Iowa Brain-Behavior Modeling Toolkit: An Open-Source MATLAB Tool for Inferential and Predictive Modeling of Imaging-Behavior and Lesion-Deficit Relationships.

The traditional analytical framework taken by neuroimaging studies in general, and lesion-behavior studies in particular, has been inferential in nature and has focused on identifying and interpreting statistically significant effects within the sample under study. While this framework is well-suited for hypothesis testing approaches, achieving the modern goal of precision medicine requires a different framework that is predictive in nature and that focuses on maximizing the predictive power of models and evaluating their ability to generalize beyond the data that were used to train them. However, few tools exist to support the development and evaluation of predictive models in the context of neuroimaging or lesion-behavior research, creating an obstacle to the widespread adoption of predictive modeling approaches in the field. Further, existing tools for lesion-behavior analysis are often unable to accommodate categorical outcome variables and often impose restrictions on the predictor data. Researchers therefore often must use different software packages and analytical approaches depending on whether they are addressing a classification vs. regression problem and on whether their predictor data correspond to binary lesion images, continuous lesion-network images, connectivity matrices, or other data modalities. To address these limitations, we have developed a MATLAB software toolkit that supports both inferential and predictive modeling frameworks, accommodates both classification and regression problems, and does not impose restrictions on the modality of the predictor data. The toolkit features both a graphical user interface and scripting interface, includes implementations of multiple mass-univariate, multivariate, and machine learning models, features built-in and customizable routines for hyper-parameter optimization, cross-validation, model stacking, and significance testing, and automatically generates text-based descriptions of key methodological details and modeling results to improve reproducibility and minimize errors in the reporting of methods and results. Here, we provide an overview and discussion of the toolkit's features and demonstrate its functionality by applying it to the question of how expressive and receptive language impairments relate to lesion location, structural disconnection, and functional network disruption in a large sample of patients with left hemispheric brain lesions. We find that impairments in expressive vs. receptive language are most strongly associated with left lateral prefrontal and left posterior temporal/parietal damage, respectively. We also find that impairments in expressive vs. receptive language are associated with partially overlapping patterns of fronto-temporal structural disconnection, and that the associated functional networks are also similar. Importantly, we find that lesion location and lesion-derived network measures are highly predictive of both types of impairment, with predictions from models trained on these measures explaining ~30-40% of the variance on average when applied to data from patients not used to train the models. We have made the toolkit publicly available, and we have included a comprehensive set of tutorial notebooks to support new users in applying the toolkit in their studies.

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'.

Dissociable Roles of the Dorsolateral and Ventromedial Prefrontal Cortex in Human Categorization.

Models of human categorization predict the prefrontal cortex (PFC) serves a central role in category learning. The dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC) have been implicated in categorization; however, it is unclear whether both are critical for categorization and whether they support unique functions. We administered three categorization tasks to patients with PFC lesions (mean age, 69.6 years; 5 men, 5 women) to examine how the prefrontal subregions contribute to categorization. These included a rule-based (RB) task that was solved via a unidimensional rule, an information integration (II) task that was solved by combining information from two stimulus dimensions, and a deterministic/probabilistic (DP) task with stimulus features that had varying amounts of category-predictive information. Compared with healthy comparison participants, both patient groups had impaired performance. Impairments in the dlPFC patients were largest during the RB task, whereas impairments in the vmPFC patients were largest during the DP task. A hierarchical model was fit to the participants' data to assess learning deficits in the patient groups. PFC damage was correlated with a regularization term that limited updates to attention after each trial. Our results suggest that the PFC, as a whole, is important for learning to orient attention to relevant stimulus information. The dlPFC may be especially important for rule-based learning, whereas the vmPFC may be important for focusing attention on deterministic (highly diagnostic) features and ignoring less predictive features. These results support overarching functions of the dlPFC in executive functioning and the vmPFC in value-based decision-making.

Strategies to enhance treatment fidelity and music-based intervention reporting in dementia research.

