Sensing, feeling and regulating: investigating the association of focal brain damage with voluntary respiratory and motor control.

Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire, and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia and left medial temporal lobe showed reduced performance relative to individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60 bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnoea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'.

Stimulation of caudal inferior and middle frontal gyri disrupts planning during spoken interaction.

Turn-taking is a central feature of conversation across languages and cultures.1,2,3,4 This key social behavior requires numerous sensorimotor and cognitive operations1,5,6 that can be organized into three general phases: comprehension of a partner's turn, preparation of a speaker's own turn, and execution of that turn. Using intracranial electrocorticography, we recently demonstrated that neural activity related to these phases is functionally distinct during turn-taking.7 In particular, networks active during the perceptual and articulatory stages of turn-taking consisted of structures known to be important for speech-related sensory and motor processing,8,9,10,11,12,13,14,15,16,17 while putative planning dynamics were most regularly observed in the caudal inferior frontal gyrus (cIFG) and the middle frontal gyrus (cMFG). To test if these structures are necessary for planning during spoken interaction, we used direct electrical stimulation (DES) to transiently perturb cortical function in neurosurgical patient-volunteers performing a question-answer task.7,18,19 We found that stimulating the cIFG and cMFG led to various response errors9,13,20,21 but not gross articulatory deficits, which instead resulted from DES of structures involved in motor control8,13,20,22 (e.g., the precentral gyrus). Furthermore, perturbation of the cIFG and cMFG delayed inter-speaker timing-consistent with slowed planning-while faster responses could result from stimulation of sites located in other areas. Taken together, our findings suggest that the cIFG and cMFG contain critical preparatory circuits that are relevant for interactive language use.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features relevant for decisions. However, the manner in which reward and risk representations are temporally organized in the brain remains elusive. Here we leverage the spatiotemporal precision of intracranial electroencephalography, along with a simple card game designed to elicit the unfolding computation of a set of reward and risk variables, to uncover this temporal organization. Reward outcome representations across wide-spread regions follow a sequential order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We further highlight the role of the anterior insula in generalizing between reward prediction error and risk prediction error codes. Together our results emphasize the importance of neural dynamics for understanding value-based decisions under uncertainty.

Sensing, Feeling, and Regulating: Investigating the Association of Focal Brain Damage with Voluntary Respiratory and Motor Control.

Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal, or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia, and left medial temporal lobe showed reduced performance than individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60-bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal, or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing. Highlights: Impaired human respiratory regulation is associated with cortical/subcortical brain lesionsFrontolimbic/temporal regions contribute to rhythmic breathing and hand motor controlFrontolimbic/temporal damage is associated with anxiety during tachypnea/irregular breathingThe human forebrain is vital for affective and interoceptive experiences during breathing.

Mortality Associated With Proportionality of Secondary Mitral Regurgitation After Transcatheter Mitral Valve Repair: North American Mitraclip for Functional Mitral Regurgitation Registry.

The association, if any, between the effective regurgitant orifice area (EROA) to left ventricular end-diastolic volume (LVEDV) ratio and 1-year mortality is controversial in patients who undergo mitral transcatheter edge-to-edge repair (m-TEER) with the MitraClip system (Abbott Vascular, Santa Clara, CA). This study's objective was to determine the association between EROA/LVEDV and 1-year mortality in patients who undergo m-TEER with MitraClip. In patients with severe secondary (functional) mitral regurgitation (MR), we analyzed registry data from 11 centers using generalized linear models with the generalized estimating equations approach. We studied 525 patients with secondary MR who underwent m-TEER. Most patients were male (63%) and were New York Heart Association class III (61%) or IV (21%). Mitral regurgitation was caused by ischemic cardiomyopathy in 51% of patients. EROA/LVEDV values varied widely, with median = 0.19 mm2/ml, interquartile range [0.12,0.28] mm2/ml, and 187 patients (36%) had values <0.15 mm2/ml. Postprocedural mitral regurgitation severity was substantially alleviated, being 1+ or less in 74%, 2+ in 20%, 3+ in 4%, and 4+ in 2%; 1-year mortality was 22%. After adjustment for confounders, the logarithmic transformation (Ln) of EROA/LVEDV was associated with 1-year mortality (odds ratio 0.600, 95% confidence interval 0.386 to 0.933, p = 0.023). A higher Society of Thoracic Surgeons risk score was also associated with increased mortality. In conclusion, lower values of Ln(EROA/LVEDV) were associated with increased 1-year mortality in this multicenter registry. The slope of the association is steep at low values but gradually flattens as Ln(EROA/LVEDV) increases.

Activity-induced gene expression in the human brain.

