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.

Stuttering severity relates to frontotemporal low-beta synchronization during pre-speech preparation.

OBJECTIVE: The neurophysiological dynamics of the occurrence of a stuttering event are largely unknown. This sensor-level EEG study investigated whether already the intention to speak alters the formation of the speech production network in stuttering. METHODS: We studied alpha (8-13 Hz), low beta (15-25 Hz) and high beta (25-30 Hz) power modulation in 19 adults with developmental stuttering (AWS) and 19 fluently speaking control participants during speech intention. RESULTS: Both groups show that the anticipation of overt reading coincides with broadband low-frequency suppression in posterior sensors, a common sign of network formation for speech production. Prior to fluent speech, frontotemporal alpha and low-beta power were weaker in AWS with mild stuttering but stronger in AWS with severe stuttering. These correlations were not significant prior stuttered speech. Further, post hoc comparisons confirmed the difference between AWS with mild and severe stuttering in low beta power. CONCLUSIONS: AWS with more severe stuttering seem to show stronger maintenance of the current cognitive or sensorimotor state, as stuttering severity was associated with increased beta power. Increased beta power levels may influence subsequent speech preparation and execution processes. SIGNIFICANCE: Upcoming breakdowns of the speech production network as evident in actual stuttering are related to beta power during the intention to speak.

White matter tract strength correlates with therapy outcome in persistent developmental stuttering.

Persistent stuttering is a prevalent neurodevelopmental speech disorder, which presents with involuntary speech blocks, sound and syllable repetitions, and sound prolongations. Affected individuals often struggle with negative feelings, elevated anxiety, and low self-esteem. Neuroimaging studies frequently link persistent stuttering with cortical alterations and dysfunctional cortico-basal ganglia-thalamocortical loops; dMRI data also point toward connectivity changes of the superior longitudinal fasciculus (SLF) and the frontal aslant tract (FAT). Both tracts are involved in speech and language functions, and the FAT also supports inhibitory control and conflict monitoring. Whether the two tracts are involved in therapy-associated improvements and how they relate to therapeutic outcomes is currently unknown. Here, we analyzed dMRI data of 22 patients who participated in a fluency-shaping program, 18 patients not participating in therapy, and 27 fluent control participants, measured 1 year apart. We used diffusion tractography to segment the SLF and FAT bilaterally and to quantify their microstructural properties before and after a fluency-shaping program. Participants learned to speak with soft articulation, pitch, and voicing during a 2-week on-site boot camp and computer-assisted biofeedback-based daily training for 1 year. Therapy had no impact on the microstructural properties of the two tracts. Yet, after therapy, stuttering severity correlated positively with left SLF fractional anisotropy, whereas relief from the social-emotional burden to stutter correlated negatively with right FAT fractional anisotropy. Thus, posttreatment, speech motor performance relates to the left dorsal stream, while the experience of the adverse impact of stuttering relates to the structure recently associated with conflict monitoring and action inhibition.

Fluency shaping increases integration of the command-to-execution and the auditory-to-motor pathways in persistent developmental stuttering.

Fluency-shaping enhances the speech fluency of persons who stutter, yet underlying conditions and neuroplasticity-related mechanisms are largely unknown. While speech production-related brain activity in stuttering is well studied, it is unclear whether therapy repairs networks of altered sensorimotor integration, imprecise neural timing and sequencing, faulty error monitoring, or insufficient speech planning. Here, we tested the impact of one-year fluency-shaping therapy on resting-state fMRI connectivity within sets of brain regions subserving these speech functions. We analyzed resting-state data of 22 patients who participated in a fluency-shaping program, 18 patients not participating in therapy, and 28 fluent control participants, measured one year apart. Improved fluency was accompanied by an increased connectivity within the sensorimotor integration network. Specifically, two connections were strengthened; the left inferior frontal gyrus showed increased connectivity with the precentral gyrus at the representation of the left laryngeal motor cortex, and the left inferior frontal gyrus showed increased connectivity with the right superior temporal gyrus. Thus, therapy-associated neural remediation was based on a strengthened integration of the command-to-execution pathway together with an increased auditory-to-motor coupling. Since we investigated task-free brain activity, we assume that our findings are not biased to network activity involved in compensation but represent long-term focal neuroplasticity effects.

Two cortical representations of voice control are differentially involved in speech fluency.

