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Preprint submitted to Current Neurology and Neuroscience Reports (2015).
Published in final edited form as:
Curr Neurol Neurosci Rep. 2015 Sep; 15(9):579. DOI: 10.1007/s11910-015-0579-4
The neurobiological grounding of persistent stuttering:
From structure to function
Nicole E. Neef
1,
*, Alfred Anwander
1
, and Angela D. Friederici
1
1
Max Planck Institute for Human Cognitive and Brain Sciences,
Department of Neuropsychology, Leipzig, Germany.
* Corresponding author:
Nicole E. Neef
Max Planck Institute for Human Cognitive and Brain Sciences
Department of Neuropsychology
Stephanstr. 1a, 04103 Leipzig, Germany
Phone: +49 341 9940 2230
http://www.cbs.mpg.de/~neef
Preprint submitted to Curr Neurol Neurosci Rep (2015). Final draft: 06/2015
The neurobiological grounding of persistent chronic stuttering: From structure to function
2
Abstract
Neuroimaging and transcranial magnetic stimulation provide insights into the neuronal
mechanisms underlying speech disfluencies in chronic persistent stuttering. In the
present paper, the goal is not to provide an exhaustive review of existing literature, but
rather to highlight robust findings. We, therefore, conducted a meta–analysis of diffusion
tensor imaging studies which have recently implicated disrupted white matter
connectivity in stuttering. A reduction of fractional anisotropy in persistent stuttering
has been reported at several different loci. Our meta–analysis revealed consistent
deficits in the left dorsal stream and in the interhemispheric connections between the
sensorimotor cortices. In addition, recent fMRI meta–analyses link stuttering to reduced
left fronto–parieto–temporal activation while greater fluency is associated with boosted
co–activations of right fronto–parieto–temporal areas. However, the physiological
foundation of these irregularities is not accessible with MRI. Complementary,
transcranial magnetic stimulation (TMS) reveals local excitatory and inhibitory
regulation of cortical dynamics. Applied to a speech motor area TMS revealed reduced
speech–planning–related neuronal dynamics at the level of the primary motor cortex in
stuttering. Together, this review provides a focused view of the neurobiology of
stuttering to date, and may guide the rational design of future research. This future
needs to account for the perpetual dynamic interactions between auditory,
somatosensory, and speech motor circuits that shape fluent speech.
Keywords
Persistent developmental stuttering, Meta–analysis, Speech production, Diffusion tensor
imaging, Transcranial magnetic stimulation, Diffusion MRI tractography
Keywords
AF arcuate fasciculus
ALE activation likelihood estimation
DTI diffusion tensor imaging
FA fractional anisotropy
FDR false discovery rate
IFG inferior frontal gyrus
IPL inferior parietal lobe
M1 primary motor cortex
MEP motor evoked potential
MFG middle frontal gyrus
MTG middle temporal gyrus
SLF superior longitudinal fasciculus
SMA supplementary motor area
SMG supramarginal gyrus
SPL superior parietal lobe
STG superior temporal gyrus
TBSS tract–based spatial statistics
TMS transcranial magnetic stimulation
VBS Voxel based statistics
The neurobiological grounding of persistent chronic stuttering: From structure to function
3
Introduction
Stuttering is a speech disorder which most often occurs between the age of 3 and 6 years
[1]. Lifespan incidence is higher than 5 %, with high rates of recovery (52–87 %) [2, 3].
Lifespan prevalence is 0.72 % with a sex ratio of 2.3 [4]. Neither etiology nor
pathogenesis is known [5]; thus, stuttering is characterized by its symptoms. The
hallmark signs of stuttering are involuntary sound and syllable repetitions, sound
prolongations, and speech blocks [6]. In some cases, additional facial and limb
movements such as grimacing, hand tapping, or stamping with one’s foot accompany
these speech motor signs. Strategies to avoid stuttering include word substitutions,
sentence reordering, but also to fall silent in certain situations. Failure in communication
provokes negative emotions such as fear and embarrassment. The course of stuttering
varies across individuals and distinct phenotypes emerge. Depending on severity,
stuttering critically compromises quality of life [7].
