The recent gene flow between GL wolves and eastern coyotes is surprising given that coyote abundance is usually limited by wolves in areas where they coexist by direct killing (e.g. Paquet 1992) and interference competition (Murray Berger & Gese 2007).

However, once coyotes are established in an area, their extirpation is unlikely as spatial heterogeneity in habitat and in wolf distribution facilitate the persistence of coyotes in wolf-abundant areas (Murray Berger & Gese 2007).

Coyotes are usually found in more urban and agricultural regions, whereas wolves occur in more remote pristine areas.

These habitats are closely juxtaposed in the Great Lakes region and consequently, coyotes and GL wolves often live in close proximity, increasing the opportunity for interspecific interactions and matings.


The extent of hybridization varies throughout the Great Lakes area.

Microsatellite data indicate that the wolves north of the Great Lakes are much more impacted by hybridization with coyotes and other gray wolf popula- tions than areas to the south, a result supported by previous mtDNA analyses (Lehman et al. 1991).

A clear cline in body size from large individuals in the northwest to small individuals in the southeast has been observed and hypothesized to result from varying degrees of hybridiza- tion between North American wolf-like canids (Kyle et al. 2006).

However, the extent to which this morphological cline is due to differential hybridization or adaptation and environmental constraints (Schmitz & Lavigne 1987) remains to be determined.

A similar cline in body size has been observed in wolves from Minnesota, again interpreted as corresponding to different degrees of hybridization between GL wolves and western gray wolves (Mech & Paul 2008), although contrary to the situation in Ontario, the Minnesota wolves appear less impacted by hybridization in our analysis (Fig. 2c).


A substantial change in the frequency of maternally inherited mitochondrial DNA haplotypes between historic and recent GL wolves was previously described (Leonard & Wayne 2008), and was further supported by the haplotype distributions and levels of mtDNA differentiation found in the present study.

The dramatic change in haplotype composition reflects recent hybridization and introgression of both coyote and western gray wolf mtDNA into the GL wolf population (Leonard & Wayne 2008) and hence a change in the genetic composition of that population (Leonard & Wayne 2008, 2009).

Autosomal microsatellite data detected comparatively slight - but significant - genetic differentiation between historic and modern GL wolves, but high levels of differentiation between GL wolves and western gray wolves, eastern and western coyotes.

This suggests that, despite population bottlenecks in the early 1900s and gene flow from coyotes and western gray wolves, the GL population has retained genetic distinction from coyotes and wolves elsewhere.

Gene flow that occurred after the bottleneck could have in part restored previous genotypic diversity.

It is also possible that the demographic bottleneck in US GL wolves was not sufficient to create a signal of a bottleneck over the entire Great Lakes population.

These two factors are not mutually exclusive and both may have contributed to the lack of signal for demographic change.


The exact level of introgression of coyote and/or western gray wolf nuclear genetic material is unknown.

However, the discovery of admixed individuals in the microsatellite analysis, and the mixed profile of Y-chromosome and mtDNA haplotypes in GL wolves shows that recent introgression must have occurred.

In addition to the data presented here, the results of Roy et al. ( 1994) which found lower microsatellite differentiation between wolves and coyotes in the Great Lakes area than elsewhere, also support recent hybridization.

With evidence for ancient hybridization, introgression into GL wolves was apparently not only a human-mediated phenomenon.

However, despite high levels of introgression from coyotes, autosomal markers support GL wolves as a discrete wolf taxon.


The habitat in the Great Lakes region has changed dramatically over the last century, especially due to the large-scale conversion of forests to agriculture.

These habitat changes, in combination with direct persecution of the gray wolves, led to the decline of the wolf and enabled the natural colonization of the area by coyotes.

The habitat continues to change, as many farms are abandoned and the forests are now expanding.

Nonetheless, it is very unlikely that coyotes will cease to be a part of this ecosystem in the fore- seeable future.

Hybridization between the GL wolves and especially eastern coyotes appears to be ongoing, and thus still has the potential to further undermine the integrity of the GL wolves.

The hybridization does not appear to impact all GL wolves equally, so more information on the variation in ecological factors and the extent of hybridization in the different regions could help determine which circumstances favour hybridization, and provide guidelines for manage- ment to maintain GL wolf integrity in the future.


Koblmuller et al. ( 2009) analysed molecular genetic data of the wolf in the Great Lakes (GL) region of the USA and concluded that the animal was a unique ecotype of grey wolf and that genetic data supported the population as a discrete wolf taxon.

However, some of the literature that the researchers used to support their position actually did not, and additional confusion arises from indefinite use of terminology.

Herein, we discuss the problems with designation of a wolf population as a taxon or ecotype without proper definition and assessment of criteria.


Koblmuller et al. ( 2009) wrote ‘The GL wolf is morphologically distinct from both western grey wolves (Canis lupus) and coyotes (Canis latrans) (Nowak 2002)’.

However, Nowak (2002) did not draw this conclusion nor did his plots of the first and second canonical variables show this (Nowak 2002: Figures 6 and 8).

Nowak’s (2002: Figure 8) could be interpreted as indicating either overlap between western C. lupus and wolves from Michigan or a continuum between the two types.

Furthermore, similar analyses by Nowak (2009: Figures 15.1 and 15.2) show complete overlap between Minnesota wolves and western wolves and partial overlap between Michigan wolves and Minnesota and western wolves.

Regardless, skull morphology (size and dimensions) is influenced by genetics and environment.

Morphological variation is not a definitive indicator of phylogenetic ancestry (and hence taxonomy) or local adaptation (and hence ecotype status) without controlled experimentation.

Morphology may indicate ancestry (and be useful in taxonomy—e.g. domestic animal breeds differ in morphology because of ancestry) or environment (and reflect ecology—e.g. nutrition will influence body size), but these factors must be empirically assessed.


A second discrepancy is found in the Note at the end of Koblmuller et al. ( 2009) stating ‘Additional genetic analyses of the GL wolf was recently published by Wheeldon & White (2009) which further supports the conclusions presented here’.


On the contrary, Wheeldon & White (2009) concluded that the genetic makeup of historic (c. 100 years ago) and extant wolves of the GL region resulted from hybridization between grey wolves (C. lupus) and eastern wolves (Canis lycaon), whereas Koblmuller et al. ( 2009) reported that the wolf of the GL region has experienced a high degree of ancient and recent hybridization with western grey wolves and coyotes (Canis latrans, see also Leonard & Wayne 2008).


The genetic data (and mitochondrial DNA, mtDNA, data in particular,) used in these analyses are complicated, and the discrepancy of interpretations arises to some extent from assignment of mtDNA haplotypes to named taxa.


Koblmuller et al. ( 2009) found some recent wolves of the GL region had mtDNA haplotypes that occurred in a mtDNA clade with mtDNA haplotypes of western grey wolves, and others had mtDNA haplotypes that occurred in a mtDNA clade with mtDNA haplotypes of coyotes.


Historic wolves of the GL region had only mtDNA haplotypes that occurred in an mtDNA clade with mtDNA haplotypes of coyotes.


However, Wheeldon & White (2009) reported some of the same coyote clade mtDNA haplotypes (i.e. C1 and C13) in historic wolves of the GL region that they interpreted as C. lycaon haplotypes of New World origin.


These haplotypes and others were identified by Leonard & Wayne (2008) in wolves of the GL region.


Leonard & Wayne (2008) recognized mtDNA haplotypes of historic wolves in the GL region as ‘genetically distinct’, with an average mtDNA control-region sequence divergence about 6% different from coyotes and 19% different from grey wolves, and they referred to them as the ‘GL wolf’.


However, Koblmuller et al. ( 2009: Fig. 2) found that historic GL-wolf mtDNA haplotypes cluster in phylogenetic analysis with coyote mtDNA haplotypes, not as a distinct monophyletic group.


Wheeldon & White (2009) considered historic mtDNA haplotypes in wolves of the GL region as C. lycaon.


These mtDNA analyses were appropriate and the authors (Leonard & Wayne 2008; Koblmuller et al. 2009; Wheeldon & White 2009) considered legitimate hypotheses to explain the patterns observed.

However, the relationships are not definitive, as evidenced by the different interpretations.

It is very important to note that it is not uncommon for mtDNA phylogenetic relationships to be different from the overall relationships of species or populations.


For example, there are paraphyletic mtDNA phylogenies between distinct species: mule deer ⁄ blacktailed deer Odocoileus hemionus and white-tailed deer Odocoileus virginianus (Cronin et al. 1988) and grizzly ⁄ brown bears Ursus arctos, and polar bears Ursus maritimus (Cronin et al. 1991).


The point is that mtDNA and other molecular patterns can help understand current and historic processes, but do not necessarily reflect species and population status.


The use of molecular markers other than mtDNA (as Koblmuller et al. 2009 and Wheeldon & White 2009 did) helps to overcome this limitation.


We note that the mtDNA and Y-chromosome DNA sequence data and microsatellite DNA allele frequencies analysed by Koblmuller et al. ( 2009) were not accessible in these studies, and should be made available for other workers to assess the results and replicate analyses.


A third problem with the Koblmuller’s et al. ( 2009) study is undefined terminology and unclear application of taxonomy.

Koblmuller et al. ( 2009) used the terms ‘ecotype’, ‘species and subspecies’, ‘unique population’, ‘wolf-like canid’, ‘discrete wolf taxon’, ‘population integrity’, ‘morphologically distinct’ and ‘hybridization and introgression’ without clear definitions or criteria.


We recognize that authors must use terms to communicate effectively, and some terms’ meanings are assumed to be self evident.

We also recognize that Koblmuller et al. ( 2009) and other authors on wolf taxonomy acknowledged the potential problems of interpreting historical and extant patterns of molecular variation (limited samples, lineage sorting, ancient and current hybridization, uncertain use of species and subspecies designations).

However, clear and consistent definition of terminology is necessary for formal taxonomic designation or quantification of population status for legal and regulatory implications (e.g. endangered species status of wolves of the GL region).

Full discussion and definition of these terms is beyond the scope of this article (see Cronin 2006, 2007), but a few comments are warranted.


