Neural α Oscillations and Pupil Size Differentially Index Cognitive Demand under Competing Audiovisual Task Conditions.

Cognitive demand is thought to modulate two often used, but rarely combined, measures: pupil size and neural α (8-12 Hz) oscillatory power. However, it is unclear whether these two measures capture cognitive demand in a similar way under complex audiovisual-task conditions. Here we recorded pupil size and neural α power (using electroencephalography), while human participants of both sexes concurrently performed a visual multiple object-tracking task and an auditory gap detection task. Difficulties of the two tasks were manipulated independent of each other. Participants' performance decreased in accuracy and speed with increasing cognitive demand. Pupil size increased with increasing difficulty for both the auditory and the visual task. In contrast, α power showed diverging neural dynamics: parietal α power decreased with increasing difficulty in the visual task, but not with increasing difficulty in the auditory task. Furthermore, independent of task difficulty, within-participant trial-by-trial fluctuations in pupil size were negatively correlated with α power. Difficulty-induced changes in pupil size and α power, however, did not correlate, which is consistent with their different cognitive-demand sensitivities. Overall, the current study demonstrates that the dynamics of the neurophysiological indices of cognitive demand and associated effort are multifaceted and potentially modality-dependent under complex audiovisual-task conditions.SIGNIFICANCE STATEMENT Pupil size and oscillatory α power are associated with cognitive demand and effort, but their relative sensitivity under complex audiovisual-task conditions is unclear, as is the extent to which they share underlying mechanisms. Using an audiovisual dual-task paradigm, we show that pupil size increases with increasing cognitive demands for both audition and vision. In contrast, changes in oscillatory α power depend on the respective task demands: parietal α power decreases with visual demand but not with auditory task demand. Hence, pupil size and α power show different sensitivity to cognitive demands, perhaps suggesting partly different underlying neural mechanisms.

Context-independent scaling of neural responses to task difficulty in the multiple-demand network.

The multiple-demand (MD) network is sensitive to many aspects of cognitive demand, showing increased activation with more difficult tasks. However, it is currently unknown whether the MD network is modulated by the context in which task difficulty is experienced. Using functional magnetic resonance imaging, we examined MD network responses to low, medium, and high difficulty arithmetic problems within 2 cued contexts, an easy versus a hard set. The results showed that MD activity varied reliably with the absolute difficulty of a problem, independent of the context in which the problem was presented. Similarly, MD activity during task execution was independent of the difficulty of the previous trial. Representational similarity analysis further supported that representational distances in the MD network were consistent with a context-independent code. Finally, we identified several regions outside the MD network that showed context-dependent coding, including the inferior parietal lobule, paracentral lobule, posterior insula, and large areas of the visual cortex. In sum, a cognitive effort is processed by the MD network in a context-independent manner. We suggest that this absolute coding of cognitive demand in the MD network reflects the limited range of task difficulty that can be supported by the cognitive apparatus.

Eccentric cycling involves greater mental demand and cortical activation of the frontoparietal network.

Eccentric, compared to concentric exercise, is proposed to involve different neuro-motor processing strategies and a higher level of mental demand. This study compared eccentric and concentric cycling at matched perceived effort and torque for the mental demand and related-cortical activation patterns. Nineteen men (30 ± 6 years) performed four different 5-min cycling conditions at 30 RPM on a semi-recumbent isokinetic cycle ergometer: (1) concentric at a moderate perceived effort (23 on the CR100® scale) without torque feedback; (2) concentric and (3) eccentric at the same average torque produced in the first condition; and (4) eccentric at the same moderate perceived effort than the first concentric condition. The conditions two to four were randomized. After each condition, mental demand was monitored using the NASA Task Load Index scale. Changes in oxy-(O2 Hb) and deoxy-(HHb) hemoglobin during exercise were measured over both prefrontal cortices and the right parietal lobe from a 15-probe layout using a continuous-wave NIRS system. Mental demand was significantly higher during eccentric compared to concentric cycling (+52%, p = 0.012) and when the exercise intensity was fixed by the torque rather than the perceived effort (+70%, p < 0.001). For both torque- or perceived effort-matched exercises, O2 Hb increased significantly (p < 0.001) in the left and right prefrontal cortices, and right parietal lobe, and HHb decreased in the left, and right, prefrontal cortices during eccentric compared to concentric cycling. This study supports that acute eccentric cycling, compared to concentric cycling, involves a higher mental demand, and frontoparietal network activation.

