ÖSSZEFOGLALÓ KÖZLEMÉNY FUNCTIONAL MAGNETIC RESONANCE IMAGING IN NEUROLOGY Auer Tibor1, Schwarcz Attila1, 2, Horváth Réka A.3, Barsi Péter2, 4, Janszky József3 Department of Neurosurgery, University of Pécs, Pécs 2 Pécs Diagnostic Institute of University of Pécs, Pécs 3 Department of Neurology, University of Pécs, Pécs 4 Semmelweis University, Budapest

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FUNKCIONÁLIS MÁGNESESREZONANCIAVIZSGÁLATOK A NEUROLÓGIÁBAN Auer T, MD; Schwarcz A, MD, PhD; Horváth RA, MD; Barsi P, MD, PhD; Janszky J, MD, PhD Ideggyogy Sz 2008;61(1–2):16–23. The present contribution discusses the clinical use of functional MRI (fMRI) and its role in the most common neurological diseases. FMRI was found a reliable and reproducible examination tool resulting in a wide distribution of fMRI methods in presurgical evaluation of epilepsy in determining the relationship of eloquent areas and the epileptic focus. Preliminary data suggest that fMRI using memory paradigms can predict the postoperative memory decline in epilepsy surgery by determining whether a reorganization of memory functions took place. Speech-activated fMRI became the most used tool in determining hemispheric dominance. Visual and senso-motor cortex can also be routinely investigated by fMRI which helps in decision on epilepsy surgery. FMRI combined with EEG is a new diagnostic tool in epilepsy and sleep disorders. FMRI can identify the penumbra after stroke and can provide an additional information on metabolic state of the threatened brain tissue. FMRI has a predictive role in poststroke recovery. In relapsing-remitting MS an adaptive reorganization can be demonstrated by fMRI affecting the visual, motor, and memory systems, despite preserved functional performance. Much more extensive reorganization can be demonstrated in secondary progressive MS. These findings suggest that the different stages of MS are related to different stages of the reorganization and MS becomes progressive when there is no more reserve capacity in the brain for reorganization. FMRI offers the capability of detecting early functional hemodynamic alterations in Alzheimer’s disease before morphological changes. FMRI can be a valuable tool to test and monitor treatment efficacy in AD. FMRI can also provide information about the mechanisms of different therapeutic approaches in Parkinson disorder including drug treatment and deep brain stimulation.

A funkcionális MR (fMR) egyre növekvô szerepet kap a neurológiai betegségek kivizsgálásában. Összefoglalónkban az fMR szerepét tárgyaljuk a leggyakoribb kórképekben. Mivel az fMR megbízható és reprodukálható vizsgálóeljárás, az utóbbi idôben az epilepszia mûtét elôtti kivizsgálásának alapvetô eszközévé vált az elokvens területek és az epilepsziás góc viszonyának meghatározásában. Elôzetes adatok alapján a memóriaaktivált fMR képes elôre jelezni az epilepsziamûtét utáni memóriaproblémákat. Beszédaktivált fMR a féltekei dominancia meghatározásának leggyakrabban használt eszköze. Az agy látás- és mozgásközpontjai rutinszerûen meghatározhatók fMR segítségével, amely lényegesen megkönnyíti az epilepsziasebészeti kivizsgálást. Az fMR EEG-vel kombinálva ígéretes új diagnosztikai eljárás lehet mind az epileptológiában, mind az alvásmedicinában. Az fMR hasznos vizsgálóeljárás a veszélyeztetett, de menthetô agyi területek meghatározásában akut cerebrovascularis eseményt követôen. Az fMR prognosztikai jelentôségû a stroke hosszú távú funkcionális kimenetelében és rehabilitációjában. fMR segítségével a látás, motoros és memóriarendszerek adaptív reorganizációját láthatjuk tünetmentes relapszusremisszió kórformájú sclerosis multiplexben (SM). Kiterjedtebb reorganizációt látunk szekunder progresszív SMben. Ez felveti annak a lehetôségét, hogy az SM különbözô formái és stádiumai a reorganizáció különbözô formáinak és stádiumának felelnek meg: az SM akkor kezd progrediálni, amikor az agyban kimerültek az adaptív reorganizációs mechanizmusok. Az fMR még a morfológiai eltérések elôtt jelezheti a kezdôdô Alzheimer-kórt. Egyes vizsgálatok eredményei szerint az fMR segítségével követhetjük a dementia kezelésének hatékonyságát. Az fMR segítségével nyomon követhetjük a Parkinson-kór gyógyszeres és funkcionális idegsebészeti terápiáját, és segít a terápiás hatás megértésében.