Similar to other behaviourally defined disorders, the cause of stuttering is multifactorial
and is associated with various genetic and environmental risk factors. The large
presence of familial stuttering and the high concordance rate in twins support a genetic
role in stuttering [8]. To date, few linkage studies have nominated contributing genes [9,
10]. Genome–wide significance [10] still awaits replication [11••] and more genome–
wide association studies are required [12]. It remains to be seen whether future efforts
will demonstrate the polygenetic basis of stuttering and thus shed light on the questions
of involved transmission models, chromosomes, genes, or sex factors.
The phenomenon of stuttering has given rise to manifold theories, each shaped by the
perspective of a certain field such as for example analytic psychology [13], speech and
language pathology [1, 5, 14], psychology [15, 16], linguistics [17–19], biomechanics
[20–22] and neuroscience [23–27]. Neuroscience–based hypotheses have included an
aberrant dominant hemisphere structure [28–30], basal ganglia dysfunction [23], a
disconnection syndrome [31], altered brain timing networks [25, 26, 32, 33], or an
altered sensorimotor integration [20, 34, 35], mostly interrelating with each other. This
multiplicity of causes is plausible due to the fact that a broad assortment of linguistic,
cognitive, and sensorimotor processes are involved in speech production. Speech is a
very complex sensorimotor action, and its intimate connection to language, a defining
feature of human cognition, makes speech and stuttering a very complicated field of
study for neuroscientists and neurologists. In the last 30 years, studies on the
neurobiology of stuttering have improved our understanding of potential mechanisms,
but there are still fundamental questions open. Here, we will summarize the main
neuroscientific findings on chronic persistent stuttering.
The continuous speech stream
The ultimate readout of language planning and speech motor control is articulation that
results in an audible, smooth, continuous stream of speech. Articulation is a demanding
coordinative challenge because it requires the orchestration of respiratory, laryngeal,
The neurobiological grounding of persistent chronic stuttering: From structure to function
4
and supralaryngeal structures by using approximately 100 muscles [36]. The
respiratory system regulates the outflow of air during speech and thus provides energy
for the acoustic targets of speech. The laryngeal system generates the quasiperiodic and
tone–like sound fundamental for pitch modulation, vowels, and voiced consonants (e.g.,
[b], [z], and [m]). Voiceless and aspirated consonants (e.g., [p], [s], and [h]) require
timely voice offsets transmitted by short transient glottal abductions. The
supralaryngeal system comprises the pharyngeal, oral, and nasal cavities whose
architecture and configuration shape the timbre and sound of the generated acoustic
signal. The supralaryngeal system, also called the vocal tract, can be constricted at
different places, for example via lip closure; lip protrusion; tongue tip or body elevation,
or retraction; and velum elevation. Characteristic sound features of speech vowels are
generated by articulatory gestures such as jaw lowering, tongue body elevation, and lip
protrusion. In contrast, distinct acoustic features of consonants are generated by the
magnitude of obstruction, resulting in bursts due to closure and friction–like noise due
to fine–tuned constriction.
During speaking, our articulators are continuously in motion [37]. Our thoughts are
transformed into coupled articulatory patterns that carry specific melodies and
rhythms. Prosody and articulation are built upon motor units that act on multiple
timescales. Their execution happens simultaneously, in an overlapping or subsequent
manner continuously adapting to ever–changing contexts due to changes in speaking
rate, co–articulation, or emotional load. Imagine a machine buildup of all necessary
effectors and degrees of freedom enabling the spatio–temporal dynamics of sound
production. Why would such a machine only produce scattered sounds but not smooth,
fluid speech? One aspect is the unsolved problem of prosodic modeling in speech
synthesis [38]. The other problem is a missing feedback system in current speech
synthesis programs. Human speech production is closely coupled to its perception. The
key to fluent speech is a production–perception interaction. The timely sequencing and
context–dependent binding of speech units are constantly monitored and adjusted by an
effective sensorimotor integration [39]. Feedback–related control couples not only
perception and production processes but also internal models that closely relate to the
sound envelop of a corresponding utterance [40] possibly translating auditory targets
into motor commands. For this reason, it is necessary to consider the output and input
systems as well as internal models, interfaces, and monitors to comprehensively
elucidate the neurobiology of stuttering.