Response of multiple demand network to visual search demands.

Neuroimaging studies for human participants have shown that the activity in the multiple-demand (MD) network is associated with various kinds of cognitive demand. However, surprisingly, it remains unclear how this MD network is related to a core component of cognition, the process of searching for a target among distractors. This was because previous neuroimaging studies of visual search were confounded by task difficulty or time on task. To circumvent these limitations, we examined human brain activity while participants perform two different visual search tasks. The performance of a task was limited by increased attentional demand, while the other task was primarily limited by poor quality of input data or neural noise. Throughout the MD network, increased activity and strengthened functional connectivity among the MD regions were observed under the search task recruiting capacity-limited attentional resources. The present findings provide unequivocal evidence that the MD network mediates visual search, as well as other capacity-limited cognitive processes.

Task-induced brain connectivity promotes the detection of individual differences in brain-behavior relationships.

Although both resting and task-induced functional connectivity (FC) have been used to characterize the human brain and cognitive abilities, the potential of task-induced FCs in individualized prediction for out-of-scanner cognitive traits remains largely unexplored. A recent study Greene et al. (2018) predicted the fluid intelligence scores using FCs derived from rest and multiple task conditions, suggesting that task-induced brain state manipulation improved prediction of individual traits. Here, using a large dataset incorporating fMRI data from rest and 7 distinct task conditions, we replicated the original study by employing a different machine learning approach, and applying the method to predict two reading comprehension-related cognitive measures. Consistent with their findings, we found that task-based machine learning models often outperformed rest-based models. We also observed that combining multi-task fMRI improved prediction performance, yet, integrating the more fMRI conditions can not necessarily ensure better predictions. Compared with rest, the predictive FCs derived from language and working memory tasks were highlighted with more predictive power in predominantly default mode and frontoparietal networks. Moreover, prediction models demonstrated high stability to be generalizable across distinct cognitive states. Together, this replication study highlights the benefit of using task-based FCs to reveal brain-behavior relationships, which may confer more predictive power and promote the detection of individual differences of connectivity patterns underlying relevant cognitive traits, providing strong evidence for the validity and robustness of the original findings.

The dynamics of pain reappraisal: the joint contribution of cognitive change and mental load.

This study was designed to investigate the neural mechanism of cognitive modulation of pain via a reappraisal strategy with high temporal resolution. The EEG signal was recorded from 29 participants who were instructed to down-regulate, up-regulate, or maintain their pain experience. The L2 minimum norm source reconstruction method was used to localize areas in which a significant effect of the instruction was present. Down-regulating pain by reappraisal exerted a robust effect on pain processing from as early as ~100 ms that diminished the activity of limbic brain regions: the anterior cingulate cortex, right orbitofrontal cortex, left anterior temporal region, and left insula. However, compared with the no-regulation condition, the neural activity was similarly attenuated in the up- and down-regulation conditions. We suggest that this effect could be ascribed to the cognitive load that was associated with the execution of a cognitively demanding reappraisal task that could have produced a general attenuation of pain-related areas regardless of the aim of the reappraisal task (i.e., up- or down-regulation attempts). These findings indicate that reappraisal effects reflect the joint influence of both reappraisal-specific (cognitive change) and unspecific (cognitive demand) factors, thus pointing to the importance of cautiously selected control conditions that allow the modulating impact of both processes to be distinguished.

Surgeon Workload in Colorectal Surgery: Perceived Drivers of Procedural Difficulty.