Recent studies have identified two distinct cortical representations of voice control in humans, the ventral and the dorsal laryngeal motor cortex. Strikingly, while persistent developmental stuttering has been linked to a white-matter deficit in the ventral laryngeal motor cortex, intensive fluency-shaping intervention modulated the functional connectivity of the dorsal laryngeal motor cortical network. Currently, it is unknown whether the underlying structural network organization of these two laryngeal representations is distinct or differently shaped by stuttering intervention. Using probabilistic diffusion tractography in 22 individuals who stutter and participated in a fluency shaping intervention, in 18 individuals who stutter and did not participate in the intervention and in 28 control participants, we here compare structural networks of the dorsal laryngeal motor cortex and the ventral laryngeal motor cortex and test intervention-related white-matter changes. We show (i) that all participants have weaker ventral laryngeal motor cortex connections compared to the dorsal laryngeal motor cortex network, regardless of speech fluency, (ii) connections of the ventral laryngeal motor cortex were stronger in fluent speakers, (iii) the connectivity profile of the ventral laryngeal motor cortex predicted stuttering severity (iv) but the ventral laryngeal motor cortex network is resistant to a fluency shaping intervention. Our findings substantiate a weaker structural organization of the ventral laryngeal motor cortical network in developmental stuttering and imply that assisted recovery supports neural compensation rather than normalization. Moreover, the resulting dissociation provides evidence for functionally segregated roles of the ventral laryngeal motor cortical and dorsal laryngeal motor cortical networks.

Differentiation of brain metastases from small and non-small lung cancers using apparent diffusion coefficient (ADC) maps.

BACKGROUND: Brain metastases are particularly common in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC showing a less  aggressive clinical course and lower chemo- and radio sensitivity compared to SCLC. Early adequate therapy is highly desirable and depends on a reliable classification of tumor type. The apparent diffusion coefficient is a noninvasive neuroimaging marker with the potential to differentiate between major histological subtypes. Here we determine the sensitivity and specificity of the apparent diffusion coefficient to distinguish between NSCLC and SCLC. METHODS: We enrolled all NSCLC and SCLC patients diagnosed between 2008 and 2019 at the University Medical Center Göttingen. Cranial MR scans were visually inspected for brain metastases and the ratio of the apparent diffusion coefficient (ADC) was calculated by dividing the ADC measured within the solid part of a metastasis by a reference ADC extracted from an equivalent region in unaffected tissue on the contralateral hemisphere. RESULTS: Out of 411 enrolled patients, we detected 129 patients (83 NSCLC, 46 SCLC) with sufficiently large brain metastases with histologically classified lung cancer and no hemorrhage. We analyzed 185 brain metastases, 84 of SCLC and 101 of NSCLC. SCLC brain metastases showed an ADC ratio of 0.68 ± 0.12 SD, and NSCLC brain metastases showed an ADC ratio of 1.47 ± 0.31 SD. Receiver operating curve statistics differentiated brain metastases of NSCLC from SCLC with an area under the curve of 0.99 and a 95% CI of 0.98 to 1, p < 0.001. Youden's J cut-point is 0.97 at a sensitivity of 0.989 and a specificity of 0.988. CONCLUSIONS: In patients with lung cancer and brain metastases with solid tumor parts, ADC ratio enables an ad hoc differentiation of SCLC and NSCLC, easily achieved during routine neuroradiological examination. Non-invasive MR imaging enables an early-individualized management of brain metastases from lung cancer. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00023016).

Enlarged Area of Mesencephalic Iron Deposits in Adults Who Stutter.

PURPOSE: Childhood onset speech fluency disorder (stuttering) is possibly related to dopaminergic dysfunction. Mesencephalic hyperechogenicity (ME) detected by transcranial ultrasound (TCS) might be seen as an indirect marker of dopaminergic dysfunction. We here determined whether adults who stutter since childhood (AWS) show ME. METHODS: We performed TCS in ten AWS and ten matched adults who never stuttered. We also assessed motor performance in finger tapping and in the 25 Foot Walking test. RESULTS: Compared to controls, AWS showed enlarged ME on either side. Finger tapping was slower in AWS. Walking cadence, i.e., the ratio of number of steps by time, tended to be higher in AWS than in control participants. DISCUSSION: The results demonstrate a motor deficit in AWS linked to dopaminergic dysfunction and extending beyond speech. Since iron deposits evolve in childhood and shrink thereafter, ME might serve as an easily quantifiable biomarker helping to predict the risk of persistency in children who stutter.

The emergence of dyslexia in the developing brain.

