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.

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.

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).

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.

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.

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.

NRSN1 associated grey matter volume of the visual word form area reveals dyslexia before school.

Literacy learning depends on the flexibility of the human brain to reconfigure itself in response to environmental influences. At the same time, literacy and disorders of literacy acquisition are heritable and thus to some degree genetically predetermined. Here we used a multivariate non-parametric genetic model to relate literacy-associated genetic variants to grey and white matter volumes derived by voxel-based morphometry in a cohort of 141 children. Subsequently, a sample of 34 children attending grades 4 to 8, and another sample of 20 children, longitudinally followed from kindergarten to first grade, were classified as dyslexics and controls using linear binary support vector machines. The NRSN1-associated grey matter volume of the 'visual word form area' achieved a classification accuracy of ~ 73% in literacy-experienced students and distinguished between later dyslexic individuals and controls with an accuracy of 75% at kindergarten age. These findings suggest that the cortical plasticity of a region vital for literacy might be genetically modulated, thereby potentially preconstraining literacy outcome. Accordingly, these results could pave the way for identifying and treating the most common learning disorder before it manifests itself in school.

Left posterior-dorsal area 44 couples with parietal areas to promote speech fluency, while right area 44 activity promotes the stopping of motor responses.

Area 44 is a cytoarchitectonically distinct portion of Broca's region. Parallel and overlapping large-scale networks couple with this region thereby orchestrating heterogeneous language, cognitive, and motor functions. In the context of stuttering, area 44 frequently comes into focus because structural and physiological irregularities affect developmental trajectories, stuttering severity, persistency, and etiology. A remarkable phenomenon accompanying stuttering is the preserved ability to sing. Speaking and singing are connatural behaviours recruiting largely overlapping brain networks including left and right area 44. Analysing which potential subregions of area 44 are malfunctioning in adults who stutter, and what effectively suppresses stuttering during singing, may provide a better understanding of the coordination and reorganization of large-scale brain networks dedicated to speaking and singing in general. We used fMRI to investigate functionally distinct subregions of area 44 during imagery of speaking and imaginary of humming a melody in 15 dextral males who stutter and 17 matched control participants. Our results are fourfold. First, stuttering was specifically linked to a reduced activation of left posterior-dorsal area 44, a subregion that is involved in speech production, including phonological word processing, pitch processing, working memory processes, sequencing, motor planning, pseudoword learning, and action inhibition. Second, functional coupling between left posterior area 44 and left inferior parietal lobule was deficient in stuttering. Third, despite the preserved ability to sing, males who stutter showed bilaterally a reduced activation of area 44 when imagine humming a melody, suggesting that this fluency-enhancing condition seems to bypass posterior-dorsal area 44 to achieve fluency. Fourth, time courses of the posterior subregions in area 44 showed delayed peak activations in the right hemisphere in both groups, possibly signaling the offset response. Because these offset response-related activations in the right hemisphere were comparably large in males who stutter, our data suggest a hyperactive mechanism to stop speech motor responses and thus possibly reflect a pathomechanism, which, until now, has been neglected. Overall, the current results confirmed a recently described co-activation based parcellation supporting the idea of functionally distinct subregions of left area 44.

Predicting early signs of dyslexia at a preliterate age by combining behavioral assessment with structural MRI.

BACKGROUND: Recent studies suggest that neurobiological anomalies are already detectable in pre-school children with a family history of developmental dyslexia (DD). However, there is a lack of longitudinal studies showing a direct link between those differences at a preliterate age and the subsequent literacy difficulties seen in school. It is also not clear whether the prediction of DD in pre-school children can be significantly improved when considering neurobiological predictors, compared to models based on behavioral literacy precursors only. METHODS: We recruited 53 pre-reading children either with (N=25) or without a family risk of DD (N=28). Quantitative T1 MNI data and literacy precursor abilities were assessed at kindergarten age. A subsample of 35 children was tested for literacy skills either one or two years later, that is, either in first or second grade. RESULTS: The group comparison of quantitative T1 measures revealed significantly higher T1 intensities in the left anterior arcuate fascicle (AF), suggesting reduced myelin concentration in preliterate children at risk of DD. A logistic regression showed that DD can be predicted significantly better (p=.024) when neuroanatomical differences between groups are used as predictors (80%) compared to a model based on behavioral predictors only (63%). The Wald statistic confirmed that the T1 intensity of the left AF is a statistically significant predictor of DD (p<.05). CONCLUSIONS: Our longitudinal results provide evidence for the hypothesis that neuroanatomical anomalies in children with a family risk of DD are related to subsequent problems in acquiring literacy. Particularly, solid white matter organization in the left anterior arcuate fascicle seems to play a pivotal role.

Speech dynamics are coded in the left motor cortex in fluent speakers but not in adults who stutter.