BACKGROUND: To understand how surgeon expectation of case difficulty relates to workload for colon and rectal procedures and to identify possible surgeon-perceived drivers contributing to case difficulty. MATERIALS AND METHODS: For 3 mo, surgeons were asked to complete a modified NASA-Task Load Index (NASA-TLX) questionnaire following each surgical case. Questions included items on distractions, fatigue, procedural difficulty, and expectation plus the validated NASA-TLX items. All but expectation were rated on a 20-point scale (0 = low, 20 = high). Expectation was rated on a 3-point scale (i.e., more difficult than expected, as expected, less difficult than expected). Surgeons also reported perceived drivers contributing to case ease or difficulty. Patient and procedural data were analyzed for procedures with completed surveys. RESULTS: Seven surgeons (three female) rated 122 procedures over the research period using a modified NASA-TLX survey. Mean surgeon-perceived workload was highest for effort (mean [M] = 10.83, standard deviation [SD] = 5.66) followed by mental demand (M = 10.18, SD = 5.17), and physical demand (M = 9.19, SD = 5.60). Procedural difficulty varied significantly by procedure type (P < 0.001). Thirty-five percent of cases were considered more difficult than expected. Surgeon-perceived workload and most subscales differed significantly according to expectation level. There was no significant difference in patient factors by expectation level. Surgeons most frequently reported patient anatomy, body habitus, and operative team characteristics as drivers to difficulty and ease of cases. CONCLUSIONS: Procedural difficulty significantly differed across procedure type. More than one-third of cases were more difficult than expected, during which surgeons attributed this to operative team characteristics as well as issues in patient anatomy and body habitus.

Effects of dual-task demands on the complexity and task performance of submaximal isometric handgrip force control.

PURPOSE: To determine the effect of cognitive-motor dual-task load on temporal structure irregularity (complexity) of motor output and task performance of submaximal isometric contractions. METHODS: Twelve young, sedentary subjects performed handgrip isometric contractions until failure at 50% of maximal voluntary contraction under mathematical self-regulated dual-task (own pace; SDT), regulated dual-task (imposed pace; RDT), and control. Force signal complexity was calculated by sample entropy at the initial, middle, and final thirds. Task performance was assessed by muscle fatigue (time to failure and rate of median frequency of the radial flexor of the carpus), force and math task error, and self-perceived difficulty. RESULTS: Only RDT decreased complexity with respect to control (17.4% ± 12.6%, p = 0.005), all conditions decreased complexity by the final third (Control: 52.8% ± 18.7%, p < 0.001; SDT: 41.1% ± 32.1%, p = 0.003; RDT: 19.1% ± 21.9%, p = 0.035). Conditions did not affect time to failure, and only RDT decreased the rate of median frequency (0.1%/s ± 0.1%/s, p = 0.020). Inferior force error rate was increased by conditions (SDT: 1.5% ± 0.8%, p < 0.001; RDT: 2% ± 1.5%, p = 0.002). Math error was only augmented by RDT (from 9.9 ± 6.7 to 51.7 ± 18.8, p < 0.001), categorized as "very hard" in 85.7% of participants (p = 0.015). CONCLUSION: Only the RDT condition reduced complexity and neuromuscular fatigue while increasing force error rate of the handgrip's motor output, without affecting time to failure. A highly demanding dual-task may become a strategy to modify the organization of the hand force motor output, which may contribute to its motor adaptations.

Neural Mechanisms for Adaptive Learned Avoidance of Mental Effort.

