originalia | original articles dza akupunktur · akupunktur, raucherentwöhnung, fmrt, rct,...

AkupunkturG e r m a n J o u r n a l o f A c u p u n c t u r e & R e l a t e d T e c h n i q u e s

D e u t s c h e Z e i t s c h r i f t f ü r

DZA

Originalia | Original articles

DOI : 10. 10 16/ j .dza .20 14 .0 .004 1818 Dt. Z tschr. f. Akupunktur 57, 3 / 20 14

K. Theodoratou1, F. Christidi2, P. Toulas3, D.A. Verganelakis3

An fMRI Study prior and post acupuncture treatment during the first 24 hours of smoking cessation

fMRT-Studie vor und nach Akupunkturbehandlung während der ersten 24 Stunden nach Beginn der

Raucherentwöhnung

Konstantina TheodoratouMD, MSc, Med. Psych.President of ICMARTPresident of SAMAG

69 Poseidonos Ave., 17456Athens, [email protected]

1President of ICMART, President of SAMAG, Alimos, Greece. 2Aiginiteion Hospital, Athens. 3Medical Diagnostic Center “Encephalos-Euromedica”, Halandri, Greece.

AbstractSubstance dependence or addiction is nowadays understood in a multifactorial etiological model, which includes psychologi-cal, neurobiological, genetic, social and environmental factors. The cigarette is a very effi cient and highly engineered drug de-livery system. When tobacco is smoked, nicotine rapidly reaches peak levels in the bloodstream and enters the brain. Recent re-search has shown how nicotine acts on the brain to produce a number of eff ects. Nicotine withdrawal symptoms include irri-tability, craving, depression, anxiety, cognitive and attention defi cits, sleep disturbances, and increased appetite. These symp-toms may begin within a few hours after the last cigarette, quickly driving people back to tobacco use. Many behavioral factors can also aff ect the severity of withdrawal symptoms. For some people, the feel, smell, and sight of a cigarette and the ritual of obtaining, handling, lighting, and smoking the cigarette are all associated with the pleasurable eff ects of smok-ing and can make withdrawal or craving worse. Acupuncture has been used in the treatment of nicotine dependence. This study will demonstrate the potential eff ects of acupuncture treatment for smoking cessation using the brain scanning method of fMRI to 10 heavy smokers and 5 non smokers. The fMRI has been applied prior and post acupuncture treatment during the fi rst 24 hours of smoking cessation.

KeywordsAcupuncture, smoking cessation, fMRI, RCT, sham acupuncture

ZusammenfassungSubstanzabhängigkeit oder Sucht wird heutzutage im Kontext eines multifaktoriellen ätiologischen Modells gesehen, das psy-chologische, neurobiologische, genetische, soziale und umwelt-bedingte Faktoren umfasst. Die Zigarette ist ein überaus effi zientes und hoch entwickeltes System der Wirkstoff applika-tion. Beim Tabak rauchen erreicht das Nikotin im Blutstrom rasch Spitzenwerte und gelangt ins Gehirn. In neueren For-schungsarbeiten konnte gezeigt werden, wie das Nikotin das Gehirn beeinfl usst und eine Reihe von Wirkungen auslöst. Zu den Nikotinentzugssymptomen zählen Reizbarkeit, Suchtdruck, Depressivität, Angstzustände, kognitive und Aufmerksamkeits-defi zite, Schlafstörungen und vermehrter Appetit. Diese Symp-tome können innerhalb weniger Stunden nach der letzten Zigarette einsetzen und die Betroff enen unverzüglich in den Tabakkonsum zurücktreiben. Zudem können zahlreiche verhal-tensrelevante Faktoren den Schweregrad der Entzugserschei-nungen beeinfl ussen. Für manche Menschen verbinden sich die Haptik, der Geruch und der Anblick einer Zigarette sowie das Ritual, sich Zigaretten zu beschaff en, sie in die Hand zu neh-men, anzuzünden und zu rauchen mit den angenehmen Seiten des Rauchens. Das kann die Entzugserscheinungen oder den Suchtdruck verschärfen. Akupunktur wurde zur Behandlung der Nikotinabhängigkeit eingesetzt. Die vorliegende Studie zeigt das Potenzial einer Akupunkturbehandlung bei Nikotinabhängigkeit. Zu diesem Zweck wurde das Gehirnscanning per fMRT bei zehn starken Rauchern und fünf Nichtrauchern eingesetzt. Die fMRT erfolgte vor und nach der Akupunkturbehandlung während der ersten 24 Stunden nach Beginn der Raucherentwöhnung.

