- Research article
- Open Access
- Open Peer Review
Apathy is associated with executive functioning in first episode psychosis
© Faerden et al; licensee BioMed Central Ltd. 2009
- Received: 01 September 2008
- Accepted: 08 January 2009
- Published: 08 January 2009
The underlying nature of negative symptoms in psychosis is poorly understood. Investigation of the relationship between the different negative subsymptoms and neurocognition is one approach to understand more of the underlying nature. Apathy, one of the subsymptoms, is also a common symptom in other brain disorders. Its association with neurocognition, in particular executive functioning, is well documented in other brain disorders, but only studied in one former study of chronic patients with schizophrenia. This study investigates the association between apathy and neurocognitive functioning in patients with first episode psychosis (FEP), with the hypothesis that apathy is more associated with tests representing executive function than tests representing other neurocognitive domains.
Seventy-one FEP patients were assessed with an extensive neuropsychological test battery. Level of apathy was assessed with the abridged Apathy Evaluation Scale (AES-C-Apathy).
AES-C-Apathy was only significantly associated with tests from the executive domain [Semantic fluency (r = .37, p < .01), Phonetic fluency (r = .25, p < .05)] and working memory [Letter Number Span (r = .26; p =< .05)]; the first two representing the initiation part of executive function. Confounding variables such as co-occuring depression, positive symptoms or use of antipsychotic medication did not significantly influence the results.
We replicated in FEP patients the relationship between apathy and executive functioning reported in another study for chronic patients with schizophrenia. We also found apathy in FEP to have the same relationship to executive functioning, as assessed with the Verbal fluency tests, as that reported in patients with other brain disorders, pointing to a common underlying nature of this symptom across disorders.
- Executive Function
- Negative Symptom
- Executive Functioning
- Neurocognitive Function
- Verbal Fluency Test
Negative symptoms are common in patients with psychosis, but the underlying mechanisms are still poorly understood . Neurocognitive deficits are also common in schizophrenia spectrum disorders, and are thought to be more closely linked to the biological underpinnings of the disorder than clinical symptoms . As negative symptoms is repeatedly shown to have a consistent relationship with neurocognitive deficits [3–6], a further exploration of their relationship may aid the search for the mechanisms behind negative symptoms. A recent review by Harvey et al suggested four models as potential explanations for their association : 1) the two categories of symptoms represent the same identical features or alternate manifestations of the same basic underlying process, or 2) the two features of the illness are separable but share similar underlying etiological factors, or 3) the two are of separate, but related etiologies, or 4) the two dimensions are distinct from each other and with separate etiology. The review concluded by inviting innovations in the assessment of negative symptoms to come closer to an understanding of negative symptoms and other aspects of psychosis .
One problem in studies of negative symptoms is the heterogeneity of patient samples examined, with an admixture of chronic samples marked by treatment failures, institutionalization, hopelessness and subsequent social consequences that are difficult to distinguish from primary negative symptoms based solely on behavioral observations. Another problem is the diverse nature of the negative symptoms per se, as it includes several subsymptoms (apathy or avolition, anhedonia, alogia, asociality, flat affect and inattention) that might have different etiologies. Based on the recognition of this diversity, the "NIMH-MATRICS consensus statement on negative symptoms" has suggested that studies specific to the nature of these negative subsymptoms is one way to move forward . So far, very few studies on the association between negative symptoms and neurocognitive function have included analysis on the subsymptom level. We have thus found only four studies addressing the specific relationship between any of the negative subsymptoms and neurocognitive function [8–11]; the subsymptoms studied being alogia [8, 10] flat affect [8, 11] and apathy .
Apathy, defined as lack of motivation or goal directed behavior , has lately been targeted as an important negative subsymptom that need further study [13–15]. However, the only study concerned with the association between apathy and neurocognition in psychosis is based on a small sample of chronic patients with schizophrenia and a narrow test battery . Here, a high level of apathy was associated with lower performance IQ scores and poor performance on tests assessing executive function and visual- and verbal memory. The authors called for new studies in order to generalize their findings, due to the small sample size and lack of a comprehensive neuropsychological test battery. Studying patients with their first episode of psychosis (FEP) is of particular interest, since the negative symptoms in such a sample cannot be secondary to chronic effects, treatment failures or social deprivation.
