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SYSTEMATIC REVIEW Open Access
Unravelling functional neurology: doesspinal manipulation have an effect on thebrain? - a systematic literature reviewAnne-Laure Meyer1,2,3* , Michel-Ange Amorim1,2, Martin Schubert4, Petra Schweinhardt5 andCharlotte Leboeuf-Yde1,2,3,6
Abstract
Background: A recent hypothesis purports that spinal manipulation may cause changes at a brain level. FunctionalNeurology, a mainly chiropractic approach, promotes the use of spinal manipulation to improve ‘brain function’ asif it were a proven construct. No systematic review has been performed to investigate how well founded thishypothesis is.
Objective: To investigate whether spinal manipulation has an effect on ‘brain function’ that is associated with anyclinical benefits.
Method: In this systematic review, the literature was searched in PubMed, Embase, and PEDro (final search February2018). We included randomized or non-randomized controlled studies, in which spinal manipulation was performed toany region of the spine, applied on either symptomatic or asymptomatic humans, and compared to a sham or toanother type of control. The outcome measures had to be stated as direct or proxy markers of ‘brain function’. Articleswere reviewed blindly by at least two reviewers, using a quality checklist designed for the specific needs of the review.Studies were classified as of ‘acceptable’, ‘medium’, or ‘low’ methodological quality. Results were reported in relation to(i) control intervention (sham, ‘inactive control’, or ‘another physical stimulus’) and (ii) study subjects (healthy,symptomatic, or with spinal pain” subjects/spinal pain”), taking into account the quality. Only results obtained frombetween-group or between-intervention comparisons were considered in the final analysis.
Results: Eighteen of 1514 articles were included. Studies were generally of ‘low’ or ‘medium’ methodological quality,most comparing spinal manipulation to a control other than a sham. Thirteen out of the 18 studies could be includedin the final analysis. Transitory effects of different types of ‘brain function’ were reported in the three studies comparingspinal manipulation to sham (but of uncertain credibility), in “subclinical neck/spinal pain” subjects or in symptomaticsubjects. None of these three studies, of ‘medium’ or ‘acceptable’ quality, investigated whether the neurophysiologicaleffects reported were associated with clinical benefits. The remaining 10 studies, generally of ‘low’ or ‘medium’ quality,compared spinal manipulation to ‘inactive control’ or ‘another physical stimulus’ and similarly reported significantbetween-group differences but inconsistently.
Conclusion: The available evidence suggests that changes occur in ‘brain function’ in response to spinal manipulationbut are inconsistent across and - sometimes - within studies. The clinical relevance of these changes is unknown. It istherefore premature to promote the use of spinal manipulation as a treatment to improve ‘brain function’.
Keywords: Spinal manipulation, Brain, Functional Neurology, Chiropractic, Systematic review
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: almeyer@ifec.net1CIAMS, Univ. Paris-Sud, Université Paris-Saclay, 91405 Orsay Cedex, France2CIAMS, Université d’Orléans, 45067 Orléans, FranceFull list of author information is available at the end of the article
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 https://doi.org/10.1186/s12998-019-0265-8
Résumé
Introduction: Une hypothèse récente propose que la manipulation vertébrale causerait des changementsneurophysiologiques au niveau du cerveau. En Neurologie Fonctionnelle, approche principalement présente enchiropraxie, l’utilisation de la manipulation vertébrale est déjà promue comme capable d’améliorer le fonctionnementdu cerveau. A ce jour, aucune revue systématique de la littérature n’a été conduite afin de connaître l’étendue et laqualité de l’évidence scientifique susceptible de justifier cet usage de la manipulation vertébrale.
Objectif: Déterminer, à travers une revue systématique et critique de la littérature, si la manipulation vertébrale a uneffet (spécifique) sur le cerveau et, si oui, si celui-ci est associé à un effet clinique.
Méthode: Le moteur de recherche PubMed et deux bases de données, Embase et PEDro, ont fait l’objet d’une recherchebibliographique (actualisée en février 2018). Les critères d’inclusion étaient: essais contrôlés, randomisés ou non, danslesquels la manipulation vertébrale avait été comparée à un placébo ou à un autre type de contrôle, chez des sujetssymptomatiques ou asymptomatiques. La manipulation vertébrale pouvait avoir été effectuée au niveau de n’importequelle région de la colonne vertébrale et les critères de jugement utilisés devaient être indiqués comme capables demesurer, directement ou indirectement, une forme ‘d’activité cérébrale’. La qualité méthodologique des études a étéévaluée de manière indépendante par au moins deux chercheurs à l’aide d’une grille de qualité créée pour les besoins decette revue. Les études ont été classifiées comme étant de qualité méthodologique ‘acceptable’, ‘moyenne’, ou ‘faible’.Les résultats ont été rapportés de façon narrative, en fonction du type de contrôle utilisé (placébo, ‘inactif’, ou ‘autrestimulus physique’) et du type de sujets d’étude (sans problème de santé, symptomatiques, ou présentant des « douleursrachidiennes subcliniques »), en tenant compte de la qualité méthodologique. Seuls les résultats issus de comparaisonsinter-groupes ont été pris en compte dans notre analyse finale.
Résultats: Dix-huit articles parmi les 1514 titres obtenus ont été inclus. Les études étaient pour la plupart de qualitéméthodologique ‘faible’ ou ‘moyenne’ et avaient principalement comparé la manipulation vertébrale à une interventionautre que placébo. Les résultats rapportés dans 13 des 18 articles inclus ont finalement été pris en compte. Un effettransitoire sur différentes formes ‘d’activité cérébrale’ a été rapporté à l’issue de trois études dans lesquelles lamanipulation vertébrale avait été comparée à un placébo (de crédibilité cependant incertaine), chez des sujets présentantdes « douleurs rachidiennes subcliniques » (n = 2) ou souffrant de cervicalgies non spécifiques aiguës / subaiguës (n = 1).Une potentielle association avec un effet clinique n’a pas été étudiée dans ces trois études, de qualité méthodologique‘moyenne’ (n = 2) ou ‘acceptable’ (n = 1). Dans les 10 études restantes, la plupart de qualité méthodologique ‘faible’ ou‘moyenne’, la manipulation vertébrale avait été comparée à un contrôle ‘inactif’ ou à un ‘autre stimulus physique’. Desdifférences inter-groupes y ont également été rapportées, parfois de façon inconsistante.
Conclusion: La littérature scientifique suggère que des changements neurophysiologiques surviennent au niveau ducerveau en réponse à la manipulation vertébrale mais, de façon inconsistante. La pertinence clinique de ces changementsn’est pas connue. Ainsi, il est prématuré d’attribuer à la manipulation vertébrale des bénéfices cliniques via un effet sur lecerveau.
Mots clés: Manipulation vertébrale, Cerveau, Neurologie Fonctionnelle, Chiropraxie, Revue systématique
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 2 of 30
IntroductionSpinal manipulation (SM) is widely used by varioushealth practitioners, including physiotherapists, osteo-paths and chiropractors, to treat mainly musculoskel-etal conditions, but some also use it for a variety ofother health-related problems [1, 2]. While the litera-ture tends to support the benefit of SM as a usefultreatment in the musculoskeletal area, no clear evi-dence exists in relation to non-musculoskeletal condi-tions [3].This lack of evidence contrasts with claims of some
therapists, including (but not restricted to) those whopractice using the theoretical concepts of FunctionalNeurology (FN), a mainly chiropractic approach, foundedby a chiropractor, FR Carrick [4]. In addition to musculo-skeletal conditions, “functional neurologists” (i.e. FN prac-titioners) also provide treatment for complex disorderssuch as neurodevelopmental disorders, neurodegenerativedisorders, and post-traumatic stress disorders [5]. Alsobased on these FN concepts, some therapists claim to en-hance human performances (e.g. physical performances),including in asymptomatic individuals [5].In line with FN, a current hypothesis is that the clin-
ical benefits observed following SM would be, at leastpartially, due to neurophysiological changes within thebrain [6, 7]. Some practitioners already use this conceptclaiming it to be a fact that SM has a clinically relevanteffect on the brain, as shown through several sources ofinformation in a recent scoping review on FN [5]. Fur-thermore, for some proponents of this hypothesis, atleast for the “functional neurologists”, a multitude ofconditions results from dysfunction within the brain [5].It is stated that malfunctioning clusters of neurons, de-scribed as primarily located within the brain, could be thesingle cause of virtually any type of symptom and/or dis-order that a person may have. Examples extracted form aFN textbook are attention deficit and hyperactivity dis-order, depression, mechanical low back pain, and mi-graines [7]. In addition, these ‘malfunctions’ are stated tobe reversible through the use of stimulation of the nervoussystem, including by SM [5]. This would give SM the po-tential to be used for both musculoskeletal and non-mus-culoskeletal conditions. In fact, it is even stated that SM isone of the most easily available methods for manual prac-titioners to improve ‘brain function’ [7].Within the scientific literature, differently framed hy-
potheses exist in relation to the potential mechanismsinvolving the brain, which could explain clinical bene-fits following SM [6, 8, 9]. The one mechanism thatseems to prevail relates to the chiropractic concept of‘subluxation’, which has developed over time [10].Currently some authors purport that ‘subluxations’modify afferent inputs to the central nervous system [6,11]. These authors state, in addition to this, that the
‘subluxation’ is at the source of maladaptive neuralplastic changes, including in the cerebral cortex, whichin turn result in altered processing and integration ofsubsequent afferent inputs and, consequently, alteredmotor outputs [11]. As a consequence, SM is claimedto restore afferent inputs to the central nervous system(including to the brain) and result in appropriate motoroutputs from the central nervous system [11].Potential neurophysiological effects of SM on the
brain have been the focus of several recent experi-mental studies. As the brain is involved in a multi-tude of functions, its activities or alteration ofactivities after an intervention can be explored in sev-eral ways. Not surprisingly then, the studies in thisfield of research use various approaches and outcomemeasures to test the hypothesis that SM has an effecton ‘brain function’. For example, some studies investi-gated the potential effect of SM on brain areas in-volved in pain processing [9] and autonomicfunctions [8], whereas others reported on the poten-tial effect of SM on cortical somatosensory integrationof stimuli from the upper limb [6]. Therefore, in thepresent systematic review ‘brain function’ is used as ageneric expression referring to processes in which thebrain is involved.Because studies are quite heterogeneous, it is diffi-
cult to understand and interpret the evidence in thisarea. Nevertheless, this task is needed to understandif assertions of the ‘brain-mediated’ hypothesis propo-nents are substantiated by scientific evidence. A nar-rative review on the topic by Haavik and Murphy waspublished in 2012 [6]. In this review, they concludedthat some evidence supports a brain mechanism ofaction for SM but that it remains to be investigatedwhether this correlates to clinical benefits. They alsostated that such studies were underway [6]. Giventhat 7 years have passed since this narrative review,the aforementioned studies exploring potential associ-ations between clinical and ‘brain function’ changespost-SM were likely published, and thus may provideimportant updates to the state of the field. For thesereasons, we undertook a systematic critical review ofthe literature, which had as its overall aim to investi-gate whether SM has an effect on ‘brain function’ thatis associated with any clinical benefits in healthy and/or symptomatic subjects. The specific research ques-tions were:
In relation to sham controlled studies, i.e. ‘effect’studies:1 - Is there an effect of SM on ‘brain function’?2 - If there is an effect, for how long does it last?3 - If there is an effect, is it associated with any clinical
benefits?
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 3 of 30
In relation to other controlled studies (‘inactivecontrol’ or ‘another physical stimulus’), i.e. the‘differences in outcome’ studies:4 - Is there a difference in ‘brain function’ after SM vs.
an ‘inactive control’?5 - Is there a difference in ‘brain function’ after SM vs.
‘another physical stimulus’?
MethodsA systematic critical review of the literature was car-ried out to shed light on the research questionsabove. The review was registered in the PROSPEROinternational prospective register of systematic reviews(CRD42017074966). Some deviations from the originalprotocol were required in response to the materialavailable in the reviewed articles, which was unknownat the time of planning the review. These were: (i)the wording of the research questions was improved,(ii) the review was restricted to spinal manipulativetherapy (i.e. did not include extremities), and (iii) theresults were analyzed depending on three categoriesof study subjects instead of the two we planned.Regarding the latter, it was initially planned toanalyze the results depending on whether study sub-jects were (i) healthy or (ii) symptomatic. However, athird type of study subjects was identified, namely“subclinical neck/spinal pain” subjects. Further detailson these study subjects are given in a subsequent sec-tion (see Data analysis and synthesis).
Search for literatureA systematic literature search was conducted in threeelectronic databases: PubMed, Embase and PEDro in April2017 (updated between January and February 2018). Thesearch strategy was initially developed for PubMed (avail-able in Additional file 1) and then adapted to the twoother databases in collaboration with a health scienceresearch librarian. In short, the strategy was designed byassociating (i) terms related to SM, for example “manipu-lation, spinal”, “musculoskeletal manipulations”, or “high-velocity low-amplitude spinal manipulation”, (ii) termsrelated to brain or brain structures, for example “brain”,“cerebrum”, or “cerebellum”, and (iii) terms related to thedifferent ways of assessing ‘brain function’, for example“transcranial magnetic stimulation”, “electroencephalog-raphy”, or “positron-emission tomography”.