SchlüsselwörterAkupunktur, Raucherentwöhnung, fMRT, RCT, Scheinakupunktur

BackgroundQuitting smoking remains a challenge for almost all health professionals. Acupuncture has been widely reported to be a popular and safe intervention for smoking cessation. Several controlled studies have evaluated acupuncture as an aid to smoking cessation. Smoking-related cues are used to study brain reactivity following smoking, acute or extended nicotine abstinence, considering that the craving elicited by smoking-related cues is often reported by smokers as the precipitating factor of relapse when trying to quit smoking [1].

ObjectiveThis study will demonstrate the potential eff ects of acupuncture treatment for smoking cessation using the brain scanning method of fMRI to smokers (underwent acupuncture and sham acupuncture) and to control group/non smokers.

Methods

SampleThe study sample was composed of 15 subjects. Data collection was accomplished in the Acupuncture Medical Clinic, 69 Posei-donos Ave., Athens Greece.

7


Dt Z tschr f Akup. 57, 3 / 20 14 1919 DZA

An fMRI Study prior and post acupuncture treatment

during the first 24 hours of smoking cessation

K. Theodoratou,

F. Christidi, P. Toulas,

D.A. Verganelakis

Participants were volunteers willing to quit smoking, joined on May and June 2013. The inclusion criteria were age between 28–42 and currently smoking > 15 cigarettes per day and no previous experience of acupuncture treatment. Study exclusions included pathologic condition, pregnancy, cardiac pacemaker or defi brillator, actively mental disorder, severe cognitive impair-ment, current signifi cant substance abuse disorder and currently receiving another intervention for smoking cessation. All were volunteers willing to participate in a treatment protocol involv-ing acupuncture, they signed all necessary consent forms and completed an intake questionnaire that collected demographic information and the baseline dependent variables. They also fi lled in the Fagerström test for Nicotine Dependence and their score were 7–9 (high dependence). All treatments given during the course of the study were provided to subjects free of charge. Standardized acupuncture treatments were administered by one highly trained and experienced acupuncturist. Acupuncture points were prepared with 75 % alcohol prep pads. Acupuncture points used: Du-20, LI-20, LI-4, TB-5, ST-36, LIV-3. The real ac-upuncture needle (sterile, disposable, 25 mm long, 0.22 mm di-ameter, Shen Long, Wujiang City Shenglong Medical Health Products CO, LTD, P.R.China) was inserted to a depth of 0.8 cm, perpendicular to the surface of the skin. The sham acupuncture needle (sterile, disposable, 30 mm long, 0.30 diameter, Steitberger Placebo-needles, Asia-med GmbH & Co.KG Germany) was not inserted to the skin but to a plastic ring and stuck on the skin.Treatments were administered without manual stimulation and lasted approximately 20 minutes, with participants lying on medical beds. Interaction was limited to the time required for needle placement and withdrawal. The participants were not informed of the real or sham acupuncture condition.Smokers were blindly divided into two groups: Group A received real acupuncture, Group B received sham acupuncture. Group C was the control group with the non smokers.fMRI has been applied prior and post acupuncture treatment to 10 heavy smokers and 5 non smokers during the fi rst 24 hours of smoking cessation. Smokers passed through two separate fMRI sessions. Between these sessions, all subjects agreed to abstain from smoking for 10 h.