Keywords: functional magnetic resonance imaging, neurology, neurosurgery, epilepsy

Kulcsszavak: funkcionális mágnesesrezonancia-vizsgálat, neurológia, idegsebészet, epilepszia

Corresponding author: József Janszky, Department of Neurology, University of Pécs, 7623 Pécs, Rét u. 2. Hungary. Phone: (+36-72) 535-910, fax: (+36-72) 535-911. E-mail: [email protected] Érkezett: 2007. szeptember 24.

Elfogadva: 2007. október 26.

www.lam.hu A szerkesztôség felkérésére írt tanulmány.

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Auer: Functional magnetic resonance imaging in neurology

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he advantages of functional MR (fMRI) in comparison with other functional neuroimaging methods especially PET and SPECT are that this technique includes, in addition to their multiplanar imaging ability, low invasiveness and lack of radiation; furthermore fMRI has a far better resolution in time and space. Moreover, the costs of fMRI are lower and can be easy used in standard hospital environment. These advantages are the main causes why fMRI become the most used functional neuroimaging method nowadays. In the recent years this technique has become possible in Hungary including our center where the most important fMRI techniques in clinical neurology and neurosurgery are routinely used1, 2. In our previous studies we reported the technical details of the basic techniques and forms of fMRI and the role of this method in neurosurgery at out center1, 2. The physiological basis of fMRI in investigating brain functions are based on the sensitivity of MRI to local magnetic effects induced by changes in the oxygenation status of hemoglobin. These effects may also be exploited to detect small modulation in red blood cell oxygen content related to local variations in oxygen supply and consumption in tissues. In the brain cortex, such variations may be induced by external stimuli or internal cognitive processes. Thus, having magnetic property, capillary blood deoxyhemoglobin acts as a natural endogeneous contrast agent during blood oxygen level-dependent (BOLD) imaging1, 3. Visualizing BOLD signal (such as fast changes of oxygen level) with special MRI techniques called fMRI. BOLD signal visualized by the fMRI accurately reflects local filed potentials3. This confirms the idea that BOLD activation reflects neural activity in projecting neurons arriving in the dentic arbors at a site of the brain. The activation also includes local neural processing, but the dominant influence is likely to be exerted by excitatory afferents to the brain region. These advances lead to an explosion of the fMRI studies on the functional anatomy of normal human brain. It is on the basis of results from normal brain studies in the past decade and the increasing input from neuropsychologists and other neuroscientists using scanning to define systems level cerebral physiology that future applications to clinical neurology will be based. Thus, fMRI revolutionized studying neurological disorders. This includes lesion characterization and selecting, planning, and monitoring of therapy in surgically remediable brain disorders but also may have implications in drug therapy and rehabilitation of neurological disorders. Furthermore, initial results have provided insight into the pathophysiological

changes of different diseases especially in reorganization of normal human brain functions after neural injury. FMRI combined with EEG (EEG-fMRI) can be a new diagnostic tool in epilepsy and sleep disorders. The present contribution discusses the clinical use of functional MRI methods and their role in the most common neurological diseases including epilepsy, stroke, Parkinson disorder, Alzheimer’s disorder, and multiple sclerosis.

