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.

Data-driven MRI analysis reveals fitness-related functional change in default mode network and cognition following an exercise intervention.

Previous research has indicated that cardiorespiratory fitness (CRF) is structurally and functionally neuroprotective in older adults. However, questions remain regarding the mechanistic role of CRF on cognitive and brain health. The purposes of this study were to investigate if higher pre-intervention CRF was associated with greater change in functional brain connectivity during an exercise intervention and to determine if the magnitude of change in connectivity was related to better post-intervention cognitive performance. The sample included low-active older adults (n = 139) who completed a 6-month exercise intervention and underwent neuropsychological testing, functional neuroimaging, and CRF testing before and after the intervention. A data-driven multi-voxel pattern analysis was performed on resting-state MRI scans to determine changes in whole-brain patterns of connectivity from pre- to post-intervention as a function of pre-intervention CRF. Results revealed a positive correlation between pre-intervention CRF and changes in functional connectivity in the precentral gyrus. Using the precentral gyrus as a seed, analyses indicated that CRF-related connectivity changes within the precentral gyrus were derived from increased correlation strength within clusters located in the Dorsal Attention Network (DAN) and increased anti-correlation strength within clusters located in the Default Mode Network (DMN). Exploratory analysis demonstrated that connectivity change between the precentral gyrus seed and DMN clusters were associated with improved post-intervention performance on perceptual speed tasks. These findings suggest that in a sample of low-active and mostly lower-fit older adults, even subtle individual differences in CRF may influence the relationship between functional connectivity and aspects of cognition following a 6-month exercise intervention.

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.

Do Not Cut Off Your Tail: A Mega-Analysis of Responses to Auditory Perturbation Experiments.

PURPOSE: The practice of removing "following" responses from speech perturbation analyses is increasingly common, despite no clear evidence as to whether these responses represent a unique response type. This study aimed to determine if the distribution of responses to auditory perturbation paradigms represents a bimodal distribution, consisting of two distinct response types, or a unimodal distribution. METHOD: This mega-analysis pooled data from 22 previous studies to examine the distribution and magnitude of responses to auditory perturbations across four tasks: adaptive pitch, adaptive formant, reflexive pitch, and reflexive formant. Data included at least 150 unique participants for each task, with studies comprising younger adult, older adult, and Parkinson's disease populations. A Silverman's unimodality test followed by a smoothed bootstrap resampling technique was performed for each task to evaluate the number of modes in each distribution. Wilcoxon signed-ranks tests were also performed for each distribution to confirm significant compensation in response to the perturbation. RESULTS: Modality analyses were not significant (p > .05) for any group or task, indicating unimodal distributions. Our analyses also confirmed compensatory reflexive responses to pitch and formant perturbations across all groups, as well as adaptive responses to sustained formant perturbations. However, analyses of sustained pitch perturbations only revealed evidence of adaptation in studies with younger adults. CONCLUSION: The demonstration of a clear unimodal distribution across all tasks suggests that following responses do not represent a distinct response pattern, but rather the tail of a unimodal distribution. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24282676.

Functional connectivity MRI quality control procedures in CONN.