ProcedureThe technique that was used throughout this study for the eff ects of acupuncture was functional Magnetic Resonance Imaging (fMRI). fMRI is a powerful technique for the non-invasive study of brain functional centers, such as vision, speech, motor, cognitive, etc. fMRI can determine neuronal activity based on the Blood-Oxygenation-Level-Dependent (BOLD) physiological phenomenon, where local neuronal activities are accompanied by local increase in metabolism which generates a local demand for oxygen and nutrients. The latter is satisfi ed by a surplus local increase in blood supply which overall generates a locally relative small increase of the MRI signal [2]. Numerous publications describe fMRI’s usefulness in cognitive and neuropsychological studies where specifi cally designed paradigms elicit brain’s functionality. In neurosurgical settings, the application of fMRI aims to identify the spatial correlation between the pathology to be extracted via surgery and the adjacent functional centers. Thus, it helps towards a safe pre-operative planning, enabling the maximization of pathological tissue removal with the

minimum possible post-operative defi cit. fMRI has numerous applications in medicine, such as, in Alzheimer, Epilepsy, Schizophrenia, cognitive studies, assessment of therapies, assessment of new drugs, assessment of comatose patients, as well as in other fi elds such as neuromarketing, etc [3].The main advantages of fMRI are its non-invasive nature, its reproducibility, its low cost, its spatial and temporal resolution and its robustness. Moreover, comparing fMRI and EEG or MEG, the former is capable towards studying both cortical and intrasulcal brain volumes. Finally, brain studies with fMRI do not require the injection of contrast media. However, fMRI studies are limited to group studies that fulfi ll the following requirements: i) examinees must be free of pacemakers, any metallic implants, electronic devices for vital organs, cochlear implants and in general they must be free of any metalic-magnetic materials-apparatus. Also, female subjects must not be pregnant; ii) examinees must be cooperative, performing paradigms as instructed. Motion artifacts due to head or respiratory movements or cardiac pulsations can infl uence experimental data. After obtaining a detailed medical history of all participants, as well as reading, understanding and signing the consensus form for participating to the current study, clear instructions were given for the minimization of any unnecessary head and body motion. Cushions and tapes were used for the minimization of head motion. During the fMRI scans, attention was paid to monitor participants’ performance. Brain imaging was performed in a 1.5 T GE Signa HDxt magnet using an eight element high signal-to-noise ratio head coil. The parameters of the anatomical images were: 3-d T1 mprage with 248 axial images, TE = 4.7 ms, TR = 11 ms, Th/Sp = 1.4/–0.7 mm, FOV: 26, 320 × 320, NEX: 0.7. Echo Planar Imaging (EPI) gradient echo was the pulse sequence used in order to record the fMRI data, with 1,000 images throught each imaging brain, TE = 65 ms, TR = 3000 ms, Th/Sp = 5/1.5 mm, FOV: 24, 96 × 96, NEX: 1.After accumulating 3-dimensional anatomical images, the actual fMRI experiment was performed during which a series of smoking related pictures was presented to each participant via a set of non-magnetic goggles. The visual stimuli for the fi rst experiment was consisting of 10 pictures having a theme concerning smoking, i.e. lighted cigarettes, non-lighted cigarettes, ashtrays, smokers while smoking, etc (Fig. 1). The second experiment was consisting of the same pictures but this time were presented in a black and white mode. All pictures were normalized with respect to light intensity and the theme was centralized in the image plane.

Fig. 1: Black and white smoking related pictures.



DZA


DZA 20 20 Dt Z tschr f Akup. 57, 3 / 20 14

The design of the fMRI experiment was a block type one: for 30 s a white background with a small cross in the middle was presented, corresponding to the non-active period. For the next 30 s a block of a series of 10 pictures were presented each lasting for 3 s. This period was corresponding to the active one. A 30 s period of non-activity followed. A second period of 30 s of pictures presentation of the same block of pictures followed. Finally, the paradigm was terminated after a 30 s of non-activity. The series of pictures being presented was the same (Fig. 2).fMRI data was analyzed using the BRAINWAVE software (General Electric). Statistical analysis was performed on a voxel-by-voxel basis using statistical parameters such as the Z-score (number of standard deviations above the mean), as well as p-values. The produced and considered activation maps exhibit voxels with a Z-score larger than a given statistical threshold. Only statistically signifi cant pixels were considered with a p-value of 0.05 and a correspond Z-score of 4.59, demonstrating a 95 % confi dence level regarding the correlation between the active-passive block design pattern of the paradigm and the fMRI data (Fig. 3).