Apathy is considered a symptom arising from the prefrontal cortex  or from dysfunction in the frontal-subcortical circuits . It's relationship to neurocognitive function has been extensively studied in other brain disorders, such as Alzheimer – (AD) , Parkinson – (PD)  and Huntington disease (HD)  in addition to traumatic brain injury (TBI) . Common to studies of all the above disorders is the finding of a consistent relationship between high levels of apathy and poorer performance on tests representing executive function [19–24]. In addition, significant associations are found to other neurocognitive domains, especially working memory [19, 24], psychomotor speed , attention  and episodic memory [20, 21], but for these domains the pattern of association is less systematic.
The aim of the present study is to improve our understanding of apathy in FEP patients. Consequently, we wish to investigate the association between apathy and neurocognitive function. First, we hypothesize that also in FEP patients the degree of apathy will be significantly related to tests representing executive function, and less with tests representing other neurocognitive domains. Secondly, we hypothesize that this relationship is not influenced by confounding variables, such as depression, use of antipsychotic medication or positive symptoms, supporting the notion of a linked etiology between the two areas.
Sociodemographic and clinical variables for 71 FEP patients
DUP (weeks) median/range
PANSS total score
Schizophrenia spectrum group
Affective psychosis gorup
Other psychosis group
Assessment of apathy
Apathy was assessed by the clinical version of the Apathy Evaluation scale (AES-C), an 18-item Likert scale ranging from 0–4 (0 = not at all and 4 = very much) . The scale is based on Marin's definition of apathy as " diminished motivation and goal directed behavior, not attributed to diminished level of consciousness, general cognitive impairment or emotional distress" . Examples of the questions are: "Are you interested in things?", "Is it important for you to get things done during the day?" and "Do you feel motivated?" The scale has been used across different medical disciplines. We have previously shown that a shortened 12-item AES-C scale (AES-C-Apathy) was a better assessor of apathy than the full version in a population with a FEP . This abridged version was used in all the analyses in the present study.
Assessment of other symptoms and diagnosis
Symptoms were assessed by the Structural Clinical Interview of the PANSS (SCI-PANSS) . Depression was assessed with the Calgary Depression Scale for schizophrenia (CDSS) . Diagnostic assessment was carried out with the Structural Clinical Interview for DSM-IV (SCID-I interview) .
2.3 Neuropsychological assessments
Neuropsychological test results for 71 FEP patients
NART (N = 66)
WASI (N = 71)
Grooved Pegboard (N = 70)
Digit Symbol (N = 71)
Digit Span forward (N = 71)
CVLT-II (N = 71)
ROCF long term memory (N = 65)
Letter Number Span (N = 65)
Phonetic fluency (N = 71)
Semantic fluency (N = 71)
Category switching (N = 71)
Color-Word Interference (N = 71)
All participants gave written informed consent to participate, and the study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. The data file has received an Audit Certificate from the Center for Clinical research at Ullevål University Hospital.
The three investigators who did all the clinical assessments in the current study completed the common training and reliability program of the TOP study. Training in the AES-C was done by scoring videos, supervised by two experienced clinicians who had previously used the scale with other patient groups , and reliability testing of the AES-C was completed by seven live interviews with random study patients. The SCID training was based on the UCLA training program , and supervised by UCLA. For DSM-IV diagnostics, mean overall kappa for the standard diagnosis of training videos was 0.77, and mean overall kappa for a randomly drawn subset of actual study patients was also 0.77 (95% CI 0.60–0.94). Inter-rater reliability (Intra Class Coefficient (ICC) 1.1) for the different psychometric scales were: PANSS positive subscale 0.82 (95% CI 0.66–0.94) PANSS negative subscale 0.76 (95% CI 0.58–0.93), PANSS general subscale 0.73 (95% CI 0.54–0.90), GAF-S 0.86 (95% CI 0.77–0.92), GAF-F 0.85 (95% CI 0.76–0.92) and AES-C 0.98 (95% CI 0.92–0.99).