Quality control (QC) for functional connectivity magnetic resonance imaging (FC-MRI) is critical to ensure the validity of neuroimaging studies. Noise confounds are common in MRI data and, if not accounted for, may introduce biases in functional measures affecting the validity, replicability, and interpretation of FC-MRI study results. Although FC-MRI analysis rests on the assumption of adequate data processing, QC is underutilized and not systematically reported. Here, we describe a quality control pipeline for the visual and automated evaluation of MRI data implemented as part of the CONN toolbox. We analyzed publicly available resting state MRI data (N = 139 from 7 MRI sites) from the FMRI Open QC Project. Preprocessing steps included realignment, unwarp, normalization, segmentation, outlier identification, and smoothing. Data denoising was performed based on the combination of scrubbing, motion regression, and aCompCor - a principal component characterization of noise from minimally eroded masks of white matter and of cerebrospinal fluid tissues. Participant-level QC procedures included visual inspection of raw-level data and of representative images after each preprocessing step for each run, as well as the computation of automated descriptive QC measures such as average framewise displacement, average global signal change, prevalence of outlier scans, MNI to anatomical and functional overlap, anatomical to functional overlap, residual BOLD timeseries variability, effective degrees of freedom, and global correlation strength. Dataset-level QC procedures included the evaluation of inter-subject variability in the distributions of edge connectivity in a 1,000-node graph (FC distribution displays), and the estimation of residual associations across participants between functional connectivity strength and potential noise indicators such as participant's head motion and prevalence of outlier scans (QC-FC analyses). QC procedures are demonstrated on the reference dataset with an emphasis on visualization, and general recommendations for best practices are discussed in the context of functional connectivity and other fMRI analysis. We hope this work contributes toward the dissemination and standardization of QC testing performance reporting among peers and in scientific journals.

Improving the study of brain-behavior relationships by revisiting basic assumptions.

Neuroimaging research has been at the forefront of concerns regarding the failure of experimental findings to replicate. In the study of brain-behavior relationships, past failures to find replicable and robust effects have been attributed to methodological shortcomings. Methodological rigor is important, but there are other overlooked possibilities: most published studies share three foundational assumptions, often implicitly, that may be faulty. In this paper, we consider the empirical evidence from human brain imaging and the study of non-human animals that calls each foundational assumption into question. We then consider the opportunities for a robust science of brain-behavior relationships that await if scientists ground their research efforts in revised assumptions supported by current empirical evidence.

Auditory feedback control in adults who stutter during metronome-paced speech I. Timing Perturbation.

PURPOSE: This study determined whether adults who stutter (AWS) exhibit deficits in responding to an auditory feedback timing perturbation, and whether external timing cues, which increase fluency, attenuate any disruptions due to altered temporal auditory feedback. METHODS: Fifteen AWS and sixteen adults who do not stutter (ANS) read aloud a multisyllabic sentence either with normal pacing or with each syllable paced at the rate of a metronome. On random trials, an auditory feedback timing perturbation was applied, and timing responses were compared between groups and pacing conditions. RESULTS: Both groups responded to the timing perturbation by delaying subsequent syllable boundaries, and there were no significant differences between groups in either pacing condition. Furthermore, no response differences were found between normally paced and metronome-paced conditions. CONCLUSION: These findings are interpreted as showing that 1) AWS respond normally to pure timing perturbations, and 2) metronome-paced speech has no effect on online speech timing control as assessed in the present experiment.

Precision fMRI reveals that the language-selective network supports both phrase-structure building and lexical access during language production.

A fronto-temporal brain network has long been implicated in language comprehension. However, this network's role in language production remains debated. In particular, it remains unclear whether all or only some language regions contribute to production, and which aspects of production these regions support. Across 3 functional magnetic resonance imaging experiments that rely on robust individual-subject analyses, we characterize the language network's response to high-level production demands. We report 3 novel results. First, sentence production, spoken or typed, elicits a strong response throughout the language network. Second, the language network responds to both phrase-structure building and lexical access demands, although the response to phrase-structure building is stronger and more spatially extensive, present in every language region. Finally, contra some proposals, we find no evidence of brain regions-within or outside the language network-that selectively support phrase-structure building in production relative to comprehension. Instead, all language regions respond more strongly during production than comprehension, suggesting that production incurs a greater cost for the language network. Together, these results align with the idea that language comprehension and production draw on the same knowledge representations, which are stored in a distributed manner within the language-selective network and are used to both interpret and generate linguistic utterances.

Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies.

Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer's disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.

Brain-wide connectome inferences using functional connectivity MultiVariate Pattern Analyses (fc-MVPA).

