Knowns and unknowns about the neurobiology of stuttering.

Stuttering occurs in early childhood during a dynamic phase of brain and behavioral development. The latest studies examining children at ages close to this critical developmental period have identified early brain alterations that are most likely linked to stuttering, while spontaneous recovery appears related to increased inter-area connectivity. By contrast, therapy-driven improvement in adults is associated with a functional reorganization within and beyond the speech network. The etiology of stuttering, however, remains enigmatic. This Unsolved Mystery highlights critical questions and points to neuroimaging findings that could inspire future research to uncover how genetics, interacting neural hierarchies, social context, and reward circuitry contribute to the many facets of stuttering.

Dissecting structural connectivity of the left and right inferior frontal cortex in children who stutter.

Inferior frontal cortex pars opercularis (IFCop) features a distinct cerebral dominance and vast functional heterogeneity. Left and right IFCop are implicated in developmental stuttering. Weak left IFCop connections and divergent connectivity of hyperactive right IFCop regions have been related to impeded speech. Here, we reanalyzed diffusion magnetic resonance imaging data from 83 children (41 stuttering). We generated connection probability maps of functionally segregated area 44 parcels and calculated hemisphere-wise analyses of variance. Children who stutter showed reduced connectivity of executive, rostral-motor, and caudal-motor corticostriatal projections from the left IFCop. We discuss this finding in the context of tracing studies from the macaque area 44, which leads to the need to reconsider current models of speech motor control. Unlike the left, the right IFCop revealed increased connectivity of the inferior posterior ventral parcel and decreased connectivity of the posterior dorsal parcel with the anterior insula, particularly in stuttering boys. This divergent connectivity pattern in young children adds to the debate on potential core deficits in stuttering and challenges the theory that right hemisphere differences might exclusively indicate compensatory changes that evolve from lifelong exposure. Instead, early right prefrontal connectivity differences may reflect additional brain signatures of aberrant cognition-emotion-action influencing speech motor control.

Anomalous morphology in left hemisphere motor and premotor cortex of children who stutter.

Stuttering is a neurodevelopmental disorder that affects the smooth flow of speech production. Stuttering onset occurs during a dynamic period of development when children first start learning to formulate sentences. Although most children grow out of stuttering naturally, ∼1% of all children develop persistent stuttering that can lead to significant psychosocial consequences throughout one's life. To date, few studies have examined neural bases of stuttering in children who stutter, and even fewer have examined the basis for natural recovery versus persistence of stuttering. Here we report the first study to conduct surface-based analysis of the brain morphometric measures in children who stutter. We used FreeSurfer to extract cortical size and shape measures from structural MRI scans collected from the initial year of a longitudinal study involving 70 children (36 stuttering, 34 controls) in the 3-10-year range. The stuttering group was further divided into two groups: persistent and recovered, based on their later longitudinal visits that allowed determination of their eventual clinical outcome. A region of interest analysis that focused on the left hemisphere speech network and a whole-brain exploratory analysis were conducted to examine group differences and group × age interaction effects. We found that the persistent group could be differentiated from the control and recovered groups by reduced cortical thickness in left motor and lateral premotor cortical regions. The recovered group showed an age-related decrease in local gyrification in the left medial premotor cortex (supplementary motor area and and pre-supplementary motor area). These results provide strong evidence of a primary deficit in the left hemisphere speech network, specifically involving lateral premotor cortex and primary motor cortex, in persistent developmental stuttering. Results further point to a possible compensatory mechanism involving left medial premotor cortex in those who recover from childhood stuttering.

Auditory-motor adaptation is reduced in adults who stutter but not in children who stutter.

Previous studies have shown that adults who stutter produce smaller corrective motor responses to compensate for unexpected auditory perturbations in comparison to adults who do not stutter, suggesting that stuttering may be associated with deficits in integration of auditory feedback for online speech monitoring. In this study, we examined whether stuttering is also associated with deficiencies in integrating and using discrepancies between expected and received auditory feedback to adaptively update motor programs for accurate speech production. Using a sensorimotor adaptation paradigm, we measured adaptive speech responses to auditory formant frequency perturbations in adults and children who stutter and their matched nonstuttering controls. We found that the magnitude of the speech adaptive response for children who stutter did not differ from that of fluent children. However, the adaptation magnitude of adults who stutter in response to auditory perturbation was significantly smaller than the adaptation magnitude of adults who do not stutter. Together these results indicate that stuttering is associated with deficits in integrating discrepancies between predicted and received auditory feedback to calibrate the speech production system in adults but not children. This auditory-motor integration deficit thus appears to be a compensatory effect that develops over years of stuttering.

