Modality independent or modality specific? Common computations underlie confidence judgements in visual and auditory decisions.

The mechanisms that enable humans to evaluate their confidence across a range of different decisions remain poorly understood. To bridge this gap in understanding, we used computational modelling to investigate the processes that underlie confidence judgements for perceptual decisions and the extent to which these computations are the same in the visual and auditory modalities. Participants completed two versions of a categorisation task with visual or auditory stimuli and made confidence judgements about their category decisions. In each modality, we varied both evidence strength, (i.e., the strength of the evidence for a particular category) and sensory uncertainty (i.e., the intensity of the sensory signal). We evaluated several classes of computational models which formalise the mapping of evidence strength and sensory uncertainty to confidence in different ways: 1) unscaled evidence strength models, 2) scaled evidence strength models, and 3) Bayesian models. Our model comparison results showed that across tasks and modalities, participants take evidence strength and sensory uncertainty into account in a way that is consistent with the scaled evidence strength class. Notably, the Bayesian class provided a relatively poor account of the data across modalities, particularly in the more complex categorisation task. Our findings suggest that a common process is used for evaluating confidence in perceptual decisions across domains, but that the parameter settings governing the process are tuned differently in each modality. Overall, our results highlight the impact of sensory uncertainty on confidence and the unity of metacognitive processing across sensory modalities.

Distinct early and late neural mechanisms regulate feature-specific sensory adaptation in the human visual system.

A canonical feature of sensory systems is that they adapt to prolonged or repeated inputs, suggesting the brain encodes the temporal context in which stimuli are embedded. Sensory adaptation has been observed in the central nervous systems of many animal species, using techniques sensitive to a broad range of spatiotemporal scales of neural activity. Two competing models have been proposed to account for the phenomenon. One assumes that adaptation reflects reduced neuronal sensitivity to sensory inputs over time (the "fatigue" account); the other posits that adaptation arises due to increased neuronal selectivity (the "sharpening" account). To adjudicate between these accounts, we exploited the well-known "tilt aftereffect", which reflects adaptation to orientation information in visual stimuli. We recorded whole-brain activity with millisecond precision from human observers as they viewed oriented gratings before and after adaptation, and used inverted encoding modeling to characterize feature-specific neural responses. We found that both fatigue and sharpening mechanisms contribute to the tilt aftereffect, but that they operate at different points in the sensory processing cascade to produce qualitatively distinct outcomes. Specifically, fatigue operates during the initial stages of processing, consistent with tonic inhibition of feedforward responses, whereas sharpening occurs ~200 ms later, consistent with feedback or local recurrent activity. Our findings reconcile two major accounts of sensory adaptation, and reveal how this canonical process optimizes the detection of change in sensory inputs through efficient neural coding.

Does computerized cognitive training improve diabetes self-management and cognition? A randomized control trial of middle-aged and older veterans with type 2 diabetes.

AIMS: This randomized control trial compared an adaptive computerized cognitive training intervention with a non-adaptive version. The primary hypothesis predicted better diabetes self-management in type 2 diabetes patients at 6 months post-intervention than baseline in the adaptive arm, with seven secondary outcomes. METHODS: Intent-to-treat analysis of veterans without dementia aged 55+ from the Bronx, NY and Ann Arbor, MI (N = 90/per arm) used linear mixed model analyses. RESULTS: Contrary to the hypothesis, only memory showed more improvement in the adaptive arm (p < 0.01). Post-hoc analyses combined the two arms; self-management improved at six-months post-intervention (p < 0.001). Memory, executive functions/attention, prospective memory, diastolic blood pressure, and systolic blood pressure improved (p < 0.05); hemoglobin A1c and medication adherence did not improve significantly. CONCLUSIONS: The adaptive computerized cognitive training was not substantially better than non-adaptive, but may improve memory. Post-hoc results for the combined arms suggest computer-related activities may improve diabetes self-management and other outcomes for middle-aged and older patients with type 2 diabetes. Practice effects or awareness of being studied cannot be ruled out.

Spatial structure, phase, and the contrast of natural images.

