Developmental Stuttering Suppl Motor Cortex Busan2020

Journal of Fluency Disorders 64 (2020) 105763
Contents lists available at ScienceDirect
Journal of Fluency Disorders

journal homepage: www.elsevier.com/locate/jfludis
Developmental stuttering and the role of the supplementary motor

T
cortex
Pierpaolo Busan*
IRCCS Ospedale San Camillo, Venice, Italy
A R T IC LE I N F O ABS TRA CT
Keywords: Developmental stuttering is a frequent neurodevelopmental disorder with a complex neurobio-

Developmental stuttering logical basis. Robust neural markers of stuttering include imbalanced activity of speech and
Supplementary motor Area motor related brain regions, and their impaired structural connectivity. The dynamic interaction
Neural networks of cortical regions is regulated by the cortico-basal ganglia-thalamo-cortical system with the
Motor system
supplementary motor area constituting a crucial cortical site. The SMA integrates information
Basal ganglia
from different neural circuits, and manages information about motor programs such as self-in-
itiated movements, motor sequences, and motor learning. Abnormal functioning of SMA is in-
creasingly reported in stuttering, and has been recently indicated as an additional “neural marker”
of DS: anatomical and functional data have documented abnormal structure and activity of the
SMA, especially in motor and speech networks. Its connectivity is often impaired, especially
when considering networks of the left hemisphere. Compatibly, recent data suggest that, in DS,
SMA is part of a poorly synchronized neural network, thus resulting in a likely substrate for the
appearance of DS symptoms. However, as evident when considering neural models of stuttering,
the role of SMA has not been fully clarified. Herein, the available evidence is reviewed, which
highlights the role of the SMA in DS as a neural “hub”, receiving and conveying altered in-
formation, thus “gating” the release of correct or abnormal motor plans.
Introduction
Developmental stuttering (DS) is a neurodevelopmental disorder that appears in childhood (approximately 5% of the pediatric
population). It is characterized by the presence of blocks and repetitions, especially in the first part of words and sentences, leading to
speech dysfluency. In addition, associated movements may be evident, especially of the oro-facial districts, which are not strictly
related to the intended speech motor program. The majority of children with DS recover normal speech fluency in an unassisted way,
but stuttering may persist in adulthood (present in about 1% of the general population) thus affecting the quality of life. DS is a
multifactorial disorder, wherein factors such as genetic and neural abnormalities are important in appearance and maintenance of the
disturbance (e.g. Barnes et al., 2016; Drayna & Kang, 2011; Alm, 2004; Craig-McQuaide, Akram, Zrinzo, & Tripoliti, 2014; Etchell,
Civier, Ballard, & Sowman, 2018). In this context, Benito-Aragon et al. (2020) recently sustained the hypothesis that DS may be due
to lysosomal dysfunction, thus resulting in impaired organization of speech neuronal circuits.
Abbreviations: DS, developmental stuttering; DIVA, Directions Into Velocities of Articulators; EEG, Electroencephalography; FAT, Frontal Aslant
Tract; GODIVA, Gradient Order Directions Into Velocities of Articulators; MEG, Magnetoencephalography; SMA, Supplementary Motor Area; TMS,
Transcranial Magnetic Stimulation
⁎
Corresponding author at: IRCCS Ospedale San Camillo s.r.l., Via Alberoni, 70, 30126 Venice (Lido), Italy.
E-mail address: pbusan@units.it.
https://doi.org/10.1016/j.jfludis.2020.105763
Received 5 June 2018; Received in revised form 5 April 2020; Accepted 8 April 2020
Available online 20 April 2020
0094-730X/ © 2020 Elsevier Inc. All rights reserved.
P. Busan Journal of Fluency Disorders 64 (2020) 105763
The defective neural substrates of DS
Previous research has identified, by means of neuroimaging, a series of “neural markers” that may be evident in persons who
stutter (reviewed in Etchell et al., 2018). These markers have a role in motor planning, motor preparation and execution, and lead to
hypo-activation of speech and motor structures of the left hemisphere (Chang, Kenney, Loucks, & Ludlow, 2009; compare with Neef,
Anwander, & Friederici, 2015). At the same time, hyper-activation of homologue regions of the right hemisphere is observed,
especially during speech and motor tasks (Brown, Ingham, Ingham, Laird, & Fox, 2005; Budde, Barron, & Fox, 2014; Neef, Anwander
et al., 2015). However, abnormal neural patterns have been reported in DS during very different tasks, ranging from speech to non-
speech motor tasks, as well as in resting conditions. As a consequence, hyper- or hypo-activation of specific neural regions may be
related to specific tasks (also considering the different state dependence of the brain). More specifically, abnormal neural networks
involve regions such as the left inferior frontal cortex, premotor associative regions, temporal cortex, and primary sensorimotor areas
(Etchell et al., 2018). In addition to this functional evidence, DS has been strongly related to the presence of abnormal structure of
both gray and white matter, and thus in connectivity patterns responsible for neural communication in these regions. For example,
children who stutter (persistent and recovered) may result in a lower amount of gray matter in various fronto-temporal regions, as
well as in the SMA and in deeper cortical regions such as the anterior cingulate cortex (Chang, Erickson, Ambrose, Hasegawa-
Johnson, & Ludlow, 2008). The brain of persons who stutter also has impaired fiber connections among regions such as the left
inferior frontal cortex, premotor associative areas, and primary sensorimotor cortex (Sommer, Koch, Paulus, Weiller, & Büchel, 2002;
Watkins, Smith, Davis, & Howell, 2008). Impaired connections are also evident in structures such as the corpus callosum, cortico-
spinal and cortico-bulbar pathways, and long-range white matter systems connecting frontal and posterior regions of the brain, thus
influencing sensorimotor integration and speech implementation (Chang & Zhu, 2013; Chang et al., 2008; Chang, Horwitz, Ostuni,
Reynolds, & Ludlow, 2011; Chang, Zhu, Choo, & Angstadt, 2015; Chang et al., 2018; Chow & Chang, 2017; Civier, Kronfeld-Duenias,
Amir, Ezrati-Vinacour, & Ben-Shachar, 2015; Connally, Ward, Howell, & Watkins, 2014; Cykowski, Fox, Ingham, Ingham, & Robin,
2010; Kell, Neumann, Behrens, von Gudenberg, & Giraud, 2018; Lu et al., 2009, Lu, Chen et al., 2010; Lu, Peng et al., 2010; Sommer
et al., 2002; Watkins et al., 2008). Functionally, DS is characterized by abnormal cortico-spinal and cortico-bulbar outputs during
speech and non-speech movements, as well as during rest (reviewed in Busan, Battaglini, & Sommer, 2017). More specifically,
indexes of intra-cortical functioning and modulation of the primary motor cortex are abnormally regulated in stuttering (Busan et al.,
2009, 2016; Neef, Paulus, Neef, von Gudenberg, & Sommer, 2011), and correlated to stuttering severity (Busan et al., 2013; Neef,
Hoang, Neef, Paulus, & Sommer, 2015). In fact, positive and negative correlations between abnormal brain structure (and function)
and indexes of stuttering severity are often reported (Giraud et al., 2008).
Overall, this evidence suggests that the influence of neural information that reaches the primary motor cortex from the associative
motor one (such as the supplementary motor area, SMA) may play an important role in the modulation of the final motor output in DS
(Neef, Jung et al., 2011). In fact, stuttering is also related to defective functioning of the cortico-basal-thalamo-cortical system, in
which basal ganglia and SMA are fundamental “hubs” (reviewed in Alm, 2004; Chang & Guenther, 2020; Craig-McQuaide et al., 2014;
Etchell et al., 2018). More specifically, it has been suggested that stuttering is related to the presence of a hyper-dopaminergic state,
in conjunction with abnormal basal ganglia functioning (Wu et al., 1997). This abnormal neural functioning may affect correct firing
of the connected networks, especially when considering cortical regions that are related with basal ganglia output, such as the SMA.
The basal ganglia system is composed of closed loops circuits. Structures such as the caudate and the putamen constitute the principal
basal ganglia input regions, mainly receiving from the cortex. On the other hand, the substantia nigra and the globus pallidus con-
stitute the main output structures, propagating neural signals back to cortical sites via thalamic pathways. This system should be
useful to favor intended motor acts, and inhibit competing ones (Mink, 1996). The SMA is likewise integrated in these cortico-basal-
thalamo-cortical loops. Interestingly, even if preliminary studies reported inconsistent patterns (Ingham, 2001), abnormal structure
and function of the SMA has often been reported in studies on stuttering (Braun et al., 1997; Fox et al., 1996, 2000; Ingham, Fox,
Ingham, & Zamarripa, 2000; Ingham, Grafton, Bothe, & Ingham, 2012). In fact, abnormal activity of the SMA has only recently been
recognized as a further and possible “neural marker” of DS (Neef, Anwander et al., 2015). This is quite surprising considering that the
SMA is part of a system that is fundamental to gain correct preparation and implementation of motor acts, and also considering that
this region seems to have a very important role (at least from a functional point of view) in the physiopathology of other basal
ganglia-related motor disorders such as Parkinson’s Disease (Hamada, Ugawa, Tsuji, & Effectiveness of rTMS on Parkinson's Disease
Study Group, Japan; Koch et al., 2005; Shirota et al., 2013). Accordingly, the available data on SMA dysfunction in DS are reviewed
herein: this cortical region may be one of the “pivotal hubs” of the dysfunctional neural networks of stuttering, receiving and con-
veying altered neural information, and “gating” the release of correct or abnormal motor plans.
Anatomical and functional subdivisions of SMA
SMA is a fundamental part of the cortico-basal-thalamo-cortical system (Alm, 2004, for a review in relation to DS). The SMA
integrates various neural signals from different brain networks, but has preferable (functional) connections with basal ganglia,
managing information about the motor programs to be executed (e.g. favoring them with respect to concurrent movements, see basal
ganglia “direct” and “indirect” pathways). SMA has also a role in self-initiated (voluntary) motor programs, implementation and
(mental) preparation of complex motor sequences, practice and learning of motor skills, and release of motor plans (or triggering of
planned actions) such as speech (Nachev, Kennard, & Husain, 2008; Picard & Strick, 1996; Seitz, 2003; Shibasaki et al., 1993; Tanji,
1994; but see also Bohland, Bullock, & Guenther, 2010; Grafton, 1994; Ruan et al., 2018; Seitz, Nickel, & Azari, 2006; Zilles et al.,
1995).
2
It is known that the SMA is mainly composed of a proper-SMA, posteriorly, a region mainly connected with motor structures, and
a pre-SMA, anteriorly, a region preferably connected with pre-frontal brain regions which transmits information about the cognitive
aspects of motor programs (Johansen-Berg et al., 2004; Picard & Strick, 1996; see also Klein et al., 2007; Nachev et al., 2008; Ruan
et al., 2018). More specifically, Ruan et al. (2018) showed that the SMA and pre-SMA are reciprocally (functionally) connected to
basal ganglia and the cerebellum. However, while the proper-SMA is mainly (functionally) connected to sensorimotor primary and
associative regions, the pre-SMA is (functionally) more connected to “higher-order” regions such as the frontal and temporo-parietal
cortex. This anatomical and functional subdivision (i.e. proper-SMA vs. pre-SMA) is useful to manage different aspects of motor
behavior such as planning and execution, inhibition (e.g. competing motor acts), skill learning and recall (e.g. definition of movement
patterns and sequences, procedural learning), and sensorimotor integration for action generation, thus allowing neural interchange
between cognitive and complex motor information, such as regulating attention to one’s own actions or self-referencing of move-
ments (compare with Ikeda et al., 1999; Rochas et al., 2013; Ruan et al., 2018; Seitz et al., 2006). In any case, modularity is far from
being clearly discrete in these networks (Nachev et al., 2008; Picard & Strick, 1996). As a consequence, the different aspects of the
motor program (e.g. the correct sequencing of the motor acts, and thus motor automaticity and the correct management of motor
timing; e.g. Narayana et al., 2012) are better managed by the intervention of a SMA “complex” (i.e. proper-SMA and pre-SMA). The
SMA “complex” may be viewed as part of an “internal timing network” (mainly composed of cortico-striato-thalamo-cortical neural
networks), which is involved in the planning and execution of voluntary (i.e. internally generated) motor programs. The “internal
timing network” is usually opposed to an “external timing network” (mainly composed of structures such as the cerebellum and lateral
premotor cortex) that mainly relies on external cues to manage motor acts (compare with Alm, 2004; see also Etchell, Johnson, &
Sowman, 2014 for a perspective on stuttering). Thus, the SMA “complex” may also have a fundamental role in the correct im-
plementation of motor speech programs (Alario, Chainay, Lehericy, & Cohen, 2006; Picard & Strick, 1996; Seitz et al., 2006): for
example, the SMA exchanges information with structures such as the cingulate cortex (Ball et al., 1999; Seitz et al., 2006; Wang,
Ulbert, Schomer, Marinkovic, & Halgren, 2005; see also Craig-McQuaide et al., 2014, for a perspective in DS), especially when word
generation is “internal” or “voluntary-driven” (Crosson et al., 2001).
The role of SMA in DS
The abnormal structure, activity, or connectivity of the SMA “complex” has been increasingly implicated in the literature on
stuttering (Belyk, Kraft, & Brown, 2015; Brown et al., 2005; Budde et al., 2014; Neef, Anwander et al., 2015; see also Belyk, Kraft, &
Brown, 2017). Compatibly, artificial stimulation or injuries of the SMA “complex” may result in induced (i.e. neurogenic) stuttering or
speech dysfluencies (Abe, Yokoyama, & Yorifuji, 1993; Abe, Yokoyama, & Yorifji, 1992; Ackermann, Hertrich, Ziegler, Bitzer, & Bien,
1996; Alexander, Naeser, & Palumbo, 1987; Dinoto et al., 2018; Van Borsel, Van Lierde, Van Cauwenberge, Guldemont, & Van
Orshoven, 1998; see also Ackermann & Riecker, 2011; Penfield & Welch, 1951). However, it is not easy to clearly distinguish between
dysfunctions of the proper-SMA and pre-SMA. Similarly, associations between the abnormal structure (and abnormal activity) of the
SMA “complex” and the appearance (and characteristics) of stuttering symptoms need to be better defined. In this context, SMA
abnormalities seem to have a counterpart in both stuttering “trait” and “state”, i.e. have been observed during dysfluencies and when
DS symptoms are not evident (Budde et al., 2014; Connally et al., 2018). Thus, in the following paragraphs, the role of the SMA in DS
will be analyzed by describing the structural and functional abnormalities of this region in different conditions, ranging from the
resting state to motor and speech tasks in adults and children (data referring to children who stutter will be indicated; compare with
Table 1). Characteristics of neural pathways related to the SMA “complex” and their functional connectivity will also be considered.
Finally, recent evidence from the author’s research group (showing that the SMA may be part of a network resulting in a “delayed”
neural activation in DS; Busan et al., 2019) will also be considered with respect to neural models of stuttering. Thus, the possible role
of the SMA “complex” in stuttering persistence and recovery will be highlighted. The last sections will be useful to consider open
questions and future perspectives in research on DS.
Anatomical differences in the SMA “complex” of DS
The brain of persons who stutter is characterized by structural differences compared to fluent speakers. These differences may also
involve the SMA “complex”: this is evident at the level of both gray matter and connection pathways.
Abnormalities of gross morphology in the SMA of DS