Eligibility criteriaThe eligible studies in this review had to include at leastone control group, with or without random allocation.Two- or several-arm trials were accepted as well ascrossover designs. These studies had to be conducted onhumans, with no restriction regarding their study
population such as age, sex, healthy or symptomatic sub-jects, or type of symptoms.The tested intervention had to consist of manually
performed, instrumentally assisted, or mechanicallyassisted SM. Studies with combined or concomitanttherapies were excluded, as it would not be possible toseparate results obtained from the SM and the othertherapies. However, if all the study groups of a reportwere subjected to the same combined or concomitanttherapies (e.g. pain medication), i.e. the only differencebetween the study groups being that one group was sub-jected to the tested intervention (e.g. pain medicationAND spinal manipulation) but not the other (i.e. painmedication only), the article could be included.The control group could be subjected to a sham pro-
cedure, an ‘inactive control’, or ‘another physical stimu-lus’ (other than SM). However, only studies using asham as comparator could be considered to investigatethe effect of SM (i.e. effect specific to SM) on the brainand could therefore be used to answer the search ques-tions 1 to 3 of the present review. The control was con-sidered as ‘another physical stimulus’ when it involved atleast a manual contact (e.g. passive movement of a spineregion, or joint preloading), or when it included otherforms of manual therapies (e.g. joint mobilization, thera-peutic touch). ‘Inactive control’ would consist of, for ex-ample, placing the study subject in side posture withoutmanual contact or just resting.Given our overall aim, the inclusion criteria were
not limited to specific outcome measures or to spe-cific measurement procedures. Studies were includedif their authors stated that the outcome measureswere used to assess ‘brain function’, meaning this wasnot necessarily expected that the outcome measureswere valid or markers exclusive of ‘brain function’.This lenient criterion was chosen for two reasons: (i)some outcome measures are known also to dependon segmental activity (e.g. the V-wave) [12] and (ii)the outcome measures used by “functional neurolo-gists” are not necessarily valid [13]. These potentialissues will be discussed later in the review.There was no restriction in relation to the date of pub-
lication of the studies but only articles in English orFrench were included.
ScreeningEligibility criteria were applied twice to the titles bythe first author, who also searched the reference listsof the included full texts for additional relevant stud-ies. Thereafter, the abstracts and then the relevant fulltexts were read independently by two authors (ALMand CLY) to determine if they could be included inthe review.
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 4 of 30
Extraction of informationThree types of specific checklists were developed for thisreview relating to: main descriptive features of includedarticles (Tables 1, 2 and 3), methodological quality as-sessment (Tables 4, 5, 6, 7 and 8), and report of results(Table 9, 10 and 11). Information of interest was ex-tracted from the Methods and Results sections only.
Descriptive informationMain descriptive features of the included articles were re-ported in three tables, one for each type of control, i.e.sham, ‘inactive’, and ‘another physical stimulus’ (see Ta-bles 1, 2 and 3). The descriptive data were extracted fromeach included article independently by ALM and CLY andwere later compared to minimize extraction errors.
Information related to methodological qualityA quality checklist was designed in order to evaluatemainly risk of bias of the type of studies included in thepresent review. This checklist was developed based onconcepts described in the CONSORT statements [30]and on usual concepts in relation to risk of bias, such asthose used by the Cochrane collaboration [31] and thescale proposed in the PEDro database [32]. The itemsused for the quality assessment and their rationale aredescribed in Additional file 2.When deemed necessary, three researchers (MAA, MS
and PS), with an expertise in at least one of the out-comes used in the included studies, provided commentsin relation to the methodology and technical aspects ofthe studies they assessed. These comments could beused to discuss the findings in relation to each researchobjectives. Some of these comments have been includedin this report (see Tables 4, 5, 6 and 7, col.10). Each ex-pert (MAA, MS and PS) dealt with articles withintheir own areas of expertise only. One of the authors(MAA), with special expertise on the types of statis-tical analyses used in experimental studies, reviewedall the statistical analyses. The articles were groupedby type of outcomes or families of outcomes in fivemethodological quality checklists of similar items (seeTables 4, 5, 6, 7 and 8). This was done in order tofacilitate the overview of the comments of the expertsin relation to each type of outcomes or families ofoutcomes. As we did not have access to experts onall the outcomes used in the included studies, com-ments related to methodology and technical aspectscould not always be provided (as mentioned in Tables5, 6 and 8, col.10).Each article was independently reviewed for each meth-
odological quality item by at least two of the authors(ALM and CLY or ALM, CLY and PS). Data were latercompared to minimize extraction errors. Discrepancies
were planned to be resolved by discussion between theauthors.
Information related to the resultsThe outcomes of the selected studies were reported inthree tables (see Tables 9, 10 and 11), one for each type ofcontrol (sham, ‘inactive’, and ‘another physical stimulus’).For each of these tables, results were reported grouped by(i) type of study subjects (healthy, symptomatic, and with“subclinical neck/spinal pain”), (ii) type of outcomes, and(iii) consecutively by year of publication.In accordance with the recommendations of Bland and
Altman (2011) [33], we planned to report only resultsthat reflected clearly differences between-groups (in trialsconsisting of at least two separate groups of study sub-jects). In crossover designs, differences should be testedbetween-types of interventions. This means that resultsof studies that did not perform and clearly report com-parisons between-groups or, in the case of crossoverstudies, failed to report between-types of interventionswould not be taken into consideration to answer our re-search questions. Therefore, if authors reported only sig-nificant within-groups or within-types of interventions,without taking into account the difference between read-ings of the two interventions, this would be ignored.However, our review revealed both unusual and con-
fusing statistical reporting. We therefore decided to takeinto consideration also some results in a ‘benefit of thedoubt’ approach, such as instances when none of the re-viewers was able to decide whether the authors had, infact, performed an appropriate between-groups or be-tween-types of intervention analysis.Only the primary outcomes of the included studies
were considered.
Classifying articles by their methodological qualityEach article was checked for each quality item, giving ei-ther half of a point or one point for each fulfilled item asdescribed in Additional file 2. The quality score was ar-bitrarily divided into ‘acceptable’ (68 to 100% of max-imum number of points), ‘medium’ (34 to 67% ofmaximum number of points) and ‘low’ (0 to 33% ofmaximum number of points), to indicate the quality ofthe methodological aspects mainly in relation to risk ofbias of studies.
Data analysis and synthesisThe various tables were used to report narratively themain findings in relation to our five research questions,taking into account the methodological quality of the in-dividual studies, so that we would have more confidencein the studies of better quality than those with additionalmethodological deficiencies.
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 5 of 30
For each type of control, the findings were reported bytype of study subjects: healthy, symptomatic, or “subclin-ical neck/spinal pain’” subjects. Following the definitiongiven by the authors of the respective studies, the “sub-clinical neck/spinal pain” subjects appeared to us as an in-dependent category of study subjects, neither healthy norin pain at the time of study. Although this latter definitionchanges somewhat from one publication to another, studysubjects were usually described as having a history of“mild intermittent spinal pain, ache or tension (subclinicalspinal pain), and evidence of dysfunction in the spinaland/or pelvic joints” [24]; spinal/pelvic dysfunction refer-ring to the chiropractic concept of ‘subluxation’ [14, 20,25, 27, 28]. In some of these studies, these study sub-jects were also defined as not yet having sought treat-ment for their complaint [14, 15, 24, 27].
ResultsFigure 1 shows a flow diagram of the study selectionprocess. Of the 1514 initially screened articles, 18 ful-filled our inclusion criteria and were included in the re-view. These were published in English between 2000 and2018. The majority of studies (n = 10), all on “subclinical
neck/spinal pain” subjects, were conducted by researchteams that included one specific author [14, 15, 20, 21,23–28].All articles reported an ethics approval from an ethics
committee or from a review board, with or without anidentification number of the application and approval.As for conflict of interest, 11 studies declared to havenone [8, 9, 14–16, 18, 21, 22, 24, 26, 28], whereas theissue of conflict was not mentioned at all in the others[17, 19, 20, 23, 25, 27, 29].
Description of studies (n = 18)Detailed descriptive information of each study is avail-able in Tables 1, 2 and 3 and briefly summarized below.The size of the study samples of the 18 included
studies ranged from 10 to 72. Ten were conducted on“subclinical neck/spinal pain” subjects (Tables 1, 2and 3), four on pain free healthy subjects (Tables 2and 3), and four on symptomatic subjects (Tables 1, 2and 3), including one on subjects with experimentallyinduced low-back myalgia [22]. In five of the tenstudies considered in the present review, as conductedon “subclinical neck/spinal pain” subjects, the study
Fig. 1 Description of the search for literature in a systematic review on the effect of spinal manipulation on ‘brain function’
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 6 of 30
Table
1Descriptio
nof
threestud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
asham
interven
tion
1st
author
Yr Ref
Design
Type
ofstud
ysubjects
Num
berof
stud
ysubjects
(males/
females)
-Age
(rang
e)-M
ean
-Typeof
spinalmanipulation
-Typeof
control
-Sham
How
was
cerebralactivity
measured?
Whe
nwas
cerebralactivity
measured?
Clinicalou
tcom
esassessed
(measuremen
ttool
andtim
eof
assessmen
t)
Spars
2017
[9]
Rand
omized
controlled
trial
Symptom
aic:volunteers(unkno
wn
origin)with
mechanicaln
eckpain
<6
weeks
ofdu
ratio
n
24(4
/8)
manipulation
grou
p/(4
/8)
sham
grou
p
-?/?
-36
manipulation
grou
p/40
sham
grou
p
-HVLAmidthoracic(X1)
-‘No’control
-Sham:sim
ilarpo
sitio
ning
ofthesubjectand
investigator’shand
swhich
wereplaced
across
theskin
with
minim
alpressure
(to
mim
ictheHVLAproced
ure)
Bloo
doxygen
ationlevel-
depe
nden
tsign
al(in
respon
seto
noxiou
sstim
uli)
Before
After:immed
iately
Pain
intensity
(11-po
int
numericalpain
ratin
gscale)
(beforespinal
manipulationor
sham
proced
ures
andafter
thefinalfM
RI)
Lelic
2016
[14]
Crossover
controlled
trial(orde
rof
interven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:
volunteers(orig
inun
know
n)with
recurren
tspinalache
,painor
stiffne
ssandeviden
ceof
spinaldysfun
ctionbu
twho
didno
tyetsoug
httreatm
entfor
thisandpain
freeat
thetim
eof
the
stud
y.
19(9
/10)
-? -26
-HVLA(whe
rene
eded
,in
anyspinelevelo
rsacroiliac
joints,n
bun
know
n_may
beat
severallevels)
-‘No’control
-Sham:p
assive
andactive
movem
entsof
thehe
ad,
spine,andbo
dy,sim
ilarto
whatwas
done
forHVLA
interven
tion,
with
out
loadingandthrust
SEPam
plitu
des:N30
peaks
Streng
thof
brainsources:
contralateral
somatosen
sory
cortex,
prefrontalcortex,
cing
ulatecortex,and
bilateralsecon
dary
somatosen
sory
cortex
Before
After:exact
timeun
know
nNon
e
Baarbé
2018
[15]
Rand
omized
controlled
trial
“Sub
clinicalne
ck/spinalp
ain”:
volunteers(unkno
wnorigin)with
recurren
tmild
neck
pain
andmuscle
tension,
butminim
alacutepain
onthe
dayof
testingandwho
neversoug
httreatm
entforthisne
ckcomplains.
27(6
/8)
interven
tion
grou
p/(5
/8)
sham
grou
p
-18–27
intervention
group/19–24
sham
grou
p-21(fo
rbo
thgrou
ps)
-HVLAcervical(X2to
4pe
rsubject)
-‘No’control
-Sham:n
eckge
ntlymoved
into
lateralflexion
and
rotatio
nin
asimilarmanne
rto
theactualne
ckmanipulation,
with
out
applying
theHVLAthrust
Cereb
ellarinhibitio
nBefore
After:exact
timeun
clear(said
tobe
immed
iatelyafter
motor
acqu
isition
task,i.e.
cerebe
llarinhibitio
nwas
re-
measuredabou
t20
min
after
spinalmanipulation)
Non
e
Articlesarepresen
tedby
(i)type
ofstud
ysubjects,i.e.sym
ptom
aticor
“sub
clinical
neck/spina
lpain”
subjects,and
(ii)consecutivelyby
year
ofpu
blication
fMRI
Functio
nalm
agne
ticresona
nceim
aging,
HVLAHighvelocity
low
amplitu
de,n
bNum
ber,SEPSo
matosen
sory
evok
edpo
tential
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 7 of 30
Table
2Descriptio
nof
eigh
tstud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
aninactive
control
1st
author
Yr Ref
Design
Type
ofstud
ysubjects
Num
berof
stud
ysubjects
(males/
females)
-Age
(rang
e)-M
ean
-Typeof
spinal
manipulation
-Typeof
control
How
was
cerebral
activity
measured?
Whe
nwas
cerebralactivity
measured?
Clinicalou
tcom
esassessed
(measuremen
ttool
andtim
eof
assessmen
t)
Kelly
2000
[16]
Rand
omized
controlledtrial
Health
y:volunteerchiro
practic
stud
entswith
eviden
ceof
uppe
rcervical“sub
luxatio
n”.
36(9
/9)
interven
tion
grou
p/(11
/7)
control
grou
p
-20-37
(bothgrou
ps)
-24(bothgrou
ps)
-Tog
gle(X1)
-Con
trol:2
min
ofresting
Men
tal
rotatio
nreactio
n-tim
etask
Before
After:exact
timeun
know
nNon
e
Dishm
an2002
[17]
Non
-rando
mized
controlledtrial
Health
y:he
althycollege
stud
ents,volun
teers
24(?/?)
(repartition
ineach
grou
pno
trepo
rted
)
-?/?
