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Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS)

TL;DR: It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting.
About: This article is published in Clinical Neurophysiology.The article was published on 2017-01-01 and is currently open access. It has received 1062 citations till now. The article focuses on the topics: Transcranial direct-current stimulation & Dorsolateral prefrontal cortex.

Summary (7 min read)

Highlights

  • A group of European experts reviewed current evidence for therapeutic efficacy of tDCS.
  • Level B evidence (probable efficacy) was found for fibromyalgia, depression and craving.

1. Principles and mechanisms of action of transcranial direct current stimulation

  • Alterations of neuroplasticity and cortical excitability are important pathophysiological factors in many neuropsychiatric diseases.
  • As shown by a navigated TMS study, M1 excitability changes become steadily significant after the end of tDCS application rather than during stimulation (Santarnecchi et al., 2014).
  • In patients with cerebral diseases, besides neuronal damage, other important pathological processes may exist in the axonal microenvironment, such as inflammation.
  • In other words, tDCS might be able to influence several pathological processes and pathogenetic cascades in the central nervous system, well beyond the sole change of neuronal excitability.
  • The local cellular influence of DC fields into the brain is complex, depending on the distance and orientation of the axonal or somatodendritic axis with respect to the electric field (Purpura and McMurtry, 1965; Gluckman et al., 1996; Bikson et al., 2004).

2. Clinical applications of tDCS: literature data analysis

  • For each potential clinical indication of tDCS, a bibliographic search was carried out by several experts independently, using specific keywords that will be specified at the beginning of each section.
  • First, the studies were classified (I to IV) according to decreasing value of evidence.
  • A Class II study is a randomized, placebo-controlled trial performed with a smaller sample size (n≥10, but <25) or that lacks at least one of the above-listed criteria a–e.
  • Level A (“definitely effective or ineffective”) requires at least two convincing Class I studies or one convincing Class I study and at least two convincing Class II studies.
  • For each indication, only clinical results reported in controlled studies, published before the end of the bibliographic search (September 1st, 2016), based on repeated tDCS sessions with sham tDCS control procedure, and including at least 10 patients receiving active stimulation, were included in the evidence-based analysis.

3. Pain

  • The literature review included studies related to ongoing chronic pain, or acute postoperative pain, and therefore excludes publications on the use of tDCS to relieve pain experimentally induced in healthy subjects, reviewed elsewhere (Mylius et al., 2012).
  • In all indications, the authors first screened literature data for original clinical trials, excluding any other papers, such as reviews, editorials, or experimental studies regarding animals or healthy subjects.
  • As a conclusion, the present level of evidence for the analgesic effect of M1 stimulation is weaker for tDCS than for rTMS (Lefaucheur et al., 2014).
  • It has been suggested that rTMS might activate similar networks as epidural motor cortex stimulation (Lefaucheur et al., 2010), of which analgesic effect is obtained according to the placement of cathode(s) over the precentral gyrus (Holsheimer et al., 2007a,b), in contrast to tDCS for which the precentral electrode is classically an anode.

4. Parkinson's disease

  • In advanced Parkinson’s disease (PD), the emergence of fluctuations, dyskinesias, difficulties with gait and postural control, cognitive impairment and non-motor symptoms refractory to conventional therapy poses therapeutic challenges.
  • In the literature, there are only three sham-controlled therapeutic tDCS trials based on repeated sessions of tDCS delivered over the motor cortex and including at least 10 PD patients in the active tDCS condition: two were parallel-designed and the other crossover-designed randomized controlled trials (RCTs) (Table 2).
  • In one parallel-designed RCT (Benninger et al., 2010), the safety and efficacy of anodal tDCS applied to the motor and prefrontal cortices in 8 sessions over 2.5 weeks were investigated.
  • The long-lasting persistence of effects in the both RCTs points out to plasticity phenomena.
  • Other results concerned small series of patients and mostly singlesession protocols with short-lasting effects.

5. Other movement disorders

  • Actually, published tDCS studies on movement disorders other than PD are rare and have been recently reviewed (Ferrucci et al., 2016).
  • Active stimulation significantly decreased the number of motor and phonic tics in both patients at the end of the 5-day treatment.
  • Regarding tDCS and dystonia, a PubMed search (keywords: tDCS AND dystonia) identified 32 papers, including 15 original clinical studies and 147 patients.
  • Most studies are case reports or small case series.
  • Approximately only half of the studies included at least 10 patients.