The sensitivity of the human visual system is thought to be shaped by environmental statistics. A major endeavor in vision science, therefore, is to uncover the image statistics that predict perceptual and cognitive function. When searching for targets in natural images, for example, it has recently been proposed that target detection is inversely related to the spatial similarity of the target to its local background. We tested this hypothesis by measuring observers' sensitivity to targets that were blended with natural image backgrounds. Targets were designed to have a spatial structure that was either similar or dissimilar to the background. Contrary to masking from similarity, we found that observers were most sensitive to targets that were most similar to their backgrounds. We hypothesized that a coincidence of phase alignment between target and background results in a local contrast signal that facilitates detection when target-background similarity is high. We confirmed this prediction in a second experiment. Indeed, we show that, by solely manipulating the phase of a target relative to its background, the target can be rendered easily visible or undetectable. Our study thus reveals that, in addition to its structural similarity, the phase of the target relative to the background must be considered when predicting detection sensitivity in natural images.

Metformin Reduces Repeat Mild Concussive Injury Pathophysiology.

Mild traumatic brain injury (mTBI) can initiate complex pathophysiological changes in the brain. Numerous cellular and molecular mechanisms underlying these pathologic changes are altered after injury, including those involved in energy utilization, excitotoxicity, ionic disturbances, and inflammation. It is thought that targeting multiple mechanisms may be necessary to produce meaningful reductions in brain pathology and to improve outcome. Previous studies have reported that the anti-diabetic drug metformin can also affect inflammatory, cell survival, and metabolic outcomes, possibly by acting on multiple targets and/or pathways. We therefore questioned whether metformin treatment can reduce pathology after repeat mild closed head injury (rmCHI) in male C57Bl/6 mice. We found that metformin, administered acutely after each head impact, resulted in markedly reduced white matter damage, astrogliosis, loss of hippocampal parvalbumin neurons, and improved mitochondrial function. In addition, both motor and cognitive functions were significantly improved when tested after discontinuation of the treatment. These studies suggest that metformin may be beneficial as a treatment for repeat concussion.

Long-term trajectories and current BMI are associated with poorer cognitive functioning in middle-aged adults at high Alzheimer's disease risk.

INTRODUCTION: We examined relationships of body mass index (BMI) with cognition in middle-aged adults at Alzheimer's disease (AD) risk due to parental family history. METHODS: Participants are offspring of AD patients from the Israel Registry of Alzheimer's Prevention (N = 271). Linear regressions assessed associations of BMI and cognition, and whether associations differed by maternal/paternal history. Analyses of covariance examined associations of long-term trajectories of BMI with cognition. RESULTS: Higher BMI was associated with worse language (P = .045). Interactions of BMI with parental history were significant for episodic memory (P = .023), language (p = .027), working memory (P = .006), global cognition (P = .008); associations were stronger among participants with maternal history. Interactions of BMI trajectories with parental history were significant for episodic memory (P = .017), language (P = .013), working memory (P = .001), global cognition (P = .005), with stronger associations for maternal history. DISCUSSION: Higher BMI and overweight/obese trajectories were associated with poorer cognition in adults with maternal history of AD, but not those with paternal history.

Neural Perturbations Associated With Recurrent Binge Alcohol in Male and Female Rats.

BACKGROUND: Binge drinking, characterized by brief periods of high intoxication interspersed with periods of abstinence, appears to be particularly damaging to the brain. Binge drinking is increasing among American women, yet few preclinical studies have assessed sex differences in the neurobehavioral effects of binge alcohol. METHODS: Adult Long-Evans rats were administered 4 g/kg ethanol (EtOH; or an isocaloric control dose) via intragastric gavage once-weekly. Brains were collected after 3 or 8 binge doses, and immunohistochemistry for mature neurons (NeuN), microglia (Iba1), neurogenesis (DCX), and reactive astrogliosis (vimentin) performed. Stereology was used to quantify target cell populations in the hippocampus and medial prefrontal cortex (mPFC). In a separate cohort of animals, cognition (spatial navigation and reversal learning), affect (tickling-evoked ultrasonic vocalizations), and task-induced c-fos activation were assessed after 3 or 8 binge doses. RESULTS: Blood EtOH concentration did not differ significantly between females (175 ± 3.6 mg/dl) and males (180 ± 3.7 mg/dl) and did not change significantly over time, indicating that tolerance did not develop. After 3 or 8 binge doses, the number of granule neurons in the hippocampal dentate gyrus of both sexes was significantly reduced in comparison with controls, although there was no binge effect on newly generated neurons. Moreover, 8 (but not 3) binge doses significantly increased the total number of microglia and the number of partially activated microglia in the hippocampus and mPFC in both sexes. There was no detectable reactive astrogliosis (vimentin) in either region at any timepoint. There was no effect of binge alcohol on behavior outcomes in either sex, but binged rats showed increased cellular activation in the mPFC following reversal learning. CONCLUSIONS: Our data indicate that recurrent binge alcohol results in similar neural damage and neuroimmune activation in alcohol-vulnerable corticolimbic brain regions in males and females.