Creative solutions are needed to address the well-being of the growing number of individuals living with dementia. Music-based interventions (MBIs) are promising and can be cost-effective; however, empirical evidence for MBIs is limited and published findings have not been widely translated into practice. Here, we describe how we implemented strategies to enhance rigor in a randomized clinical trial of an MBI for persons with dementia. We examined the impact of a singing-based MBI on feelings, emotions, and social engagement, relative to a non-music treatment (verbal discussion), delivered in small group format (25 minutes, 3 times/week for 2 weeks). We implemented National Institutes of Health Behavior Change Consortium strategies regarding: (i) design, (ii) interventionist training, (iii) treatment delivery, (iv) treatment receipt, and (v) treatment skills enactment. We applied the MBI Reporting Criteria including: (i) theoretical framework, (ii) musical content, (iii) dosage, (iv) interventionist, (v) treatment fidelity, (vi) setting, and (vii) delivery unit. We analyzed data with a separate linear mixed model for each dependent variable. 32 older adults with dementia (65-97 years) participated. The MBI yielded significant positive effects on all measured outcomes (all p's < .05). Application of established guidelines enhanced methodological rigor and MBI reproducibility. To support translation of research into practice, clinicians should understand how to implement an MBI reported in research. Our study illustrates practical steps to address the need for improved MBI research in persons with dementia and can provide a model for others to enhance evidence-based practice with this population.

Music-based interventions (MBIs) can be very effective in improving the psychosocial well-being of persons with dementia. Nonetheless, scientific evidence to support the use and appropriate application of MBIs for this population is very limited and often not applied in care settings. Here, we describe how we used established guidelines to conduct a rigorous experiment of an MBI for persons with dementia in nursing homes. Specifically, we examined the impact of a live singing-based MBI on feelings, emotions, and social engagement, relative to a non-music treatment (verbal discussion). We implemented National Institutes of Health Behavior Change Consortium strategies regarding study design and implementation and the MBI Reporting Criteria to thoroughly describe implementation principles and components of the MBI. We learned that the MBI resulted in significant, positive effects on all measured outcomes. Application of established guidelines helped ensure that our study was rigorous and the MBI could be reproduced in practice. Clinicians should understand how to implement an MBI reported in research. Our study illustrates practical steps to appropriately describe an MBI and addresses the need for improved MBI research in persons with dementia. Our work provides a model for how such an approach could be used in other similar work.

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.

Anterolateral temporal lobe localization of dysnomia after temporal lobe epilepsy surgery.

Objectives: To evaluate what factors influence naming ability after temporal lobectomy in patients with drug-resistant epilepsy. Methods: 85 participants with drug-resistant epilepsy who underwent temporal lobe (TL) resective surgery were retrospectively identified (49 left TL and 36 right TL). Naming ability was assessed before and >3 months post-surgery using the Boston Naming Test (BNT).Multivariate lesion-symptom mapping was performed to evaluate whether lesion location related to naming deficits. Multiple regression analyses were conducted to examine if other patient characteristics were significantly associated with pre-to post-surgery changes in naming ability. Results: Lesion laterality and location were important predictors of post-surgical naming performance. Naming performance significantly improved after right temporal lobectomy ( p = 0.015) while a decrement in performance was observed following left temporal lobectomy ( p = 0.002). Lesion-symptom mapping showed the decline in naming performance was associated with surgical resection of the anterior left middle temporal gyrus (Brodmann area 21, r =0.41, p = <.001). For left hemisphere surgery, later onset of epilepsy was associated with a greater reduction in post-surgical naming performance ( p = 0.01). Significance: There is a wide range of variability in outcomes for naming ability after temporal lobectomy, from significant improvements to decrements observed. If future studies support the association of left anterior middle temporal gyrus resection and impaired naming this may help in surgical planning and discussions of prognosis.

Mask wearing during neuropsychological assessment negatively impacts performance on verbal tests in older patients.

