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The Fatigue in Chronic Fatigue Syndrome - Is it Central? by Cort Johnson  (Sept. 2005)

The ARGUMENT

Where does the fatigue in chronic fatigue syndrome (ME/CFS) originate?  In the muscles? In the glands? In the brain? Fatigue can either be induced by problems in the periphery (i.e. the muscles. glands, etc.) or it can have an central (i.e. brain) origin. In a series of papers Chaudhuri and Behan have asserted the particular type of fatigue found in chronic fatigue syndrome (ME/CFS) could only originate in the central nervous system. Several studies do indicate that central nervous dysfunction is present in CFS. Not only do CFS patients display impaired motor performance but measurements of the part of the brain devoted to motor activity, the motor cortex, have shown reduced motor cortex activity. Other tests indicate CFS patients are unable to activate normal amounts of muscle during exercise. The cause of this inadequate muscle activation appears to lie not in reduced nerve conduction from the motor cortex but in impaired activation of the circuits leading to the motor cortex.

Chaudhuri and Behan posit that disrupted circuitry in the deep brain structures called the basal ganglia cause the phenomena known as central fatigue. They posit that disrupted informational flows from the basal ganglia to the cerebral cortex interrupt the process of ‘sustained attention’ that is critical to carrying out tasks. This interruption leads to a greater sense of effort, reduced motivation and ultimately to the increased fatigue during both physical and cognitive activities found not only in ME/CFS but in other diseases with prominent fatigue.

Introduction - In what part of the body does the fatigue in CFS originate? Is it the muscles? The immune system? The mitochondria? The brain?

There’s more to CFS than the fatigue that its unfortunate name suggests. People with CFS often experience cognitive problems, sleep impairment, allergies and sensitivities, headaches, low grade fever, orthostatic intolerance, etc., etc. For many, however, fatigue – particularly after exercise – is the symptom that most colors their experiences.

Fatigue, though, is a simple term for rather complex phenomena. This paper looks at the different types of fatigue that occur in diseases, describes which type is found in CFS and suggests a possible origin. It is primarily based on a series of papers by Chaudhuri and Behan (Chaudhuri and Behan 2000a, 2000b, 2004a, 2004b, Chaudhuri et. al. 2003)

Weakness vs. Fatigue - The first thing to note is the difference between weakness and fatigue. Weakness is the ability to mount a specific amount of muscular force. Fatigue, a subjective term, denotes a feeling of tiredness or exhaustion. The distinction between these two terms is confused a bit by the definition of ‘muscular fatigue’ which is the inability to mount a specific a specific amount of force (weakness) over time Many neuromuscular disorders that cause extreme muscle weakness do not leave their victims feeling fatigued; they’re simply weak. Similarly victims of fatigue are not necessarily weak.

Transitory vs. Chronic Fatigue - Transitory episodes of fatigue occur in healthy people when they are under stress, have poor sleep, during menstruation and during the acute phase of viral infections (Chaudhuri and Behan 2000). Fatigue is part of a constellation of signs and symptoms (lethargy, poor concentration, fever) that make up what is called ‘illness behavior’ which is evoked during the acute phase of viral infections. Illness behavior occurs when pro-inflammatory cytokines such as IL-1b, Il-6 and TNF-a interact with the brain.

Stress, poor sleep, hormonal abnormalities and viral infections have all been suggested to contribute to the fatigue in CFS but none, as yet, can provide a satisfactory answer for it.

Peripheral vs Central Fatigue - Pathologic fatigue can originate in the periphery (i.e. muscles) or it can be central (brain - induced) in nature or it can be both. Most often it is the result of one or the other.

Early muscle fatigability is seen in defects in muscle function, neuromuscular transmission (myasthenic diseases), diseases of the peripheral nerves and low motor neuron syndromes. While some CFS patients do display some muscular weakness it does not reach the level found in those with neuromuscular disorders such as myasthenia gravis or metabolic muscle diseases. The weakness CFS patients display in tests appears  to be more the result of inactivity than an underlying pathology affecting the muscles (Chaudhuri and Behan 2000).

