The speech neuroprosthesis.

Loss of speech after paralysis is devastating, but circumventing motor-pathway injury by directly decoding speech from intact cortical activity has the potential to restore natural communication and self-expression. Recent discoveries have defined how key features of speech production are facilitated by the coordinated activity of vocal-tract articulatory and motor-planning cortical representations. In this Review, we highlight such progress and how it has led to successful speech decoding, first in individuals implanted with intracranial electrodes for clinical epilepsy monitoring and subsequently in individuals with paralysis as part of early feasibility clinical trials to restore speech. We discuss high-spatiotemporal-resolution neural interfaces and the adaptation of state-of-the-art speech computational algorithms that have driven rapid and substantial progress in decoding neural activity into text, audible speech, and facial movements. Although restoring natural speech is a long-term goal, speech neuroprostheses already have performance levels that surpass communication rates offered by current assistive-communication technology. Given this accelerated rate of progress in the field, we propose key evaluation metrics for speed and accuracy, among others, to help standardize across studies. We finish by highlighting several directions to more fully explore the multidimensional feature space of speech and language, which will continue to accelerate progress towards a clinically viable speech neuroprosthesis.

A bilingual speech neuroprosthesis driven by cortical articulatory representations shared between languages.

Advancements in decoding speech from brain activity have focused on decoding a single language. Hence, the extent to which bilingual speech production relies on unique or shared cortical activity across languages has remained unclear. Here, we leveraged electrocorticography, along with deep-learning and statistical natural-language models of English and Spanish, to record and decode activity from speech-motor cortex of a Spanish-English bilingual with vocal-tract and limb paralysis into sentences in either language. This was achieved without requiring the participant to manually specify the target language. Decoding models relied on shared vocal-tract articulatory representations across languages, which allowed us to build a syllable classifier that generalized across a shared set of English and Spanish syllables. Transfer learning expedited training of the bilingual decoder by enabling neural data recorded in one language to improve decoding in the other language. Overall, our findings suggest shared cortical articulatory representations that persist after paralysis and enable the decoding of multiple languages without the need to train separate language-specific decoders.

A high-performance neuroprosthesis for speech decoding and avatar control.

Speech neuroprostheses have the potential to restore communication to people living with paralysis, but naturalistic speed and expressivity are elusive1. Here we use high-density surface recordings of the speech cortex in a clinical-trial participant with severe limb and vocal paralysis to achieve high-performance real-time decoding across three complementary speech-related output modalities: text, speech audio and facial-avatar animation. We trained and evaluated deep-learning models using neural data collected as the participant attempted to silently speak sentences. For text, we demonstrate accurate and rapid large-vocabulary decoding with a median rate of 78 words per minute and median word error rate of 25%. For speech audio, we demonstrate intelligible and rapid speech synthesis and personalization to the participant's pre-injury voice. For facial-avatar animation, we demonstrate the control of virtual orofacial movements for speech and non-speech communicative gestures. The decoders reached high performance with less than two weeks of training. Our findings introduce a multimodal speech-neuroprosthetic approach that has substantial promise to restore full, embodied communication to people living with severe paralysis.

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.

Not All Patients With Locally Advanced Rectal Cancer Benefit From Neoadjuvant Therapy.

BACKGROUND: While neoadjuvant combined modality therapy (NA-CMT) is beneficial for most patients with locally advanced rectal cancer some patients may experience disease progression during treatment. The purpose of this study is to identify characteristics associated with progression during NA-CMT. METHODS: A single institution retrospective review of patients with stage II-III rectal cancer receiving NA-CMT was conducted from 2008-2019. Patients with incomplete or unknown NA-CMT treatment and those who received chemotherapy in addition to NA-CMT were excluded. Initial staging MRI was compared to post-operative pathology to determine progression. Definitions: responders (complete response or regression) and non-responders (stable disease or progression). RESULTS: 156 patients were included: 25 (16.1%) complete responders, 79 (50.6%) had evidence of regression, 34 (21.8%) were stable non-responders, and 18 (11.5%) were progressors. Those who progressed had worse overall survival. Factors associated with non-responders included black race (OR 4.5, 95% CI: 1.10-18.7) and increasing distance from the anal verge (OR 1.2, 95% CI: .2-2.9). Distance from the anal verge was determined via MRI. Recurrence was significantly more common among non-responders (15, 30.61%) when compared to responders (14, 13.46%), P = .012. CONCLUSION: Patients who progress despite NA-CMT have overall worse survival compared to patients who do respond. While this study failed to identify modifiable or predictive risk factors for progression, the multivariate logistic regression model suggests that race and tumor biology may play a role in progression. Future studies should focus on early identification of patients who may not benefit from NA-CMT in an effort to develop alternative treatment algorithms.