Face masks are recommended to minimize the spread of COVID-19 and are required in many health care settings. Although masks have documented health advantages, they also negatively impact communication, an essential element of clinical neuropsychological assessment. Using a large clinical data set from a major academic medical center, we investigated the effect of mask wearing on neuropsychological test performance. Specifically, we examined performance on eight standard, widely used neuropsychological tests between a prepandemic (unmasked) and postpandemic (masked) group, composed of 754 and 837 adult patients, respectively. We compared performance on verbally mediated versus visually mediated tests, hypothesizing that the postpandemic group, compared to the prepandemic group, would perform significantly lower on the verbally mediated tests but not on the visually mediated tests. In partial support of the hypothesis, we found that the postpandemic group performed significantly worse on the Auditory Verbal Learning Test (AVLT; p = .001). Secondary analyses showed that age moderated the mask-related effect (p = .038), whereby patients 65 and older had significantly worse performance on Digit Span (p = .0027) and the AVLT (p = .0002) with masks on, while patients younger than 65 showed no significant differences. There were no significant differences on any visually mediated tests. These findings suggest that mask wearing during neuropsychological assessment compromises performance on verbally mediated tests in older patients. These findings are particularly relevant for neuropsychologists practicing in geriatric settings. Neuropsychologists performing assessments with masks should be aware that masks may artificially deflate patient scores for reasons unrelated to cognition or clinical condition. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The structure of apathy symptoms.

INTRODUCTION: Apathy is common in many neurological, psychiatric, and medical disorders and is related to a number of important clinical outcomes. Nonetheless, research on apathy is hindered by different ways of defining and measuring it, which has led to heterogeneity in research findings. METHOD: The current study aimed to investigate the factor structure of apathy symptoms using a novel item pool. We examined whether the use of this item pool has incremental validity above and beyond a widely used measure in predicting cognition and everyday functioning. Participants included 249 informants who reported on an individual with (n = 210) or without (n = 39) a neurological or psychiatric condition. RESULTS: Results showed the best fitting model of apathy symptoms was a bifactor model with apathy as a general dimension and three specific symptom factors including reduced interest and initiative, reduced emotional and verbal expression, and reduced social engagement. Incremental validity in predicting cognition was demonstrated for this more robust assessment of apathy symptoms. CONCLUSIONS: Results are most aligned with one set of proposed diagnostic criteria for apathy which differs from other criteria in that it does not distinguish between cognitive and behavioral symptoms and includes a separate social dimension. Future research could aim to replicate this model in additional clinical samples and explore the incremental validity of the newly developed Apathy Symptom Inventory (ASI) in comparison to other recently developed measures.

Neuropsychiatric outcomes following strokes involving the cerebellum: a retrospective cohort study.

Introduction: Given the wide-ranging involvement of cerebellar activity in motor, cognitive, and affective functions, clinical outcomes resulting from cerebellar damage can be hard to predict. Cerebellar vascular accidents are rare, comprising less than 5% of strokes, yet this rare patient population could provide essential information to guide our understanding of cerebellar function. Methods: To gain insight into which domains are affected following cerebellar damage, we retrospectively examined neuropsychiatric performance following cerebellar vascular accidents in cases registered on a database of patients with focal brain injuries. Neuropsychiatric testing included assessment of cognitive (working memory, language processing, and perceptual reasoning), motor (eye movements and fine motor control), and affective (depression and anxiety) domains. Results: Results indicate that cerebellar vascular accidents are more common in men and starting in the 5th decade of life, in agreement with previous reports. Additionally, in our group of twenty-six patients, statistically significant performance alterations were not detected at the group level an average of 1.3 years following the vascular accident. Marginal decreases in performance were detected in the word and color sub-scales of the Stroop task, the Rey Auditory Verbal Learning Test, and the Lafayette Grooved Pegboard Test. Discussion: It is well established that the acute phase of cerebellar vascular accidents can be life-threatening, largely due to brainstem compression. In the chronic phase, our findings indicate that recovery of cognitive, emotional, and affective function is likely. However, a minority of individuals may suffer significant long-term performance impairments in motor coordination, verbal working memory, and/or linguistic processing.

