Altered functional connectivity in persistent developmental stuttering.
Ontology highlight
ABSTRACT:
SUBMITTER: Yang Y
PROVIDER: S-EPMC4705486 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
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Project description:Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers.
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Project description:Motor balance in developmental stuttering (DS) was investigated with Transcranial Magnetic Stimulation (TMS), with the aim to define novel neural markers of persistent DS in adulthood. Eleven DS adult males were evaluated with TMS on tongue primary motor cortex, compared to 15 matched fluent speakers, in a "state" condition (i.e. stutterers vs. fluent speakers, no overt stuttering). Motor and silent period thresholds (SPT), recruitment curves, and silent period durations were acquired by recording tongue motor evoked potentials. Tongue silent period duration was increased in DS, especially in the left hemisphere (P<0.05; Hedge's g or Cohen's dunbiased = 1.054, i.e. large effect size), suggesting a "state" condition of higher intracortical inhibition in left motor cortex networks. Differences in motor thresholds (different excitatory/inhibitory ratios in DS) were evident, as well as significant differences in SPT. In fluent speakers, the left hemisphere may be marginally more excitable than the right one in motor thresholds at lower muscular activation, while active motor thresholds and SPT were higher in the left hemisphere of DS with respect to the right one, resulting also in a positive correlation with stuttering severity. Pre-TMS electromyography data gave overlapping evidence. Findings suggest the existence of a complex intracortical balance in DS tongue primary motor cortex, with a particular interplay between excitatory and inhibitory mechanisms, also in neural substrates related to silent periods. Findings are discussed with respect to functional and structural impairments in stuttering, and are also proposed as novel neural markers of a stuttering "state" in persistent DS, helping to define more focused treatments (e.g. neuro-modulation).
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Project description:Vibrational energy created at the larynx during speech will deflect vestibular mechanoreceptors in humans (Todd et al., 2008; Curthoys, 2017; Curthoys et al., 2019). Vestibular-evoked myogenic potential (VEMP), an indirect measure of vestibular function, was assessed in 15 participants who stutter, with a non-stutter control group of 15 participants paired on age and sex. VEMP amplitude was 8.5 dB smaller in the stutter group than the non-stutter group (p = 0.035, 95% CI [-0.9, -16.1], t = -2.1, d = -0.8, conditional R 2 = 0.88). The finding is subclinical as regards gravitoinertial function, and is interpreted with regard to speech-motor function in stuttering. There is overlap between brain areas receiving vestibular innervation, and brain areas identified as important in studies of persistent developmental stuttering. These include the auditory brainstem, cerebellar vermis, and the temporo-parietal junction. The finding supports the disruptive rhythm hypothesis (Howell et al., 1983; Howell, 2004) in which sensory inputs additional to own speech audition are fluency-enhancing when they coordinate with ongoing speech.
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Project description:Stuttering is a common but poorly understood speech disorder. Consistent evidence for the involvement of genetic factors in stuttering has motivated studies aimed at identifying causative genetic variants that could shed light on the underlying molecular and cellular deficits in this disorder. Such studies have begun to identify causative genes. The purpose of this review is to summarize the gene discoveries to date, and to cover the subsequent functional studies that are beginning to provide insights into how these gene mutations might cause stuttering. Surprisingly, the first variant genes to be associated with stuttering are those encoding the lysosomal targeting system, GNPTAB, GNPTG, and NAGPA. Although mutations in NAGPA have not been associated with a disorder in humans, mutations in GNPTAB and GNPTG cause mucolipidosis types II and III, which are rare autosomal recessive lysosomal storage disorders, associated with pathology of bone, connective tissue, liver, spleen, and brain. Analysis of mutations in these genes has so far identified predominantly missense mutations in stuttering, in contrast to the truncating and other mutations that result in very low GNPTAB/G enzyme activity and are historically associated with mucolipidosis. Genetic evidence for the role of lysosomal targeting mutations in stuttering has now been buttressed by biochemical studies of the mutant enzymes found in this disorder. While data on the GlcNAc-phosphotransferase encoded by GNPTAB/G remains limited and only suggestive, a study of the enzyme encoded by NAGPA has shown that the mutations found in stuttering reduce the overall cellular activity of this enzyme by about half, and that they result in deficits in intracellular processing and trafficking that lead to a reduced cellular half life. How these deficits result in the presumed speech-specific neuropathology associated with stuttering is not yet known. However these findings have opened several new lines of inquiry, including studies in mice carrying human stuttering mutations, that represent promising approaches to this disorder.
