Localization of stuttering based on causal brain lesions.

Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering. Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16-77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45-87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18-43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering. In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (PFWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (PFWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (PFWE < 0.05). We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies.

Inefficient speech-motor control affects predictive speech comprehension: atypical electrophysiological correlates in stuttering.

Listeners predict upcoming information during language comprehension. However, how this ability is implemented is still largely unknown. Here, we tested the hypothesis proposing that language production mechanisms have a role in prediction. We studied 2 electroencephalographic correlates of predictability during speech comprehension-pre-target alpha-beta (8-30 Hz) power decrease and the post-target N400 event-related potential effect-in a population with impaired speech-motor control, i.e. adults who stutter (AWS), compared to typically fluent adults (TFA). Participants listened to sentences that could either constrain towards a target word or not, modulating its predictability. As a complementary task, participants also performed context-driven word production. Compared to TFA, AWS not only displayed atypical neural responses in production, but, critically, they showed a different pattern also in comprehension. Specifically, while TFA showed the expected pre-target power decrease, AWS showed a power increase in frontal regions, associated with speech-motor control. In addition, the post-target N400 effect was reduced for AWS with respect to TFA. Finally, we found that production and comprehension power changes were positively correlated in TFA, but not in AWS. Overall, the results support the idea that processes and neural structures prominently devoted to speech planning also support prediction during speech comprehension.

Elevated iron concentration in putamen and cortical speech motor network in developmental stuttering.

Theoretical accounts of developmental stuttering implicate dysfunctional cortico-striatal-thalamo-cortical motor loops through the putamen. However, the analysis of conventional MRI brain scans in individuals who stutter has failed to yield strong support for this theory in terms of reliable differences in the structure or function of the basal ganglia. Here, we performed quantitative mapping of brain tissue, which can be used to measure iron content alongside markers sensitive to myelin and thereby offers particular sensitivity to the measurement of iron-rich structures such as the basal ganglia. Analysis of these quantitative maps in 41 men and women who stutter and 32 individuals who are typically fluent revealed significant group differences in maps of R2*, indicative of higher iron content in individuals who stutter in the left putamen and in left hemisphere cortical regions important for speech motor control. Higher iron levels in brain tissue in individuals who stutter could reflect elevated dopamine levels or lysosomal dysfunction, both of which are implicated in stuttering. This study represents the first use of these quantitative measures in developmental stuttering and provides new evidence of microstructural differences in the basal ganglia and connected frontal cortical regions.

Stuttering related and psychosocial predictors of impact of stuttering.

OBJECTIVE: To investigate the psychosocial factors having an impact on persons with a stuttering problem. Methods: The correlation study was conducted from October 2016 to February 2018 at hospitals, speech clinics and educational institutes of Lahore. The sample comprised of young adults aged 16-30 years of either gender with stuttering problem. Data was collected using Stuttering Severity Instrument-4, Social Interaction Anxiety Scale-Urdu, Big Five Measure-20, Overall Assessment of the Speaker's Experience of Stuttering and the Urdu version of the shortened form of the Coping Orientation to Problems Experienced inventory. Data was analysed using SPSS 23. RESULTS: Of the 78 subjects, 66(84.6 %) were males and 12 (15.4 %) were females. There were 21(27%) subjects aged 16-19 years and 57(73%) with age range of 20-30 years. The overall mean age was 21.96±3.89 years. Mean age of onset was 4.59±1.29 years, while gradual onset and progressive stuttering was reported by 74(94.9 %). The Bilingual users 49(63%) reported to have frequent stuttering. Among the 43(55.1%) who had received treatment, 30(38%) received speech therapy and 26(33.3%) reported dissatisfaction. Stuttering severity and social anxiety were significantly positively correlated with all domains of impact of stuttering (p<0.05). Age, and duration were negatively correlated with day-to-day communication (p<0.05) and previous speech treatment showed negative association with impact on general knowledge about stuttering (p<0.05). Avoidance coping strategy had a significant relationship with all domains of impact (p<0.05). CONCLUSIONS: Severity of stuttering and social anxiety were found to have repercussions on people who stuttered, while avoidance coping was practised more to deal with the negative impact on reactions toward stuttering and quality of life.