The degree to which a peripheral dysfunction contributes to the fatigue in CFS is unclear. The presence of enteroviruses in the muscles of CFS patients is controversial but suggests peripherally induced fatigue could be a factor for a subset of patients (Lane et. al. 2004, Dalakas 2003). While some abnormalities in muscle histology (structure) were seen in one study, consistent abnormalities in muscle biochemistry and metabolism have not been seen. The evidence thus far suggests peripherally induced fatigue does not appear to play a large role in most CFS patients; i.e. CFS is not primarily a disorder of impaired muscle function.

Central fatigue is characterized by feelings of constant tiredness or exhaustion. In contrast to peripheral fatigue central fatigue is largely a result of central nervous system (CNS) activity. What makes central (i.e. brain induced) fatigue stand apart from peripheral (i.e. muscle induced) induced fatigue is its extension into cognitive activities. In diseases of central fatigue both physical and mental activities evoke weariness. In diseases of peripheral fatigue only physical activities evoke fatigue.

Diseases That Induce Central Fatigue - The authors list 22 neurological disorders and CFS that are associated with central fatigue. Some of interest in CFS include cerebral vasculitis, channelopathies (ciguatera, RNase L), hypothalamic disease, post Guillain Barre syndrome, post-infective fatigue states (post-polio, Lyme, Q-fever, viral fatigue) and sleep disorders.

Narrowing their focus further the author’s list 12 diseases with fatigue symptoms similar to those found in CFS. They are found in the following categories:

Genetic – mitochondrial cytopathy, myotonic dysfunction

Viral - HIV induced encephalopathy, post-polio syndrome, chronic hepatitis C (added)

‘Diet’ - Vitamin B-12 deficiency, ciguatera poisoning

Brain/CNS - Parkinson’s Disease, Alzheimer’s disease, multiple sclerosis, motor neuron disease, myotonic dysfunction, migraine, epilepsy, paroxysmal dsykinesia.

(Editorial addition – Primary biliary cirrhosis (liver) and overtraining syndrome are also diseases with prominent fatigue.)

Since there doesn’t appear to be a strong genetic component to CFS, the above list strongly suggests the type of fatigue found in CFS has an immune or central nervous system origin (or both).

Defining Central Fatigue - Chaudhuri and Behan (2000) define central fatigue as the failure to initiate and/or sustain attentional tasks and physical activity. The inability to maintain ‘focused attention’ is a key liability in central fatigue since ‘focused attention" (an automatic process) is necessary to incorporate the mental, physical and sensory inputs involved in completing a task. That is, if focused attention is impaired then integrating the various types of information needed to complete any task becomes difficult and the task become inordinately effortful.

Where in the brain might this centrally induced fatigue arise? Some observations by Chaudhuri and Behan give us a starting place.

The Central Motor System and Fatigue - Three of the five observations Chaudhuri and Behan use to support their claim that the fatigue in CFS is largely central concern decreased central motor activation or drive. Some are quite complex, they will be explained later.

• CFS patients have delayed central motor conduction similar to that seen in multiple sclerosis (MS) patients
• The delayed facilitation of central motor evoked potential (MEP) seen the post-exercise  period suggests depressed cortical excitability is present in CFS.
• CFS patients display increased perception of effort that is associated with reduced central motor drive during exercise
• CFS patients are unable to fully activate their muscles during intense exercise despite having  normal muscle activity (muscle metabolism, contraction)
• There is insufficient histological evidence of muscle injury to suggest structural muscle problems in CFS. Histology is the science of the minute structures of cells, tissues and organs.

Motor Performance in CFS – Numerous studies indicate CFS patients exhibit impaired motor performance (Starr et. al. 2000. Davey et. al. 2001, Davey et. al. 2003). Motor performance tests usually involve doing a simple task like flexing a finger or limb. While these tests may seem simple almost to the point of banality the mental activity needed to repeatedly tap a finger or flex a muscle is actually quite complex These tests often show reduced repetitive movements over time and reduced reaction time to a stimulus.

Reduced motor performance can be due to a disruption in the nerve conduction pathways leading from the motor cortex to the muscles, to a problem with the motor cortex itself, or with the circuits providing information to the motor cortex. Normal sensory nerve conduction times suggest the motor performance problems do not lie downstream of the motor cortex. Several studies, however, have found reduced motor cortex excitability in CFS patients during the performance of simple motor tasks.