Epilepsy CORTICAL REORGANIZATION OF CEREBRAL FUNCTIONS IN EPILEPSY

Epilepsy serves a “model disorder” for many functional neuroimaging methods because in some localization-related epilepsies the epileptogenic focus should be surgically removed in order to arrive seizure freedom. Because epilepsy surgery is not a life-saving operation only that brain region can be removed which does not significantly contribute to normal brain process. This “insignificant” contribution can be resulted due to representation of certain brain processes in a network and one region removing from this network will be compensated by the other network elements (for example in the case of functions with bilateral representations the region contralateral to the resection can also represent the functions of the removed structure). The second reason for the “insignificant” contribution is that some brain functions can be quickly reorganized after brain surgery. The third reason is that the functions of the epileptogenic focus can be reorganized and shifted to healthy brain areas before the operation due to the presence of structural lesion or due chronic functional disturbance caused by frequent seizures or interictal epileptic activity4, 5. Brain regions thought to be contributed significantly in the healthy brain functions without compensatory reorganization capacity, are called eloquent areas. One of the challenges in presurgical evaluation of epilepsy is to differentiate eloquent areas from the other brain tissue and to determine their relationship to the epileptic focus. This work-up may require the whole arsenal of functional investigations including video-EEG, neuropsychological tests, fMRI, SPECT, PET, functional TCD6, Wada tests, or even using pre- or intraoperative intracranial electrode stimulation in order to asses of the functional properties of epileptic focus7. Thus, any new methods investigating brain functions were first validated by invasive or

Ideggyogy Sz 2008;61(1–2):16–23.

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A

Broca region

Wernicke region

B

Figure 1. Speech-activated fMRI. A Patient suffering from temporal lobe epilepsy (TLE) with left-sided (typical) speech lateralization. Broca’s and Wernicke’s region are demonstrated (arrows). B In this patient with left-sided TLE, the fMRI revealed a right-sided (atypical) speech representation most probably due to chronic epileptic disturbance of the left hemisphere. The pictures follow the radiological convention (the right side of the brain is on the left). Areas in red or yellow represent activation, while areas in blue showed areas with lowered activation than normal level (called deactivation). During this paradigm the patients were asked for a covert word generation

well-known tools using in epilepsy surgery. Numerous studies demonstrated reliability and reproducibility of fMRI examinations, which resulted in

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a wide distribution of fMRI methods in presurgical evaluation of epilepsy. The most frequent surgically remediable epilepsy is the temporal lobe epilepsy (TLE). The epileptogenic region of the TLE is usually localized in the medial temporal structures, their removal is superior to drug therapy in curing TLE8, and lead to complete cessation of seizures in 60-90%7, 9, 10. Consequently, the resection of these structures – anterior partial temporal lobectomy or selective amygdalohippocampectomy – is the most frequently used surgical procedure in intractable TLE7. Conversely, the possible side-effect of the mesiotemporal resections is the risk for the memory impairment, because the mesiotemporal structures play a crucial role in memory functions. Although the neuropsychological tests and the presence of structural damage of the mesiotemporal structures predict the postoperative memory loss in some degree, the intracarotid amobarbytal (Wada) test is the “gold standard” for testing the memory functions of the mesiotemporal structures and for predicting the postoperative memory problems. In the past five years, there were some studies using fMRI in visualizing the memory functions of the mesiotemporal structures, showing that the non-invasive fMRI investigating memory functions (memory-fMRI) may replace the invasive Wada test11. By using fMRI, more patients can more easily investigated than in Wada test and the results can be compared with normal subjects due to its non-invasive nature. Preliminary data suggest that memory fMRI can predict the postoperative memory decline in TLE by determining whether a reorganization of memory functions took place and the representation of memory shifted to the structures contralateral to the epileptic focus12. To avoid postsurgical speech disturbances, language lateralization has to be known prior to epilepsy surgery. FMRI can be used in the majority of patients otherwise undergoing the Wada test, speech-activated fMRI acquisition and assessment have become easy and reproducible, and fMRI provides typical (left-sided speech) and atypical (rightsided speech) results in large numbers of individual cases in concordance with Wada test (Figure 1.). In TLE there is a high correlation between Wada and fMRI tests, however, the risk of falsely categorizing language dominance using fMRI seemed to be particularly high in extratemporal localizationrelated epilepsy13. FMRI provide a unique utility to investigate the reorganization of language functions in epilepsy patients. In a recent study by using speech-activated fMRI, we investigated whether the frequency of