-25interven
tion
grou
p/27
control
grou
p
-HVLAL5-S1(X1)
-Con
trol:side
posturepo
sitio
ning
with
outlower
limb
flexion
,truncal
torque,o
rmanual
contact
MEP
amplitu
des
Before
After:
-immed
iately(20to
120s)
-5min
−10
min
Non
e
Dishm
an2008
a
[18]
Rand
omized
controlledtrial
Health
y:he
althychiro
practic
stud
ents,volun
teers
72(21/5)
interven
tion
grou
p/(15
/8)
control
1/(14/9)
control2
-?(3
grou
ps,saidto
bebe
tweentheir20s
and30s)
-?(3
grou
ps)
-HVLAL5-S1(X1)
-Con
trol
1:L5-S1
preloading
-Con
trol
2:side
posturepo
sitio
ning
MEP
amplitu
des
Before
(10MEP
recorded
durin
g100s)
After:immed
iately(10MEP
recorded
durin
g100s)
Non
e
Fryer
2012
[16]
Crossover
controlledtrial
(order
ofinterven
tions
rand
omized
)
Health
y:he
althyun
iversity
stud
ents,volun
teers
14(10/4)
-18-50
-23
-HVLAL5-S1(X2to
4)-Con
trol:b
ilateral
side
-posture
positio
ning
with
out
trun
caltorqu
e,or
manualcon
tact
MEP
latencies
and
amplitu
des
Silent
perio
ds
Before
After:exact
timeun
know
n(according
totheDiscussion
approxim
ately10
min
after)
Non
e
Ogu
ra2011
[19]
Crossover
controlledtrial
(order
ofinterven
tions
“cou
nterbalanced
”)
Symptom
atic:volun
teers,
recruitedat
thelocalu
niversity,
with
mechanicalcervicalp
ain
andshou
lder
stiffne
ss.
12(12/0)
-21–40
-28
-Instrumen
tally
assisted
manipulation
(locatio
nandnb
ofspinallevelsadjusted
unknow
n)-Con
trol:20min
ofresting
Region
alcerebral
metabolic
rate
(rate
ofglucose
consum
ption)
Nobe
fore
measuremen
tAfter:b
etween35
to55
min
post-interven
tionor
resting
-StressRespon
seScale
(immed
iatelyafterinterven
tions)
-Europ
eanOrganizationfor
Research
andTreatm
entof
CancerQualityof
Life
Questionn
aire-Core30
(immed
iatelyafterinterven
tions)
-Painintensity
(visualanalogu
escale)
(beforeandim
med
iately
afterspinalmanipulation,
not
before-after-20
min
ofresting)
Inam
i2017
[8]
Crossover
controlledtrial
(order
ofinterven
tions
rand
omized
)
Symptom
atic:volun
teers
(unclear
origin
–prob
ablythe
sameas
Ogu
raet
al.2011)
with
mechanicalcervicalp
ainand
shou
lder
stiffne
ss.
21(21/0)
-? -26
-Instrumen
tally
assisted
manipulation(whe
rene
eded
,anywhe
reat
thespine,sacroiliac
jointsand/or
scapulae,m
eanof
8pe
rsubject)
-Con
trol:20min
ofresting
Region
alcerebral
metabolic
rate
(rate
ofglucose
consum
ption)
Nobe
fore
measuremen
tAfter:b
etween35
min
to1.05
h.po
st-in
terven
tionor
resting
Pain
intensity
(visualanalogu
escale)
(beforeandim
med
iately
afterspinalmanipulation,
and
before
andafter20
min
ofresting,
onlyfor9/21
subjects)
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 8 of 30
Table
2Descriptio
nof
eigh
tstud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
aninactive
control(Co
ntinued)
1st
author
Yr Ref
Design
Type
ofstud
ysubjects
Num
berof
stud
ysubjects
(males/
females)
-Age
(rang
e)-M
ean
-Typeof
spinal
manipulation
-Typeof
control
How
was
cerebral
activity
measured?
Whe
nwas
cerebralactivity
measured?
Clinicalou
tcom
esassessed
(measuremen
ttool
andtim
eof
assessmen
t)
Haavik-
Taylor
2007aa
[20]
Crossover
controlledtrial
(order
ofinterven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:
volunteers(unkno
wnorigin)
with
ahistoryof
recurringne
ckpain
orstiffne
ssandwith
eviden
ceof
cervicalspinal
dysfun
ction,
pain
freeat
the
timeof
thestud
y.
13(5
/8)
-22-45
-31
-HVLAcervical(X2to
3pe
rsubject)
-Con
trol
1:passivehe
admovem
entwith
out
loadingandthrust
-Con
trol
2:no
thing
MEP
amplitu
des
CSP
duratio
ns
Before
After:
-with
in0–10
min
-with
in10–20min
-with
in20–30min
Non
e
Haavik-
Taylor
2010b
[21]
Crossover
controlledtrial
(order
ofinterven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:
stud
entandun
iversity
staff
mem
bers,volun
teers,with
reoccurringne
ckprob
lemsand
eviden
ceof
cervicalspine
dysfun
ction,
pain
freeat
the
timeof
thestud
y.
11(4
/7)
-22-40
-29
-HVLAcervical(nb
unknow
n,may
beat
severallevels)+20
min
oftyping
task
-Con
trol:20min
oftyping
task
only
SEPMU/M
+Upe
akratio
s:-P14-N18
complex
-ParietalN
20(N20-P25
complex)
-FrontalN30
(P22-N30
complex)
Before
After:
exacttim
eun
clear(saidto
beim
med
iatelyafterHVLA+20
min
oftyping
task
orafter20
min
typing
task
only,b
utalso
said
tobe
with
in25
min
post
interven
tions,i.e.p
ossiblywith
in45
min
afterspinalmanipulation)
Non
e
Articlesarepresen
tedby
(i)type
ofstud
ysubjects,i.e.h
ealth
y,symptom
aticor
“sub
clinical
neck/spina
lpain”
subjects,(ii)
type
ofou
tcom
esor
family
ofou
tcom
es,and
(iii)consecutivelyby
year
ofpu
blication
CSPCortical
silent
perio
d,HVLAHigh-velocity
low-amplitu
de,M
EPMotor
evok
edpo
tential,nb
Num
ber,SEPSo
matosen
sory
evok
edpo
tential
a Article
presen
tedin
Tables
2an
d3
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 9 of 30
Table
3Descriptio
nof
nine
stud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
anothe
rph
ysical
stim
ulus
1stauthor
Yr Ref
Design
Type
ofstud
ysubjects
Num
berof
stud
ysubjects(m
ales/
females)
-Age
(rang
e)-M
ean
-Typeof
spinalmanipulation
-Typeof
control
How
was
cerebral
activity
measured?
Whe
nwas
cerebral
activity
measured?
Clinicalou
tcom
esassessed
(measuremen
ttool
andtim
eof
assessmen
t)
Dishm
an2008
a
[18]
Rand
omized
controlled
trial
Health
y:he
althychiro
practic
stud
ents,
volunteers.
72(21/5)
interven
tion
grou
p/(15/8)
control1
/(14/9)
control2
-?(3
grou
ps,
said
tobe
betw
eentheir
20sand30s)
-?(3
grou
ps)
-HVLAL5-S1(X1)
-Con
trol
1:L5-S1preloading
-Con
trol
2:side
posture
positio
ning
MEP
amplitu
des
Before
(10
MEP
recorded
durin
g100s)
After:
immed
iately
(10MEP
recorded
durin
g100s)
Non
e
Gay
2014
[22]
Rand
omized
controlled
trial
Symptom
atic:volun
teersfro
maprevious
clinicaltrial,recruitedat
thelocalu
niversity,
hospitaland
surrou
ndingcommun
ity,w
hocompleted
anexercise-in
jury
protocol
toindu
cemyalgiain
thelow
back.
24 (1/5)
manipulation
grou
p/(1
/7)
mob
ilizatio
ngrou
p/(5
/5)
therapeutic
touch
grou
p(7
/17)
-?/?
/?(re
quiredto
bebe
tween18
and
44)
−21
manipulation
grou
p/21
mob
ilizatio
ngrou
p/23
therapeutic
touchgrou
p
-HVLA(X1,prob
ablyin
the
lumbarspine)
-Con
trol
1:gradeIIIlumbar
spinalmob
ilizatio
n-Con
trol
2:therapeutic
touch
(ligh
tpressure
with
acontact
tothesacroiliacjoints)
Functio
nal
conn
ectivity
Before
After:
immed
iately
Pain
intensity
(101-
pointnu
merical
ratin
gscale)
(beforeand
immed
iatelyafter
ineach
grou
p)
Haavik-Taylor
2007aa
[20]
Crossover
controlled
trial(orde
rof
interven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:volun
teers
(unkno
wnorigin)with
ahistoryof
recurring
neck
pain
orstiffne
ssandwith
eviden
ceof
cervicalspinaldysfun
ction,
pain
freeat
the
timeof
thestud
y.
13(5
/8)
−22-45
−31
-HVLAcervical(X2to
3pe
rsubject)
-Con
trol
1:passivehe
admovem
entwith
outloading
andthrust
-Con
trol
2:no
thing
MEP
amplitu
des
CSP
duratio
nsBefore
After:
-with
in0–10
min
-with
in10–
20min
-with
in20–
30min
Non
e
Haavik-Taylor
2008
[23]
Crossover
controlled
trial(orde
rof
interven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:adu
lts(unkno
wnorigin)with
ahistoryof
reoccurringne
ckpain
orstiffne
ssandwith
eviden
ceof
cervicalspinaldysfun
ction,
pain
freeat
thetim
eof
thestud
y.
12(7
/5)
−19-45
−27
-HVLAcervical(nbun
know
n,may
beat
severallevels)
-Con
trol:p
assive
head
movem
entwith
outloading
andthrust
MEP
amplitu
des
CSP
duratio
nsSICI
SICF
Before
After:exact
time
unknow
n
Non
e
Haavik2016
[24]
Crossover
controlled
trial
“Sub
clinicalne
ck/spinalp
ain”:volun
teers
(unkno
wnorigin)with
ahistoryof
spinal
symptom
sandwith
eviden
ceof
spinal
and/or
pelvicdysfun
ctionbu
twho
didno
tyetsoug
httreatm
entforthisandpain
free
atthetim
eof
thestud
y.
12(?)
-? −28
-HVLAcervical(nbun
know
n,may
beat
severallevels)
-Con
trol:p
assive
head
movem
entwith
outloading
andthrust
MEP
amplitu
des
Slop
eof
the
steepe
stpartof
the
curve(k)
Stim
ulus
intensity
requ
iredto
obtain
arespon
sethat
is50%
ofthemax
(S50)
Before
After:exact
time
unknow
n
Non
e
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 10 of 30
Table
3Descriptio
nof
nine
stud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
anothe
rph
ysical
stim
ulus
(Con
tinued)
1stauthor
Yr Ref
Design
Type
ofstud
ysubjects
Num
berof
stud
ysubjects(m
ales/
females)
-Age
(rang
e)-M
ean
-Typeof
spinalmanipulation
-Typeof
control
How
was
cerebral
activity
measured?
Whe
nwas
cerebral
activity
measured?
Clinicalou
tcom
esassessed
(measuremen
ttool
andtim
eof
assessmen
t)
Haavik-Taylor
2007b
[25]
Twogrou
ps“pseud
o-rand
omized
”trial
“Sub
clinicalne
ck/spinalp
ain”:volun
teers
(orig
inun
know
n)with
reoccurringne
ckprob
lemsandeviden
ceof
cervicalspine
dysfun
ction,
pain
freeat
thetim
eof
the
stud
y.
24(7
/5)
interven
tion
grou
p/(4
/8)
controlg
roup
−20-53
interven
tion
grou
p/21–35
controlg
roup
−30
interven
tion
grou
p/27
controlg
roup
-HVLAcervical(X2to
3pe
rsubject)
-Con
trol:p
assive
head
movem
entwith
outloading
andthrust
SEPlatenciesand
amplitu
des:P14–18
complex,N
20(P14-
N20
andN20-P27)
andN30
(P22-N30)
peaks
Before
After:
-with
in0–10
min
-with
in10–
20min
-with
in20–
30min
Non
e
Haavik-Taylor
2010a
[26]
Crossover
controlled
trial(orde
rof
interven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:volun
teers
(orig
inun
know
n)with
reoccurringne
ckprob
lemsandeviden
ceof
cervicalspine
dysfun
ction,
pain
freeat
thetim
eof
the
stud
y.
13 (5/8)
−18-40
−28
-HVLAcervical(nbun
know
n,may
beat
severallevels)
-Con
trol:p
assive
head
movem
entwith
outloading
andthrust
SEPMU/M
+Upe
akratio
s:P14-N18
complex,N
20-P25
complex,and
P22-
N30
complex
ratio
s
Before
After:
with
in25
min
Non
e
Niazi2015
[27]
Crossover
controlled
trial
(order
ofinterven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:volun
teers
(orig
inun
know
n)with
recurring,
interm
itten
tlow-grade
spinalpain,ache,or
tension,
with
eviden
ceof
spine
dysfun
ction,
butwhich
didno
tsoug
httreatm
entforthisprob
lem
andarepain
freeat
thetim
eof
thestud
y.