The precise excitability regulation of neuronal circuits in the primary motor cortex is central to the successful and fluent production of speech. Our question was whether the involuntary execution of undesirable movements, e.g. stuttering, is linked to an insufficient excitability tuning of neural populations in the orofacial region of the primary motor cortex. We determined the speech-related time course of excitability modulation in the left and right primary motor tongue representation. Thirteen fluent speakers (four females, nine males; aged 23-44) and 13 adults who stutter (four females, nine males, aged 21-55) were asked to build verbs with the verbal prefix 'auf'. Single-pulse transcranial magnetic stimulation was applied over the primary motor cortex during the transition phase between a fixed labiodental articulatory configuration and immediately following articulatory configurations, at different latencies after transition onset. Bilateral electromyography was recorded from self-adhesive electrodes placed on the surface of the tongue. Off-line, we extracted the motor evoked potential amplitudes and normalized these amplitudes to the individual baseline excitability during the fixed configuration. Fluent speakers demonstrated a prominent left hemisphere increase of motor cortex excitability in the transition phase (P = 0.009). In contrast, the excitability of the right primary motor tongue representation was unchanged. Interestingly, adults afflicted with stuttering revealed a lack of left-hemisphere facilitation. Moreover, the magnitude of facilitation was negatively correlated with stuttering frequency. Although orofacial midline muscles are bilaterally innervated from corticobulbar projections of both hemispheres, our results indicate that speech motor plans are controlled primarily in the left primary speech motor cortex. This speech motor planning-related asymmetry towards the left orofacial motor cortex is missing in stuttering. Moreover, a negative correlation between the amount of facilitation and stuttering severity suggests that we discovered a main physiological principle of fluent speech production and its role in stuttering.

Cortical lamina-dependent blood volume changes in human brain at 7 T.

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8-1.6mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans.

Genetic dyslexia risk variant is related to neural connectivity patterns underlying phonological awareness in children.

Phonological awareness is the best-validated predictor of reading and spelling skill and therefore highly relevant for developmental dyslexia. Prior imaging genetics studies link several dyslexia risk genes to either brain-functional or brain-structural factors of phonological deficits. However, coherent evidence for genetic associations with both functional and structural neural phenotypes underlying variation in phonological awareness has not yet been provided. Here we demonstrate that rs11100040, a reported modifier of SLC2A3, is related to the functional connectivity of left fronto-temporal phonological processing areas at resting state in a sample of 9- to 12-year-old children. Furthermore, we provide evidence that rs11100040 is related to the fractional anisotropy of the arcuate fasciculus, which forms the structural connection between these areas. This structural connectivity phenotype is associated with phonological awareness, which is in turn associated with the individual retrospective risk scores in an early dyslexia screening as well as to spelling. These results suggest a link between a dyslexia risk genotype and a functional as well as a structural neural phenotype, which is associated with a phonological awareness phenotype. The present study goes beyond previous work by integrating genetic, brain-functional and brain-structural aspects of phonological awareness within a single approach. These combined findings might be another step towards a multimodal biomarker for developmental dyslexia.

The Neurobiological Grounding of Persistent Stuttering: from Structure to Function.

Neuroimaging and transcranial magnetic stimulation provide insights into the neuronal mechanisms underlying speech disfluencies in chronic persistent stuttering. In the present paper, the goal is not to provide an exhaustive review of existing literature, but rather to highlight robust findings. We, therefore, conducted a meta-analysis of diffusion tensor imaging studies which have recently implicated disrupted white matter connectivity in stuttering. A reduction of fractional anisotropy in persistent stuttering has been reported at several different loci. Our meta-analysis revealed consistent deficits in the left dorsal stream and in the interhemispheric connections between the sensorimotor cortices. In addition, recent fMRI meta-analyses link stuttering to reduced left fronto-parieto-temporal activation while greater fluency is associated with boosted co-activations of right fronto-parieto-temporal areas. However, the physiological foundation of these irregularities is not accessible with MRI. Complementary, transcranial magnetic stimulation (TMS) reveals local excitatory and inhibitory regulation of cortical dynamics. Applied to a speech motor area, TMS revealed reduced speech-planning-related neuronal dynamics at the level of the primary motor cortex in stuttering. Together, this review provides a focused view of the neurobiology of stuttering to date and may guide the rational design of future research. This future needs to account for the perpetual dynamic interactions between auditory, somatosensory, and speech motor circuits that shape fluent speech.

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.

Speech restructuring group treatment for 6-to-9-year-old children who stutter: A therapeutic trial.

For children who stutter (CWS), there is good evidence of the benefits of treatment for pre-school age, but an evidence gap for elementary school age. Here we report on the effectiveness of a fluency shaping treatment for 6- to 9-year-old children. The main treatment component is the reinforcement of soft voice onsets. An intensive in-patient group treatment phase lasts 6 days, followed by a 6-month maintenance phase with 3 in-patient weekend group refresher courses. Child and a parent participate together in various treatment activities. In this controlled intervention study (waitlist control, intention-to-treat design) assessments were performed before treatment (T1), 4 weeks after the intensive phase (T2), at the end of the maintenance phase (T3), and 1 year later (T4). Participants were 119 children (108 boys, 11 girls, age 5.5­10.4 years). Control conditions included a subgroup with delayed treatment (N=25) as well as the assessment of complexity of utterances, inter-rater reliability, and speech naturalness. From before treatment to 1-year follow-up, percent stuttered syllables and OASES-S (Overall Assessment of the Speaker's Experience with Stuttering - School-age) scores decreased with large effect size. Speech naturalness improved during this period but did not reach the level of non-stuttering children. Complexity of utterances increased during the intensive phase, but only temporarily. Twenty children (16.8 %, including dropouts) showed no demonstrable treatment benefit. Fluency shaping treatment can be effectively applied to young school children. It is assumed that parental support, group therapy, intensive treatment, and regular exercises at home are essential.

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.