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.

Generalizable spelling using a speech neuroprosthesis in an individual with severe limb and vocal paralysis.

Neuroprostheses have the potential to restore communication to people who cannot speak or type due to paralysis. However, it is unclear if silent attempts to speak can be used to control a communication neuroprosthesis. Here, we translated direct cortical signals in a clinical-trial participant (ClinicalTrials.gov; NCT03698149) with severe limb and vocal-tract paralysis into single letters to spell out full sentences in real time. We used deep-learning and language-modeling techniques to decode letter sequences as the participant attempted to silently spell using code words that represented the 26 English letters (e.g. "alpha" for "a"). We leveraged broad electrode coverage beyond speech-motor cortex to include supplemental control signals from hand cortex and complementary information from low- and high-frequency signal components to improve decoding accuracy. We decoded sentences using words from a 1,152-word vocabulary at a median character error rate of 6.13% and speed of 29.4 characters per minute. In offline simulations, we showed that our approach generalized to large vocabularies containing over 9,000 words (median character error rate of 8.23%). These results illustrate the clinical viability of a silently controlled speech neuroprosthesis to generate sentences from a large vocabulary through a spelling-based approach, complementing previous demonstrations of direct full-word decoding.

The association of U.S. state-level abortion restrictions with medication abortion service delivery innovations during the early COVID-19 pandemic.

OBJECTIVES: To assess whether state-level abortion restrictions resulted in differential uptake of innovative medication abortion practices such as changing ultrasound requirements, offering telehealth, or dispensing medications without a physical exam during the early COVID-19 pandemic. METHODS: We used data from a prospective national survey of abortion providers to assess the association between a novel index of state-level abortion hostility and adoption of medication abortion services innovations during the pandemic. RESULTS: Clinics in states with low or medium hostility were more likely to adopt innovative practices than those in high or extreme hostility states. CONCLUSIONS: Clinics in abortion hostile states were less likely to adopt clinical recommendations and public health best practices for abortion care during the COVID-19 pandemic.

Comparing Donor Site Morbidity for Autologous Breast Reconstruction: Thigh vs. Abdomen.

Although abdominally-based free flaps have long been the gold standard, the profunda artery perforator (PAP) flap has emerged as an important alternative option for autologous breast reconstruction. The aim of this study was to directly compare the donor site morbidity of using the PAP versus deep inferior epigastric perforator (DIEP) free flap. Methods: We performed a retrospective review of patients undergoing autologous breast reconstruction using a DIEP and/or PAP flap from January 2017 to December 2020. In total, 30 PAP flap patients were matched with 60 DIEP flap patients. Outcomes included donor site wound dehiscence, length of stay, narcotic consumption, and pain scores. Patient-reported outcomes for the thigh versus abdomen were compared using questions derived from the BREAST-Q. Results: There was no significant difference in length of stay (P = 0.182), reoperation rates (P = 0.999), flap failure rates (P = 0.999), or donor site complications (P = 0.999). Both groups had similar mean pain scores, maximum pain scores, daily and total narcotic requirements. In comparing the thigh or abdomen as a donor site, there was no difference in frequency of negative symptoms (difficulty with daily activities, discomfort, tightness, and negative impact on ability to work) or satisfaction scores as related to their appearance in and out of clothing and the appearance of the scar. Conclusions: The thigh and abdomen are both suitable donor sites for autologous breast reconstruction with similar flap-related and patient-reported outcomes. The ultimate decision regarding whether to use a PAP or DIEP flap for breast reconstruction should be tailored based on patient anatomy and preference.

Incorporating uncertainty in learning to defer algorithms for safe computer-aided diagnosis.