Developmental dyslexia, a severe deficit in literacy learning, is a neurodevelopmental learning disorder. Yet, it is not clear whether existing neurobiological accounts of dyslexia capture potential predispositions of the deficit or consequences of reduced reading experience. Here, we longitudinally followed 32 children from preliterate to school age using functional and structural magnetic resonance imaging techniques. Based on standardised and age-normed reading and spelling tests administered at school age, children were classified as 16 dyslexic participants and 16 controls. This longitudinal design allowed us to disentangle possible neurobiological predispositions for developing dyslexia from effects of individual differences in literacy experience. In our sample, the disorder can be predicted already before literacy learning from auditory cortex gyrification and aberrant downstream connectivity within the speech processing system. These results provide evidence for the notion that dyslexia may originate from an atypical maturation of the speech network that precedes literacy instruction.

No Evidence for Dystonia-Like Sensory Overflow of Tongue Representations in Adults Who Stutter.

Persistent developmental stuttering (PDS) disrupts speech fluency in about 1% of adults. Although many models of speech production assume an intact sensory feedback from the speech organs to the brain, very little is actually known about the integrity of their sensory representation in PDS. Here, we studied somatosensory evoked potentials (SEPs) in adults who stutter (AWS), with the aim of probing the integrity of sensory pathways. In addition, we tested the processing of dual sensory input to address a putative link between stuttering and focal dystonia. In 15 AWS (aged 15-55 years; three females) and 14 matched fluent speaking adults (ANS), we recorded SEPs at C5' and C6' induced by stimulating separately or simultaneously the tongue or the cheek at the corner of the mouth. We determined latencies (N13, P19, and N27) and peak-to-peak amplitudes (N13-P19, P19-N27). We divided amplitudes from simultaneous stimulation by the sum of those from separate stimulation. Amplitude ratios did not differ between groups, indicating normal processing of dual sensory input. This does not support a clinical analogy between focal dystonia and persistent stuttering. SEP latencies as a measure of transmission speed in sensory pathways were significantly shorter in stuttering subjects than in fluent speaking participants, however, this might have been related to a trend for a height difference between groups, and was not confirmed in a replication dataset. In summary, we did not find evidence for dystonia-like sensory overflow of tongue representations in AWS.

Functional Segregation of the Right Inferior Frontal Gyrus: Evidence From Coactivation-Based Parcellation.

Previous studies helped unraveling the functional architecture of the human cerebral cortex. However, a comprehensive functional segregation of right lateral prefrontal cortex is missing. Here, we delineated cortical clusters in right area 44 and 45 based on their task-constrained whole-brain activation patterns across neuroimaging experiments obtained from a large database. We identified 5 clusters that differed with respect to their coactivation patterns, which were consistent with resting-state functional connectivity patterns of an independent dataset. Two clusters in the posterior inferior frontal gyrus (IFG) were functionally associated with action inhibition and execution, while two anterior clusters were related to reasoning and social cognitive processes. A fifth cluster was associated with spatial attention. Strikingly, the functional organization of the right IFG can thus be characterized by a posterior-to-anterior axis with action-related functions on the posterior and cognition-related functions on the anterior end. We observed further subdivisions along a dorsal-to-ventral axis in posterior IFG between action execution and inhibition, and in anterior IFG between reasoning and social cognition. The different clusters were integrated in distinct large-scale networks for various cognitive processes. These results provide evidence for a general organization of cognitive processes along axes spanning from more automatic to more complex cognitive processes.

Adults who stutter lack the specialised pre-speech facilitation found in non-stutterers.

OBJECTIVES: Persistent developmental stuttering is a speech fluency disorder defined by its symptoms, where the underlying neurophysiological causes remain uncertain. This study examined the underlying neurophysiological mechanisms of the speech planning process, using facilitation in the motor cortex during speech preparation as an analogue. METHODS: transcranial magnetic stimulation (TMS) pulses induced motor evoked potentials (MEPs), which were recorded from the tongue. Eighteen adults who stutter (AWS) and 17 adults who do not stutter (ANS) completed three experiments, which involved reading a German prefix+verb utterance from a screen. Each experiment involved 120 trials with three distinct levels of speech production: immediate speech, delayed speech without pacing and delayed speech with predefined pacing. TMS was applied shortly before speech onset. Trial MEPs were normalised to average non-speech MEPs. MEP amplitude, MEP facilitation ratio (amplitude: pre-speech offset) and group difference were the outcomes of interest analysed by multiple regression, as well as speech reaction time analysed by correlation. RESULTS: MEP values were 11·1%-23·4% lower in AWS than ANS (by standardised Beta), across all three experiments. MEP facilitation ratio slopes were also 4·9%-18·3% flatter in AWS than ANS across all three experiments. Reaction times for AWS were only significantly slower than for ANS in immediate speech and predefined pacing experiments. No stuttering was detected during the trials. The group difference in immediate speech was 100% and 101% greater than the other two experiments respectively. DISCUSSION: While performance of both ANS and AWS worsens under disturbed speech conditions, greater disturbance conditions affected controls worse than AWS. Future research and therapy in stuttering should focus on non-disturbed speech.