With regard to the taxonomic names and origins of the wolf of the GL region, Koblmuller et al. ( 2009) discussed alternative origins (Kyle et al. 2006) considering their molecular data:


It is a small subspecies (C. l. lycaon) of C. lupus (perhaps from C. lupus · Canis rufus hybridization).


It is a distinct species (C. lycaon).


It is a hybrid between C. lupus and C. latrans.


Regarding subspecies status, it is widely acknowledged that designation of subspecies is quite subjective and many currently named subspecies have not been rigorously assessed (e.g. Wilson & Brown 1953; Mayr 1970; Cronin 1993, 2006, 2007; Zink 2004 and references therein).

Also, because there is not a consensus on the species status of C. lycaon and C. rufus (e.g. Schwartz & Vucetich 2009) interbreeding between the various C. lupus, C. rufus and C. lycaon populations could be considered as either mixing of differentiated groups or simply gene flow among C. lupus populations, albeit complicated by potential gene flow with C. latrans.

We suggest that for North American Canis it is wise to avoid typological thinking and designation of formal taxonomic names to what are essentially geographic populations with varying levels of past and present gene flow.

In this context, it is important to use the terms ‘hybridization and introgression’ carefully to differentiate interbreeding between groups differentiated with definitive criteria from simple gene flow over geography.


Koblmuller et al. ’s (2009) consideration of the wolf of the GL region as both a ‘unique population or ecotype’ and a ‘taxon’ is also problematic because of the lack of definition and criteria.

One definition of ecotypes is populations with convergent morphological, demographic and behavioural adaptations to similar ecological conditions (Cronin et al. 2005).

This is a reasonable ecological designation, although adaptation has not actually been demonstrated in the case of the wolf of the GL region.

The morphological differences between the GL wolves and other wolves could be due to either local adaptation (supporting an ecotype designation) or hybridization with coyotes (not supporting an ecotype designation unless the hybrids subsequently adapt to local conditions).

The important point is that ecotypes are designated based on ecological criteria, not phylogenetic criteria, and therefore are not taxonomic units.


However, Koblmuller et al. ( 2009) also describe molecular data that support recognition of the wolves of the GL region as a ‘discrete wolf taxon’ (without naming the taxonomic level or name).

Taxonomy is based on phylogenetic relationships, so members of a taxon share more recent common ancestry with each other than with other taxa.

Because of gene flow and recent common ancestral populations, phylogenetic relationships at, and below, the species level are seldom definitive.


Considering the mixed ancestry of the extant wolves of the GL region including historic GL wolves, other wolves, and coyotes, it is not surprising these wolves have a gene pool different from other wild canids.

In addition, there is apparent contradiction by Koblmuller et al. ( 2009) in that they call the wolves of the GL region a discrete taxon but note there is likely recent and ongoing interbreeding with coyotes and other wolves.

If they are discrete, there would not be continued gene flow with other groups.


Regardless, one could call the wolves of the GL region a taxon (based on ancestry and phylogeny) or an ecotype (based on local adaptation) but the term applied needs definition and assessment of clear criteria.

We suggest that the wolves in the GL region can simply be called a wolf population with mixed ancestry.

Continuing research on the patterns and processes occurring in the complex mix of canids in the GL region may allow more definitive identification of taxon or ecotype status.


This view allows more focus on the population’s ecological and demographic status and does not prevent management and conservation (e.g. the Endangered Species Act can consider distinct population segments in addition to species and subspecies).

As discussed by Schwartz & Vucetich (2009), Koblmuller et al. ( 2009) used the term population integrity without clear definition.

Integrity could refer to taxonomic ‘purity’ or individual and population fitness.

It is generally acknowledged that the GL wolf population is fit, with abundant genetic variation.

However, molecular genetic data indicate the wolf of the GL region is not taxonomically ‘pure’ as there is evidence of past and ongoing gene flow among various proposed species and subspecies (Leonard & Wayne 2008; Wheeldon & White 2009).

We suggest maintaining a fit wolf population is an important management consideration, regardless of ancestry and molecular genetic patterns (see Schwartz & Vucetich 2009; Wheeldon & White 2009).

Designation of the population as a species, subspecies, taxon, or ecotype will remain largely subjective without rigorous use of definitions and assessment of measurable criteria for each term.


Cronin & Mech (2009) suggested that in our recent study on the genetics of the Great Lakes wolves (Koblmueller et al. 2009) we misrepresented the literature in two cases and engaged in ‘indefinite use of terminology’.

Nowak (2002) used morphological data to assess the status of wolves from Eastern North America.

On the basis of this analysis and historical data, he clearly advocates recognizing the Great Lakes wolf as subspecies Canis lupus lycaon.

For this reason, we find it appropriate to use this citation in support of morphological differentiation between C. l. lycaon and other subspecies of gray wolves in North America.

For a discussion of morphological and ecological differences in Great Lakes wolves, see Kolenosky & Standfield (1975).


The second ‘discrepancy’ Cronin & Mech raised concerns the sentence ‘Note added in proof’ in which we state the genetic data of Wheeldon & White (2009) support our conclusions.

Wheeldon & White (2009) sequenced a fragment of the mitochondrial control region from three historic Great Lakes area wolves.

They identified two haplotypes, both of which were identical to sequences found in our much larger sample of historic Great Lakes area wolves.

For this reason and considering the importance of authenticity in ancient DNA studies, we find our statement appropriate.

As this statement was a note in proof, we wanted to limit our comment to a sentence, but thought it was necessary to direct the reader to another relevant, recently published article.

As discussed by Cronin & Mech, Wheeldon & White’s (2009) conclusions differ from our own with regard to the history and origin of the Great Lakes wolves.

We maintain that the discrepancy in interpretation reflects different a priori assumptions about the phylogenetic relationships among North American canids.


Based on phylogenetic analysis of mtDNA control region sequences, previous and recent studies suggest widespread hybridization between coyotes and current and historic Great Lakes wolves (Lehman et al. 1991; Wilson et al. 2000, 2003; Leonard & Wayne 2008; Kays et al. 2009; Rutledge et al. 2009).

Such hybridization causes reticulations in mtDNA phylogenetic trees and confounds evolutionary inference.

Nonetheless, primarily on the basis of a clustering of mtDNA sequences of wolves from the Algonquin Provincial Park and surrounding areas (plus red wolves) with coyotes and a weakly supported genetic similarity based on microsatellites loci, Wilson et al. ( 2000) hypothesized that the Great Lakes wolf (including the red wolf C. rufus) is a distinct species that has evolved in North America and is closely related to the coyote.

This underlying assumption is maintained in subsequent publications.

We (Koblmueller et al. 2009) feel that the separate origin hypothesis is controversial and the data are not sufficient to support Wheeldon & White’s (2009) a priori assumptions about the phylogenetic position of Great Lakes wolves.

The intent of our study was to use more genetic markers (in our case additional autosomal and Y-chromosomal microsatellite loci) to clarify the evolutionary history of these ‘problematic’ taxa in an objective fashion.

As argued in our study, we suggest that these new data support the Great Lakes wolf as a distinct ecotype of the gray wolf.


The strongest argument for a sister group relationship of Great Lakes wolves (plus red wolves) and coyotes has been the finding that historic Great Lakes wolves were dominated by mitochondrial haplotypes closely related to western coyotes.

However, as explained by Cronin & Mech in the fourth paragraph of their comment, analyses of a single genetic marker ‘do not necessarily reflect species and population status’.

Introgressive hybridization leading to complete replacement of mtDNA (through drift or selection) on a regional scale (e.g. Melo-Ferreira et al. 2005; Nyingi & Agnese 2007; Good et al. 2008) or even throughout a species’ distribution range (e.g. Nevado et al. 2009) seems to be more common than previously thought.

To obtain a more complete picture of the history of these wolves and their relationships with other wolves and coyotes, more data, in addition to mtDNA, are required.

Wheeldon & White (2009) attempted to satisfy this requirement by typing eight nuclear microsatellites.

Unfortunately, those loci were not sufficiently informative (see their PCA scatterplot, figure 1 in Wheeldon & White 2009).

Our study included the analysis of 26 independent autosomal microsatellite markers, which allowed us to draw much stronger conclusions, clearly demonstrating that Great Lakes wolves are related more closely to western gray wolves than to coyotes, despite ongoing gene flow in the Great Lakes region.

This scenario also is supported by our Y-chromosomal data (although we regret that only four historic Great Lakes wolf samples could be successfully genotyped at all six Y-chromosomal loci).


We strongly believe that all published data should be made available to any interested party.

Many of the mitochondrial DNA sequences included in Koblmueller et al. ( 2009) were taken from the literature (for details see Material and Methods section).

The mtDNA haplotypes novel to our study have been submitted to GenBank (GQ849369-GQ849391).

No Y-chromosome DNA sequences are available because none was generated in this study.

Our Y-chromosome haplotypes are based on length polymorphisms at six microsatellite loci (again, we refer interested parties to the Materials and Methods section of Koblmueller et al. 2009 for more details).

Requests for data not in public repositories (e.g. there is no generally recognized public repository for length polymorphism data) should be made directly to the authors.


Cronin and Mech suggest that instead of clarifying the taxonomy of the wolves from around the Great Lakes, which was one of our goals, we create confusion through ‘undefined terminology and unclear application of taxonomy’ and then suggest that ‘for North American Canis, it is wise to avoid typological thinking and designation of formal taxonomic names’.

The species level status of gray wolves (Canis lupus) and coyotes (Canis latrans) have been consistently supported in the literature and genetic studies have found little evidence of hybridization between them outside the Great Lakes area (Pilgrim et al. 1998; Hailer & Leonard 2008).

Discarding this large body of work and calling them all Canis sp. does not clarify the situation, but obscure it.

For this reason, we use the well defined species designations of gray wolves and coyotes.

The taxonomy of the Great Lakes wolves is less clear and a number of different evolutionary scenarios have been proposed (see above).

Testing among these different hypotheses was the subject of our study, and for that reason, we did not initially advocate a specific taxonomy of Great Lakes wolves.

We found that the genetic data were not compatible with the hypothesis that the Great Lakes area wolves are a recently evolved species related more closely to coyotes than to wolves.