The Motor Cortex – Part of the cerebral cortex, the motor cortex activates the motor neurons that innervate the skeletal musculature. Motor cortex activity is particularly important in fine movements. The motor cortex is not only involved in the mechanistic propagation of muscle activity, however, it is also involved in the preparation for movement and in thinking about movement. Functional MRI’s (fMRI’s) have found that simply reading words referring to movement increases blood flows to the motor cortex.

Ever increasing MEP during exercise is probably due to the motor cortex’s need to recruit more and more motor units of a muscle as it becomes become fatigued.  High MEP’s in the post-exercise facilitation phase is believed to either be an attempt to maintain muscle contraction in the face of fatigue or to keep the muscles or brain primed for more muscle activity. During the depression phase following the facilitation phase motor cortex excitability drops down to below baseline for a time..

Several studies have found abnormalities in MEP amplitude during exercise or the facilitation period in CFS. MEP immediately after exercise was significantly lower in CFS and depressed patients than controls and MEP facilitation 30 minutes after exercise was significantly less in CFS patients than other control groups in one study (Samii et.al. 1996). MEP's were lower both during exercise and in the facilitation period in another (Starr et. al. 2000). MEP was normal in another but a larger than normal ‘twitch response’ (see below) during exercise suggested an abnormality in the ‘electromechanical response’ to exercise was present. Interestingly given the feeling of always contracted muscles some CFS patients evidence, the authors noted background levels of muscle contraction effect the twitch/MEP relationship (Sacco et. al. 1999). Is resting muscle contraction in CFS increased? Corticospinal excitability or inhibition were normal in two other studies (Davey et. al. 2001, Zaman et. al 2001).

The gold standard for measuring motor drive to the muscles involves stimulating the motor nerve and measuring the magnitude of the ‘muscle twitch’ that ensues. That has not been done in CFS but a substitute test involving interpolating the twitch force evoked during TMS suggested that CFS patients not only were not activating normal amounts of muscles during exercise but that the reduced muscle activation seen was due central inactivation; i.e. it was due to problems in the brain (Sacco et. al .1999).

Stimulation of the motor cortex at the beginning of exercise involving a maximal effort should have no effect on the twitch response – one should be able to voluntarily recruit all the muscles needed. As fatigue progresses, however, apparently the brain is either not capable or is unwilling to recruit all the motor units it can. During this period TMS is able to evoke a strong twitch response. As all the motor unit of a muscle become recruited during exhaustive exercise, however, the twitch response fades. An early study (Kent-Braun 1993) found that even at the beginning of exercise before fatigue had a chance to occur electric stimulation could increase the maximum voluntary contraction elicited in CFS patients. A later study found the twitch force in CFS continued to increase in CFS patients during exercise far longer than it did in healthy controls (Sacco 1999). This in concert with decreased muscle rmsEMG levels suggested CFS patients were less able to activate their muscles during exercise than normal.

Electromyography (EMS) - Another way to examine motor drive is to measure how much electrical activity is present in the muscles during exercise. The electrical activity a muscle is producing can be measured by an electromyography (EMG). Several studies have indicated CFS patients display greater reductions in rmsEMG activity during exercise than do controls and that the gap between the two groups becomes greater and greater as the exercise gets more and more fatiguing (Sacco et. al. 1999). This also suggests that as exercise progresses CFS patients are less and less able to recruit normal amounts of muscle.

But is the problem with the motor cortex itself or with the information it is receiving? A 1991 study concluded that the fatigue in CFS is due to a dysfunction upstream of the primary motor cortex. Starr suggested the impairments seen are due to reduced premovement potentials because of impaired drive to the motor cortex (Starr et. al. 2000). Increased reaction and movement times in both visual and motor imaging tasks suggest that, instead of deficiencies in informational processing, CFS patients have a disrupted ‘motor response’ associated with response preparation (Davey et. al. 2003, de Lange et. al. 2004). That a measure believed to reflect cortical inhibition, SP duration, was prolonged in CFS patients suggested increased motor cortex inhibition (Sacco et. al. 1999) The brain is a maze of inhibitory and activating circuits. The overactivation of an inhibitory circuit could cause reduced motor cortex activity.