IFNAR1 gene mutation may contribute to developmental stuttering in the Chinese population.

BACKGROUND: Developmental stuttering is the most common form of stuttering without apparent neurogenic or psychogenic impairment. Recently, whole-exome sequencing (WES) has been suggested to be a promising approach to study Mendelian disorders. METHODS: Here, we describe an application of WES to identify a gene potentially responsible for persistent developmental stuttering (PDS) by sequencing DNA samples from 10 independent PDS families and 11 sporadic cases. Sanger sequencing was performed for verification with samples obtained from 73 additional patients with sporadic cases. RESULTS: We first searched for cosegregating variants/candidate genes in a Chinese family (Family 0) by sequencing DNA obtained from 3 affected members and 3 controls. Next, we sequenced DNA samples obtained from 9 additional Chinese families (Families 1-9) with stuttering to verify the identified candidate genes. Intriguingly, we found that two missense variants (Leu552Pro and Lys428Gln) of interferon-alpha/beta receptor 1 (IFNAR1) cosegregated with stuttering in three independent families (Families 0, 5 and 9). Moreover, we found two additional mutations (Gly301Glu and Pro335del) in the IFNAR1 gene in 4 patients with sporadic cases by using WES or Sanger sequencing. Further receptor mutagenesis and cell signaling studies revealed that these IFNAR1 variants may impair the activity of type I IFN signaling. CONCLUSION: Our data indicate that IFNAR1 might be a potential pathogenic gene of PDS in the Chinese population.

Cerebral laterality as assessed by hand preference measures and developmental stuttering.

The causes of developmental stuttering, a neurodevelopmental communicative disorder, have not been elucidated to date. Neuroimaging studies suggest that atypical cerebral laterality could be one of such causal factors. Moreover, handedness, a behavioural index for cerebral laterality, has been linked to stuttering and recovery from it. However, findings are conflicting, possibly due to sample selection procedures, which typically rely on self-reported stuttering, and to the fact that handedness is typically assessed with regards to its direction rather than degree. We investigated the possible relationship between handedness and stuttering. This is the first study where children who stutter (CWS) were selected using clinical criteria as well as speech samples and where a non-Western population was studied. Findings from 83 CWS aged 3-9 years (mean = 6.43, SD = 1.84) and 90 age- and sex-matched children who do not stutter (mean = 6.45, SD = 1.71) revealed no differences in their hand preference scores as evaluated by parent-completed Edinburgh Handedness Inventory, for both direction and degree. The severity of stuttering was not found to correlate with the degree of handedness. We suggest that parents and professionals not treat left- or mixed-hand preference as a reason for concern with regards to stuttering.

Estimates of functional cerebral hemispheric differences in monolingual and bilingual people who stutter: dichotic listening paradigm.

Recent studies indicate functional cerebral hemispheric processing differences between monolinguals and bilinguals who stutter, as well as monolinguals and bilinguals who do not stutter. Eighty native German speakers, half of whom were also proficient speakers of English as a second language (L2), were assessed on a dichotic listening paradigm using CV syllables as stimuli. The participants were organised into four different groups according to speech status and language ability: 20 monolinguals who stutter, 20 bilinguals who stutter, 20 monolinguals who do not stutter, and 20 bilinguals who do not stutter. A right ear advantage (REA) was observed across all groups with no significant group differences in regard to hemispheric asymmetry. Although MWS (18 dB) and BWS (16 dB) crossed over to an LEA at an earlier point compared to the MWNS (5 dB) and BWNS (2 dB), the difference between groups was minor and not significant. Thus, a significant difference in REA resistance, as proposed by other researchers, was not reflected in the current study neither for people who stutter nor for bilinguals. In addition, no meaningful relationship was found between dichotic listening and stuttering severity, as well as the four language modalities (listening, speaking, reading, writing). Thus, we contend that neither stuttering nor bilingualism has any non-trivial effect on functional cerebral hemispheric differences in language processing in dichotic listening.