Neural underpinnings of persistent stuttering: From structure to
function
Chronic persistent stuttering is highly heterogeneous with regard to symptoms,
avoidance behavior, applied strategies to overcome disfluencies, and severity. Therefore,
it is not surprising that imaging studies have produced diverse, puzzling, and sometimes
contradictory results [41]. It has been suggested that the “core” of the stuttered
The neurobiological grounding of persistent chronic stuttering: From structure to function
5
response may have nothing to do with changes in functional imaging observed at rest,
during speech, or following therapy [42]. This review will not outline the diverging
neuroimaging findings of the last 30 years. In fact, we rather have concentrated on
published findings from diffusion tensor imaging (DTI) in an informative meta–analysis
to obtain the most robust white matter changes in persistent stuttering currently
reported. Subsequently, we relate these structural findings to irregular brain function as
described in two recent activation likelihood estimation (ALE) meta–analyses [43••,
44••]. To account for the fact that the neural organization of speaking employs recurrent
networks working at a high temporal resolution, we complement the view by reviewing
results of those few transcranial magnetic stimulation (TMS) studies available.
DTI — The left dorsal stream and interhemispheric somatosensory
connections are affected in stuttering
Fractional anisotropy (FA) is the most frequently reported parameter of DTI. It
measures the directionality of water molecule mobility on a submillimeter scale. This
directedness is especially high along the myelinated axons of the white matter, though
orientation distribution of axons and the degree of myelination are not the only
influencing factors. Axon diameter distribution and the axonal tissue fraction or density
affects the magnitude of the FA as well. Moreover, the macroscopic geometrical
arrangement of white matter bundles such as crossing or fanning fibers comes into play
especially at the low resolutions of 2–3 mm³ usually employed in human diffusion
weighted MRI. However, a reduced FA is commonly interpreted as less coherent white
matter structure [45]. Group comparisons of neuroimaging parameters are not trivial, as
individually shaped brains need to be aligned to a common space. To render DTI group
statistics possible, this normalization is most often achieved by the projection of voxels
with the highest FA in the center of each gyrus or white matter tract to a skeleton that
represents a common tract–based template for the studied group (tract–based spatial
statistics, TBSS [46]).
To date, nine DTI studies have reported whole–brain FA reductions from white matter
regions in cases with persistent stuttering (Table 1). Sixty widespread loci result from
the seven studies that examined subjects older than 14. Loci number and variability
increase when adding studies in children (aged 3 to 12) as well (Fig. 1a). To reduce
dimensionality, we calculated an informative meta–analysis of the coordinates of
decreased FA using the ALE method. This method was introduced for the meta–analysis
of functional MRI activation maps and detects three–dimensional conjunctions of
coordinates, weighted by sample size [47]. The 60 loci that were included were from
seven studies which interrogated 121 persons who stutter and 124 fluent speakers aged
14 to 52 years. Higher FA values in persons who stutter were not considered because
increases are infrequently reported. The current analysis yielded three clusters of lower
FA values in persons who stutter (p<0.001; FDR q<0.05; Fig. 1b), located in the left
hemisphere and in the corpus callosum.