10 (10/0)
-?(re
quiredto
bebe
tween18
and40)
−28
-HVLA(whe
rene
eded
,inany
spinelevelo
rsacroiliacjoints,
nbun
know
n_may
beat
severallevels)
-Con
trol:p
assive
andactive
movem
entsof
thesubject’s
head,spine
,and
body
into
themanipulationsetup
positio
ns,w
ithou
tloading
andthrust
V-waveam
plitu
deBefore
After:
exacttim
eun
know
n
Non
e
Christiansen
2018
[28]
Crossover
controlled
trial(orde
rof
interven
tions
rand
omized
)
“Sub
clinicalne
ck/spinalp
ain”:elite
Taekwon
doathletes,from
theAuckland
area,w
ith“sub
clinicalspinalpain”and
eviden
ceor
spinedysfun
ction,
pain
freeat
thetim
eof
thestud
y.
12(6
/6)
-?(re
quiredto
bebe
tween17
and50)
−25
-HVLA(whe
rene
eded
,inany
spinelevelo
rsacroiliacjoints,
nbun
know
n_may
beat
severallevels)
-Con
trol:p
assive
andactive
movem
entsof
thesubject’s
head
andspineinto
the
manipulationsetuppo
sitio
ns,
with
outloadingandthrust
V-waveam
plitu
deBefore
After:
-immed
iately
−30
min
−60
mins
Non
e
Articlesarepresen
tedby
(i)type
ofstud
ysubjects,i.e.h
ealth
y,symptom
aticor
“sub
clinical
neck/spina
lpain”
subjects,(ii)
type
ofou
tcom
esor
family
ofou
tcom
es,and
(iii)consecutivelyby
year
ofpu
blication
CSPCortical
silent
perio
d,HVLAHigh-velocity
low-amplitu
de,M
EPMotor
evok
edpo
tential,nb
Num
ber,SEPSo
matosen
sory
evok
edpo
tential,SICF
Shortinterval
intra-cortical
inhibitio
n,SICI
Shortinterval
intra-cortical
facilitation,
SMSp
inal
man
ipulation
a Article
presen
tedin
Tables
2an
d3
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 11 of 30
subjects were not explicitly described as such [20, 21, 23,25, 26]. However, the description provided by their au-thors clearly referred to the definition of “subclinicalneck/spinal pain” subjects [24].All the included studies were controlled trials, includ-
ing two to three experimental groups, most of them witha random allocation (n = 14) and mostly conducted usinga crossover design (n = 10). Only one study reported thedates and duration of data collection [9].Most of the included articles investigated high-velocity
low-amplitude SM, whereas three investigated instru-mentally or mechanically assisted techniques. The areawhere SM was provided varied across studies to includeall areas of the spine, whereas one study did not indicatewhere [19]. In most of them SM was provided ‘wheredeemed necessary’.Most studies used as a control group some passive
type of procedure, considered in the present systematicreview as ‘another physical stimulus’, or used a com-pletely ‘inactive control’, whereas three attempted to usesome types of sham comparators [9, 14, 15]. One studycompared SM to two other manual therapies, i.e. spinalmobilization and therapeutic touch of the lumbosacralarea [22].The outcomes of all these studies were either de-
scribed as reflecting some type of ‘brain function(s)’ or assuggesting some type of ‘brain function(s)’, meaning thatsome outcomes could also reflect, for example, neuro-physiological changes at a segmental level (e.g. V-wave,motor evoked potentials, or cortical silent periods) [12,34]. The outcome measures and measurement tools usedin the selected studies are briefly described in Add-itional file 3. In two studies, outcomes were assessedonly after intervention or control, presumably for ethicalreasons [8, 19]. As can be seen in Tables 1, 2 and 3, inall other studies outcomes were assessed before and afterintervention at various time points. However, six studiesdid not specify the time of re-assessment at all and fourdid not report it clearly.The four studies conducted on symptomatic subjects
described in their Methods section that they alsoassessed clinical outcomes, mainly pain intensity (seeTables 1, 2 and 3) [8, 9, 19, 22]. However, only two ofthem had as one of their research objectives to investi-gate whether a relation exists between potential neuro-physiological changes and pain intensity changes afterintervention, and none of these two assessed this againsta sham intervention [19, 22].
Data extraction (n = 18)The data extraction process was relatively problem freewith only few exceptions. These concerned some articlesin which the statistics and/or results sections were un-clear [9, 14, 21–23, 26, 27]. This was resolved through
multiple discussions. In addition, experts’ opinions weresought in these areas and the experts (MAA, MS andPS) also reported difficulty to interpret some of the stud-ies [9, 14, 21, 23, 26].
Data synthesis: methodological quality of the studies (n =18)The level of methodological quality was generally ‘low’(n = 7) or ‘medium’ (n = 8), except for three articles thatwere considered to be of ‘acceptable’ quality (see Table12 for a summary). The most frequently encounteredmethodological weaknesses were: (i) the success of theblinding of the subjects was uncertain or unsuccessful(the three ‘effect’ studies), (ii) no clear reporting whetherthe study was conducted on naïve subjects (most of the‘differences in outcome’ studies), (iii) no reportingwhether the assessor was blinded to treatment group(most studies), and (iv) no reporting whether the personwho analyzed the data was blinded to treatment group(most studies). In addition, the experts (MAA, MS andPS) sometimes commented on unusual procedures (fordetailed information see Tables 4, 5, 6, 7 and 8 col.10).In two of the studies it was clear that the authors did
not report having performed a between-group analysis[20, 25]. Thus their results were not taken into accountfor our five research questions, and were therefore notreported in Tables 10 and 11. Another study did appearto compare the outcomes of SM on two different handmuscles rather than to compare the effect of SM to acontrol intervention (see Table 5 col.10) [23]. This art-icle was therefore not reported in Table 11.Also, three studies did not report results in relation to all
the statistical between-group comparisons that they stated intheir respective Methods sections that they would do [14,22, 27]. For these studies, only the results from between-group comparisons, if present, were therefore reported.A total of 13 studies were finally used to answer our
five research questions. One of these studies appears intwo of the three results tables (Tables 10 and 11) [18].
Data synthesis: answers to research questions (n = 13)Sham controlled studies (Table 9), i.e. ‘effect’ studies (n = 3)Only three studies used a sham comparator and weretherefore considered as potentially able to provide an-swers to the research questions 1 to 3 [9, 14, 15]. How-ever, in two of these the credibility of the sham isunclear [9, 15], and in the third, the sham was recog-nized as such by most of the study subjects [14]. Twowere considered of ‘medium’ methodological quality[14, 15] and one of ‘acceptable’ methodological quality[9] (see Table 12). These studies, reporting on symp-tomatic subjects or on “subclinical neck/spinal pain”subjects, investigated the potential effect of SM on‘brain function’ by using three different outcome
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 12 of 30
Table
4Qualityitemsandscoreof
onestud
yusingareactio
n-tim
etask
includ
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’
1stAutho
rYr
ofpu
blication
Ref
-Were
stud
ysubjectsin
sham
controlled
stud
ies
repo
rted
tobe
blind?
(Yes
/No/
Unclear)
-Ifyes/
unclear,
was
the
blinding
tested
for
success?
(Yes
/No)
-Ifyes,was
it successful?
(Yes
/No)
-Werestud
ysubjects
instud
ieswith
controlg
roup
repo
rted
tobe
naive?
(Yes
/No/Unclear)
-Was
theorigin
ofthe
subjectsrepo
rted
(Yes
/No)
-Ifyes,do
esitallow
toexclud
eany
interest?(Yes
/No/
Unclear)
Were
stud
ysubjects
repo
rted
tohave
been
rand
omly
allocated
tostud
ygrou
ps?
(Yes
/No
/Unclear)
Werestud
ygrou
pscomparable
inrelatio
nto
symptom
swhe
nstud
ying
symptom
atic
subjects
(durationand
pain
intensity)(NA
whe
ncross-
over
stud
yde
sign
)?(Yes
/No)
Werethe
interven
tion
and
control(s)
well
describ
ed(atleast
whe
reand
how)?(Yes
/No)
Was
the
assessor
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Were
losses
and
exclusions
ofstud
ysubjects
repo
rted
orob
viou
sin
result
section
(includ
ing
intables
or graphs)?
(Yes
/No/
Unclear)
Was
the
person
who
statistically
analyzed
thedata
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Com
men
tsby
thetechnical
expe
rts(i)
onthestatistical
analysis,and
(ii)in
relatio
nto
themetho
dology
and/or
technicalaspects
Qualityscore(risk
ofbias,alsoinclud
ingan
externalvalidity
criteria)andclassification
Kelly
2000
[29]
-Yes
(but
inrelatio
nto
theou
tcom
e)-Yes
-No
1: -The
authorsused
aStud
ent
tteststo
compare
means
insteadof
usingamixed
-mod
elANOVA
,followed
bypo
st-hoc
testsifne
eded
.-The
authorsdidno
tstud
yho
wRT
(forcorrectansw
ers)varied
with
angle,which
isthemain
analysiscond
uctedin
the
literatureon
such
data.
Therefore,with
outsuch
a(usuallylinear)tren
danalysis
itisno
tpo
ssibleto
unde
rstand
iftheoverallm
eaneffect
observed
bytheauthorsisdu
eto
achange
inslop
e(re
flecting
achange
inprocessing
speed)
orin
intercep
t(re
flectinga
change
instim
ulus
encoding
).3: -Between-grou
pdifference
pre-po
stsign
ificant
onlywith
one-side
dt-test.
-The
betw
een-grou
pdifference
pre-po
stisno
trepo
rted
forthesimple
RTtask
butitseem
sthat
acontrib
ution
ofthesimpleRT
totheRT
ofthe
complex
task
cann
otbe
exclud
ed.
-Unclear
whe
ther
errorswerealso
coun
ted.
3.5/6(58%
)med
ium
NA
=Unclear
0.5pt
Yes1pt
NA(health
ysubjects)
-Yes
0.5pt
-Yes
0.5pt
No0pt
Yes1pt
No0pt
NANot
applicab
le,R
TRreactiontim
e
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 13 of 30
Table
5Qualityitemsandscores
ofsevenstud
iesusingtranscranialmagne
ticindu
cedou
tcom
emeasuresinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulation
on‘brain
functio
n’1stAutho
rYr
ofpu
blication
Ref
-Werestud
ysubjectsin
sham
controlledstud
iesrepo
rted
tobe
blind?
(Yes
/No/Unclear)
-Ifyes/un
clear,was
theblinding
tested
forsuccess?
(Yes
/No)
-Ifyes,was
itsuccessful?
(Yes
/No)
-Werestud
ysubjectsin
stud
ieswith
controlg
roup
repo
rted
tobe
naive?
(Yes
/No/Unclear)
-Was
theorigin
ofthe
subjectsrepo
rted
(Yes
/No)
-Ifyes,do
esitallow
toexclud
eanyinterest?
(Yes
/No/Unclear)
Werestud
ysubjects
repo
rted
tohave
been
rand
omly
allocatedto
stud
ygrou
ps?(Yes
/No/
Unclear)
Werestud
ygrou
pscomparablein
relatio
nto
symptom
swhe
nstud
ying
symptom
atic
subjects(duration
andpain
intensity)(NA
whe
ncross-over
stud
yde
sign
)?(Yes
/No)
Werethe
interven
tion
and
control(s)
well
describ
ed(atleast
whe
reand
how)?(Yes
/No)
Was
the
assessor
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Were
losses
and
exclusions
ofstud
ysubjects
repo
rted
orob
viou
sin
result
section
(includ
ing
intables
or graphs)?
(Yes
/No/
Unclear)
Was
the
person
who
statistically
analyzed
thedata
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Com
men
tsby
thetechnicalexperts(i)
onthestatisticalanalysis,and
(ii)in
relatio
nto
themetho
dology
and/or
technicalaspects
Qualityscore(risk
ofbias,
also
includ
ingan
external
validity
criteria)and
classification
Dishm
an2002
[17]
-No
-Yes
-No
2: -MEP
metho
dology
does
notcorrespo
ndto
standard:n
omotor
threshold,
noforcecontrol,
andlack
ofrand
omintervalsbe
tweenstim
ulus
-The
coilpo
sitio
ning
seem
sno
tapprop
riate
tolower
legMEPs.
2.5/6(42%
)med
ium
NA
=No0pt
Unclear
("cou
nterbalanced
")0.5pt
NA(health
ysubjects)
-Yes
0.5pt
-Yes
0.5pt
No0pt
Yes1pt
No0pt
Haavik-Taylor
2007a
[20]
-No
-No
-NA
1: -The
authorsstated
having
used
plan
ned
compa
rison
sinsteadof
postho
canalysis
inorde
rto
minim
izeType
1error.How
ever,
plan
nedcomparison
sdo
notminim
ize
Type
1error.
-The
ymen
tionrunn
ingaon
e-way
repe
ated
measures
ANOVA
with
thefactor
“interven
tion”.
How
ever,the
degreesof
freed
omof
theF
fortheresult
clearly
show
that
authors
treated“in
terven
tion”
asa
betw
een-subjectsfactor,
which
isno
tcorrect.
2/6(33%
)low
NA
=No0pt
Yes1pt
NA(SCPsubjects
/cross-over)
-Yes
0.5pt
-Yes
0.5pt
No0pt
No0pt
No0pt
Dishm
an2008
[18]
-No
-Yes
-No
2: -MEP
metho
dology
isno
tstandard:lack
ofprecisemotor
threshold,
andlack
ofrand
omintervalsbe
tweenstim
ulus.
-Fig.1Cindicatesan
inhibitio
nin
thetim
eintervalpriorto
SM,w
hich
may
berespon
sibleforsign
ificant
differences
and
relativeincrease
ofam
plitu
deafterSM
.