Higher BMI is associated with smaller regional brain volume in older adults with type 2 diabetes.

AIMS/HYPOTHESIS: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes. METHODS: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories-'normal', 'overweight' and 'obese'-using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64-84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n = 198). RESULTS: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r = -0.25, p = 0.001) and the middle temporal gyrus (r = -0.19; p = 0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F = 4.34, p = 0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes. CONCLUSIONS/INTERPRETATION: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted. Graphical abstract.

Short-term computerized cognitive training does not improve cognition compared to an active control in non-demented adults aged 80 years and above.

BACKGROUND: Older adults, especially those above age 80, are the fastest growing segment of the population in the United States and at risk for age-related cognitive decline and dementia. There is growing evidence that cognitive activity and training may allow adults to maintain or improve cognitive functioning, but little is known about the potential benefit in the oldest old. In this randomized trial, the effectiveness of a computerized cognitive training program (CCT program) was compared to an active control games program to improve cognition in cognitively normal individuals aged 80 and older. METHODS: Sixty-nine older adults were randomized to a 24-session CCT program (n = 39) or an active control program (n = 30). Participants completed a pre- and post- training neuropsychological assessment. The primary outcome measure was a global cognitive composite, and the secondary outcomes were the scores on specific cognitive domains (of memory, executive function/attention, and language). RESULTS: Using linear mixed models, there were no significant differences between the CCT and the active control program on the primary (p = 0.662) or any of the secondary outcomes (language functioning, p = .628; attention/executive functioning, p = .428; memory, p = .749). CONCLUSION: This study suggests that short-term CCT had no specific benefit for cognitive functioning in non-demented individuals aged 80 and older.

Exercise-driven restoration of the alcohol-damaged brain.

There are vast literatures on the neural effects of alcohol and the neural effects of exercise. Simply put, exercise is associated with brain health, alcohol is not, and the mechanisms by which exercise benefits the brain directly counteract the mechanisms by which alcohol damages it. Although a degree of brain recovery naturally occurs upon cessation of alcohol consumption, effective treatments for alcohol-induced brain damage are badly needed, and exercise is an excellent candidate from a mechanistic standpoint. In this chapter, we cover the small but growing literature on the interactive neural effects of alcohol and exercise, and the capacity of exercise to repair alcohol-induced brain damage. Increasingly, exercise is being used as a component of treatment for alcohol use disorders (AUD), not because it reverses alcohol-induced brain damage, but because it represents a rewarding, alcohol-free activity that could reduce alcohol cravings and improve comorbid conditions such as anxiety and depression. It is important to bear in mind, however, that multiple studies attest to a counterintuitive positive relationship between alcohol intake and exercise. We therefore conclude with cautionary notes regarding the use of exercise to repair the brain after alcohol damage.

Recruitment of Older Veterans with Diabetes Risk for Alzheimer's Disease for a Randomized Clinical Trial of Computerized Cognitive Training.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent in the general United States population, and in the veteran population. T2DM has consistently been linked to increased risk for cognitive impairment, dementia, and Alzheimer's disease. Computerized cognitive training (CCT) is practical and inexpensive cognitive interventions that is an alternative to medication. OBJECTIVE: To report the recruitment methods and challenges to date in an ongoing two-site randomized controlled trial (RCT) of CCT on cognitive function and T2DM management in an older non-demented veteran population. METHODS: Veterans are recruited primarily by targeted mailings or by direct contact at clinics and presentations. RESULTS: From 1,459 original contacts, 437 expressed initial interest, 111 provided informed consent, and 97 completed baseline assessments. Participants from the two VA Medical Centers differed in demographics and baseline characteristics. Comparing recruitment methods, the proportion of individuals contacted who were ultimately consented was significantly less from mailings (5%) than other sources (20%), primarily face- to-face clinic visits (χ2 (1) = 38.331, p < 0.001). CONCLUSIONS: Mailings are cost-effective, but direct contact improved recruitment. Not using or lacking access to computers and ineligibility were major reasons for non-participation. Within-site comparisons of demographically diverse sites can address confounding of demographic and other site differences.

Recurrent binge ethanol is associated with significant loss of dentate gyrus granule neurons in female rats despite concomitant increase in neurogenesis.