6. Motor stroke

  • The recovery of motor function after stroke is one of the most important issues addressed in neurorehabilitation medicine.
  • As for the other indications, the authors excluded from the analysis all studies that do not have a control condition using sham tDCS, a sample size with at least 10 patients receiving active tDCS, and a design consisting of repeated daily sessions.
  • Two large RCTs, fulfilling the criteria for class I, did not show any significant clinical effect of tDCS on motor function recovery (Hesse et al., 2011; Rossi et al., 2013).
  • The time of the intervention after stroke onset has very likely significant impact on the efficacy of a given tDCS paradigm.
  • Indeed, the most important factor for predicting brain stimulation efficacy in motor stroke seems to be the integrity of the stimulated cortical region and the corresponding corticospinal tract, as assessed by MEP recordings (Talelli et al., 2006, van Kuijk et al., 2009) or neuroimaging methods (Riley et al., 2011; Bradnam et al., 2012).

7. Aphasia

  • Aphasia is a highly disabling language disorder frequently caused by a left-lateralized hemispheric stroke (Laska et al., 2001).
  • There are several other studies based on single sessions or smaller sample size with the same tDCS montage.
  • Two of these studies showed improvement in verbal fluency but included only 6 nonfluent aphasics (Vines et al., 2011; Cipollari et al., 2015), while the other two studies were performed on respectively 10 (Kang et al., 2011) and 37 patients (Jung e al., 2011), the latter study being based on an open-label protocol.
  • To conclude, some beneficial results were reported using anodal tDCS over Broca's and Wernicke's areas, cathodal tDCS over the right homologue of Broca's area, or a bihemispheric stimulation of both inferior frontal gyri.

8. Multiple sclerosis

  • Multiple sclerosis (MS) is one of the most common neurological diseases and a serious cause of disability in young adults.
  • With disease evolution, patients could accumulate several neurological dysfunctions or disease-related complications including motor deficit, fatigue, tremor, spasticity, sensory disturbances, pain, genital or urinary symptoms, and psychiatric or cognitive disorders.
  • Finally, three studies with a parallel-arm design investigated the effect of tDCS on sensory aspects of MS.
  • They found a significant improvement of tactile discriminatory thresholds and sensation scores after anodal tDCS compared to sham stimulation, again without any impact on depression scores (Mori et al., 2013).

9. Epilepsy

  • The study of their therapeutic potential in epilepsy remains underdeveloped.
  • In Liu et al. (2015), anodal tDCS (2 mA) was applied for 20 min over the left DLPFC (F3), with the cathode over the right supraorbital area, for 5 consecutive days, according to a depression therapy protocol.
  • In the first study of 28 patients with a parallel-arm design (20 patients in the active arm and only 8 patients in the sham arm) (San-Juan et al., 2016), the cathode was positioned over the most active area of interictal epileptiform discharges defined on scalp EEG.
  • The mean seizure frequency significantly decreased after active but not sham tDCS in both studies, even associated with a reduction of interictal epileptiform discharges on scalp EEG immediately after tDCS (San-Juan et al., 2016).

10. Disorders of consciousness

  • Disorders of consciousness, such as minimally conscious state (MCS) and vegetative state (VS), are highly challenging clinical conditions for treatment.
  • In conclusion, some beneficial results of tDCS protocols have been shown in patients with disorders of consciousness, especially targeting the left DLPFC in MCS.
  • The reported data are very preliminary, obtained in small samples, with heterogeneous outcome measures, including either clinical or functional connectivity variables.
  • Therefore, no recommendation can be made, especially regarding the number of sessions and the amount and clinical profile of the patients to treat.

11. Alzheimer’s disease

  • Since its updating in the early 2000s, tDCS has been widely used in neuropsychological studies to act on cognitive and behavioural features, e.g., attention, memory and working memory, computation, decision-making, and so on, in either healthy humans or patients with various neuropsychiatric diseases (Shin et al., 2015; Hill et al., 2016).
  • The initial single-session study showed memory improvement in 10 patients having received active anodal tDCS of the left DLPFC (Boggio et al., 2009a).
  • The initial single-session studies showed beneficial effect on word or visual recognition memory, but this result was not confirmed by a subsequent multiple-session RCT (Boggio et al., 2012).
  • Including 15 AD patients, visual recognition memory was improved after active vs. sham anodal tDCS of the both temporal cortices at one month after the intervention, but the statistical interaction “time x group” was not significant.