2.5.1 Data and statistical analyses
Correlation between neuropsychological tests, AES-C-Apathy and possible confounding variables
Digit span forwards
ROCF long term memory
Letter Number Span
Since apathy, negative symptoms and neurocognitive function have been found to be under influence from secondary sources, we took steps to control for this. Depression has been tested as a possible confounding variable for apathy in different studies in other medical disciplines [18, 21], in addition positive symptoms and current use of antipsychotic medication has in some studies been found to influence either negative symptoms or neurocognitive function . The association between these three variables and neurocognition were firstly examined in a correlation analysis followed by a hierarchical multiple regression analysis with the neurocognitive test results as the dependent. The possible confounders and AES-C-Apathy were the independent variables, with AES-C-Apathy entered in the last step.
3.1 The relationship between apathy, neuropsychological test performance and confounding variables
Three of the neuropsychological tests in the comprehensive TOP battery showed a statistically significant inverse association to AES-C-Apathy (Table 3). Out of these two (Semantic- and Phonetic fluency part of the Verbal Fluency tests) represented the initiation part of executive function, and the third (Letter Number Span) represented working memory. AES-C-Apathy was most strongly correlated with the Semantic fluency test (r = .37, p = .002), explaining 12% of its variance. For the two other tests (Phonetic fluency and Letter Number Span) the relationship to AES-C-Apathy was statistically significant, but of a smaller magnitude (r = .25, r = .26). AES-C-Apathy was neither significantly associated with any other tests, nor premorbid or current IQ.
Univariate and hierarchial multivariate regression analysis with neuropsychological tests as dependent and AES-C-Apathy and possible counfounders as independent variables
Letter Number Span
The main result of the present study is the replicated finding of a significant relationship between apathy and executive function in psychotic disorders, as found previously in one study of patients with chronic schizophrenia . The two findings are corresponding even if the two studies applied different measures both for apathy and executive function, indicating a robust relationship. In addition, in both studies the relationship was not influenced by current level of depression. This supports the view that the presence of apathy and deficits in executive functioning are related in psychotic disorders, and that the relationship is not due to definitional issues since different scales and tests were used.
Additionally, this finding is in line with findings of an association between apathy and the specific executive functioning test of verbal fluency in several other brain disorders [18–20, 22]. Two of these studies used the AES in assessing apathy [19, 22], eliminating the challenge of comparing results between different scales.
This finding of a consistent relationship between apathy and tests of executive function across different brain disorders and across different levels of chronicity is supported by several studies that implicate prefrontal areas and frontal-subcortical circuitry involving the anterior cingular gyrus in both apathy and executive function [43–47].
In our opinion, our findings thus support the idea of a common or linked etiology between these negative symptoms and neurocognitive deficits as put forward in Harvey et al's model 2 and 3 . This is in opposition to Harvey's own conclusions, that suggests that the two have different etiologies based on a lack of published studies showing significant relationships. In addition, our findings might imply that there are specific mechanisms behind the different negative subsymptoms. This is supported by a recent study finding that verbal memory was the only neuropsychological test to differentiate between those with and without flat affect, making the authors' suggest that this could reflect a unique neural substrate for this negative subsymptom .
We did not, as Roth et al, find associations between high levels of apathy and reduced IQ and memory, associations with apathy that are also found in other disorders. This could be due to the differences between the studies such as assessment of apathy, FEP patients being less chronically ill and diagnostically more diverse. But in order to understand more of the different negative subsymptoms, these associations should also be further studied.
The strength of our study is the use of a specific and validated assessment for the negative subsymptom of apathy together with a comprehensive neuropsychological test battery with tests for several different aspects of executive function. The main limitations to our study are: 1) that we only had access to instruments measuring one of the specific negative subsymptoms and thus cannot conclude anything about the specificity of our finding in regard to the other subsymptoms. 2) that for some patients the clinical assessment of apathy and the neuropsychological testing took place with a time difference and this could weaken our chances to detect weaker associations.