The neurobiological grounding of persistent chronic stuttering: From structure to function
6
Subsequent deterministic DTI tractography served to estimate the course of the white
matter connections passing through the significant clusters of the current meta–
analysis. The chosen high–quality diffusion tensor image of a representative single
young healthy subject has an isotropic resolution of 1 mm acquired on an ultra–high–
field MRI scanner using 60 diffusion directions and 4 averages [48, 49]. The first cluster
was located in the left superior longitudinal fasciculus (SLF III, 344 mm³ centered at
{–41, –53, 42}; Fig. 1c left) of the inferior parietal lobe (IPL) adjacent to the angular
gyrus and the posterior division of the supramarginal gyrus (SMG). Reconstructed
connections terminated in the postcentral gyrus, in the ventral premotor cortex, and in
the posterior–ventral area of the inferior frontal gyrus (IFG) pars opercularis as part of
Broca’s area. The second cluster was located below the fundus of the left central sulcus
in the left SLF but this time also including fibers of the arcuate fasciculus (AF, 280 mm³
centered at {–38, –22, 30}; Fig. 1c middle). Connections terminated frontally in the
ventral motor cortex, in the ventral premotor cortex, and in the posterior part of Broca’s
area, the IFG pars opercularis; parietal terminations reached the SMG and the angular
gyrus; and temporal terminations reached the posterior superior temporal gyrus (STG)
and in the middle temporal gyrus (MTG). The third cluster was placed in the posterior
midbody of the corpus callosum (240 mm³ centered at {3, –22, 25}; Fig. 1c right) where
interhemispheric fibers pass through and terminate at the postcentral and precentral
gyri close to the vertex.
Our current meta–analysis related the most robust white matter changes in stuttering to
the left dorsal language stream. This is in line with diffusion tractography studies
reporting a reduced FA in these streams [50], the absence of streamlines in a large
portion of the left AF [51], as well as a reduced tractography density of the left SLF III
[52] in persons who stutter compared to fluent speakers. The four branches of the SLF
and AF are the prominent fiber bundles mediating the interaction between frontal,
parietal, and temporal regions [53–55] – also evident in the current tractography
results.
Another robust outcome of the current meta–analysis was the reduced FA in the
interhemispheric fibers of the posterior midbody of the corpus callosum. Our
deterministic fiber tracking showed that the disrupted callosal connections most likely
connect sensorimotor regions (Fig. 1c right). The reconstructed pathways link medial
regions of the post– and precentral gyri, but the more lateral regions that are known to
control orofacial structures were not involved. Before drawing conclusions on this
restricted course, one should consider that transcallosal fibers are massively crossed by
orthogonal association and projection fibers. The DTI tractography algorithm used is
influenced by these crossing fiber populations, and the reconstruction of all callosal
connections cannot be easily solved [56]. No diffusion tractography study on stuttering
has fully reconstructed transcallosal connections. This may be due to these
methodological difficulties. Hence, the current tractogram does not allow ruling out an
involvement of fibers terminating in ventral sites of the sensorimotor cortex.
The neurobiological grounding of persistent chronic stuttering: From structure to function
7
The interpretation of the reduced FA values is not trivial. Particularly, the dorsal stream
is affected by crossing fibers from transcallosal as well as corticospinal and
corticothalamic connections or other subcortical loops. Whether FA reductions result
from a weakened intrahemispheric connectivity, a strengthened interhemispheric
connectivity, or both remains to be shown. Ultra–high–field imaging [48] in combination
with a sophisticated tracking algorithm [56] might disentangle macro–anatomy–related
changes. In contrast, FA is not affected by crossing fibers within the corpus callosum;
fibers run exclusively in one direction, reducing the number of variables that influence
FA to the degree of myelination, axon diameter distribution, and axon population
density. The axons with the largest diameter reside in the posterior midbody of the
corpus callosum [57] in healthy human subjects. From this, it follows that the
interhemispheric transmission is fastest and most efficient in this area which is capable
of transmitting reliable, precisely timed neuronal coupling. Hence, it is plausible that the
frequency–specific interhemispheric correlation structure of spontaneous oscillatory
neuronal activity is nested in the highest frequency range (32–45 Hz) between the
sensorimotor cortices compared to the temporal lobes (4–6 Hz) and the lateral parietal
areas (8–23 Hz) [58]. Large–diameter axon fibers may also determine the degree of
interhemispheric–correlated fMRI resting–state activity which is again highest in the
somatosensory cortices [59]. In stuttering, the reduced FA could be related to either
reduced myelination or altered axonal diameter distribution [60] in the affected area.
However, these two possibilities could have different outcomes: While reduced
myelination would cause a deficient interhemispheric interaction, increased density of
large–diameter axon fibers could result in a strengthened interhemispheric interaction.
For this reason, it would be desirable to employ advanced methods that better resolve
the axon diameter distribution “in vivo” [61, 62].