12. Tinnitus

  • Tinnitus is a phantom perception of a sound in the absence of a corresponding external sound source and occurs in 5–15% of the population (Axelsson and Ringdahl, 1989; Heller, 2003; Gallus et al., 2015).
  • From literature data, only 4 original sham-controlled studies including at least 10 patients who received active tDCS for multiple sessions were retained for analysis (Table 7).
  • These changes in the auditory cortical area led to the hypothesis that it should be possible to treat tinnitus by modulating these abnormalities through the stimulation of the brain.
  • In a double-blind placebo-controlled follow-up study including 20 patients, Garin et al. (2011) also found a significant effect of a single session of anodal tDCS of the left temporal cortex (1 mA for 20 minutes) in comparison to cathodal and sham stimulation on tinnitus loudness immediately and still one hour after stimulation.
  • Second, in a large parallel-arm sham-controlled study (Pal et al., 2015), 42 patients (21 in the active group and 21 in the sham group) received 5 daily sessions of tDCS (2 mA, 20 min, 1 week) with one large anode placed over the prefrontal cortices (F3Fz-F4) and two smaller cathodes placed bilaterally over the temporal auditory cortical areas (T3+T4).

13. Depression

  • The rationale for the use of tDCS in the treatment of depressive disorders is based on the knowledge of functional and structural abnormalities in the left and right dorsolateral and ventromedial prefrontal cortex, amygdala and hippocampus in depressed patients (Campbell et al., 2004; Hamilton et al., 2008; Koenigs and Grafman, 2009).
  • The Table 8 presents the results obtained in sham-controlled studies including at least 10 patients receiving repeated daily sessions of active anodal tDCS of the left DLPFC, according to the two main montages, with the cathode over the right orbitofrontal cortex or the right DLPFC.
  • More recent meta-analyses (Shiozawa et al., 2014; Meron et al., 2015) and an analysis of individual patient data (Brunoni et al., 2016a), including the large SELECT-TDCS trial conducted by Brunoni et al. (2013b), suggest superiority of active tDCS compared to sham treatment.
  • Three studies have investigated the efficacy of long-term antidepressant treatment using tDCS (Dell’Osso et al., 2013; Martin et al., 2013; Valiengo et al., 2013).

14. Schizophrenia

  • The majority of treated patients with schizophrenia retain disabling symptoms.
  • Meanwhile, the authors cannot make any recommendation about the efficacy of this montage to relieve schizophrenia symptoms, either positive or negative.
  • The results of the two sham-controlled studies using this montage (Smith et al., 2015; Palm et al., 2016b) being conflicting (Table 9), no recommendation can be made for the use of anodal tDCS of the left DLPFC with a contralateral orbitofrontal cathode in schizophrenia, even regarding cognitive deficits.
  • With the cathode placed over the right DLFPC (bihemispheric DLPFC stimulation), a small RCT, including 15 patients and specifically addressing the treatment of negative symptoms, showed a significant decrease in PANSS total score and negative subscale after active stimulation compared to sham condition (Gomes et al., 2015).

15. Substance abuse, addiction and craving

  • Addiction to substances such as alcohol, drugs, nicotine, or food, is a major health issue, because of the difficulty to achieve a permanent cure with a high rate of relapses, despite detoxification and pharmacological or psychological interventions (Fant et al., 2009; Heinz et al., 2009).
  • The rationale of using tDCS as a treatment for substance addiction and craving is that the DLPFC, which plays a major role in top-down inhibitory control mechanisms and reward mechanisms, was claimed to be dysfunctional in these disorders (Goldstein and Volkow, 2002; Wilson et al., 2004).
  • The analyzed results cover patients addicted to alcohol, cocaine, crack, or smoking.
  • Actually, in alcoholics, one study showed a reduction of craving for visual alcohol cues after a single session of active bihemispheric tDCS of the DLPFC, similarly for a right anode + left cathode montage and a left anode + right cathode montage (Boggio et al., 2008b).
  • No difference in food consumption was observed after active vs. sham tDCS.

16. Other psychiatric disorders

  • Regarding clinical applications of tDCS in psychiatric disorders other than depression, schizophrenia and addiction, there are only very limited data available in the literature.
  • TDCS AND obsessive compulsive disorder) identified 17 papers, including 5 original clinical studies and 12 patients, also known as A PubMed search (keywords.
  • The montage used was an anode placed over the left DLPFC (F3) with a cathode on the right shoulder.
  • One study (60 patients) did not find significant differences between active and sham tDCS regarding the effect of bihemispheric tDCS of the DLFPC (left anode + right cathode) on behavioral performance in go/no-go tasks (Cosmo et al., 2015).
  • Obviously, reported results are too preliminary to make any recommendation for the use of tDCS in all these psychiatric conditions.

