed preparation for mental and physical activity supporting daily life. This result is in accordance with the observation that CCFS patients are in a poor condition in the morning and in a relatively good condition in the afternoon.
Low hormonal secretion may be the main cause of the inactivity, dullness, and stagnant condition in CCFS.
4. Mammalian circadian clock
Circadian rhythms are driven by endogenous biological clocks that regulate many biochemical, physiological and behavioral processes in a wide range of life forms [14].In mammals, there is a master circadian clock in the supurachiasmatic nucleus of the anterior hypothalamus. Deranged circadian rhythms are well recognized in jet lag. One may have symptoms (dysfunction of the autonomic nervous system, sleep–wake rhythm, and mental and physical activity), similar to those seen in CCFS patients. We believe that CCFS patients suffer from an atypical but continuous jet lag condition in their daily life. They are dazed and inattentive. The wakefulness level of the brain is somewhat poor in the patients. The limbic system dysfunction causes deteriorated cortical function secondarily.
5. Higher cerebral (cortical) function
To investigate the cognitive function as one of the cortical functions, we examined event-related-potentials (ERPs) using a visual oddball paradigm. Two hundred and sixty-four healthy children (controls) and 319 CCFS patients participated in this study. The relationship between their autonomic functions (component analysis of cardiographic R–R interval) or frontal lobe function (KANA-pick up test) [15] and ERP results was also analyzed. The CCFS patients were divided into three categories; type I (n 1⁄4 53): the ERP latency after target stimuli significantly longer than that in controls (P , 0:001); type II (n 1⁄4 63): the FRP latency after target stimuli significantly shorter, and the ERP amplitude induced by non-target stimuli significantly higher in the patients (P , 0:001); and type III (n 1⁄4 203): the latencies and amplitudes of ERP with both target and nontarget stimuli not significantly different. Type I was a delayed type, possibly of child dementia. Type II may be a hypersensitive and hyperactive type, followed by a typical exhaustion. Component analysis of the cardiographic R–R interval revealed significant suppression of the peak of the high frequency component (HFC; parasympathetic component) in the CCFS patients.
6. Image analysis of the central nervous system (CNS) >
The observations reported above indicate that CCFS possibly originates from the central nervous system-derived fatigue, and involves impairment of cognitive, learning, and memorization function.
6.1. SPECT and Xe-CT [10,11]
To investigate the correlation between regional cerebral blood flow and central nervous system symptoms in CCFS manifesting as school refusal, we examined cerebral blood flow using SPECT with 111 MBq 123I-iodoamphetamine and Xe-CT. None of the patients exhibited evidence of focal structural abnormalities on magnetic resonance imaging. In the SPECT study, cerebral blood flow was found to be markedly lower in the patients with school phobia manifesting as CCFS, when expressed as the corticocerebellar ratio in the frontal, temporal, and occipital lobes. Xe-CT images were obtained by xenon-enhanced CT after 3-min inhalation of a 30% xenon, 30% oxygen and 40% nitrogen gas mixture. Xe-CT of 230 CCFS patients revealed a significant decrease in cerebral blood flow in both the frontal and left thalamic areas of the patients (Fig. 2).
6.2. MRS [12]
For monitoring of the cerebral metabolic level, 42 patients with CCFS manifesting as school refusal and 20 age-matched control subjects were studied using localized proton magnetic MRS. Spectra were obtained for a 1.5 £ 1.5 £ 1.5–1.7 £ 1.7 cm 3 volume of bilateral frontal white matter. The peak areas of N-acetylaspartate (NAA), choline esters (Cho), and total creatine (tCr: creatine plus phosphocreatine) were determined for each voxel. Then the NAA/tCr and Cho/tCr ratios were calculated on the basis of the signal intensity of each compound. Cho/tCr was significantly elevated in the CCFS patients (P , 0:05) (Table 2) [16]. This result suggested that excessive cholinergic activity was followed by impairment of higher cortical functions. An elevated choline level in the brain is important for glucose metabolism and energy production in mitochondria.
7. Glucose metabolism [7]
Abnormal glucose metabolism is commonly observed in autonomic nervous system dysfunction, e.g. amyloid neuropathy. We conducted a 3-h OGTT in 81 CCFS patients (40 males and 41 females; 11–19 years).
