The Real-World Usability, Feasibility, and Performance Distributions of Deploying a Digital Toolbox of Computerized Assessments to Remotely Evaluate Brain Health: Development and Usability Study.

BACKGROUND: An ongoing global challenge is managing brain health and understanding how performance changes across the lifespan. OBJECTIVE: We developed and deployed a set of self-administrable, computerized assessments designed to measure key indexes of brain health across the visual and auditory sensory modalities. In this pilot study, we evaluated the usability, feasibility, and performance distributions of the assessments in a home-based, real-world setting without supervision. METHODS: Potential participants were untrained users who self-registered on an existing brain training app called BrainHQ. Participants were contacted via a recruitment email and registered remotely to complete a demographics questionnaire and 29 unique assessments on their personal devices. We examined participant engagement, descriptive and psychometric properties of the assessments, associations between performance and self-reported demographic variables, cognitive profiles, and factor loadings. RESULTS: Of the 365,782 potential participants contacted via a recruitment email, 414 (0.11%) registered, of whom 367 (88.6%) completed at least one assessment and 104 (25.1%) completed all 29 assessments. Registered participants were, on average, aged 63.6 (SD 14.8; range 13-107) years, mostly female (265/414, 64%), educated (329/414, 79.5% with a degree), and White (349/414, 84.3% White and 48/414, 11.6% people of color). A total of 72% (21/29) of the assessments showed no ceiling or floor effects or had easily modifiable score bounds to eliminate these effects. When correlating performance with self-reported demographic variables, 72% (21/29) of the assessments were sensitive to age, 72% (21/29) of the assessments were insensitive to gender, 93% (27/29) of the assessments were insensitive to race and ethnicity, and 93% (27/29) of the assessments were insensitive to education-based differences. Assessments were brief, with a mean duration of 3 (SD 1.0) minutes per task. The pattern of performance across the assessments revealed distinctive cognitive profiles and loaded onto 4 independent factors. CONCLUSIONS: The assessments were both usable and feasible and warrant a full normative study. A digital toolbox of scalable and self-administrable assessments that can evaluate brain health at a glance (and longitudinally) may lead to novel future applications across clinical trials, diagnostics, and performance optimization.

Early auditory processing abnormalities alter individual learning trajectories and sensitivity to computerized cognitive training in schizophrenia.

BACKGROUND: Auditory system plasticity is a promising target for neuromodulation, cognitive rehabilitation and therapeutic development in schizophrenia (SZ). Auditory-based targeted cognitive training (TCT) is a 'bottom up' intervention designed to enhance the speed and accuracy of auditory information processing, which has been shown to improve neurocognition in certain SZ patients. However, the dynamics of TCT learning as a function of training exercises and their impact on neurocognitive functioning and therapeutic outcomes are unknown. METHODS: Forty subjects (SZ, n = 21; healthy subjects (HS), n = 19) underwent comprehensive clinical, cognitive, and auditory assessments, including measurements of auditory processing speed (APS) at baseline and after 1-h of TCT. SZ patients additionally completed 30-hours of TCT and repeated assessments ~10-12 weeks later. RESULTS: SZ patients were deficient in APS at baseline (d = 0.96, p < 0.005) relative to HS. After 1-h of TCT, analyses revealed significant main effects of diagnosis (d = 1.75, p = 0.002) and time (d = 1.04, p < 0.001), and a diagnosis × time interaction (d = 0.85, p = 0.02) on APS. APS learning effects were robust after 1-h in SZ patients (d = 1.47, p < 0.001) and persisted throughout the 30-h of training. Baseline APS was associated with verbal learning gains after 30-h of TCT (r = 0.51, p = 0.02) in SZ. CONCLUSIONS: TCT learning metrics may have prognostic utility and aid in the prospective identification of individuals likely to benefit from TCT. Future experimental medicine studies may advance predictive algorithms that enhance TCT-related clinical, cognitive and functional outcomes.

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications.

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project.

BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Remote Assessment of Cardiovascular Risk Factors and Cognition in Middle-Aged and Older Adults: Proof-of-Concept Study.