A recent study also found strongly diminished central activation during exercise in CFS patients (Schillings et. al. 2004). Although electrical stimulation tests before exercise indicated CFS patients had the same muscle capacity as controls, CFS patients exerted a much (much) smaller maximum voluntary contraction of their biceps muscle (87-144) than did the control group. Significantly greater muscle activation by electrical stimulation during maximal muscle contraction indicated once again CFS patients were activating fewer of their muscles than were controls. The researchers  concluded this was due to a ‘failure of central activation’, i.e. a failure of the brain to fully recruit all the muscles (Schillings et. al 2004).

The authors put the reduced muscle activation seen in CFS patients in perspective by noting it was similar in magnitude to that measured in some stroke victims and ALS patients (Schillings et. al. 2004). Is this not a remarkable fact? CFS patients may be fatigued simply because they don’t use all their muscles. In fact their brains put into operation about as much of their muscles as some stroke victims.

Possible Causes of Reduced Central Activation in CFS - The authors posited several possible causes for the reduced central activation found;

• Increased perception of pain or effort could lead to negative internal feedback and impaired muscle activation. This theory posits negative feedback suggesting imminent damage prompted the brain to refuse to employ all the muscles.
• Impaired concentration and effort prevented CFS patients from fully exerting themselves. This explanation was largely discarded by the authors.
• Disrupted processing in the motor or premotor areas possibly due to altered neurotransmitter concentrations prevented proper motor cortex activation (Shillings et al. 2004).

The Location of the Problem - That many progressive neurodegenerative diseases that produce central fatigue involve injury to the pathways descending from the hypothalamus (basal ganglia, reticular, autonomic) suggests this part of the brain is involved in the genesis of centrally induced fatigue.

Central fatigue is also often seen in people with lesions in the pathways in the brain associated with arousal and attention. A lesion is simply a wound or injury. These include the reticular and limbic systems and the basal ganglia.

Note that most of these systems interact either directly or are one step removed from interacting with the basal ganglia.

THE BASAL GANGLIA – Chaudhuri and Behan believe the genesis of central fatigue begins in one of deepest parts of the brain, the basal ganglia. Sitting in the interior of the brain, the basal ganglia consists of six interconnected nuclei (caudate nucleus and putamen (striatum), globus pallidus, substantia nigra, subthalamic nucleus, amygdala that provide a link with the limbic system and the hypothalamus.

The basal ganglia (and cerebellum) gets information from the cerebral (i.e. motor cortex), bounces it around its nuclei (processes it) and then sends it back to the cerebral cortex via the thalamus. Two circuits, a motor circuit and an ‘association’ or complex loop, connect the basal ganglia with the cerebral cortex. Chaudhuri and Behan believe the key disruption in central fatigue occurs in the non-motor or complex circuit (Chaudhuri and Behan 2000a). Why the non-motor circuit when we have been taking about reduced motor performance? Perhaps because lesions in the motor circuit are known to cause spectacular (and horrifying) symptoms not found in CFS. The continuous writhing movements of Huntington’s disease and the violent limb flinging of Ballismus are caused by damage to the subthalamic nucleus of the basal ganglia. The odd combination of rigidity and tremor seen in Parkinson’s disease are due to damage to the substantia nigra of the basal ganglia. Instead of having problems with circuits devoted specifically to movement Chaudhuri and Behan believe CFS patients have problems with circuits involved in information processing  

Based on current models of how the basal ganglia works Chaudhuri and Behan posit three disruptions that could be responsible for the central fatigue seen in CFS and other diseases. (Warning: very complex).

• an interruption in the associated or complex loop of the basal ganglia that provides information from the basal ganglia to the prefrontal cortex. The complex loop is associated with non-motor functions; i.e. information planning and processing.
• an increase in thalamic inhibition that impairs information flow from the basal ganglia to the thalamus and cortex. Remember the increased silent period times in CFS suggested increased motor cortex inhibition. Recent FMS studies finding reduced thalamic blood flow levels and activation suggest this scenario may apply to CFS's sister disease, Fibromyalgia.
• a modification of the cortex’s response to basal ganglia inputs due to altered activity between the thalamic and subthalamic nucleus in the basal ganglia.

The authors note that interrupted signaling in the thalamic cortical loop is often found in diseases that induce central fatigue. They suggest reduced information flow through this circuit inhibits activation of the frontal lobe. Since the frontal lobe is involved in a very wide array of activities, frontal lobe impairment could cause a wide array of problems. Interestingly, given the similarities between post-polio syndrome and CFS, autopsies of polio patients showed damage to a number of deep brain structures including four of the six nuclei of basal ganglia (Chaudhuri and Behan 2000b).