Activity-induced gene expression underlies synaptic plasticity and brain function. Here, using molecular sequencing techniques, we define activity-dependent transcriptomic and epigenomic changes at the tissue and single-cell level in the human brain following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Genes related to transcriptional regulation and microglia-specific cytokine activity displayed the greatest induction pattern, revealing a precise molecular signature of neuronal activation in the human brain.

Failure to breathe persists without air hunger or alarm following amygdala seizures.

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level-dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.

Immediate neural impact and incomplete compensation after semantic hub disconnection.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

A frontal cortical network is critical for language planning during spoken interaction.

Many brain areas exhibit activity correlated with language planning, but the impact of these dynamics on spoken interaction remains unclear. Here we use direct electrical stimulation to transiently perturb cortical function in neurosurgical patient-volunteers performing a question-answer task. Stimulating structures involved in speech motor function evoked diverse articulatory deficits, while perturbations of caudal inferior and middle frontal gyri - which exhibit preparatory activity during conversational turn-taking - led to response errors. Perturbation of the same planning-related frontal regions slowed inter-speaker timing, while faster responses could result from stimulation of sites located in other areas. Taken together, these findings further indicate that caudal inferior and middle frontal gyri constitute a critical planning network essential for interactive language use.

Projected Outcomes of Optimized Statin and Ezetimibe Therapy in US Military Veterans with Coronary Artery Disease.

Importance: Many patients with coronary artery disease (CAD) do not achieve the guideline-directed goals for low-density lipoprotein cholesterol (LDL-C) levels. Objective: To estimate reductions in the rates of adverse events associated with CAD in a large US military veteran population that may be achieved through use of optimized statin therapy alone or with ezetimibe compared with the prevailing lipid-lowering therapy (LLT). Design, Setting, and Participants: In this observational cohort study, US military veterans with CAD were identified by coronary angiography between June 2015 and September 2020 across 82 US Department of Veterans Affairs health care facilities. Exposures: The exposures were observed LLT, LLT with an optimized statin regimen, and LLT with optimized statin and ezetimibe. Main Outcomes and Measures: Observed rates of death, myocardial infarction, stroke, and coronary revascularization, and potential reductions in those outcomes with optimized LLT based on expected further reductions in LDL-C levels and application of formulas from The Cholesterol Treatment Trialists' Collaboration. Results: The analysis cohort comprised 111 954 veterans (mean [SD] age, 68.4 [8.8] years; 109 390 men [97.7%]; 91 589 White patients [81.8%]; 17 592 Black patients [15.7%]). The median (IQR) observation period for this study was 3.4 (2.1-4.0) years. At the time of index angiography, 66 877 patients (59.7%) were treated with statin therapy, and 623 patients (0.6%) were treated with ezetimibe. At 6 months, the number of patients with statin prescriptions increased to 74 400 (68.7%), but the number of patients with high-intensity statin prescriptions was only 57 297 (52.9%). At 6 months, ezetimibe use remained low (n = 1168 [1.1%]), and LDL-C levels were 70 mg/dL or more in 56 405 patients (52.1%). At 4 years, observed incidences of death, myocardial infarction, stroke, and coronary revascularization were 21.6% (95% CI, 21.3%-21.8%), 5.0% (95% CI, 4.9%-5.2%), 2.2% (95% CI, 2.1%-2.3%), and 15.4% (95% CI, 15.2%-15.7%), respectively. With optimized statin treatment, projected absolute reductions in these incidences were 1.3% (95% CI, 0.9%-1.7%), 0.8% (95% CI, 0.7%-1.0%), 0.2% (95% CI, 0.1%-0.3%), and 2.3% (95% CI, 2.0%-2.7%), respectively. With optimized statin and ezetimibe treatment, projected absolute reductions were 1.8% (95% CI, 1.2%-2.4%), 1.1% (95% CI, 0.9%-1.3%), 0.3% (95% CI, 0.2%-0.4%), and 3.1% (95% CI, 2.6%-3.6%), respectively. Conclusions and Relevance: In this cohort study of veterans with CAD, suboptimal LLT was prevalent in the clinical setting. Optimization of statin therapy was projected to produce clinically relevant reductions in the risks of death and cardiovascular events. Despite a lesser lipid-lowering efficacy of ezetimibe, its widespread use on a population level in conjunction with optimized statin therapy may be associated with further meaningful reductions in cardiovascular risk.

Functional geometry of auditory cortical resting state networks derived from intracranial electrophysiology.