White matter developmental trajectories associated with persistence and recovery of childhood stuttering.

Stuttering affects the fundamental human ability of fluent speech production, and can have a significant negative impact on an individual's psychosocial development. While the disorder affects about 5% of all preschool children, approximately 80% of them recover naturally within a few years of stuttering onset. The pathophysiology and neuroanatomical development trajectories associated with persistence and recovery of stuttering are still largely unknown. Here, the first mixed longitudinal diffusion tensor imaging (DTI) study of childhood stuttering has been reported. A total of 195 high quality DTI scans from 35 children who stutter (CWS) and 43 controls between 3 and 12 years of age were acquired, with an average of three scans per child, each collected approximately a year apart. Fractional anisotropy (FA), a measure reflecting white matter structural coherence, was analyzed voxel-wise to examine group and age-related differences using a linear mixed-effects (LME) model. Results showed that CWS exhibited decreased FA relative to controls in the left arcuate fasciculus, underlying the inferior parietal and posterior temporal areas, and the mid body of corpus callosum. Further, white matter developmental trajectories reflecting growth rate of these tract regions differentiated children with persistent stuttering from those who recovered from stuttering. Specifically, a reduction in FA growth rate (i.e., slower FA growth with age) in persistent children relative to fluent controls in the left arcuate fasciculus and corpus callosum was found, which was not evident in recovered children. These findings provide first glimpses into the possible neural mechanisms of onset, persistence, and recovery of childhood stuttering. Hum Brain Mapp 38:3345-3359, 2017. © 2017 Wiley Periodicals, Inc.

White matter neuroanatomical differences in young children who stutter.

The ability to express thoughts through fluent speech production is a most human faculty, one that is often taken for granted. Stuttering, which disrupts the smooth flow of speech, affects 5% of preschool-age children and 1% of the general population, and can lead to significant communication difficulties and negative psychosocial consequences throughout one's lifetime. Despite the fact that symptom onset typically occurs during early childhood, few studies have yet examined the possible neural bases of developmental stuttering during childhood. Here we present a diffusion tensor imaging study that examined white matter measures reflecting neuroanatomical connectivity (fractional anisotropy) in 77 children [40 controls (20 females), 37 who stutter (16 females)] between 3 and 10 years of age. We asked whether previously reported anomalous white matter measures in adults and older children who stutter that were found primarily in major left hemisphere tracts (e.g. superior longitudinal fasciculus) are also present in younger children who stutter. All children exhibited normal speech, language, and cognitive development as assessed through a battery of assessments. The two groups were matched in chronological age and socioeconomic status. Voxel-wise whole brain comparisons using tract-based spatial statistics and region of interest analyses of fractional anisotropy were conducted to examine white matter changes associated with stuttering status, age, sex, and stuttering severity. Children who stutter exhibited significantly reduced fractional anisotropy relative to controls in white matter tracts that interconnect auditory and motor structures, corpus callosum, and in tracts interconnecting cortical and subcortical areas. In contrast to control subjects, fractional anisotropy changes with age were either stagnant or showed dissociated development among major perisylvian brain areas in children who stutter. These results provide first glimpses into the neuroanatomical bases of early childhood stuttering, and possible white matter developmental changes that may lead to recovery versus persistent stuttering. The white matter changes point to possible structural connectivity deficits in children who stutter, in interrelated neural circuits that enable skilled movement control through efficient sensorimotor integration and timing of movements.

Neural network connectivity differences in children who stutter.

Affecting 1% of the general population, stuttering impairs the normally effortless process of speech production, which requires precise coordination of sequential movement occurring among the articulatory, respiratory, and resonance systems, all within millisecond time scales. Those afflicted experience frequent disfluencies during ongoing speech, often leading to negative psychosocial consequences. The aetiology of stuttering remains unclear; compared to other neurodevelopmental disorders, few studies to date have examined the neural bases of childhood stuttering. Here we report, for the first time, results from functional (resting state functional magnetic resonance imaging) and structural connectivity analyses (probabilistic tractography) of multimodal neuroimaging data examining neural networks in children who stutter. We examined how synchronized brain activity occurring among brain areas associated with speech production, and white matter tracts that interconnect them, differ in young children who stutter (aged 3-9 years) compared with age-matched peers. Results showed that children who stutter have attenuated connectivity in neural networks that support timing of self-paced movement control. The results suggest that auditory-motor and basal ganglia-thalamocortical networks develop differently in stuttering children, which may in turn affect speech planning and execution processes needed to achieve fluent speech motor control. These results provide important initial evidence of neurological differences in the early phases of symptom onset in children who stutter.