17. At-home do-it-yourself DCS and neural enhancement

  • Also, it allows distribution of machines for home use, which is not the case for rTMS.
  • Recommendations have even been recently proposed for a safe use of remotely-supervised at-home tDCS (Charvet et al., 2015), highlighting training of the user or caregiver, medical supervision, monitoring of compliance, and assessment of the clinical benefit or side-effects.
  • Because of the wide diffusion of tDCS or tDCS-like machines that can be bought freely on the internet, it will be difficult to restrict the use of these machines and ensure correct application.
  • Another study showed that the accuracy performance in a working memory task was significantly decreased during and after a single session of tDCS over the DLPFC using a commercial tDCS machine that is freely available on the internet as a cognitive enhancer (Steenbergen et al., 2015).
  • The International Federation of Clinical Neurophysiology (IFCN) recently warns against the use of DIY devices and methods of NIBS unless they have shown both efficacy and safety (see recommandation in the following document:.

18. Perspectives of targets other than cortical (cerebellum and spinal cord)

  • Readers should be informed that research currently develops to explore the possibility of using transcutaneous DC stimulation on other neural targets, such as cerebellum and spinal cord, in order to promote functional neural changes (Priori et al., 2014).
  • Much work remains to be done to design further therapeutic studies using cerebellar tDCS, according to the parameters of stimulation (electrode montage, polarity), the possible mechanisms of action, and the underlying pathological conditions and interactions with ongoing drug treatments.
  • These results provide evidence that transcutaneous spinal direct current stimulation is able to interfere with spinal cord conduction properties and to modulate conduction in the lemniscal and spino-thalamic pathways.
  • The resulting excitability changes induced by tsDCS may also extent to corticospinal tracts or even intracortical circuits (Bocci et al., 2015a,b,c).

19. Perspectives of treatment by transcranial electrical stimulation methods other than

  • Most of the complex historical stimulation protocols are proprietary commercial “blends” and will probably not survive the test of time against physically simpler and better evaluated protocols such as tDCS or sinusoidal tACS (Paulus, 2011).
  • The upper frequency limit of tACS has not yet been determined and it touches e.g. the question if mobile phone emission can influence brain function.
  • Within this frequency, tACS appears too fast to entrain brain circuit oscillations, and therefore the stimulation probably directly interferes with cortical excitability via neuronal membrane activation changes.

20. Summary of recommendations

  • This work presents for the first time a comprehensive evidence-based analysis of the reported clinical efficacy of various tDCS montages that could lead to therapeutic applications in the neurological, otorhinolaryngological, and psychiatric domains.
  • In addition, a high level of evidence of efficacy (comparing active vs. sham condition) should not open the door to clinical use in daily routine practice without any limitations.
  • Therefore, it remains to be determined how to optimize tDCS protocols and techniques to give them “therapeutic relevance” in routine clinical practice.
  • This is a well known problem for any conclusion reported in literature reviews or meta-analyses based only on published studies, which should be considered with caution, even when analysis methods seem very stringent (Easterbrook et al., 1991).
  • Furthermore, different drug treatments may even reduce tDCS efficacy, leading to a worse outcome compared to unmedicated patients, as shown for the use of benzodiazepines in depressed patients treated by 5 tDCS sessions, with the anode over the left DLPFC and the cathode over the right DLPFC (Brunoni et al., 2013a).

Conflict of interest

  • Simone Rossi have received grants from EBNeuro S.p.A, Florence, Italy and travel support from MagVenture, Farum, Denmark and Magstim Co., Whitland, Carmarthenshire, UK, respectively.
  • Walter Paulus is on the scientific advisory board of EBS technologies, Berlin, Germany.
  • Frank Padberg has received speaker honorarium from Mag&More GmbH, Munich, Germany and equipment support from neuroConn GmbH, Ilmenau, Germany, and Brainsway Inc., Jerusalem, Israel.
  • The other authors have no conflicting interests related to this article to declare.

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Citations
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Journal ArticleDOI
TL;DR: The state of non-invasive brain stimulation research in humans is summarized, some current debates about properties and limitations of these methods are discussed, and recommendations for how these challenges may be addressed are given.
Abstract: In the past three decades, our understanding of brain–behavior relationships has been significantly shaped by research using non-invasive brain stimulation (NIBS) techniques. These methods allow non-invasive and safe modulation of neural processes in the healthy brain, enabling researchers to directly study how experimentally altered neural activity causally affects behavior. This unique property of NIBS methods has, on the one hand, led to groundbreaking findings on the brain basis of various aspects of behavior and has raised interest in possible clinical and practical applications of these methods. On the other hand, it has also triggered increasingly critical debates about the properties and possible limitations of these methods. In this review, we discuss these issues, clarify the challenges associated with the use of currently available NIBS techniques for basic research and practical applications, and provide recommendations for studies using NIBS techniques to establish brain–behavior relationships.

