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.

One of the most well-established age-related changes in neural activity disappears after controlling for visual acuity.

Numerous studies using a variety of imaging techniques have reported age-related differences in neural activity while subjects carry out cognitive tasks. Surprisingly little attention has been paid to the potential impact of age-associated changes in sensory acuity on these findings. Studies in the visual modality frequently report that their subjects had "normal or corrected- to-normal vision." However, in most cases, there is no indication that visual acuity was actually measured, and it is likely that the investigators relied largely on self-reported visual status of subjects, which is often inaccurate. We investigated whether differences in visual acuity influence one of the most commonly observed findings in the event-related potentials literature on cognitive aging, a reduction in posterior P3b amplitude, which is an index of cognitive decision-making/updating. Well-matched young (n=26) and old adults (n=29) participated in a visual oddball task. Measured visual acuity with corrective lenses was worse in old than young adults. Results demonstrated that the robust age-related decline in P3b amplitude to visual targets disappeared after controlling for visual acuity, but was unaffected by accounting for auditory acuity. Path analysis confirmed that the relationship between age and diminished P3b to visual targets was mediated by visual acuity, suggesting that conveyance of suboptimal sensory data due to peripheral, rather than central, deficits may undermine subsequent neural processing. We conclude that until the relationship between age-associated differences in visual acuity and neural activity during experimental tasks is clearly established, investigators should exercise caution attributing results to differences in cognitive processing.

Investigating age-related changes in anterior and posterior neural activity throughout the information processing stream.

Event-related potential (ERP) and other functional imaging studies often demonstrate age-related increases in anterior neural activity and decreases in posterior activity while subjects carry out task demands. It remains unclear whether this "anterior shift" is limited to late cognitive operations like those indexed by the P3 component, or is evident during other stages of information processing. The temporal resolution of ERPs provided an opportunity to address this issue. Temporospatial principal component analysis (PCA) was used to identify underlying components that may be obscured by overlapping ERP waveforms. ERPs were measured during a visual oddball task in 26 young, 26 middle-aged, and 29 old subjects who were well-matched for IQ, executive function, education, and task performance. PCA identified six anterior factors peaking between ∼140 ms and 810 ms, and four posterior factors peaking between ∼300 ms and 810 ms. There was an age-related increase in the amplitude of anterior factors between ∼200 and 500 ms, and an age-associated decrease in amplitude of posterior factors after ∼500 ms. The increase in anterior processing began as early as middle-age, was sustained throughout old age, and appeared to be linear in nature. These results suggest that age-associated increases in anterior activity occur after early sensory processing has taken place, and are most prominent during a period in which attention is being marshaled to evaluate a stimulus. In contrast, age-related decreases in posterior activity manifest during operations involved in stimulus categorization, post-decision monitoring, and preparation for an upcoming event.

The dissociation between early and late selection in older adults.

Older adults exhibit a reduced ability to ignore task-irrelevant stimuli; however, it remains to be determined where along the information processing stream the most salient age-associated changes occur. In the current study, ERPs provided an opportunity to determine whether age-related differences in processing task-irrelevant stimuli were uniform across information processing stages or disproportionately affected either early or late selection. ERPs were measured in young and old adults during a color-selective attention task in which participants responded to target letters in a specified color (attend condition) while ignoring letters in a different color (ignore condition). Old participants were matched to two groups of young participants on the basis of neuropsychological test performance: one using age-appropriate norms and the other using test scores not adjusted for age. There were no age-associated differences in the magnitude of early selection (attend-ignore), as indexed by the size of the anterior selection positivity and posterior selection negativity. During late selection, as indexed by P3b amplitude, both groups of young participants generated neural responses to target letters under the attend versus ignore conditions that were highly differentiated. In striking contrast, old participants generated a P3b to target letters with no reliable differences between conditions. Individuals who were slow to initiate early selection appeared to be less successful at executing late selection. Despite relative preservation of the operations of early selection, processing delays may lead older participants to allocate excessive resources to task-irrelevant stimuli during late selection.

The impact of visual acuity on age-related differences in neural markers of early visual processing.

The extent to which age-related differences in neural markers of visual processing are influenced by changes in visual acuity has not been systematically investigated. Studies often indicate that their subjects had normal or corrected-to-normal vision, but the assessment of visual acuity seems to most frequently be based only on self-report. Consistent with prior research, to be included in the current study, subjects had to report normal or corrected-to-normal vision. Additionally, visual acuity was formally tested using a Snellen eye chart. Event-related potentials (ERPs) were studied in young adults (18-32years old), young-old adults (65-79years old), and old-old adults (80+ years old) while they performed a visual processing task involving selective attention to color. Age-related differences in the latency and amplitude of ERP markers of early visual processing, the posterior P1 and N1 components, were examined. All results were then re-analyzed after controlling for visual acuity. We found that visual acuity declined as a function of age. Accounting for visual acuity had an impact on whether older and younger adults differed significantly in the size and latency of the posterior P1 and N1 components. After controlling for visual acuity, age-related increases in P1 and N1 latency did not remain significant, and older adults were found to have a larger P1 amplitude than young adults. Our results suggest that until the relationship between age-associated differences in visual acuity and early ERPs is clearly established, investigators should be cautious when interpreting the meaning of their findings. Self-reports about visual acuity may be inaccurate, necessitating formal measures. Additional investigation is needed to help establish guidelines for future research, especially of very old adults.