BACKGROUND: Adults with cardiovascular disease risk factors (CVRFs) are also at increased risk of developing cognitive decline and dementia. However, it is often difficult to study the relationships between CVRFs and cognitive function because cognitive assessment typically requires time-consuming in-person neuropsychological evaluations that may not be feasible for real-world situations. OBJECTIVE: We conducted a proof-of-concept study to determine if the association between CVRFs and cognitive function could be detected using web-based, self-administered cognitive tasks and CVRF assessment. METHODS: We recruited 239 participants aged ≥50 years (mean age 62.7 years, SD 8.8; 42.7% [n=102] female, 88.7% [n=212] White) who were enrolled in the Health eHeart Study, a web-based platform focused on cardiac disease. The participants self-reported CVRFs (hypertension, high cholesterol, diabetes, and atrial fibrillation) using web-based health surveys between August 2016 and July 2018. After an average of 3 years of follow-up, we remotely evaluated episodic memory, working memory, and executive function via the web-based Posit Science platform, BrainHQ. Raw data were normalized and averaged into 3 domain scores. We used linear regression models to examine the association between CVRFs and cognitive function. RESULTS: CVRF prevalence was 62.8% (n=150) for high cholesterol, 45.2% (n=108) for hypertension, 10.9% (n=26) for atrial fibrillation, and 7.5% (n=18) for diabetes. In multivariable models, atrial fibrillation was associated with worse working memory (ß=-.51, 95% CI -0.91 to -0.11) and worse episodic memory (ß=-.31, 95% CI -0.59 to -0.04); hypertension was associated with worse episodic memory (ß=-.27, 95% CI -0.44 to -0.11). Diabetes and high cholesterol were not associated with cognitive performance. CONCLUSIONS: Self-administered web-based tools can be used to detect both CVRFs and cognitive health. We observed that atrial fibrillation and hypertension were associated with worse cognitive function even in those in their 60s and 70s. The potential of mobile assessments to detect risk factors for cognitive aging merits further investigation.

Central auditory processing deficits in schizophrenia: Effects of auditory-based cognitive training.

BACKGROUND: Sensory processing abnormalities are common in schizophrenia (SZ) and impact everyday functions, such as speech perception in noisy environments. Auditory-based targeted cognitive training (TCT) is a "bottom up" cognitive remediation intervention designed to enhance the speed and accuracy of low-level auditory information processing. However, the effects of TCT on behavioral measures of central auditory processing (CAP) and the role of CAP function on verbal learning outcomes in SZ are unknown. METHODS: SZ (n = 42) and healthy subjects (CTL; n = 18) underwent comprehensive clinical, neurocognitive, and auditory assessments, including tests of hearing sensitivity and speech recognition (Words-in-Noise (WIN), Quick Speech-in-Noise (SIN)). SZ patients were randomized to receive either treatment-as-usual (TAU); or 30-h of TCT + TAU using a stratified, parallel design. SZ patients repeated assessments ~10-12 weeks later. RESULTS: Patients exhibited deficits in both WIN (p < 0.05, d = 0.50) and SIN (p < 0.01, d = 0.63). A treatment × time interaction on WIN (p < 0.05, d = 0.74), but not SIN discriminability, was seen in the TCT group relative to TAU. Specific enhancements in the 4-dB over background range drove gains in WIN performance. Moreover, SZ patients with greater CAP deficits experienced robust gains in verbal learning after 30-h of TCT relative to SZ patients without CAP impairment (p < 0.01, d = 1.28). CONCLUSION: Findings demonstrate that intensive auditory training enhances the fidelity of auditory processing and perception, such that specific CAP deficits were 'normalized' and were predictive of gains in verbal learning after TCT. It is conceivable that patients with deficiencies in CAP measures may benefit most from TCT and other interventions targeting auditory dysfunction in SZ.

Unintended Consequences of White Noise Therapy for Tinnitus-Otolaryngology's Cobra Effect: A Review.

