Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Disparities in seizure outcomes revealed by large language models.

OBJECTIVE: Large-language models (LLMs) can potentially revolutionize health care delivery and research, but risk propagating existing biases or introducing new ones. In epilepsy, social determinants of health are associated with disparities in care access, but their impact on seizure outcomes among those with access remains unclear. Here we (1) evaluated our validated, epilepsy-specific LLM for intrinsic bias, and (2) used LLM-extracted seizure outcomes to determine if different demographic groups have different seizure outcomes. MATERIALS AND METHODS: We tested our LLM for differences and equivalences in prediction accuracy and confidence across demographic groups defined by race, ethnicity, sex, income, and health insurance, using manually annotated notes. Next, we used LLM-classified seizure freedom at each office visit to test for demographic outcome disparities, using univariable and multivariable analyses. RESULTS: We analyzed 84 675 clinic visits from 25 612 unique patients seen at our epilepsy center. We found little evidence of bias in the prediction accuracy or confidence of outcome classifications across demographic groups. Multivariable analysis indicated worse seizure outcomes for female patients (OR 1.33, P ≤ .001), those with public insurance (OR 1.53, P ≤ .001), and those from lower-income zip codes (OR ≥1.22, P ≤ .007). Black patients had worse outcomes than White patients in univariable but not multivariable analysis (OR 1.03, P = .66). CONCLUSION: We found little evidence that our LLM was intrinsically biased against any demographic group. Seizure freedom extracted by LLM revealed disparities in seizure outcomes across several demographic groups. These findings quantify the critical need to reduce disparities in the care of people with epilepsy.

Disparities in Genetic Testing for Neurologic Disorders.

BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

Enhancing cognitive control with transcranial magnetic stimulation in subject-specific frontoparietal networks.

BACKGROUND: Cognitive control processes, including those involving frontoparietal networks, are highly variable between individuals, posing challenges to basic and clinical sciences. While distinct frontoparietal networks have been associated with specific cognitive control functions such as switching, inhibition, and working memory updating functions, there have been few basic tests of the role of these networks at the individual level. METHODS: To examine the role of cognitive control at the individual level, we conducted a within-subject excitatory transcranial magnetic stimulation (TMS) study in 19 healthy individuals that targeted intrinsic ("resting") frontoparietal networks. Person-specific intrinsic networks were identified with resting state functional magnetic resonance imaging scans to determine TMS targets. The participants performed three cognitive control tasks: an adapted Navon figure-ground task (requiring set switching), n-back (working memory), and Stroop color-word (inhibition). OBJECTIVE: Hypothesis: We predicted that stimulating a network associated with externally oriented control [the "FPCN-B" (fronto-parietal control network)] would improve performance on the set switching and working memory task relative to a network associated with attention (the Dorsal Attention Network, DAN) and cranial vertex in a full within-subjects crossover design. RESULTS: We found that set switching performance was enhanced by FPCN-B stimulation along with some evidence of enhancement in the higher-demand n-back conditions. CONCLUSION: Higher task demands or proactive control might be a distinguishing role of the FPCN-B, and personalized intrinsic network targeting is feasible in TMS designs.

Building an ethnically and racially diverse neurology workforce.

As diversity among patient populations continues to grow, racial and ethnic diversity in the neurology workforce is increasingly essential to the delivery of culturally competent care and for enabling inclusive, generalizable clinical research. Unfortunately, diversity in the workforce is an area in which the field of neurology has historically lagged and faces formidable challenges, including an inadequate number of trainees entering the field, bias experienced by trainees and faculty from minoritized racial and ethnic backgrounds, and 'diversity tax', the disproportionate burden of service work placed on minoritized people in many professions. Although neurology departments, professional organizations and relevant industry partners have come to realize the importance of diversity to the field and have taken steps to promote careers in neurology for people from minoritized backgrounds, additional steps are needed. Such steps include the continued creation of diversity leadership roles in neurology departments and organizations, the creation of robust pipeline programmes, aggressive recruitment and retention efforts, the elevation of health equity research and engagement with minoritized communities. Overall, what is needed is a shift in culture in which diversity is adopted as a core value in the field.

Disparities in seizure outcomes revealed by large language models.

