Title:Cerebrovascular function and cognition in childhood: a systematic review of transcranial doppler studies

Transcription

1 Author's response to reviews Title:Cerebrovascular function and cognition in childhood: a systematic review of transcranial doppler studies Authors: Mireille J Bakker (mireille.j.bakker@gmail.com) Jessica Hofmann (Jessica.Hofmann@unisa.edu.au) Owen F Churches (Owen.Churches@flinders.edu.au) Nicholas A Badcock (nicholas.badcock@mq.edu.au) Mark Kohler (Mark.Kohler@unisa.edu.au) Hannah AD Keage (Hannah.Keage@unisa.edu.au) Version:2Date:11 February 2014 Author's response to reviews: see over

2 11 February 2014 Dear Josefino Rodis, BMC Editorial Office, We are pleased to resubmit our manuscript Cerebrovascular function and cognition in childhood: a systematic review of transcranial doppler studies. We would like to thank the Reviewers for their time, along with their thoughtful and positive comments. All three Reviewers noted the importance of the manuscript to the field. The Response to Reviews is detailed overleaf. All changes in text are highlighted in yellow. Notably, we have also included Conflict of Interests and Author Contribution sections. We look forward to your response. Yours sincerely, Cognitive Neuroscience Laboratory School of Psychology, Social Work and Social Policy Adelaide South Australia 5000 GPO Box 2471 Adelaide South Australia 5001 Australia t: e: Hannah.Keage@ unisa.edu.au Dr Hannah Keage on behalf of authors

3 Response to Reviewers' comments: We thank the three Reviewers for their comments. REVIEWER 1 1. Please comment on reproducibly and intra-subject variability of TCD measurements. This is an important point, and we have added the following information in the Discussion, page 17 paragraph 1: Similar to other psychophysiological measurements, the evidence base for the reliability of TCD requires more work. In a recent paper, McDonnell et al. (2013) reported that the test-retest reliability (three testing sessions over a few weeks) of the TCD-measured cerebrovascular response (change in blood flow velocity relative to inhalation of gas with 95% O 2 and 5% CO 2 ) was strong, particularly for measurements taken in sitting as opposed to supine. Sanchez et al. (2010) reported elevated systolic velocities apparent in a group of five children with Sickle cell disease remained so over a six month period. These studies provide evidence for the reliability of TCD measures however further work is required, particularly in relation to ftcd measures. 2. Please refer briefly to cognitive function tests used in pediatric populations. The information on cognitive tests has been expanded on page 7, paragraph 2: A broad range of behavioural and cognitive domains were assessed such as the intelligence quotient (IQ; including the Wechsler Intelligence Scale for Children, Wechsler Preschool and Primary Scale of Intelligence and the Woodcock-Johnson Psycho-Educational Battery), neonatal behaviour (e.g. Neonatal Behaviour Assessment Scales), language (e.g. Test of Language Development-Primary Third Edition and British Picture Vocabulary Scale-II, Test of Word Reading Efficiency), memory (e.g. Children's Memory Scale and the California Verbal Learning Test for Children), and executive function (e.g. Conners's Continuous Performance Test and Trail Making Test). All studies are summarised in Table Please provide references for PRISMA guidelines. A reference to the PRISMA guidelines has been inserted on page 6, paragraph Which of the parameters (if any) measured by TCD was more frequently associated with impaired cognitive function? We feel these details have been stated in the discussion (particularly the first and concluding paragraphs), e.g. Poor cognitive performance appears to be associated with decreased blood flow velocities in premature infants, and increased velocities in Sickle cell disease children using TCD methods (page 18, paragraph 3). We acknowledge that there were no measures consistently associated with cognition in healthy children however this is due to a lack of studies (which we have also noted and discussed as a good potential avenue for future research). If the Editor feels that we need to include more discussion, we would be happy to do so. Page 2

4 5. In the studies including children with SCD (table 1) it seems that age is a significant factor as TCD parameters were mostly associated with cognitive performance in ages <4 years-old, but not in ages of 8-12 years. Please comment. We agree with the Reviewer that there could be a potential age-interaction in the association between TCD measures (particularly systolic velocity) and cognition in the Sick cell disease groups. All of three studies looking at children under four years found an association, whereas the ten studies looking at children over four years were not as consistent: five found the same relationship, four found no relationship, and one study found the reverse relationship (positive as opposed to negative association between systolic velocity and cognitive performance). We feel that suggesting an age-interaction however is too premature, as this picture may be purely due to more studies being conducted in older children. We hope that the rearranged Table 1 makes it clearer as to how many studies have younger as opposed to older participants. 6. In the discussion please comment on the strengths and limitations among different studies on the associations of TCD measures with cognitive performance. E.g. - Did all studies used validated measures of cognitive function? Were the same devices used in all studies? How could the different methodologies used in the studies, affect the interpretation of results among studies? We thank the Reviewer for this suggestion. We feel we have introduced a number of these discussion points, but obviously have not gone into enough depth. We have therefore expanded on a number of points: - Page 18, paragraph 2: Although all studies employed standardised cognitive and behavioural measures, they varied greatly, which made direct comparisons difficult. We were therefore unable to investigate how associations between TCD and cognitive measures may vary as a function of cognitive domain. This would be a good avenue of future research. - Page 17, paragraph 2: Many studies did not detail the manufacturer of the TCD set-up employed. Specifications vary greatly between different manufacturers, for example sampling rates vary between 1Hz and 100Hz. It is unknown if TCD measurements produced are equivalent between commercially available set-ups. Future papers must note the TCD manufacturer and associated recording parameters. Further, simple experimental design elements were often missing in identified studies, such as the time period used to collect resting TCD measures (e.g. 30 seconds, 1 minute or 2 minutes). A concerted effort to include these experimental design factors is required. 7. Conclusion: the sentence on obesity and hypertension seems irrelevant at the conclusion. The sentence should be omitted or the authors should previously in the manuscript provide data from studies on TCD, hypertension and cognitive function the results. We thank the Reviewer for this suggestion and have now removed this sentence. 8) Discretionary Revisions: Table 1 would be more convenient to read if it was spliced in 3 different tables e.g. table 1 for children with SCD, table 2 for premature infants and table 3 for ftcd Table 1 has been adjusted according the suggestions of Reviewer 1 (and Reviewer 2). We have grouped the studies based group/diagnostic membership, and then on age characteristics of the subjects, ranging from infants up to adolescence. Page 3

5 REVIEWER 2 1. It would be helpful to look at the time between TCD and cognitive testing. The time between TCD measurement and cognitive testing varied considerably between studies. We have tried to provide as much information as practicable in Table The table with all the literature could be arranged as studies in children followed-up from infancy, studies in sickle cell disease, studies in autism and developmental delay and ftcd studies. We thank the Reviewer for this suggestion, which is similar to a suggestion from Reviewer 1. We have therefore amended Table 1 accordingly. REVIEWER 3 1) Minor essential revisions: Would have a statement stating something like this: TCD is a bit of a hodgepodge in regard to operator etc. It is very difficult to analyze data from multiple papers done with different operators, different machines etc; most without age-matched control data. Furthermore in these sample there are no validity reliability assessments so the data is a bit on the weak side. However having said that, the conclusions seem to fit the data since there are a lot of papers and there is some concordance on conclusions as the writers state. We agree with Reviewer 3. We feel that additional details, particularly those in relation to Reviewer 1 point 6, are in this vein. Page 4