2/6(33%
)low
NA
=No0pt
Yes1pt
NA(health
ysubjects)
-Yes
0.5pt
-Yes
0.5pt
No0pt
No0pt
No0pt
Haavik-Taylor
2008
[23]
-No
-No
-NA
1: -The
authorsmen
tionrunn
ing2-way
ANOVA
sforrepe
ated
measureswith
thefactors“m
uscle”
and“in
terven
tion”
wereappliedto
compare
theeffects
ofSM
onthetw
odifferent
uppe
rlim
bmuscles.H
owever,the
degreesof
freed
omof
theFfortheresults
clearly
show
that
authorstreatedthetw
ofactorsbe
tween-
subjects,w
hich
isno
tcorrect.
-The
yusettestsinsteadof
post-hoc
test
fortestingpairw
isecomparison
ssubseq
uent
totheANOVA
.
2/6(33%
)low
NA
=No0pt
Yes1pt
NA(SCPsubjects
/cross-over)
-Yes
0.5pt
-Yes
0.5pt
No0pt
No0pt
No0pt
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 14 of 30
Table
5Qualityitemsandscores
ofsevenstud
iesusingtranscranialmagne
ticindu
cedou
tcom
emeasuresinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulation
on‘brain
functio
n’(Con
tinued)
1stAutho
rYr
ofpu
blication
Ref
-Werestud
ysubjectsin
sham
controlledstud
iesrepo
rted
tobe
blind?
(Yes
/No/Unclear)
-Ifyes/un
clear,was
theblinding
tested
forsuccess?
(Yes
/No)
-Ifyes,was
itsuccessful?
(Yes
/No)
-Werestud
ysubjectsin
stud
ieswith
controlg
roup
repo
rted
tobe
naive?
(Yes
/No/Unclear)
-Was
theorigin
ofthe
subjectsrepo
rted
(Yes
/No)
-Ifyes,do
esitallow
toexclud
eanyinterest?
(Yes
/No/Unclear)
Werestud
ysubjects
repo
rted
tohave
been
rand
omly
allocatedto
stud
ygrou
ps?(Yes
/No/
Unclear)
Werestud
ygrou
pscomparablein
relatio
nto
symptom
swhe
nstud
ying
symptom
atic
subjects(duration
andpain
intensity)(NA
whe
ncross-over
stud
yde
sign
)?(Yes
/No)
Werethe
interven
tion
and
control(s)
well
describ
ed(atleast
whe
reand
how)?(Yes
/No)
Was
the
assessor
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Were
losses
and
exclusions
ofstud
ysubjects
repo
rted
orob
viou
sin
result
section
(includ
ing
intables
or graphs)?
(Yes
/No/
Unclear)
Was
the
person
who
statistically
analyzed
thedata
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Com
men
tsby
thetechnicalexperts(i)
onthestatisticalanalysis,and
(ii)in
relatio
nto
themetho
dology
and/or
technicalaspects
Qualityscore(risk
ofbias,
also
includ
ingan
external
validity
criteria)and
classification
2: Theconclusion
sarefarfe
tche
das
assumptions
andde
ductionaremade
which
cann
otno
tbe
backed
bytheresults.
Fryer
2012
[16]
-No
-Yes
-No
2:Thecoilpo
sitio
ning
seem
sno
tapprop
riate
tolower
legMEPs.
2.5/6(42%
)med
ium
NA
=No0pt
Yes1pt
NA(health
ysubjects)
-Yes
0.5pt
-Yes
0.5pt
No0pt
Unclear
0.5pt
No0pt
Haavik
2016
[24]
-Unclear
(mostsubjectswere
“noviceto
chiro
practic”)
-No
-NA
2: -The
recruitm
entcurves
lack
measure
ofvariance.
-Feedb
ackfro
mbackgrou
ndEM
Gislacking,
which
isaconcep
tualconcernandcould
explainob
served
increasedin
amplitu
des.
2/6(33%
)low
NA
=No0pt
No0pt
NA(SCPsubjects
/cross-over)
-Yes
0.5pt
-Yes
0.5pt
No0pt
Yes1pt
No0pt
Baarbé
2018
[15]
-Yes
-No
-NA
Non
ein
relatio
nto
statistics
Noexpertwas
availablein
relationto
thetechnical
aspectsof
thisou
tcom
emeasure
3.5/6(58%
)med
ium
=Unclear
0.5pt
NA
Yes1pt
NA(SCPsubjects)
-Yes
0.5pt
-Yes
0.5pt
No0pt
Yes1pt
No0pt
EMGElectrom
yograp
hy,M
EPMotor-evo
kedpo
tential,NANot
applicab
le,SCP
“sub
clinical
neck/spina
lpain”,SM
Spinal
man
ipulation
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 15 of 30
Table
6Qualityitemsandscores
offour
stud
iesusingou
tcom
emeasuresin
relatio
nto
somatosen
sory-evokedpo
tentialsinclud
edin
asystem
aticreview
ontheeffect
ofspinal
manipulationon
‘brain
functio
n’1stAutho
rYr
ofpu
blication
Ref
-Werestud
ysubjectsin
sham
controlledstud
ies
repo
rted
tobe
blind?
(Yes
/No/
Unclear)
-Ifyes/un
clear,
was
theblinding
tested
for
success?
(Yes
/No)
-Ifyes,was
itsuccessful?(Yes
/No)
-Werestud
ysubjectsin
stud
ieswith
controlg
roup
repo
rted
tobe
naive?
(Yes
/No/
Unclear)
-Was
theorigin
ofthesubjects
repo
rted
(Yes
/No)
-Ifyes,do
esit
allow
toexclud
eanyinterest?(Yes
/No/Unclear)
Werestud
ysubjectsrepo
rted
tohave
been
rand
omly
allocatedto
stud
ygrou
ps?
(Yes
/No/Unclear)
Werestud
ygrou
pscomparable
inrelatio
nto
symptom
swhe
nstud
ying
symptom
atic
subjects
(durationand
pain
intensity)(NA
whe
ncross-
over
stud
yde
sign
)?(Yes
/No)
Werethe
interven
tion
and
control(s)
well
describ
ed(atleast
whe
reand
how)?(Yes
/No)
Was
theassessor
repo
rted
tobe
blindto
grou
pallocatio
n?(Yes
/No)
Were
losses
and
exclusions
ofstud
ysubjects
repo
rted
orob
viou
sin
result
section
(includ
ing
intables
or graphs)?
(Yes
/No/
Unclear)
Was
the
person
who
statistically
analyzed
thedata
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Com
men
tsby
thetechnicalexperts(i)
onthestatistical
analysis,and
(ii)in
relatio
nto
themetho
dology
and/or
technicalaspects
Qualityscore(risk
ofbias,alsoinclud
ing
anexternalvalidity
criteria)and
classification
Haavik-Taylor
2007b
[25]
-No
-No
-NA
1: -Norepo
rtof
thetestingof
theno
rmality
ofthedata
distrib
ution.
-Tominim
izeType
1error,po
stho
ctestswou
ldbe
approp
riate
(insteadof
planne
dcomparison
s).
-Nobe
tweengrou
pcomparison
was
perfo
rmed
.Noexpertwas
availablein
relationto
thetechnicalaspectsof
thisou
tcom
emeasure
2/6(33%
)low
NA
=No0pt
Unclear
("pseud
orando
mized
")0.5p
t
NA
(SCPsubjects)
-Yes
0.5p
t-Yes
0.5p
tNo(but
data
were
code
dby
aninde
pend
ent
person
toredu
ceanybias
durin
ganalysis)0.5p
t
No0pt
No0pt
Haavik-Taylor
2010a
[26]
-No
-No
-NA
1:Bo
thparametric
andno
nparam
etric
results
onthesame
data
arerepo
rted
.Usually,eith
erdata
areno
rmallydistrib
uted
andparametric
testscanbe
used
ordata
areno
tno
rmally
distrib
uted
andno
n-parametric
testsmustbe
used
.Noexpertwas
availablein
relationto
thetechnicalaspectsof
thisou
tcom
emeasure
2.5/6(42%
)med
ium
NA
=No0pt
Yes1p
tNA(SCP
subjects/
cross-over)
-Yes
0.5pt
-Yes
0.5pt
No(id
emHaavik-Taylor
2007a)
0.5p
t
No0pt
No0pt
Haavik-Taylor
2010b
[21]
-No
-Yes
-Unclear
(“stude
ntsand
staffp
opulation
attheUniversity
ofAuckland”)
1:Seecommen
tsin
relatio
nto
Haavik-Taylor
2010a
Noexpertwas
availablein
relationto
thetechnicalaspectsof
thisou
tcom
emeasure
2.5/6(42%
)med
ium
NA
=No0pt
Yes1pt
NA(SCP
subjects/
cross-over)
-Yes
0.5pt
-Yes
0.5pt
No(id
emHaavik-Taylor
2007b)
0.5pt
No0pt
No0pt
Lelic
2016
[14]
-Unclear
(saidto
benaïve)
-Yes
-No(sham
interven
tionwas
discovered
assuch
bymostof
thesubjects)
1:Unu
sualrepo
rtingof
statistics:no
repo
rtof
which
werethe
expe
rimen
talfactorsandho
wthey
weretreated(but
prob
ablypre/po
stwas
treatedwith
in-sub
jectsand
interven
tions
asbe
tween-subjects),andof
thede
tailedresults
fortheFtestsof
theANOVA
.Noexpertwas
availablein
relationto
thetechnicalaspectsof
thisou
tcom
emeasure
2.5/6(42%
)med
ium
=No0pt
NA
Yes1pt
NA(SCP
subjects/
cross-over)
-Yes
0.5pt
-No0pt
No0pt
Yes1pt
No0pt
NANot
applicab
le,SCP
“sub
clinical
neck/spina
lpain”
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 16 of 30
Table
7Qualityitemsandscores
offour
stud
iesusingne
uroimagingou
tcom
emeasuresinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’
1stAutho
rYr
ofpu
blication
Ref
-Were
stud
ysubjectsin
sham
controlled
stud
ies
repo
rted
tobe
blind?
(Yes
/No/
Unclear)
-Ifyes/
unclear,
was
the
blinding
tested
for
success?
(Yes
/No)
-Ifyes,was
it successful?
(Yes
/No)
-Werestud
ysubjectsin
stud
ieswith
control
grou
prepo
rted
tobe
naive?
(Yes
/No/
Unclear)
-Was
theorigin
ofthe
subjectsrepo
rted
(Yes
/No)
-Ifyes,do
esitallow
toexclud
eanyinterest?(Yes
/No/Unclear)
Werestud
ysubjects
repo
rted
tohave
been
rand
omly
allocatedto
stud
ygrou
ps?(Yes
/No/
Unclear)
Werestud
ygrou
pscomparable
inrelatio
nto
symptom
swhe
nstud
ying
symptom
atic
subjects
(durationand
pain
intensity)(NA
whe
ncrossover
stud
yde
sign
)?(Yes
/No)
Werethe
interven
tion
and
control(s)
well
describ
ed(atleast
whe
reand
how)?(Yes
/No)
Was
the
assessor
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Were
losses
and
exclusions
ofstud
ysubjects
repo
rted
orob
viou
sin
result
section
(includ
ing
intables
or graphs)?
(Yes
/No/
Unclear)
Was
the
person
who
statistically
analyzed
thedata
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Com
men
tsby
thetechnicalexperts(i)
onthestatisticalanalysis,and
(ii)in
relatio
nto
themetho
dology
and/or
technicalaspects
Qualityscore(risk
ofbias,also
includ
ingan
externalvalidity
criteria)and
classification
Ogu
ra2011
[19]
-No
-Yes
-Unclear
(recruitedon
the
campu
sof
Toho
kuUniversity)
1:Theextent
thethresholdforthevoxel
clustersize
was
defined
as“10to
50voxels
minim
um”.Thepu
rposeof
thisvarying
thresholdisun
clear.
3:Lenien
tstatisticalthreshold:
Z=3,extent
threshold;
10voxels.
2/6(33%
)low
NA
=No0pt
Unclear
(“cou
nterbalanced
”)0.5pt
NA(cross-
over)
-No0pt
-Yes
0.5pt
No0pt
Yes1pt
No0pt
Inam
i2017
[8]
-No
-No
-NA
1:Theph
rasing
“(e.g.,10
voxelsminim
um)”
sugg
estsagain(see
thecommen
tin
relatio
nto
Ogu
ra2011)that
thisthresholdwas
not
fixed
.2/6(33%
)low
NA
=No0pt
Yes1pt
NA(cross-
over)
-Yes
0.5pt
-Yes
0.5pt
No0pt
No0pt
No0pt
Gay
2014
[22]
-No
-No
-Unclear
(recruitedfro
mthecampu
sof
the
University
ofFloridaand
UFHealth
Hospitaland
thelocalcom
mun
ity)
1: -Autho
rs“corrected
forthenu
mbe
rof
separate
RM-ANOVA
scond
uctedacross
the
120RO
I-to-RO
Ipairsby
usingapvalueless
than
.01as
sign
ificant.”(p.618).Thisthreshold
(p=0.01)correctio
nformultip
lecomparison
sisno
tconservativeen
ough
.-The
rewas
neith
erbe
tween-grou
psstatistical
testat
“pre”,no
rat
“post”.
3:Lenien
tstatisticalthreshold:
p=0.01
with
120comparison
s.