Based on their clinical experiences Chaudhuri and Behan assert that reduced self-motivation seen in people with central fatigue is at least partly due to the increased effort perceived by them. In order to initiate and perform any task sets of emotive, motor and sensory cues need to be integrated in such a manner as to propel one onto the series of actions needed to accomplish it. An inability to efficiently process these cues could cause an apparently easy activity to appear highly effortful. Since the basal ganglia are highly involved in processing the cues needed for task performance they are a logical place for a disruption that causes central fatigue to occur. One section of the basal ganglia, for instance, the caudate nuclei, connects motivational values to visual information.

Chaudhuri and Behan suspect that disrupted ion channel/neurotransmitter activity in the basal ganglia alters the 'neuronal excitability of the cortical, limbic and brainstem areas. The disruptions in these deep brain areas could be responsible for the wide variety of symptoms seen in CFS. They believe the down regulated HPA axis activity (hypocortisolism) in CFS is probably an adaptive response to alterations in neurotransmitter activity rather than the primary cause of the fatigue in CFS. The immunological aberrations seen in CFS, in turn, reflect the disrupted HPA axis activity (Chaudhuri and Behan 2000b).

Support for the Theory - Several studies have provided support for Chaudhuri and Behan’s model since it was published in 2001. Reduced activity during task activity was found in the caudate nuclei of the basal ganglia of CFS patients relative to controls (de Lange et. al. 2004). Three small magnetic resonance spectroscopy (MRS) studies have found increased choline peaks in the basal ganglia of CFS patients that are possibly indicative of increased reparative gliosis (membrane turnover perhaps due to infection) (Tomoda et. al. 2001, Puri et. al. 2002, Chaudhuri et. al. 2003) (See Choline on the Brain?). Another study found increased thalamic activation in CFS patients. Thalamic overactivation in CFS may indicate the need for increased attention to previously non-effortful tasks, a common finding for disorders characterized by reduced prefrontal perfusion (McHale et. al. 2000).

Remember that all information from the basal ganglia (and the cerebellum) goes through the thalamus on the way to the cerebral cortex. The thalamus, formerly thought to be simply a sensory relay station for signals leading to the brain, is now believed to participate in motor function and planning and motor and cognitive coordination. Intriguingly the thalamus receives information regarding the ‘motor state’ from both the muscles and the cerebrum. Chaudhuri and Behan, however, suggested thalamic inhibition may occur in central fatigue. As noted earlier thalamic inhibition has recently been found in Fibromyalgia. 

Research into the origin of other fatiguing illnesses such as multiple sclerosis (MS) may provide clues to the fatigue experienced in CFS. MS patients with fatigue exhibit significantly lower activation of the cortical and subcortical areas of the brain devoted to motor planning and execution than do MS patients without fatigue. Several studies have indicated dysfunction in the subcortical circuits linking the basal ganglia, thalamus and frontal cortex occurs in MS. Just as in CFS patients fatigued MS patients display increased thalamic activation. The brain, a very malleable organ, does not sit still when one part of it is disturbed - it adjusts to the disturbance by routing information around the damaged area and ramping up activity elsewhere. In what may also be a compensatory reaction to impaired brain activity elsewhere, both fatigued MS and CFS patients exhibit a marked activation of the anterior cingulate region of the brain (Schmalling et. al. 2003). A part of the frontal lobe, the anterior cingulate is involved in the early stages of motor learning or planning and in ‘attentional tasks’. Interestingly, interferon A treatment, which often causes great fatigue, also results in increased anterior cingulate activation (Capuron et .al. 2005).This, of course, suggests an intriguing neuro-immune connection to fatigue centered in anterior cingulate. Two of the enzymes implicated in CFS, RNase L and PKR, are activated by IFN’s (See RNase L in CFS).

Update - A recent update on the CDC's CFS webpage reported that a PET scan study examining interferon's effect on patients with malignant melanoma found that interferon treatment resulted in increased basal ganglia activity, particularly in the putamen and globus pallidus nuclei. This ties together increased the increased immune activity (interferon) that may be occurring in CFS with the altered function in the basal ganglia circuitry hypothesized by Chaudhuri and Behan How intriguing this is! 