First we replicated the finding in FEP patients, as was found in chronic patients, of a significant relationship between apathy and executive functioning. Second, we found that apathy in FEP have the same relationship to the Verbal Fluency test, as reported in other brain disorders, pointing to a common underlying nature of this symptom across disorders.
This study was supported by a study grant from the Psychiatric Division of the Ullevål University Hospital, the South-Eastern Norway Regional Health Authority, Josef and Haldis Andresens Grant and the Emil Strays Grant. The funding sources had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, or the decision to submit the paper for publication.
- Kirkpatrick B, Fenton WS, Carpenter WT, Marder SR: The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006, 32 (2): 214-9. 10.1093/schbul/sbj053.View ArticlePubMedPubMed CentralGoogle Scholar
- Elvevag B, Goldberg TE: Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol. 2000, 14 (1): 1-21.View ArticlePubMedGoogle Scholar
- O'Leary DS, Flaum M, Kesler ML, Flashman LA, Arndt S, Andreasen NC: Cognitive correlates of the negative, disorganized, and psychotic symptom dimensions of schizophrenia. J Neuropsychiatry Clin Neurosci. 2000, 12 (1): 4-15.View ArticlePubMedGoogle Scholar
- Heydebrand G, Weiser M, Rabinowitz J, Hoff AL, DeLisi LE, Csernansky JG: Correlates of cognitive deficits in first episode schizophrenia. Schizophr Res. 68 (1): 1-9. 10.1016/S0920-9964(03)00097-5.Google Scholar
- Rund BR, Melle I, Friis S, Larsen TK, Midboe LJ, Opjordsmoen S, et al: Neurocognitive dysfunction in first-episode psychosis: correlates with symptoms, premorbid adjustment, and duration of untreated psychosis. Am J Psychiatry. 2004, 161 (3): 466-72. 10.1176/appi.ajp.161.3.466.View ArticlePubMedGoogle Scholar
- Keefe RS, Bilder RM, Harvey PD, Davis SM, Palmer BW, Gold JM, et al: Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 2006, 31 (9): 2033-46. 10.1038/sj.npp.1301072.View ArticlePubMedGoogle Scholar
- Harvey PD, Koren D, Reichenberg A, Bowie CR: Negative symptoms and cognitive deficits: what is the nature of their relationship?. Schizophr Bull. 2006, 32 (2): 250-8. 10.1093/schbul/sbj011.View ArticlePubMedGoogle Scholar
- Stolar N, Berenbaum H, Banich MT, Barch D: Neuropsychological correlates of alogia and affective flattening in schizophrenia. Biol Psychiatry. 35 (3): 164-72. 10.1016/0006-3223(94)91148-7.Google Scholar
- Roth RM, Flashman LA, Saykin AJ, McAllister TW, Vidaver R: Apathy in schizophrenia: reduced frontal lobe volume and neuropsychological deficits. Am J Psychiatry. 2004, 161 (1): 157-9. 10.1176/appi.ajp.161.1.157.View ArticlePubMedGoogle Scholar
- Sumiyoshi C, Sumiyoshi T, Nohara S, Yamashita I, Matsui M, Kurachi M, et al: Disorganization of semantic memory underlies alogia in schizophrenia: an analysis of verbal fluency performance in Japanese subjects. Schizophr Res. 74 (1): 91-100. 10.1016/j.schres.2004.05.011.Google Scholar
- Gur RE, Kohler CG, Ragland JD, Siegel SJ, Lesko K, Bilker WB, et al: Flat Affect in Schizophrenia: Relation to Emotion Processing and Neurocognitive Measures 4419. Schizophr Bull. 32 (2): 279-87. 10.1093/schbul/sbj041. 2006 Apr 1;Google Scholar
- Marin RS: Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci. 1991, 3 (3): 243-54.View ArticlePubMedGoogle Scholar