Rather, our data show Great Lakes area wolves are gray wolves (Canis lupus).

Within gray wolves, genetic partitions have been identified that are associated with habitat (i.e. Carmichael et al. 2001, 2007; Pilot et al. 2006; Leonard et al. 2007; Musiani et al. 2007; Munoz-Fuentes et al. 2009).

These habitat-associated genetic units have not currently been given subspecific status; they have just been referred to as ‘ecotypes’ in previous studies.


In gray wolves, the criteria for designating subspecies are not clearly defined, but historically have been based on phenotypic rather than genetic data.

For this reason, we refer to the Great Lakes wolf as an ‘ecotype’ to emphasize the association between genetics and ecological factors and do not attempt to define subspecies.


Cronin & Mech say ‘phylogenetic relationships at the species level are seldom definitive’.

We operate on the working hypothesis that ‘species’ exist.

A philosophical discussion on the existence of species is beyond the scope of this response (see Hey 2006).

We agree with Cronin & Mech that ‘maintaining a fit wolf population is an important management consideration’.

The data we present in Koblmueller et al. ( 2009) are all neutral genetic markers.

They show that Great Lakes wolf-like canids are closely related to gray wolves that have in the past, and are today, hybridizing with coyotes.

These data do not directly allow an assessment of fitness.

The observation that the wolves around the Great Lakes began hybridizing with coyotes after a period of persecution and habitat modification by humans may suggest causality.

Furthermore, the level of hybridization and introgression was not uniform across the region.

For these reasons, we suggested in Koblmueller et al. ( 2009) and maintain here that ‘more information on the variation in ecological factors and the extent of hybridization in the different regions could help determine, which circumstances favour hybridization, and provide guidelines for management to maintain Great Lakes wolf integrity in the future’.


Low back pain (LBP) is a common, challenging medical and socioeconomic problem in working-age adults.

1,2 LBP is the significant cause of years lived with disability, work absenteeism and high compensation in modern societies.

2,3 Although the majority of LBP patients recover within six weeks without medical treatment, almost 20% of these cases become chronic.

4 More than 90% of chronic low back pain (CLBP) patients presenting to the primary care have non- specific LBP.

4 Physical and psychosocial factors are commonly associ- ated with CLBP.

2 However, trunk muscle weakness or delayed activation, an important deficit of the neural control unit of the spinal stabilizing system, and impairment in lumbar pro- prioception have been frequently reported as a contributing factor of persistent LBP.

5---12 The consequences of altered trunk muscle activation, and impaired hip strategy and lum- bar proprioception may be the determining factors in the alterations in static balance ability in CLBP patients.

5---9,11---13 Balance ability is the performance of maintaining the cen- tre of gravity of the body within the base of support.

11 Compared with the asymptomatic controls, CLBP patients presented a higher velocity of centre of pressure (CoP) and a larger CoP area, which is thought to represent a decreased ability to control postural balance, during one- legged stand condition 6 and greater difficulty adapting to changing conditions.

14 Therefore, treatment interventions improving trunk muscle strength and proprioception may improve the pain-related and balance outcomes of CLBP individuals who do not have problems in visual and vestibular systems which play important roles for controlling postural balance.

15 Although there is no a clear conclusion on which type of non-pharmacologic therapy is the most effective for treat- ing CLBP, exercise therapy is recommended as a first-line intervention for CLBP patients.

2,16 Proprioceptive neuromus- cular facilitation (PNF) training has been used for treating CLBP cases by physical therapists to gain neuromuscular responses by facilitating proprioceptors.

17---22 The patterns of PNF training have diagonal and spiral directions that has been proposed to hasten the performance of numer- ous muscles through its patterns and to be more effective than conventional single-direction exercises.

17 They also are in accordance with the topographic arrangement of the muscles being used in daily activities and sports.

17,19,23 Moreover, PNF training may stimulate the proprioceptors of the muscles and joints in the lumbar region and may be useful for improving sensorimotor regulation and balance performance.

21 Previous studies suggested three commonly applied PNF techniques for CLBP, namely, rhythmic stabiliza- tion (RS), combination of isotonics (COI) and 'chop and lift' (CL) as described previously.

17---24 Many authors have proposed the effectiveness of the PNF training in pain-related outcomes, trunk muscle activity and range of motion to manage CLBP.

18---22,25 However, studies supporting the effect of PNF training on the balance ability in CLBP are scarce.


To the authors' knowledge, only Young et al. 22 reported that PNF training improved the balance of seniors with CLBP.

Although the authors 22 used the CoP measurement device, which is recommended as an optimal outcome for postural balance, 26,27 they did not screen other potential disorders, such as vestibular and visual disorders, or lower extremity strength, which could affect the bal- ance of CLBP patients.

Furthermore, the blinding method to eliminate the measurement bias was not stated.

Addi- tionally, they investigated the effects of PNF training in seniors with CLBP, but the findings could not be general- ized to other age groups, especially working-age adults.

A robust methodology to evaluate the effects of the PNF train- ing on pain-related and balance parameters in working-age people is still needed.


Thus, this study aimed to investigate the effectiveness of a three-week PNF training in pain inten- sity, functional disability and static balance in working-age patients with CLBP.

It was hypothesized that CLBP partici- pants receiving three-week PNF training may have greater decreased pain intensity, and improving functional ability and static balance than those receiving the general trunk exercises.


Conducted at the Physical Therapy Laboratory at Mae Fah Luang University, Thailand, this study was an assessor-blinded, randomized, controlled trial, with two measurement points: baseline assessment and at the end of the three-week intervention.

This study was approved by the Ethics Committee for Human Research at Mae Fah Luang University (REH 59122), Chiang Rai, Thailand, based on the Declaration of Helsinki.

This trial was prospectively registered at the Thai Clinical Trial Registry (TCTR20161219001) in December 2016.


Between February and May 2017, CLBP patients were recruited to the study.

An advertisement was used in the Physical Therapy Department of Mae Fah Luang University Hospital in Chiang Rai, Thailand, for the purpose of patient recruitment.

Male or female non-specific CLBP patients, aged 18---50 years, with pain intensity at least two points of the 0---10 numerical rating scale (NRS) were invited to par- ticipate in this study.

A medical doctor who was unaware of the intervention screened the patients using oral illness his- tory taking and a physical examination for eligibility before participation.

The patients were excluded if they presented any of the following criteria: history of lumbopelvic surgery, specific LBP (e.g., disc herniation, spondylolisthesis and sacroiliac joint dysfunction) screened by using an X-ray investigation and clinical tests, cancer, autoimmune dis- eases, neurologic deficits, lower limb arthritis, vestibular and visual disorders, pregnancy, cardiopulmonary disorders or having exercise contraindications.

Those who regularly performed PNF or general trunk exercise training were also excluded.

All eligible participants signed an informed con- sent form before participation.


A repeated measures ANOVA formula was used to calculate the sample size.

The sample size was estimated with a 90% power of test, an alpha level of 0.05 and standard deviation (SD) of 1.30 and 0.96 for the PNF training and the control groups, respectively to detect a between-group clinically significant change in two scores of the 11-point NRS at three- weeks intervention.

28 The attrition rate of 10% was added to the estimation to confirm it even with a potential drop-out.

In total, a sample size of 44 was obtained.


Before starting the study, participants were randomly allocated into two groups: three-week PNF training (22 par- ticipants) and control (22 participants) groups, using block randomization with block sizes of two and four.

The ran- domization results were concealed in sealed and opaque envelopes with consecutive numbering.

Randomization was performed by a researcher assistant who was unaware of the intervention and evaluation processes.

All training ses- sions of both groups were conducted at the Physical Therapy Laboratory three times a week over three weeks.

The exer- cise interventions of both groups were implemented by a researcher with over 10-year experience of exercise ther- apy in LBP who was unaware of the outcome measurement.

All participants were scheduled and checked for their inter- vention adherence.


The three-week PNF training intervention was modified from the study of Areeudomwong et al. 18 This training aimed at improving trunk muscle strength, trunk stabilization and controlled movements.

17,18,23 For three weeks, the partici- pants attended each individual training session lasting for about 30---40 min three times a week.

They received three sets of 15 repetitions for each PNF training, with a 30 s rest between repetitions.

A 60 s rest after completing the 15 rep- etitions was provided.

The training intervention was divided into three phases and progression of training was based on the individual's performance.


For week 1, the participants were trained in alternate isometric contractions of the trunk flexors and extensors against maximum force.

The training was provided by the physical therapist for 10 s in a sitting position (Fig. 1A).


For week 2, the participants concentrated in alternating isometric concentric and eccentric contractions of the trunk agonistic muscles with a 5 s resisted concentric contraction of the trunk flexors in forward bending, followed by a 5 s resisted eccentric contraction of the trunk flexors in the return to trunk neutral position and a 5 s hold resisted iso- metric contraction of the trunk muscles in a neutral position.

The same method was applied in the backward bending of the trunk (Fig. 1B).


For week 3, the participants focused on training the upper extremities by alternately performing the chop and lift movement patterns in diagonal and spiral directions for 10 s. The maximum resistance was generated by the physical therapist (Fig. 1C).


The general trunk exercise programme consisted of trunk curl-up (Fig. 2A), diagonal trunk curl (Fig. 2B) and single- legged extension (Fig. 2C).

These exercises promote the strengthening of the lumbopelvic muscles, as proposed by Imai et al. 29 and Koumantakis et al. 30 The participants attended three exercises lasting for about 30 min three times a week over three weeks.

All exercises were per- formed in three sets of 10 repetitions, with a 30 s rest between repetitions and a 60 s rest between sets.


All the participants were asked for any adverse effects of the intervention upon the completion of intervention.

They were also asked to avoid medications and other treatments throughout the study period.

A log book was given to each participant for recording other co-interventions.


All outcome measures were assessed by an assessor who was blinded to the randomization procedure.

The primary out- come measure was pain intensity, which was estimated using the 11-point NRS, with scores ranging from 0 (no pain) to 10 (very severe pain).

31 It showed high reliability (r = 0.95---0.96) and validity (r = 0.86---0.95).

32 The participants circled the numerical value on the segmented scale to indicate pain level.

A clinically important change for the 11-point NRS is approximately two points for the CLBP.