Humans tend to avoid mental effort. Previous studies have demonstrated this tendency using various demand-selection tasks; participants generally avoid options associated with higher cognitive demand. However, it remains unclear whether humans avoid mental effort adaptively in uncertain and nonstationary environments. If so, it also remains unclear what neural mechanisms underlie such learned avoidance and whether they remain the same regardless of cognitive-demand types. We addressed these issues by developing novel demand-selection tasks where associations between choice options and cognitive-demand levels change over time, with two variations using mental arithmetic and spatial reasoning problems (males/females: 29:4 and 18:2). Most participants showed avoidance, and their choices depended on the demand experienced on multiple preceding trials. We assumed that participants updated the expected cost of mental effort through experience, and fitted their choices by reinforcement learning models, comparing several possibilities. Model-based fMRI analyses revealed that activity in the dorsomedial and lateral frontal cortices was positively correlated with the trial-by-trial expected cost for the chosen option commonly across the different types of cognitive demand. Analyses also revealed a trend of negative correlation in the ventromedial prefrontal cortex. We further identified correlates of cost-prediction error at time of problem presentation or answering the problem, the latter of which partially overlapped with or were proximal to the correlates of expected cost at time of choice cue in the dorsomedial frontal cortex. These results suggest that humans adaptively learn to avoid mental effort, having neural mechanisms to represent expected cost and cost-prediction error, and the same mechanisms operate for various types of cognitive demand.SIGNIFICANCE STATEMENT In daily life, humans encounter various cognitive demands and tend to avoid high-demand options. However, it remains unclear whether humans avoid mental effort adaptively under dynamically changing environments. If so, it also remains unclear what the underlying neural mechanisms are and whether they operate regardless of cognitive-demand types. To address these issues, we developed novel tasks where participants could learn to avoid high-demand options under uncertain and nonstationary environments. Through model-based fMRI analyses, we found regions whose activity was correlated with the expected mental effort cost, or cost-prediction error, regardless of demand type. These regions overlap, or are adjacent with each other, in the dorsomedial frontal cortex. This finding helps clarify the mechanisms for cognitive-demand avoidance, and provides empirical building blocks for the emerging computational theory of mental effort.

Activation of brainstem and midbrain nuclei during cognitive control in medicated patients with schizophrenia.

Evidence suggests that cognitive control functions as well as the underlying brain network, anchored by the prefrontal cortex (PFC) and the dorsal anterior cingulate cortex (dACC), are dysfunctional in schizophrenia. Catecholamine producing midbrain and brainstem nuclei are densely connected with the PFC and dACC and exert profound contributions to cognitive control processes. Dysfunctions within the underlying neurotransmitter systems are considered to play a central role in the occurrence of various symptoms of schizophrenia. We sought to investigate the putatively abnormal activation pattern of the dopaminergic midbrain nuclei, that is, ventral tegmental area (VTA) and substantia nigra as well as that of the noradrenergic locus coeruleus (LC) in patients with schizophrenia during cognitive control. A total of 28 medicated patients and 27 healthy controls were investigated with the manual version of the Stroop task using event-related fMRI. The main finding was a reduced BOLD activation in the VTA during both Stroop task conditions in patients in comparison to controls, which correlated significantly with the degree of negative symptoms. We further detected a comparable LC activation in in patients and healthy controls. However, in controls LC activation was significantly correlated with the Stroop interference time, which was not observed in patients. The finding of reduced VTA activation in schizophrenia patients lends further support to the assumed dysfunction of the DA system in schizophrenia. In addition, despite comparable LC activation, the nonsignificant correlation with the Stroop interference time might indicate altered LC functioning in schizophrenia and, thus, needs further investigations.

Are Individuals Who Engage in More Frequent Self-Regulation Less Susceptible to Mental Fatigue?

The aim of this study was to investigate whether individuals who engage in more frequent self-regulation are less susceptible to mental fatigue. Occupational cognitive demand and participation in sports or exercise were quantified as activities requiring self-regulation. Cardiorespiratory fitness was also assessed. On separate occasions, participants either completed 90 min of an incongruent Stroop task (mental exertion condition) or watched a 90-min documentary (control condition). Participants then completed a cycling time-to-exhaustion (physical endurance) test. There was no difference in the mean time to exhaustion between conditions, although individual responses varied. Occupational cognitive demand, participation in sports or exercise, and cardiorespiratory fitness predicted the change in endurance performance (p = .026, adjusted R2 = .279). Only cognitive demand added significantly to the prediction (p = .024). Participants who reported higher levels of occupational cognitive demand better maintained endurance performance following mental exertion.

Distress and worry as mediators in the relationship between psychosocial risks and upper body musculoskeletal complaints in highly automated manufacturing.