To summarize, non–invasive “in vivo” DTI provides the most important insights into
connectivity changes of brain networks in stuttering. Short– and long–range widely
integrated, parallel, and often redundant neuronal subcircuits supply speech fluency. It
is likely that connectivity changes of speech–relevant perisylvian brain areas lead to
disruption of speech functions. Our meta–analysis emphasized the important role of left
hemisphere cortico–cortical connections, namely the SLF and the AF, and transcallosal
connections of the posterior midbody for fluent speech production. However, right
hemisphere connectivity [50, 51, 63••, 64–66] as well as axons of the corticospinal tract
[50, 63–68], thalamic [64, 67], and cerebellar [50, 63••, 64, 65] connections have also
been reported to show irregularities in stuttering. Similar to other behavioral and
cognitive processes, fluent speech production depends on the embedding of various
areas in the human connectome [69••]. The following section of functional imaging
changes in stuttering mainly summarizes the altered recruitment of cortical and
subcortical areas suggesting irregular input and output operations within the speech–
related connectome.
The neurobiological grounding of persistent chronic stuttering: From structure to function
8
Table 1 Diffusion tensor imaging studies published between August 2002 and May 2015
DTI/DSI – Study
Method
PWS
Ctr
Gender
Age
range
p value
Contrasts
TBSS/VBS
Sommer et al. [31]
VBS
15
15
M/F
18 – 44
0.001
PWS < Ctr
Watkins et al. [65]
TBSS
17
13
M/F
14 – 27
0.0025
PWS < Ctr
PWS > Ctr
Chang et al. [64]
TBSS
9
12
M
9 – 12
0.001
PWS < Ctr
PWS > Ctr
Kell et al. [106]
TBSS
13
13
M
18 – 44
0.001
0.05*
PWS < Ctr
PWS > Ctr
Connally et al. [50]
TBSS
29
37
M/F
14 – 45
0.002**
PWS < Ctr
PWS > Ctr
Cai et al. [66]
TBSS
20
18
M/F
18 – 47
0.002**
PWS < Ctr
Cykowski [125]
TBSS
13
14
M
Nan
0.05*
PWS < Ctr
Civier et al. [67]
TBSS
14
14
M/F
19 – 52
0.001
0.05
#
PWS < Ctr
PWS < Ctr
Chang et al. [63••]
TBSS
37
40
M/F
3 – 10
0.001
PWS < Ctr
PWS > Ctr
Fibertracking
Affected tracts
Connally et al. [50]
probablistic
29
37
L corticospinal tract, L & R AF
Chang et al. [52]
probablistic
15
14
L SLF, L AF
Cieslak et al. [51]
deterministic,
DSI
8
8
L & R AF, L temporal–striatal tract
Kronfeld–Duenias
et al. [68]
deterministic
15
19
L & R frontal aslant tract, L corticospinal
tract
VBS = voxel based statistics, TBSS = tract–based spatial statistics, PWS = persons who stutter, Ctr
= controls, M = male, F = female, SLF = superior longitudinal fasciculus, AF = arcuate fasciciulus
*Corrected p values; **k ≥ 10;
#
Corrected p value (one-tailed)
fMRI – Right frontal over–activation characterizes stuttering while
right parieto–temporal co–activation characterizes greater fluency
So far, we have only elaborated on structural imaging, focusing particularly on white
matter integrity and thus the connectome. A lot is already known about the underlying
function of the connections that come into focus here. Predominantly, left dorsal paths
subserve linguistic as well as speech motor functions. The AF, the medial part of the
dorsal stream, connects the IFG pars opercularis to the STG and mediates complex
syntax [70, 71] and phonology [72•]. Sublexical repetition of speech [73], speech
planning [72•], and articulation [74] map to the lateral part of the dorsal stream and the
indirect anterior portion of the SLF connecting the precentral gyrus to the SMG and the
The neurobiological grounding of persistent chronic stuttering: From structure to function
9
STG [55]. Articulatory phonetic skills rely on an effective auditory–motor integration
partly mediated by the recurrent networks of these dorsal streams [53, 75••, 76].