Auer: Functional magnetic resonance imaging in neurology

left-sided interictal epileptic activity is associated with atypical (right-sided) speech and found that higher left-sided spike frequency in TLE was associated with a left-right shift of speech representation, suggesting that chronic frequent interictal activity – independent of the presence of epileptogenic lesion – may induce a reorganization of speech lateralization. Surprisingly, this effect was not related to the age when seizures began, suggesting that reorganization of brain functions can occur at any age in cases of chronic disturbance and an operation affecting eloquent areas can be possible even in adults14. That study also confirmed that the reorganization of brain functions is not only caused by morphological abnormalities but also by functional disturbances. Concerning eloquent brain areas, visual system15 and senso-motor system16 (Figure 2.) as well as language13 (Figure 1.) and memory11 can be routinely visualized by fMRI which makes the decision on epilepsy surgery and on the extent of resection more easily.

A

B

THE FUNCTIONAL ORGANIZATION OF THE HUMAN BRAIN IN CORTICAL DYSGENESES

In a recent study we investigated epilepsy patients with malformations of cortical development (MCD). Due to atypical nature of these epileptogenic lesions, it is uncertain whether they contribute significantly to normal brain processes, because MCD may have neuronal elements and connectivity with the other brain regions17, 18. Moreover, in patients with MCD, the whole brain can be atypically organized, thus, in planning surgery of MCD patients, mapping cerebral functional is crucial. Using fMRI, we found that two-thirds of MCD are contributed to the elementary visual or motor functions, while MCD less frequently showed activity during complex cognitive fMRI paradigms such as in language or memory processes. During simple paradigms, all mild-type MCD (such as disturbances of cortical organization polymicrogyria, schizencephaly, and mild-type cortical dysplasia) showed activity, while other severe MCDs (hemimegalencephaly, severe cortical dysplasia, and heterotopia) showed activity in only 44% (Figure 2.). Both focal neurological signs and focal EEG slowing independently correlated with MCD inactivity, confirming that fMRI shows neural functions of MCD. That study confirmed that fMRI visualizes the MCD functions and their relationship to the eloquent cortex, providing useful information before epilepsy surgery and suggesting that surgery of cortical organization disturbances should be cautiously

Figure 2. Basic fMRI paradigms. A During visual stimulation, the primary visual cortex in the occipital lobe shows a symmetric activation in both hemispheres despite the presence of a widespread right-sided temporo-parieto-occipital heterotopia. B During finger movements activation is seen around the central sulcus. This patient had schizencephalia and this fMRI examination proved that the caudal part of the dysgenesis also contributed to the motor functions

performed because these malformations may participate in normal brain functions5. STUDYING PATHOMECHANISM OF HUMAN EPILEPSY BY FMRI

The fMRI combined with simultaneous EEG (EEGfMRI) is a new technique which was developed in the last 5 years. It combines the advantages of EEG (specificity to functional abnormalities underlying epilepsy and high temporal resolution) with the advantages of fMRI (high spatial resolution). At present, this technique can demonstrate epileptic functional disturbance with the highest spatial and temporal resolution. Although the technique is not available or not used in most presurgical centers, in the future it can be one of the major tools in identifying pathological electrophysiological event in epilepsy and their site of origin (“spike mapping”). Moreover, it is a novel method in investigating sleep and its disorders.

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EEG-fMRI provides a unique opportunity to study the pathophysiology of epilepsy in humans. For example, a recent study defined the neural correlates of generalized spike-wave discharges in order to understand the mechanism underlying idiopathic generalized epilepsy (IGE). Symmetrical reduced activation in the cortex and a bilateral thalamic hyperactivity was found suggesting that IGE is a disorder of thalamo-fronto-cortical network19. Ictal fMRI can be performed only in rare cases where there is no loss of consciousness and there are no rough movements during epileptic seizures. In a recent study, using a novel approach for postprocessing ictal fMRI data, epileptic activity including seizure spread could be visualized. This has been the first study that describes a whole-brain activity during a clinical epileptic seizure in time and space simultaneously and helps in a better understanding of the pathophysiology of the seizure spread20. Moreover, the identification of the putative pacemaker by ictal fMRI area can be crucial for presurgical evaluation of epilepsy patients without detectable epileptogenic lesions20.