As a result of changes in manufacturing including an upward trend in automation and the advent of the fourth industrial revolution, the requirement for supervisory monitoring and consequently, cognitive demand has increased in automated manufacturing. The incidence of musculoskeletal disorders has also increased in the manufacturing sector. A model was developed based on survey data to test if distress and worry mediate the relationship between psychosocial factors (job control, cognitive demand, social isolation and skill discretion), stress states and symptoms of upper body musculoskeletal disorders in highly automated manufacturing companies (n = 235). These constructs facilitated the development of a statistically significant model (RMSEA 0.057, TLI 0.924, CFI 0.935). Cognitive demand was shown to be related to higher distress in employees, and distress to a higher incidence of self-reported shoulder and lower back symptoms. The mediation model incorporating stress states (distress, worry) as mediators is a novel approach in linking psychosocial risks to musculoskeletal disorders. Practitioners' Summary With little requirement for physical work in many modern automated manufacturing workplaces, there is often minimal management focus on Work-Related Musculoskeletal Disorders (WRMSDs) as important occupational health problems. Our model provides evidence that psychosocial factors are important risk factors in symptoms of WRMSD and should be managed.

Effects of Cognitive Inhibition Preceding Voluntary Step Responses to Visual Stimuli in Young and Older Adults.

OBJECTIVES: Age-related changes in executive functions, especially inhibitory control, correlate to decreased balance control and increased fall risk. However, only a few studies focused on the performance of tasks integrating balance and inhibitory control. This study aims to determine the effects of cognitive inhibition preceding the initiation of voluntary steps in young and older adults. METHODS: Performance of 3 stepping tasks (a Simon, Flanker, and a combined Simon-Flanker task [SFT]) were analyzed in 23 young adults and 43 older adults. Each task included congruent and incongruent trials in different step directions. Analyses focused on temporal aspects of step responses as identified by changes in Center of Pressure (CoP) and foot position. A 3-way repeated-measures ANOVA was used to evaluate "inhibition," "age," and "task" effects. RESULTS: With large effect sizes, "inhibition" as well as "age" resulted in longer durations of an initial preparatory phase as well as the step response phase. The SFT showed the largest "task" effects. Duration of CoP movement had the largest impact on total step execution in older adults. A significant interaction effect of "age*inhibition" was found on the duration of CoP movement, but not on CoP onset. DISCUSSION: Overall, our results demonstrate that cognitive inhibition has more impact in older adults, the longer duration of CoP movements in older adults may reflect an ineffective step preparation. Our examination of the duration of subsequent phases which comprise perceptual processing and conflict resolution, response initiation, and step execution sheds light on how cognitive inhibition affects voluntary stepping behavior in young and older adults.

Acute effects of mango leaf extract on cognitive function in healthy adults: a randomised, double-blind, placebo-controlled crossover study.

Introduction: Extracts made from the leaves of the edible mango plant (Mangifera indica L., Anacardiaceae) have a long history of medicinal usage, most likely due to the presence of high levels of mangiferin, a polyphenol compound. Previous research has demonstrated that mango leaf extract (MLE) can beneficially modulate cognitive function in both animals and humans. This study aimed to assess the effects of an acute dose of 300 mg MLE (standardised to contain ≥60% mangiferin) on cognitive performance and mood in healthy adults. Methods: In this double-blind, placebo-controlled, crossover study, 114 healthy men and women (18-43 years) received either MLE or a matched placebo at each testing visit (separated by at least 7 days). Cognitive performance (including the cognitive demand battery) and mood were measured at 30, 180, and 300 min post-dose. Results: The results showed that, compared to placebo, the group taking MLE displayed a significant increase in serial 3 s and serial 7 s subtraction errors overall. There were no other significant effects on cognitive performance. Discussion: The results of the current study suggest that the consumption of 300 mg MLE in the absence of an observed multitasking psychological stressor does not improve cognitive performance or mood at up to 300 min post-dose. Due to the very limited nature of the effects and since they were observed among many analyses, these findings should be treated with caution.Clinical trial registration: http://ClinicalTrials.gov, identifier [NCT05182450].

Balancing Act: Acute and Contextual Vestibular Sensations of Cranial Electrotherapy Stimulation Using Survey and Sensor Outcomes in a Non-Clinical Sample.