Objective: Large-language models (LLMs) in healthcare have the potential to propagate existing biases or introduce new ones. For people with epilepsy, social determinants of health are associated with disparities in access to care, but their impact on seizure outcomes among those with access to specialty care remains unclear. Here we (1) evaluated our validated, epilepsy-specific LLM for intrinsic bias, and (2) used LLM-extracted seizure outcomes to test the hypothesis that different demographic groups have different seizure outcomes. Methods: First, we tested our LLM for intrinsic bias in the form of differential performance in demographic groups by race, ethnicity, sex, income, and health insurance in manually annotated notes. Next, we used LLM-classified seizure freedom at each office visit to test for outcome disparities in the same demographic groups, using univariable and multivariable analyses. Results: We analyzed 84,675 clinic visits from 25,612 patients seen at our epilepsy center 2005-2022. We found no differences in the accuracy, or positive or negative class balance of outcome classifications across demographic groups. Multivariable analysis indicated worse seizure outcomes for female patients (OR 1.33, p = 3×10-8), those with public insurance (OR 1.53, p = 2×10-13), and those from lower-income zip codes (OR ≥ 1.22, p ≤ 6.6×10-3). Black patients had worse outcomes than White patients in univariable but not multivariable analysis (OR 1.03, p = 0.66). Significance: We found no evidence that our LLM was intrinsically biased against any demographic group. Seizure freedom extracted by LLM revealed disparities in seizure outcomes across several demographic groups. These findings highlight the critical need to reduce disparities in the care of people with epilepsy.

Antiamyloid Monoclonal Antibody Therapy for Alzheimer Disease: Emerging Issues in Neurology.

With recent data demonstrating that lecanemab treatment can slow cognitive and functional decline in early symptomatic Alzheimer disease (AD), it is widely anticipated that this drug and potentially other monoclonal antibody infusions targeting ß-amyloid protein will imminently be realistic options for some patients with AD. Given that these new antiamyloid monoclonal antibodies (mAbs) are associated with nontrivial risks and burdens of treatment that are radically different from current mainstays of AD management, effectively and equitably translating their use to real-world clinical care will require systematic and practice-specific modifications to existing workflows and infrastructure. In this Emerging Issues in Neurology article, we provide practical guidance for a wide audience of neurology clinicians on logistic adaptations and decision making around emerging antiamyloid mAbs. Specifically, we briefly summarize the rationale and available evidence supporting antiamyloid mAb use in AD to facilitate appropriate communication with patients and care partners on potential benefits. We also discuss pragmatic approaches to optimizing patient selection and treatment monitoring, with a particular focus on the value of incorporating shared decision making and multidisciplinary collaboration. In addition, we review some of the recognized limitations of current knowledge and highlight areas of future evolution to guide the development of sustainable and flexible models for treatment and follow-up. As the field enters a new era with disease-modifying treatment options for AD, it will be critical for neurology practices to prepare and continually innovate to ensure optimal outcomes for patients.

Toward more diverse, inclusive, and equitable neuromodulation.

Racial and ethnic disparities exist for many nervous system disorders that are intervention targets for neuromodulation investigators. Yet, to date, there has been both a lack of racial and ethnic diversity and a lack of emphasis on diversity in neuromodulation research. In this paper, we suggest three potential reasons for the lack of racial and ethnic diversity in neuromodulation research: 1) the lack of diversity in the neuromodulation workforce, 2) incompatibility between the technologies employed and phenotypic traits (e.g., hair texture) commonly present in minoritized populations, and 3) minoritized populations' reluctance to participate in clinical trials. We argue that increasing diversity in the neuromodulation workforce, in conjunction with mutual collaboration between current neuromodulation researchers and underrepresented communities in neuromodulation, can aid in removing barriers to diversity, equity, and inclusion in neuromodulation research. This is important, because greater diversity, equity, and inclusion in neuromodulation research brings with it the development of novel, yet safe and effective, treatment approaches for brain disorders and enhances the rigor and generalizability of discoveries in the field.

Always Look on the Bright Side: Associations of Optimism With Functional Outcomes After Stroke.