5/7(71%
)acceptable
NA
=No0pt
Yes1pt
Yes1pt
Yes0.5pt
-Yes
0.5pt
Yes1pt
Yes1pt
No0pt
Sparks
2017
[9]
-Yes
-No
-NA
1:Theauthorsused
analph
a=0.01
threshold
forthefM
RIanalysis.Itisno
tconservative
enou
ghin
myop
inion(asdiscussedby
Eklund
etal.2015,andLieb
erman
&
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 17 of 30
Table
7Qualityitemsandscores
offour
stud
iesusingne
uroimagingou
tcom
emeasuresinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’(Con
tinued)
1stAutho
rYr
ofpu
blication
Ref
-Were
stud
ysubjectsin
sham
controlled
stud
ies
repo
rted
tobe
blind?
(Yes
/No/
Unclear)
-Ifyes/
unclear,
was
the
blinding
tested
for
success?
(Yes
/No)
-Ifyes,was
it successful?
(Yes
/No)
-Werestud
ysubjectsin
stud
ieswith
control
grou
prepo
rted
tobe
naive?
(Yes
/No/
Unclear)
-Was
theorigin
ofthe
subjectsrepo
rted
(Yes
/No)
-Ifyes,do
esitallow
toexclud
eanyinterest?(Yes
/No/Unclear)
Werestud
ysubjects
repo
rted
tohave
been
rand
omly
allocatedto
stud
ygrou
ps?(Yes
/No/
Unclear)
Werestud
ygrou
pscomparable
inrelatio
nto
symptom
swhe
nstud
ying
symptom
atic
subjects
(durationand
pain
intensity)(NA
whe
ncrossover
stud
yde
sign
)?(Yes
/No)
Werethe
interven
tion
and
control(s)
well
describ
ed(atleast
whe
reand
how)?(Yes
/No)
Was
the
assessor
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Were
losses
and
exclusions
ofstud
ysubjects
repo
rted
orob
viou
sin
result
section
(includ
ing
intables
or graphs)?
(Yes
/No/
Unclear)
Was
the
person
who
statistically
analyzed
thedata
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Com
men
tsby
thetechnicalexperts(i)
onthestatisticalanalysis,and
(ii)in
relatio
nto
themetho
dology
and/or
technicalaspects
Qualityscore(risk
ofbias,also
includ
ingan
externalvalidity
criteria)and
classification
Cun
ning
ham
2009).
3: -Unclear
whe
ther
statisticalthresholdapplied
across
thewho
lebrainor
justfortheregion
ofinterest.
-Itisun
clearho
wtheregion
ofinterestwas
defined
5.5/7(79%
)acceptable
=Unclear
0.5pt
NA
Yes1pt
Yes1pt
-Yes
0.5pt
-Yes
0.5pt
Yes1pt
Yes1pt
No0pt
fMRI
functio
nalm
agne
ticresona
nceim
aging,
NANot
applicab
le
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 18 of 30
Table
8Qualityitemsandscores
oftw
ostud
iesusingV-waveas
outcom
emeasuresinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’
1stAutho
rYr
ofpu
blication
Ref
-Were
stud
ysubjectsin
sham
controlled
stud
ies
repo
rted
tobe
blind?
(Yes
/No/
Unclear)
-Ifyes/
unclear,
was
the
blinding
tested
for
success?
(Yes
/No)
-Ifyes,was
it successful?
(Yes
/No)
-Were
stud
ysubjects
instud
ies
with
control
grou
prepo
rted
tobe
naive?
(Yes
/No
/Unclear)
-Was
the
origin
ofthe
subjects
repo
rted
(Yes
/No)
-Ifyes,
does
itallow
toexclud
eany
interest?
(Yes
/No
/Unclear)
Were
stud
ysubjects
repo
rted
tohave
been
rand
omly
allocated
tostud
ygrou
ps?
(Yes
/No
/Unclear)
Werestud
ygrou
pscomparable
inrelatio
nto
symptom
swhe
nstud
ying
symptom
atic
subjects
(durationand
pain
intensity)(NA
whe
ncross-
over
stud
yde
sign
)?(Yes
/No)
Werethe
interven
tion
and
control(s)
well
describ
ed(atleast
whe
reand
how)?(Yes
/No)
Was
the
assessor
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Were
losses
and
exclusions
ofstud
ysubjects
repo
rted
orob
viou
sin
result
section
(includ
ing
intables
or graphs)?
(Yes
/No/
Unclear)
Was
the
person
who
statistically
analyzed
thedata
repo
rted
tobe
blind
togrou
pallocatio
n?(Yes
/No)
Com
men
tsby
thetechnicalexperts(i)
onthe
statisticalanalysis,and
(ii)in
relatio
nto
the
metho
dology
and/or
technicalaspects
Qualityscore(risk
ofbias,alsoinclud
ingan
externalvalidity
criteria)
andclassification
Niazi
2015
[27]
-No
-No
-NA
Non
ein
relatio
nto
statistics
Noexpertwas
availablein
relationto
the
technicalaspectsof
thisoutcom
emeasure
2.5/6(42%
)med
ium
NA
=No0pt
Yes1pt
NA(SCP
subjects)
-Yes
0.5pt
-No0pt
No0pt
Yes1pt
No0pt
Christiansen
2018
[28]
-No
-Yes
-Yes
Non
ein
relatio
nto
statistics
Noexpertwas
availablein
relationto
the
technicalaspectsof
thisoutcom
emeasure
5/6(83%
)acceptable
NA
=Unclear
0.5pt
Yes1pt
NA(SCP
subjects)
-Yes
0.5pt
-No0pt
Yes1pt
Yes1pt
Yes1pt
NANot
applicab
le,SCP
“sub
clinical
neck/spina
lpain”
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 19 of 30
Table
9Results
from
threestud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
asham
interven
tion
1st
Autho
rYear
Ref
Type
ofstud
ysubjects
Outcomevariable
Was
astatisticallysign
ificant
differencebe
tweengrou
psob
served
?Was
therearelatio
nship
betw
eenbrainchange
sandanyclinical
outcom
e?
Timeof
assessmen
tQuality
classification
Sparks
2017
[9]
Symptom
atic
(mechanicaln
eck
pain
<of
6weeks
ofdu
ratio
n)
Bloo
doxygen
ation-level
depe
nden
tsign
al(in
respon
seto
noxiou
sstim
uli)
Yes(p<.05)
Statisticallysign
ificant
increase
ofactivationin
the
insularandsensorim
otor
cortices
post-SM
comparedto
control;
andin
theanterio
randpo
steriorcing
ulate,supp
lemen
tary
motor
area,and
precen
tralgyruspo
st-con
trol
comparedto
SM
Pain
intensity
assessed
butno
relatio
nship
tested
Immed
iatelyafter
Accep
table
Lelic
2016
[14]
“Sub
clinicalne
ck/
spinalpain”
N30
somatosen
sory
evoked
potentialp
eak
amplitu
des
Yes(significantpo
st-in
terven
tiondifferencebetween-grou
psrepo
rted
butwith
outinclusionof
thecorrespo
ndingp-value
andmen
tionof
thestatisticalthresholdforsign
ificance)
Statisticallysign
ificant
decrease
post-SM
(p=.02)
butno
statisticallysign
ificant
change
spo
st-con
trol
(p=.4)
Noclinicalou
tcom
einclud
edNot
repo
rted
Med
ium
Baarbé
2018
[15]
Cereb
ellarinhibitio
nYes(p<.001)
Statisticallysign
ificant
redu
cepo
st-SM
comparedto
control
Noclinicalou
tcom
einclud
edUnclear
(according
toFig.
1im
med
iatelyafterthemotor
acqu
isition
task,i.e.abo
ut20
min
afterinterven
tion)
Med
ium
Results
arerepo
rted
(i)grou
pedby
type
ofstud
ysubjects
(sym
ptom
aticor
with
“sub
clinical
neck/spina
lpain”),an
d(ii)consecutivelyby
year
ofpu
blication
SMSp
inal
man
ipulation
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 20 of 30
Table
10Results
from
sevenstud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
aninactive
control
1st
Autho
rYear
Ref
Type
ofstud
ysubjects
Outcome
Was
astatisticallysign
ificant
differencebe
tweengrou
psob
served
?Timeof
assessmen
tQuality
classification
Kelly
2000
[29]
Health
yReactio
n-tim
eto
amen
tal
rotatio
ntask
Yes(p<.05)
Statisticallysign
ificant
decrease
post-SM
comparedto
control
Unkno
wn
Med
ium
Dishm
an2002
[17]
MEP
amplitu
des
Yes(p<.05)
Statisticallysign
ificant
increase
from
20to
120s.po
st-SM
comparedto
control
-Immed
iatelyafter(each20sdu
ring120s
afterSM
orcontrol)
−5min
−10
min
Med
ium
Dishm
an2008
[18]
MEP
amplitu
des
Yes(p<.05)
Statisticallysign
ificant
increase
at10
s.po
st-SM
comparedto
control
Immed
iatelyafter(each10sdu
ring100s
afterSM
orcontrol)
Low
Fryer
2012
[16]
MEP
amplitu
des
Yes(p=.04)
Statisticallysign
ificant
decrease
post-SM
comparedto
control
Unkno
wn(app
roximately10
min
afteron
einterven
tionor
theothe
r)Med
ium
MEP
latencies
No
CSP
duratio
nsNo
Ogu
ra2011
[19]
Symptom
atic
(mechanicaln
eckpain
andshou
lder
stiffne
ss)
Region
alcerebral
metabolicrate
Yes(p<.001)
Statisticallysign
ificant
increase
post-SM
comparedto
controlintheinferio
rprefrontalcortex,anteriorcing
ulatecortex,and
middletempo
ralg
yrus;and
statisticallysign
ificant
decrease
post-SM
comparedto
controlinthecerebe
llar
verm
isandvisualassociationcortex
Betw
een35
to55
min
Low
Inam
i2017
[8]
Region
alcerebral
metabolicrate
Yes(p<.05)
Statisticallysign
ificant
increase
post-SM
comparedto
controlintheBroca’sarea,
anterio
rcing
ulatecortex,som
atosen
sory
associationcortex,W
ernike’sarea,visual
associationcortex,cereb
ellarverm
is,and
visualcortex;and
statisticallysign
ificant
decrease
post-SM
comparedto
controlintheinferio
rparietallob
ule,fro
ntalpo
le,
inferio
rfro
ntalgyrus,parstriang
ularis,p
remotor
area/sup
plem
entary
motor
area,
prim
arymotor
cortex,frontaleyefield,d
orsolateralp
refro
ntalcortex,ang
ular
gyrus,
fusiform
gyrus,inferio
rtempo
ralg
yrus,and
tempo
ralp
ole.
Betw
een35
to65
min
Low
Haavik
2010b
[21]
“Sub
clinicalne
ck/spinal
pain”
P14-N18
SEP
peak
ratio
No
Unclear
(saidto
bewith
in25
min
post-SM
orcontrol,po
ssibly45
min
afteron
einterven
tionor
theothe
r)
Med
ium
N20-P25
SEP
peak
ratio
No
P22-N30
SEP
peak
ratio
Yes(p=.00005)
Statisticallysign
ificant
decrease
post-SM
comparedto
control
Results
arerepo
rted
(i)grou
pedby
type
ofstud
ysubjects
(health
y,symptom
atic,o
rwith
“sub
clinical
neck/spina
lpain”),(ii)grou
pedby
type
ofou
tcom
es,and
(iii)consecutivelyby
year
ofpu
blication
CSPCortical
silent
perio
d,MEP
Motor
evok
edpo
tential,SEPSo
matosen
sory
evok
edpo
tential,SM
Spinal
man
ipulation
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 21 of 30
Table
11Results
from
four
stud
iesinclud
edin
asystem
aticreview
ontheeffect
ofspinalmanipulationon
‘brain
functio
n’,com
parin
gspinalmanipulationto
anothe
rph
ysical
stim
ulus
1stAutho
rYear
Ref
Type
ofstud
ysubjects
Outcome
Was
astatisticallysign
ificant
differencebe
tweengrou
psob
served
?Timeof
assessmen
tQuality
classification
Dishm
an2008
[18]
Health
yMEP
amplitu
des
Yes(p<0.05)
Statisticallysign
ificant
increase
at10
s.po
st-SM
comparedto
control
Immed
iatelyafter(each10
s.du
ring100s.after
SMor
control)
Low
Haavik
2010a
[26]
“Sub
clinicalne
ck/
spinalpain”
P14-N18
SEPpe
akratio
No
Unclear
(saidto
bewith
in25
min
post-SM
orcontrol)
Med
ium
N20-P25
SEPpe
akratio
No
P22-N30
SEPpe
akratio
Yes(p=.003)
Statisticallysign
ificant
decrease
post-SM
comparedto
control
Haavik
2016
[24]
MEP
amplitu
des
Yes(p=.01)
Statisticallysign
ificant
increase
post-SM
comparedto
control
Not-rep
orted
Low
k(slope
ofthesteepe
stpartof
thecurve)
No
S 50(stim
ulus
intensity
toob
tain
arespon
se50%
ofthemaxim
um)
No
Christiansen
2018
[28]
V-waveam
plitu
des
Yes(p<0.01–0.03)
Statisticallysign
ificant
increase
ateach
timepo
intpo
st-SM
comparedto
control
-Immed
iatelyafter
−30
min
after
−60
min
after
Accep
table
Results
arerepo
rted
(i)grou
pedby
type
ofstud
ysubjects
(health
y,symptom
atic,o
rwith
“sub
clinical
neck/spina
lpain”),(ii)grou
pedby
type
ofou
tcom
es,and
(iii)consecutivelyby
year
ofpu
blication
MEP
Motor
evok
edpo
tential,SEPSo
matosen
sory
evok
edpo
tential,SM
Spinal
man
ipulation
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 22 of 30
measures, which did not allow us to compare their re-spective results (Tables 9, 10 and 11).