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Project description:IntroductionIndividuals with persistent developmental stuttering display deficits in aligning motor actions to external cues (i.e., sensorimotor synchronization). Diffusion imaging studies point to stuttering-associated differences in dorsal, not ventral, white matter pathways, and in the cerebellar peduncles. Here, we studied microstructural white matter differences between adults who stutter (AWS) and fluent speakers using two complementary approaches to: (a) assess previously reported group differences in white matter diffusivity, and (b) evaluate the relationship between white matter diffusivity and sensorimotor synchronization in each group.MethodsParticipants completed a sensorimotor synchronization task and a diffusion MRI scan. We identified the cerebellar peduncles and major dorsal- and ventral-stream language pathways in each individual and assessed correlations between sensorimotor synchronization and diffusion measures along the tracts.ResultsThe results demonstrated group differences in dorsal, not ventral, language tracts, in alignment with prior reports. Specifically, AWS had significantly lower fractional anisotropy (FA) in the left arcuate fasciculus, and significantly higher mean diffusivity (MD) in the bilateral frontal aslant tract compared to fluent speakers, while no significant group difference was detected in the inferior fronto-occipital fasciculus. We also found significant group differences in both FA and MD of the left middle cerebellar peduncle. Comparing patterns of association with sensorimotor synchronization revealed a novel double dissociation: MD within the left inferior cerebellar peduncle was significantly correlated with mean asynchrony in AWS but not in fluent speakers, while FA within the left arcuate fasciculus was significantly correlated with mean asynchrony in fluent speakers, but not in AWS.ConclusionsOur results support the view that stuttering involves altered connectivity in dorsal tracts and that AWS may rely more heavily on cerebellar tracts to process timing information. Evaluating microstructural associations with sensitive behavioral measures provides a powerful tool for discovering additional functional differences in the underlying connectivity in AWS.
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Project description:The aim of this study was to identify differences in functional and effective brain connectivity between persons who stutter (PWS) and typically developing (TD) fluent speakers, and to assess whether those differences can serve as biomarkers to distinguish PWS from TD controls. We acquired resting-state functional magnetic resonance imaging data in 44 PWS and 50 TD controls. We then used Independent Component Analysis (ICA) together with Hierarchical Partner Matching (HPM) to identify networks of robust, functionally connected brain regions that were highly reproducible across participants, and we assessed whether connectivity differed significantly across diagnostic groups. We then used Granger Causality (GC) to study the causal interactions (effective connectivity) between the regions that ICA and HPM identified. Finally, we used a kernel support vector machine to assess how well these measures of functional connectivity and granger causality discriminate PWS from TD controls. Functional connectivity was stronger in PWS compared with TD controls in the supplementary motor area (SMA) and primary motor cortices, but weaker in inferior frontal cortex (IFG, Broca's area), caudate, putamen, and thalamus. Additionally, causal influences were significantly weaker in PWS from the IFG to SMA, and from the basal ganglia to IFG through the thalamus, compared to TD controls. ICA and GC indices together yielded an accuracy of 92.7% in classifying PWS from TD controls. Our findings suggest the presence of dysfunctional circuits that support speech planning and timing cues for the initiation and execution of motor sequences in PWS. Our high accuracy of classification further suggests that these aberrant brain features may serve as robust biomarkers for PWS.
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Project description: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.
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Project description:A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI.
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