Results – DiscussionIn our study, at fi rst scan, the inclusion of smoking-related cues (color and black-and-white images) compared to the control neutral condition of a simple cross induced a pattern of fMRI

activation in frontal, temporal, parietal and occipital cerebral regions, as well as cerebellum. Increased brain response areas included – though not exclusively and specifi cally – dorsolateral prefrontal, primary motor gyrus, parahippocampal gyrus and hippocampus, insula, posterior cingulate cortex, somatosensory cortex, visual areas and external basal ganglia. Slightly diff erent fMRI responses were found in black-and-white smoking-related images compared to the color smoking images. Of interest, the observed activation in parahippocampal gyrus, hippocampus, insula, cingulate cortex and basal ganglia were observed when we included black & white smoking visual cues. At second scan, brain activation following real acupuncture elicits fMRI response in frontal, temporal, parietal and occipital cerebral regions, as well as cerebellum. However, primary motor and somatosensory cortices, hippocampus and insula were not activated but orbitofrontal gyri were found to respond to smoking-related cues. In the post-acupuncture scan, basal ganglia activation was found as in the pre-acupuncture scan for black-and-white smoking cues. Of interest, in the sham-acupuncture group, primary motor and somatosensory cortices showed brain activation but hippocampus, parahippocampal gyri and posterior cingulum did not show any activation either in color or black-and-white visual cues. Recent meta-analytic fi ndings support that comparing smoking-related and neutral cues, larger fMRI activation can be found in the extended visual system, precuneus, anterior and posterior cingulate gyrus, dorsal and medial prefrontal cortex, insula and dorsal striatum [4]. The exposure of a smoker to smoking-related cues has been shown to increase brain activation in the mesolimbic (nucleus accumbens, amygdala, and hippocampus) and the mesocortical (prefrontal cortex, orbitofrontal cortex, and anterior cingulate) dopamine circuits [5–7], which play an important role in the development and maintenance of drug addiction and mediates higher cognitive processes of attention, reward, goal directed behavior, conditional learning and memory.A number of brain areas continue to be reactive to smoking related cues and some regions show increased reactivity, which may facilitate craving and habitual responding to smoking-related cues and indicate vulnerability to relapse while trying to quit smoking [4]. Prefrontal, parietal and primary somatosensory cortices are involved in imagined and executed

Fig. 3: fMRI pictures: activation maps superimposed upon anatomical T1 images.

Fig. 2: The block design temporal pattern.

Dt Z tschr f Akup. 57, 3 / 20 14 2 12 1 DZA


movement [8]. Greater brain activity in action planning- and decision making-related areas has been associated with greater abstinence-induced craving [7], the posterior cingulate is involved in attention to reward-associated stimuli [10]. Smoking-related cues may be processed either like rare targets activating attentional-related brain regions or like addictive drugs activating mesolimbic reward system [6]. Attentional mechanisms (e.g. bias) in combination with motivational and reward-related mechanisms (e.g. subjective craving) play a role in smoking-related cue brain reactivity [11]. The dorsolateral prefrontal cortex, the putamen, the posterior cingulate cortex and the primary motor cortex have been associated with the attentional bias to smoking-related cues, whereas the orbitofrontal cortex, the insula and the superior temporal gyrus have been associated with smoking-related cue-induced craving and smoking urges [11]. Apart from the role of amygdala to stimulus-reward learning [12], the hippocampus has been broadly considered to be important for contextual conditioning, specifi cally in the processing of contextual cues associated with drug-taking experiences [13]. In addition, increased brain activity within the insula is associated with increased interoceptive awareness [14]. Furthermore, acute and extended smoking abstinence is associated with enhanced dorsal striatal reactivity to smoking-related cues [7, 15]. Brain reactivity to smoking-related cues following 24-h smoking abstinence in several brain areas including basal ganglia can be interpreted under the assumption of the incentive-sensitization theory of drug use and provide evidence over persisting relapse vulnerability after abstinence. Basal ganglia activation has also been observed after extended abstinence [15]. Acupuncture has been used in the treatment of nicotine dependence mostly for the withdrawal symptoms. A recent meta-analysis of brain activity in response to acupuncture showed increased activation following acupuncture needle stimulation in the sensorimotor cortical network, inclu ding the insula, thalamus, anterior cingulate cortex, and primary and secondary somatosensory cortices, and reduced activation in the limbic-paralimbic neocortical network,