Background Psychological health is as an important contributor to recovery after cardiovascular disease, but the roles of both optimism and depression in stroke recovery are not well characterized. Methods and Results A total of 879 participants in the SRUP (Stroke Recovery in Underserved Populations) 2005 to 2006 Study, aged ≥50 years, with incident stroke admitted to a rehabilitation facility were included. Optimism was assessed by the question: "Are you optimistic about the future?" Depression was defined by Center for Epidemiologic Studies Depression scale score >16. Participants were categorized into 4 groups: optimistic/without depression (n=581), optimistic/with depression (n=197), nonoptimistic/without depression (n=36), and nonoptimistic/with depression (n=65). Functional Independence Measure scores were used to assess stroke outcomes at discharge, 3 months after discharge, and 1 year after discharge with adjusted linear mixed models to estimate score trajectories. Participants were a mean age of 68 years (SD, 13 years), 52% were women, and 74% were White race. The optimistic/without depression group experienced the most recovery of total Functional Independence Measure scores in the first 3 months, 24.0 (95% CI, 22.5-25.4), followed by no change in the following 9 months, -0.3 (95% CI, -2.3 to 1.7), similar to the optimistic/with depression group with rapid recovery in 0 to 3 months, 21.1 (95% CI, 18.6-23.6) followed by minimal change in 3 to 12 months, 0.7 (95% CI, -2.8 to 4.1). The nonoptimistic groups demonstrated slow but continued recovery throughout the 12-month period, with overall change, 25.4 (95% CI, 17.6-33.2) in the nonoptimistic/without depression group and 17.6 (95% CI, 12.0-23.1) in the nonoptimistic/with depression group. There was robust effect modification between optimism and depression (Pinteraction<0.001). Conclusions In this longitudinal cohort, optimism and depression are synergistically associated with functional recovery after stroke. Measuring optimism status may help identify individuals at risk for worse poststroke recovery.

Efficacy of Transcranial Alternating Current Stimulation in the Enhancement of Working Memory Performance in Healthy Adults: A Systematic Meta-Analysis.

BACKGROUND: Transcranial alternating current stimulation (tACS)-a noninvasive brain stimulation technique that modulates cortical oscillations in the brain-has shown the capacity to enhance working memory (WM) abilities in healthy individuals. The efficacy of tACS in the improvement of WM performance in healthy individuals is not yet fully understood. OBJECTIVE/HYPOTHESIS: This meta-analysis aimed to systematically evaluate the efficacy of tACS in the enhancement of WM in healthy individuals and to assess moderators of response to stimulation. We hypothesized that active tACS would significantly enhance WM compared with sham. We further hypothesized that it would do so in a task-dependent manner and that differing stimulation parameters would affect response to tACS. MATERIALS AND METHODS: Ten tACS studies met the inclusion criteria and provided 32 effects in the overall analysis. Random-effect models assessed mean change scores on WM tasks from baseline to poststimulation. The included studies involved varied in stimulation parameters, between-subject and within-subject study designs, and online vs offline tACS. RESULTS: We observed a significant, heterogeneous, and moderate effect size for active tACS in the enhancement of WM performance over sham (Cohen's d = 0.5). Cognitive load, task domain, session number, and stimulation region showed a significant relationship between active tACS and enhanced WM behavior over sham. CONCLUSIONS: Our findings indicate that active tACS enhances WM performance in healthy individuals compared with sham. Future randomized controlled trials are needed to further explore key parameters, including personalized stimulation vs standardized electroencephalography frequencies and maintenance of tACS effects, and whether tACS-induced effects translate to populations with WM impairments.

Defending Racial and Ethnic Diversity in Undergraduate and Medical School Admission Policies.

This Viewpoint argues that reversing or restricting the use of race and ethnicity in academic admission policies could also threaten the diversity of medical schools, both directly by restricting race consciousness in medical school admission practices and indirectly by reducing the overall number of minoritized undergraduate students attending US colleges and universities who could apply to medical school.

Investigating the influence of an effort-reward interaction on cognitive fatigue in individuals with multiple sclerosis.