Binge drinking is becoming increasingly common among American women and girls. We have previously shown significant cell loss, downregulation of neurotrophins and microgliosis in female rats after a single 4-day ethanol exposure. To determine whether recurrent binge exposure would produce similar effects, we administered ethanol (5 g/kg) or iso-caloric control diet once-weekly for 11 weeks to adult female rats. As we have previously shown exercise neuroprotection against binge-induced damage, half the rats were given access to exercise wheels. Blood ethanol concentration (BEC) did not differ between sedentary and exercised groups, nor did it change across time. Using stereology, we quantified the number and/or size of neurons in the medial prefrontal cortex (mPFC) and hippocampal dentate gyrus (DG), as well as the number and activation state of microglia. Binged sedentary rats had significant cell loss in the dentate gyrus, but exercise eliminated this effect. Compared to sedentary controls, sedentary binged rats and all exercised rats showed increased neurogenesis in the DG. Number and nuclear volume of neurons in the mPFC were not changed. In the hippocampus and mPFC, the number of microglia with morphology indicative of partial activation was increased by recurrent binge ethanol and decreased by exercise. In summary, we show significant binge-induced loss of DG granule neurons despite increased neurogenesis, suggesting an unsuccessful compensatory response. Although exercise eliminated cell loss, our results indicate that infrequent, but recurrent exposure to clinically relevant BEC is neurotoxic.

Age Modulates the Association of Caffeine Intake With Cognition and With Gray Matter in Elderly Diabetics.

BACKGROUND: The association between caffeine and cognitive performance has not been tested in older individuals with type 2 diabetes (T2D). Its association with brain volume in T2D has been tested only in animals. METHODS: We examined the association of caffeine with cognitive function and brain volume in a sample of elderly diabetics participating in the Israel Diabetes and Cognitive Decline Study (n = 638) and the moderating effect of age on this association. In a subsample (n = 185) with magnetic resonance imaging, we also examined these associations with gray and white matter volumes (GM/WM). RESULTS: Using linear regression adjusting for cognition-related covariates, we found that higher caffeine intake was associated with better function in overall cognition (p = .018), attention/working memory (p = .002), executive functioning (p = .047), and semantic categorization (p = .026). Interaction analyses of caffeine intake with age were significant for semantic categorization (p = .025), and approached significance for overall cognition (p = .066). This association was driven by the older group (above-median) for whom the association of caffeine intake with semantic categorization (p = .001), attention/working memory (p = .007), executive functioning (p = .005), and overall cognition (p = .002) were significant. In the magnetic resonance imaging subsample, there was an interaction (p = .034) of caffeine intake with age for GM volume; in the older group, higher caffeine intake was associated with greater GM volume (ß = .198, p = .033). CONCLUSIONS: Caffeine intake may have a beneficial role in cognitive functioning of elderly adults with T2D, which may be moderated by age. Greater GM volume may be a mechanism underlying the association of higher caffeine intake with better cognitive function.

Associations of hemoglobin A1c with cognition reduced for long diabetes duration.

INTRODUCTION: Associations of some risk factors with poor cognition, identified prior to age 75, are reduced or reversed in very old age. The Protected Survivor Model predicts this interaction due to enhanced survival of those with extended risk factor duration. In a younger sample, this study examines the association of cognition with the mean hemoglobin A1c risk factor over the time at risk, according to its duration. METHODS: The interaction of mean hemoglobin A1c (average = 9.8%), evaluated over duration (average = 116.8 months), was examined for overall cognition and three cognitive domains in a sample of 150 "young-old" veterans (mean age = 70) with type 2 diabetes. RESULTS: The predicted interactions were significant for overall cognition and attention, but not executive functions/language and memory. DISCUSSION: Findings extend the Protected Survivor Model to a "young-old" sample, from the very old. This model suggests focusing on individuals with good cognition despite prolonged high risk when seeking protective factors.

Binge ethanol effects on prefrontal cortex neurons, spatial working memory and task-induced neuronal activation in male and female rats.