BDNF mediates improvement in cognitive performance after computerized cognitive training in healthy older adults.

Introduction: The often-cited mechanism linking brain-derived neurotrophic factor (BDNF) to cognitive health has received limited experimental study. There is evidence that cognitive training, physical exercise, and mindfulness meditation may improve cognition. Here, we investigated whether improvements in cognition after these three types of structured interventions are facilitated by increases in BDNF. Methods: A total of 144 heathy older adults completed a 5-week intervention involving working memory/cognitive training, physical exercise, mindfulness meditation, or an active control condition. Serum BDNF levels and Digit Symbol Test (DST) performance were measured pre- and post-intervention. Results: Linear mixed models suggested that only the cognitive training group demonstrated augmentation of BDNF and DST performance relative to the control condition. Path analysis revealed that changes in BDNF mediate intervention-related improvement in task performance. Regression analyses showed that, across all intervention conditions, increased BDNF levels were associated with increased DST scores. Discussion: This study appears to be the first to suggest that BDNF helps mediate improvements in cognition after working memory training in healthy older adults. Highlights: Older adults were randomized to physical activity, mindfulness, cognitive training (computerized cognitive training (CCT), or control.CCT, but no other condition, led to increased serum brain-derived neurotrophic factor (BDNF) levels.CCT led to improvement on the untrained Digit Symbol Test (DST) of speed/working memory.Path analysis: increases in BDNF mediate intervention-related improvement on DST.Increases in BDNF associated with improved DST across all experimental groups.

Mechanisms underlying age- and performance-related differences in working memory.

This study took advantage of the subsecond temporal resolution of ERPs to investigate mechanisms underlying age- and performance-related differences in working memory. Young and old subjects participated in a verbal n-back task with three levels of difficulty. Each group was divided into high and low performers based on accuracy under the 2-back condition. Both old subjects and low-performing young subjects exhibited impairments in preliminary mismatch/match detection operations (indexed by the anterior N2 component). This may have undermined the quality of information available for the subsequent decision-making process (indexed by the P3 component), necessitating the appropriation of more resources. Additional anterior and right hemisphere activity was recruited by old subjects. Neural efficiency and the capacity to allocate more resources to decision-making differed between high and low performers in both age groups. Under low demand conditions, high performers executed the task utilizing fewer resources than low performers (indexed by the P3 amplitude). As task requirements increased, high-performing young and old subjects were able to appropriate additional resources to decision-making, whereas their low-performing counterparts allocated fewer resources. Higher task demands increased utilization of processing capacity for operations other than decision-making (e.g., sustained attention) that depend upon a shared pool of limited resources. As demands increased, all groups allocated additional resources to the process of sustaining attention (indexed by the posterior slow wave). Demands appeared to have exceeded capacity in low performers, leading to a reduction of resources available to the decision-making process, which likely contributed to a decline in performance.

Does compensatory neural activity survive old-old age?

One mechanism that may allow older adults to continue to successfully perform certain cognitive tasks is to allocate more resources than their younger counterparts. Most prior studies have not included individuals beyond their 70s. Here, we investigated whether compensatory increases in neural activity previously observed in cognitively high-performing young-old adults would continue into old-old age. Event-related potentials were recorded from 72 cognitively high performing subjects, aged 18 to 96 years old, while they participated in a subject-controlled novelty oddball paradigm in which they determined viewing duration of standard, target, and novel visual stimuli. Compared to young and middle-aged subjects, both young-old and old-old subjects exhibited an impairment of preliminary mismatch/match detection operations, indexed by an attenuated anterior N2 component. This may have placed a greater burden on the subsequent controlled decision-making process, indexed by the P3, necessitating the allocation of more resources. The relationship between age and resource allocation, as measured by P3 amplitude, from midlife to very old age (45-96 years old) followed an inverted u-shaped curve (quadratic function). It peaked between the late 60s and early 70s. Thereafter, there was an inverse relationship between age and resource appropriation. This relationship remained significant after controlling for differences in task performance and MMSE. Examining the size of the P3 component across different age groups suggests that although cognitively high performing adults in their early 80s exhibit a reduction in P3 amplitude, they have a relatively well-preserved capacity to appropriate resources. However, by the late 80s, there is a robust decline (relative to young-old adults) in the size of the P3. Our results indicate that when carrying out controlled processing linked to directing attention to salient events, cognitively high performers reach the boundary of their capacity, albeit relatively late in life. This limits their ability to appropriate additional resources as compensatory activity for age-related impairments in earlier visual processing, and suggests that such a mechanism does not tend to "survive" old-old age.

Cognitive Impairment in Aging Physicians: Current Challenges and Possible Solutions.