Abnormal neural response to phonological working memory demands in persistent developmental stuttering.

Persistent developmental stuttering is a neurological disorder that commonly manifests as a motor problem. Cognitive theories, however, hold that poorly developed cognitive skills are the origins of stuttering. Working memory (WM), a multicomponent cognitive system that mediates information maintenance and manipulation, is known to play an important role in speech production, leading us to postulate that the neurophysiological mechanisms underlying stuttering may be associated with a WM deficit. Using functional magnetic resonance imaging, we aimed to elucidate brain mechanisms in a phonological WM task in adults who stutter and controls. A right-lateralized compensatory mechanism for a deficit in the rehearsal process and neural disconnections associated with the central executive dysfunction were found. Furthermore, the neural abnormalities underlying the phonological WM were independent of memory load. This study demonstrates for the first time the atypical neural responses to phonological WM in PWS, shedding new light on the underlying cause of stuttering.

Structural connectivity of right frontal hyperactive areas scales with stuttering severity.

A neuronal sign of persistent developmental stuttering is the magnified coactivation of right frontal brain regions during speech production. Whether and how stuttering severity relates to the connection strength of these hyperactive right frontal areas to other brain areas is an open question. Scrutinizing such brain-behaviour and structure-function relationships aims at disentangling suspected underlying neuronal mechanisms of stuttering. Here, we acquired diffusion-weighted and functional images from 31 adults who stutter and 34 matched control participants. Using a newly developed structural connectivity measure, we calculated voxel-wise correlations between connection strength and stuttering severity within tract volumes that originated from functionally hyperactive right frontal regions. Correlation analyses revealed that with increasing speech motor deficits the connection strength increased in the right frontal aslant tract, the right anterior thalamic radiation, and in U-shaped projections underneath the right precentral sulcus. In contrast, with decreasing speech motor deficits connection strength increased in the right uncinate fasciculus. Additional group comparisons of whole-brain white matter skeletons replicated the previously reported reduction of fractional anisotropy in the left and right superior longitudinal fasciculus as well as at the junction of right frontal aslant tract and right superior longitudinal fasciculus in adults who stutter compared to control participants. Overall, our investigation suggests that right fronto-temporal networks play a compensatory role as a fluency enhancing mechanism. In contrast, the increased connection strength within subcortical-cortical pathways may be implied in an overly active global response suppression mechanism in stuttering. Altogether, this combined functional MRI-diffusion tensor imaging study disentangles different networks involved in the neuronal underpinnings of the speech motor deficit in persistent developmental stuttering.

Online cathodal transcranial direct current stimulation to the right homologue of Broca's area improves speech fluency in people who stutter.

AIM: Previous functional imaging studies demonstrate that people who stutter (PWS) exhibit over- and under-activation of Broca's and Wernicke's areas and their right hemisphere homologues when speaking. However, it is unclear whether this altered activation represents the neural cause of speech dysfluency or a secondary compensatory activation in PWS. To clarify the functional significance of the altered activation pattern in classic language areas and their right homologues, we examined whether the severity of stuttering was affected when the activation of these areas was modulated by brain stimulation. METHODS: While PWS read passages aloud, we applied transcranial direct current stimulation (tDCS) using electrode montages that included an anodal or cathodal electrode placed over one of the language areas and its right hemisphere homologue, with the second electrode placed over the contralateral supraorbital region. Each participant underwent both anodal and cathodal tDCS sessions, each of which included a sham stimulation. Effects of stimulation polarity and electrode location on the frequency of stuttering were analyzed. RESULTS: We observed a significant interaction between polarity and location on the frequency of stuttering. Follow-up analyses revealed that a tDCS montage including the cathodal electrode over right Broca's area (RB) significantly reduced the frequency of stuttering. CONCLUSION: The results indicated that stuttering severity was ameliorated when overactivation in RB was reduced by tDCS. This observation further suggests that speech dysfluency in PWS may be caused either by functional alteration in RB or by abnormal activation in speech motor control areas that are connected with RB.