Does Black vs. White race affect practitioners' appraisal of Parkinson's disease?

Black patients are diagnosed with Parkinson's disease (PD) at half the rate as White patients. The reasons for this large disparity are unknown. Here, we review evidence that practitioner bias may contribute. A key sign of PD is hypomimia or decreased facial expressivity. However, practitioner bias surrounding facial expressivity in Black people versus White people may lead practitioners to appraise Black patients with hypomimia as having higher levels of facial expressivity. Furthermore, practitioner bias may cause them to characterize reduced facial expressivity as being due to negative personality traits, as opposed to a medical sign, in Black patients with hypomimia. This racial bias in the evaluation of hypomimia in Black versus White patients could profoundly impact subsequent referral decisions and rates of diagnosis of PD. Therefore, exploring these differences is expected to facilitate addressing health care disparities through earlier and more accurate detection of PD in Black patients.

Localization of a Medial Temporal Lobe-Precuneus Network for Time Orientation.

OBJECTIVE: Time orientation is a fundamental cognitive process in which one's personal sense of time is matched with a universal reference. Time orientation is commonly assessed through mental status examination, yet its neural correlates remain unclear. Large lesions have been associated with deficits in time orientation, but the regional anatomy implicated in time disorientation is not well established. The current study investigates the anatomy of time disorientation and its network correlates in patients with focal brain lesions. METHODS: Time orientation was assessed 3 months or more after lesion onset using the Benton Temporal Orientation Test (BTOT) in 550 patients with acquired, focal brain lesions, 39 of whom were impaired. Multivariate lesion-symptom mapping and lesion network mapping were used to evaluate the anatomy and networks associated with time disorientation. Performance on a variety of neuropsychological tests was compared between the time oriented and time disoriented group. RESULTS: Lesion-symptom mapping showed that lesions of the precuneus, medial temporal lobes (MTL), and occipito-temporal cortex were associated with time disorientation (r = 0.264, p < 0.001). Lesion network mapping using normative connectome data demonstrated that these regional findings occurred along a network that includes white and gray matter connecting the precuneus and MTL. There was a strong behavioral and anatomical association of time disorientation with memory impairment, such that the 2 processes could not be fully disentangled. INTERPRETATION: We interpret these findings as novel evidence for a network involving the precuneus and the medial temporal lobe in supporting time orientation. ANN NEUROL 2023;94:421-433.

Music Therapy Increases Social and Emotional Well-Being in Persons With Dementia: A Randomized Clinical Crossover Trial Comparing Singing to Verbal Discussion.

The number of people living with Alzheimer's disease and related dementias (ADRD) is growing proportional to our aging population. Although music-based interventions may offer meaningful support to these individuals, most music therapy research lacks well-matched comparison conditions and specific intervention focus, which limits evaluation of intervention effectiveness and possible mechanisms. Here, we report a randomized clinical crossover trial in which we examined the impact of a singing-based music therapy intervention on feelings, emotions, and social engagement in 32 care facility residents with ADRD (aged 65-97 years), relative to an analogous nonmusic condition (verbal discussion). Both conditions were informed by the Clinical Practice Model for Persons with Dementia and occurred in a small group format, three times per week for two weeks (six 25-minute sessions), with a two-week washout at crossover. We followed National Institutes of Health Behavior Change Consortium strategies to enhance methodological rigor. We predicted that music therapy would improve feelings, positive emotions, and social engagement, significantly more so than the comparison condition. We used a linear mixed model approach to analysis. In support of our hypotheses, the music therapy intervention yielded significant positive effects on feelings, emotions, and social engagement, particularly for those with moderate dementia. Our study contributes empirical support for the use of music therapy to improve psychosocial well-being in this population. Results also highlight the importance of considering patient characteristics in intervention design and offer practical implications for music selection and implementation within interventions for persons with ADRD.

