Cognitive dysfunction and increased phosphorylated tau are associated with reduced O-GlcNAc signaling in an aging mouse model of metabolic syndrome.

Metabolic syndrome (MetS), characterized by hyperglycemia, obesity, and hyperlipidemia, can increase the risk of developing late-onset dementia. Recent studies in patients and mouse models suggest a putative link between hyperphosphorylated tau, a component of Alzheimer's disease-related dementia (ADRD) pathology, and cerebral glucose hypometabolism. Impaired glucose metabolism reduces glucose flux through the hexosamine metabolic pathway triggering attenuated O-linked N-acetylglucosamine (O-GlcNAc) protein modification. The goal of the current study was to investigate the link between cognitive function, tau pathology, and O-GlcNAc signaling in an aging mouse model of MetS, agouti KKAy+/- . Male and female C57BL/6, non-agouti KKAy-/- , and agouti KKAy+/- mice were aged 12-18 months on standard chow diet. Body weight, blood glucose, total cholesterol, and triglyceride were measured to confirm the MetS phenotype. Cognition, sensorimotor function, and emotional reactivity were assessed for each genotype followed by plasma and brain tissue collection for biochemical and molecular analyses. Body weight, blood glucose, total cholesterol, and triglyceride levels were significantly elevated in agouti KKAy+/- mice versus C57BL/6 controls and non-agouti KKAy-/- . Behaviorally, agouti KKAy+/- revealed impairments in sensorimotor and cognitive function versus age-matched C57BL/6 and non-agouti KKAy-/- mice. Immunoblotting demonstrated increased phosphorylated tau accompanied with reduced O-GlcNAc protein expression in hippocampal-associated dorsal midbrain of female agouti KKAy+/- versus C57BL/6 control mice. Together, these data demonstrate that impaired cognitive function and AD-related pathology are associated with reduced O-GlcNAc signaling in aging MetS KKAy+/- mice. Overall, our study suggests that interaction of tau pathology with O-GlcNAc signaling may contribute to MetS-induced cognitive dysfunction in aging.

Embodied nonlinear dynamics of cognitive performance.

Study participants are typically unable to generate binary button-press sequences that pass as classically random sequences, such as from successive "fair coin" flips. Instead, their sequences repeat or alternate between responses too often. These deviations from randomness are commonly explained in terms of limitations or idiosyncrasies in cognitive processing. This article tests a novel hypothesis that randomness departures in participant-generated binary sequences are driven by coordination dynamics; alternating and repeating sequences are related to bimanual coordination attractors. Participants (N = 128) were asked to generate sequences that were representative of a random sequence, by successively pressing either of two buttons across 1,600 trials. Statistical analyses identify the binary button-press dynamics with a discrete sine-circle version of the Haken, Kelso, Bunz bimanual coordination model. Permutation analyses revealed the most common one- to five-trial subsequences were identified with the most dynamically stable coordinative relationships, consistent with bimanual coordination predictions. The sequences were consistent with scaling noises. Thus, participants' sequences departed from classical randomness by virtue of membership in a more inclusive category of variability that subsumes classical randomness. Recurrence quantification analysis revealed the mixture of stochasticity and determinism in the sequences was better approximated by the sine-circle model than by phase-randomized surrogate data sets that preserved both the power spectral densities and distributions of each participant's sequence. A relationship between randomness production and two-alternative forced-choice performance is established that constrains response time distribution models. The article's organization illustrates a nonreductive approach to inference for cognitive systems, inspired by statistical physics concepts such as renormalization group theory and universality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Farey Trees Explain Sequential Effects in Choice Response Time.

The latencies of successive two-alternative, forced-choice response times display intricately patterned sequential effects, or dependencies. They vary as a function of particular trial-histories, and in terms of the order and identity of previously presented stimuli and registered responses. This article tests a novel hypothesis that sequential effects are governed by dynamic principles, such as those entailed by a discrete sine-circle map adaptation of the Haken Kelso Bunz (HKB) bimanual coordination model. The model explained the sequential effects expressed in two classic sequential dependency data sets. It explained the rise of a repetition advantage, the acceleration of repeated affirmative responses, in tasks with faster paces. Likewise, the model successfully predicted an alternation advantage, the acceleration of interleaved affirmative and negative responses, when a task's pace slows and becomes more variable. Detailed analyses of five studies established oscillatory influences on sequential effects in the context of balanced and biased trial presentation rates, variable pacing, progressive and differential cognitive loads, and dyadic performance. Overall, the empirical patterns revealed lawful oscillatory constraints governing sequential effects in the time-course and accuracy of performance across a broad continuum of recognition and decision activities.