28 The secondary outcomes were composed of disability and static balance.

The Thai version of the Roland---Morris Disability Questionnaire (RMDQ) was employed to assess disability.

33 The questionnaire consists of 24 items to assess disability specific to LBP.

The participants put a tick on the blank in front of each item if they had such disability on the evaluation day.

The total score ranged from 0 (no dis- ability) to 24 (maximum disability).

The Thai RMDQ showed high reliability (K = 0.71---0.93).


the CoP over the assessment period in the X- and Y-axes.

The ellipse sway area and CoP velocity are the recommended outcome measures for postural balance.

26,27,35 The OLST was performed three times for each condition, with a 30 s rest period between trials.

26 The average value of the OLST trials in each condition represented the static balance, with a less ellipse sway area and CoP velocity indi- cating better balance performance.


Prior to data collection, the reliability test for the mea- surement of the OLST was determined by the assessor.

Intra-rater reliability showed high reliability (ICC = 0.90; 95% confidence interval, CI = 0.70---0.97, p < 0.001).


The characteristics of the participants were presented using descriptive statistics.

Data were analyzed using SPSS ver- sion 20 (IBM Corporation, Armonk, NY, USA) and based on the intention-to-treat approach.

The mean, SD and the 95% CI of the values were calculated for each variable.

The Shapiro---Wilk test showed that all data were normally dis- tributed.

A 2 × 2 (group × time) repeated measures ANOVA was used to compare between-group differences for each outcome.

If a significant interaction effect was observed, multiple comparisons with Bonferroni adjustment would be applied.

The significance level was set to 0.05.

The effect size (ES) was calculated using the difference between two means divided by a pooled SD.

The interpretation of the ES was performed on the basis of Cohen's recommendation, where d = 0.20 is the small ES, d = 0.50 is the medium ES and d = 0.80 is the large ES.


Fifty CLBP patients were initially screened for eligibility.

Forty-four eligible participants met the inclusion criteria, willed to participate in this study, and were allocated to either the PNF training or the control group equally.

Six patients were excluded from the study because they had disc herniation and sacroiliac joint dysfunction (Fig. 3).

All participants attended the three weeks of the study, and none of the participants reported any adverse effects and used other co-interventions during the intervention period.

Table 1 showed the baseline characteristics of the partici- pants and they were homogenous between the groups.


The effect of the significant group × time interaction on pain intensity was observed (p < 0.001).

The PNF training group showed a statistically significant higher reduction in pain intensity than the control group after the completion of three-week intervention period (between-group differ- ence 1.22 ± 0.32 points, 95% CI: 0.58 to 1.88, p < 0.001) (Table 2).

A moderate effect size was found (d = 0.50).

A sig- nificant interaction effect on functional disability was also found (p < 0.001).

The PNF training group demonstrated a statistically significant greater reduced functional disability than the controls after the three-week intervention period ceased (between-group difference 2.23 ± 0.50 score, 95% CI: 1.22 to 3.24, p < 0.001) (Table 2) with a moderate effect size (d = 0.56).


In measuring the CoP outcomes while per- forming OLST with the EO condition, significant interaction effects on the ellipse sway area and CoP velocity were detected (p < 0.001).

The PNF training group provided a sta- tistically significant greater reduction in the ellipse sway area and CoP velocity than the controls (between-group difference 129.09 ± 27.33 mm 2 , 95% CI: 64.93 to 175.25, p = 0.003 for ellipse sway area and between-group differ- ence 6.68 ± 1.12 mm/s, 95% CI: 4.41 to 8.95, p = 0.004 for CoP velocity) (Table 2).

Moderate effect sizes (d = 0.56 and d = 0.67 for the ellipse sway area and CoP velocity, respec- tively) were demonstrated.


Table 2 shows the results of the CoP outcomes while per- forming OLST with the EC condition.

A significant group by time interaction effect of the ellipse sway area (p = 0.02) and CoP velocity (p = 0.007) was found.

The PNF training group provided a statistically significant greater reduction in all CoP outcomes than the control group (between---group difference 336.27 ± 112.28 mm 2 , 95% CI: 109.67 to 562.87, p = 0.005 for the ellipse sway area and between-group dif- ference 6.77 ± 1.37 mm/s, 95% CI: 4.01 to 9.54, p < 0.001 for


This study investigated the effectiveness of a three-week PNF training programme on pain-related and static balance parameters among working-age individuals with CLBP.

The findings of this study supported our hypothesis that the PNF training provided positive, but small, effects not only by decreasing pain intensity and disability but also by improving static balance.


The selection of the PNF training aimed at promoting the activation of the trunk muscles through the diagonal and spiral directions, consistent with the topographic arrange- ment of the muscles being used in daily living.

17 The previous studies found that impaired trunk muscle activation and coordination resulting in excessive movement and instabil- ity of the lumbar spine may be associated with greater pain and functional disability.

37---39 Moreover, altered trunk mus- cle activation was found to be related to a disturbance in mechanoreceptors and possibly to an association with inac- curate information processing from the higher centres of the central nervous system related to motor control.

8,38,39 Three-week PNF training group of the present study had statistically significant more decreased pain and functional disability than the controls.

The ES for the between-group differences was moderate, suggesting a moderate clinical effect of three-week PNF training for treating CLBP patients; however, the between group differences did not surpass the reported of clinically important change of two points of the NRS 28 and 3.5 scores of the RMDQ. 40 This finding is in agreement with those of other studies despite some dif- ferences in the training protocols and outcome measures.

George et al. 25 revealed an additional positive effects of a three-week PNF training for trunk muscles plus general trunk exercises on pain intensity measured by a visual ana- logue scale (VAS) and function measured by the Oswestry Disability Index compared with general trunk exercises alone in CLBP patients.

Young et al. 22 reported that a six-week PNF training improved pain intensity measured by a VAS in seniors with CLBP.


The RS, COI and CL techniques were chosen for this study, and they could hasten the perfor- mance of numerous muscles through their patterns.

17,23 The RS technique may promote trunk stability, and the COI and CL techniques promote muscle co-contraction and mobi- lization to enhance joint controlled mobility and human movement.

17,23 Therefore, the improvements in pain inten- sity and function may result from the better activation of the trunk muscles to increase lumbar stabilization in daily activities.

18,23,25 The finding of this study showed a greater improvement in the static balance in the EO and EC conditions after three-week PNF training than in the controls.

This result is consistent with the study of George et al., 25 which reported better static balance after receiving a PNF programme than after trunk strengthening exercises in seniors with CLBP.


The previous studies showed that pain, altered lumbopelvic mus- cle activation and impairment of the lumbar proprioception could be contributing factors in the lack of balance ability of CLBP patients.

13,35,41 Ruhe et al. 35 reported a linear relation- ship between increasing pain and increasing COP velocity.

Mok et al. 13 proposed that CLBP patients present impaired hip strategy during balance challenge which may be because of decreased lumbar proprioception and improper activation of lumbopelvic muscles.

Balance dysfunction in CLBP indi- viduals may associate with altered proprioceptive input or central processing.

41 The improvements in static balance in this study may be related to the significant subsidence of pain intensity 35 and improved muscle activity, such as the transversus abdominis and lumbar erector spinae muscles, to stabilize the lumbar spine as described previously.

18,25 Additionally, PNF training is speculated to stimulate the pro- prioceptors of the muscles and joints of the lumbar spine, and it may improve sensorimotor regulation and balance performance.


This study has several advantages.

First, the study was designed as an assessor-blinded, randomized controlled trial to eliminate selection and measurement bias.

42 Second, this study used the criteria to exclude other conditions that could affect balance ability, such as vestibular disorders, visual disorders, or lower limb problems, to include CLBP patients who did not have such conditions.

Third, as all par- ticipants completed the interventions, participant attrition was not an issue.


This study has its limitations.

It only considered the effects of PNF training on pain, disability and static bal- ance.

Further studies should examine other outcomes, such as quality of life, fear of movement, or dynamic balance.


The application of a three-week PNF training programme could provide a greater reduction in pain intensity, and improving the functional ability and static balance than the general trunk exercises in working-age patients with CLBP.

As the magnitudes of difference do not reach the clini- cal meaningful level, the therapists should prescribe either intervention to the patients based on its effectiveness and costs.


First we like to compliment the authors on their efforts for addressing the issue to determine the long term effects of PNF-training in patients with chronic low back pain [1].

Nevertheless we need to address some remarks and comments in the hope the authors can clarify and provide some further details.


In the method the PNF training protocol is described as: 'modified from the studies of Areeudomwong et al.' [ 2].

This study in turn is describing the method as 'modified from the studies of Kofotolis and Kellis [3] and Voight et al.' [ 4].

The description is illustrated with photos, the Figures 1a, b and c. The illustrations and the description of the techniques are not synchronized.


Described by the authors is in week 1: '...to alternate isometric contractions...' Isometric is defined as: 'tension built up in a muscle, but the muscle neither shortens nor lengthens' [5].

Hence no movement is intended during this technique: 'Rhythmic Stabilization', in which a grip on both sides is required to address also the antagonists without movement [6-8].

The description in the text and the picture connects more to a grip variation fitting to the technique 'Stabilizing reversal' in which one needs a change of hands to facilitate the alternating muscle activation of agonists and antagonists [6].


Week 2 is described as: '...alternating concentric and eccentric contractions of trunk agonistic muscles...' this means that there is a consistent resistance for the agonists, in this case either the flexors or the extensors.

Concentric contractions are defined as contractions in which the muscle generates force as it shortens and eccentric contractions, in which the muscle generates force as it lengthens [5].


The whole description in the text fits to the technique 'combinations of isotonics', in which there is no change of the therapist hands to the antagonist, since the objective is to facilitate only the agonists in an intra-muscular coordination of shortening and lengthening without relaxation in between [6,9].


In the figures 1-b, there is clearly no eccentric stimulus recognizable.

The two pictures in figures 1-b rather illustrate the technique of 'dynamic reversals', in which alternating isotonic (concentric) contractions are performed addressing the agonist and antagonist in alternation to enhance the inter-muscular coordination of these two groups of muscles [6].