Separation of trait and state in stuttering.

Stuttering is a disorder in which the smooth flow of speech is interrupted. People who stutter show structural and functional abnormalities in the speech and motor system. It is unclear whether functional differences reflect general traits of the disorder or are specifically related to the dysfluent speech state. We used a hierarchical approach to separate state and trait effects within stuttering. We collected sparse-sampled functional MRI during two overt speech tasks (sentence reading and picture description) in 17 people who stutter and 16 fluent controls. Separate analyses identified indicators of: (1) general traits of people who stutter; (2) frequency of dysfluent speech states in subgroups of people who stutter; and (3) the differences between fluent and dysfluent states in people who stutter. We found that reduced activation of left auditory cortex, inferior frontal cortex bilaterally, and medial cerebellum were general traits that distinguished fluent speech in people who stutter from that of controls. The stuttering subgroup with higher frequency of dysfluent states during scanning (n = 9) had reduced activation in the right subcortical grey matter, left temporo-occipital cortex, the cingulate cortex, and medial parieto-occipital cortex relative to the subgroup who were more fluent (n = 8). Finally, during dysfluent states relative to fluent ones, there was greater activation of inferior frontal and premotor cortex extending into the frontal operculum, bilaterally. The above differences were seen across both tasks. Subcortical state effects differed according to the task. Overall, our data emphasise the independence of trait and state effects in stuttering.

Reduced perfusion in Broca's area in developmental stuttering.

OBJECTIVE: To study resting cerebral blood flow in children and adults with developmental stuttering. METHODS: We acquired pulsed arterial spin labeling magnetic resonance imaging data in 26 participants with stuttering and 36 healthy, fluent controls. While covarying for age, sex, and IQ, we compared perfusion values voxel-wise across diagnostic groups and assessed correlations of perfusion with stuttering severity within the stuttering group and with measures of motor speed in both groups. RESULTS: We detected lower regional Cerebral Blood Flow (rCBF) at rest in the stuttering group compared with healthy controls in Broca's area bilaterally and the superior frontal gyrus. rCBF values in Broca's area bilaterally correlated inversely with the severity of stuttering and extended posteriorly into other portions of the language loop. We also found increased rCBF in cerebellar nuclei and parietal cortex in the stuttering group compared with healthy controls. Findings were unchanged in child-only analyses and when excluding participants with comorbid illnesses or those taking medication. CONCLUSIONS: rCBF is reduced in Broca's region in persons who stutter. More severe stuttering is associated with even greater reductions in rCBF to Broca's region, additive to the underlying putative trait reduction in rCBF relative to control values. Moreover, a greater abnormality in rCBF in the posterior language loop is associated with more severe symptoms, suggesting that a common pathophysiology throughout the language loop likely contributes to stuttering severity. Hum Brain Mapp 38:1865-1874, 2017. © 2017 Wiley Periodicals, Inc.

Estimates of functional cerebral hemispheric differences in monolingual and bilingual people who stutter: Visual hemifield paradigm.

The relationship between stuttering and bilingualism to functional cerebral hemispheric processing was examined using a visual hemifield paradigm. Eighty native German speakers, half of whom were also proficient speakers of English as a second language (L2), were recruited. The participants were organised into four different groups according to speech status and language ability: 20 monolinguals who stutter, 20 bilinguals who stutter, 20 monolinguals who do not stutter, and 20 bilinguals who do not stutter. All participants completed a task involving selective identification of common objects simultaneously presented to both visual fields. Overall, an LVF advantage was observed across all groups with no significant group differences in regard to hemispheric asymmetry. However, both bilingual groups showed faster reaction times and fewer identification errors than the two monolingual groups. A prevailing finding was that bilingualism seems to offset deficits in executive functioning associated with stuttering. Hence, the results lend support to previous findings implicating the benefits of bilingualism.