Research updates in neuroimaging studies of children who stutter.

In the past two decades, neuroimaging investigations of stuttering have led to important discoveries of structural and functional brain differences in people who stutter, providing significant clues to the neurological basis of stuttering. One major limitation, however, has been that most studies so far have only examined adults who stutter, whose brain and behavior likely would have adopted compensatory reactions to their stuttering; these confounding factors have made interpretations of the findings difficult. Developmental stuttering is a neurodevelopmental condition, and like many other neurodevelopmental disorders, stuttering is associated with an early childhood onset of symptoms and greater incidence in males relative to females. More recent studies have begun to examine children who stutter using various neuroimaging techniques that allow examination of functional neuroanatomy and interaction of major brain areas that differentiate children who stutter compared with age-matched controls. In this article, I review these more recent neuroimaging investigations of children who stutter, in the context of what we know about typical brain development, neuroplasticity, and sex differences relevant to speech and language development. Although the picture is still far from complete, these studies have potential to provide information that can be used as early objective markers, or prognostic indicators, for persistent stuttering in the future. Furthermore, these studies are the first steps in finding potential neural targets for novel therapies that may involve modulating neuroplastic growth conducive to developing and maintaining fluent speech, which can be applied to treatment of young children who stutter.

Contemporary clinical conversations about stuttering: What does brain imaging research mean to clinicians?

PURPOSE: To discuss among neuroscientists and community speech-language pathologists what brain imaging research means to clinicians. METHOD: Two university neuroscientists and two speech-language pathologists in private practice discussed the matter. Written conversational turns in an exchange were limited to 100 words each. When that written dialogue was concluded, each participant provided 200 words of final reflection about the matter. RESULT: For now, neuroscience treatments are not available for clinicians to use. But sometime in the future, a critical mass of neuroscientists will likely produce such treatments. The neuroscientists expressed diverse views about the methods that might be used for that to occur. CONCLUSION: Neuroscience does have practical clinical application at present and, in a way, that does not exclude a concurrent influence of the social model of disability. As such, the current practices of clinicians are supported by basic neuroscience research.

Evidence for planning and motor subtypes of stuttering based on resting state functional connectivity.

We tested the hypothesis, generated from the Gradient Order Directions Into Velocities of Articulators (GODIVA) model, that adults who stutter (AWS) may comprise subtypes based on differing connectivity within the cortico-basal ganglia planning or motor loop. Resting state functional connectivity from 91 AWS and 79 controls was measured for all GODIVA model connections. Based on a principal components analysis, two connections accounted for most of the connectivity variability in AWS: left thalamus - left posterior inferior frontal sulcus (planning loop component) and left supplementary motor area - left ventral premotor cortex (motor loop component). A k-means clustering algorithm using the two connections revealed three clusters of AWS. Cluster 1 was significantly different from controls in both connections; Cluster 2 was significantly different in only the planning loop; and Cluster 3 was significantly different in only the motor loop. These findings suggest the presence of planning and motor subtypes of stuttering.

Brain response to errors in children who stutter.

PURPOSE: Heightened rates of social anxiety have been reported in adults who stutter (AWS), but it is unclear whether anxiety is heightened also in children who stutter (CWS). Objective neurophysiological responses such as the error-related negativity (ERN) have been associated with anxiety, and ERN was reported to be increased in AWS. In this study, we examined whether ERN and error positivity (Pe) are increased in CWS. We further characterized ERN associations with age and anxiety in CWS relative to children who do not stutter (CWNS). METHODS: EEG data were recorded from twenty-four CWS and twenty-four matched CWNS aged 3-9 years as they performed a Go/No-Go task. Parent-reported anxiety, and child-reported speech-associated attitude measures were collected. Linear regression models tested the effects of age, group, and their interaction, and the effects of anxiety, group, and their interaction on ERN and Pe. RESULTS: Contrary to expectations, no ERN or Pe difference were observed between CWS and CWNS. However, larger ERN amplitudes were associated with older age in CWS but not CWNS, suggesting altered development of the error monitoring system in CWS. Association of Pe with anxiety also differed between groups: smaller Pe amplitudes were associated with higher level of parent-reported child anxiety in CWNS but not in CWS. Neither anxiety nor self-reported communication attitude differed between groups. CONCLUSIONS: Brain responses to errors were overall comparable between CWS and CWNS. However, CWS differed in how error monitoring responses varied with age and with anxiety levels. More research is warranted to examine how these factors contribute to persistent stuttering.