Cranial electrotherapy stimulation (CES) delivers low-intensity electrical currents to the brain to treat anxiety, depression, and pain. Though CES is considered safe and cost-effective, little is known about side effects emerging across different contexts. Our objective was to investigate how varying physical and cognitive demands impact the frequency and intensity of CES vestibular sensations in a sample of healthy young adults. We used a 2 (stimulation: sham, active) × 2 (physical demand: static sway, dynamic sit-to-stand) × 2 (cognitive demand: single-task remain silent, dual-task count backward) repeated measures design. Vestibular sensations were measured with surveys and wearable sensors capturing balance changes. Active stimulation did not influence reported vestibular sensations. Instead, high physical demand predicted more sensation reports. High cognitive demand, but not active stimulation, predicted postural sway unsteadiness. Significant effects of active stimulation on balance were observed only during the dynamic sit-to-stand transitions. In summary, CES induces vestibular sensations only for a specific outcome under certain circumstances. Our findings imply that consumers can safely maximize the benefits of CES while ensuring they are taking steps to minimize any potential side effects by considering their context and circumstances.

Visual search in infantile nystagmus syndrome.

CLINICAL RELEVANCE: Research on infantile nystagmus syndrome (INS) and visual search is limited. Conducting this research could assist practitioners in understanding how INS affects the real-life visual activities of patients and aid in developing new clinical visual function assessments for INS. BACKGROUND: The aim of this work is to investigate how subjects with INS perform visual search tasks, and, particularly, to assess how INS subjects perform when targets are located at their null position or away from it, and when under additional cognitive demands. METHODS: INS subjects (N = 15) and controls (N = 20) performed conjunction and feature search tasks, both with and without mental arithmetic. Search performance was assessed using log-transformed total search time, gaze-dependent search time, and accuracy. Cognitive demand was quantified by pupil size and the NASA task-load index score. RESULTS: INS subjects showed longer search times compared to controls in conjunction search (P < 0.01), but not in feature search. Within INS and control subjects, the total search times were significantly increased by the addition of mental arithmetic (P < 0.0001). There was no difference in gaze-dependent search times between null target position and 15° away from null target position of subjects in conjunction search (P > 0.05). Accuracies were 100% for both control and INS subjects in both conjunction and feature search. CONCLUSION: Conjunction visual search was impaired in adult INS subjects, and further worsened under increased cognitive demand. The null position did not affect the visual search performance in INS.

Pupil Size Sensitivity to Listening Demand Depends on Motivational State.

Motivation plays a role when a listener needs to understand speech under acoustically demanding conditions. Previous work has demonstrated pupil-linked arousal being sensitive to both listening demands and motivational state during listening. It is less clear how motivational state affects the temporal evolution of the pupil size and its relation to subsequent behavior. We used an auditory gap detection task (N = 33) to study the joint impact of listening demand and motivational state on the pupil size response and examine its temporal evolution. Task difficulty and a listener's motivational state were orthogonally manipulated through changes in gap duration and monetary reward prospect. We show that participants' performance decreased with task difficulty, but that reward prospect enhanced performance under hard listening conditions. Pupil size increased with both increased task difficulty and higher reward prospect, and this reward prospect effect was largest under difficult listening conditions. Moreover, pupil size time courses differed between detected and missed gaps, suggesting that the pupil response indicates upcoming behavior. Larger pre-gap pupil size was further associated with faster response times on a trial-by-trial within-participant level. Our results reiterate the utility of pupil size as an objective and temporally sensitive measure in audiology. However, such assessments of cognitive resource recruitment need to consider the individual's motivational state.

Functional reorganization of brain activity in children with attention-deficit/hyperactivity disorder: Evidence from the modulatory effect of cognitive demand during visuospatial attention task.