Estimates of functional cerebral hemispheric differences in monolingual and bilingual people who stutter: Dual-task paradigm.

The inter-relationship of stuttering and bilingualism to functional cerebral hemispheric processing was examined on a dual-task paradigm. Eighty native German (L1) speakers, half of whom were sequential bilinguals (L2 = English), were recruited. The participants (mean age = 38.9 years) were organised into four different groups according to speech status and language ability: 20 bilinguals who stutter (BWS), 20 monolinguals who stutter (MWS), 20 bilinguals who do not stutter (BWNS), and 20 monolinguals who do not stutter (MWNS). All participants completed a dual-task paradigm involving simultaneous speaking and finger tapping. No performance differences between BWS and BWNS were found. In contrast, MWS showed greater dual-task interference compared to BWS and MWNS, as well as greater right- than left-hand disruption. A prevailing finding was that bilingualism seems to offset deficits in executive functioning associated with stuttering. Cognitive reserve may have been reflected in the present study, resulting in a bilingual advantage.

Stuttering as a trait or state - an ALE meta-analysis of neuroimaging studies.

Stuttering is a speech disorder characterised by repetitions, prolongations and blocks that disrupt the forward movement of speech. An earlier meta-analysis of brain imaging studies of stuttering (Brown et al., 2005) revealed a general trend towards rightward lateralization of brain activations and hyperactivity in the larynx motor cortex bilaterally. The present study sought not only to update that meta-analysis with recent work but to introduce an important distinction not present in the first study, namely the difference between 'trait' and 'state' stuttering. The analysis of trait stuttering compares people who stutter (PWS) with people who do not stutter when behaviour is controlled for, i.e., when speech is fluent in both groups. In contrast, the analysis of state stuttering examines PWS during episodes of stuttered speech compared with episodes of fluent speech. Seventeen studies were analysed using activation likelihood estimation. Trait stuttering was characterised by the well-known rightward shift in lateralization for language and speech areas. State stuttering revealed a more diverse pattern. Abnormal activation of larynx and lip motor cortex was common to the two analyses. State stuttering was associated with overactivation in the right hemisphere larynx and lip motor cortex. Trait stuttering was associated with overactivation of lip motor cortex in the right hemisphere but underactivation of larynx motor cortex in the left hemisphere. These results support a large literature highlighting laryngeal and lip involvement in the symptomatology of stuttering, and disambiguate two possible sources of activation in neuroimaging studies of persistent developmental stuttering.

Influence of Methylphenidate on the Frequency of Stuttering: A Randomized Controlled Trial.

BACKGROUND: Recently, a case report described a decrease in frequency of stuttering after intake of methylphenidate (MPH). OBJECTIVE: This study was undertaken to investigate if this effect could again be reproduced in a population of young healthy male adult persons with developmental stuttering. METHODS: A double-blind randomized crossover trial, with a 2-week washout period, including 15 Dutch-speaking young healthy persons with developmental stuttering, assessed the effects of a single dose of 20 mg MPH compared with placebo on stuttering. Dependent and 1-sample t tests were used to detect significant differences. The end point was the number of stutter moments and self-perceived improvement. RESULTS: MPH yielded a significant decrease in the number of stutter moments when reading and speaking (P = 0.002), which was not the case with placebo (P = 0.090). There was a significant improvement from baseline after intake of MPH as compared with placebo (P = 0.003). Self-perceived improvement with MPH was not significantly better as compared with placebo (P = 0.28). CONCLUSIONS: This study showed that the participants had an objective statistically significant decrease in the frequency of stuttering with MPH, and this was not the case with placebo. This was also the case for a reduction in stutter moments when reading out loud and speaking spontaneously. However, this result was not subjectively perceived by the participants.