The functional anatomy underlying stuttering has mostly been studied with positron
emission tomography [77–82] and functional magnetic resonance imaging [83–87]. Two
activation likelihood meta–analyses on stuttering were recently published [43••, 44••].
The meta–analyses considered 23 functional imaging studies published over the past 30
years; these included 213 [44••], and 222 [43••] persons who stutter and 186 [44••],
and 188 [43••] control subjects, and Fig. 1d, e summarizes their outcome.
These meta–analyses highlight the neuro–functional hallmark signs of persistent chronic
stuttering. What is striking is the consistent over–activation of the frontal motor areas of
the right hemisphere encompassing the primary motor cortex, the premotor cortex, the
pre–supplementary motor area (pre–SMA), the supplementary motor area (SMA), the
IFG, the insula, and the frontal and the rolandic operculum [43••, 44••] (Fig. 1d). An
opposite pattern of cortical activity emerges in the left hemisphere. Here, frontal regions
show no over–activation but instead a reduced activation of the M1 larynx area
combined with reduced activity in the planum temporale and the middle temporal
gyrus. The left cerebellar vermis and the left red nucleus also display robust imaging
changes that emerge from a comparison of speech–related hemodynamic differences
between persons who stutter and fluent speakers. The only region that shows a higher
activation is the right parietal lobe. Stronger activations are located in the anterior
intraparietal sulcus and in the IPL PFcm. The remarkable right hemisphere over–
activation in stuttering suggests an imbalanced hemispheric lateralization [28, 29]. It is
not yet clear whether this imbalance causes stuttering, whether it is the result of
impeded left fronto–parieto–temporal signal processes, or if it reflects compensatory
mechanisms [31, 78, 84, 88–90].
Every investigation of stuttering tries to find out how fluency of speech production can
be attained. Therefore, imaging contrasts that relate brain activations to greater fluency
in persons who stutter are of special interest. In the right hemisphere, such contrasts
show a shift of activation patterns to parietal areas spanning several loci in the IPL,
heavy involvement of the temporal lobe (Heschl’s gyrus, planum temporale, and STG)
and the cerebellum. Greater fluency is associated with the recruitment of superior
temporal and inferior parietal regions in both hemispheres, whereas severe stuttering is
associated with dysfunction of a distributed network of classical motor areas engaging
sensorimotor regions amongst the central sulcus including the left and right
somatosensory cortex, the left larynx motor cortex, extended regions of the IFG
including the left pars opercularis, the left pars triangularis and right pars orbitalis,
bilateral SMA, and the cerebellum (Fig. 1e). Fluency–related activations in unimodal and
heteromodal association areas of the parietal and right temporal lobe, the right pars
opercularis, and the posterior ventral part of right Broca’s region strongly suggest an
important role of internal models and feedforward– and feedback– relevant control
mechanisms during speaking. In fluent speakers, lateralization of speech production
seems to start in the left temporal and parietal regions [91], namely the somatosensory
The neurobiological grounding of persistent chronic stuttering: From structure to function
10
cortex, the auditor cortex, and the planum temporale which might be the source of the
early sound feature–related cortical entrainment observed in left Broca’s area and the
left premotor cortex even ahead of external speech production [40]. Equivalent studies
in stuttering are missing, leaving the question open as to whether right lateralization
already occurs in the planning stage. However, one TMS study has indeed observed
missing lateralization at an early stage.