Stuttering is characterized by abnormal gray matter volumes in brain areas such as the bilateral inferior frontal regions, temporal
cortex, and SMA (reviewed in Etchell et al., 2018; see Chang, 2014 for specific updates in children who stutter). In this context, a very
recent study by Garnett et al. (2018) suggests that children who persist in stuttering are characterized by reduced cortical thickness in
regions such as the left primary motor cortex and premotor regions (compared to fluent and recovered children). However, this
difference is not equally evident in the SMA: in fact, an age-related decrease was evident in the left SMA “complex” (SMA and pre-
SMA), but only in children who recovered from stuttering when evaluating indexes of local gyrification. A similar finding has been
recently reported by Koenraads et al. (2019): these authors showed that children with a history of stuttering (recovered or persisting)
had smaller gray matter volumes in the left inferior frontal gyrus and SMA. This could suggest that the SMA may have an important
role in stuttering persistence as well as in recovery processes. More specifically, persistency may be related to involvement of the SMA
“complex”, as it may be part of a defective motor and speech network. On the other hand, recovered children may be able to
“overcome” impaired networks, thus “by-passing” blocks and dysfluencies. As a consequence, they may learn to better (and earlier)
3
Table 1
Studies reporting abnormalities of the SMA “complex” in stuttering reviewed herein. Studies are grouped by considering their fundamental char-
acteristics (i.e. adults vs. children, structural vs. functional findings, “local” vs. “network” findings, motor and speech tasks vs. resting state). Reviews
and meta-analyses have been not included in the Table (e.g. Ackermann & Riecker, 2011; Belyk et al., 2015, 2017; Brown et al., 2005; Budde et al.,
2014; Chang, 2014; Chang et al., 2019; Etchell et al., 2014, 2018; Garnett, Chow, & Chang, 2019; Neef, Anwander et al., 2015). TMS, EEG (other
than Busan et al., 2019), tDCS, and MEG data have been not included in the Table for methodological reasons.
Stuttering group/ Structural Structural Functional Functional Resting state Data obtained from
SMA abnormalities abnormalities in abnormalities of abnormalities of the abnormalities of SMA abnormalities in the injures and
in DS the SMA “complex” SMA connections SMA “complex” during connectivity during SMA “complex” and stimulation during
motor-speech tasks motor-speech tasks its connectivity neurosurgery
Adults who stutter _ Cai et al., 2014; Blomgren et al., 2003 Chang et al., 2011 Ingham et al., 2012 Abe et al., 1992
Kronfeld-Duenias Braun et al., 1997 Lu et al., 2009 Desai et al., 2017 Abe et al., 1993
et al., 2016 Busan et al., 2019a Lu, Peng et al., 2010 Lu et al., 2012 Ackermann et al.,
Neef et al., 2018 Chang et al., 2009 Busan et al., 2019a Lu et al., 2016 1996
De Nil et al., 2000 Kell et al., 2018 Qiao et al., 2017 Alexander et al.,
Fox et al., 1996 Xuan et al., 2012 1987
Fox et al., 2000 Yang et al. 2016 Corrivetti et al.,
Ingham et al., 2000 2019
Ingham et al., 2004 Kemerdere et al.,
Ingham et al., 2012 2016
Sakai et al., 2009 Kinoshita et al.,
Stager et al., 2003 2015
Toyomura et al., 2011 Penfield & Welch,
Children who Chang et al., 2008 Misaghi et al., _ _ Benito-Aragon et al., 1951
stutter Garnett et al., 2018 2018 2020
Koenraads et al., Chang & Zhu, 2013 Chang et al., 2018
2019 Chang et al., 2015 Chang et al., 2016
Chang & Zhu, 2013
Qiao et al., 2017
a
TMS-induced activity.
refine neural activity in networks involving the SMA “complex” (compare with Garnett et al., 2018; Garnett, Chow, & Chang, 2019),
or, on the other hand, may learn to not rely on impaired networks (thus resulting in less involvement of the SMA). In summary, as
suggested by Chang et al. (2008), the SMA “complex” may be structurally impaired when faced with a history of stuttering, especially
in childhood: this allows one to hypothesize a “functional” role for the SMA in stuttering persistence and maintenance (as a part of a
defective network in DS). For this reason, in the next section, attention will be given to the structure of neural pathways that allow
communication between the SMA “complex” and other regions of the brain.
Abnormalities of SMA connections in stuttering

Structural abnormalities may also be evident in the neural pathways of the SMA “complex” in DS. For example, Chang and Zhu
(2013) reported that children who stutter are characterized by weaker connections among regions such as the SMA (mainly on the
left side), basal ganglia, left premotor cortex, (right) cerebellum, right frontal (and sensorimotor) regions, and cingulate cortex.
Chang et al. (2015) reported lower white matter integrity around SMA regions in children who stutter, even in relation to age (i.e.
changes were stagnant or “dissociated” in children who stutter). Compatibly, Cai et al. (2014) showed that DS is characterized by
defective white matter connections at a wider network level in cortical speech circuits (negative correlations with stuttering severity
were also evident). This was especially true for structures of the left hemisphere such as the left ventral premotor cortex and left
primary motor regions. They also showed that the left SMA of persons who stutter is characterized by a lower level of connectivity,
especially with left temporo-parietal regions, (right) premotor, and inferior frontal cortex. Interestingly, connectivity of the SMA
“complex” often resulted in a negative correlation with stuttering severity (some positive correlations were also evident, such as those
individuated on connections with right inferior frontal regions). However, in DS, the left SMA is as an important connection node,
while the left premotor cortex, inferior frontal regions, and parietal cortex show weaker connection weights.
In this context, the frontal aslant tract (FAT) seems to be one of the more critical pathways in stuttering, considering that it allows
neural connection between regions such as the SMA and inferior frontal cortex (Dick, Garic, Graziano, & Tremblay, 2019). More
specifically, this tract is part of the motor system, with a role in speech production, sequencing and initiation (Chernoff, Sims, Smith,
Pilcher, & Mahon, 2019; Dick et al., 2019; Fujii et al., 2015; Kinoshita et al., 2015). The left FAT seems to be more involved in
controlling planning, timing, and coordination of sequential motor acts (such as speech actions), while the right FAT seems to be
more involved in inhibitory control of actions as well as in conflict monitoring (i.e. resolution of conflicts among potentially com-
petitive motor acts; reviewed in Dick et al., 2019). Kronfeld-Duenias, Amir, Ezrati-Vinacour, Civier & Ben-Shachar (2016) reported
lower fiber integrity of the FAT in stuttering, bilaterally, while Kemerdere et al. (2016) reported that its stimulation induced dys-
fluencies in fluent speakers (during neurosurgery; note that an induced deficit of the fronto-striatal tract -mainly connecting the SMA
“complex” with basal ganglia may cause impairments of movements and speech, especially in their starting phase; compare with
Kinoshita et al., 2015). Similarly, Corrivetti et al. (2019) showed that stimulations of the posterior fronto-striatal tract, FAT, corpus
callosum, and cortico-spinal tract (thus involving cortical regions such as the precentral gyrus and pars opercularis) may result, in
4
neurosurgery patients, in speech motor disturbances such as speech arrests, stuttering, or vocalizations. In this context, Misaghi,
Zhang, Gracco, De Nil & Beal (2018) reported higher fractional anisotropy and higher axial diffusivity in the right FAT of children
who stutter, thus suggesting a higher functionality of this tract. Compatibly, Neef et al. (2018) showed that stuttering severity is
positively related with the connection strength of pathways such as the right FAT and projections in correspondence of the right
precentral sulcus. Overall, the evidence for FAT suggests that it connects neural networks involved in planning, control, and initiation
of (intended vs. competing) movements and motor sequences, especially when they are self-initiated, such as speech. It also suggests
that its role in stuttering could be related to error monitoring in speech production (perhaps resulting in enhanced mechanisms of
inhibition or response suppression; compare with Neef et al., 2018). Thus, altered integrity of this pathway (especially in the left
hemisphere) may be speculatively related with “slowed” information transfer or reduced synchrony of communication between the
SMA “complex” and connected regions, such as the inferior frontal cortex, having a role in speech, motor control, and organization.
Young, Morshed, Mansoori, Cha, and Berger (2020) recently suggested that disruptions of FAT may be not associated with long-term
language deficits, thanks to neural re-organization (compare with Kinoshita et al., 2015). In DS, functional re-organization may start
during childhood, reinforcing, for example, homologue patterns of the right hemisphere. However, this does not seem to be sufficient
to avoid speech disruptions or dysfluencies, at least in persistent stuttering: thus, the possibility that these augmented patterns of
connectivity remain at a “sub-optimal” functional level, or that they may result in higher levels of inhibition (thus favoring stuttering;
compare with Neef et al., 2018), also exists.
In summary, impaired connections of the SMA (especially when considering regions of the inferior frontal cortex in the left
hemisphere) may provide a fundamental contribution to disruption of correct elaboration of information in motor and speech net-
works. This may likely result in heightened motor difficulty and variability, and thus in stuttering. It remains to be better defined if
these altered patterns of connections are causally related to stuttering or if they are the result of “adaptive” or “maladaptive” processes
of neural re-organization. Similarly, the role of the fronto-striatal pathway should be better defined in DS, especially when con-
sidering complex motor sequences and possible involvement in favoring (or inhibiting) intended (vs. competing) movements
(compare with Kinoshita et al., 2015).
Functional abnormalities of the SMA “complex” in DS
SMA impairment in stuttering may frequently bring about functional abnormalities (compare with Braun et al., 1997; Brown
et al., 2005; Chang et al., 2009; De Nil et al., 2008; Fox et al., 1996; Ingham et al., 2000, 2012). For example, the SMA “complex” may
result in bilaterally increased or reduced neural activity depending on the requested task (e.g. speech vs. non-speech motor tasks). In
this context, the majority of studies have been conducted on adults with persistent stuttering, but interesting data on children are also
available (Chang et al., 2018; Chang, Garnett, Etchell, & Chow, 2019). In the following sections, the evidence will be subdivided by
considering abnormal activations of SMA during different tasks such as data obtained during fluency and dysfluency, as well as by
considering abnormalities of the functional strength of neural pathways of the SMA and related networks.
Abnormal activity of the SMA in DS