In figure 1-c, the illustration of the chop and lift would require a specific manual facilitation which is missing.

The PNF-concept clearly describes a goal oriented use of basic principles of facilitations such as, manual contact with a lumbrical grip, traction and/or approximation to achieve an irradiation into the target pattern from the trunk to reinforce the addressed muscles [6,10,11].


The appropriate use of these principles and procedures for facilitation is totally missing.

The same mistakes occur in the publication of Areeudomwong et al. [ 2] and of Kofotolis and Kellis [3].


The publication of Voight et al. [ 4] is not describing a protocol for a specified indication, but represents merely an opinion article about biomechanical and neurophysiological explanations of the chop and lift procedure.


A critical view on the description and illustrations from Voight et al. [ 4] is required since they are clearly different from those originally described by Knott and Voss [12] and later by Voss et al. [ 13], or Adler et al. [ 6].


Incomplete and improper use of the PNF-concept is frequently recognized and has been addressed [11].

The PNF-concept has been defined as a comprehensive rehabilitation approach focusing on a motor learning effect [11].

This comprehensive approach is defined by a specific use of basic principles & procedures for facilitation while using specific techniques to address specified treatment objectives [6,14].

Furthermore the reference of Adler et al. [ 6] is used.

This reference is one of the instruction books advocated by the international PNF association (IPNFA) (IPNFA.org/PNF-literature/PNF-text books).


Comparing the description from Areeudomwong et al. [ 2], from Kofotolis and Kellis [3] and from Voight et al. [ 4] with those from Adler et al. [ 6], demonstrates the flaws in the performances used in the first three publications.


We would recommend all researchers addressing the use of components from the PNF-concept to use adequate PNF-techniques and facilitations as defined and described by Knott and Voss [12] and their successors, Adler et al. [ 6] and the IPNFA [14].


We would like to sincerely thank you for the opportunity to extensively discuss based on the comments of Smedes et al. [ 1] regarding our recently published article [2], which examined the effects of PNF training including techniques on rhythmic stabilization, combination of isotonics, chop, and lift in working-age people suffering from chronic low back pain.


In that letter to the editor, the authors commented on our publication that the performed PNF techniques deviated from the original methods proposed by Knott and Voss [3], and Adler et al. [ 4].

Furthermore, the figure describing each technique illustrated was not matched with the text we wrote.


The authors stated that the description and figure of rhythmic stabilization in our article should be stabilizing reversal because Figure 1a demonstrated a grip variation.

At this point, when we considered Figure 1, it is clearly defined for demonstrating rhythmic stabilization without a grip variation.

The figure showed rhythmic stabilization to facilitate co-contraction of both trunk flexors and extensors.

The description of the rhythmic stabilization technique in our article was shortened due to the word limitation of the journal of publication; the concept of this technique and hand grip placement were not altered from the original established by Adler et al. [ 4].

In our experiment, the therapist informed the patients to resist agonists isometrically using one hand.

When the patients responded ultimately, another hand was started to resist antagonists without movement as the resistance changes by commanding the patient "stay still, match the therapist again in the front or the back."


We do agree with the comments on Figure 1b for the unclear situation on eccentric contraction facilitation.

Indeed, we did that in our treatment session but did not put the figure into the manuscript because the number of figures has been limited by the journal of publication.

In brief, after complete concentric stimulations of trunk flexors and extensors at the end of a desired range of motion, the therapist applied resistance for trunk flexors or extensors in eccentric fashion and asked the patients to move slowly to the starting position without relaxation between the different types of muscle activations and the hands remain on the same surface.


For figure 1c, the chop and lift used in our study were based on dynamic reversals to facilitate controlled movements.


We disagree with the comments on our study for the incorrect use of PNF-techniques and mistaking principles.

We strictly followed the PNF-concept to promote trunk stabilization and controlled trunk mobility that proposed problems of chronic low back pain [4-9].

Manual contact via lumbrical grip, visual cue and approximation, and traction were also used for stimulating desired responses.


Finally, we would like to thank the authors for giving us the opportunity to describe and provide more information on our study to the readers who are interested in PNF techniques for applying to their treatments for eliminating the suffering of chronic low back pain patients.


To evaluate the magnitude and progression of dental changes associated with long-term mandibular advancement splint (MAS) treatment of obstructive sleep apnea (OSA).


Retrospective study of adults treated for primary snoring or mild to severe OSA with MAS for a minimum of 8 years.

The series of dental casts of patients were analyzed with a digital caliper for changes in overbite, overjet, dental arch crowding and width, and inter-arch relationships.

The progression of these changes over time was determined and initial patient and dental characteristics were evaluated as predictors of the observed dental side effects of treatment.


A total of 77 patients (average age at start of treatment: 47.5 ± 10.2 years, 62 males) were included in this study.

The average treatment length was 11.1 ± 2.8 years.

Over the total treatment interval evaluated there was a signifi cant (p < 0.001) reduction in the overbite (2.3 ± 1.6 mm), overjet (1.9 ± 1.9 mm), and mandibular crowding (1.3 ± 1.8 mm).

A corresponding signifi cant (p < 0.001) increase of mandibular intercanine (0.7 ± 1.5 mm) and intermolar (1.1 ± 1.4 mm) width as well as incidence of anterior crossbite and posterior open bite was observed.

Overbite and mandibular intermolar distance were observed to decrease less with time, while overjet, mandibular intercanine distance, and lower arch crowding all decreased continuously at a constant rate.


After an average observation period of over 11 years, clinically signifi cant changes in occlusion were observed and were progressive in nature.

Rather than reaching a discernible end-point, the dental side effects of MAS therapy continue with ongoing MAS use.


O bstructive sleep apnea (OSA) often leads to poor sleep quality, daytime sleepiness, and an increased risk of motor vehicle accidents, hypertension, and stroke.

1 Oral appliances, which function to hold the mandible in a forward position and enlarge the airway during sleep, are indicated as a primary treatment option for snoring and mild to moderate OSA.

These appliances are also being implemented as a alternative for pa- tients with severe OSA who are unwilling or unable to toler- ate continuous positive airway pressure for the management of their disease.

1 To this end a number of recent studies have docu- mented the effi cacy of mandibular advancement splints (MAS) in improvements in daytime sleepiness, AHI, and mean arterial blood pressure and/or cardiovascular health.

2-10 The MAS is the main type of oral appliance currently used, and though well tolerated, has identifi ed short-term and long- term side effects.

Initial transient effects may include excess salivation or mouth dryness, temporomandibular joint and den- tal discomfort and irritation of intra-oral tissues.

11 The skeletal and dental changes that occur after prolonged MAS treatment have been previously described in terms of appliance design, amount of mandibular protrusion, and duration of wear.


With the longest observation period yet to be reported, the results from this study confi rm that long-term MAS treatment leads to signifi cant changes in occlusion for the majority of patients.

These dental changes were found to be progressive in nature, and continue with ongoing MAS use.

degrees of changes in mandibular crowding, posterior occlu- sal contacts and in mandibular arch width.

The progression at which these changes occur is still unclear.

It has been pro- posed that dental changes may decrease with time, 16,19 while others 20 have found that changes tend to be progressive in na- ture.

Interestingly, Battagel, in a study of 30 patients averag- ing 3.64 years of MAS use, found no statistically significant correlation between the duration of MAS wear and the change in OB and OJ.

15 However these previous attempts to classify the time course of occlusal changes with MAS use may have been over too short an observation period to appreciate their progression.


Though MAS adherence rates vary, potential reasons for discontinuing treatment are occlusal side effects and compli- cations.

21 It is hoped that an improved understanding of the progression of these dental changes may help in designing op- timal treatment protocols that allow for maximum adherence to prescribed MAS treatment.

The present study characterizes the dental changes associated with MAS therapy over the longest observation period published to date, as well as an examination of the progression of these side effects over time.


The specific aims of this study are to report on the magni- tude and progression of dental changes associated with long- term MAS treatment, as well as to investigate the relationship between the observed changes, the initial occlusion, and the BMI.


De-identified demographic data and dental study casts of patients (Table 1) who were treated a minimum of years with a MAS for snoring or OSA were retrieved from the Sleep Apnea Dental Clinic at the University of British Columbia and the private practice of a co-author.

In these clinics it is typical protocol to produce dental casts for any follow-up ap- pointment requiring major repair or replacement of the MAS.

Thus patients had a variable number of intermediate records available; however, all had ≥ 8 years between their initial and most recent set of records.

Patients were excluded if they had missing dental study casts from either their initial or most re- cent set of records, and most patients reported wearing the ap- pliance nightly.

The total period of MAS use was calculated as the interval between initial appliance placement and the date of the most recent study casts.

Initial severity of OSA for treated patients ranged from primary snoring to severe OSA.

The Clinical Research Ethics Board of the University of Brit- ish Columbia approved this study.


All patients were treated with a custom made, titratable, bi- block mandibular advancement appliance (Klearway; Space Maintainers Laboratories Canada Ltd., Calgary, Canada), made of thermoplastic material with embedded metal clasps.

The up- per and lower members of the appliance are connected via an adjustable screw assembly, which fits in the area of the palatal vault and allows for titration in 0.25-mm increments.

The ini- tial mandibular advancement was set at two-thirds of maximum mandibular protrusion, and then further advancements were prescribed by 0.25-mm increments until self-reported reso- lution of snoring and daytime sleepiness symptoms, or until uncomfortable for the patient.

Improvement in OSA was then often verified by a follow-up overnight sleep study with the appliance in place.


The dental study casts were measured with a digital caliper with a resolution of 0.1 mm by a single investigator.

Charac- teristics assessed included OJ and OB (mean values for the central incisors were used), dental crowding, intermolar and intercanine distances, as well as the number of posterior teeth with open occlusal contacts and anterior teeth in crossbite.

18 Fifteen sets of models were measured a second time after a 2-week interval to assess method error.

Descriptive measures and paired t-tests were used to report changes over the entire observation period (final - initial records), while method er- rors were calculated using Dahlberg's formula.

Spearman and Pearson correlation coefficients were used to determine the influence of initial patient characteristics on the magnitude of occlusal changes.