Implications of age at lesion onset for neuropsychological outcomes: A systematic review focusing on focal brain lesions.

Theories of the relation between age at lesion onset and outcomes posit different views of the young brain: resilient and plastic (i.e., the so-called "Kennard Principle"), or vulnerable (i.e., the Early Vulnerability Hypothesis). There is support for both perspectives in previous research and questions about the "best" or "worst" times to sustain brain injury remain. Here, we present a systematic review investigating the influence of age at focal brain lesion onset on cognitive functioning. This systematic review identifies and qualitatively synthesizes empirical studies from 1985 to 2021 that investigated age at lesion onset as a variable of interest associated with neuropsychological outcomes. A total of 45 studies were identified from PubMed, PsycINFO, and CINAHL databases. Almost all studies indicated that brain injury earlier in the developmental period predicts worse cognitive outcomes when compared to onset either later in the developmental period or in adulthood. More specifically, the overwhelming majority of studies support an "earlier is worse" model for domains of intellect, processing speed, attention and working memory, visuospatial and perceptual skills, and learning and memory. Relatively more variability in outcomes exists for domains of language and executive functioning. Outcomes for all domains are influenced by various other age and injury variables (e.g., lesion size, lesion laterality, chronicity, a history of epilepsy). Continued interdisciplinary understanding and communication about the influence of age at lesion onset on neuropsychological outcomes will aid in promoting the best possible outcomes for patients.

Latent disconnectome prediction of long-term cognitive-behavioural symptoms in stroke.

Stroke significantly impacts the quality of life. However, the long-term cognitive evolution in stroke is poorly predictable at the individual level. There is an urgent need to better predict long-term symptoms based on acute clinical neuroimaging data. Previous works have demonstrated a strong relationship between the location of white matter disconnections and clinical symptoms. However, rendering the entire space of possible disconnection-deficit associations optimally surveyable will allow for a systematic association between brain disconnections and cognitive-behavioural measures at the individual level. Here we present the most comprehensive framework, a composite morphospace of white matter disconnections (disconnectome) to predict neuropsychological scores 1 year after stroke. Linking the latent disconnectome morphospace to neuropsychological outcomes yields biological insights that are available as the first comprehensive atlas of disconnectome-deficit relations across 86 scores-a Neuropsychological White Matter Atlas. Our novel predictive framework, the Disconnectome Symptoms Discoverer, achieved better predictivity performances than six other models, including functional disconnection, lesion topology and volume modelling. Out-of-sample prediction derived from this atlas presented a mean absolute error below 20% and allowed personalize neuropsychological predictions. Prediction on an external cohort achieved an R2 = 0.201 for semantic fluency. In addition, training and testing were replicated on two external cohorts achieving an R2 = 0.18 for visuospatial performance. This framework is available as an interactive web application (http://disconnectomestudio.bcblab.com) to provide the foundations for a new and practical approach to modelling cognition in stroke. We hope our atlas and web application will help to reduce the burden of cognitive deficits on patients, their families and wider society while also helping to tailor future personalized treatment programmes and discover new targets for treatments. We expect our framework's range of assessments and predictive power to increase even further through future crowdsourcing.

White matter disconnection of left multiple demand network is associated with post-lesion deficits in cognitive control.

Cognitive control modulates other cognitive functions to achieve internal goals and is important for adaptive behavior. Cognitive control is enabled by the neural computations distributed over cortical and subcortical areas. However, due to technical challenges in recording neural activity from the white matter, little is known about the anatomy of white matter tracts that coordinate the distributed neural computations that support cognitive control. Here, we leverage a large sample of human patients with focal brain lesions (n = 643) and investigate how lesion location and connectivity profiles account for variance in cognitive control performance. We find that lesions in white matter connecting left frontoparietal regions of the multiple demand network reliably predict deficits in cognitive control performance. These findings advance our understanding of the white matter correlates of cognitive control and provide an approach for incorporating network disconnection to predict deficits following lesions.