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.

Altered morphology of the nucleus accumbens in persistent developmental stuttering.

PURPOSE: Neuroimaging studies in persistent developmental stuttering repeatedly report altered basal ganglia functions. Together with thalamus and cerebellum, these structures mediate sensorimotor functions and thus represent a plausible link between stuttering and neuroanatomy. However, stuttering is a complex, multifactorial disorder. Besides sensorimotor functions, emotional and social-motivational factors constitute major aspects of the disorder. Here, we investigated cortical and subcortical gray matter regions to study whether persistent developmental stuttering is also linked to alterations of limbic structures. METHODS: The study included 33 right-handed participants who stutter and 34 right-handed control participants matched for sex, age, and education. Structural images were acquired using magnetic resonance imaging to estimate volumetric characteristics of the nucleus accumbens, hippocampus, amygdala, pallidum, putamen, caudate nucleus, and thalamus. RESULTS: Volumetric comparisons and vertex-based shape comparisons revealed structural differences. The right nucleus accumbens was larger in participants who stutter compared to controls. CONCLUSION: Recent theories of basal ganglia functions suggest that the nucleus accumbens is a motivation-to-movement interface. A speaker intends to reach communicative goals, but stuttering can derail these efforts. It is therefore highly plausible to find alterations in the motivation-to-movement interface in stuttering. While behavioral studies of stuttering sought to find links between the limbic and sensorimotor system, we provide the first neuroimaging evidence of alterations in the limbic system. Thus, our findings might initialize a unified neurobiological framework of persistent developmental stuttering that integrates sensorimotor and social-motivational neuroanatomical circuitries.

Shifted dynamic interactions between subcortical nuclei and inferior frontal gyri during response preparation in persistent developmental stuttering.

Persistent developmental stuttering is associated with basal ganglia dysfunction or dopamine dysregulation. Here, we studied whole-brain functional connectivity to test how basal ganglia structures coordinate and reorganize sensorimotor brain networks in stuttering. To this end, adults who stutter and fluent speakers (control participants) performed a response anticipation paradigm in the MRI scanner. The preparation of a manual Go/No-Go response reliably produced activity in the basal ganglia and thalamus and particularly in the substantia nigra. Strikingly, in adults who stutter, substantia nigra activity correlated positively with stuttering severity. Furthermore, functional connectivity analyses yielded altered task-related network formations in adults who stutter compared to fluent speakers. Specifically, in adults who stutter, the globus pallidus and the thalamus showed increased network synchronization with the inferior frontal gyrus. This implies dynamic shifts in the response preparation-related network organization through the basal ganglia in the context of a non-speech motor task in stuttering. Here we discuss current findings in the traditional framework of how D1 and D2 receptor activity shapes focused movement selection, thereby suggesting a disproportional involvement of the direct and the indirect pathway in stuttering.

ATP2C2 and DYX1C1 are putative modulators of dyslexia-related MMR.

Background: Dyslexia is a specific learning disorder affecting reading and spelling abilities. Its prevalence is ~5% in German-speaking individuals. Although the etiology of dyslexia largely remains to be determined, comprehensive evidence supports deficient phonological processing as a major contributing factor. An important prerequisite for phonological processing is auditory discrimination and, thus, essential for acquiring reading and spelling skills. The event-related potential Mismatch Response (MMR) is an indicator for auditory discrimination capabilities with dyslexics showing an altered late component of MMR in response to auditory input. Methods: In this study, we comprehensively analyzed associations of dyslexia-specific late MMRs with genetic variants previously reported to be associated with dyslexia-related phenotypes in multiple studies comprising 25 independent single-nucleotide polymorphisms (SNPs) within 10 genes. Results: First, we demonstrated validity of these SNPs for dyslexia in our sample by showing that additional inclusion of a polygenic risk score improved prediction of impaired writing compared with a model that used MMR alone. Secondly, a multifactorial regression analysis was conducted to uncover the subset of the 25 SNPs that is associated with the dyslexia-specific late component of MMR. In total, four independent SNPs within DYX1C1 and ATP2C2 were found to be associated with MMR stronger than expected from multiple testing. To explore potential pathomechanisms, we annotated these variants with functional data including tissue-specific expression analysis and eQTLs. Conclusion: Our findings corroborate the late component of MMR as a potential endophenotype for dyslexia and support tripartite relationships between dyslexia-related SNPs, the late component of MMR and dyslexia.