Limited but specific engagement of the mature language network during linguistic statistical learning.

Statistical learning (SL) is the ability to detect and learn regularities from input and is foundational to language acquisition. Despite the dominant role of SL as a theoretical construct for language development, there is a lack of direct evidence supporting the shared neural substrates underlying language processing and SL. It is also not clear whether the similarities, if any, are related to linguistic processing, or statistical regularities in general. The current study tests whether the brain regions involved in natural language processing are similarly recruited during auditory, linguistic SL. Twenty-two adults performed an auditory linguistic SL task, an auditory nonlinguistic SL task, and a passive story listening task as their neural activation was monitored. Within the language network, the left posterior temporal gyrus showed sensitivity to embedded speech regularities during auditory, linguistic SL, but not auditory, nonlinguistic SL. Using a multivoxel pattern similarity analysis, we uncovered similarities between the neural representation of auditory, linguistic SL, and language processing within the left posterior temporal gyrus. No other brain regions showed similarities between linguistic SL and language comprehension, suggesting that a shared neurocomputational process for auditory SL and natural language processing within the left posterior temporal gyrus is specific to linguistic stimuli.

Efficient functional localization of language regions in the brain.

Important recent advances in the cognitive neuroscience of language have been made using functional localizers to demarcate language-selective regions in individual brains. Although single-subject localizers offer insights that are unavailable in classic group analyses, they require additional scan time that imposes costs on investigators and participants. In particular, the unique practical challenges of scanning children and other special populations has led to less adoption of localizers for neuroimaging research with these theoretically and clinically important groups. Here, we examined how measurements of the spatial extent and functional response profiles of language regions are affected by the duration of an auditory language localizer. We compared how parametrically smaller amounts of data collected from one scanning session affected (i) consistency of group-level whole-brain parcellations, (ii) functional selectivity of subject-level activation in individually defined functional regions of interest (fROIs), (iii) sensitivity and specificity of subject-level whole-brain and fROI activation, and (iv) test-retest reliability of subject-level whole-brain and fROI activation. For many of these metrics, the localizer duration could be reduced by 50-75% while preserving the stability and reliability of both the spatial extent and functional response profiles of language areas. These results indicate that, for most measures relevant to cognitive neuroimaging studies, the brain's language network can be localized just as effectively with 3.5 min of scan time as it can with 12 min. Minimizing the time required to reliably localize the brain's language network allows more effective localizer use in situations where each minute of scan time is particularly precious.

Tocilizumab as a Potential Adjunctive Therapy to Corticosteroids in Cryptococcal Post-infectious Inflammatory Response Syndrome (PIIRS): a Report of Two Cases.

PURPOSE: Non-HIV cryptococcal meningoencephalitis (CM) in previously healthy individuals is often complicated by a post-infectious inflammatory response syndrome (c-PIIRS) characterized by neurologic deterioration after appropriate antifungal therapy with sterilization of CSF fungal cultures. c-PIIRS results from an excessive inflammatory response to fungal antigens released during fungal lysis, mediated by IFN-γ, IL-6, and activated T-helper cells, leading to immune-mediated host damage that responds to pulse-corticosteroid taper therapy (PCT). Typically, oral steroids may take up to a year to taper, and occasionally, patients will be refractory to steroid therapy or may demonstrate high-risk lesions such as those involving intracranial arteries. Also, patients can have problematic side effects from prolonged corticosteroids. Hence, appropriate adjunctive agents are needed to reduce corticosteroid doses in the treatment of c-PIIRS. Due to a possible role of IL-6 in pathogenesis, IL-6 receptor blockade by tocilizumab may be useful in the treatment of c-PIIRS. METHODS: Two previously healthy patients with non-HIV cPIIRS were seen at the NIH. Due to concerns for intracranial vascular rupture in an area of inflammation (Patient 1) and intractable symptoms on high-dose oral corticosteroids (Patient 2) with evidence of persistent CSF inflammation, patients were treated with 4-8 mg/kg tocilizumab every 2 weeks while maintained on a constant dose of prednisone. RESULTS: Two patients exhibited rapid immunological improvement following treatment with tocilizumab. Patient 1 remained vascularly stable, and Patient 2 had near resolution of headaches with improvement in mental status as evidenced by improved MOCA score. The two had improved CSF inflammatory parameters and no significant side effects. Both CSF cultures remained negative throughout treatment. CONCLUSIONS: Tocilizumab may be a safe adjunctive treatment for CM-related PIIRS suggesting further study.