Brain activity during the preparation and production of spontaneous speech in children with persistent stuttering.

Speech production forms the basis for human verbal communication. Though fluent speech production is effortless and automatic for most people, it is disrupted in speakers who stutter, who experience difficulties especially during spontaneous speech and at utterance onsets. Brain areas comprising the basal ganglia thalamocortical (BGTC) motor loop have been a focus of interest in the context of stuttering, given this circuit's critical role in initiating and sequencing connected speech. Despite the importance of better understanding the role of the BGTC motor loop in supporting overt, spontaneous speech production, capturing brain activity during speech has been challenging to date, due to fMRI artifacts associated with severe head motions during speech production. Here, using an advanced technique that removes speech-related artifacts from fMRI signals, we examined brain activity occurring immediately before, and during, overt spontaneous speech production in 22 children with persistent stuttering (CWS) and 18 children who do not stutter (controls) in the 5-to-12-year age range. Brain activity during speech production was compared in two conditions: spontaneous speech (i.e., requiring language formulation) and automatic speech (i.e., overlearned word sequences). Compared to controls, CWS exhibited significantly reduced left premotor activation during spontaneous speech production but not during automatic speech. Moreover, CWS showed an age-related reduction in left putamen and thalamus activation during speech preparation. These results provide further evidence that stuttering is associated with functional deficits in the BGTC motor loop, which are exacerbated during spontaneous speech production.

Neural oscillatory activity and connectivity in children who stutter during a non-speech motor task.

BACKGROUND: Neural motor control rests on the dynamic interaction of cortical and subcortical regions, which is reflected in the modulation of oscillatory activity and connectivity in multiple frequency bands. Motor control is thought to be compromised in developmental stuttering, particularly involving circuits in the left hemisphere that support speech, movement initiation, and timing control. However, to date, evidence comes from adult studies, with a limited understanding of motor processes in childhood, closer to the onset of stuttering. METHODS: We investigated the neural control of movement initiation in children who stutter and children who do not stutter by evaluating transient changes in EEG oscillatory activity (power, phase locking to button press) and connectivity (phase synchronization) during a simple button press motor task. We compared temporal changes in these oscillatory dynamics between the left and right hemispheres and between children who stutter and children who do not stutter, using mixed-model analysis of variance. RESULTS: We found reduced modulation of left hemisphere oscillatory power, phase locking to button press and phase connectivity in children who stutter compared to children who do not stutter, consistent with previous findings of dysfunction within the left sensorimotor circuits. Interhemispheric connectivity was weaker at lower frequencies (delta, theta) and stronger in the beta band in children who stutter than in children who do not stutter. CONCLUSIONS: Taken together, these findings indicate weaker engagement of the contralateral left motor network in children who stutter even during low-demand non-speech tasks, and suggest that the right hemisphere might be recruited to support sensorimotor processing in childhood stuttering. Differences in oscillatory dynamics occurred despite comparable task performance between groups, indicating that an altered balance of cortical activity might be a core aspect of stuttering, observable during normal motor behavior.

Brain developmental trajectories associated with childhood stuttering persistence and recovery.

Stuttering is a neurodevelopmental disorder affecting 5-8 % of preschool-age children, continuing into adulthood in 1 % of the population. The neural mechanisms underlying persistence and recovery from stuttering remain unclear and little information exists on neurodevelopmental anomalies in children who stutter (CWS) during preschool age, when stuttering symptoms typically first emerge. Here we present findings from the largest longitudinal study of childhood stuttering to date, comparing children with persistent stuttering (pCWS) and those who later recovered from stuttering (rCWS) with age-matched fluent peers, to examine the developmental trajectories of both gray matter volume (GMV) and white matter volume (WMV) using voxel-based morphometry. A total of 470 MRI scans were analyzed from 95 CWS (72 pCWS and 23 rCWS) and 95 fluent peers between 3 and 12 years of age. We examined overall group and group by age interactions in GMV and WMV in preschool age (3-5 years old) and school age (6-12 years old) CWS and controls, controlling for sex, IQ, intracranial volume, and socioeconomic status. The results provide broad support for a possible basal ganglia-thalamocortical (BGTC) network deficit starting in the earliest phases of the disorder and point to normalization or compensation of earlier occurring structural changes associated with stuttering recovery.