When considering abnormal activity of the SMA in DS, most studies have evaluated resting state conditions and motor (e.g.
speech) planning and execution. Not rarely, stuttering severity and dysfluencies have been positively or negatively related with these
indexes of neural dysfunction (Braun et al., 1997; Ingham et al., 2004, 2012), allowing further insights about the role of the SMA in
DS.
Abnormal activity of the SMA in DS during resting state. Abnormal activity of the SMA “complex” seems to be a stuttering “trait” (i.e.
evident even in the absence of dysfluency; see Budde et al., 2014, for a brief discussion on neural “states” and “traits” related to DS)
that is observed even when no specific task is requested (i.e. resting state). For instance, Ingham et al. (2012) reported increased
activation in regions such as the sensorimotor cortex and basal ganglia in stuttering, as well as in the SMA “complex” (preferably in
the left pre-SMA; less activity was observed in the right one). On the other hand, Desai et al. (2017) found that stuttering was
characterized by less activity in Broca’s region and the superior frontal gyrus. Xuan et al. (2012) reported that stuttering was
characterized by bilaterally reduced or increased amplitude of low frequency fluctuations (considered as an index of resting state
activity), depending on the region considered, especially in the sensorimotor primary cortex and the associative one (comprising
SMA). In general, abnormal functional connectivity of the neural system was also observed. These differences between stuttering and
fluent speakers suggest that, in DS, neural abnormalities may also be evident when no motor or speech task is requested, thus
suggesting a more general neural dysfunction that may be clinically evident during “complex” motor and speech execution. However,
data in the resting state are not able to convey a unique and defined pattern of SMA dysfunction in stuttering. Thus, characterization
of neural abnormalities during motor and speech tasks may be useful to better understand their role in the defective neural networks
of DS.
Abnormal activity of the SMA in DS during motor and speech preparation and execution. The SMA may have abnormal activity in
stuttering, especially during tasks involved in motor and speech preparation (or execution). For example, Brown et al. (2005)
conducted a meta-analysis that found a general increase in the activation of the SMA “complex” during dysfluencies (i.e. during a
stuttering “state”; compare with Budde et al., 2014). Another meta-analysis (Neef, Anwander et al., 2015) also showed that neural
activity in regions of the right hemisphere, such as the pars orbitalis or the (bilateral) SMA, were related to disfluencies; on the other
hand, increased activation of cortical regions such as the temporal cortex, pars opercularis, middle frontal gyrus, and inferior parietal
5
lobule were more associated with fluency. Compatibly, Ingham et al. (2000) reported that overt and imagined stuttering were related
to increased activity of the SMA (the right premotor regions were also activated, mainly during “real” stuttering, suggesting that they
may be useful in compensation attempts; compare with Busan et al., 2019). In this context, Fox et al. (2000) showed that the neural
activity of the bilateral SMA “complex” was positively related with both stuttering and fluent speech production. However, a
difference between conditions was related to hemispheric laterality: stuttering was related to activations of the right hemisphere
(activations of the cerebellum were also observed, with a suggested “compensatory” function). Similarly, Ingham et al. (2004) also
showed that the neural activity of the SMA “complex” may be positively related to higher levels of stuttering rates.
Previous studies showed that abnormal neural activity of the SMA “complex” is not exclusively related to the presence of dys-
fluencies. For example, increased activity of the posterior sections of the SMA “complex” was observed in DS in relation to oro-
laryngeal non-speech movements, while its anterior section was more involved during speech tasks (see Braun et al., 1997). An
increase in neural activity in the left hemisphere was generally and positively related to stuttering, while bilateral (or right hemi-
sphere) activations were more related to non-speech oral motor tasks or to compensatory attempts (thus, negatively related to
dysfluencies). De Nil, Kroll, Kapur, and Houle (2000) showed that DS resulted in a higher involvement of the left SMA during overt
reading, while Blomgren, Nagarajan, Lee, Li, and Alvord (2003) reported greater involvement of the left SMA in fluent speakers in a
lexical access task. Chang et al. (2009) reported that tasks such as planning of speech movements resulted in reduced activations of
fronto-parietal networks in DS, also comprising the pre-SMA; however, broader differences in neural networks were also evident
(between stuttering and fluent speakers) during perception, planning, and production of speech and in non-speech vocal tract
movements, involving different circuits such as the bilateral frontal and temporo-parietal networks, as well as the sensorimotor
cortex. Fox et al. (1996) observed that the SMA was over-activated during reading conditions in DS and that bilateral SMA activations
may be reduced during “chorus” speech. Thus, moving toward fluency, less SMA activity was observed during a well-known fluency-
inducing technique (i.e. “chorus” speech). Compatibly, Toyomura, Fujii, and Kuriki (2011) showed consistent neural activations of
SMA in DS, preferably during a “solo” speech condition, even with the presence of correlations between stuttering severity and neural
activity (in both “solo” and “chorus” speech conditions; see Ingham et al., 2012, for comparisons of monologue and reading condi-
tions). These authors suggested that the over-activity commonly found in this part of the cortex may be more likely related to the
motor effort needed for speech production in stuttering (De Nil et al., 2008). Stager, Jeffries, and Braun (2003) reported higher
activity in the right SMA in persons who stutter (vs. fluent speakers) during different fluency-evoking conditions (i.e. paced speech
and singing), while Sakai, Masuda, Shimotomai, and Mori (2009) demonstrated that persons who stutter activated the SMA “com-
plex”, preferably in the left hemisphere, during delayed auditory feedback (another well-known fluency-inducing condition): this was
mainly evident compared to normal auditory feedback, even if this activity remained lower vs. fluent speakers (especially in the right
hemisphere) in both conditions.
Abnormalities in neural activation of SMA have been investigated in stuttering, not only by neuroimaging techniques but also
using neurophysiological tools such as electroencephalography (EEG) and magnetoencephalography (MEG). For example, stuttering
may be negatively related with beta band power (and thus, positively related to its de-synchronization) during motor speech pre-
paration (Mock, Foundas, & Golob, 2016). In this context, various studies reported that DS may be related to abnormalities in motor
and speech preparation, especially before speech tasks or dysfluencies: the presence of aberrant motor and speech preparation
“readiness” potentials (i.e. a typical neural activity that is evident before movement execution) may be observed (Achim, Braun, &
Collin, 2008; Vanhoutte et al., 2015, 2016; Walla, Mayer, Deecke, & Thurner, 2004). These indexes of motor preparation are usually
in relation with the activity of the SMA “complex” and associative motor regions, and useful to transmit correct motor instructions to
the primary motor cortex (e.g. Deecke & Kornhuber, 1978). Compatibly, stuttering may result in a general lower excitability or lower
activity of the sensorimotor cortex, especially before stuttering moments (i.e., again, during a “preparation” phase; compare with
Mersov, Cheyne, Jobst, & De Nil, 2018; Vanhoutte et al., 2016). On the other hand, DS may be related to aberrant beta de-syn-
chronization, which is mainly evident before dysfluency (and thus related to motor planning and execution; Mersov et al., 2018). This
may cause a series of abnormalities that influence subsequent coordination or synchronization of speech motor networks in stut-
tering. In fact, Salmelin, Schnitzler, Schmitz, and Freund (2000) observed that, in DS, the motor cortex was activated before asso-
ciative motor regions that are useful for speech and motor planning, while the reverse was true for fluent participants. On the other
hand, Ning, Peng, Liu, and Yang (2017) showed that speech motor planning seems to occur “earlier” in stuttering in comparison to
fluent speakers. Undoubtedly, methodological differences may be present in different studies, but all suggest that stuttering may be
the consequence of “atypical” neural synchronization.
In summary, SMA in DS is characterized by abnormal activity: altered (decreased or increased) neural activity may be present.
The available data indicate that these abnormalities are mainly related to the presence of dysfluencies or to increased motor efforts
(also comprising compensation attempts). On the other hand, “external” (“rhythmic”) cues or interventions that are useful to favor
fluency may usually “normalize” abnormal patterns. More importantly, the SMA is part of a defective system in DS, where impaired
exchange of neural information (involved in motor and speech preparation or execution) may be evident. As a consequence, in the
next section, defective “functional” connectivity of SMA will be discussed.
Abnormal functional connectivity of the SMA in DS