In an examination of all available data points, a mixed-effect polynomial regression analysis was used to analyze the data for the rate at which changes occur over the course of treatment.

To determine the influence of ini- tial occlusion on the rate of change, patients were also further subdivided into groups of normal or excessive initial OJ and OB for this analysis.

Statistical significance was determined at p < 0.05.


The records of a total of 77 patients with an average treat- ment time of 11.1 years were included for analysis in this study.

Twenty-six patients presented with mild and moderate OSA, while 28 had severe OSA prior to initiation of treatment.

The remaining 23 patients were either snorers or had only base- line oximetry performed.

They were predominantly male and mildly obese (mean BMI 29 kg/m 2 ).

Further description of the patient's baseline characteristics can be seen in Table 1.

The as- sessed method error for the dental measurements ranged from 0.13 to 0.64 mm.


Over the total treatment interval evaluated there was a sig- nificant change in the relationship between the upper and lower arches where a decrease in the OJ and OB was observed.

Ad- ditionally the lower arch was found to have expanded signifi- cantly, as measured by increases in mandibular intercanine and intermolar distances, as well as a decrease in mandibular arch Long-Term Occlusal Effects of Mandibular Advancement Splints crowding (Table 2).

No signifi cant changes were observed in maxillary variables.


Two important characteristics that anecdotally weigh heavily in a patient's perception of the quality of occlusion, posterior openbite and anterior crossbite, both demonstrated signifi cant changes in the sample population.

A posterior openbite, which for the purposes of this study is defi ned by the loss of occlusal contact on at least 2 posterior teeth, developed in 51% (39/77) of the sample.

Similarly 62% (48/77) of the sample developed an anterior crossbite of at least one tooth-defi ned as a lack of positive horizontal overlap of the upper anterior teeth over the lower anterior teeth.

However of those patients that developed a crossbite, an average of 4 teeth were involved.


Of the occlusal parameters that changed signifi cantly dur- ing treatment (p < 0.001), additional analysis was performed to characterize how these changes progressed with time.

Mixed effects polynomial regression analyses were performed to deter- mine the relationship of these variables to time in treatment.

The scope of the population data for both OJ and OB are illustrated in Figure 1.

Once this relationship was established the rate of change per year could be calculated, demonstrating signifi cant differences in how these changes progressed over time.

Looking at the entire sample population, OB was observed to decrease less with time, while OJ decreased continuously at a constant rate.


The progression in OB and OJ changes were further exam- ined in terms of initial occlusal characteristics (Figures 2 and 3, respectively), which revealed that the initial amount of OJ had no effect on the progression of change.

However the initial amount of OB did alter the pattern of future changes, as patients with a small initial OB were found to have the rate of change fi rst decrease, and then later increase in magnitude as treatment time was extended beyond 9 years.

Conversely, patients with The data for each individual patient is connected by a gray line.

The overall relationship of all data is represented by the black line, demonstrating the decreasing but leveling off, and linear rate of changes for overbite and overjet respectively.

Examining the mandibular arch characteristics, we found sig- nifi cant change over time in the intercanine width, which contin- uously increased at a constant rate, while mandibular intermolar distance was found to increase most rapidly initially and then taper off with small increases occurring after 12 years of treat- ment time (Figures 4 and 5) The changes in the rate at which mandibular arch crowding decreases appears to be more com- plex, with early rapid decrease followed by small changes until after 12 years of treatment when the rate rises again (Figure 6).


In assessing initial patient characteristics for predictors of occlusal changes, we found that patient age, sex, and pre- treatment BMI were unrelated to the amount of both OJ and OB reduction, as well as the occurrence of anterior crossbite or posterior openbite.

The amount of total change in overjet was signifi cantly correlated to initial AHI (r = 0.28), though no other relationships with occlusal variables were found.


Initial OJ was not signifi cantly related to the occurrence of anterior crossbite or posterior openbite.

Initial OJ was positively correlated to the total observed change in both OB (r = 0.28) and OJ (r = 0.33).

Initial overbite was signifi cantly negatively correlated (r = -0.37) to anterior crossbite and positively cor- related (r = 0.44) to total observed change in overbite caused by MAS treatment.


The present results demonstrate the dental changes associ- ated with MAS treatment of OSA over the longest observation The magnitude of the changes presently reported are slightly greater than those previously described for long-term (> 5 years) studies.

Martinez et al. found a mean OB reduction of 0.81 mm and OJ reduction of 1.1 mm from 15 OSA patients with 4.8 years of MAS use.

16 Similarly, Marklund found reduc- tions in both OB and OJ of 0.6 mm from a 5-year follow-up of 187 OSA patients.

18 Almeida and colleagues 18 in an exami- nation of 70 patients over a 7-year period recorded reductions of 1.91 mm and 1.24 mm in overbite and overjet, respectively.

These minor differences may be due in part to varying observa- tion periods and smaller sample sizes.

The smaller amounts of change reported by Marklund 17 maybe further influenced by her use of monoblock, non-adjustable appliances.


Importantly, the dental changes occurring from MAS use are not limited to decreases in OB and OJ, but rather include a number of parameters of the dentition (Table 2).

Mandibu- lar crowding decreases, just as mandibular intercanine and in- termolar width increase over the course of treatment.

We also found on average that an openbite developed on more than two lower posterior teeth.

These findings are in line with those pre- viously reported by other long-term studies.

16,18,22 The physiol- ogy of biologic tooth movement has been well characterized, 23 and it is understood that even very low applied forces, if applied for a sustained amount of time (such as for several hours dur- ing nighttime wear of an appliance) will result in tooth move- ment.

All MAS appliances position the mandible forward and retain it in place by contacting the dentition.

The force required to suspended the mandible and associated soft tissues thus is transmitted to the dental arches and likely results in the occlusal changes reported.

24 It should be understood then that the den- tal side effects of MAS treatment are a product of protruding the mandible to achieve a therapeutic effect rather than spe- cific appliance design.

25 This is likely why studies examining side effects comparing different appliance designs have found very little difference in terms of magnitude of these second- ary effects of dental movement.

12,13 Indeed, by extension into the orthodontic literature, one can see that attempts to provide more or less tooth-appliance contact or even rigidly splinting the mandibular teeth together with a cast metal framework does little to mitigate the dental movement.

26 All but one of the 77 patients examined experienced greater than 0.2 mm of occlusal change in terms of overjet and overbite, which speaks to the confidence at which one can expect to see dental movement with this type of therapy.


The development of posterior open bite and anterior teeth in crossbite were also common among the patients of this study.

A posterior openbite may occur as the lower arch, and in particu- lar the lower incisors are protruded forward as a result of pro- longed MAS treatment.

Commonly observed in the orthodontic treatment of retrognathic malocclusions with functional appli- ances, 27 this type of tooth movement causes an occlusal inter- ference as the patient is now unable to close the posterior teeth down together completely due to the premature contact of the anterior teeth.

Similarly, crossbites of anterior teeth will occur as the lower arch moves forward and the overjet and overbite are reduced to the point where the lower teeth protrude beyond the upper anterior teeth.


These two facets of occlusion have also been previously reported in the literature.

Vezina et al. re- ported both anterior and posterior openbite in a small propor- tion of patients who had been treated with MAS for an average of over 3.5 years, though no openbites were found in patients treated for 6 months or less.

12 Rose and colleagues, after a treat- ment period of at least two years in 34 patients, found a poste- rior openbite had developed in 26% of the patients studied.

25 Upon examining the time frame at which occlusal changes occur with MAS treatment, we found that the reduction in over- jet is progressive and continues at a constant rate so as long as the MAS treatment continues.


This is a logical finding con- sidering that the main mechanism of action with a MAS ap- pears to be the protrusion of the mandible and associated soft tissues, improving the caliber of the upper airway. 28 As long as this continues to occur, forces will also continue to be applied to the teeth resulting in tooth movement.

Overbite however was found to decrease less with time in our sample population.


This may be explained by the inseparable relationship of overjet and overbite.

As the mandible and lower arch are protruded forward, the overbite will decrease less and less until eventually there is no longer any further vertical overlap of the anterior teeth.

At this point the lower arch can continue to be protruded for- ward without any further interference from the upper anterior teeth.


Our results align with those of Marklund, who reported on the progression of occlusal changes in a subset of 51 patients treated for at least 5 years with a mono-block style of MAS.

17 Marklund found overall that dental side effects increased with treatment time as well as more frequent use of the device.

She also stated that overjet decreased continuously during the ob- served 5-year treatment period, whereas overbite changes di- minished with time in the sample population studied.


Conflicting results were previously reported by Pantin et al. in a retrospective survey of 106 patients recalled and examined following an average duration of MAS treatment of 31 ± 18 months.

19 They found that the proportion of patients with oc- clusal change increased with length of use of the mandibular advancement splint up to 2 years.

Beyond 2 years, the propor- tion remained relatively constant.

The authors further stated that this implies that a patient's period of greatest vulnerability to these complications is within the first 2 years of treatment.


This key difference with the present study may be partially ex- plained by differences in study design.

Unlike our longitudinal examination of patients, Pantin et al. performed a cross-sec- tional analysis, where patients were examined only once at a particular point in time.

Additionally very few (n = 27) of these patients were in MAS treatment longer than 48 months.


Pre-treatment BMI was found to be unrelated to any ob- served occlusal changes.

This may not be surprising consider- ing the extended observation period, throughout which patients may see their BMI vary widely, masking any direct relationship that may exist between these variables.


We found that the initial AHI was positively related to the magnitude of observed reduc- tion in overjet.

The influence of AHI on change in overjet may be explained by the fact that patients with more severe OSA 1290 Journal of Clinical Sleep Medicine, Vol. 10, No. 12, 2014 BT Pliska, H Nam, H Chen et al. could be more likely to have their mandibles advanced a greater amount to see a relief in symptoms compared to patients with a milder degree of the disease.

29 It has been previously shown that the relationship between the force applied to the arches and amount of mandibular advancement is almost linear, with the force increasing with increasing mandibular advancement.

24 In Mandibular advancement splints are an effective, noninva- sive treatment option for snoring and obstructive sleep apnea.