This study examined whether an alteration in the effort-reward relationship, a theoretical framework based on cognitive neuroscience, could explain cognitive fatigue. Forty persons with MS and 40 healthy age- and education-matched cognitively healthy controls (HC) participated in a computerized switching task with orthogonal high- and low-demand (effort) and reward manipulations. We used the Visual Analog Scale of Fatigue (VAS-F) to assess subjective state fatigue before and after each condition during the task. We used mixed-effects models to estimate the association and interaction between effort and reward and their relationship to subjective fatigue and task performance. We found the high-demand condition was associated with increased VAS-F scores (p < .001), longer response times (RT) (p < .001) and lower accuracy (p < .001). The high-reward condition was associated with faster RT (p = .006) and higher accuracy (p = .03). There was no interaction effect between effort and reward on VAS-F scores or performance. Participants with MS reported higher VAS-F scores (p = .02). Across all conditions, participants with MS were slower (p < .001) and slower as a function of condition demand compared with HC (p < .001). This behavioural study did not find evidence that an effort-reward interaction is associated with cognitive fatigue. However, our findings support the role of effort in subjective cognitive fatigue and both effort and reward on task performance. In future studies, more salient reward manipulations could be necessary to identify effort-reward interactions on subjective cognitive fatigue.

Digitalized transcranial electrical stimulation: A consensus statement.

OBJECTIVE: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES. METHODS: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. RESULTS: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity. CONCLUSIONS: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. SIGNIFICANCE: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.

Through Thick and Thin: Baseline Cortical Volume and Thickness Predict Performance and Response to Transcranial Direct Current Stimulation in Primary Progressive Aphasia.

Objectives: We hypothesized that measures of cortical thickness and volume in language areas would correlate with response to treatment with high-definition transcranial direct current stimulation (HD-tDCS) in persons with primary progressive aphasia (PPA). Materials and Methods: In a blinded, within-group crossover study, PPA patients (N = 12) underwent a 2-week intervention HD-tDCS paired with constraint-induced language therapy (CILT). Multi-level linear regression (backward-fitted models) were performed to assess cortical measures as predictors of tDCS-induced naming improvements, measured by the Western Aphasia Battery-naming subtest, from baseline to immediately after and 6 weeks post-intervention. Results: Greater baseline thickness of the pars opercularis significantly predicted naming gains (p = 0.03) immediately following intervention, while greater thickness of the middle temporal gyrus (MTG) and lower thickness of the superior temporal gyrus (STG) significantly predicted 6-week naming gains (p's < 0.02). Thickness did not predict naming gains in sham. Volume did not predict immediate gains for active stimulation. Greater volume of the pars triangularis and MTG, but lower STG volume significantly predicted 6-week naming gains in active stimulation. Greater pars orbitalis and MTG volume, and lower STG volume predicted immediate naming gains in sham (p's < 0.05). Volume did not predict 6-week naming gains in sham. Conclusion: Cortical thickness and volume were predictive of tDCS-induced naming improvement in PPA patients. The finding that frontal thickness predicted immediate active tDCS-induced naming gains while temporal areas predicted naming changes at 6-week suggests that a broader network of regions may be important for long-term maintenance of treatment gains. The finding that volume predicted immediate naming performance in the sham condition may reflect the benefits of behavioral speech language therapy and neural correlates of its short-lived treatment gains. Collectively, thickness and volume were predictive of treatment gains in the active condition but not sham, suggesting that pairing HD-tDCS with CILT may be important for maintaining treatment effects.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Brain-Derived Neurotrophic Factor Gene Polymorphism Predicts Response to Continuous Theta Burst Stimulation in Chronic Stroke Patients.