Auditory rhythm discrimination in adults who stutter: An fMRI study.

Rhythm perception deficits have been linked to neurodevelopmental disorders affecting speech and language. Children who stutter have shown poorer rhythm discrimination and attenuated functional connectivity in rhythm-related brain areas, which may negatively impact timing control required for speech. It is unclear whether adults who stutter (AWS), who are likely to have acquired compensatory adaptations in response to rhythm processing/timing deficits, are similarly affected. We compared rhythm discrimination in AWS and controls (total n = 36) during fMRI in two matched conditions: simple rhythms that consistently reinforced a periodic beat, and complex rhythms that did not (requiring greater reliance on internal timing). Consistent with an internal beat deficit hypothesis, behavioral results showed poorer complex rhythm discrimination for AWS than controls. In AWS, greater stuttering severity was associated with poorer rhythm discrimination. AWS showed increased activity within beat-based timing regions and increased functional connectivity between putamen and cerebellum (supporting interval-based timing) for simple rhythms.

Combined Cognitive Training and Transcranial Direct Current Stimulation in Neuropsychiatric Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Treatments for cognitive dysfunction in neuropsychiatric conditions are urgently needed. Cognitive training and transcranial direct current stimulation (tDCS) hold promise, and there is growing interest in combined or multimodal treatments, though studies to date have had small samples and inconsistent results. METHODS: A systematic review and meta-analysis was completed. Retained studies included cognitive training combined with active or sham tDCS in a neuropsychiatric population and reported a posttreatment cognitive outcome. Meta-analyses included effect sizes comparing cognitive training plus active tDCS and cognitive training plus sham tDCS in 5 cognitive domains. Risk of bias in included studies and across studies was explored. RESULTS: Fifteen studies were included: 10 in neurodegenerative disorders and 5 in psychiatric disorders (n = 629). There were several tDCS montages, though two-thirds of studies placed the anode over the left dorsolateral prefrontal cortex. A wide variety of cognitive training types and outcome measures were reported. There was a small, statistically significant effect of combined treatment on measures of attention/working memory, as well as small and non-statistically significant effects favoring combined treatment on global cognition and language. There was no evidence of bias in individual studies but some evidence of nonreporting or small-study bias across studies. CONCLUSIONS: These results may provide preliminary support for the efficacy of combined cognitive training and tDCS on measures of attention/working memory. More data are needed, particularly via studies that explicitly align the cognitive ability of interest, stimulation target, training type, and outcome measures.

A comparison of structural morphometry in children and adults with persistent developmental stuttering.

This cross-sectional study aimed to differentiate earlier occurring neuroanatomical differences that may reflect core deficits in stuttering versus changes associated with a longer duration of stuttering by analysing structural morphometry in a large sample of children and adults who stutter and age-matched controls. Whole-brain T1-weighted structural scans were obtained from 166 individuals who stutter (74 children, 92 adults; ages 3-58) and 191 controls (92 children, 99 adults; ages 3-53) from eight prior studies in our laboratories. Mean size and gyrification measures were extracted using FreeSurfer software for each cortical region of interest. FreeSurfer software was also used to generate subcortical volumes for regions in the automatic subcortical segmentation. For cortical analyses, separate ANOVA analyses of size (surface area, cortical thickness) and gyrification (local gyrification index) measures were conducted to test for a main effect of diagnosis (stuttering, control) and the interaction of diagnosis-group with age-group (children, adults) across cortical regions. Cortical analyses were first conducted across a set of regions that comprise the speech network and then in a second whole-brain analysis. Next, separate ANOVA analyses of volume were conducted across subcortical regions in each hemisphere. False discovery rate corrections were applied for all analyses. Additionally, we tested for correlations between structural morphometry and stuttering severity. Analyses revealed thinner cortex in children who stutter compared with controls in several key speech-planning regions, with significant correlations between cortical thickness and stuttering severity. These differences in cortical size were not present in adults who stutter, who instead showed reduced gyrification in the right inferior frontal gyrus. Findings suggest that early cortical anomalies in key speech planning regions may be associated with stuttering onset. Persistent stuttering into adulthood may result from network-level dysfunction instead of focal differences in cortical morphometry. Adults who stutter may also have a more heterogeneous neural presentation than children who stutter due to their unique lived experiences.