Stuttering may result in decreased or increased functional connectivity of the SMA “complex” in wider neural networks also
comprising deeper structures such as the cingulate cortex (reviewed in Etchell et al., 2018; see also Chang et al., 2018). Interestingly,
this is also evident in children, where stuttering may result in decreased functional connectivity of the SMA-basal ganglia network,
further supporting the idea that this disturbance involves neural networks that are useful to manage the timing and control of self-
paced movements, such as speech (see Chang & Zhu, 2013; compare with Chang, 2014; Chang et al., 2019). As is evident in the
6
following sections, these abnormalities may be found during rest and during execution of motor and speech tasks.
Abnormal functional connectivity of the SMA in DS during resting state. When considering resting state conditions, Chang et al. (2018)
showed that in children who stutter, the SMA “complex” is characterized by decreased functional connectivity with regions such as
the posterior cingulate cortex (involved in regulating attention), which also predicted stuttering persistence. The same group further
showed that a complex pattern of decreased or increased functional connectivity of the SMA was evident when considering a series of
different neural structures, ranging from temporal, parietal, and occipital regions to prefrontal, precentral, and premotor regions.
Chang, Chow, Wieland, and McAuley (2016) reported that resting state connectivity is reduced in children who stutter when
considering connections from basal ganglia to the SMA “complex”, even in relation to difficulties encountered in a rhythm
discrimination task. Similarly, Chang and Zhu (2013) showed that children who stutter had lower resting state functional
connectivity mainly between basal ganglia and the left SMA, as well as between the left SMA and the (bilateral) superior temporal
gyrus. On the other hand, stronger functional connectivity was evident between basal ganglia and the right superior frontal gyrus, as
well as among the left SMA, the left cerebellum, and right sensorimotor regions. In this context, Yang, Jia, Siok, & Tan (2016)
demonstrated reduced functional connectivity between the SMA “complex” (mainly in the right hemisphere) and basal ganglia: in this
case, they suggest the existence of specific compensatory mechanisms, related, for example, to inhibition of unwanted and competing
motor acts imposed by the basal ganglia system. Lu et al. (2012, 2016) showed weaker causal connections from the left inferior
frontal regions to the pre-SMA in stuttering (with stronger connections to the left cerebellum; Lu et al., 2016), as well as greater
resting state functional connectivity of the left SMA after “fluency-shaping” interventions (Lu et al., 2012). Stuttering may also result in
a “default” higher functional connectivity of SMA and primary motor cortex, with weaker influences from the inferior frontal gyrus in
both adults and children (Qiao et al., 2017). Benito-Aragon et al. (2020) recently showed that the functional connectivity is impaired
in children who stutter, when considering brain regions related to DS (also comprising the SMA “complex”): importantly, this finding
was related to expression levels of specific genes, suggesting that DS may be due to lysosomal dysfunction, thus resulting in poor
organization of speech neural networks.
In summary, the abnormal (i.e. mainly impaired) functional interactions involving the cortico-basal-thalamo-cortical networks
(i.e. the neural system useful for motor and speech planning and execution, and motor timing control) and their connections with
circuits that are not directly involved in organizing motor sequences (but which are involved in motor and speech execution) may
have an important role in the physiopathology of (persistent) stuttering, starting from childhood. This altered connectivity may have
a primary “causal” role with respect to “simple” dysfunctions of isolated brain regions in stuttering. On the other hand, augmented
connectivity may (mainly) represent compensatory attempts or “maladaptive” neural processes.
Abnormal functional connectivity of the SMA in DS during motor and speech preparation and execution. When considering the
functionality of SMA connections during motor and speech tasks, Lu, Peng et al. (2010) showed that during speech (i.e. a picture-
naming task) stuttering may be characterized by stronger connectivity flowing from the basal ganglia to the thalamus, as well as from
the thalamus to the pre-SMA. Lu et al. (2009) used a covert naming task to show that DS was characterized by positive connections
among the SMA “complex” and diffuse networks of brain regions such as the right precentral gyrus and right superior frontal gyrus.
Negative projections to the left inferior frontal gyrus were also evident, as well as positive connections to the left temporal cortex (in
general, abnormal patterns of connection with bilateral temporal cortices were observed). On the other hand, Kell et al. (2018)
showed that speech of persistent persons who stutter was characterized, for example, by functional hyper-connectivity in regions such
as inferior parietal cortex, inferior frontal cortex, and the SMA “complex” (a positive correlation with stuttering severity was also
evident). Chang et al. (2011) showed that speech and non-speech motor tasks in persons who stutter were characterized, for example,
by higher functional connectivity of regions such as the SMA “complex” with the right inferior frontal cortex.
As a whole, this evidence is often associated with the presence of a stuttering “trait” (i.e. not exclusively in presence of overt
dysfluencies). This confirms that DS is characterized by abnormalities in the correct flow of neural information in systems devoted to
motor and speech implementation, initiation, or inhibition. In this context, a recent study by Busan et al. (2019) demonstrated (using
combined transcranial magnetic stimulation [TMS] and EEG) that, in persistent stuttering, the supplementary motor cortex is
characterized by a lower level of activation after the delivery of a magnetic stimulus, starting from a resting state condition. This
resulted (about 100-150 ms after TMS delivery) in lower or delayed activation, with respect to fluent speakers, of “functionally”
connected motor and speech networks of the left hemisphere, such as the premotor ventral cortex, inferior frontal cortex, and parietal
associative regions. Successively, the brain of persons who stutter seems to respond to this lack of neural activity (and “functional”
connectivity) by strongly recruiting fronto-temporal (ventral) regions of the right hemisphere (starting from about 260 ms after TMS
delivery) that, finally, will “re-activate” the premotor and SMA regions (especially in the right hemisphere). This “re-activation” has
been mainly interpreted as representing “compensatory” attempts (“adaptive” or “maladaptive”, favoring intended movements or
inhibiting competing ones). Overall, this process takes about 460 ms in DS, while fluent speakers seem able to complete it in about
200 msec. This evidence offers a functional and dynamic counterpart to stuttering symptoms. Specifically, delayed or not “syn-
chronized” activation of the SMA “complex” and related networks may result in a functional breakdown of the neural systems that
manage complex and dynamic motor tasks such as speech programming and execution: speech should rely on fast and highly
synchronized motor sequences, i.e. coordinating different speech muscles. Compatibly, asynchronies in oro-facial muscles of persons
who stutter, also during fluent speech, may be observed (Zimmermann, 1980; compare with MacKay & MacDonald, 1984) which may
be evident during finger tapping tasks (see Smits-Bandstra & De Nil, 2007).
In summary, the available evidence suggests the presence of a certain level of variability in the functional connectivity of the SMA
“complex” in DS, which also depends on the requested task. Speculatively, higher levels of functional connectivity during motor and
7
speech tasks may be (mainly) in relation with neural effort or attempts to overcome motor and speech difficulties (compare with
section 4.2.1.2). On the other hand, as noted by Busan et al. (2019), impaired connectivity of the SMA “complex” is more likely to
result (especially in the left hemisphere) in “delayed” and less “synchronized” networks, speculatively favoring speech disruptions.
SMA and neural modeling of DS
In the previous sections, it has been described how the SMA “complex” is involved in neural mechanisms of stuttering. The idea
that the SMA is directly involved in this disturbance is not new (Caruso, Abbs, & Gracco, 1988; Forster & Webster, 2001; Packman,
Code, & Onslow, 2007; Smits-Bandstra & De Nil, 2007; Webster, 1998): previous behavioral research led to the hypothesis that the
problems that persons who stutter normally encounter in different motor tasks, even those not strictly speech-related, may rely on
defective functioning of neural systems that comprise the SMA (e.g. Smits-Bandstra & De Nil, 2007; Webster, 1993). As noted above,
the SMA region is fundamental in order to organize skilled movements, such as complex motor sequences. In this context, several
theories and models have been proposed in which dysfunction of the SMA region may be fundamental in DS. As one example, Van
Riper (1982) theorized that stuttering is a disruption in the neural programming of speech movements representing a motor sequence
(compare with MacKay & MacDonald, 1984), while Alm (2004) suggested that stuttering emerges as an impaired capacity of cortico-
basal-thalamo-cortical loops initiating and supporting speech motor sequences. Compatibly, Packman et al. (2007) proposed that
dysfluencies, i.e. difficulties in motor initiation and sequencing, may arise from “functional” disruptions of the SMA.
Neural models of DS: the intervention of the SMA “complex”