Early learning differences between intra- and interpersonal interlimb coordination.

Intrinsic coordination patterns exist between limbs such that 1) coordination at these states is inherently stable, 2) any other pattern requires learning to produce, and 3) this learning is subject to interference from a systemic bias towards intrinsic patterns. The dynamics that govern intrapersonal interlimb coordination also govern interpersonal coordination. However, intrapersonal coordination exhibits greater coupling strength and thus more stable intrinsic dynamics than interpersonal coordination. Because the strength of intrinsic coordination tendencies has consequences for learning coordination patterns, the differences in coupling strength between intra- and interpersonal coordination should impact the ability to perform new coordination patterns via greater or less interference from intrinsic dynamics. This was investigated by measuring participants' performance as they learned a new coordination pattern alone (intrapersonal) or in pairs (interpersonal). Participants were implicitly tasked with learning the pattern as they separately controlled the vertical and horizontal position of an on-screen cursor to trace a circling target. We observed better performance of dyads on first trial and steeper learning trajectories for individuals. Overall, these results indicate that individuals experienced greater interference from stronger intrinsic coordination dynamics during early learning but could overcome this interference and achieve similar performance to that of dyads with very little practice.

Linking ADHD and Behavioral Assessment Through Identification of Shared Diagnostic Task-Based Functional Connections.

A mixed literature implicates atypical connectivity involving attentional, reward and task inhibition networks in ADHD. The neural mechanisms underlying the utility of behavioral tasks in ADHD diagnosis are likewise underexplored. We hypothesized that a machine-learning classifier may use task-based functional connectivity to compute a joint probability function that identifies connectivity signatures that accurately predict ADHD diagnosis and performance on a clinically-relevant behavioral task, providing an explicit neural mechanism linking behavioral phenotype to diagnosis. We analyzed archival MRI and behavioral data of 80 participants (64 male) who had completed the go/no-go task from the longitudinal follow-up of the Multimodal Treatment Study of ADHD (MTA 168) (mean age = 24 years). Cross-mutual information within a functionally-defined mask measured functional connectivity for each task run. Multilayer feedforward classifier models identified the subset of functional connections that predicted clinical diagnosis (ADHD vs. Control) and split-half performance on the Iowa Gambling Task (IGT). A sample of random models trained on functional connectivity profiles predicted validation set clinical diagnosis and IGT performance with 0.91 accuracy and d' > 2.9, indicating very high sensitivity and specificity. We identified the most diagnostic functional connections between visual and ventral attentional networks and the anterior default mode network. Our results show that task-based functional connectivity is a biomarker of ADHD. Our analytic framework provides a template approach that explicitly ties behavioral assessment measures to both clinical diagnosis, and functional connectivity. This may differentiate otherwise similar diagnoses, and promote more efficacious intervention strategies.

Modeling Response Time with Power Law Distributions.

This article overviews several contemporary models that assume power law scaling is a plausible description of the skewed right tails that are typical of response time distributions. The properties and markers of these distribution functions have implications for cognitive and neurophysiological dynamics. The power law hypothesis suggests studies should collect larger samples, and that analyses may combine individual subjects' data into a single set for a distribution-function contrasts. Techniques for contrasting response time measurements are illustrated on data from a previously published study comparing the performance of children diagnosed with dyslexia and a group of age-matched controls in flanker, color naming, word naming, and arithmetic performance.

Prodromal Alzheimer's Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task.

Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein.

Loss of function mutations in the gene ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis, the former designated as an inherited form of Parkinson's disease (PD). The function of ATP13A2 is unclear but in vitro studies indicate it is a lysosomal protein and may interact with the presynaptic protein alpha-synuclein (aSyn) and certain heavy metals. Accumulation of aSyn is a major component of lewy bodies, the pathological hallmark of PD. Atp13a2-deficient (13a2) mice develop age-dependent sensorimotor deficits, and accumulation of insoluble aSyn in the brain. To better understand the interaction between ATP13A2 and aSyn, double mutant mice with loss of Atp13a2 function combined with overexpression of human wildtype aSyn were generated. Female and male wildtype (WT), 13a2, aSyn, and 13a2-aSyn mice were tested on a battery of sensorimotor tests including adhesive removal, challenging beam traversal, spontaneous activity, gait, locomotor activity, and nest-building at 2, 4, and 6 months of age. Double mutant mice showed an earlier onset and accelerated alterations in sensorimotor function that were age, sex and test-dependent. Female 13a2-aSyn mice showed early and progressive dysfunction on the beam and in locomotor activity. In males, 13a2-aSyn mice showed more severe impairments in spontaneous activity and adhesive removal. Sex differences were also observed in aSyn and 13a2-aSyn mice on the beam, cylinder, and adhesive removal tests. In other tasks, double mutant mice displayed deficits similar to aSyn mice. These results indicate loss of Atp13a2 function exacerbates the sensorimotor phenotype in aSyn mice in an age and sex-dependent manner.