Apraxia of speech with phonological alexia and agraphia following resection of the left middle precentral gyrus: illustrative case.

BACKGROUND: Apraxia of speech is a disorder of speech-motor planning in which articulation is effortful and error-prone despite normal strength of the articulators. Phonological alexia and agraphia are disorders of reading and writing disproportionately affecting unfamiliar words. These disorders are almost always accompanied by aphasia. OBSERVATIONS: A 36-year-old woman underwent resection of a grade IV astrocytoma based in the left middle precentral gyrus, including a cortical site associated with speech arrest during electrocortical stimulation mapping. Following surgery, she exhibited moderate apraxia of speech and difficulty with reading and spelling, both of which improved but persisted 6 months after surgery. A battery of speech and language assessments was administered, revealing preserved comprehension, naming, cognition, and orofacial praxis, with largely isolated deficits in speech-motor planning and the spelling and reading of nonwords. LESSONS: This case describes a specific constellation of speech-motor and written language symptoms-apraxia of speech, phonological agraphia, and phonological alexia in the absence of aphasia-which the authors theorize may be attributable to disruption of a single process of "motor-phonological sequencing." The middle precentral gyrus may play an important role in the planning of motorically complex phonological sequences for production, independent of output modality.

A Neurosurgical Functional Dissection of the Middle Precentral Gyrus during Speech Production.

Classical models have traditionally focused on the left posterior inferior frontal gyrus (Broca's area) as a key region for motor planning of speech production. However, converging evidence suggests that it is not critical for either speech motor planning or execution. Alternative cortical areas supporting high-level speech motor planning have yet to be defined. In this review, we focus on the precentral gyrus, whose role in speech production is often thought to be limited to lower-level articulatory muscle control. In particular, we highlight neurosurgical investigations that have shed light on a cortical region anatomically located near the midpoint of the precentral gyrus, hence called the middle precentral gyrus (midPrCG). The midPrCG is functionally located between dorsal hand and ventral orofacial cortical representations and exhibits unique sensorimotor and multisensory functions relevant for speech processing. This includes motor control of the larynx, auditory processing, as well as a role in reading and writing. Furthermore, direct electrical stimulation of midPrCG can evoke complex movements, such as vocalization, and selective injury can cause deficits in verbal fluency, such as pure apraxia of speech. Based on these findings, we propose that midPrCG is essential to phonological-motoric aspects of speech production, especially syllabic-level speech sequencing, a role traditionally ascribed to Broca's area. The midPrCG is a cortical brain area that should be included in contemporary models of speech production with a unique role in speech motor planning and execution.

Outcomes in Previously Healthy Cryptococcal Meningoencephalitis Patients Treated With Pulse Taper Corticosteroids for Post-infectious Inflammatory Syndrome.

BACKGROUND: Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. METHODS: Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. RESULTS: The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P < .0003), which was accompanied by improvements in CSF glucose, white blood cell (WBC) count, protein, cellular and soluble inflammatory markers 1 week after receiving corticosteroids (CS) (P < .003). All patients with papilledema and visual field deficits also exhibited improvement (P < .0005). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement. Brain MRI showed significant improvement of radiological findings (P = .001). CSF cultures remained negative. CONCLUSIONS: PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.

Noninvasive neurostimulation of left ventral motor cortex enhances sensorimotor adaptation in speech production.

Sensorimotor adaptation-enduring changes to motor commands due to sensory feedback-allows speakers to match their articulations to intended speech acoustics. How the brain integrates auditory feedback to modify speech motor commands and what limits the degree of these modifications remain unknown. Here, we investigated the role of speech motor cortex in modifying stored speech motor plans. In a within-subjects design, participants underwent separate sessions of sham and anodal transcranial direct current stimulation (tDCS) over speech motor cortex while speaking and receiving altered auditory feedback of the first formant. Anodal tDCS increased the rate of sensorimotor adaptation for feedback perturbation. Computational modeling of our results using the Directions Into Velocities of Articulators (DIVA) framework of speech production suggested that tDCS primarily affected behavior by increasing the feedforward learning rate. This study demonstrates how focal noninvasive neurostimulation can enhance the integration of auditory feedback into speech motor plans.

Common cortical architectures for phonological working memory identified in individual brains.