544 citations

Journal ArticleDOI
TL;DR: The objective of this review was to update evidence‐based medicine recommendations for treating motor symptoms of Parkinson's disease with new recommendations for treatment of central nervous system symptoms.
Abstract: Objective The objective of this review was to update evidence-based medicine recommendations for treating motor symptoms of Parkinson's disease (PD). Background The Movement Disorder Society Evidence-Based Medicine Committee recommendations for treatments of PD were first published in 2002 and updated in 2011, and we continued the review to December 31, 2016. Methods Level I studies of interventions for motor symptoms were reviewed. Criteria for inclusion and quality scoring were as previously reported. Five clinical indications were considered, and conclusions regarding the implications for clinical practice are reported. Results A total of 143 new studies qualified. There are no clinically useful interventions to prevent/delay disease progression. For monotherapy of early PD, nonergot dopamine agonists, oral levodopa preparations, selegiline, and rasagiline are clinically useful. For adjunct therapy in early/stable PD, nonergot dopamine agonists, rasagiline, and zonisamide are clinically useful. For adjunct therapy in optimized PD for general or specific motor symptoms including gait, rivastigmine is possibly useful and physiotherapy is clinically useful; exercise-based movement strategy training and formalized patterned exercises are possibly useful. There are no new studies and no changes in the conclusions for the prevention/delay of motor complications. For treating motor fluctuations, most nonergot dopamine agonists, pergolide, levodopa ER, levodopa intestinal infusion, entacapone, opicapone, rasagiline, zonisamide, safinamide, and bilateral STN and GPi DBS are clinically useful. For dyskinesia, amantadine, clozapine, and bilateral STN DBS and GPi DBS are clinically useful. Conclusions The options for treating PD symptoms continues to expand. These recommendations allow the treating physician to determine which intervention to recommend to an individual patient. © 2018 International Parkinson and Movement Disorder Society.

538 citations


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TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.
Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

3,947 citations


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TL;DR: The presence of publication bias in a cohort of clinical research studies is confirmed and it is suggested that conclusions based only on a review of published data should be interpreted cautiously, especially for observational studies.

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TL;DR: The development of stimulus selectivity in the primary sensory cortex of higher vertebrates is considered in a general mathematical framework and a synaptic evolution scheme of a new kind is proposed in which incoming patterns rather than converging afferents compete.
Abstract: The development of stimulus selectivity in the primary sensory cortex of higher vertebrates is considered in a general mathematical framework. A synaptic evolution scheme of a new kind is proposed in which incoming patterns rather than converging afferents complete. The change in the efficacy of a given synapse depends not only on instantaneous pre- and postsynaptic activities but also on a slowly varying time-averaged value of the postsynaptic activity. Assuming an appropriate nonlinear form this dependence, development of selectivity is obtained under quite general conditions on the sensory environment. One does not require nonlinearity of the neuron's integrative power nor does one need to assume any particular form for intracortical circuitry. This is first illustrated in simple cases, e.g., when the environment consists of only two different stimuli presented alternately in a random manner. The following formal statement then holds: the state of the system converges with probability 1 to points of maximum selectivity in the state space. We next consider the problem of early development of orientation selectivity and binocular interaction in primary visual cortex. Giving the environment an appropriate form, we obtain orientation tuning curves and ocular dominance comparable to what is observed in normally reared adult cats or monkeys. Simulations with binocular input and various types of normal or altered environments show good agreement with the relevant experimental data. Experiments are suggested that could test our theory further.

2,493 citations


"Evidence-based guidelines on the th..." refers methods in this paper

  • ...according to the concept of metaplasticity (Abraham and Tate, 1997; Turrigiano and Nelson, 2004; Müller-Dahhaus and Ziemann, 2015), especially following the ‘‘Bienenstock–Cooper–M unro (BCM) model” (Bienenstock et al., 1982)....

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TL;DR: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed, and results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervalued of alternative rein forcers, and deficits in inhibitory control for drug responses.
Abstract: OBJECTIVE: Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. METHOD: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. RESULTS: The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to tr...

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"Evidence-based guidelines on the th..." refers background in this paper

  • ...The rationale of using tDCS as a treatment for substance addiction and craving is that the DLPFC, which plays a major role in top-down inhibitory control mechanisms and reward mechanisms, was claimed to be dysfunctional in these disorders (Goldstein and Volkow, 2002; Wilson et al., 2004)....

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