The available neural models usually consider stuttering to be characterized by difficulties in the synchronization of speech and
motor components (perhaps causing repetition of speech programs), or by difficulties in generating the correct motor and speech
programs (thus leading to deficits in motor preparation and speech execution), resulting in a delayed speech elaboration (Howell,
2004; Perkins, Kent, & Curlee, 1991; Postma & Kolk, 1993). In this context, Max, Guenther, Gracco, Ghosh, and Wallace (2004)
suggested that stuttering may be considered as the result of an “unstable” internal model of speech motor acts. However, more recent
computational models of DS have been proposed (see Chang & Guenther, 2020; Civier, Bullock, Max, & Guenther, 2013; Civier,
Tasko, & Guenther, 2010) based on classical models of speech production (i.e. Directions Into Velocities of Articulators, DIVA, and
Gradient Order - DIVA, i.e. GODIVA; Bohland et al., 2010; Guenther, 1994, 2016; Guenther, Ghosh, & Tourville, 2006; Guenther &
Vladusich, 2012; Tourville & Guenther, 2011). Chang and Guenther (2020), based on the DIVA model, suggested that stuttering is
mainly due to cortico-basal-thalamo-cortical dysfunction, impairing the initiation of speech motor programs. They individuated three
different “defective” loci that could lead to dysfluencies: (i) impairment within the basal ganglia, (ii) impaired neural projections
among the components of cortico-basal-thalamo-cortical networks, and (iii) impaired cortical processing. Civier et al. (2010) first
proposed that stuttering could result from overreliance on auditory feedback, with a consequent delay in speech motor activations:
the lack of correct auditory feedback may re-start the motor program, leading to stuttering. On the other hand, Civier et al. (2013)
also considered the role of the associative motor cortex in the appearance of DS symptoms, modeling the role of basal ganglia,
elevated (or imbalanced) levels of dopamine, premotor cortices, and white matter impairments (and thus the ability to exchange
information) in causing the different symptoms of stuttering, such as blocks or repetitions. The authors concluded that in DS, acti-
vations of impaired neural networks are “delayed”, thus resulting in abnormal timing of neural connections (even on a large-scale
basis), causing dysfluency. In these models, even if the role of cortico-basal-thalamo-cortical networks was emphasized, the SMA
“complex” was not considered to have a primary or causal role in the disturbance. However, the SMA may be fundamental in aspects
such as the correct selection (and sequencing) of motor programs, as well as in gating the outflow and release of motor commands to
speech articulators (e.g. Tourville & Guenther, 2011). The abnormal functioning of the cortico-basal-thalamo-cortical network (thus
comprising the SMA “complex”) may result in neural impairments of related circuits, thus influencing correct movement and speech
implementation (Alm, 2004; Chang & Guenther, 2020; Civier et al., 2013; Connally et al., 2018). This is in good accordance with the
model proposed by Giraud et al. (2008) where defective exchange of neural information between cortico-basal-thalamo-cortical
networks and motor and speech circuits of the left hemisphere: homologue regions of the right hemisphere may be useful to com-
pensate these dysfunctions, resulting in a certain level of neural “delay”, and thus in stuttering. In this context, the recent findings of
Busan et al. (2019) confirm that stuttering may be related to the presence of a “delay” in the exchange of information among specific
neural circuits comprising the SMA “complex” (i.e. cortico-striato-thalamo-cortical networks). Following a magnetic pulse delivered
on motor associative regions of the medial frontal cortex, the SMA and the fronto-parietal networks of the left hemisphere (i.e.
inferior frontal cortex, premotor regions and inferior parietal regions) were underactivated in DS, but, compatible with the model
proposed by Giraud et al. (2008), this was followed by a response (i.e. higher activation) of fronto-temporal and premotor regions of
the right hemisphere (suggesting “adaptive” or “maladaptive” compensation: the system tries to favor intended movements, while
competing ones should be inhibited). This sustains the concept that the SMA may be a fundamental “hub” in DS, influencing the
activity of extended motor and speech networks (see Fig. 1).
In conclusion, because stuttering is increasingly considered as a motor control disorder (e.g. Ludlow & Loucks, 2003), mainly
based on dysfunctional long-range neural networks (e.g. Lu et al., 2009), the role of the SMA “complex” (i.e. a region useful to
integrate different neural signals and connecting different neural networks) may assume greater importance with respect to classical
models of stuttering physiopathology. This suggestion is also justified by the available observations about the extended range of
“functional” connectivity of the SMA in healthy humans, ranging from fronto-parietal regions to the sensorimotor and temporal cortex
in both hemispheres (this is evident even for “deeper” regions such as basal ganglia and cingulate cortex; Kim et al., 2010). Thus, the
SMA “complex” should be considered as a possible “gate” where exchange of motor information should be always efficient and
8
Fig. 1. SMA is a fundamental “functional” hub in DS. (A) The altered “functional” connectivity of the SMA “complex” in stuttering (compared to
fluent speakers) obtained after transcranial magnetic stimulation (TMS) of the SMA during resting state is represented. The approximated time of
activation of every node, after TMS delivery, is also indicated: SMA is characterized by a lower level of activation in DS resulting in a lower or
delayed activation (with respect to fluent speakers) of “functionally” connected motor and speech networks of the left hemisphere (e.g. premotor
ventral cortex, inferior frontal regions, and parietal regions). The brain of persons who stutter responds by recruiting fronto-temporal regions of the
right hemisphere that, finally, will “re-activate” premotor and SMA regions on the same side (compare with Busan et al., 2019); (B) The principal
“functional” connections of the SMA “complex” in healthy humans (compare with Kim et al., 2010) are represented in a simplified graph (black lines).
Differences in “functional” connectivity of the SMA “complex” in DS (see Busan et al., 2019) are superimposed, indicating the time range of activation
of each node after TMS delivery (blue boxes indicate lower levels of activation in DS vs. fluent speakers; red boxes indicate higher levels of activation
in DS vs. fluent speakers). It is proposed that the SMA “complex” may be a fundamental “functional” hub in DS, interacting with “dysfunctional” levels
of activity in speech and motor neural networks of the left hemisphere, and, successively, with augmented levels of activation in similar regions of
the right one (likely in an “adaptive” or “maladaptive” manner). Dotted lines connecting the SMA complex with thalamus and basal ganglia indicate
abnormal connections on the basis of previous literature.
synchronized with a series of different brain regions to allow correct implementation and execution of complex motor sequences such
as speech. As a consequence, inefficiency of this system (compare for example with Cai et al., 2014) may contribute to DS disruptions.
Possible role of the SMA in recovery and persistence of DS
Stuttering may “drive” different compensatory strategies that may result, especially in adults, in different neural activations
(compare for example with Ingham et al., 2012; see also concerns about possible neural differences between stuttering males and
females, e.g. Busan et al., 2013; Chang et al., 2009; Chang & Zhu, 2013; Choo, Burnham, Hicks, & Chang, 2016; Ingham, 2001;
Ingham et al., 2004). However, unassisted recovery is more probable during childhood. In this context, one piece of evidence that
allows differentiating between persistent and recovered children who stutter is based on structural indexes of the SMA (Garnett et al.,
2018): an age-related decrease was evident in local gyrification of regions such as the SMA and pre-SMA in children who recovered
from stuttering (Garnett et al., 2018). The authors suggested that this phenomenon may be related with the possibility that decreasing
gyrification may represent synaptic pruning to support more efficient neural connections in execution of motor behaviors, and thus
better long-range connectivity of the SMA “complex”. In this context, Forster and Webster (2001) hypothesized that stuttering re-
covery may be related with the possible maturation of cortical regions such as the SMA. However, this evidence may be also viewed
as the possibility that recovered children may learn to involve different circuits in speech motor programming and execution. As
9
reported above, the SMA “complex” is part of an “internal timing network” involved in the planning and execution of voluntary (i.e.
internally generated) motor programs, usually opposed to an “external timing network” that uses external (i.e. sensorial) cues to
perform motor acts. Speculatively, recovered children may be able to better rely on this second system in order to obtain fluent
speech, thus resulting in less utilization of the SMA “complex”. This vision may be partially supported by the evidence that recovered
adults showed reduced speaking-related functional connectivity between inferior frontal regions and speech motor regions such as
the SMA (see Kell et al., 2018). In this case, the authors proposed a more causative role of the inferior frontal cortex in stuttering,
suggesting that the “uncoupling” of this region from the rest of the system (comprising the SMA “complex” and cortico-basal-thalamo-
cortical networks) may help to re-gain fluency. Compatibly, Cai et al. (2014) showed that the left SMA “complex” of persistent persons
who stutter was characterized by a stronger “centrality” (i.e. a higher amount of neural information is driven by neural networks using
the SMA as a “hub”) in comparison to fluent speakers. The “pivotal” role of the SMA in (voluntary) motor preparation and in
subsequent motor coordination and synchronization (and thus in stuttering; again, compare with Cai et al., 2014) is supported by the
evidence that the more important fluency-inducing effects are driven by interventions based on the utilization of external rhythmic
cues, such as a metronome, chorus reading, or altered auditory feedback. All these interventions are speculatively useful to improve
motor preparation in DS (Kalinowski & Saltuklaroglu, 2003; Kalinowski & Stuart, 1996; Toyomura et al., 2011; Toyomura, Fujii, &
Kuriki, 2015), “by-passing” impaired nodes (such as the SMA), or helping their correct functioning. For example, chorus reading may
normalize the over-activation of the SMA “complex” in order to obtain temporary fluency in DS (e.g. Fox et al., 1996).
SMA and open questions in DS research
Defective mechanisms of SMA functioning are fundamental even in the pathogenesis of other basal-ganglia motor disorders such
as Parkinson’s disease (Hamada et al., 2008; Koch et al., 2005; Shirota et al., 2013; see also Casarotto et al., 2019; Casula et al., 2017).
Interestingly, Parkinson’s disease may be also characterized by the presence of speech dysfluencies, as well as by particular motor
blocks resembling those observed in stuttering, such as “freezing of gait”. Thus, it is likely that SMA abnormalities of DS may have not
a direct “causal” role, but, more properly, may have a “functional” role in the disturbance and in its symptoms. In fact, especially in
persistent DS in adulthood, it is not easy to separate between causal and compensatory mechanisms, considering that processes of
“adaptive” and “maladaptive” plasticity continuously occur (Ingham et al., 2012). Thus, from this point of view, the effective role of
the SMA “complex” in stuttering is still an open question and should be better defined to gain further insights, which may be useful for
more focused rehabilitative solutions. In fact, better knowledge of its structural and functional connectivity in the brain of persons
who stutter could allow further understanding about the motor programs affected during different tasks that impair or facilitate
speech fluency, such as time pressure or chorus reading, respectively. Interestingly, the SMA “complex” may also have a role in the
neural and motor consequences of rewarding behaviors (Sohn & Lee, 2007); thus, the relations of stuttering and SMA with processes
of reward and motor acquisition, as well as the relations of cortico-basal-thalamo-cortical networks with other deeper structures such
as the cingulate cortex (Connally et al., 2018), and the influence of “arousal” (e.g. anxiety) on the DS motor system are of interest and