Figure 1 DTI (a–c) and fMRI (d, e) imaging changes associated with persistent
chronic stuttering (a) Loci of reduced FA as reported in multiple studies were shown
on a transparent isosurface of the MNI brain. Red spheres indicate foci from studies of
persons aged 14 to 52 who stutter, and orange spheres indicate loci from children aged
The neurobiological grounding of persistent chronic stuttering: From structure to function
11
3 to 10 who stutter [63]. (b) Blue illustrates clusters of reduced FA in persistent
stuttering as derived from a meta–analysis using the activation likelihood estimation
(ALE) method (p<0.001; FDR q<0.05). (c) Diffusion tractography derived from full brain
deterministic fiber tracking [125] in an ultra–high–resolution DTI data set of a single
subject [49]. Tracts are shown that cross a sphere with a diameter of 5 mm surrounding
the MNI coordinates of the meta–analysis after a linear registration to the subject’s
native space. (d) Trait stuttering is captured by contrasts between persons who stutter
and fluent speakers. Therefore, it reveals brain areas that are either more active (red
and orange dots) or less active (blue and light blue dots) in persons who stutter
compared to fluent speakers. Right hemisphere over–activations reside in the precentral
gyrus, lip motor cortex, rolandic operculum, insula, IFG pars opercularis, IFG pars
orbitalis, pre–SMA, middle frontal gyrus, IPL and SPL. Left hemisphere over–activations
reside in the SMA and in the SPL. Left hemisphere under–activations are located in the
left larynx motor cortex, left MTG, left superior temporal sulcus, cerebellar vermis, and
the red nucleus [43••, 44••]. Trait stuttering contrasts enlighten brain abnormalities
that cause stuttering or that compensate for it. (e) Supplementary, state stuttering
analyses capture within–group contrasts which enlighten areas in the brain that are
more active when fluency is enhanced (green and light green dots) compared to areas
that are more active when fluency is worse (purple and violet dots). Disfluency related
activations reside in Broca’s area in the right IFG pars orbitalis, the left IFG pars
opercularis and pars triangularis, bilaterally in the SMA, the somatosensory cortex, and
the cerebellum, and in the left precuneus and the left globus pallidus. Fluency–related
activations reside mostly in the right hemisphere, namely the Heschl gurus, the planum
temporale, the posterior STG, MTG, SMG, IPL, IFG pars opercularis and the MFG. Left
hemisphere correlates are in the IPL [43••, 44••]. State stuttering contrasts might reveal
causes of stuttering events, attempts to compensate for stuttering, or the correlates of
stuttering as a motor act [44••].
TMS indicates a restricted range of neuronal dynamics at the level of
the primary motor cortex in stuttering
Both DTI and fMRI elucidate the spatial distribution of large–scale neuronal dysfunction
in persistent stuttering, but its physiological basis remains unclear. Nonlinear neuronal
dynamics consist of excitatory and inhibitory activation, but these cannot be
discriminated with in vivo neuroimaging. The only non–invasive technique that allows
to measure excitatory and inhibitory brain function in healthy humans is TMS [92]. A
TMS pulse induces currents in conductive tissue such as the human cortex. When
applied to the motor cortex, neurons are stimulated and evoke motor potentials (MEP)
serving as a readout measure of excitability dynamics of local circuits. State–dependent
excitability regulation is quantified by comparing baseline MEP amplitudes with
amplitudes resulting under test conditions. Fortunately, the primary motor cortex is the
final overarching cortical output region [93] that generates speech behavior. Almost all
The neurobiological grounding of persistent chronic stuttering: From structure to function
12
dysfunctional computations accumulate at this site, making it an attractive target for
stuttering research even in the nonspeech domain [94–96].
Paired–pulse TMS protocols are suitable for testing intracortical inhibitory and
excitatory circuits [97]. Compared to single–pulse responses, MEP amplitudes are
reliably reduced when a subthreshold pulse is followed by a superthreshold pulse with a
short interstimulus interval of 2 to 3 ms. This inhibition is likely caused by excited
GABAergic interneurons [98, 99]. In stuttering, ipsilateral and contralateral tongue
representations in the left and right hemisphere showed a delayed inhibition of
intracortical circuits [100]. The opposite phenomenon, intracortical facilitation, can be
generated when applying paired pulses with longer interstimulus intervals of 10 to 15
ms. In this case, MEP amplitudes are amplified driven by the sensory input on excitatory
motor circuits [101••]. In stuttering, this facilitation is remarkably reduced in the
primary motor tongue area of both hemispheres [100]. Thus, intracortical excitability
regulation is hampered in an area that controls one of the main effectors of articulation.
The combined reductions of intracortical inhibition and facilitation indicate a restricted
range of neuronal dynamics at rest.