Excessive alcohol intake is associated with a multitude of health risks, especially for women. Recent studies in animal models indicate that the female brain is more negatively affected by alcohol, compared to the male brain. Among other regions, excessive alcohol consumption damages the frontal cortex, an area important for many functions and decision making of daily life. The objective of the present study was to determine whether the medial prefrontal cortex (mPFC) in female rats is selectively vulnerable to alcohol-induced damage. In humans, loss of prefrontal grey matter resulting from heavy alcohol consumption has been documented, however this volume loss is not necessarily due to a decrease in the number of neurons. We therefore quantified both number and nuclear volume of mPFC neurons following binge alcohol, as well as performance and neuronal activation during a prefrontal-dependent behavioral task. Adult male and female Long-Evans rats were assigned to binge or control groups and exposed to ethanol using a well-established 4-day model of alcohol-induced neurodegeneration. Both males and females had significantly smaller average neuronal nuclei volumes than their respective control groups immediately following alcohol binge, but neither sex showed a decrease in neuron number. Binged rats of both sexes initially showed spatial working memory deficits. Although they eventually achieved control performance, binged rats of both sexes showed increased c-Fos labeling in the mPFC during rewarded alternation, suggesting decreased neural efficiency. Overall, our results substantiate prior evidence indicating that the frontal cortex is vulnerable to alcohol, but also indicate that sex-specific vulnerability to alcohol may be brain region-dependent.

Waist circumference is correlated with poorer cognition in elderly type 2 diabetes women.

INTRODUCTION: Waist circumference is associated with type 2 diabetes (T2D) and cognition, yet the relationship between waist circumference and cognition in individuals with T2D is not well understood. METHODS: We studied the relationship of waist circumference with five cognitive outcomes (executive functioning, language/semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 845 cognitively normal elderly with type 2 diabetes (T2D). RESULTS: In women, waist circumference was correlated with significantly lower language and/or semantic categorization performance (P < .0001), executive functioning (P = .026), and overall cognition (P = .003) after controlling for age, education, BMI, and cardiovascular, diabetes-related, APOE ε4, and inflammatory potential confounders. Attention/working memory (P = .532) and episodic memory (P = .144) were not associated with waist circumference. These correlations were not found in men. DISCUSSION: These results suggest that central adiposity in elderly women with T2D may increase their risk for dementia.

Shorter adult height is associated with poorer cognitive performance in elderly men with type II diabetes.

We studied the relationship of adult body height with five cognitive outcomes (executive functioning, semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 897 cognitively normal elderly with type 2 diabetes. Regression analyses controlling for sociodemographic, cardiovascular, and diabetes-related risk factors and depression demonstrated that in males, shorter stature was associated with poorer executive functioning (p = 0.001), attention/working memory (p = 0.007), and overall cognition (p = 0.016), but not with episodic memory (p = 0.715) or semantic categorization (p = 0.948). No relationship between height and cognition was found for females. In cognitively normal type 2 diabetes male subjects, shorter stature, a surrogate for early-life stress and poor nutrition, was associated with cognitive functions.

Dietary advanced glycation end products are associated with decline in memory in young elderly.

We recently reported that serum methylglyoxal (sMG) is associated with a faster rate of decline in a global measure of cognition in the very elderly. We here provide for the first time evidence in which high levels of dietary AGE (dAGE) are associated with faster rate of decline in memory in 49 initially non-demented young elderly (p=0.012 in mixed regression models adjusting for sociodemographic and cardiovascular factors). Since modifying the levels of AGEs in the diet may be relatively easy, these preliminary results suggest a simple strategy to diminish cognitive compromise in the elderly and warrant further investigation.

The association of duration of type 2 diabetes with cognitive performance is modulated by long-term glycemic control.

OBJECTIVES: It is unclear why duration of type 2 diabetes (T2D) is associated with increased cognitive compromise. High hemoglobin A1c (HbA1c) has also been associated with dementia, and is the primary contributor to T2D complications. Here we investigated whether the association of duration of T2D with cognitive functioning is modulated by HbA1C levels. METHODS: This study examined nondemented community-dwelling T2D elderly (N = 897) participating in the Israel Diabetes and Cognitive Decline study, who were assessed with a broad neuropsychological battery. Subjects were all from the Maccabi Healthcare Services, which has a Diabetes Registry with complete HbA1c measurements since 1998. Partial correlations were performed to examine the modulating effect of HbA1c on the relationship of duration of T2D with five cognitive measures, controlling for sociodemographic and cardiovascular risk factors. RESULTS: An interaction of duration of T2D with HbA1c was associated with executive functioning (p = 0.006), semantic categorization (p = 0.019), attention/working memory (p = 0.011), and overall cognition (p = 0.006), such that the associations between duration of T2D and cognitive impairment increased as HbA1c levels increased-but not for episodic memory (p = 0.984). CONCLUSIONS: Because duration of T2D was associated with cognition in higher HbA1c levels and overall no associations were found in lower HbA1c levels, our results suggest that individuals with T2D may limit their risk of future cognitive decline by maintaining long-term good glycemic control.