including the medial prefrontal cortex, caudate nucleus, amygdala, posterior cingulate cortex, and parahippocampus [16]. It has been also found that acupuncture manipulation in comparison to sham or tactile stimulation selectively activates several cerebellar areas [17]. The acupuncture treatment decreased brain activation in response to the smoking-related visual cues in the major neural pathways involved in cue reactivity, such as the amygdala, the hippocampus, and the prefrontal cortex [18]. Chae and colleagues (2010) investigated the eff ect of acupuncture on selective attention bias for smoking-related visual cues in smokers as an index of severity of drug dependence, comparing two groups who received real or sham acupuncture [19]. Acupuncture treatment ameliorated the smoking withdrawal symptoms and resulted in marked attenuated attentional bias towards smoking cues. Reduced attentional bias was also associated with reduced cigarette withdrawal symptoms [19]. Acupuncture reduces not only the withdrawal symptoms but also the sympathetic responses to smoking-related visual cues during nicotine abstinence [19]. The use of acupuncture induced inhibitory eff ects, via the mesocortico-limbic dopaminergic pathway and possibly by modulating postsynaptic neuronal

3BLASERNEEDLE

Schmerzfreie Behandlung

Zuverlässige Technologie

Made in GermanyFig. 4

An fMRI Study prior and post acupuncture treatment

during the first 24 hours of smoking cessation

K. Theodoratou,

F. Christidi, P. Toulas,

D.A. Verganelakis



DZA


DZA 2 2 2 2 Dt Z tschr f Akup. 57, 3 / 20 14

activity in the nucleus accumbens and the striatum, on behavioral sensitization and withdrawal symptoms in several animal models of nicotine addiction [20].

ConclusionWe report here the fi ndings of our study of smoking cessation via acupuncture by means of the fMRI technique. Despite the fact that methodological issues did not allow the generalization of our fi ndings, our preliminary study using two samples of both genders provides evidence over a pattern of slightly diff erent brain activation following real and sham acupuncture after short-term (< 24 h) smoking abstinence, with diff erences being observed in areas commonly involved in drug addiction and smoking maintenance/abstinence literature.

Bibliography 1. Shiff man S, Balabanis MH, Gwaltney CJ, et al. Prediction of lapse from

associations between smoking and situational antecedents assessed by ecological momentary assessment. Drug Alcohol Depend. 2007;91:159–68

2. Kapsalakis I, Kapsalaki E, Gotsis E, et al. Preoperative Evaluation with fMRI of Patients with Intracranial Gliomas. Radiology Research & Practice. Volume 2012, Article ID 727810

3. Kapsalaki EZ, Verganelakis DA, Kapsalakis IZ, et al. The Role of Functional MRI in Intracranial Glioma Resection. In P. Bright (ed), Neuroimaging: Clinical Applications. 2012; In Tech.

4. Engelmann JM, Versace F, Robinson JD, et al. Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies. Neuroimage. 2012;60:252–62

5. David SP, Munafo MR, Johansen-Berg H, et al. Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: A functional magnetic resonance imaging study. Biol. Psychiatry. 2005;58:488–94

6. Due DL, Huettel SA, Hall WG, et al. Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: Evidence from functional magnetic resonance imaging. Am. J. Psychiatry. 2002;159:954–60

7. McClernon FJ, Kozink RV, Lutz AM, et al. 24-h smoking abstinence potentiates fMRI-bold activation to smoking cues in cerebral cortex and dorsal striatum. Psychopharmacology (Berl.). 2009;204:25–35

8. Gerardin E, Sirigu A, Lehericy S, et al. Partially overlapping neural networks for real and imagined hand movements. Cerebral Cortex. 2000;10:1093–104

9. Devinsky, O., Morrell, M.J., Vogt, B.A. Contributions of anterior cingulate cortex to behaviour. Brain. 1995;118:279–306

10. Smith DM, Freeman JH, Jr, Nicholson D, et al. Limbic thalamic lesions, appetitively motivated discrimination learning, and training-induced neuronal activity in rabbits. The Journal of Neuroscience. 2002; 22:8212–21

11. Kang OS, Chang DS, Jahng GH, et al. Individual diff erences in smoking-related cue reactivity in smokers: An eye-tracking and fmri study. Prog. Neuropsycho-pharmacol. Biol. Psychiatry, 2012;38:285–93