Deep neural networks are increasingly being used for computer-aided diagnosis, but erroneous diagnoses can be extremely costly for patients. We propose a learning to defer with uncertainty (LDU) algorithm which identifies patients for whom diagnostic uncertainty is high and defers them for evaluation by human experts. LDU was evaluated on the diagnosis of myocardial infarction (using discharge summaries), the diagnosis of any comorbidities (using structured data), and the diagnosis of pleural effusion and pneumothorax (using chest x-rays), and compared with 'learning to defer without uncertainty information' (LD) and 'direct triage by uncertainty' (DT) methods. LDU achieved the same F1 score as LD but deferred considerably fewer patients (e.g. 36% vs. 69% deferral rate for diagnosing pleural effusion with an F1 score of 0.96). Furthermore, even when many patients were assigned the wrong diagnosis with high confidence (e.g. for the diagnosis of any comorbidities) LDU achieved a 17% increase in F1 score, whereas DT was not applicable. Importantly, the weight of the defer loss in LDU can be easily adjusted to obtain the desired trade-off between diagnostic accuracy and deferral rate. In conclusion, LDU can readily augment any existing diagnostic network to reduce the risk of erroneous diagnoses in clinical practice.

Neuroprosthesis for Decoding Speech in a Paralyzed Person with Anarthria.

BACKGROUND: Technology to restore the ability to communicate in paralyzed persons who cannot speak has the potential to improve autonomy and quality of life. An approach that decodes words and sentences directly from the cerebral cortical activity of such patients may represent an advancement over existing methods for assisted communication. METHODS: We implanted a subdural, high-density, multielectrode array over the area of the sensorimotor cortex that controls speech in a person with anarthria (the loss of the ability to articulate speech) and spastic quadriparesis caused by a brain-stem stroke. Over the course of 48 sessions, we recorded 22 hours of cortical activity while the participant attempted to say individual words from a vocabulary set of 50 words. We used deep-learning algorithms to create computational models for the detection and classification of words from patterns in the recorded cortical activity. We applied these computational models, as well as a natural-language model that yielded next-word probabilities given the preceding words in a sequence, to decode full sentences as the participant attempted to say them. RESULTS: We decoded sentences from the participant's cortical activity in real time at a median rate of 15.2 words per minute, with a median word error rate of 25.6%. In post hoc analyses, we detected 98% of the attempts by the participant to produce individual words, and we classified words with 47.1% accuracy using cortical signals that were stable throughout the 81-week study period. CONCLUSIONS: In a person with anarthria and spastic quadriparesis caused by a brain-stem stroke, words and sentences were decoded directly from cortical activity during attempted speech with the use of deep-learning models and a natural-language model. (Funded by Facebook and others; ClinicalTrials.gov number, NCT03698149.).

Free Flap Reconstruction of Posterior Trunk Soft-Tissue Defects: Single-Institution Experience and Systematic Literature Review.

BACKGROUND: The posterior trunk is a technically demanding location for microvascular free tissue transfer. In this study, the authors report their own institutional experience with soft-tissue free flap reconstruction of the posterior trunk and provide a systematic review of the literature regarding this uncommon clinical scenario. METHODS: A systematic review was performed using the PubMed database in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A single-institution retrospective review was also performed including all patients who received a soft-tissue free flap for a posterior trunk defect between 1990 and 2019. RESULTS: The database search yielded 15 articles, representing 61 patients; the most commonly used flap was the latissimus dorsi (45.9 percent) and the most commonly reported defect location was the lumbosacrum (42.3 percent). Retrospective review of the authors' database identified 26 patients, with the latissimus dorsi being the most common flap and the sacrum the most common defect site. The authors' institutional case series showed a 30.7 percent major complication rate and 7.7 percent total flap loss rate; 38.4 percent of flaps required vein grafting. CONCLUSIONS: In this study, the authors provided a systematic literature review and described their own long-term institutional experience with these rare and difficult reconstructions. Although the overall complication rate is high, these reconstructions are frequently necessary, and an algorithmic approach can improve outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The impact of sarcopenia on oncologic abdominal wall reconstruction.