should be further investigated (compare with Yang, Jia, Siok, & Tan, 2017). In this context, the SMA “complex” is functionally
connected to the limbic system, especially when considering structures such as the cingulate cortex (compare with Craig-McQuaide
et al., 2014, for a perspective in stuttering). The cingulate cortex shows modulations of its neural activity when facing emotional
stimuli (e.g. Rolls, 2019). It is also related to tasks where response preparation and anticipatory reactions are induced (Lorberbaum
et al., 2004), and this may be of relevance to the physiopathology of stuttering (De Nil & Kroll, 2001). It may be plausible that
atypical modulations of the SMA “complex” by the limbic system (or vice versa) may interfere with the correct implementation of
motor plans, or with correct motor initiation. Compatibly, Chow and Chang (2017) reported abnormalities in white matter tracts of
the cingulate cortex in persistent and recovered stuttering, which are also close to the SMA “complex” (compare with Garnett, Chow,
& Chang, 2019), while Chang et al. (2018) showed that decreased functional connectivity between the SMA and the cingulate cortex
may predict stuttering persistence.
As already indicated, the symptoms of DS are alleviated by interventions that restore “correct” management of the rhythmic
aspects of motor programming, such as choral speech, metronome, and altered auditory feedback (Kalinowski & Saltuklaroglu, 2003;
Kalinowski & Stuart, 1996; Toyomura et al., 2011, 2015). In this context, the functional role of the SMA “complex” in DS should be
further investigated by combining, for example, behavioral evidence with neuroimaging and neurophysiological methods, to better
relate behavioral improvements with functional abnormalities of neural substrates. In this context, recent studies investigating the
effect of neuromodulation on stuttering by stimulating structures such as the left inferior frontal regions have been carried out
(Chesters, Watkins, & Möttönen, 2017; Chesters, Möttönen, & Watkins, 2018). Compatibly, the activity of the SMA “complex” can also
be modulated by investigating the effects on stuttering severity and neural circuits. In this regard, Garnett, Chow, Choo & Chang
(2019) evaluated the effects of a single session of transcranial direct current stimulation (tDCS) on stuttering, showing that tDCS was
able to attenuate the correlation between stuttering severity and activity of the right thalamocortical networks, especially in persons
who severely stuttered. Moreover, Mejías and Prieto (2019) published a single case study using an excitatory rTMS protocol on the
SMA region on the basis of findings highlighted by Busan et al. (2019) that showed rapid and significant improvement in the fluency
of a stimulated patient that were maintained during treatment. Evidently, these observations should be extended, but, considering the
“pivotal” role of the SMA in the management of motor timing and sequences, and its wide connectivity, neuromodulation of the SMA
“complex” may be able to influence long-range neural networks, perhaps leading to stronger effects. In fact, different outcomes may
be obtained when considering variables such as protocol of stimulation or the neural region (and connections) that will be primarily
stimulated (e.g. proper-SMA vs. pre-SMA). Thus, further understanding of the functional roles of these regions in DS will also help to
implement better neuromodulation protocols, with better defined a-priori hypotheses about their desired effects.
10
Conclusions
Abnormalities of the SMA region in DS may be in strict relation with the core symptoms of the disturbance, such as repetitions,
prolongations, and blocks. In fact, they may at least partially reflect the inability of the SMA “complex” to fully organize or implement
“demanding” motor sequences (such as those needed for fluent speech) in terms of, for example, muscular coordination (compare with
Howell, 2004). However, it would be more appropriate to consider the SMA as part of a network that, starting from basal ganglia,
may be dysfunctional in DS (compare with Alm, 2004; Chang & Guenther, 2020; Craig-McQuaide et al., 2014). Thus, starting from
these observations (refer to Hertrich, Dietrich, & Ackermann, 2016, for the role of the SMA “complex” in speech implementation,
organization, and execution), it can be speculated that one of the most important roles of the SMA “complex” in stuttering might be
related to abnormalities in its capability to correctly release speech initiation, as well as in releasing the correct procedural and
“predictive” mechanisms. For example, the pre-SMA may be useful in temporal predictions of up-coming events, in management of
conflicts, and in inhibitory function of competing motor acts. In this context, the SMA “complex” can be viewed as an interface
between cortical and sub-cortical networks (e.g. cortical motor circuits and basal ganglia). Dysfluencies may arise from abnormal
functioning of both the proper-SMA and pre-SMA, considering that procedural tasks, such as speech (especially if associated with
accelerated repetition rates), may result in increased neural requests in both structures.
In conclusion, the present review offers a focused view about the role of SMA in DS. More specifically, based on the available
neuroimaging and neurophysiological findings, the SMA “complex” may be not “causally” related to stuttering (deficits in white
matter and basal ganglia systems are more evident), but, more appropriately, the SMA may have a “functional” role, influencing the
appearance of DS symptoms and correct functioning of the neural system. Thus, the SMA can be considered as a possible and
fundamental neural “hub” in DS, receiving and conveying altered neural information from and towards different neural networks,
such as those referring to basal ganglia and inferior frontal regions, “gating” the release of correct or abnormal motor plans. Further
research and modeling will be needed to increase our understanding of the role of the SMA in this motor impairment, especially when
considering implications for neurorehabilitation: acting on the SMA and its networks could give further insights into the unanswered
questions of DS.
Declaration of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Disclosure of relevant financial and/or non-financial support
Did you or your colleagues receive any financial support for conducting the research described in this paper? No.
Funding sources
This work was supported by Beneficentia Stiftung (Vaduz, Liechtenstein; grant to P.B.) and by the Italian Ministry of Health
(project code: GR-2018-12366027; grant to P.B.). The funding sources had no role in the study.
Acknowledgments
The author gratefully acknowledges the contribution and funding of the Italian Ministry of Health (project code: GR-2018-
12366027). The author also wishes to thank Beneficentia Stiftung (Vaduz, Liechtenstein) for its role in funding, as well as the Editors
and anonymous reviewers who helped to improve the manuscript. Finally, the author is grateful to Dr. Patrick Moore for linguistic
revision.
References
Abe, K., Yokoyama, R., & Yorifji, S. (1992). On stuttering-like hesitation resulting from infarct in the midbrain and the mesial thalami. Rinsho Shinkeigaku, 32,
822–825.
Abe, K., Yokoyama, R., & Yorifuji, S. (1993). Repetitive speech disorder resulting from infarcts in the paramedian thalami and midbrain. Journal of Neurology,
Neurosurgery & Psychiatry, 56, 1024–1026.
Achim, A., Braun, C. M., & Collin, I. (2008). Event-related potentials distinguish fluent and stuttered speech. Journal of Neurotherapy, 11, 15–23.
Ackermann, H., & Riecker, A. (2011). The contribution(s) of the insula to speech production: a review of the clinical and functional imaging literature. Brain Structure &
Function, 214, 419–433.
Ackermann, H., Hertrich, I., Ziegler, W., Bitzer, M., & Bien, S. (1996). Acquired dysfluencies following infarction of the left mesiofrontal cortex. Aphasiology, 10,
409–417.
Alario, F. X., Chainay, H., Lehericy, S., & Cohen, L. (2006). The role of the supplementary motor area (SMA) in word production. Brain Research, 1076, 129–143.
Alexander, M., Naeser, M., & Palumbo, C. (1987). Correlations of subcortical CT lesion sites and aphasia profiles. Brain, 110, 961–991.
Alm, P. A. (2004). Stuttering and the basal ganglia circuits: a critical review of possible relations. Journal of Communication Disorders, 37, 325–369.
Ball, T., Schreiber, A., Feige, B., Wagner, M., Lucking, C. H., & Kristeva-Feige, R. (1999). The role of higher-order motor areas in voluntary movement as revealed by
high-resolution EEG and fMRI. Neuroimage, 10, 682–694.
Barnes, T. D., Wozniak, D. F., Gutierrez, J., Han, T. U., Drayna, D., & Holy, T. E. (2016). A mutation associated with stuttering alters mouse pup ultrasonic vocali-
zations. Current Biology, 26, 1009–1018.
Belyk, M., Kraft, S. J., & Brown, S. (2017). Stuttering as a trait or a state revisited: motor system involvement in persistent DS – Corrigendum. European Journal of
Neuroscience, 45, 622–624.
Belyk, M., Kraft, S. J., & Brown, S. (2015). Stuttering as a trait or state-an ALE meta-analysis of neuroimaging studies. European Journal of Neuroscience, 41, 275–284.
11
Benito-Aragon, C., Gonzalez-Sarmiento, R., Liddell, T., Diez, I., d’Oleire Uquillas, F., Ortiz-Teran, L., Bueicheku, E., et al. (2020). Neurofilament-lysosomal genetic
intersections in the cortical network of stuttering. Progress in Neurobiology, 184, 101718.
Blomgren, M., Nagarajan, S. S., Lee, J. N., Li, T., & Alvord, L. (2003). Preliminary results of a functional MRI study of brain activation patterns in stuttering and
nonstuttering speakers during a lexical access task. Journal of Fluency Disorders, 28, 337–355.
Bohland, J. W., Bullock, D., & Guenther, F. H. (2010). Neural representations and mechanisms for the performance of simple speech sequences. Journal of Cognitive
Neuroscience, 22, 1504–1529.
Braun, A. R., Varga, M., Stager, S., Schulz, G., Selbie, S., Maisog, J. M., et al. (1997). Altered patterns of cerebral activity during speech and language production in DS.
An H2(15)O positron emission tomography study. Brain, 120, 761–784.
Brown, S., Ingham, R. J., Ingham, J. C., Laird, A. R., & Fox, P. T. (2005). Stuttered and fluent speech production: an ALE meta-analysis of functional neuroimaging
studies. Human Brain Mapping, 25, 105–117.
Budde, K. S., Barron, D. S., & Fox, P. T. (2014). Stuttering, induced fluency, and natural fluency: a hierarchical series of activation likelihood estimation meta-analyses.
Brain & Language, 139, 99–107.
Busan, P., Battaglini, P. P., & Sommer, M. (2017). Transcranial magnetic stimulation in DS: Relations with previous neurophysiological research and future per-
spectives. Clinical Neurophysiology, 128, 952–964.
Busan, P., Battaglini, P. P., Borelli, M., Evaristo, P., Monti, F., & Pelamatti, G. (2009). Investigating the efficacy of paroxetine in DS. Clinical Neuropharmacology, 32,
183–188.
Busan, P., D’Ausilio, A., Borelli, M., Monti, F., Pelamatti, G., Pizzolato, G., et al. (2013). Motor excitability evaluation in DS: a transcranial magnetic stimulation study.
Cortex, 49, 781–792.
Busan, P., Del Ben, G., Bernardini, S., Natarelli, G., Bencich, M., Monti, F., et al. (2016). Altered modulation of silent period in tongue motor cortex of persistent DS in
relation to stuttering severity. PLoS ONE, 11, e0163959.
Busan, P., Del Ben, G., Russo, L. R., Bernardini, S., Natarelli, G., Arcara, G., et al. (2019). Stuttering as a matter of delay in neural activation: a combined TMS/EEG
study. Clinical Neurophysiology, 130, 61–76.
Cai, S., Tourville, J. A., Beal, D. S., Perkell, J. S., Guenther, F. H., & Ghosh, S. S. (2014). Diffusion imaging of cerebral white matter in persons who stutter: evidence for
network-level anomalies. Frontiers in Human Neuroscience, 8, 54.
Caruso, A. J., Abbs, J. H., & Gracco, V. L. (1988). Kinematic analysis of multiple movement coordination during speech in stutterers. Brain, 111, 439–456.
Casarotto, S., Turco, F., Comanducci, A., Perretti, A., Marotta, G., Pezzoli, G., et al. (2019). Excitability of the supplementary motor area in Parkinson’s disease depends
on subcortical damage. Brain Stimulation, 12, 152–160.
Casula, E. P., Stampanoni Bassi, M., Pellicciari, M. C., Ponzo, V., Veniero, D., Peppe, A., et al. (2017). Subthalamic stimulation and levodopa modulate cortical
reactivity in Parkinson’s patients. Parkinsonism & Related Disorders, 34, 31–37.
Chang, S. E., Zhu, D. C., Choo, A. L., & Angstadt, M. (2015). White matter neuroanatomical differences in young children who stutter. Brain, 138, 694–711.
Chang, S. E. (2014). Research updates in neuroimaging studies of children who stutter. Seminars in Speech Language, 35, 67–79.
Chang, S. E., & Guenther, F. H. (2020). Involvement of the cortico-basal ganglia-thalamo-cortical loop in developmental stuttering. Frontiers in Psychology, 10, 3088.
Chang, S. E., & Zhu, D. C. (2013). Neural network connectivity differences in children who stutter. Brain, 136, 3709–3726.