Summary of finding in relation to the research questions 1–3In summary, and in relation to our three first researchquestions, three studies reported a transient (immedi-ately to about 20 min post-intervention) effect on ‘brainfunction’ of varied types after SM vs. a sham comparatorin symptomatic subjects and in “subclinical neck/spinalpain” subjects. However, in these studies SM was com-pared to sham procedures with unclear credibility, ordiscovered as such by the study subjects. Also, the ex-perimental findings were untested in relation to clinicalbenefits. Detailed results are reported in the nextsection.
1 - Is there an effect of SM on ‘brain function’? (n = 3)Symptomatic subjects (n = 1)One study of ‘acceptable’ methodological quality [9],
conducted on subjects suffering from mechanical neckpain, reported an effect on activation in response to nox-ious stimuli, as measured by fMRI using the blood oxy-genation level-dependent (BOLD) signal, after SM vs. asham comparator. As shown previously, mechanicalnoxious stimulation resulted in increased activation inseveral brain areas associated with pain processing. Agroup comparison was reported, although it was unclearwhether it was performed on the pre- post-interventiondifferences, as it should. This indicated increased
activation in the SM group relative to the sham group inthe insular cortex, supramarginal gyrus and superiorparietal lobe (presumably in sensory association/integra-tion areas). On the other hand, there was increased acti-vation in the sham group relative to the SM group inthe cingulate cortex, the supplementary motor area, andthe middle temporal gyrus.“Subclinical neck/spinal pain” subject (n = 2)Two studies on “subclinical neck/spinal pain” sub-
jects [14, 15], both of ‘medium’ methodological qual-ity, reported an effect of SM vs. a sham comparator.One of these studies found a statistically significantdecrease of N30 somatosensory evoked potential peakamplitudes post-SM compared to a sham group [14].The other one reported a statistically significant de-crease of cerebellar inhibition following SM comparedto a sham intervention [15].
2 - If there is an effect, for how long does it last? (n = 3)Symptomatic subjects (n = 1)The effect reported by Sparks et al. 2017 [9] (in a
study of ‘acceptable’ methodological quality) on symp-tomatic subjects was immediate, with no effect investi-gated beyond this time point.“Subclinical neck/spinal pain” subject (n = 2)The effect reported by Baarbé et al. 2018 [15] (in a
study of ‘medium’ methodological quality) on “subclin-ical neck pain” subjects was measured after interventiononly once, at about 20 min post-intervention. Anotherpotentially relevant study (Lelic et al. 2016) [14], also of
Table 12 Summary of quality scores and quality classification for 18 articles included in a systematic review on the effect of spinalmanipulation on ‘brain function’
Type of study First author / Year [ref] Scorea (risk of bias and external validity) Quality classification
Sham studies Sparks, 2017 [9] 5.5/7 (79%) acceptable
Baarbéé, 2018 [15] 3.5/6 (58%) medium
Lelic, 2016 [14] 2.5/6 (42%) medium
Comparison studies Christiansen, 2018 [28] 5/6 (83%) acceptable
Gay, 2014 [22] 5/7 (71%) acceptable
Kelly, 2000 [29] 3.5/6 (58%) medium
Dishman, 2002 [17]Haavik-Taylor, 2010a [26]Haavik-Taylor, 2010b [21]Fryer, 2012 [16]Niazi, 2015 [27]
2.5/6 (42%) medium
Haavik-Taylor, 2007a [20]Haavik-Taylor, 2007b [25]Haavik-Taylor, 2008 [28]Dishman, 2008 [23]Ogura, 2011 [19]HaaviK, 2016 [24]Inami, 2017 [8]
2/6 (33%) low
aThe quality score for each study could range from 0 to 6 or 7, depending on their respective study design and the type of study subjects included. Each qualityscore was then converted on percentage to allow comparisons. Quality classification: ‘low’: 0–33%; ‘medium’: 34–67%; ‘acceptable’: 68%-100
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 23 of 30
‘medium’ methodological quality, did not report the timeof assessment after interventions.
3- If there is an effect, is it associated with any clinicalbenefits? (n = 3)Symptomatic subjects (n = 1)The study by Sparks et al. 2017 [9] on subjects suf-
fering from mechanical neck pain (a study consideredto be of ‘acceptable’ methodological quality), inaddition to assessing brain activation in response to anoxious stimulus by means of fMRI, assessed pain in-tensity pre- post-interventions. However, they did notinvestigate whether there was an association betweenpain intensity changes and cerebral activity changes,making it impossible to answer this third researchquestion. It is worth noting that the authors investi-gated whether there was a correlation between sub-jective ratings of the noxious stimulus intensity andchange in activation in the insular cortex, but nosuch relationship was found.“Subclinical neck/spinal pain” subjects (n = 2)None of the two studies on “subclinical neck/spinal
pain” subjects [14, 15], both of ‘medium’ methodologicalquality, included clinical outcomes.
Other types of controls, specifically ‘inactive control’(Table 10) or ‘another physical stimulus (Table 11),i.e the (‘differences in outcome’ studies (n = 10)
4 - Is there a difference in ‘brain function’ after SM vs. an‘inactive control’? (n = 7)Seven studies could be used for the fourth researchquestion [8, 16–19, 21, 29], four considered to be of‘medium’ methodological quality and three of ‘low’methodological quality (see Table 12). These studies,reporting on three different types of subjects, investi-gated the potential changes on ‘brain function’ in re-sponse to SM by using varied outcome measures and/orexperimental protocols, which makes comparisons be-tween studies difficult.
Summary of findings in relation to the fourth re-search questionIn these studies, of ‘low’ or ‘medium’ methodological
quality, there were, in general, statistically significant dif-ferences in outcome between SM and the controls butnot necessarily in the same direction. When brain areaswere compared, differences were found, but again withsome conflicting results. Detailed results are reported inthe next section.
Healthy subjects (n = 4)In healthy subjects, an immediate and transient in-
crease of motor-evoked potential amplitudes after
lumbar SM was reported in two studies [17, 18],whereas one reported a decrease of motor-evokedpotential amplitude after lumbar SM (approximately10 min after intervention) [16]. The third reported nostatistically significant findings for motor-evokedlatencies and cortical silent period durations [16].Two of these studies were considered of ‘medium’methodological quality [16, 17] and one of ‘low’methodological quality [18].A fourth study [29], of ‘medium’ quality, reported a
statistically significant greater decrease of reaction-timeto a mental reaction task post-SM vs. post-resting with-out reporting the time of reassessment.
Symptomatic subjects (n = 2)The two studies conducted on symptomatic subjects
were from the same research team and both of ‘low’methodological quality [8, 19]; the first that waspublished being considered by its authors as a “proofof concept” study [19], which apparently led to theirsecond experiment [8]. Both reported a statisticallysignificant increase of regional cerebral metabolic rate(glucose uptake) in some brain areas and a statisti-cally significant decrease of glucose uptake in otherbrain areas, sometimes with conflicting results (seeTable 10).
“Subclinical neck/spinal pain” subjects (n = 1)In a study on “subclinical neck pain subjects” of
‘medium’ methodological quality [21], the authorsreported a statistically significant decrease of the P22-N30 somatosensory potential peak ratio post-SM buta statistically significant increase of this ratio post-control intervention. They found no statisticallysignificant between-group differences for the othersomatosensory evoked potential peak ratios theyinvestigated.
5 - Is there a difference in ‘brain function’ after SM vs.‘another physical stimulus’? (n = 4)Four articles were able to be used in relation to ourfifth research question [18, 24, 26, 28]. Two were of‘low’, one of ‘medium’, and one of ‘acceptable’methodological quality (see Table 12). Again, as theywere conducted on different types of study subjectsand/or most often used different outcomes measures,the possibility of making comparisons between studieswas limited.
Summary of findings in relation to the fifth researchquestionSome statistically significant differences in outcome
between SM and the controls were reported but resultswere mixed, in studies of ‘low’ to ‘acceptable’
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 24 of 30
methodological quality. Detailed results are reported in thenext section.
Healthy subjects (n = 1)One study of ‘low’ methodological quality [18], con-
ducted on healthy chiropractic students, reported at 10 spost-intervention statistically significant greater motor-evoked potential amplitudes in the SM group vs. a pre-loading control group.
“Subclinical neck/spinal pain” subjects (n = 3)One study on “subclinical neck/spinal pain” subjects
[26], of ‘medium’ methodological quality, found a statis-tically significant decrease of the P22-N30 somatosen-sory potential peak ratio post-SM vs. post-control [26].There were no statistically significant between-group dif-ferences for the other somatosensory evoked potentialpeak ratios investigated.Haavik et al. 2016 [24], in a study of ‘low’ methodo-
logical quality, reported a statistically significant increasein motor-evoked potential amplitudes in the SM groupcompared to the control group. They did not find anystatistically significant between-group differences for twoother variables they studied.Christiansen et al. 2018 [28], in a study of ‘acceptable’
methodological quality, conducted on elite taekwondoathletes with “subclinical spinal pain”, found a statisti-cally significant greater V-wave amplitude post-SM vs.post-control at each time point of assessment (immedi-ately, 30, and 60 min after).
DiscussionSummary of findings and their interpretationThis systematic review consists of 18 relevant articles.Once classical risk of bias aspects, necessary in this typeof experimental design, had been taken into account,most of these articles were considered of ‘low’ or‘medium’ methodological quality. In addition, their stat-istical methods and results sections were often difficultto interpret because of unclear and/or unusual descrip-tions. For methodological reasons, the results of only 13of these 18 articles were considered for final analysis.These 13 articles reported on (i) whether SM has an
effect on ‘brain function’ compared to a sham interven-tion, and (ii) whether SM alters ‘brain function’ in a dif-ferent way compared to an ‘inactive control’ or ‘anotherphysical stimulus’, and this on different type of studysubjects. Based on the studies using a sham interventionas comparator to SM, it seems that SM does have an ef-fect on ‘brain function’. As a result, we also studied ourtwo other main objectives, namely (i) how long this effectwould last, and (ii) whether this effect was associatedwith clinical benefits.
The three studies using a sham intervention as com-parator, two of ‘medium’ and one of ‘acceptable’ methodo-logical quality, provided some evidence to support thehypothesis that SM has supra-segmental neurophysio-logical effects. It was thus shown that SM seems to havethe potential to transiently alter (i) somatosensory integra-tion of afferent inputs from the upper limb [14], (ii) cere-bellar inhibition [15], both on “subclinical neck/spinalpain” subjects and (iii) activation of several brain areas as-sociated with pain processing on acute or subacute mech-anical neck pain subjects [9]. However, none reportedwhether such effects were lasting and none investigatedwhether these were associated with any clinical benefits.Also, according to the authors of these three studies, whatthese effects mean for the brain remains to be established.The 10 studies not using a sham intervention as
comparator, most of which were of ‘low’ or ‘medium’methodological quality, also reported statistically sig-nificant between-group differences but not necessarilyin the same direction and also not systematically foreach of the outcomes they studied. Most of thesestudies reported on healthy or on “subclinical neck/spinal pain” subjects.In summary, based on both the ‘effect’ studies and
the ‘differences in outcome’ studies, it seems thatsomething does indeed happen within the brain in re-sponse to SM. However, what this means remainselusive both in the brain and at a clinical level, andthe researchers provide only hypotheses rather thaninterpretations. In addition, the reported findings haveto be interpreted with caution given the general levelof methodological quality (‘low’ or ‘medium’) of theincluded studies.Showing that SM is reflected by brain activity does not
necessarily mean that something ‘positive’ and clinicallyrelevant happens in response to SM. The significance ofany putative effect on ‘brain function’ must thus be putinto perspective by comparing it to effects in response toother types of (comparable) physical stimuli or othertypes of treatment. The question is therefore: Are thefindings in relation to ‘brain function’ specific to SM?For various methodological reasons, none of the stud-ies could clearly answer this question. Furthermore,in order to claim brain involvement in the effects ofSM it should be expected that changes in ‘brain func-tion’ following SM can be shown related to the de-sired clinical effects of SM. However, no informationrelated to any clinical significance of such findingswas unearthed in this review.
Methodological considerations of our own reviewThree databases were searched and only one authorapplied eligibility criteria to the titles. Thus, it is pos-sible that not all relevant articles on the topic were
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 25 of 30
found. Nevertheless, the additional search of referencelists produced only three additional titles. All the fol-lowing steps of the screening process and of the dataextraction were made independently by at least twoof the reviewers.Most of the articles we obtained reported on experi-
mental studies, in which no clinical outcomes were in-cluded. Studies of this type are not strictly comparableto ordinary clinical studies using the randomized clinicaltrial design, for which well-established critical appraisaltools exist. The quality checklist used in the present re-view was therefore not standard. For example, someusual risk of bias items, such as allocation concealmentwere not assessed, as they were judged less relevant fornon-clinical randomized controlled trials. Regarding al-location concealment, we assumed that it would be diffi-cult to predict which study subjects would react howregarding the outcome variables used in the includedstudies. Nevertheless, most of the items we selected con-sisted of accepted items to evaluate risk of bias [31, 32].These items related to selection, performance, detection,attrition, and analysis risk of bias. Additional methodo-logical concerns specific to the different studies, voicedby the experts, were summarized in a separate columnof the quality checklists for the readers who would be in-terested in more information. These comments can beused as a basis for discussion on how to proceed withfuture studies of this type.Because several of the statistical analyses and/or report-
ing were unclear and/or unusual, we finally resorted to a‘benefit-of-the-doubt’ approach. Thus, after many discus-sions and attempts at interpreting some confusing reports,we deviated from our previous criterion, which was toinclude in the data synthesis only results of the studiesthat reported clearly differences between-groups or be-tween-types of interventions. However, such exceptionswere noted explicitly in the Results section, either in thetext [9] or in Table 9 [14].Studies were included also when the outcome variables
they tested were not necessarily a reflection of ‘brain func-tion’ only, i.e. some would depend on both segmental andsupra-segmental changes (e.g. motor evoked potential am-plitudes, V-waves, and cortical silent period duration) [12,34]. This means that results obtained via these outcomevariables must be interpreted with caution; a fact that isoften admitted by the authors of the reports. On the otherhand, being unrestrictive allowed us to cover the literatureon the topic more exhaustively.Many different outcome variables are used in research
to measure brain activity, and this was also the case forthe articles we included. Their heterogeneity in relation to(i) study subjects (healthy, symptomatic, and “subclinicalneck/spinal pain”), (ii) outcome variables (16 different out-come variables for 18 articles), (iii) experimental protocols
for each single variable, and (iv) generally rather lowmethodological quality, makes comparison of studies diffi-cult and one or several meta-analyses impossible.