OBJECTIVES: The efficacy of repetitive transcranial magnetic stimulation (rTMS) in clinically relevant neuroplasticity research depends on the degree to which stimulation induces robust, reliable effects. The high degree of interindividual and intraindividual variability observed in response to rTMS protocols, such as continuous theta burst stimulation (cTBS), therefore represents an obstacle to its utilization as treatment for neurological disorders. Brain-derived neurotrophic factor (BDNF) is a protein involved in human synaptic and neural plasticity, and a common polymorphism in the BDNF gene (Val66Met) may influence the capacity for neuroplastic changes that underlie the effects of cTBS and other rTMS protocols. While evidence from healthy individuals suggests that Val66Met polymorphism carriers may show diminished or facilitative effects of rTMS compared to their homozygous Val66Val counterparts, this has yet to be demonstrated in the patient populations where neuromodulatory therapies are most relevant. MATERIALS AND METHODS: We examined the effects of BDNF Val66Met polymorphism on cTBS aftereffects in stroke patients. We compared approximately 30 log-transformed motor-evoked potentials (LnMEPs) obtained per time point: at baseline and at 0, 10, 20, and 30 min after cTBS-600, from 18 patients with chronic stroke using single TMS pulses. We used linear mixed-effects regression with trial-level data nested by subject for higher statistical power. RESULTS: We found a significant interaction between BDNF genotype and pre-/post-cTBS LnMEPs. Val66Val carriers showed decrease in cortical excitability, whereas Val66Met carriers exhibited a modest increase in cortical excitability for 20 min poststimulation, followed by inhibition 30 min after cTBS-600. CONCLUSIONS: Our findings strongly suggest that BDNF genotype differentially affects neuroplastic responses to TMS in individuals with chronic stroke. This provides novel insight into potential sources of variability in cTBS response in patients, which has important implications for optimizing the utility of this neuromodulation approach. Incorporating BDNF polymorphism genetic screening to stratify patients prior to use of cTBS as a neuromodulatory technique in therapy or research may optimize response rates.

Glutamate-Weighted Magnetic Resonance Imaging (GluCEST) Detects Effects of Transcranial Magnetic Stimulation to the Motor Cortex.

Transcranial magnetic stimulation (TMS) is used in several FDA-approved treatments and, increasingly, to treat neurological disorders in off-label uses. However, the mechanism by which TMS causes physiological change is unclear, as are the origins of response variability in the general population. Ideally, objective in vivo biomarkers could shed light on these unknowns and eventually inform personalized interventions. Continuous theta-burst stimulation (cTBS) is a form of TMS observed to reduce motor evoked potentials (MEPs) for 60 min or longer post-stimulation, although the consistency of this effect and its mechanism continue to be under debate. Here, we use glutamate-weighted chemical exchange saturation transfer (gluCEST) magnetic resonance imaging (MRI) at ultra-high magnetic field (7T) to measure changes in glutamate concentration at the site of cTBS. We find that the gluCEST signal in the ipsilateral hemisphere of the brain generally decreases in response to cTBS, whereas consistent changes were not detected in the contralateral region of interest (ROI) or in subjects receiving sham stimulation.

Genetic and Neurophysiological Biomarkers of Neuroplasticity Inform Post-Stroke Language Recovery.

BACKGROUND: There is high variability in post-stroke aphasia severity and predicting recovery remains imprecise. Standard prognostics do not include neurophysiological indicators or genetic biomarkers of neuroplasticity, which may be critical sources of variability. OBJECTIVE: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF) contributes to variability in post-stroke aphasia, and to assess whether BDNF polymorphism interacts with neurophysiological indicators of neuroplasticity (cortical excitability and stimulation-induced neuroplasticity) to improve estimates of aphasia severity. METHODS: Saliva samples and motor-evoked potentials (MEPs) were collected from participants with chronic aphasia subsequent to left-hemisphere stroke. MEPs were collected prior to continuous theta burst stimulation (cTBS; index for cortical excitability) and 10 minutes following cTBS (index for stimulation-induced neuroplasticity) to the right primary motor cortex. Analyses assessed the extent to which BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to predict aphasia severity beyond established predictors. RESULTS: Val66Val carriers showed less aphasia severity than Val66Met carriers, after controlling for lesion volume and time post-stroke. Furthermore, Val66Val carriers showed expected effects of age on aphasia severity, and positive associations between severity and both cortical excitability and stimulation-induced neuroplasticity. In contrast, Val66Met carriers showed weaker effects of age and negative associations between cortical excitability, stimulation-induced neuroplasticity and aphasia severity. CONCLUSIONS: Neurophysiological indicators and genetic biomarkers of neuroplasticity improved aphasia severity predictions. Furthermore, BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to improve predictions. These findings provide novel insights into mechanisms of variability in stroke recovery and may improve aphasia prognostics.

Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods.

BACKGROUND: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. OBJECTIVE: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators, among diverse older adults. METHODS: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. RESULTS: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. CONCLUSION: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.