Chang, S. E., Angstadt, M., Chow, H. M., Etchell, A. C., Garnett, E. O., Choo, A. L., et al. (2018). Anomalous network architecture of the resting brain in children who
stutter. Journal of Fluency Disorders, 55, 46–67.
Chang, S. E., Erickson, K. I., Ambrose, N. G., Hasegawa-Johnson, M. A., & Ludlow, C. L. (2008). Brain anatomy differences in childhood stuttering. Neuroimage, 39,
1333–1344.
Chang, S. E., Garnett, E. O., Etchell, A., & Chow, H. M. (2019). Functional and neuroanatomical bases of developmental stuttering: current insights. Neuroscientist, 25,
566–582.
Chang, S. E., Horwitz, B., Ostuni, J., Reynolds, R., & Ludlow, C. L. (2011). Evidence of left inferior frontal-premotor structural and functional connectivity deficits in
adults who stutter. Cerebral Cortex, 21, 2507–2518.
Chang, S. E., Kenney, M. K., Loucks, T. M. J., & Ludlow, L. (2009). Brain activation abnormalities during speech and non-speech in stuttering speakers. Neuroimage, 46,
201–212.
Chang, S. E., Chow, H. M., Wieland, E. A., & McAuley, J. D. (2016). Relation between functional connectivity and rhythm discrimination in children who do and do not
stutter. Neuroimage Clinical, 12, 442–450.
Chernoff, B. L., Sims, M. H., Smith, S. O., Pilcher, W. H., & Mahon, B. Z. (2019). Direct electrical stimulation of the left frontal aslant tract disrupts sentence planning
without affecting articulation. Cognitive Neuropsychology, 36, 178–192.
Chesters, J., Möttönen, R., & Watkins, K. E. (2018). Transcranial direct current stimulation over left inferior frontal cortex improves speech fluency in adults who
stutter. Brain, 141, 1161–1171.
Chesters, J., Watkins, K. E., & Möttönen, R. (2017). Investigating the feasibility of using transcranial direct current stimulation to enhance fluency in people who
stutter. Brain & Language, 164, 68–76.
Choo, A. L., Burnham, E., Hicks, K., & Chang, S. E. (2016). Dissociations among linguistic, cognitive, and auditory-motor neuroanatomical domains in children who
stutter. Journal of Communication Disorders, 61, 29–47.
Chow, H. M., & Chang, S. E. (2017). White matter developmental trajectories associated with persistence and recovery of childhood stuttering. Human Brain Mapping,
38, 3345–3359.
Civier, O., Bullock, D., Max, L., & Guenther, F. H. (2013). Computational modeling of stuttering caused by impairments in a basal ganglia thalamo-cortical circuit
involved in syllable selection and initiation. Brain & Language, 126, 263–278.
Civier, O., Kronfeld-Duenias, V., Amir, O., Ezrati-Vinacour, R., & Ben-Shachar, M. (2015). Reduced fractional anisotropy in the anterior corpus callosum is associated
with reduced speech fluency in persistent DS. Brain & Language, 143, 20–31.
Civier, O., Tasko, S. M., & Guenther, F. H. (2010). Overreliance on auditory feedback may lead to sound/syllable repetitions: simulations of stuttering and fluency-
inducing conditions with a neural model of speech production. Journal of Fluency Disorders, 35, 246–279.
Connally, E. L., Ward, D., Howell, P., & Watkins, K. E. (2014). Disrupted white matter in language and motor tracts in DS. Brain & Language, 131, 25–35.
Connally, E. L., Ward, D., Pilatsikas, C., Finnegan, S., Jenkinson, M., Boyles, R., et al. (2018). Separation of trait and state in stuttering. Human Brain Mapping, 39,
3109–3126.
Corrivetti, F., de Schotten, M. T., Poisson, I., Froelich, S., Descoteaux, M., Rheault, F., et al. (2019). Dissociating motor-speech from lexico-semantic systems in the left
frontal lobe: insight from a series of 17 awake intraoperative mappings in glioma patients. Brain Structure & Function, 224, 1151–1165.
Craig-McQuaide, A., Akram, H., Zrinzo, L., & Tripoliti, E. (2014). A review of brain circuitries involved in stuttering. Frontiers in Human Neuroscience, 8, 884.
Crosson, B., Sadek, J. R., Maron, L., Gokcay, D., Mohr, C. M., Auerbach, E. J., et al. (2001). Relative shift in activity from medial to lateral frontal cortex during
internally versus externally guided word generation. Journal of Cognitive Neuroscience, 13, 272–283.
Cykowski, M. D., Fox, P. T., Ingham, R. J., Ingham, J. C., & Robin, D. A. (2010). A study of the reproducibility and etiology of diffusion anisotropy differences in DS: a
potential role for impaired myelination. Neuroimage, 52, 1495–1504.
De Nil, L. F., & Kroll, R. M. (2001). Searching for the neural basis of stuttering treatment outcome: recent neuroimaging studies. Clinical Linguistics & Phonetics, 15,
163–168.
De Nil, L. F., Beal, D. S., Lafaille, S. J., Kroll, R. M., Crawley, A. P., & Gracco, V. L. (2008). The effects of simulated stuttering and prolonged speech on the neural
activation patterns of stuttering and nonstuttering adults. Brain & Language, 107, 114–123.
De Nil, L. F., Kroll, R. M., Kapur, S., & Houle, S. (2000). A positron emission tomography study of silent and oral single word reading in stuttering and nonstuttering
adults. Journal of Speech Language and Hearing Research, 43, 1038–1053.
Deecke, L., & Kornhuber, H. H. (1978). An electrical sign of participation of the mesial “supplementary” motor cortex in human voluntary finger movement. Brain
Research, 159, 473–476.
12
Desai, J., Huo, Y., Wang, Z., Bansal, R., Williams, S. C., Lythgoe, D., et al. (2017). Reduced perfusion in Broca’s area in DS. Human Brain Mapping, 38, 1865–1874.
Dick, A. S., Garic, D., Graziano, P., & Tremblay, P. (2019). The frontal aslant tract (FAT) and its role in speech, language and executive function. Cortex, 111, 148–163.
Dinoto, A., Busan, P., Formaggio, E., Bertolotti, C., Menichelli, A., Stokelj, D., et al. (2018). Stuttering-like hesitation in speech during acute/post-acute phase of
immune-mediated encephalitis. Journal of Fluency Disorders, 58, 70–76.
Drayna, D., & Kang, C. (2011). Genetic approaches to understanding the causes of stuttering. Journal of Neurodevelopmental Disorders, 3, 374–380.
Etchell, A. C., Civier, O., Ballard, K., & Sowman, P. F. (2018). A systematic literature review of neuroimaging research on DS between 1995 and 2016. Journal of
Fluency Disorders, 55, 6–45.
Etchell, A. C., Johnson, B. W., & Sowman, P. F. (2014). Behavioral and multimodal neuroimaging evidence for a deficit in brain timing networks in stuttering: a
hypothesis and theory. Frontiers in Human Neuroscience, 8, 467.
Forster, D. C., & Webster, W. G. (2001). Speech-motor control and interhemispheric relations in recovered and persistent stuttering. Developmental Neuropsychology, 19,
125–145.
Fox, P. T., Ingham, R. J., Ingham, J. C., Hirsch, T. B., Downs, J. H., Martin, C., et al. (1996). A PET study of the neural systems of stuttering. Nature, 382, 158–161.
Fox, P. T., Ingham, R. J., Ingham, J. C., Zamarripa, F., Xiong, J. H., & Lancaster, J. L. (2000). Brain correlates of stuttering and syllable production. A PET performance-
correlation analysis. Brain, 123, 1985–2004.
Fujii, M., Maesawa, S., Motomura, K., Futamura, M., Hayashi, Y., Koba, I., et al. (2015). Intraoperative subcortical mapping of a language-associated deep frontal tract
connecting the superior frontal gyrus to Broca’s area in the dominant hemisphere of patients with glioma. Journal of Neurosurgery, 122, 1390–1396.
Garnett, E. O., Chow, H. M., & Chang, S. E. (2019). Neuroanatomical correlates of childhood stuttering: MRI indices of white and gray matter development that
differentiate eventual persistence versus recovery. Journal of Speech, Language & Hearing Research, 62, 2986–2998.
Garnett, E. O., Chow, H. M., Choo, A. L., & Chang, S. E. (2019). Stuttering severity modulates effects of non-invasive brain stimulation in adults who stutter. Frontiers in
Human Neuroscience, 13, 411.
Garnett, E. O., Chow, H. M., Nieto-Castanon, A., Tourville, J. A., Guenther, F. H., & Chang, S. E. (2018). Anomalous morphology in left hemisphere motor and premotor
cortex of children who stutter. Brain, 141, 2670–2684.
Giraud, A. L., Neumann, K., Bachoud-Levi, A. C., von Gudenberg, A. W., Euler, H. A., Lanfermann, H., et al. (2008). Severity of dysfluency correlates with basal ganglia
activity in persistent DS. Brain & Language, 104, 190–199.
Grafton, S. T. (1994). Cortical control of movement. Annals of Neurology, 36, 3–4.
Guenther, F. H. (1994). A neural network model of speech acquisition and motor equivalent speech production. Biological Cybernetics, 72, 43–53.
Guenther, F. H. (2016). Neural control of speech. Cambridge, USA: Mit Press.
Guenther, F. H., & Vladusich, T. (2012). A neural theory of speech acquisition and production. Neurolinguistics, 25, 408–422.
Guenther, F. H., Ghosh, S. S., & Tourville, J. A. (2006). Neural modeling and imaging of the cortical interactions underlying syllable production. Brain & Language, 96,
280–301.
Hamada, H., Ugawa, Y., Tsuji, S., & Effectiveness of rTMS on Parkinson’s Disease Study Group, Japan (2008). High-frequency rTMS over the supplementary motor area
for treatment of Parkinson’s disease. Movement Disorders, 23, 1524–1531.
Hertrich, I., Dietrich, S., & Ackermann, H. (2016). The role of the supplementary motor area for speech and language processing. Neuroscience & Biobehavioral Reviews,
68, 602–610.
Howell, P. (2004). Assessment of some contemporary theories of stuttering that apply to spontaneous speech. Contemporary Issues in Communication Sciences &
Disorders, 31, 122–139.
Ikeda, A., Yazawa, S., Kunieda, T., Ohara, S., Terada, K., Mikuni, N., et al. (1999). Cognitive motor control in human pre-supplementary motor area studied by
subdural recording of discrimination/selection-related potentials. Brain, 122, 915–931.
Ingham, R. J. (2001). Brain imaging studies of developmental stuttering. Journal of Communication Disorders, 34, 493–516.
Ingham, R. J., Fox, P. T., Ingham, J. C., & Zamarripa, F. (2000). Is overt stuttered speech a prerequisite for the neural activations associated with chronic DS? Brain &
Language, 75, 163–194.
Ingham, R. J., Fox, P. T., Ingham, J. C., Xiong, J., Zamarripa, F., Hardies, L. J., et al. (2004). Brain correlates of stuttering and syllable production: gender comparison
and replication. Journal of Speech, Language & Hearing Research, 47, 321–341.
Ingham, R. J., Grafton, S. T., Bothe, A. K., & Ingham, J. C. (2012). Brain activity in adults who stutter: similarities across speaking tasks and correlations with stuttering
frequency and speaking rate. Brain & Language, 122, 11–24.
Johansen-Berg, H., Behrens, T. E. J., Robson, M. D., Drobnjak, I., Rushworth, M. F. S., Brady, J. M., et al. (2004). Changes in connectivity profiles define functionally
distinct regions in human medial frontal cortex. Proceedings of the National Academy of Sciences of the United States of America, 101, 13335–13340.
Kalinowski, J., & Saltuklaroglu, T. (2003). Choral speech: the amelioration of stuttering via imitation and the mirror neuronal system. Neuroscience & Biobehavioral
Reviews, 27, 339–347.
Kalinowski, J., & Stuart, A. (1996). Stuttering amelioration at various auditory feedback delays and speech rates. European Journal of Disorders of Communication, 31,
259–269.
Kell, C. A., Neumann, K., Behrens, M., von Gudenberg, A. W., & Giraud, L. (2018). Speaking-related changes in cortical functional connectivity associated with assisted
and spontaneous recovery from DS. Journal of Fluency Disorders, 55, 135–144.
Kemerdere, R., de Champfleur, N. M., Deverdun, J., Cochereau, J., Moritz-Gasser, S., Herbet, G., et al. (2016). Role of the left frontal aslant tract in stuttering: a brain
stimulation and tractographic study. Journal of Neurology, 263, 157–167.
Kim, J. H., Lee, J. M., Jo, H. J., Kim, S. H., Lee, J. H., Kim, S. T., et al. (2010). Defining functional SMA and pre-SMA subregions in human MFC using resting state fMRI:
functional connectivity-based parcellation method. Neuroimage, 49, 2375–2386.
Kinoshita, M., de Champfleur, N. M., Deverdun, J., Moritz-Gasser, S., Herbet, G., & Duffau, H. (2015). Role of frontostriatal tract and frontal aslant tract in movement
and speech: an axonal mapping study. Brain Structure & Function, 220, 3399–3412.
Klein, J. C., Behrens, T. E. J., Robson, M. D., Mackay, C. E., Higham, D. J., & Johansen-Berg, H. (2007). Connectivity-based parcellation of human cortex using diffusion
MRI: Establishing reproducibility, validity and observer independence in BA 44/45 and SMA/pre-SMA. Neuroimage, 34, 204–211.
Koch, G., Brusa, L., Caltagirone, C., Peppe, A., Oliveri, M., Stanzione, P., et al. (2005). rTMS of supplementary motor area modulates therapy-induced dyskinesias in
Parkinson disease. Neurology, 65, 623–625.
Koenraads, S. P. C., El Marroun, H., Muetzel, R. L., Chang, S. E., Vernooij, M. W., Baatenburg de Jong, R. J., et al. (2019). Stuttering and gray matter morphometry: a
population-based neuroimaging study in young children. Brain & Language, 194, 121–131.
Kronfeld-Duenias, V., Amir, O., Ezrati-Vinacour, R., Civier, O., & Ben-Shachar, M. (2016). The frontal aslant tract underlies speech fluency in persistent DS. Brain
Structure & Function, 221, 365–381.