The effect of manganese exposure in Atp13a2-deficient mice.

Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn-treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo.

Long-range correlations and patterns of recurrence in children and adults' attention to hierarchical displays.

In order to make sense of a scene, a person must pay attention to several levels of nested order, ranging from the most differentiated details of the display to the integrated whole. In adults, research shows that the processes of integration and differentiation have the signature of self-organization. Does the same hold for children? The current study addresses this question with children between 6 and 9 years of age, using two tasks that require attention to hierarchical displays. A group of adults were tested as well, for control purposes. To get at the question of self-organization, reaction times were submitted to a detrended fluctuation analysis and a recurrence quantification analysis. H exponents show a long-range correlations (1/f noise), and recurrence measures (percent determinism, maximum line, entropy, and trend), show a deterministic structure of variability being characteristic of self-organizing systems. Findings are discussed in terms of organism-environment coupling that gives rise to fluid attention to hierarchical displays.

Fractal coordination in adults' attention to hierarchical visual patterns.

A display that contains hierarchically nested levels of order requires the perceiver to selectively attend to one of the levels. We investigate the degree to which such selective attention is sustained by a soft-assembled emergent coordinative process, one that does not require designated executive control. In the case of emergent soft-assembly, performance from one trial to the next should show characteristic interdependence, visible in the fractal structure of reaction time. To test this hypothesis, we asked participants across three experiments to decide whether two displays matched in a certain way (e.g., in a local element). In order to gauge this coordinative process, task constraints were experimentally manipulated (e.g., familiarity, predictability, and task instruction). Obtained reaction-time data were subjected to a spectral analysis to measure the degree of interdependence among trials. As predicted, results show correlated structure across trials, significantly different from what would be predicted by an independent-process view of selective attention. Results also show that the obtained spectral scaling exponents track the degree of coupling in the task as a function of the degree of task constraints. Findings are discussed in terms of the relative organism-environment coupling to sustain an adaptive behavior.

Dyslexic and skilled reading dynamics are self-similar.

The shape of a word pronunciation time distribution supplies information about the dynamic interactions that support reading performance. Speeded word-naming pronunciation and response time distributions were collected from 20 sixth grade Dutch students with dyslexia and 23 age-matched controls. The participants' pronunciation times were modeled and contrasted with a lognormal inverse power-law mixture distribution. Identical contrasts were also conducted on the same participants' response time distributions derived from flanker, color-naming, and arithmetic tasks. Results indicated that children with dyslexia yield slower, broader, and more variable pronunciation time distributions than their age-matched counterparts. This difference approximated a self-similar rescaling between the two group's aggregate pronunciation time distributions. Moreover, children with dyslexia produced similar, but less prominent trends toward slower and more variable performance across the three non-reading tasks. The outcomes support a proportional continuum rather than a localized deficit account of dyslexia. The mixture distribution's success at describing the participants' pronunciation and response time distributions suggests that differences in proportional contingencies among low-level neurophysiological, perceptual, and cognitive processes likely play a prominent role in the etiology of dyslexia.

Dynamic structure of joint-action stimulus-response activity.

The mere presence of a co-actor can influence an individual's response behavior. For instance, a social Simon effect has been observed when two individuals perform a Go/No-Go response to one of two stimuli in the presence of each other, but not when they perform the same task alone. Such effects are argued to provide evidence that individuals co-represent the task goals and the to-be-performed actions of a co-actor. Motivated by the complex-systems approach, the present study was designed to investigate an alternative hypothesis--that such joint-action effects are due to a dynamical (time-evolving) interpersonal coupling that operates to perturb the behavior of socially situated actors. To investigate this possibility, participants performed a standard Go/No-Go Simon task in joint and individual conditions. The dynamic structure of recorded reaction times was examined using fractal statistics and instantaneous cross-correlation. Consistent with our hypothesis that participants responding in a shared space would become behaviorally coupled, the analyses revealed that reaction times in the joint condition displayed decreased fractal structure (indicative of interpersonal perturbation processes modulating ongoing participant behavior) compared to the individual condition, and were more correlated across a range of time-scales compared to the reaction times of pseudo-pair controls. Collectively, the findings imply that dynamic processes might underlie social stimulus-response compatibility effects and shape joint cognitive processes in general.