The present findings make it clear that many of the significant dental changes that occur will continue to progress over the duration of treatment, and as MAS treatment of OSA will con- tinue indefinitely, the prudent clinician will be aware of these changes and discuss them openly with patients in their care.


It was with interest that we reviewed the December 15, 2014, Journal of Clinical Sleep Medicine article by Pliska et al. entitled “Obstructive Sleep Apnea and Mandibular Advancement Splints: Occlusal Effects and Progression of Changes Associated with a Decade of Treatment.” [ 1] As noted in the accompanying commentary, mandibular advancement devices (MAD) are now utilized as one first-line option for mild to moderate obstructive sleep apnea (OSAS) and may be used in specific cases for severe OSAS [2].

Consideration of potential long-term consequences of MADs assumes greater importance, and the authors have thus done a service via this addition to the sleep medicine literature.


In a more limited setting, we have also been aware of these occlusal changes.

We would like to offer an alternative, but perhaps not mutually exclusive, explanation for the progressive declines in incisor overjet and overbite with resulting posterior open bites.

We hypothesize that it may not be the teeth moving with time but rather a persistent posturing forward of the mandible.

It is recognized that mornings after wearing an MAD that patients may have a difficult time posturing the mandible back to the normal occlusion.

If not addressed by the patient or dental sleep specialist, this could eventuate in an irreversible anterior mandibular position with altered occlusion.


One limitation to the Pliska study is an absence of occlusal bite records, and accordingly no documentation of the condyle position in the glenoid fossae.

If the dental casts were hand articulated during measurements, it could be difficult to ascertain whether teeth moved or if the mandible postured forward to a stable but inappropriate position.

Furthermore, we would argue that an MAD itself (particularly a fixed device) should act to stabilize teeth position and thus reduce the likelihood of movement over time.


Regardless of the etiology, this paper brings to the forefront the necessity for careful and continued long-term management plans in patients using MADs.

In fact, the first author of this letter (an oral maxillofacial surgeon with over a quarter century of experience in dental sleep medicine) has further strengthened his protocol for follow-up care as a consequence of Pliska and co-authors’ study.

Finally, as the accompanying Journal of Clinical Sleep Medicine commentary stated, this is an area fertile for investigation [2].

Computer imaging for dental and facial skeleton treatment planning is now available.

Techniques such as this offer the prospect for further research studies, as well as improved documentation and follow-up in patient care.


We thank Dr. Ford and colleagues [1] for their interest and commentary regarding our article [2] detailing the occlusal changes associated with long-term use of mandibular advancement splints (MAS).

We also are thankful for the opportunity to clarify what is a common misconception regarding these associated dental changes.


As described in their letter, it is a usual clinical finding for patients to feel some muscle fatigue and difficulty fully occluding their teeth in the morning following a night of MAS use.

This is especially true if patients are new to this form of therapy, and this feeling fades within a few hours.

However, we do believe that the changes we reported are in fact due to the teeth moving orthodontically within the bone, and this position is well supported by the available literature.


While it is true that the dental casts in our study were not mounted into centric relation on an articulator, they were all orthodontically trimmed to a wax bite taken in centric occlusion.

Previously, Marklund has reported no significant changes between centric relation and centric occlusion with MAS use [3].

Regardless, the appropriate method to distinguish dental movement from “an irreversible anterior mandibular position” is with radiographic imaging.

Such studies employing cephalometric analysis of MAS treatment consistently demonstrate the forward movement and proclination of the mandibular dentition, while the maxillary teeth are tipped posteriorly [4][5][6][7].

Pointedly however, similar changes in the forward position of the mandible are not observed.

Robertson described the occlusal changes of 100 patients (age 49 ± 8.5 years) over a period of up to 30 months, stating that occlusal changes can be attributed to appliance-induced dental changes and not forward mandibular repositioning [6].

Rose in an examination of 34 patients (age 52.9 ± 9.6 years) after an average of 30 months of MAS treatment found significant alterations in the occlusion, but no skeletal changes in the position of the mandible were noted [5].

Similarly, Hammond noted no change in mandibular position in 64 adult patients who had been using MAS on average for 25 months, stating neither an orthopedic effect nor a functional adaptation from prolonged MAS use was observed [7].


Our research team is currently finalizing work on a study investigating the cephalometric changes associated with long-term (+10 years) MAS use of a similar population, the results of which will be forthcoming.

We believe that such an examination will help to confirm the conclusions drawn from these previously published shorter-term studies.


As MAS use becomes increasingly popular with an ever-wider range of OSAS patients, the treating clinician should be well aware of the expected occlusal changes which are irreversible in the absence of corrective orthodontic treatment.

However, we believe that for the vast majority of patients, the health benefits and improved quality of life afforded by MAS treatment of their OSAS far outweigh the inconvenience of these noted dental changes.


One of the most important endeavours inspiring neurosci- entists has been the characterization of the functional neuroanatomy of the human brain.

In this mission, the advent of neuroimaging proved paramount for supporting the exploration of brain-behaviour relationships, which for the past 20 years has been providing powerful insights con- cerning the anatomical bases of normal and pathological cognition.

As a result of this effort, the study of brain-func- tion relationships has experienced profound transform- ations.

Conceptually, the adoption of a connectional (hodological) systems perspective has derived a formulation of cognition subserved by hierarchically organized inter- active brain networks (Bassett et al., 2018).

Methodologically, the development of novel computational approaches has begun the characterization of complex interaction patterns subtended by structural and functional brain networks and addressed their roles in cognition and behaviour.

Additionally, this novel perspective has insti- gated the compilation of brain maps, integrating informa- tion on interactive properties operating dynamically across complex hierarchical neural systems.


Anticipating this transformation, pioneering work pub- lished 20 years ago in Brain (Godefroy et al., 1998) con- ceptualized the regularities characterizing different classes of elementary associations between brain structures and their ability to substantiate specific human behaviours (or the lack thereof) as 'brain modes'.


In the original paper, brain modes were defined as pre- established sets of functional interactions between cerebral regions contributing to the emergence of a neurological symptom.

These entities were conceived as the means to unveil the brain's functional organization.

Each mode was considered with regards to specific cognitive processes or behaviours.

Anticipating the importance of a connectional perspective, this notion and the framework it generated must now be considered among the first attempts to con- ceptualize neurological symptoms as emerging from inter- actions between multiple anatomical structures organized in networks (Geschwind, 1965; Catani and Ffytche, 2005; Bartolomeo, 2011), as opposed to models emphasizing in- dividual regional contributions.


Originally, four classes of brain modes: unicity, equiva- lence, association and summation, were intended to cap- ture the full array of potential brain-behaviour relationships (Fig. 1 and Table 1).

The unicity mode defined the simplest brain-function association in which a single function was linked to a single injured brain struc- ture.

The equivalence mode, the most frequently observed in clinical practice, epitomized a situation in which damage to two separate structures provoked in both cases a similar behavioural deficit.

The association mode described the scenario involving two brain regions in which both had to be damaged in order to generate a neurological deficit.

Finally, the summation mode charac- terized an interaction type in which lesions in two or more brain regions resulted in specific behavioural or clinical deficits; nonetheless, when these same structures were all simultaneously damaged, deficits proved greater than the sum of the individual lesion effects.


The originally described brain modes can be illustrated by examples of neurological and neuropsychological observa- tions in humans, yet some exceptions and limitations apply.


The simplest brain mode, unicity, could depict the func- tional contributions of isolated nodes, which are hardly present in the highly and intricately connected mammalian nervous systems.

Thus, this mode has been theoretically hypothesized but remains to be documented clinically.

The equivalence brain mode has been documented theoret- ically and also clinically.

Indeed, in the original paper describing brain modes, single lesions localized at two dif- ferent levels along the cortico-spinal tract were character- ized as equally responsible for motor weakness (Godefroy et al., 1998; see also Arnoux et al., 2018).

Likewise, other associations compatible with this brain mode have been documented as subtending symptoms such as aphasia, memory loss, executive and attentional deficits (Alexander et al., 1987; Mesulam, 1990; Kremin, 1994; Kreisler et al., 2000; Godefroy et al., 2009; Martinaud et al., 2009; Toba et al., 2018a, b).

For instance, verbal paraphasias have been linked to either temporal or caudate lesions, whereas non-fluent aphasia depends on the presence of frontal or putamen lesions (Kreisler et al., 2000).


The association brain mode has been identified theoretically but remains to be better documented clinically, as it requires rare-to- find patients with selective lesions damaging multiple re- gions within the same network.

This mode was originally illustrated in patients with unilateral lenticulostriate lesions (Godefroy et al., 1992) showing executive function impair- ment only when, additionally, they suffered an associated cortical infarct.

It has also been documented in cases of Balint syndrome, reduplicative paramnesia, confabulations and global aphasia (Shallice, 1988; Wolfe et al., 1994; 'Brain modes' revisited BRAIN 2020: 143; 1088-1098 | 1089 Downloaded from https://academic.oup.com/brain/article/143/4/1088/5640486 by Institut Armand-Frappier user on 16 May 2024 Caplan, 1995).

For example, Wolfe et al. ( 1994) explored a patient with bilateral subcortical lacunae in the basal gang- lia and periventricular white matter, who presented a crit- ical level of dysexecutive syndrome after the occurrence of posterior cortical lesions.


Finally, the summation mode has been documented both theoretically and clinically.

For ex- ample, in language impairments, non-fluent aphasia was associated with lesions of putamen and surrounding struc- tures while mutism was associated with large lesion of the three frontal gyri and putamen (Kreisler et al., 2000; Seghier et al., 2014).


Importantly, confirming the accuracy of naturally occur- ring lesions to illustrate specific brain modes requires de- tailed documentation concerning the role of lesion-spared regions, which has not always been available in neuro- logical clinical records, as it requires the detailed whole- brain characterization of structurally and functionally sound versus impaired areas.


As with any pioneering work, the first conceptualization of brain modes suffered from a number of limitations, in part caused by shortcomings in the statistical and computational approaches available at the time they were first character- ized.

Importantly, many of these limitations can now be overcome with the use of more current methodological approaches.


First, original lesion analyses were conducted only on regions of interest corresponding to anatomical structures, or to regions demarcated by brain landmarks such as sulci or gyri, as attempts to decrease region of interest size led to poor interexaminer agreement (Godefroy et al., 1998).