Current functional Magnetic Resonance Imaging technology is able to resolve billions of individual functional connections characterizing the human connectome. Classical statistical inferential procedures attempting to make valid inferences across this many measures from a reduced set of observations and from a limited number of subjects can be severely underpowered for any but the largest effect sizes. This manuscript discusses fc-MVPA (functional connectivity Multivariate Pattern Analysis), a novel method using multivariate pattern analysis techniques in the context of brain-wide connectome inferences. The theory behind fc-MVPA is presented, and several of its key concepts are illustrated through examples from a publicly available resting state dataset, including an analysis of gender differences across the entire functional connectome. Finally, Monte Carlo simulations are used to demonstrate the validity and sensitivity of this method. In addition to offering powerful whole-brain inferences, fc-MVPA also provides a meaningful characterization of the heterogeneity in functional connectivity across subjects.

Quantitatively characterizing reflexive responses to pitch perturbations.

Background: Reflexive pitch perturbation experiments are commonly used to investigate the neural mechanisms underlying vocal motor control. In these experiments, the fundamental frequency-the acoustic correlate of pitch-of a speech signal is shifted unexpectedly and played back to the speaker via headphones in near real-time. In response to the shift, speakers increase or decrease their fundamental frequency in the direction opposing the shift so that their perceived pitch is closer to what they intended. The goal of the current work is to develop a quantitative model of responses to reflexive perturbations that can be interpreted in terms of the physiological mechanisms underlying the response and that captures both group-mean data and individual subject responses. Methods: A model framework was established that allowed the specification of several models based on Proportional-Integral-Derivative and State-Space/Directions Into Velocities of Articulators (DIVA) model classes. The performance of 19 models was compared in fitting experimental data from two published studies. The models were evaluated in terms of their ability to capture both population-level responses and individual differences in sensorimotor control processes. Results: A three-parameter DIVA model performed best when fitting group-mean data from both studies; this model is equivalent to a single-rate state-space model and a first-order low pass filter model. The same model also provided stable estimates of parameters across samples from individual subject data and performed among the best models to differentiate between subjects. The three parameters correspond to gains in the auditory feedback controller's response to a perceived error, the delay of this response, and the gain of the somatosensory feedback controller's "resistance" to this correction. Excellent fits were also obtained from a four-parameter model with an additional auditory velocity error term; this model was better able to capture multi-component reflexive responses seen in some individual subjects. Conclusion: Our results demonstrate the stereotyped nature of an individual's responses to pitch perturbations. Further, we identified a model that captures population responses to pitch perturbations and characterizes individual differences in a stable manner with parameters that relate to underlying motor control capabilities. Future work will evaluate the model in characterizing responses from individuals with communication disorders.

Auditory feedback control in adults who stutter during metronome-paced speech II. Formant Perturbation.

PURPOSE: Prior work has shown that Adults who stutter (AWS) have reduced and delayed responses to auditory feedback perturbations. This study aimed to determine whether external timing cues, which increase fluency, resolve auditory feedback processing disruptions. METHODS: Fifteen AWS and sixteen adults who do not stutter (ANS) read aloud a multisyllabic sentence either with natural stress and timing or with each syllable paced at the rate of a metronome. On random trials, an auditory feedback formant perturbation was applied, and formant responses were compared between groups and pacing conditions. RESULTS: During normally paced speech, ANS showed a significant compensatory response to the perturbation by the end of the perturbed vowel, while AWS did not. In the metronome-paced condition, which significantly reduced the disfluency rate, the opposite was true: AWS showed a significant response by the end of the vowel, while ANS did not. CONCLUSION: These findings indicate a potential link between the reduction in stuttering found during metronome-paced speech and changes in auditory motor integration in AWS.

Probabilistic atlas for the language network based on precision fMRI data from >800 individuals.