12. Baxter MG, Murray EA. The amygdala and reward. Nat Rev Neurosci. 2002;3:563–73

13. Volkow ND, Fowler JS, Wang GJ. The addicted human brain: insights from imaging studies. J Clin Invest. 2003;111:1444–51

14. Critchley HD. Neural mechanisms of autonomic, aff ective, and cognitive integration. J Comp Neurol. 2005;493:154–66

15. Janes AC, Frederick B, Richardt S, et al. Brain fmri reactivity to smoking-related images before and during extended smoking abstinence. Exp. Clin. Psychophar-macol. 2009;17:365–73

16. Chae Y, Chang DS, Lee SH, et al. Inserting needles into the body: a meta-analysis of brain activity associated with acupuncture needle stimulation. J Pain. 2013;14:215–22

17. Yoo SS, The EK, Blinder RA, et al. Modulation of cerebellar activities by acupuncture stimulation: evidence from fMRI study. Neuroimage. 2004;22:932–40

18. Kang OS, Chang DS, Jahng GH, et al. Individual diff erences in smoking-related cue reactivity in smokers: An eye-tracking and fMRI study. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2012;38:285–93

19. Chae Y, Kang OS, Lee HJ, et al. Eff ect of acupuncture on selective attention for smoking-related visual cues in smokers. Neurol Res. 2010;32:27–30

20. Chae Y, Lee JC, Park KM, et al. Subjective and autonomic responses to smoking-related visual cues. J Physiol Sci. 2008;58:139–45

Ausschreibung des Hufeland-Forschungspreises 2014

Die Hufelandgesellschaft fördert Wissenschaft und Forschung auf dem Gebiet der Naturheilverfahren und Komplementärmedizin und setzt sich unter anderem für ein eigenständiges, mit öff entlichen Mitteln gefördertes Forschungsprogramm für die Komplementärmedizin ein. Um Forschung und Wissenschaft zu unterstützen und sichtbar zu machen, schreibt die Hufelandgesellschaft seit 2009 regelmäßig den Hufeland-Forschungspreis aus.Integrative und komplementäre Medizinansätze verfolgen meist systemische Therapieansätze und lassen sich durch einfache Ursache-Wirkmechanismen nur ungenügend abbilden. In der Versorgungsforschung wird eine Realität abgebildet, die es erlaubt, auch komplexe und systemische Therapieansätze in ihren Kurz-, aber vor allem auch Langzeitwirkungen zu beurteilen. Diese Form von Wirksamkeitsmessungen kann daher vor allem auch im ambu-lanten Medizinversorgungsbereich durchgeführt werden, wo integrative und komplementäre Therapieformen ihre Haupt anwendung erfahren.Der Preis wird deshalb für Forschungsarbeiten aus der Komplementär- oder Integrativen Medizin, insbesondere auf dem Gebiet der Versorgungs-forschung ausgeschrieben. Er ist mit 1.500 Euro dotiert.Eingereicht werden können alle relevanten Arbeiten, die einen wesentli-chen Beitrag insbesondere auf den Gebieten der primären und sekundären Prävention und Therapie unter Anwendung komplementärer und/oder integrativer Methoden leisten.Nicht berücksichtigt werden Versorgungsforschungsarbeiten, die lediglich konventionelle medizinische Konzepte abbilden.

Die ausführlichen Bewerbungskriterien sind auf http://www.hufelandgesellschaft.de/hufeland_forschungspreis_2014.html veröff entlicht.Einsendeschluss ist der 15. September 2014.

Kontakt für Rückfragen:Geschäftsstelle der HufelandgesellschaftDachverband der Ärztegesellschaften für Naturheilkunde und KomplementärmedizinMarion LaubeChausseestraße 29D-10115 Berlinwww.hufelandgesellschaft.deTel.: +49 30 2809-9320Fax: +49 30 [email protected]

Die Hufelandgesellschaft spricht für 20.000 Ärztinnen und Ärzte und ver-tritt damit die komplementärmedizinisch tätige Ärzteschaft in Deutschland. Als größter ärztlicher Dachverband der Komplementärmedizin in Deutsch-land setzt sich die Hufelandgesellschaft mit Nachdruck für die Erhaltung und Stärkung der Komplementärmedizin ein.

originalia | original articles dza akupunktur · akupunktur, raucherentwöhnung, fmrt, rct,...

Documents