- Brown RG, Pluck G: Negative symptoms: the 'pathology' of motivation and goal-directed behaviour. Trends Neurosci. 2000, 23 (9): 412-7. 10.1016/S0166-2236(00)01626-X.View ArticlePubMedGoogle Scholar
- Foussias G, Remington G: Negative Symptoms in Schizophrenia: Avolition and Occam's Razor. Schizophr Bull.Google Scholar
- Barch DM: Emotion, Motivation, and Reward Processing in Schizophrenia Spectrum Disorders: What We Know and Where We Need to Go. Schizophr Bull. 2008, 34 (5): 816-818. 10.1093/schbul/sbn092.View ArticlePubMedPubMed CentralGoogle Scholar
- Stuss DT, Knight RT: Principles of Frontal Lobe Function. 2002, New York: Oxford University PressView ArticleGoogle Scholar
- Tekin S, Cummings JL: Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res. 2002, 53 (2): 647-54. 10.1016/S0022-3999(02)00428-2.View ArticlePubMedGoogle Scholar
- Landes AM, Sperry SD, Strauss ME, Geldmacher DS: Apathy in Alzheimer's disease. J Am Geriatr Society. 2001, 49 (12): 1700-7. 10.1046/j.1532-5415.2001.49282.x.View ArticleGoogle Scholar
- Pluck GC, Brown RG: Apathy in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2002, 73 (6): 636-42. 10.1136/jnnp.73.6.636.View ArticlePubMedPubMed CentralGoogle Scholar
- Baudic S, Maison P, Dolbeau G, Boisse MF, Bartolomeo P, Dalla BG, et al: Cognitive impairment related to apathy in early Huntington's disease. Dement Geriatr Cogn Disord. 2006, 21 (5–6): 316-21. 10.1159/000091523.View ArticlePubMedGoogle Scholar
- Andersson S, Bergedalen AM: Cognitive correlates of apathy in traumatic brain injury. Neuropsychiatry Neuropsychol Behav Neurol. 2002, 15 (3): 184-91.PubMedGoogle Scholar
- Isella V, Melzi P, Grimaldi M, Iurlaro S, Piolti R, Ferrarese C, et al: Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease. Movement Disorders. 2002, 17 (2): 366-71. 10.1002/mds.10041.View ArticlePubMedGoogle Scholar
- McPherson S, Fairbanks L, Tiken S, Cummings JL, Back-Madruga C: Apathy and executive function in Alzheimer's disease. J Int Neuropsychol Soc. 2002, 8 (3): 373-81. 10.1017/S1355617702813182.View ArticlePubMedGoogle Scholar
- Zgaljardic DJ, Borod JC, Foldi NS, Rocco M, Mattis PJ, Gordon MF, et al: Relationship between self-reported apathy and executive dysfunction in nondemented patients with Parkinson disease. Cogn Behav Neurol. 2007, 20 (3): 184-92. 10.1097/WNN.0b013e318145a6f6.View ArticlePubMedPubMed CentralGoogle Scholar
- WHO Colloborating Centre for Drug Statistics Methodolegy: 2008, ATC Index with DDD's. OsloGoogle Scholar
- Marin RS, Biedrzycki RC, Firinciogullari S: Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991, 38 (2): 143-62. 10.1016/0165-1781(91)90040-V.View ArticlePubMedGoogle Scholar
- Faerden A, Nesvag R, Barrett EA, Agartz I, Finset A, Friis S, et al: Assessing apathy: the use of the Apathy Evaluation Scale in first episode psychosis. Eur Psychiatry. 2008, 23 (1): 33-9. 10.1016/j.eurpsy.2007.09.002.View ArticlePubMedGoogle Scholar
- Kay SR, Fiszbein AOL: The positive and negative syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987, 16: 261-76.View ArticleGoogle Scholar
- Addington D, Addington J, Maticka-Tyndale E, Joyce J: Reliability and validity of a depression rating scale for schizophrenics. Schizophr Res. 1992, 6 (3): 201-8. 10.1016/0920-9964(92)90003-N.View ArticlePubMedGoogle Scholar
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders DSM IV. 1994, Washington DC: American Psychiatric Association, 4Google Scholar