Two analytic traditions characterize fMRI language research. One relies on averaging activations across individuals. This approach has limitations: because of inter-individual variability in the locations of language areas, any given voxel/vertex in a common brain space is part of the language network in some individuals but in others, may belong to a distinct network. An alternative approach relies on identifying language areas in each individual using a functional 'localizer'. Because of its greater sensitivity, functional resolution, and interpretability, functional localization is gaining popularity, but it is not always feasible, and cannot be applied retroactively to past studies. To bridge these disjoint approaches, we created a probabilistic functional atlas using fMRI data for an extensively validated language localizer in 806 individuals. This atlas enables estimating the probability that any given location in a common space belongs to the language network, and thus can help interpret group-level activation peaks and lesion locations, or select voxels/electrodes for analysis. More meaningful comparisons of findings across studies should increase robustness and replicability in language research.

Increased Intra-Subject Variability of Neural Activity During Speech Production in People with Autism Spectrum Disorder.

Background: Communication difficulties are a core deficit in many people with autism spectrum disorder (ASD). The current study evaluated neural activation in participants with ASD and neurotypical (NT) controls during a speech production task. Methods: Neural activities of participants with ASD (N = 15, M = 16.7 years, language abilities ranged from low verbal abilities to verbally fluent) and NT controls (N = 12, M = 17.1 years) was examined using functional magnetic resonance imaging with a sparse-sampling paradigm. Results: There were no differences between the ASD and NT groups in average speech activation or inter-subject run-to-run variability in speech activation. Intra-subject run-to-run neural variability was greater in the ASD group and was positively correlated with autism severity in cortical areas associated with speech. Conclusions: These findings highlight the importance of understanding intra-subject neural variability in participants with ASD.

Resting state functional connectivity provides mechanistic predictions of future changes in sedentary behavior.

Sedentary behaviors are increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths worldwide. Understanding the mechanistic predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. It has been posited that humans have an innate attraction towards effort minimization and that inhibitory control is required to overcome this prepotent disposition. Consequently, we hypothesized that individual differences in the functional connectivity of brain regions implicated in inhibitory control and physical effort decision making at the beginning of an exercise intervention in older adults would predict the change in time spent sedentary over the course of that intervention. In 143 healthy, low-active older adults participating in a 6-month aerobic exercise intervention (with three conditions: walking, dance, stretching), we aimed to use baseline neuroimaging (resting state functional connectivity of two a priori defined seed regions), and baseline accelerometer measures of time spent sedentary to predict future pre-post changes in objectively measured time spent sedentary in daily life over the 6-month intervention. Our results demonstrated that functional connectivity between (1) the anterior cingulate cortex and the supplementary motor area and (2) the right anterior insula and the left temporoparietal/temporooccipital junction, predicted changes in time spent sedentary in the walking group. Functional connectivity of these brain regions did not predict changes in time spent sedentary in the dance nor stretch and tone conditions, but baseline time spent sedentary was predictive in these conditions. Our results add important knowledge toward understanding mechanistic associations underlying complex out-of-session sedentary behaviors within a walking intervention setting in older adults.

Behavioral and neural correlates of speech motor sequence learning in stuttering and neurotypical speakers: an fMRI investigation.

Stuttering is a neurodevelopmental disorder characterized by impaired production of coordinated articulatory movements needed for fluent speech. It is currently unknown whether these abnormal production characteristics reflect disruptions to brain mechanisms underlying the acquisition and/or execution of speech motor sequences. To dissociate learning and control processes, we used a motor sequence learning paradigm to examine the behavioral and neural correlates of learning to produce novel phoneme sequences in adults who stutter (AWS) and neurotypical controls. Participants intensively practiced producing pseudowords containing non-native consonant clusters (e.g., "gvasf") over two days. The behavioral results indicated that although the two experimental groups showed comparable learning trajectories, AWS performed significantly worse on the task prior to and after speech motor practice. Using functional magnetic resonance imaging (fMRI), the authors compared brain activity during articulation of the practiced words and a set of novel pseudowords (matched in phonetic complexity). FMRI analyses revealed no differences between AWS and controls in cortical or subcortical regions; both groups showed comparable increases in activation in left-lateralized brain areas implicated in phonological working memory and speech motor planning during production of the novel sequences compared to the practiced sequences. Moreover, activation in left-lateralized basal ganglia sites was negatively correlated with in-scanner mean disfluency in AWS. Collectively, these findings demonstrate that AWS exhibit no deficit in constructing new speech motor sequences but do show impaired execution of these sequences before and after they have been acquired and consolidated.