Methodological considerations of the included studiesThe methodological quality was quite low in relation towell accepted risk of bias items. Admittedly, these types ofstudies require a lot of knowledge on technical aspects butthis must not remove focus from the fundamental meth-odological requirements of research, namely the necessityto collect and interpret data in an objective manner.For example, the studies considered to be of ‘low’ and
‘medium’ methodological quality often failed to reportusing either a credible sham comparator or having beenconducted on naïve subjects. As suggested by Fryer andPearce [16], the blinding or naivety of the study subjectswhen ‘objective’ outcomes are used could potentially beconsidered not as important in purely experimentalstudies. ‘Objective’ here means that study subjects can-not usually willfully or inadvertently influence outcome.However, the placebo effect implies complex neurophysi-ologic responses involving the brain [35]. In our opinion,this makes the use of a sham comparator and the evalu-ation of its success relevant also for the ‘objective’ out-come measurements used in the included studies.According to this review, the credibility of the sham
comparator used in the three ‘effect’ studies must beconsidered uncertain for two and was recognized as suchby the participants in the third. Thus it cannot be ruledout that the effect of SM on ‘brain function’ was the re-sult of contextual factors, rather than truly caused by theSM, as discussed by Rossettini et al. 2018 [36]. This wasacknowledged in one of these reports [9], where the au-thors noted that changes in cerebral activation in re-sponse to noxious stimuli post-SM may reflect subjects’expectations.In relation to the ‘difference in outcome’ studies, the
origin of the study subjects was reported in only a fewcases. Thus we do not know if they had any precon-ceived ideas/expectations with respect to the study out-comes. This problem could be compounded if severalstudies were conducted on the same study subjects.Another example was that the blinding of the assessor
and of the person who analyzed the data was generallypoorly reported. Although it is fair to recognize that thisreporting may be unusual in some fields of research (e.g.neuroimaging studies), some authors were transparentin relation to this point, which should encourage otherresearchers also to do the same.In addition, comments were provided by our experts,
suggesting that several of the experimental protocols ofthese reports lacked some of the standards, specific tosuch studies. Several comments were also provided fromthe experts on the statistical analyses, indicating that this
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was an area of concern, as the statistical analysis is atthe heart of the validity of any statistically significantfindings.Neuroimaging studies, which produce ‘visual’ answers,
are perhaps easier to interpret for people without spe-cific knowledge in neurological testing. Nevertheless,they present a challenge for formal analysis. For example,quantification of data is difficult. There are many analytictechniques available for these types of studies and there isa lack of consensus with respect to the most appropriatestatistical thresholds to be used [37]. Therefore, this typeof study needs to be replicated by other independent re-search teams. Obviously, this is required for any type ofresearch, particularly when one specific research teamdominates the area or when there are potential or realconflicts of interest.
Conceptual concernsIn relation to all the studiesThe rationale for investigating whether SM acts throughmodulation of ‘brain function’ was generally not clear in theincluded studies. Nevertheless, most studies proposed thatchanges observed at the brain level would result (at least par-tially) from a ‘bottom-up’mechanism, due to altered afferentinputs in response to SM [8, 9, 14, 15, 17, 18, 20, 21, 23–28].However, in addition to ‘bottom-up’ effects, SM mightchange brain activity through ‘top-down’ effects, i.e. throughcontextual factors. This means that in absence of trulyblinded subjects one cannot exclude a ‘top-down’ effect. Inaddition, a blinded assessor would be required. These aretwo methodological aspects often lacking in the reports wescrutinized, and therefore ‘top-down’ effects cannot be ruledout to explain some findings.
In relation to the studies using “subclinical neck/spinalpain” subjectsArticles, in which Haavik was one of the authors, included“subclinical neck/spinal pain” subjects in their studies [14,15, 20, 21, 23–28]. However, the definitions of “subclinicalneck/spinal pain” were not consistent in the various studies,so this concept remains unclear. In fact, it is uncertainwhether these “subclinical neck/spinal pain” study subjectsare clearly different from ‘ordinary’ healthy subjects interms of neurophysiological parameters, such as somato-sensory evoked potentials and motor evoked potentials [15,38]. Most authors of these articles proposed that the effectsor changes they measured in the SM groups reflect im-provement of ‘brain function’ [14, 15, 20, 21, 23–28]. This,obviously, raises the following question: If these subjectsare not different from healthy subjects, what, exactly, wouldbe improved?Additionally, these studies rest on the assumption
that it is possible to detect ‘subluxations’ in people
with “subclinical neck/spinal pain”; a concept that re-mains hypothetical. Overall, it is our considered opin-ion that some clarifications are needed regarding this“subclinical neck/spinal pain” with ‘subluxations’ con-cept to ensure appropriate interpretation of the re-sults of these studies.
Gap between scientific level of evidence and itsimplementation in clinical practiceFN practitioners use SM as a treatment of ‘brain lesions’[5] despite a lack of evidence of its clinical effect, asunearthed in this review. One example of how this con-cept is taught within FN is the seminar in which PFreud, a chiropractor, proposes to show how to ‘adjustthe brain’ [39]. Furthermore, this is stated to be basedon the latest scientific knowledge on the topic (as shownin Additional file 4).
Gap between scientific level of evidence and itsmodification for popularizationBased on this systematic review, we conclude that thereis presently no evidence indicating that SM has a benefi-cial effect on ‘brain function’ or that the diverse findingsidentified in this review would be in any way indicatorsof a health benefit in general. It is therefore prematurefor authors of this type of research to promote clinicalbenefits. Nevertheless, this can be observed in at leastsome commercial videos [40] and in an ‘information’book for patients subtitled “A quest to understandChiropractic from the inside out” [41]. This informationprovided to laymen regarding published research on thetopic claims clinical effects on ‘brain function’ followingSM, contrary to the more careful interpretations in re-search articles produced by the same researcher [14, 15,20, 21, 23–28].In an example of this overreach, Haavik wrote in her
book: “Having your spine checked regularly, to ensure yourbrain is accurately aware of what is going on in and aroundyour body, should be just as common as exercising everyday and brushing your teeth. Everyone should have accessto chiropractic care right from birth through to the daythey pass away. I believe a lot of suffering could be pre-vented if this was the case.” [41].Another example is extracted from one of Haavik’s
commercial videos [42], which is mainly based on one ofher own studies included in the present review [14]. Thisvideo starts with the following message: “Chiropracticcare really does change brain function!”. After havinggiven a lay interpretation of this study [14], it concludes:“Have you seen your chiropractor lately? You may wantto have your brain’s conductor fine-tuned too”. It wouldbe easy to interpret this as a suggestion that the brain isunable to do its job properly but that a chiropractor can
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 27 of 30
improve the situation. However, the section “Study Con-siderations” of that article [14] obviously does not sup-port such claims and the authors of that article pointout that it is not clear how long the changes observed inthe brain last. They also state that it is not known if theobserved changes are, at all, beneficial. There is thereforea gap between the guarded discussion in the peer-reviewed study and the more positive message of thecommercial material [42].
RecommendationsRecommendations for future researchFurther research should be undertaken in this area andwe recommend attention to the following:
– The clinical relevance of any brain changes shouldbe investigated using symptomatic study subjects.Also, clinical outcomes should be included and thecorrelation between these and brain changes shouldbe tested to establish if there is some type ofbenefits.
– To study the specific effect of SM, proper shamprocedures must be adopted and checked forsuccess after the intervention to control for anyunspecific effects, including placebo responses.
– Appropriate methodology in relation to randomizedcontrolled trials, with appropriate attention to thepotential sources of bias (e.g. blinding of studysubjects, assessor, and statistician) should berespected.
– In relation to the technical procedures, standardprotocols should be employed to ensurereproducibility of the outcome measures.
– Appropriate statistical methods and thresholdsshould be used.
– Any conflict of interest should be reported.– Results should be replicated by independent
research teams before their clinical acceptance.
Recommendations for the chiropractic professionPresently, the chiropractic profession might wish to con-sider the potential consequences of encouraging under-graduate- and postgraduate courses on chiropracticapproaches relating to the treatment of the brain via thespine. Obviously, this is also true for other health careproviders who may be tempted to practice followingsuch concepts in relation to SM. Moreover, statementsaimed at the public relating to this phenomenon shouldbe discussed as findings of unknown clinical effect.
ConclusionAccording to the results of the present systematic review,it is premature to promote the use of SM as a treatmentto improve ‘brain function’ from a clinical point of view.
Further, studies on this topic should (i) include symp-tomatic subjects, (ii) relate to the clinical significance byusing outcomes relevant to test associations with neuro-physiological changes, and (iii) take into considerationbasic methodological and technical requirements per-taining to this type of randomized controlled trials.
Additional files
Additional file 1: Search strategy developed for PubMed for asystematic critical review of the literature on the effect of spinalmanipulation on ‘brain function’ (DOCX 126 kb)
Additional file 2: Items selected for the quality checklists and theirrationale in relation to a systematic critical review on the effect of spinalmanipulation on ‘brain function’ (DOCX 22 kb)
Additional file 3: The various ways used in the scientific literature fortesting the hypothesis that spinal manipulation would have an effect on‘brain function’ (DOCX 83 kb)
Additional file 4: Commercial announcement of a chiropractic seminarentitled “Adjusting the Brain” (PDF 1462 kb)
AbbreviationsBOLD: Blood oxygenation level-dependent; fMRI: Functional magneticresonance imaging; FN: Functional Neurology; SM: Spinal manipulation
AcknowledgmentsThe authors would like to acknowledge Catherine Tellaa, librarian at theBibliothèque interuniversitaire de Santé Paris Descartes, for the assistance givenfor the search of literature. We are also grateful to Søren O’Neill DC, PhD, foreditorial assistance.
DeclarationsThe present systematic critical review was registered in PROSPERO, with thereference CRD42017074966.
Authors’ contributionsALM and CLY planned the review. All the authors contributed to thereviewing of the included articles. MAA, MS and PS provided comments onmethodological and technical aspects of articles depending on theirrespective areas of expertise (in Tables 4, 5, 6 and 7, col.10, each numberrefers to one of these co-authors, 1 for MAA, 2 for MS, and 3 for PS). ALMand CLY, with the assistance of MAA, MS and PS, interpreted the findings.ALM wrote the first draft. CLY, MAA, MS and PS provided comments for sub-sequent drafts. All the authors revised and approved the final manuscript.
Authors’ informationALM is a chiropractor and this work was done as part of her PhD program atthe University of Paris-Sud. MAA is a Professor in Sport sciences and physicalactivity at Université Paris-Sud where he is the Head of the CIAMS laboratory.He has a background in cognitive neuroscience and motor control. MS is aMD and PD (University lecturer) with a background in clinical and experi-mental neurophysiology and neurorehabilitation, specifically of spinal corddisorders. PS is an MD and a PhD with a background in neuroimaging(mostly functional and structural MRI, to a smaller extent, positron emissiontomography). CLY is a chiropractor and a Professor in Clinical Biomechanicsat the University of Southern Denmark. She has a background in epidemi-ology and systematic critical reviews and was the main supervisor on thisPhD project.
FundingApart from the authors being funded from their institutions, there were noexternal grants for this project.
Availability of data and materialsThe scientific articles scrutinized during the current critical review areavailable from the corresponding author on reasonable request.
Meyer et al. Chiropractic & Manual Therapies (2019) 27:60 Page 28 of 30
Ethics approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Competing interestsAuthors declare there are no conflicts of interest. CLY is a senior editorialadviser to and PS is a member of the editorial board of the journalChiropractic & Manual Therapies but played no part in the peer review of thesubmission.
Author details1CIAMS, Univ. Paris-Sud, Université Paris-Saclay, 91405 Orsay Cedex, France.2CIAMS, Université d’Orléans, 45067 Orléans, France. 3Institut FrancoEuropéen de Chiropraxie, 24 Bd Paul Vaillant Couturier, 94200 Ivry sur Seine,France. 4Spinal Cord Injury Center, University Hospital Balgrist, Zürich,Switzerland. 5Integrative Spinal Research Group, Department of ChiropracticMedicine, University Hospital Balgrist and University of Zürich, Zürich,Switzerland. 6Institute for Regional Health Research, University of SouthernDenmark, Odense, Denmark.
Received: 23 February 2019 Accepted: 2 July 2019
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