BACKGROUND AND OBJECTIVES: Sarcopenia is an objective measure of patient frailty and is a predictor of adverse surgical outcomes. We hypothesized that sarcopenia is associated with increased surgical site occurrence (SSO) and hernia occurrences in patients undergoing oncologic abdominal wall reconstruction. METHODS: Consecutive patients who underwent abdominal wall reconstruction (AWR) for an abdominal wall ablative defect at a single center from 2005 to 2015 were evaluated. The total psoas index (TPI) was used to define sarcopenia. The primary endpoint of the study was hernia occurrence; (SSO) was a secondary outcome measure. RESULTS: Eighty-six patients met the inclusion criteria. Multivariate analysis demonstrated that sarcopenia increased the risk of hernia more than threefold, trending toward significance (OR = 3.3; 95% CI: 0.69-15.4; P = .13). Multivariate logistic regression demonstrated that preoperative radiotherapy (OR = 4.8, 95% CI: 1.4-16; P = .01) and obesity (OR = 4.9, 95% CI: 1.5-16.3; P =.009) were independent predictors of developing an SSO. CONCLUSIONS: Sarcopenia, as defined by TPI, is correlated with hernia occurrence, but not SSO. These findings emphasize the importance of preoperative fitness and nutritional optimization and provide useful information for preoperative counseling and risk stratification.

Perforator Mapping of the Profunda Artery Perforator Flap: Anatomy and Clinical Experience.

BACKGROUND: Discovering alternatives to workhorse flaps that have more consistent anatomy and lower donor-site morbidity has become a focus of reconstructive surgery research. This study provides a simplified approach to profunda artery perforator flap design and harvest based on reliable anatomical landmarks. METHODS: A retrospective review was conducted of 70 patients who underwent 83 profunda artery perforator flap reconstructions for postoncologic defects from 2016 to 2018. The authors recorded and analyzed the profunda artery perforator flap sizes and clinical applications, the numbers and locations of the perforators, and the patient outcomes. RESULTS: Most of the profunda artery perforator flaps were for head and neck [46 patients (65.7 percent)] and breast [21 patients (30 percent)] reconstructions. Flaps were most commonly based on perforator A (33.7 percent) and perforator B (33.7 percent), followed by perforators B and C combined (18.1 percent). Perforators were located a mean of 7.5 cm (perforator A), 12.7 cm (B), and 17.6 cm (C) distal to the pubic tubercle parallel to the axis between the pubic tubercle and the medial femoral condyle and 7.9 cm (A), 7.3 cm (B), and 6.1 cm (C) posterior from the axis. There was no flap loss. One patient underwent successful salvage surgery after arterial flap thrombosis. Eight patients (9.6 percent) developed superficial wound dehiscence that was managed conservatively. CONCLUSIONS: Perforator mapping demonstrated consistent anatomical locations of sizeable profunda artery perforators in the inner thigh. Along with its consistent and robust vascular anatomy and minimal donor-site morbidity, the profunda artery perforator flap's volume and pliability make it a reliable option for soft-tissue reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The effect of sarcopenia on perioperative complications in abdominally based free-flap breast reconstruction.

PURPOSE: The identification of patient-specific risk factors, which predict morbidity following abdominally based microvascular breast reconstruction is difficult. Sarcopenia is a proxy for patient frailty and is an independent predictor of complications in a myriad of surgical disciplines. We predict that sarcopenic patients will be at higher risk for surgical complications following abdominally based microvascular breast reconstruction. METHODS: A retrospective study of all patients who underwent delayed abdominally based autologous breast reconstruction following postmastectomy radiation therapy from 2007 to 2013 at a single institution was conducted. Univariate and multiple logistic regression models were used to assess the effect of sarcopenia on postoperative outcomes. RESULTS: Two hundred and eight patients met the inclusion criteria, of which 30 met criteria for sarcopenia (14.1%). There were no significant differences in demographics between groups. There were no significant differences in minor (36.7% vs 44.4%; P = .43) or major (16.7% vs 25.3%; P = .36) complications between groups as well as hospital length of stay. Multivariable logistic regression demonstrated that a staged reconstruction with the use of a tissue expander was the only consistent variable, which predicted major complications (OR, 2.24; 95% CI, 1.18-4.64; P = .015). CONCLUSIONS: Sarcopenia does not predispose to minor or major surgical complications in patients who undergo abdominally based microsurgical breast reconstruction.

Ex vivo biomechanical characterization of syringe-needle ejections for intracerebral cell delivery.