The Neural Circuitry Underlying the "Rhythm Effect" in Stuttering.

Purpose Stuttering is characterized by intermittent speech disfluencies, which are dramatically reduced when speakers synchronize their speech with a steady beat. The goal of this study was to characterize the neural underpinnings of this phenomenon using functional magnetic resonance imaging. Method Data were collected from 16 adults who stutter and 17 adults who do not stutter while they read sentences aloud either in a normal, self-paced fashion or paced by the beat of a series of isochronous tones ("rhythmic"). Task activation and task-based functional connectivity analyses were carried out to compare neural responses between speaking conditions and groups after controlling for speaking rate. Results Adults who stutter produced fewer disfluent trials in the rhythmic condition than in the normal condition. Adults who stutter did not have any significant changes in activation between the rhythmic condition and the normal condition, but when groups were collapsed, participants had greater activation in the rhythmic condition in regions associated with speech sequencing, sensory feedback control, and timing perception. Adults who stutter also demonstrated increased functional connectivity among cerebellar regions during rhythmic speech as compared to normal speech and decreased connectivity between the left inferior cerebellum and the left prefrontal cortex. Conclusions Modulation of connectivity in the cerebellum and prefrontal cortex during rhythmic speech suggests that this fluency-inducing technique activates a compensatory timing system in the cerebellum and potentially modulates top-down motor control and attentional systems. These findings corroborate previous work associating the cerebellum with fluency in adults who stutter and indicate that the cerebellum may be targeted to enhance future therapeutic interventions. Supplemental Material https://doi.org/10.23641/asha.14417681.

Reliability of single-subject neural activation patterns in speech production tasks.

Speech neuroimaging research targeting individual speakers could help elucidate differences that may be crucial to understanding speech disorders. However, this research necessitates reliable brain activation across multiple speech production sessions. In the present study, we evaluated the reliability of speech-related brain activity measured by functional magnetic resonance imaging data from twenty neuro-typical subjects who participated in two experiments involving reading aloud simple speech stimuli. Using traditional methods like the Dice and intraclass correlation coefficients, we found that most individuals displayed moderate to high reliability. We also found that a novel machine-learning subject classifier could identify these individuals by their speech activation patterns with 97% accuracy from among a dataset of seventy-five subjects. These results suggest that single-subject speech research would yield valid results and that investigations into the reliability of speech activation in people with speech disorders are warranted.

Mindfulness training preserves sustained attention and resting state anticorrelation between default-mode network and dorsolateral prefrontal cortex: A randomized controlled trial.

Mindfulness training can enhance cognitive control, but the neural mechanisms underlying such enhancement in children are unknown. Here, we conducted a randomized controlled trial (RCT) with sixth graders (mean age 11.76 years) to examine the impact of 8 weeks of school-based mindfulness training, relative to coding training as an active control, on sustained attention and associated resting-state functional brain connectivity. At baseline, better performance on a sustained-attention task correlated with greater anticorrelation between the default mode network (DMN) and right dorsolateral prefrontal cortex (DLPFC), a key node of the central executive network. Following the interventions, children in the mindfulness group preserved their sustained-attention performance (i.e., fewer lapses of attention) and preserved DMN-DLPFC anticorrelation compared to children in the active control group, who exhibited declines in both sustained attention and DMN-DLPFC anticorrelation. Further, change in sustained-attention performance correlated with change in DMN-DLPFC anticorrelation only within the mindfulness group. These findings provide the first causal link between mindfulness training and both sustained attention and associated neural plasticity. Administered as a part of sixth graders' school schedule, this RCT supports the beneficial effects of school-based mindfulness training on cognitive control.