additional parameter reflecting the metabolic state of the threatened brain tissue27. FMRI is not only able to illustrate diminished functional capability of damaged brain areas, but provides information about recovery. Total infarct volume has long been used as a measure of injury and predictor of outcome in stroke studies28. Functional map of the brain injury by using fMRI is more strongly associated with the functional outcome than the total infarct volume. Moreover, the intensity of the activation in the “classical” motor network by using motor task after stroke has a predictive value: the higher the early activation in the ipsilesional motor areas is, the better the long-term post-stroke recovery is29. Our brain is highly adaptive even in case of a damage caused by stroke. This reorganization plays an important role in post-stroke recovery. Mapping language comprehension, patients during recovery from acute left-sided stroke presenting with aphasia revealed that recovery of aphasia in adults can occur rapidly with a shift of activation to the homologous region in the right hemisphere within 3 days, with continued rightward lateralization over six months30.

Stroke Multiple sclerosis Functional changes caused by stroke can be demonstrated by using fMRI. For example, cortical activation mapping during visual stimulation can accurately map functional and perfusion deficits in patients suffering from occipital stroke within the primary visual cortex21. In acute ischemic stroke, the “penumbra” is defined as brain tissue with loss of electric activity but potential recovery after recanalization of the occluded artery22. The only approved therapy for acute stroke is thrombolysis23, which is believed to save penumbral tissue by early recanalization. The “mismatch concept” has been suggested to provide an estimate of the real ischemic penumbra and is used in MRI stroke centers in acute stroke to select patients who might benefit from thrombolysis. Recent findings indicate that the subtraction of the ischemic lesion on diffusion-weighted imaging (DWI) from the blood flow abnormality on perfusion-weighted imaging (PWI) is only a weak approximation of the penumbra24; PWI cannot reliably discriminate between benign oligaemia and penumbra and DWI abnormalities do not indicate the irreversibly damaged core of infarction because normalization may occur25, 26. Penumbra can be identified by using fMRI and BOLD imaging, and compared with DWI and PWI they can provide an

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There are three major roles for fMRI in multiple sclerosis (MS): 1. assessing the reorganization of functions after MS-attacks, 2. evaluating the relationship between the morphological and functional changes in MS, and 3. understanding the progression in MS. It is an unresolved question why many patients with MS have normal level of performance despite the presence of multifocal or even diffuse and irreversible brain injuries. The reorganization of brain functions demonstrated by fMRI can be one of the explanations for morphological-functional discrepancy in MS. Even after a first single attack of MS (such as clinically isolated syndrome suggestive of multiple sclerosis) a reorganization of cortical functions can be demonstrated despite the complete clinical recovery31. In relapsing-remitting MS (RRMS) an adaptive reorganization can be demonstrated affecting the visual, motor, and memory systems. Despite preserved functional performance there is an atypical brain organization demonstrated by fMRI32. Much more extensive reorganization can be demonstrated in secondary progressive MS (SPMS). In primary progressive MS (PPMS) the classical reorganization pattern of other types of MS is not seen33.

Auer: Functional magnetic resonance imaging in neurology

These findings arise a theory explaining the different forms of MS: 1. functional recovery in RRMS is caused by a complete reorganization; 2. SPMS is a cause of the exhaustion of further reorganization capacities; 3. PPMS is caused by a disturbed reorganization. Thus, the different stages of MS are related to different stages of the reorganization and MS becomes progressive when there is no more reserve capacity in the brain for reorganization34. FMRI studies suggest that the cause of fatigue frequently seen in MS is caused by a complex reduced fMRI activation in high-order cortico-subcortical networks. Furthermore, there is a correlation between the severity of fatigue and reduction of thalamic activity35.