Aging physicians are at a higher risk of cognitive impairment, undermining patient safety and unraveling physicians' careers. Neurologists, occupational health physicians, and psychiatrists will participate in both health system policy decisions and individual patient evaluations. We address cognitive impairment in aging physicians and attendant risks and benefits. If significant cognitive impairment is found after an appropriate evaluation, precautions to confidentially support physicians' practicing safely for as long as possible should be instituted. Understanding that there is heterogeneity and variability in the course of cognitive disorders is crucial to supporting cognitively impaired, practicing physicians. Physicians who are no longer able to practice clinically have other meaningful options.

Promoting Successful Cognitive Aging: A Ten-Year Update.

A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.

Capacity-limited resources are used for managing sensory degradation and cognitive demands: Implications for age-related cognitive decline and dementia.

Older adults with sensory deficits are at higher risk for developing cognitive impairment and dementia. It remains uncertain if the link between sensory and cognitive functioning reflects a common underlying factor or whether sensory deficits directly undermine cognitive processing. This issue was addressed by comparing behavioral and event-related potential responses of 16 older and 16 young adults during a working memory paradigm that parametrically varied visual contrast level (100%, 69%, 22%) and cognitive task load (1-4 face pairs to remember). The groups were well-matched on demographic and neuropsychological variables; however, older adults had worse corrected visual acuity and contrast sensitivity. The study's major finding was an interaction between visual contrast level and task load on performance accuracy (percent of correct responses) and the allocation of resources for decision making/updating (as indexed by the P3b amplitude). The negative impact of degraded visual processing was greater at higher levels of task demand. This result suggests that a shared pool of processing resources is used to mediate cognitive operations and manage the processing of degraded images. The study also demonstrated that older adults reach the limits of their processing capacity at lower levels of task load. The interaction between visual degradation and task demand, accompanied by the age-related reduction in available processing resources highlight the increased vulnerability of older adults. Specifically, an age-associated decline in visual acuity and contrast sensitivity puts older adults at risk for depleting their limited resources in the service of processing degraded visual images. The results of this study underscore the potential importance of optimizing vision in older adults to help mitigate age-associated cognitive decline.

New-Onset Delusions Heralding an Underlying Neurodegenerative Condition: A Case Report and Review of the Literature.

OBJECTIVE: To present a striking case of new-onset psychosis in a middle-aged woman subsequently diagnosed with behavioral variant frontotemporal dementia (bvFTD). To review the data regarding key red-flag features that may suggest a diagnosis of a neurodegenerative process, and specifically bvFTD, rather than a primary psychotic disorder. To examine the role of genetics, especially mutations of the microtubule-associated protein tau (MAPT) gene, in familial cases of frontotemporal dementia (FTD). DATA SOURCES: The pertinent literature was searched online (PubMed, Google Scholar) using the following search terms: frontotemporal dementia (FTD), Pick's disease, behavioral variant FTD (bvFTD), psychosis, delusions, MAPT, and genetics. No date or language limit was applied. STUDY SELECTION: The case report was generated through detailed assessment of clinical notes, imaging studies, and laboratory results. The brain autopsy was carried out and summarized by our neuropathology team. Previously published literature was selected for inclusion in the review section based on relevance to the topic. RESULTS: A neurodegenerative etiology for psychosis (and specifically bvFTD) should be suspected in patients with progressive deficits in executive function, language, or memory. Other key warning features include the presence of a strong family history of a late-life psychotic disorder (or institutional placement or suicide), loss of empathy, impaired recognition of facial expression, or the development of emotional blunting and apathy, abnormal movements, or seizures. CONCLUSIONS: Neurodegenerative disease should be on the differential diagnosis for any patient presenting with new-onset psychosis and behavioral changes in mid to late adulthood. Should red-flag features be present, early referral to a clinic specializing in dementia is recommended for further evaluation. This case highlights that MAPT mutations can be associated with psychosis in FTD and should be considered in the genetic workup. Ongoing research into the cellular and neural circuit mechanisms of psychosis in neurodegenerative disease may shed light on pathologic processes underlying psychosis in primary psychiatric disorders.

The Brain Health Champion study: Health coaching changes behaviors in patients with cognitive impairment.

INTRODUCTION: Converging evidence suggests that increasing healthy behaviors may slow or prevent cognitive decline. METHODS: We piloted a six-month, randomized, controlled investigation of 40 patients with mild dementia, mild cognitive impairment, or subjective cognitive decline. The intervention consisted of weekly motivational interviewing phone calls and three visits with a "Brain Health Champion" health coach, who guided participants to achieve personalized goals. Changes in behavior were measured using validated questionnaires. RESULTS: Compared with the standard-of-care control group, Brain Health Champion participants had statistically significant and clinically meaningful increases in physical activity (Cohen's d = 1.37, P < .001), adherence to the Mediterranean diet (Cohen's d = 0.87, P = .016), cognitive/social activity (Cohen's d = 1.09, P = .003), and quality of life (Cohen's d = 1.23, P < .001). The magnitude of behavior change strongly predicted improvement in quality of life. DISCUSSION: Our results demonstrate the feasibility and potential efficacy of a health coaching approach in changing health behaviors in cognitively impaired and at-risk patients.