Understanding central auditory processing critically depends on defining underlying auditory cortical networks and their relationship to the rest of the brain. We addressed these questions using resting state functional connectivity derived from human intracranial electroencephalography. Mapping recording sites into a low-dimensional space where proximity represents functional similarity revealed a hierarchical organization. At a fine scale, a group of auditory cortical regions excluded several higher-order auditory areas and segregated maximally from the prefrontal cortex. On mesoscale, the proximity of limbic structures to the auditory cortex suggested a limbic stream that parallels the classically described ventral and dorsal auditory processing streams. Identities of global hubs in anterior temporal and cingulate cortex depended on frequency band, consistent with diverse roles in semantic and cognitive processing. On a macroscale, observed hemispheric asymmetries were not specific for speech and language networks. This approach can be applied to multivariate brain data with respect to development, behavior, and disorders.

Analogous cortical reorganization accompanies entry into states of reduced consciousness during anesthesia and sleep.

Theories of consciousness suggest that brain mechanisms underlying transitions into and out of unconsciousness are conserved no matter the context or precipitating conditions. We compared signatures of these mechanisms using intracranial electroencephalography in neurosurgical patients during propofol anesthesia and overnight sleep and found strikingly similar reorganization of human cortical networks. We computed the "effective dimensionality" of the normalized resting state functional connectivity matrix to quantify network complexity. Effective dimensionality decreased during stages of reduced consciousness (anesthesia unresponsiveness, N2 and N3 sleep). These changes were not region-specific, suggesting global network reorganization. When connectivity data were embedded into a low-dimensional space in which proximity represents functional similarity, we observed greater distances between brain regions during stages of reduced consciousness, and individual recording sites became closer to their nearest neighbors. These changes corresponded to decreased differentiation and functional integration and correlated with decreases in effective dimensionality. This network reorganization constitutes a neural signature of states of reduced consciousness that is common to anesthesia and sleep. These results establish a framework for understanding the neural correlates of consciousness and for practical evaluation of loss and recovery of consciousness.

Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl's gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time. We present evidence of locally distributed representations of reward and risk variables that are temporally organized across multiple regions of interest. Reward outcome representations across wide-spread regions follow a temporally cascading order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We highlight the role of the anterior insula in generalizing between reward prediction error (RePE) and risk prediction error (RiPE), within which the encoding of RePE in the distributed iEEG signal predicts RiPE. Together our results emphasize the utility of uncovering temporal dynamics in the human brain for understanding how computational processes critical for value-based decisions under uncertainty unfold.

Outcomes of Stented vs Nonstented Femoropopliteal Lesions Treated With Drug-Coated Balloon Angioplasty.

PURPOSE: Drug-coated balloon (DCB) angioplasty has been increasingly used for the treatment of lower limb peripheral artery disease (PAD). However, bail-out stenting may be necessary in cases of suboptimal angioplasty. This study investigated the outcomes of femoropopliteal disease treated with DCB with/without bail-out stenting. MATERIALS AND METHODS: This was a single-center retrospective study enrolling 166 consecutive patients (DCB+stent: n=81 vs DCB: n=85) with 253 femoropopliteal lesions (DCB+stent: n=99 vs DCB: n=154) treated with DCB with/without stenting. Bail-out stenting was performed at the operator discretion for postangioplasty dissections or otherwise suboptimal angiographic result (>30% residual stenosis). Cox regression analysis was performed to examine the outcomes of DCB with/without stenting during 2-year follow-up. RESULTS: The baseline clinical characteristics were similar between the 2 groups. About half of the patients presented with critical limb ischemia, with most of the lesions located at the superficial femoral artery. The overall mean lesion length was 147±67 mm. The most frequent bail-out stent types were bare metal stents (BMS) (53.5%) followed by drug-eluting stents (DES) (41.4%). Lesions requiring bail-out stenting were on average longer (177±67 mm vs 127±59 mm; p<0.01) and on average had higher prevalence of flow-limiting postangioplasty dissections. The overall procedural success rate was 94% without any differences between the 2 groups. Both the stented and nonstented treatment modalities were effective and safe, demonstrating similar rates of 2-year freedom from major adverse limb event (stented: 71.3% vs nonstented: 64.4%) and 2-year freedom from target lesion revascularization (stented: 77.1% vs nonstented: 72.3%) during following up. The use of DES as bail-out therapy was associated with a lower risk of 2-year death compared with the use of BMS (DES: 97.2% vs BMS: 75.8%; p=0.01). CONCLUSION: Drug-coated balloon with bail-out stenting is a viable treatment option for cases of suboptimal DCB results, promising similar efficacy with DCB-alone procedures. However, as the patency of stents at the femoropopliteal segment may be a challenge due to the biomechanical stress of the artery, the efficacy of DCB+bail-out stenting should be further evaluated. In addition, future studies are needed to determine which grades of post-DCB dissections should be treated and optimize current bail-out strategies.