Lorberbaum, J. P., Kose, S., Johnson, M. R., Arana, G. W., Sullivan, L. K., Hamner, M. B., et al. (2004). Neural correlates of speech anticipatory anxiety in generalized
social phobia. Neuroreport, 15, 2701–2705.
Lu, C., Chen, C., Ning, N., Ding, G., Guo, T., Peng, D., et al. (2010). The neural substrates for atypical planning and execution of word production in stuttering.
Experimental Neurology, 221, 146–156.
Lu, C., Chen, C., Peng, D., You, W., Zhang, X., Ding, G., et al. (2012). Neural anomaly and reorganization in speakers who stutter: a short-term intervention study.
Neurology, 79, 625–632.
Lu, C., Long, Y., Zheng, L., Shi, G., Liu, L., Ding, G., et al. (2016). Relationship between speech production and perception in people who stutter. Frontiers in Human
Neuroscience, 10, 224.
Lu, C., Ning, N., Peng, D., Ding, G., Li, K., Yang, Y., et al. (2009). The role of large-scale neural interactions for DS. Neuroscience, 161, 1008–1026.
Lu, C., Peng, D., Chen, C., Ning, N., Ding, G., Li, K., et al. (2010). Altered effective connectivity and anomalous anatomy in the basal ganglia-thalamocortical circuit of
stuttering speakers. Cortex, 46, 49–67.
Ludlow, C. L., & Loucks, T. (2003). Stuttering: a dynamic motor control disorder. Journal of Fluency Disorders, 28, 273–295.
13
MacKay, D. G., & MacDonald, M. C. (1984). Stuttering as a sequencing and timing disorder. In R. F. Curlee, & W. H. Perkins (Eds.). Nature and treatment of stuttering:
new directions (pp. 261–282). San Diego, USA: College Hill Press.
Max, L., Guenther, F. H., Gracco, V. L., Ghosh, S. S., & Wallace, M. E. (2004). Unstable or insufficiently activated internal models and feedback-biased motor control as
sources of dysfluency: a theoretical model of stuttering. Contemporary Issues in Communication Sciences & Disorders, 31, 105–122.
Mejías, G., & Prieto, J. (2019). A single case report of a patient with stuttering who improved after open label TMS. Brain Stimulation, 12, 785–786.
Mersov, A., Cheyne, D., Jobst, C., & De Nil, L. (2018). A preliminary study on the neural oscillatory characteristics of motor preparation prior to dysfluent and fluent
utterances in adults who stutter. Journal of Fluency Disorders, 55, 145–155.
Mink, J. W. (1996). The basal ganglia: focused selection and inhibition of competing motor programs. Progress in Neurobiology, 50, 381–425.
Misaghi, E., Zhang, Z., Gracco, V. L., De Nil, L. F., & Beal, D. S. (2018). White matter tractography of the neural network for speech-motor control in children who
stutter. Neuroscience Letters, 668, 37–42.
Mock, J. R., Foundas, A. L., & Golob, E. J. (2016). Cortical activity during cued picture naming predicts individual differences in stuttering frequency. Clinical
Neurophysiology, 127, 3093–3101.
Nachev, P., Kennard, C., & Husain, M. (2008). Functional role of the supplementary and pre-supplementary motor areas. Nature Reviews Neuroscience, 9, 856–869.
Narayana, S., Laird, A. R., Tandon, N., Franklin, C., Lancaster, J. L., & Fox, P. T. (2012). Electrophysiological and functional connectivity of the human supplementary
motor area. Neuroimage, 62, 250–265.
Neef, N. E., Anwander, A., & Friederici, A. D. (2015). The neurobiological grounding of persistent stuttering: from structure to function. Current Neurology &
Neuroscience Reports, 15, 63.
Neef, N. E., Anwander, A., Bütfering, C., Schmidt-Samoa, C., Friederici, A. D., Paulus, W., et al. (2018). Structural connectivity of right frontal hyperactive areas scales
with stuttering severity. Brain, 141, 191–204.
Neef, N. E., Hoang, T. N., Neef, A., Paulus, W., & Sommer, M. (2015). Speech dynamics are coded in the left motor cortex in fluent speakers but not in adults who
stutter. Brain, 138, 712–725.
Neef, N. E., Jung, K., Rothkegel, H., Pollok, B., von Gudenberg, A. W., Paulus, W., et al. (2011). Right-shift for nonspeech motor processing in adults who stutter.
Cortex, 47, 945–954.
Neef, N. E., Paulus, W., Neef, A., von Gudenberg, A. W., & Sommer, M. (2011). Reduced intracortical inhibition and facilitation in the primary motor tongue
representation of adults who stutter. Clinical Neurophysiology, 122, 1802–1811.
Ning, N., Peng, D., Liu, X., & Yang, S. (2017). Speech timing deficit of stuttering: evidence from contingent negative variations. PLoS ONE, 12, e0168836.
Packman, A., Code, C., & Onslow, M. (2007). On the cause of stuttering: integrating theory with brain and behavioral research. Journal of Neurolinguistics, 20, 353–362.
Penfield, W., & Welch, K. (1951). The supplementary motor area of the cerebral cortex: a clinical and experimental study. Archives of Neurology & Psychiatry, 66,
289–317.
Perkins, W. H., Kent, R. D., & Curlee, R. F. (1991). A theory of neuropsycholinguistic function in stuttering. Journal of Speech & Hearing Research, 34, 734–752.
Picard, N., & Strick, P. L. (1996). Motor areas of the medial wall: a review of their location and functional activation. Cerebral Cortex, 6, 342–353.
Postma, A., & Kolk, H. (1993). The covert repair hypothesis: prearticulatory repair processes in normal and stuttered disfluencies. Journal of Speech & Hearing Research,
36, 472–487.
Qiao, J., Wang, Z., Zhao, G., Huo, Y., Herder, C. L., Sikora, C. O., et al. (2017). Functional neural circuits that underlie developmental stuttering. PLoS ONE, 12,
e0179255.
Rochas, V., Gelmini, L., Krolak-Salmon, P., Poulet, E., Saoud, M., Brunelin, J., et al. (2013). Disrupting pre-SMA activity impairs facial happiness recognition: an event-
related TMS study. Cerebral Cortex, 23, 1517–1525.
Rolls, E. T. (2019). The cingulate cortex and limbic systems for emotion, action, and memory. Brain Structure & Function, 224, 3001.
Ruan, J., Bludau, S., Palomero-Gallagher, N., Caspers, S., Mohlberg, H., Eickhoff, S. B., et al. (2018). Cytoarchitecture, probability maps, and functions of the human
supplementary and pre-supplementary motor areas. Brain Structure & Function, 223, 4169–4186.
Sakai, N., Masuda, S., Shimotomai, T., & Mori, K. (2009). Brain activation in adult who stutter under delayed auditory feedback: an fMRI study. International Journal of
Speech-Language Pathology, 11, 2–11.
Salmelin, R., Schnitzler, A., Schmitz, F., & Freund, H. J. (2000). Single word reading in developmental stutterers and fluent speakers. Brain, 123, 1184–1202.
Seitz, R. J. (2003). How do we control action? In S. Maasen, W. Prinz, & G. Roth (Eds.). Voluntary action (pp. 133–152). Oxford, England: Oxford University Press.
Seitz, R. J., Nickel, J., & Azari, N. P. (2006). Functional modularity of the medial prefrontal cortex: involvement in human empathy. Neuropsychology, 20, 743–751.
Shibasaki, H., Sadato, N., Lyshkow, H., Yonekura, Y., Honda, M., Nagamine, T., et al. (1993). Both primary motor cortex and supplementary motor area play an
important role in complex finger movement. Brain, 116, 1387–1398.
Shirota, Y., Ohtsu, H., Hamada, M., Enomoto, H., Ugawa, Y., & Reseach Committee on rTMS Treatment of Parkinson’s Disease (2013). Supplementary motor area
stimulation for Parkinson disease: a randomized controlled study. Neurology, 80, 1400–1405.
Smits-Bandstra, S., & De Nil, L. F. (2007). Sequence skill learning in persons who stutter: implications for cortico-striato-thalamo-cortical dysfunction. Journal of
Fluency Disorders, 32, 251–278.
Sohn, J. W., & Lee, D. (2007). Order-dependent modulation of directional signals in the supplementary and presupplementary motor areas. Journal of Neuroscience, 27,
13655–13666.
Sommer, M., Koch, M. A., Paulus, W., Weiller, C., & Büchel, C. (2002). Disconnection of speech-relevant brain areas in persistent DS. Lancet, 360, 380–383.
Stager, S. V., Jeffries, K. J., & Braun, A. R. (2003). Common features of fluency-evoking conditions studied in stuttering subjects and controls: an H2 15O PET study.
Journal of Fluency Disorders, 28, 319–336.
Tanji, J. (1994). The supplementary motor area in the cerebral cortex. Neuroscience Research, 19, 251–268.
Tourville, J. A., & Guenther, F. H. (2011). The DIVA model: a neural theory of speech acquisition and production. Language & Cognitive Processes, 26, 952–981.
Toyomura, A., Fujii, T., & Kuriki, S. (2011). Effect of external auditory pacing on the neural activity of stuttering speakers. Neuroimage, 57, 1507–1516.
Toyomura, A., Fujii, T., & Kuriki, S. (2015). Effect of an 8-week practice of externally triggered speech on basal ganglia activity of stuttering and fluent speakers.
Neuroimage, 109, 458–468.
Van Borsel, J., Van Lierde, K., Van Cauwenberge, P., Guldemont, I., & Van Orshoven, M. (1998). Severe acquired stuttering following injury of the left supplementary
motor region: a case report. Journal of Fluency Disorders, 23, 49–58.
Van Riper, C. (1982). The nature of stuttering. New Jersey, USA: Prentice Hall.
Vanhoutte, S., Cosyns, M., van Mierlo, P., Batens, K., Corthals, P., De Letter, M., et al. (2016). When will a stuttering moment occur? The determining role of speech
motor preparation. Neuropsychologia, 86, 93–102.
Vanhoutte, S., Santens, P., Cosyns, M., van Mierlo, P., Batens, K., Corthals, P., et al. (2015). Increased motor preparation activity during fluent single word production
in DS: a correlate for stuttering frequency and severity. Neuropsychologia, 75, 1–10.
Walla, P., Mayer, D., Deecke, L., & Thurner, S. (2004). The lack of focused anticipation of verbal information in stutterers: a magnetoencephalographic study.
Neuroimage, 22, 1321–1327.
Wang, C., Ulbert, I., Schomer, D. L., Marinkovic, K., & Halgren, E. (2005). Responses of human anterior cingulate cortex microdomains to error detection, conflict
monitoring, stimulus-response mapping, familiarity, and orienting. Journal of Neuroscience, 25, 604–613.
Watkins, K. E., Smith, S. M., Davis, S., & Howell, P. (2008). Structural and functional abnormalities of the motor system in DS. Brain, 131, 50–59.
Webster, W. G. (1993). Hurried hands and tangled tongues. In E. Boberg (Ed.). Neuropsychology of stuttering (pp. 73–127). Edmonton, Canada: The University of Alberta
Press.
Webster, W. G. (1998). Brain models and the clinical management of stuttering. Canadian Journal of Speech-Language Pathology & Audiology, 22, 220–230.
Wu, J. C., Maguire, G., Riley, G., Lee, A., Keator, D., Tang, C., et al. (1997). Increased dopamine activity associated with stuttering. Neuroreport, 8, 767–770.
Xuan, Y., Meng, C., Yang, Y., Zhu, C., Wang, L., Yan, Q., et al. (2012). Resting-state brain activity in adult males who stutter. PLoS One, 7, e30570.
Yang, Y., F, Jia, Siok, W. T., & Tan, L. H. (2016). Altered functional connectivity in persistent developmental stuttering. Scientific Reports, 6, 19128.
14
Yang, Y., Jia, F., Siok, W. T., & Tan, L. H. (2017). The role of anxiety in stuttering: evidence from functional connectivity. Neuroscience, 346, 216–225.
Young, J. S., Morshed, R. A., Mansoori, Z., Cha, S., & Berger, M. S. (2020). Disruption of frontal aslant tract is not associated with long-term postoperative language
deficits. World Neurosurgery, 133, 192–195.
Zilles, K., Schlaug, G., Matelli, M., Luppino, G., Schleicher, A., Qü, M., et al. (1995). Mapping of human and macaque sensorimotor areas by integrating architectonic,
transmitter receptor, MRI and PET data. Journal of Anatomy, 187, 515–537.
Zimmermann, G. N. (1980). Articulatory behavior associated with stuttering: a cineradiographic analysis. Journal of Speech and Hearing Disorders, 23, 108–121.
Pierpaolo Busan is a psychologist, who received the Ph.D. Degree in Neuroscience at the University of Trieste (Italy), in 2009. Since 2015, he is a research fellow at
IRCCS Ospedale San Camillo, in Venice (Italy). His research interests mainly concern the neurophysiology of stuttering, investigated by different tools such as
transcranial magnetic stimulation (TMS), electroencephalography (EEG), combined TMS/EEG, magnetoencephalography (MEG) and magnetic resonance (MRI).
15

Developmental Stuttering Suppl Motor Cortex Busan2020

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Developmental Stuttering Suppl Motor Cortex Busan2020

Uploaded by

Copyright:

Available Formats

Journal of Fluency Disorders 64 (2020) 105763

Contents lists available at ScienceDirect

Journal of Fluency Disorders

Developmental stuttering and the role of the supplementary motor

Keywords: Developmental stuttering is a frequent neurodevelopmental disorder with a complex neurobio-

The defective neural substrates of DS

Anatomical and functional subdivisions of SMA

The role of SMA in DS

Anatomical diﬀerences in the SMA “complex” of DS

Abnormalities of gross morphology in the SMA of DS

Abnormalities of SMA connections in stuttering

Functional abnormalities of the SMA “complex” in DS

Abnormal activity of the SMA in DS

Abnormal functional connectivity of the SMA in DS

SMA and neural modeling of DS

Neural models of DS: the intervention of the SMA “complex”

Possible role of the SMA in recovery and persistence of DS

SMA and open questions in DS research

Disclosure of relevant ﬁnancial and/or non-ﬁnancial support

You might also like