Importance: Critical to the success of many medical therapeutics is a consideration of the brain's miraculous ability to dynamically rewire itself anatomically and neurochemically on the basis of incoming information. We argue that white noise exposure, a commonly recommended therapy for patients with tinnitus, engages these plastic processes in a way that induces maladaptive changes in the brain that degrade neurological health and compromise cognition. Observations: The pathophysiologic mechanisms commonly associated with hearing loss and tinnitus reflect cortical dedifferentiation and widespread loss of inhibitory tone throughout the central auditory pathway. Importantly, these same changes are also induced by exposure to unstructured noise, even at nontraumatic levels in the adult nervous system. Not by coincidence, the same changes appear in age-related decline of central auditory function, suggesting that both tinnitus and white noise accelerate the aging of the brain. Conclusions and Relevance: Noise exposure therapies offer a seductive short-term solution for relief but, in the long term, undermine the functional and structural integrity of the central auditory system and the brain more generally. Sound therapies using unstructured, random ("white") noise should be avoided as a treatment for tinnitus. Alternative therapeutics that drive positive, adaptive plastic changes are discussed.

Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care.

Computerized targeted cognitive training (TCT) of auditory processing has been shown to improve verbal learning in several clinical trials of schizophrenia outpatients. Less is known, however, about the effectiveness of this promising intervention in more chronic, treatment-refractory patients who are treated in non-academic settings. This study aimed to determine whether TCT improves auditory processing, verbal learning, and clinical symptoms in SZ patients mandated to receive care at a locked residential rehabilitation center. Secondarily, potential factors that moderate TCT's effectiveness including age, symptom severity, antipsychotic medication load, and duration of illness were examined. Schizophrenia patients were randomized to treatment as usual (TAU; n = 22) or TAU augmented with TCT (TAU + TCT; n = 24). Outcomes included a measure of auditory perception (Word-In-Noise test, WIN), verbal learning domain scores from the MATRICS Consensus Cognitive Battery (MCCB), and clinical symptoms (Scale for the Assessment of Positive Symptoms, SAPS; Scale for the Assessment of Negative Symptoms, SANS). TCT produced significant improvements in auditory perception (d = 0.67) and verbal learning (d = 0.65); exploratory analyses revealed a statistically significant reduction in auditory hallucinations (d = -0.64). TCT's effects were only weakly, and mostly non-significantly, moderated by age, clinical symptoms, medication, and illness duration. These findings indicate that even highly symptomatic, functionally disabled patients with chronic illness benefit from this emerging treatment. Ongoing studies will examine the predictive utility of neurophysiological biomarkers and other characteristics assessed at baseline.

The time-limited visual statistician.

The visual system can calculate summary statistics over time. For example, the multiple frames of a movie showing a dynamically changing disk can be collapsed to form a single representation of that disk's mean size. Summary representations of dynamic information may engage online updating processes that establish a running average of the mean by continuously adjusting the persisting representation of the average in tandem with the arrival of incoming information. Alternatively, summary representations may involve subsampling strategies that reflect limitations in the degree to which the visual system can integrate information over time. Observers watched movies of a disk that changed size smoothly at different rates and then reported the disk's average size by adjusting the diameter of a response disk. Critically, the movie varied in duration. Size estimates depended on the duration of the movie. They were constant and fairly accurate for movie durations up to approximately 600 ms, at which point accuracy decreased with increasing duration to imprecise levels by about 1,000 ms. Summary statistics established over time are unlikely to be updated continuously and may instead be restricted by subsampling processes, such as limited temporal windows of integration. (PsycINFO Database Record

The perceptual processing capacity of summary statistics between and within feature dimensions.

The simultaneous-sequential method was used to test the processing capacity of statistical summary representations both within and between feature dimensions. Sixteen gratings varied with respect to their size and orientation. In Experiment 1, the gratings were equally divided into four separate smaller sets, one of which with a mean size that was larger or smaller than the other three sets, and one of which with a mean orientation that was tilted more leftward or rightward. The task was to report the mean size and orientation of the oddball sets. This therefore required four summary representations for size and another four for orientation. The sets were presented at the same time in the simultaneous condition or across two temporal frames in the sequential condition. Experiment 1 showed evidence of a sequential advantage, suggesting that the system may be limited with respect to establishing multiple within-feature summaries. Experiment 2 eliminates the possibility that some aspect of the task, other than averaging, was contributing to this observed limitation. In Experiment 3, the same 16 gratings appeared as one large superset, and therefore the task only required one summary representation for size and another one for orientation. Equal simultaneous-sequential performance indicated that between-feature summaries are capacity free. These findings challenge the view that within-feature summaries drive a global sense of visual continuity across areas of the peripheral visual field, and suggest a shift in focus to seeking an understanding of how between-feature summaries in one area of the environment control behavior.