Phonological working memory is the capacity to briefly maintain and recall representations of sounds important for speech and language and is believed to be critical for language and reading acquisition. Whether phonological working memory is supported by fronto-parietal brain regions associated with short-term memory storage or perisylvian brain structures implicated in speech perception and production is unclear, perhaps due to variability in stimuli, task demands, and individuals. We used fMRI to assess neurophysiological responses while individuals performed two tasks with closely matched stimuli but divergent task demands-nonword repetition and nonword discrimination-at two levels of phonological working memory load. Using analyses designed to address intersubject variability, we found significant neural responses to the critical contrast of high vs. low phonological working memory load in both tasks in a set of regions closely resembling those involved in speech perception and production. Moreover, within those regions, the voxel-wise patterns of load-related activation were highly correlated between the two tasks. These results suggest that brain regions in the temporal and frontal lobes encapsulate the core neurocomputational components of phonological working memory; an architecture that becomes increasingly evident as neural responses are examined in successively finer-grained detail in individual participants.

A Simple 3-Parameter Model for Examining Adaptation in Speech and Voice Production.

Sensorimotor adaptation experiments are commonly used to examine motor learning behavior and to uncover information about the underlying control mechanisms of many motor behaviors, including speech production. In the speech and voice domains, aspects of the acoustic signal are shifted/perturbed over time via auditory feedback manipulations. In response, speakers alter their production in the opposite direction of the shift so that their perceived production is closer to what they intended. This process relies on a combination of feedback and feedforward control mechanisms that are difficult to disentangle. The current study describes and tests a simple 3-parameter mathematical model that quantifies the relative contribution of feedback and feedforward control mechanisms to sensorimotor adaptation. The model is a simplified version of the DIVA model, an adaptive neural network model of speech motor control. The three fitting parameters of SimpleDIVA are associated with the three key subsystems involved in speech motor control, namely auditory feedback control, somatosensory feedback control, and feedforward control. The model is tested through computer simulations that identify optimal model fits to six existing sensorimotor adaptation datasets. We show its utility in (1) interpreting the results of adaptation experiments involving the first and second formant frequencies as well as fundamental frequency; (2) assessing the effects of masking noise in adaptation paradigms; (3) fitting more than one perturbation dimension simultaneously; (4) examining sensorimotor adaptation at different timepoints in the production signal; and (5) quantitatively predicting responses in one experiment using parameters derived from another experiment. The model simulations produce excellent fits to real data across different types of perturbations and experimental paradigms (mean correlation between data and model fits across all six studies = 0.95 ± 0.02). The model parameters provide a mechanistic explanation for the behavioral responses to the adaptation paradigm that are not readily available from the behavioral responses alone. Overall, SimpleDIVA offers new insights into speech and voice motor control and has the potential to inform future directions of speech rehabilitation research in disordered populations. Simulation software, including an easy-to-use graphical user interface, is publicly available to facilitate the use of the model in future studies.

A new fun and robust version of an fMRI localizer for the frontotemporal language system.

A set of brain regions in the frontal, temporal, and parietal lobes supports high-level linguistic processing. These regions can be reliably identified in individual subjects using fMRI, by contrasting neural responses to meaningful and structured language stimuli vs. stimuli matched for low-level properties but lacking meaning and/or structure. We here present a novel version of a language 'localizer,' which should be suitable for diverse populations including children and/or clinical populations who may have difficulty with reading or cognitively demanding tasks. In particular, we contrast responses to auditorily presented excerpts from engaging interviews or stories, and acoustically degraded versions of these materials. This language localizer is appealing because it uses (a) naturalistic and engaging linguistic materials, (b) auditory presentation,

Neural correlate of the construction of sentence meaning.

The neural processes that underlie your ability to read and understand this sentence are unknown. Sentence comprehension occurs very rapidly, and can only be understood at a mechanistic level by discovering the precise sequence of underlying computational and neural events. However, we have no continuous and online neural measure of sentence processing with high spatial and temporal resolution. Here we report just such a measure: intracranial recordings from the surface of the human brain show that neural activity, indexed by γ-power, increases monotonically over the course of a sentence as people read it. This steady increase in activity is absent when people read and remember nonword-lists, despite the higher cognitive demand entailed, ruling out accounts in terms of generic attention, working memory, and cognitive load. Response increases are lower for sentence structure without meaning ("Jabberwocky" sentences) and word meaning without sentence structure (word-lists), showing that this effect is not explained by responses to syntax or word meaning alone. Instead, the full effect is found only for sentences, implicating compositional processes of sentence understanding, a striking and unique feature of human language not shared with animal communication systems. This work opens up new avenues for investigating the sequence of neural events that underlie the construction of linguistic meaning.