Parkinson’s disease According to the classic model of the motor deficits of Parkinson’s disease (PD), the internal segment of the globus pallidus has an increased inhibitory drive to the thalamus that reduces the excitatory thalamic drive to the cerebral cortex. This model is supported by brain imaging studies showing reduced regional cerebral blood flow (rCBF) and reduced BOLD activation in the basal ganglia, and in cortical regions such as the supplementary motor area (SMA) and dorsolateral prefrontal cortex (DLPFC)36, 37. Conversely, fMRI studies in PD patients using a variety of motor tasks have found hyperactivation in the contralateral primary motor cortex38 and the cerebellum39, 40. Hyperactivation in PD patients has been suggested as a strategy of the central nervous system to compensate for the defective function in the basal ganglia38–40. Cerase and coworkers showed evidence for this compensatory mechanism examining external and internal timed movement: PD patients displayed an intact capability to store and reproduce movement frequencies but with a significantly increased movement and latencies41. Meanwhile, they exhibited an overall signal increase in the cerebellum and frontostriatal circuit (putamen, SMA and thalamus) activity together with specific brain areas (right inferior frontal gyrus and insula cortex) that are also implicated in primary timekeeper processes. According to an alternative theory, hyperactivation could be related to specific signs of the disease such as rigidity42. FMRI can also provide information about mechanisms of different therapeutic approaches43. According to the basal ganglia-thalamocortical circuit model, dopamine depletion in the nigrostriatal sys-

tem leads to hypoactivation in the SMA and the primary motor cortex (M1) in Parkinson’s disease44, 45. This functional deafferentation and its reversibility by levodopa (L-dopa) treatment have been established both for SMA44 and for M145. The combination of fMRI and deep brain stimulation (DBS) is particularly attractive to study the effects of discrete perturbations at different target structures throughout the basal ganglia-thalamocortical circuitries. Therapeutically effective unilateral stimulation of the subthalamic nucleus (STN)46 or the ventral intermedius nucleus of the thalamus (VIN) can be performed safely during functional MR imaging at 1.5 and 3 T by using external pulse generator. An increase in BOLD signal was shown in the subcortical regions ipsilateral to the stimulated nucleus which may be caused by overstimulation of the target nucleus, resulting in the suppression of its spontaneous activity47.

Alzheimer’s disease FMRI can be used to study the neural correlates of complex cognitive processes, and the alterations in these processes that occur in the course of normal aging or a superimposed neurodegenerative disease. Due to the nature of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI), most of the studies have focused on different memory tasks. Medial temporal lobe (MTL) playing a crucial part in successful encoding of new memories in both young and healthy older subjects and showing significantly decreased activation during MCI and AD48–50. There is a positive correlation between fMRI activity in MTL and hippocampal gray matter volume illustrating further evidence for linked structural and functional impairment of MTL51. AD is often associated with deficit in calculation abilities and sometimes with progressive visuospatial dysfunction directing our attention to the parietal lobe involved in spatial attention. The involvement of parietal lobe in AD was demonstrated using both arithmetic task consisting of three-digit addition and subtraction51 and memory tasks49. Beside of illustrating functional substrate of AD, fMRI offers the capability of detecting early functional hemodynamic alterations in Alzheimer’s disease before gross anatomic alterations. Assessment of the diagnostic efficacy of these technologies in detecting early AD in its preclinical and prodromal stages is ongoing52. Genetic assessments in combination with other diagnostic tools, such as neuroimaging, have the

Ideggyogy Sz 2008;61(1–2):16–23.

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potential to facilitate early diagnosis. Apolipoprotein E epsilon4 (APOEε4) is the main known genetic risk factor for Alzheimer’s disease. APOEε4 carrier otherwise symptom-free subjects showed reduced task-related responses in the left inferior parietal cortex, and bilaterally in the anterior cingulate region during a semantic categorization task53. More recently, some fMRI studies of subjects at risk for AD, by virtue of their genetics or evidence of MCI have yielded variable results suggesting that there may be a phase of paradoxically increased activation early in the course of prodromal AD50. Preliminary evidence suggests that fMRI might

be a valuable tool to test and monitor treatment efficacy in AD. After cholinesterase inhibitor treatment, increased attention in AD patients is related to hyperactivity in certain brain regions54. Furthermore, the response detected by fMRI to cholinergic drugs is different between MCI and AD55. ACKNOWLEDGEMENTS This work was supported by the Bolyai Fellowship (JJ) and the “Habilitas” Scholarship MFB (TA), grants from the Hungarian Neuroimaging Foundation, from the Hungarian Medical Research Council (ETT 219/2006 and ETT 176/2006) and from the Hungarian Research Fund (OTKA-NKTH F68720).

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