Although orofacial midline muscles such as the tongue are bilaterally innervated from
corticobulbar projections of both hemispheres, speech motor plans are primarily
encoded in the left hemisphere motor cortex. However, this functional asymmetry
towards the left orofacial motor cortex is missing in stuttering [102••], suggesting that a
lack of a speech–motor–planning–induced facilitation of the left orofacial motor cortex is
a major pathophysiological cause of disfluent speech production. This lack might be
related to the under–activation of this area [32] as frequently reported in neuroimaging
studies [44••] implicating a fallible transmission or integration of speech–planning–
related feedforward signals [20, 33, 103•]. Conversely, given the regularly reported
over–activation of the right primary motor cortex in stuttering [77, 85, 87, 104–106],
one might expect to see a speech–planning–induced facilitation of this site, but this
pattern was not noted [102••].
The right hemisphere is known to play a dominant role in prosody perception and
production [107–110]. One theory on stuttering suggests a misalignment of segmental
(phonemic) and suprasegmental (prosodic) phonetic features [111]. While consonantal
voice onsets and offsets act on a fast temporal scale with a resolution of 20 to 50 ms
[112], features such as rhythm, stress, and melody patterns span the temporal frame of a
whole utterance. The underlying auditory–to–articulatory alignment requires a precise
temporal coupling at multiple timescales. Fast auditory signals are preferentially
integrated in the left auditory cortex, while slow auditory signals are preferentially
integrated in the right auditory cortex [113]. Supposing the sensorimotor control of
slower suprasegmental features to be lateralized to the right hemisphere, and slow
auditory targets such as melody and stress mainly arise from the right frontal motor
regions. This would suggest speech–planning–induced facilitation of the right larynx
area rather than the right tongue area. Especially prosodic features are regulated at the
The neurobiological grounding of persistent chronic stuttering: From structure to function
13
laryngeal level, and notably the right primary motor larynx area shows increased
hemodynamic responses in persons who stutter [44••].
Conclusion and Outlook
Speech is regulated by co–activated neuronal circuits of large–scale dynamic networks
[114] and their dysfunction results in persistent stuttering. Reduced speech–related
dynamics in the left hemisphere and augmented right hemisphere involvement are
cardinal neuronal signs possibly caused by imbalanced wiring. This review lacks a
detailed description of subcortical contributions to stuttering behavior, although there is
converging evidence for cerebellar, thalamic, as well as basal ganglia irregularities [23,
50, 65, 86, 115–118]. We attach importance to the cortical dynamics within the speech–
related connectome as a result of new meta–analyses offering a condensed view of
imaging changes associated with chronic persistent stuttering. This is by no means
intended to scale down the importance of neuroimaging findings derived from every
individual study. Quite the contrary is true; it elucidates that current methods are not
sensitive enough to fully disentangle the brain dynamics of stuttering. However, our
review provides a focused view on the brain deficits of persons affected with persistent
stuttering, which might open the gate for a rethinking of how best to proceed. Future
studies employing TMS, deep brain stimulation [118], sophisticated neuroimaging
techniques [119, 120], and selected animal studies [121, 122•, 123•, 124•] may advance
mechanistic models [75] and may eventually guide success in therapeutic efforts aiming
to facilitate fluency. The following questions are of particular interest: What are the
interhemispheric interactions that allow fluent speech production and how do they
change in stuttering? Which brain dynamics characterize single acts of stuttering and
would it be possible to interfere with those sudden interruptions of the integrity of the
speech motor network? Is it possible to employ special hearing aids to facilitate the
maturation of temporo–parieto–frontal interactions necessary for stable sensorimotor
integration? Which neuromodulatory interventions could strengthen the left fronto–
parieto–temporal network to overcome the problem that only fluency–enhancing
techniques such as chorus speaking or speaking to the rhythm of a metronome
unburden the computational load of the frontal motor network [116] and bypass the
IFG, precentral gyrus, insula, putamen, nucleus caudatus, and globus pallidus?
Acknowledgments
Nicole E. Neef was supported by the Deutsche Forschungsgemeinschaft (NE1841/1–1).
The neurobiological grounding of persistent chronic stuttering: From structure to function
14
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