Amygdala lesions are associated with improved mood after epilepsy surgery.

Neuroimaging studies in healthy and clinical populations strongly associate the amygdala with emotion, especially negative emotions. The consequences of surgical resection of the amygdala on mood are not well characterized. We tested the hypothesis that amygdala resection would result in mood improvement. In this study, we evaluated a cohort of 52 individuals with medial temporal lobectomy for intractable epilepsy who had resections variably involving the amygdala. All individuals achieved good post-surgical seizure control and had pre- and post-surgery mood assessment with the Beck Depression Inventory (BDI) ratings. We manually segmented the surgical resection cavities and performed multivariate lesion-symptom mapping of change in BDI. Our results showed a significant improvement in average mood ratings from pre- to post-surgery across all patients. In partial support of our hypothesis, resection of the right amygdala was significantly associated with mood improvement (r = 0.5, p = 0.008). The lesion-symptom map also showed that resection of the right hippocampus and para-hippocampal gyrus was associated with worsened post-surgical mood. Future studies could evaluate this finding prospectively in larger samples while including other neuropsychological outcome measures.

The role of gender in cognitive outcomes from stroke.

OBJECTIVE: Stroke can cause cognitive impairment, which can lead to challenges returning to day-to-day activities. Knowing what factors are associated with cognitive impairment post-stroke can be useful for predicting outcomes and guiding rehabilitation. One such factor is gender: previous studies are inconclusive as to whether gender influences cognitive outcomes post-stroke. Accounting for key variables, we examined whether there are gender differences in cognitive outcomes after stroke. METHOD: We analyzed data from neuropsychological assessments of 237 individuals tested in the chronic epoch (≥ 3 months) following ischemic stroke. Using ANCOVA and linear mixed modeling, we examined gender as a predictor of cognition as measured by general cognitive ability (g), Full-Scale IQ, and 18 cognitive tests, controlling for age at stroke onset, education, premorbid intelligence, and lesion volume. RESULTS: There were no significant gender differences in overall cognitive outcomes as measured by g (p = .887) or Full-Scale IQ (p = .801). There were some significant gender differences on specific cognitive tests, with women outperforming men on scores from the Rey Auditory Verbal Learning Test (ps < .01) and men outperforming women on the Wechsler Adult Intelligence Scale Arithmetic and Information subtests (ps < .01). CONCLUSIONS: Our findings indicate that men and women have similar overall cognitive outcomes after stroke, when demographic and lesion factors are accounted for. Although men and women differed in their performance on some individual cognitive tests, neither gender performed systematically better or worse. However, for learning, working memory, and verbal knowledge/comprehension, gender may be an important predictor of outcome post-stroke.

Hyperacute immune responses associate with immediate neuropathology and motor dysfunction in large vessel occlusions.

OBJECTIVE: Despite successful endovascular therapy, a proportion of stroke patients exhibit long-term functional decline, regardless of the cortical reperfusion. Our objective was to evaluate the early activation of the adaptive immune response and its impact on neurological recovery in patients with large vessel occlusion (LVO). METHODS: Nineteen (13 females, 6 males) patients with acute LVO were enrolled in a single-arm prospective cohort study. During endovascular therapy (EVT), blood samples were collected from pre and post-occlusion, distal femoral artery, and median cubital vein (controls). Cytokines, chemokines, cellular and functional profiles were evaluated with immediate and follow-up clinical and radiographic parameters, including cognitive performance and functional recovery. RESULTS: In the hyperacute phase (within hours), adaptive immune activation was observed in the post-occlusion intra-arterial environment (post). Ischemic vascular tissue had a significant increase in T-cell-related cytokines, including IFN-γ and MMP-9, while GM-CSF, IL-17, TNF-α, IL-6, MIP-1a, and MIP-1b were decreased. Cellularity analysis revealed an increase in inflammatory IL-17+ and GM-CSF+ helper T-cells, while natural killer (NK), monocytes and B-cells were decreased. A correlation was observed between hypoperfused tissue, infarct volume, inflammatory helper, and cytotoxic T-cells. Moreover, helper and cytotoxic T-cells were also significantly increased in patients with improved motor function at 3 months. INTERPRETATION: We provide evidence of the activation of the inflammatory adaptive immune response during the hyperacute phase and the association of pro-inflammatory cytokines with greater ischemic tissue and worsening recovery after successful reperfusion. Further characterization of these immune pathways is warranted to test selective immunomodulators during the early stages of stroke rehabilitation.