Summary - These findings suggest the fatigue in CFS, MS and other diseases of central fatigue originates in abnormalities in deep brain circuits involved in motor planning and execution. The problem, then, appears to lie not in a disruption in the brains signal to the muscles but in brains ability to produce the signal in the first place. They suggest that the brains of central fatigue patients are hindered in their ability to integrate the multitude of signals involved in producing muscle activation. Thus this is a 'thinking' problem not a muscle problem. These findings appear to be in agreement with Chaudhuri and Behan’s model positing that disrupted deep brain (cortical-striatal (basal ganglia)-thalamo) circuitry plays an important role in central fatigue seen in CFS and other diseases.

The Genesis of Central Fatigue – How might such a disruption occur? Both stroke and neurodegenerative disorders are known to destroy the subcortical circuits leading to the frontal cortex. Neither of these occur in CFS but neurotransmitter abnormalities can impair proper nervous system functioning and there is evidence of abnormal neurotransmitter activity. Neuronal channelopathies could alter sensitivities to neurotransmitters and/or cause defects in neurotransmitter transport and delivery that impair the proper transmission of nerve signals. Hypoxia (reduced oxygen levels), viruses, pro-inflammatory cytokines and an altered neurotransmitter balance can all cause central fatigue.

* In July 2005 the NIH opened a new RAF (request for applications) providing $4,000,000 for studies examining the neuro-immune interface in CFS.

* During the 2004-5 period the CFID Association of America funded Dr. Shungu to examine brain metabolites using H MRS technology. Part of the abstract from the CAA's website is below.

H MRS Neurometabolites as Diagnostic Markers for Chronic Fatigue Syndrome - During the past 3-4 years, our research group had the opportunity to use a brain imaging technique known as hydrogen magnetic resonance spectroscopic imaging (H MRSI) – an imaging technique that is similar to conventional MRI, except that it can measure levels of certain important brain chemicals or neurometabolites – to record the levels of such chemicals in the brain of 31 individuals suspected with CFS. Comparison of the levels of these neurometabolites with those in normal people, showed about 50% of all CFS patients had abnormal levels of the chemicals.

This proposal's overall objective will be to develop H MRSI as a tool for evaluating CFS. To accomplish this, we will test the hypotheses that (1) CFS will be associated with specific changes in the levels of certain brain chemicals, and that such changes will be measurable by H MRSI; by refining this technique, these measurable brain chemical changes could serve as diagnostic markers of CFS; and (2) that the profile of these brain chemicals in CFS will be significantly different from that in people with psychiatric diseases, such as generalized anxiety, that are very similar to and often confused with CFS. Therefore, the results of this research will be able to establish not only that CFS has a distinct profile of certain brain chemicals than healthy human brain, but also that its profile is different from that of a very similar psychiatric disorder. This finding can be the basis for using the levels of brain chemicals measured by H MRSI as markers for chronic fatigue syndrome in clinical evaluations as well as in clinical trials of promising treatments.

* From Dr. de Lange - F.C. Donders Centre for Cognitive Neuroimaging, University of Nijmegen, NL-6500 HB Nijmegen, The Netherlands - Dr. Lange recently published a paper indicating reduced gray matter volume in CFS.

'The focus of my investigations are functional and structural alterations in the brain of CFS patients. With help of functional magnetic resonance imaging, we have found that CFS patients recruit more visually related structures to solve a motor imagery task, which could point to problems with motor planning. Furthermore, there was a difference between CFS patients and controls in error processing, pointing to differences in emotional/motivational processing. In a recent study, we found that grey matter volume was markedly reduced in CFS patients, w.r.t. healthy controls. This reduction bore a relationship with physical activity: the less physically active the CFS patient, the larger the grey matter reduction. Currently we're following up on this finding, to see whether the gray matter reduction we observed can be reversed with improvements or recovery of CFS over time.'

*The longtime CFS researcher Dr. Natelson proposed a study to use microarrays to examine gene expression in the spinal fluid of CFS patients. Despite his already having the spinal fluid his request for funding to the NIH was denied and this very worthy project has been, unfortunately, been put on the back shelf.  *Update - At the 8th IACFS conference in January 2007 Dr. Natelson stated the project was back on track.

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