The capacity limitations of orientation summary statistics.

The simultaneous-sequential method was used to test the processing capacity of establishing mean orientation summaries. Four clusters of oriented Gabor patches were presented in the peripheral visual field. One of the clusters had a mean orientation that was tilted either left or right, whereas the mean orientations of the other three clusters were roughly vertical. All four clusters were presented at the same time in the simultaneous condition, whereas the clusters appeared in temporal subsets of two in the sequential condition. Performance was lower when the means of all four clusters had to be processed concurrently than when only two had to be processed in the same amount of time. The advantage for establishing fewer summaries at a given time indicates that the processing of mean orientation engages limited-capacity processes (Exp. 1). This limitation cannot be attributed to crowding, low target-distractor discriminability, or a limited-capacity comparison process (Exps. 2 and 3). In contrast to the limitations of establishing multiple summary representations, establishing a single summary representation unfolds without interference (Exp. 4). When interpreted in the context of recent work on the capacity of summary statistics, these findings encourage a reevaluation of the view that early visual perception consists of creating summary statistic representations that unfold independently across multiple areas of the visual field.

Onset rivalry: factors that succeed and fail to bias selection.

This project examined whether previous visual history can bias perceptual dominance during onset rivalry. A predictive sequence of non-rivalrous stimuli preceded dichoptically presented rivalrous displays. One of the dichoptic images was the implied next step of the preceding sequence while the other was not. Observers reported their initial dominant percept. Across five experiments, we found that motion sequences biased perceptual selection such that a rivalrous stimulus that continued a motion sequence tended to dominate one that did not. However, signals generated by complex pattern of motion information or verbal-semantic information had no influence on selection. These results are consistent with the view that onset rivalry is an early phase of rivalry that is likely insensitive to modulation by factors originating beyond the visual system.

Summary statistics of size: fixed processing capacity for multiple ensembles but unlimited processing capacity for single ensembles.

We assessed the processing capacity of establishing statistical summary representations (SSRs) of mean size in visual displays using the simultaneous-sequential method. Four clusters of stimuli, each composed of several circles with various diameters, were presented around fixation. Observers searched for the cluster with the largest or smallest mean size. In the simultaneous condition, all four clusters were presented concurrently; in the sequential condition, the clusters appeared two at a time. We found that the processing capacity of SSRs for multiple ensembles was as extreme as a fixed-rate bottleneck process (Experiment 1). A control experiment confirmed that this was not caused by having to compare the results of multiple averaging processes (Experiment 2). In contrast to computing SSRs across ensembles, computing SSRs for a single ensemble using the same stimuli was consistent with unlimited-capacity processing (Experiment 3). Contrary to existing claims, summary representations appear to be extracted independently for items within single ensembles but not multiple ensembles. A developing understanding of capacity limitations in perceptual processing is discussed.

Evidence of unlimited-capacity surface completion.

Capacity limitations of perceptual surface completion were assessed using a simultaneous-sequential method. Observers searched among multiple surfaces requiring perceptual completion in front of other objects (modal completion) or behind other objects (amodal completion). In the simultaneous condition, all surfaces were presented at once, whereas in the sequential condition, they appeared in subsets of 2 at a time. For both modal and amodal surface completion, performance was as good in the simultaneous condition as in the sequential condition, indicating that surface completion unfolds independently for multiple surfaces across the visual field (i.e., has unlimited capacity). We confirmed this was due to the formation of surfaces defined by the pacmen inducers, and not simply to the detection of individual features of the pacmen inducers. These results provide evidence that surface-completion processes can be engaged and unfold independently for multiple surfaces across the visual field. In other words, surface completion can occur through unlimited-capacity processes. These results contribute to a developing understanding of capacity limitations in perceptual processing more generally.