Large-scale lesion symptom mapping of depression identifies brain regions for risk and resilience.

Understanding neural circuits that support mood is a central goal of affective neuroscience, and improved understanding of the anatomy could inform more targeted interventions in mood disorders. Lesion studies provide a method of inferring the anatomical sites causally related to specific functions, including mood. Here, we performed a large-scale study evaluating the location of acquired, focal brain lesions in relation to symptoms of depression. Five hundred and twenty-six individuals participated in the study across two sites (356 male, average age 52.4 ± 14.5 years). Each subject had a focal brain lesion identified on structural imaging and an assessment of depression using the Beck Depression Inventory-II, both obtained in the chronic period post-lesion (>3 months). Multivariate lesion-symptom mapping was performed to identify lesion sites associated with higher or lower depression symptom burden, which we refer to as 'risk' versus 'resilience' regions. The brain networks and white matter tracts associated with peak regional findings were identified using functional and structural lesion network mapping, respectively. Lesion-symptom mapping identified brain regions significantly associated with both higher and lower depression severity (r = 0.11; P = 0.01). Peak 'risk' regions include the bilateral anterior insula, bilateral dorsolateral prefrontal cortex and left dorsomedial prefrontal cortex. Functional lesion network mapping demonstrated that these 'risk' regions localized to nodes of the salience network. Peak 'resilience' regions include the right orbitofrontal cortex, right medial prefrontal cortex and right inferolateral temporal cortex, nodes of the default mode network. Structural lesion network mapping implicated dorsal prefrontal white matter tracts as 'risk' tracts and ventral prefrontal white matter tracts as 'resilience' tracts, although the structural lesion network mapping findings did not survive correction for multiple comparisons. Taken together, these results demonstrate that lesions to specific nodes of the salience network and default mode network are associated with greater risk versus resiliency for depression symptoms in the setting of focal brain lesions.

Electrocorticography reveals the dynamics of famous voice responses in human fusiform gyrus.

Voice and face processing occur through convergent neural systems that facilitate speaker recognition. Neuroimaging studies suggest that familiar voice processing engages early visual cortex, including the bilateral fusiform gyrus (FG) on the basal temporal lobe. However, what role the FG plays in voice processing and whether it is driven by bottom-up or top-down mechanisms is unresolved. In this study we directly examined neural responses to famous voices and faces in human FG with direct cortical surface recordings (electrocorticography) in epilepsy surgery patients. We tested the hypothesis that neural populations in human FG respond to famous voices and investigated the temporal properties of voice responses in FG. Recordings were acquired from five adult participants during a person identification task using visual and auditory stimuli from famous speakers (U.S. Presidents Barack Obama, George W. Bush, and Bill Clinton). Patients were presented with images of presidents or clips of their voices and asked to identify the portrait/speaker. Our results demonstrate that a subset of face-responsive sites in and near FG also exhibit voice responses that are both lower in magnitude and delayed (300-600 ms) compared with visual responses. The dynamics of voice processing revealed by direct cortical recordings suggests a top-down feedback-mediated response to famous voices in FG that may facilitate speaker identification.NEW & NOTEWORTHY Interactions between auditory and visual cortices play an important role in person identification, but the dynamics of these interactions remain poorly understood. We performed direct brain recordings of fusiform face cortex in human epilepsy patients performing a famous voice naming task, revealing the dynamics of famous voice processing in human fusiform face cortex. The findings support a model of top-down interactions from auditory to visual cortex to facilitate famous voice recognition.