They were in the range of 215 to þ20% (20.04 ^ 8.6) of ideal body weight. The blood glucose (BG) levels at all OGTT time intervals and cumulative blood glucose (,BG) were significantly higher in CCFS than normal controls ( P -BG): 39.5 ^ 4.4 vs. 33.3 ^ 3.4 mmol/l (P , 0:01).
The insulin response was abnormally low as compared to in hyperglycemia; P IRI (cumulative immunoreactive insulin)/ P -BG] was 232 ^ 129 and. 375 ^ 27 1, respectively, in the patients and controls (P , 0:01). However, the beta cell secretory ability was normal; P -IRI was 2805 ^ 1274 and 2523 ^ 1219 pmol/l, respectively, in the patients and controls. We concluded that insulin secretion was low in the patients. A paradoxical increase in growth hormone also was observed in 19 patients after glucose loading (Fig. 3). The glucoregulatory system probably compensates for decreased cerebral blood flow by increasing the blood glucose concentration, thereby providing sufficient glucose as a primary energy source for normal brain metabolism.
8. Disturbance of energy supply
In addition to the abnormal glucose metabolism mentioned above, serum pyruvic acid was rather high (data not shown). We conclude that disturbed energy production in mitochondria is the main cause of the easy fatigability and learning/memorization dysfunction (Fig. 4).
Actually, CFS patients become exhausted more rapidly than normal subjects after graded dynamic exercise [17]. They have a relatively reduced intracellular ATP concentration. The authors of this report concluded that these data suggest a defect of oxidative metabolism with acceleration of glycolysis in the working skeletal muscle of CFS patients, and that this metabolic defect may contribute to reduced physical endurance.
9. Deterioration of will for learning and academic ability
This problem is getting serious not only in Japan but also in other developed countries. At present, children and adults live in common environmental conditions: 1. chronic shortage of sleep followed by an irritable brain; 2. continuous psychointellectual tension with excessive information in a competitive society; and 3. self-denial and/or self-suppression with a cooperative life style.
In addition to these common living environmental backgrounds, biological rhythms will fail if there are additional stress factors:
1. Reaching a responsible social position.
2. Hard study for entrance examinations and/or hard training at sports clubs. Hard training for 7 days a week is common at sports clubs in junior high schools in Japan and even in primary schools.
3. Suffering a serious traffic accident or natural disaster.
4. Exhaustion after viral infection.
5. Serious trouble with human relations, e.g. bullying.
6. Changing living environments (climate, noise, housemoving, etc.).
10. Common and serious problems in the world
School refusal caused by CCFS and deteriorated scholastic ability in children are common and serious problems not only in Japan but also throughout the world, especially in developed countries. This suggests that the roots of this problem exist not only in the educational system, but also in the physical and mental conditions of the children themselves. We are convinced that the data we have obtained during the last 18 years provide clues for resolving these problems. We emphasize that the most important key points are the mammalian circadian clock and biological rhythms. Actually, we experienced a case with recurrent hypersomnia that was closely related to desynchronization of biorhythms, particularly the circadian rhythm of hPer2 gene expression [18].
11. Brain science and education
The biological clock, which maintains life, the autonomic nervous system, and rhythms of activity and rest in humans, is disappearing from children living in the present age. The primitive biological clock seems to be affected seriously by the current global lifestyle. Children lose their will to live, let alone scholastic ability. The first thing we should do is to determine why children lose their will to live vividly. We emphasize that it is important to analyze the living environmental conditions and biological rhythms of children for solution of this problem. Acknowledgement Most of this work was performed through Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.
References
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[18] Tomoda A, Jhodoi T, Kawatani J, Hamada A, Ohmura T, Tonooka S, et al. Differences in human Per2 gene expression, body temperature, cortisol and melatonin parameters in remission and hypersomnia in a patient with recurrent hypersomnia. Chronobiol Int 2003;20:891–898.
* Corresponding author. Tel.: þ81-96-373-5195; fax: þ81-96-373-5200.
E-mail address: miketeru@kaiju.medic.kumamoto-u.ac.jp (T. Miike).
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