- Heinrichs RW, Zakzanis KK: Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998, 12 (3): 426-45. 10.1037/0894-4184.108.40.2066.View ArticlePubMedGoogle Scholar
- Green MF, Nuechterlein KH, Gold JM, Barch DM, Cohen J, Essock S, et al: Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria 4203. Biol Psychiatry. 56 (5): 301-7. 10.1016/j.biopsych.2004.06.023.Google Scholar
- Matthews CG, Kløve H: Instruction Manual for the Adult Neuropsycholology Test battery. 1964, Madison, Wisconsin: University of Wisconsin Medical SchoolGoogle Scholar
- David Wechsler: WAIS III. Wechsler Adult Intelligence Scale. Manual. 1997, The Psychological CorporationGoogle Scholar
- Delis D, Kramer JK, Kaplan E, Ober BA: CVLT-II. California verbal learning Test. Manual. Adult version. 2000, The Psychological Corporation. Harcourt Assessment Company, SecondGoogle Scholar
- Meyers J, Meyers KE: Rey Complex Figure tests and Recognition Trial. Professional Manual. 1995, Psychological Assessment Resources. IncGoogle Scholar
- Delis D, Kaplan E, Kramer JK: Delis-Kaplan Executive Function System. Examiner's Manual. 2001, San Antonio, Texas: The Psychological Corporation; Harcourt Assessment CompanyGoogle Scholar
- Vaskinn A, Sundet K: Estimating premorbid IQ: A Norwegian version of National Adult Reading Test. J Nor Psychol Assoc. 2001, 38: 1133-40.Google Scholar
- Psychological Corporation: WASI. Wechsler Abbreviated Scale of Intelligence. Manual. 1999, San Antonio. TX: The Psychological CorporationGoogle Scholar
- Andersson S, Krogstad JM, Finset A: Apathy and depressed mood in aquired brain damage: relationship to lesion localization and psychophysiological reaction. Psychol Med. 1999, 29 (2): 447-56. 10.1017/S0033291798008046.View ArticlePubMedGoogle Scholar
- Ventura J, Liberman RP, Green MF, Shaner A, Mintz J: Training and quality assurance with the Structured Clinical Interview for DSM-IV (SCID-I/P). Psychiatry Res. 79 (2): 163-73. 10.1016/S0165-1781(98)00038-9.Google Scholar
- Carpenter WT, Heinrichs DW, Wagman AM: Deficiet and nondeficiet forms of schizophrenia:the concept. Am J Psychiatry. 1988, 145: 578-83.View ArticlePubMedGoogle Scholar
- Szeszko PR, Bilder RM, Lencz T, Ashtari M, Goldman RS, Reiter G, et al: Reduced anterior cingulate gyrus volume correlates with executive dysfunction in men with first-episode schizophrenia. Schizophr Res. 43 (2–3): 97-108.Google Scholar
- Marshall GA, Monserratt L, Harwood D, Mandelkern M, Cummings JL, Sultzer DL: Positron emission tomography metabolic correlates of apathy in Alzheimer disease. Arch Neurol. 2007, 64 (7): 1015-20. 10.1001/archneur.64.7.1015.View ArticlePubMedGoogle Scholar
- Rusch N, Spoletini I, Wilke M, Bria P, Di PM, Di IF, et al: Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia. Schizophr Res. 2007, 93 (1–3): 79-89. 10.1016/j.schres.2007.01.029.View ArticlePubMedGoogle Scholar
- Lavretsky H, Ballmaier M, Pham D, Toga A, Kumar A: Neuroanatomical characteristics of geriatric apathy and depression: a magnetic resonance imaging study. Am J Geriatr Psychiatry. 2007, 15 (5): 386-94. 10.1097/JGP.0b013e3180325a16.View ArticlePubMedPubMed CentralGoogle Scholar
- Migneco O, Benoit M, Koulibaly PM, Dygai I, Bertogliati C, Desvignes P, et al: Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer's disease and nondemented patients. Neuroimage. 2001, 13 (5): 896-902. 10.1006/nimg.2000.0741.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/9/1/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.