Intracerebral implantation of cell suspensions is finding its clinical translation with encouraging results in patients with stroke. However, the survival of cells in the brain remains poor. Although the biological potential of neural stem cells (NSCs) is widely documented, the biomechanical effects of delivering cells through a syringe-needle remain poorly understood. We here detailed the biomechanical forces (pressure, shear stress) that cells are exposed to during ejection through different sized needles (20G, 26G, 32G) and syringes (10, 50, 250 µL) at relevant flow rates (1, 5, 10 µL/min). A comparison of 3 vehicles, Phosphate Buffered Saline (PBS), Hypothermosol (HTS), and Pluronic, indicated that less viscous vehicles are favorable for suspension with a high cell volume fraction to minimize sedimentation. Higher suspension viscosity was associated with greater shear stress. Higher flow rates with viscous vehicle, such as HTS reduced viability by ~10% and also produced more apoptotic cells (28%). At 5 µL/min ejection using a 26G needle increased neuronal differentiation for PBS and HTS suspensions. These results reveal the biological impact of biomechanical forces in the cell delivery process. Appropriate engineering strategies can be considered to mitigate these effects to ensure the efficacious translation of this promising therapy.

Quantification of the Extracellular Matrix Molecule Thrombospondin 1 and Its Pericellular Association in the Brain Using a Semiautomated Computerized Approach.

The structure and functions of the extracellular matrix (ECM), its spatial distribution and pericellular association of ECM molecules remain poorly understood. Colocalization of ECM molecules with cell phenotypes through immunohistochemistry can provide crucial insights into their juxtacrine signaling role as well as their structural relevance to tissue architecture. As manual quantification of images introduces intra- and inter-user bias and is cumbersome for high-throughput approaches, we implemented an automated high-throughput method to quantify the spatial distribution and cellular association of one ECM molecule, thrombospondin 1 (TSP1) with two major cell phenotypes, neurons, and astrocytes. The distribution of TSP1 was homogeneous throughout the striatum and cortex along the anterior-posterior axis. TSP1 occupied 8.85% of the striatum and 7.40% in the cortex. TSP1 also associated with 94.58% and 88.45% of neurons in the striatum and cortex. The association with astrocytes was significantly lower at 47.55% and 28.09%. These findings highlight the key role that TSP1 plays in neuron physiology in a healthy brain, but also highlights key regional difference in astrocytes secreting ECM molecules. The semiautomated approach implemented here will improve the throughput and reliability of measuring the distribution and cellular colocalization of ECM molecules.

Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume.

Salvaging or functional replacement of damaged tissue caused by stroke in the brain remains a major therapeutic challenge. In situ gelation and retention of a hydrogel bioscaffold composed of 8mg/mL extracellular matrix (ECM) can induce a robust invasion of cells within 24h and potentially promote a structural remodeling to replace lost tissue. Herein, we demonstrate a long-term retention of ECM hydrogel within the lesion cavity. A decrease of approximately 32% of ECM volume is observed over 12weeks. Lesion volume, as measured by magnetic resonance imaging and histology, was reduced by 28%, but a battery of behavioral tests (bilateral asymmetry test; footfault; rotameter) did not reveal a therapeutic or detrimental effect of the hydrogel. Glial scarring and peri-infarct astrocytosis were equivalent between untreated and treated animals, potentially indicating that permeation into host tissue is required to exert therapeutic effects. These results reveal a marked difference of biodegradation of ECM hydrogel in the stroke-damaged brain compared to peripheral soft tissue repair. Further exploration of these structure-function relationships is required to achieve a structural remodeling of the implanted hydrogel, as seen in peripheral tissues, to replace lost tissue and promote behavioral recovery. STATEMENT OF SIGNIFICANCE: In situ gelation of ECM is essential for its retention within a tissue cavity. The brain is a unique environment with restricted access that necessitates image-guided delivery through a thin needle to access tissue cavities caused by stroke, as well as other conditions, such as traumatic brain injury or glioma resection. Knowledge about a brain tissue response to implanted hydrogels remains limited, especially in terms of long-term effects and potential impact on behavioral function. We here address the long-term retention of hydrogel within the brain environment, its impact on behavioral function, as well as its ability to reduce further tissue deformation caused by stroke. This study highlights considerable differences in the brain's long-term response to an ECM hydrogel compared to peripheral soft tissue. It underlines the importance of understanding the effect of the structural presence of a hydrogel within a cavity upon host brain tissue and behavioral function. As demonstrated herein, ECM hydrogel can fill a cavity long-term to reduce further progression of the cavity, while potentially serving as a reservoir for local drug or cell delivery.