Impaired baroreflex function in mice overexpressing alpha-synuclein.

Cardiovascular autonomic dysfunction, such as orthostatic hypotension consequent to baroreflex failure and cardiac sympathetic denervation, is frequently observed in the synucleinopathy Parkinson's disease (PD). In the present study, the baroreceptor reflex was assessed in mice overexpressing human wildtype alpha-synuclein (Thy1-aSyn), a genetic mouse model of synucleinopathy. The beat-to-beat change in heart rate (HR), computed from R-R interval, in relation to blood pressure was measured in anesthetized and conscious mice equipped with arterial blood pressure telemetry transducers during transient bouts of hypertension and hypotension. Compared to wildtype, tachycardia following nitroprusside-induced hypotension was significantly reduced in Thy1-aSyn mice. Thy1-aSyn mice also showed an abnormal cardiovascular response (i.e., diminished tachycardia) to muscarinic blockade with atropine. We conclude that Thy1-aSyn mice have impaired basal and dynamic range of sympathetic and parasympathetic-mediated changes in HR and will be a useful model for long-term study of cardiovascular autonomic dysfunction associated with PD.

A fractal approach to dynamic inference and distribution analysis.

Event-distributions inform scientists about the variability and dispersion of repeated measurements. This dispersion can be understood from a complex systems perspective, and quantified in terms of fractal geometry. The key premise is that a distribution's shape reveals information about the governing dynamics of the system that gave rise to the distribution. Two categories of characteristic dynamics are distinguished: additive systems governed by component-dominant dynamics and multiplicative or interdependent systems governed by interaction-dominant dynamics. A logic by which systems governed by interaction-dominant dynamics are expected to yield mixtures of lognormal and inverse power-law samples is discussed. These mixtures are described by a so-called cocktail model of response times derived from human cognitive performances. The overarching goals of this article are twofold: First, to offer readers an introduction to this theoretical perspective and second, to offer an overview of the related statistical methods.

The self-organization of a spoken word.

Pronunciation time probability density and hazard functions from large speeded word naming data sets were assessed for empirical patterns consistent with multiplicative and reciprocal feedback dynamics - interaction dominant dynamics. Lognormal and inverse power law distributions are associated with multiplicative and interdependent dynamics in many natural systems. Mixtures of lognormal and inverse power law distributions offered better descriptions of the participant's distributions than the ex-Gaussian or ex-Wald - alternatives corresponding to additive, superposed, component processes. The evidence for interaction dominant dynamics suggests fundamental links between the observed coordinative synergies that support speech production and the shapes of pronunciation time distributions.

Multifractal dynamics in the emergence of cognitive structure.

The complex-systems approach to cognitive science seeks to move beyond the formalism of information exchange and to situate cognition within the broader formalism of energy flow. Changes in cognitive performance exhibit a fractal (i.e., power-law) relationship between size and time scale. These fractal fluctuations reflect the flow of energy at all scales governing cognition. Information transfer, as traditionally understood in the cognitive sciences, may be a subset of this multiscale energy flow. The cognitive system exhibits not just a single power-law relationship between fluctuation size and time scale but actually exhibits many power-law relationships, whether over time or space. This change in fractal scaling, that is, multifractality, provides new insights into changes in energy flow through the cognitive system. We survey recent findings demonstrating the role of multifractality in (a) understanding atypical developmental outcomes, and (b) predicting cognitive change. We propose that multifractality provides insights into energy flows driving the emergence of cognitive structure.

Dynamics of cognition.

The application of dynamical systems methods and concepts to cognitive phenomena has broadened the range of testable hypotheses and theoretical narratives available to cognitive scientists. Most research in cognitive dynamics tests the degree to which observed cognitive performance is consistent with one or another core phenomena associated with complex dynamical systems, such as tests for phase transitions, coupling among processes, or scaling laws. Early applications of dynamical systems theory to perceptual-motor performance and developmental psychology paved the way for more recent applications of dynamical systems analyses, models, and theoretical concepts in areas such as learning, memory, speech perception, decision making, problem solving, and reading, among others. Reviews of the empirical results of both foundational and contemporary cognitive dynamics are provided. WIREs Cogn Sci 2012. doi: 10.1002/wcs.1200 For further resources related to this article, please visit the WIREs website.