Evidence of left inferior frontal-premotor structural and functional connectivity deficits in adults who stutter.

The neurophysiological basis for stuttering may involve deficits that affect dynamic interactions among neural structures supporting fluid speech processing. Here, we examined functional and structural connectivity within corticocortical and thalamocortical loops in adults who stutter. For functional connectivity, we placed seeds in the left and right inferior frontal Brodmann area 44 (BA44) and in the ventral lateral nucleus (VLN) of the thalamus. Subject-specific seeds were based on peak activation voxels captured during speech and nonspeech tasks using functional magnetic resonance imaging. Psychophysiological interaction (PPI) was used to find brain regions with heightened functional connectivity with these cortical and subcortical seeds during speech and nonspeech tasks. Probabilistic tractography was used to track white matter tracts in each hemisphere using the same seeds. Both PPI and tractrography supported connectivity deficits between the left BA44 and the left premotor regions, while connectivity among homologous right hemisphere structures was significantly increased in the stuttering group. No functional connectivity differences between BA44 and auditory regions were found between groups. The functional connectivity results derived from the VLN seeds were less definitive and were not supported by the tractography results. Our data provide strongest support for deficient left hemisphere inferior frontal to premotor connectivity as a neural correlate of stuttering.

Tract profiles of the cerebellar peduncles in children who stutter.

Cerebellar-cortical loops comprise critical neural circuitry that supports self-initiated movements and motor adjustments in response to perceived errors, functions that are affected in stuttering. It is unknown whether structural aspects of cerebellar circuitry are affected in stuttering, particularly in children close to symptom onset. Here we examined white matter diffusivity characteristics of the three cerebellar peduncles (CPs) based on diffusion MRI (dMRI) data collected from 41 children who stutter (CWS) and 42 controls in the 3-11 years range. We hypothesized that CWS would exhibit decreased fractional anisotropy (FA) in the right CPs given the contralateral connectivity of the cerebellar-cortical loops and past reports of structural differences in left cortical areas in stuttering speakers. Automatic Fiber Quantification (AFQ) was used to track and segment cerebellar white matter pathways and to extract diffusivity measures. We found significant group differences for FA in the right inferior CP (ICP) only: controls showed significantly higher FA in the right ventral ICP compared to CWS, controlling for age, sex, and verbal IQ. Furthermore, FA of right ICP was negatively correlated with stuttering frequency in CWS. These results suggest an early developmental difference in the right ICP for CWS compared to age-matched peers, which may indicate an alteration in error processing, a function previously linked to the ICP. Lower FA here may impact error monitoring and sensory input processing to guide motor corrections. Further longitudinal investigations in children may provide additional insights into how CP development links to stuttering persistence and recovery.

Predicting Persistent Developmental Stuttering Using a Cumulative Risk Approach.

PURPOSE: The purpose of this study was to explore how well a cumulative risk approach, based on empirically supported predictive factors, predicts whether a young child who stutters is likely to develop persistent developmental stuttering. In a cumulative risk approach, the number of predictive factors indicating a child is at risk to develop persistent stuttering is evaluated, and a greater number of indicators of risk are hypothesized to confer greater risk of persistent stuttering. METHOD: We combined extant data on 3- to 5-year-old children who stutter from two longitudinal studies to identify cutoff values for continuous predictive factors (e.g., speech and language skills, age at onset, time since onset, stuttering frequency) and, in combination with binary predictors (e.g., sex, family history of stuttering), used all-subsets regression and receiver operating characteristic curves to compare the predictive validity of different combinations of 10 risk factors. The optimal combination of predictive factors and the odds of a child developing persistent stuttering based on an increasing number of factors were calculated. RESULTS: Based on 67 children who stutter (i.e., 44 persisting and 23 recovered) with relatively strong speech-language skills, the predictive factor model that yielded the best predictive validity was based on time since onset (≥ 19 months), speech sound skills (≤ 115 standard score), expressive language skills (≤ 106 standard score), and stuttering severity (≥ 17 Stuttering Severity Instrument total score). When the presence of at least two predictive factors was used to confer elevated risk to develop persistent stuttering, the model yielded 93% sensitivity and 65% specificity. As a child presented with a greater number of these four risk factors, the odds for persistent stuttering increased. CONCLUSIONS: Findings support the use of a cumulative risk approach and the predictive utility of assessing multiple domains when evaluating a child's risk of developing persistent stuttering. Clinical implications and future directions are discussed.