In contrast, recent lesion analyses can now be conducted at the voxel level, hence delineated at a much higher spatial resolution, allowing a more precise characterization of brain modes.


Second, the past use of structural instead of functional parcellation schemes re- sulted in regions with mixed functions, providing less in- formative evidence concerning the behavioural contributions of the analysed regions of interest.

This risk can be limited by using parcellation schemes based on both structural and functional MRI (see Glasser et al., 2016 for an example), further verified with perturbational approaches such as transcranial magnetic stimulation (TMS) (Toba et al., 2017).


Third, the original characteriza- tion of brain modes could not distinguish between grey and white matter, a limitation that is especially meaningful for the equivalence brain mode associated with white matter disconnections.

Importantly, however, the advent of diffu- sion tensor imaging (DTI) and the adoption of hodological approaches to address brain-behavioural relationships (Boes et al., 2015; Fox, 2018) has provided new insights to overcome this original limitation.


Fourth, lesion Table 1 'Brain modes' (Godefroy et al., 1998) and their equivalents in a multivariate approach (game-theory MSA).

Downloaded from https://academic.oup.com/brain/article/143/4/1088/5640486 by Institut Armand-Frappier user on 16 May 2024 characterization approaches used in the late 1990s were unable to grade the magnitude of the neural damage, hence ignoring the crucial role of lesion volume threshold effects on neurological deficits.

As such information be- comes available for other anatomical grey and white matter systems, this important aspect will be better con- trolled (see Arnoux et al., 2018 for an example of the threshold level of cortico-spinal tract injury generating sig- nificantly enduring motor deficits at 6 months).


Fifth, multi- variate analyses proposed in the original characterization of brain modes were based on one particular type of statistical approach, the so-called Classification and Regression Tree (CART) (Breiman et al., 1984).

This method was able to disentangle important factors in terms of explanatory power in a model, and provided naturally the type of lo- gical relationships between selected regions.

However, the CART approach requires large datasets and additional stat- istical analyses to assess the strength of brain-behavioural associations.

The latter limitations can now be overcome by current multivariate methods for lesion-deficit mapping providing more appropriate and reliable analysis tools (see below).


At the time they were first described, brain modes repre- sented a major conceptual advance in the field, aiming to represent any known lesion effects by their four original types.

Nonetheless, multivariate CART approaches origin- ally used for their characterization failed to identify 'para- doxical lesion cancellation' effects, initially reported in feline models (Sprague, 1966; Payne et al., 1996; Hilgetag et al., 2002) and later extended to human neurological pa- tients (Kinsbourne, 1977, 1987; Vuilleumier et al., 1996; Weddell, 2004; Johnson et al., 2008; Jha and Brown, 2011), known as the 'Sprague Effect' (Box 1).


This phenomenon described the paradoxical improve- ment of performance deficits caused by a circumscribed lesion thanks to a reversible or permanent suppression of activity in a second brain area interacting with the former (for reviews see Payne and Rushmore, 2004; Valero-Cabré et al., 2019).

Inspired by predictions of interhemispheric rivalry in spatial attention in the feline visual system, this brain mode was also characterized in humans using causal reversible perturbation by TMS (Hilgetag et al., 2001).

Intending to transiently impair lateralized visual detection performance in one visual hemifield with inhibitory repeti- tive TMS on the contralateral intraparietal sulcus, these authors found paradoxical improvements for ipsilateral visual targets.

This unexpected result revealed that a revers- ible focal suppression of human brain activity could pro- duce attentional and perceptual gains.

Further studies in animals reported paradoxical cancellation of lesion-induced


Experimental animal studies in the 1960s were the first to illustrate that interactions between brain regions were unpredictable.

In an effort to understand the independent and joint contributions of the visual cortex and the midbrain superior colliculus to visual behav- iour, James Sprague subjected either region to lesions, and then sequentially combined the lesions.

A surprising result emerged when the longstanding and seemingly intractable deficit in the de- tection and orienting to right-sided visual targets produced by lesion of left visual cortex was cancelled by ablation of the right superior colliculus (Sprague, 1966).

This result was subsequently referred to as the Sprague effect, and was conceived by Sprague and others to be a product of manipulating mutually inhibitory bilateral interactions between brain structures (Sprague, 1966; Lomber and Payne, 1996; Hilgetag et al., 1999; Lomber et al., 2002; Rushmore et al., 2006; Valero-Cabré et al., 2019).


This experimental work was used in part to formulate mechanistic understanding of visuospatial neglect (Kinsbourne, 1974, 1977, 1987, 1993).

Later findings in neurologically intact human participants (Hilgetag et al., 2001) and in human clinical cases (Vuilleumier et al., 1996; Weddell, 2004) provided considerable evidence that the mechanisms underlying the Sprague effect contributed to analogous interactions in humans.

Kinsbourne's ideas and the aforementioned clinical cases exerted major influences in understanding the brain- wide impact of unilateral brain damage in humans, wherein damage was presumed to reduce activity in connected brain regions in the ipsilateral hemisphere and increase activity in the contralateral hemi- sphere through disruption of inhibitory circuits (Murase et al., 2004; Nowak et al., 2009).

Until now, the best evidence of the Sprague effect has been observed at the interhemispheric level.


This approach guided the later use and interpretation of non-in- vasive brain stimulation studies, in which focal inhibitory stimula- tion [including low frequency TMS, continuous theta burst TMS, or cathodal transcranial direct current stimulation (tDCS)] aims to transiently take offline focal cortical regions while recording behavioural performance (Valero-Cabré et al., 2017).

This ap- proach has been successfully applied to the intact brain hemi- sphere in patients with unilateral brain damage (Oliveri et al., 1999; Brighina et al., 2003; Koch et al., 2008; Sparing et al., 2009; Koch et al., 2012; Cazzoli et al., 2012) and proved to re- store neurological deficits caused by focal brain lesions, such as hemispatial neglect.

All these studies demonstrate that the mutual inhibition/masking summation brain mode has already opened new avenues for therapeutic uses of non-invasive brain stimulation technologies.

However, this new brain mode has also opened perspectives of improving visuospatial orienting abilities in healthy humans (Hilgetag et al., 2001).


Looking to the future, we should envision that reversible neuromodulation technologies [TMS, repetitive TMS or tDCS/tACS), which are currently helping to investigate the cognitive role of cortical regions embedded in brain networks, could also be used to probe or unearth existing and novel brain modes.

Moreover, the use of these same tech- nologies for the modulation of specific site or sites implementing a given brain mode may prove useful to develop novel strategies for the restitution of neurological function.

deficits with secondary focal lesions, direct cortical cooling or non-invasive TMS deactivations of spared cortical and subcortical attentional orienting systems (Rushmore et al., 2006; reviewed in Valero-Cabré et al., 2019).

We here propose to name this additional brain mode 'mutual inhibition' or alternatively 'masking summation' and add it to the palette of existing typologies.


Since their inception, brain modes were conceived of as elementary building blocks that, adequately combined in complex fashions, could account for any specific neuro- logical deficits.

Here we revisit brain modes from the per- spectives of logic and propositional calculus as well as graph theory approaches and the concept of circuit 'motifs'.

We suggest that analogies between brain modes and elementary units used especially in the graph theory framework are particularly suited for analysing and extend- ing the existing typologies, and further exploring their im- plications for cognitive neuroanatomy.


From the perspective of logic, some of the brain modes can be characterized as standard forms of logical relation- ships between unary and binary factors, and represented with a standard truth table.

For example, with respect to a brain function, 'unicity' can be associated with identity; 'equivalence' may be equated to conjunction (AND); 'asso- ciation' could be associated to disjunction (OR); and 'mutual inhibition/masking summation' corresponds to the opposite of an exclusive disjunction (NOT XOR or XNOR).

The 'summation' brain mode may not be fully captured by binary logical operators as its outcome de- pends on the graded interactions between the nodes.

Of note, other authors have proposed weighted extensions of logical functions that can express partial conjunctions and disjunctions (Dujmović and Larsen, 2007) and which could be used to describe such relations in the context of the summation mode.

Generally, in order to characterize the graded effects of brain modes, one might also use arith- metic (rather than logical) operations, which can be ex- tended and turned into actual circuit models capturing the observed effects (cf.

Zavaglia and Hilgetag, 2016).


In the graph theory framework, brain modes can be based on different 'brain motifs' (Fig. 2).

These represent plausible types of interregional relationships with the ability to influence a given brain function.

In this regard, the uni- city mode would be the equivalent of a node (i.e. brain region) defined as the only contributor to a brain function.

Damage of a unique contributor generates a level of behav- ioural deficit that depends on the magnitude of the im- paired contribution and the extent of the lesion.

Hence, the unicity mode could be well suited to describe brain- behaviour interactions in which function emerges from single nodes.


The equivalence mode is observed when be- havioural performance in a given task benefits from mul- tiple contributions by different nodes, which contribute similarly to a behaviour.

The association mode represents the case of joint contributions of two (or several) nodes to a given behaviour, in which a critical level of clinical deficit manifests only when both nodes are injured.

The summa- tion mode is observed when two conditions apply to a given set of nodes: (i) each node provides a specific contri- bution to a given behaviour; and (ii) their contributions are both redundant (overlapping) and synergistic (complemen- tary).

Last, in the masking summation mode, two nodes interacting with each other contribute to a brain function.

Clinical deficits appear present only when one of the two nodes is lesioned; however, symptoms can paradoxically wear off when the two nodes are jointly damaged, by the fact that they are linked by rivalrous mutually inhibitory interactions.


Taken together, the equivalence, association, summation and/masking summation modes characterize a hodological framework in which behaviours (or the lack thereof during neurological diseases) emerge from nodes organized in networks.

Such interactions can be summar- ized in a simple two-node circuit model (Fig. 2) that for- malizes arithmetically the strength of functional interactions and contributions of the nodes.


Importantly, the number and complexity of brain motifs, and the elementary types of brain modes they implement, depends on the number of regions involved.

As the number of nodes increases, the complexity of directed network motifs and their contribu- tion patterns escalates (Fig. 2).