Previous studies reported that the inferior parietal lobule (IPL) had lower activation during visuospatial attention in children with attention-deficit/hyperactivity disorder (ADHD), while the functional connectivity (FC) between the IPL and other brain regions and how cognitive demand might modulate IPL's FC remain unclear. We performed a functional magnetic resonance imaging experiment recruiting two task conditions with relatively low and high cognitive demand of visuospatial attention. Forty-four children with ADHD and 36 age- and sex-matched healthy controls were included. IPL's regional activation and FC intensities were compared between groups and correlated with clinical measurements. We found that the IPL had significantly reduced activation in children with ADHD compared to healthy controls and this abnormal activation was not modulated by the cognitive demand of visuospatial attention. Importantly, further analysis revealed that the functional connectivity between IPL and inferior frontal gyrus was modulated by the cognitive demand of visuospatial attention in children with ADHD. These results revealed a modulatory effect of cognitive demand of visuospatial attention on IPL's functional connectivity but not IPL's activation in children with ADHD. More generally, these results highlight the functional reorganization of the brain activity as a possible compensatory strategy in response to the symptoms of ADHD.

Demand Coupling Drives Neurodegeneration: A Model of Age-Related Cognitive Decline and Dementia.

The societal burden of Alzheimer's Disease (AD) and other major forms of dementia continues to grow, and multiple pharmacological agents directed towards modifying the pathological "hallmarks" of AD have yielded disappointing results. Though efforts continue towards broadening and deepening our knowledge and understanding of the mechanistic and neuropathological underpinnings of AD, our previous failures motivate a re-examination of how we conceptualize AD pathology and progression. In addition to not yielding effective treatments, the phenotypically heterogeneous biological processes that have been the primary area of focus to date have not been adequately shown to be necessary or sufficient to explain the risk and progression of AD. On the other hand, a growing body of evidence indicates that lifestyle and environment represent the ultimate level of causation for AD and age-related cognitive decline. Specifically, the decline in cognitive demands over the lifespan plays a central role in driving the structural and functional deteriorations of the brain. In the absence of adequate cognitive stimulus, physiological demand-function coupling leads to downregulation of growth, repair, and homeostatic processes, resulting in deteriorating brain tissue health, function, and capacity. In this setting, the heterogeneity of associated neuropathological tissue hallmarks then occurs as a consequence of an individual's genetic and environmental background and are best considered downstream markers of the disease process rather than specific targets for direct intervention. In this manuscript we outline the evidence for a demand-driven model of age-related cognitive decline and dementia and why it mandates a holistic approach to dementia treatment and prevention that incorporates the primary upstream role of cognitive demand.

Effects of Classroom-Based Resistance Training With and Without Cognitive Training on Adolescents' Cognitive Function, On-task Behavior, and Muscular Fitness.

Aim: Participation in classroom physical activity breaks may improve children's cognition, but few studies have involved adolescents. The primary aim of this study was to examine the effects of classroom-based resistance training with and without cognitive training on adolescents' cognitive function. Methods: Participants were 97 secondary school students (45.4% females, mean age 15.78 ± 0.44). Four-year 10 classes from one school were included in this four-arm cluster randomized controlled trial. Classes were randomly assigned to the following groups: sedentary control with no cognitive training, sedentary with cognitive training, resistance training without cognitive training, and resistance training with cognitive training. Sessions varied in levels of both cognitive demand and resistance training (i.e., high vs. low) and were administered three times per week for 4 weeks (12 sessions). Inhibition, cognitive flexibility, episodic memory, on-task behavior, and muscular fitness were assessed at baseline and post-test. Linear mixed models were used to examine changes within and between groups. Results: In comparison with the control group, episodic memory improved significantly in the resistance training without cognitive training group (-9.87 units, 95% CI: -17.71 to -2.03, p = 0.014, d = 0.72). There were no group-by-time effects for inhibition or cognitive flexibility. Classroom activity breaks both with and without cognitive demand improved participants' on-task behavior in comparison with the control and sedentary group. The resistance training programs did not lead to improvements in muscular fitness. Conclusion: Participation in body weight resistance training without cognitive training led to selective improvements in episodic memory. No training effects were found for inhibition or cognitive flexibility. A longer study period may be necessary to induce improvements in muscular fitness and associated changes in inhibition and cognitive flexibility. Clinical Trial Registration: https://www.anzctr.org.au/ACTRN12621001341819.aspx, Australian New Zealand Clinical Trials Registry-ACTRN12621001341819.