Scores on Riley's stuttering severity instrument versions three and four for samples of different length and for different types of speech material.

Riley stated that the minimum speech sample length necessary to compute his stuttering severity estimates was 200 syllables. This was investigated. Procedures supplied for the assessment of readers and non-readers were examined to see whether they give equivalent scores. Recordings of spontaneous speech samples from 23 young children (aged between 2 years 8 months and 6 years 3 months) and 31 older children (aged between 10 years 0 months and 14 years 7 months) were made. Riley's severity estimates were scored on extracts of different lengths. The older children provided spontaneous and read samples, which were scored for severity according to reader and non-reader procedures. Analysis of variance supported the use of 200-syllable-long samples as the minimum necessary for obtaining severity scores. There was no significant difference in SSI-3 scores for the older children when the reader and non-reader procedures were used. Samples that are 200-syllables long are the minimum that is appropriate for obtaining stable Riley's severity scores. The procedural variants provide similar severity scores.

Corrigendum: Identifying stuttering in Arabic speakers who stutter: development of a non-word repetition task and preliminary results.

[This corrects the article DOI: 10.3389/fped.2022.750126.].

Can listeners predict whether or not a stutter follows a stretch of fluent speech?

PURPOSE: Neurophysiological studies report that people who stutter (PWS) exhibit enhanced motor preparation before they stutter. This motor preparation pattern raises the possibility of detecting upcoming stutter moments before they actually occur. This study examined whether these motor preparation differences are detectable by listeners in the corresponding acoustic signal, thereby allowing them to predict upcoming stuttering moments. If so, features in these acoustic patterns could potentially be employed by computational procedures to automate detection of upcoming stutters and to target auditory feedback alterations specifically on these locations. METHODS: Forty healthy normal-hearing participants (aged 18-30) listened to seemingly fluent speech extracts each of which was either followed by a fluent (control condition) or stuttered (experimental condition) moment after the fluent extract. Participants listened to each extract and rated the likelihood of the speaker stuttering on the next word on a scale of 1 (very unlikely) to 7 (very likely) as to whether they thought there was a subsequent stutter. Several measures were made on the speech extracts which were examined either as control requirements to ensure no differences between experimental and control material or as covariates to assess any effects they had on judgments between the two conditions. RESULTS: Listeners gave significantly higher stutter-likelihood ratings for speech originally followed by a stuttered moment although effects were small. CONCLUSIONS: Naive listeners rated speech extracts that were subsequently followed by stuttered moments as more likely to be followed by a stutter than those that were followed by fluent words after the effects of significant covariates were excluded.

Psychedelics in developmental stuttering to modulate brain functioning: a new therapeutic perspective?

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpinnings of DS -specifically, brain metabolic and default mode/social-cognitive networks (DMN/SCN) anomalies- arguing that psychedelic compounds might be considered and investigated (e.g., in randomized clinical trials) for treatment of DS. The neural background of DS is likely to be heterogeneous, and some contribution from genetically determinants of metabolic deficiencies in the basal ganglia and speech-motor cortical regions are thought to play a role in appearance of DS symptoms, which possibly results in a cascade of events contributing to impairments in speech-motor execution. In persistent DS, the difficulties of speech are often linked to a series of associated aspects such as social anxiety and social avoidance. In this context, the SCN and DMN (also influencing a series of fronto-parietal, somato-motor, and attentional networks) may have a role in worsening dysfluencies. Interestingly, brain metabolism and SCN/DMN connectivity can be modified by psychedelics, which have been shown to improve clinical evidence of some psychiatric conditions (e.g., depression, post-traumatic stress disorder, etc.) associated with psychological constructs such as rumination and social anxiety, which also tend to be present in persistent DS. To date, while there have been no controlled trials on the effects of psychedelics in DS, anecdotal evidence suggests that these agents may have beneficial effects on stuttering and its associated characteristics. We suggest that psychedelics warrant investigation in DS.