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1.  Computerized Cognitive Training in Cognitively Healthy Older Adults: A Systematic Review and Meta-Analysis of Effect Modifiers 
PLoS Medicine  2014;11(11):e1001756.
Michael Valenzuela and colleagues systematically review and meta-analyze the evidence that computerized cognitive training improves cognitive skills in older adults with normal cognition.
Please see later in the article for the Editors' Summary
Background
New effective interventions to attenuate age-related cognitive decline are a global priority. Computerized cognitive training (CCT) is believed to be safe and can be inexpensive, but neither its efficacy in enhancing cognitive performance in healthy older adults nor the impact of design factors on such efficacy has been systematically analyzed. Our aim therefore was to quantitatively assess whether CCT programs can enhance cognition in healthy older adults, discriminate responsive from nonresponsive cognitive domains, and identify the most salient design factors.
Methods and Findings
We systematically searched Medline, Embase, and PsycINFO for relevant studies from the databases' inception to 9 July 2014. Eligible studies were randomized controlled trials investigating the effects of ≥4 h of CCT on performance in neuropsychological tests in older adults without dementia or other cognitive impairment. Fifty-two studies encompassing 4,885 participants were eligible. Intervention designs varied considerably, but after removal of one outlier, heterogeneity across studies was small (I2 = 29.92%). There was no systematic evidence of publication bias. The overall effect size (Hedges' g, random effects model) for CCT versus control was small and statistically significant, g = 0.22 (95% CI 0.15 to 0.29). Small to moderate effect sizes were found for nonverbal memory, g = 0.24 (95% CI 0.09 to 0.38); verbal memory, g = 0.08 (95% CI 0.01 to 0.15); working memory (WM), g = 0.22 (95% CI 0.09 to 0.35); processing speed, g = 0.31 (95% CI 0.11 to 0.50); and visuospatial skills, g = 0.30 (95% CI 0.07 to 0.54). No significant effects were found for executive functions and attention. Moderator analyses revealed that home-based administration was ineffective compared to group-based training, and that more than three training sessions per week was ineffective versus three or fewer. There was no evidence for the effectiveness of WM training, and only weak evidence for sessions less than 30 min. These results are limited to healthy older adults, and do not address the durability of training effects.
Conclusions
CCT is modestly effective at improving cognitive performance in healthy older adults, but efficacy varies across cognitive domains and is largely determined by design choices. Unsupervised at-home training and training more than three times per week are specifically ineffective. Further research is required to enhance efficacy of the intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
As we get older, we notice many bodily changes. Our hair goes grey, we develop new aches and pains, and getting out of bed in the morning takes longer than it did when we were young. Our brain may also show signs of aging. It may take us longer to learn new information, we may lose our keys more frequently, and we may forget people's names. Cognitive decline—developing worsened thinking, language, memory, understanding, and judgment—can be a normal part of aging, but it can also be an early sign of dementia, a group of brain disorders characterized by a severe, irreversible decline in cognitive functions. We know that age-related physical decline can be attenuated by keeping physically active; similarly, engaging in activities that stimulate the brain throughout life is thought to enhance cognition in later life and reduce the risk of age-related cognitive decline and dementia. Thus, having an active social life and doing challenging activities that stimulate both the brain and the body may help to stave off cognitive decline.
Why Was This Study Done?
“Brain training” may be another way of keeping mentally fit. The sale of computerized cognitive training (CCT) packages, which provide standardized, cognitively challenging tasks designed to “exercise” various cognitive functions, is a lucrative and expanding business. But does CCT work? Given the rising global incidence of dementia, effective interventions that attenuate age-related cognitive decline are urgently needed. However, the impact of CCT on cognitive performance in older adults is unclear, and little is known about what makes a good CCT package. In this systematic review and meta-analysis, the researchers assess whether CCT programs improve cognitive test performance in cognitively healthy older adults and identify the aspects of cognition (cognitive domains) that are responsive to CCT, and the CCT design features that are most important in improving cognitive performance. A systematic review uses pre-defined criteria to identify all the research on a given topic; meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 51 trials that investigated the effects of more than four hours of CCT on nearly 5,000 cognitively healthy older adults by measuring several cognitive functions before and after CCT. Meta-analysis of these studies indicated that the overall effect size for CCT (compared to control individuals who did not participate in CCT) was small but statistically significant. An effect size quantifies the difference between two groups; a statistically significant result is a result that is unlikely to have occurred by chance. So, the meta-analysis suggests that CCT slightly increased overall cognitive function. Notably, CCT also had small to moderate significant effects on individual cognitive functions. For example, some CCT slightly improved nonverbal memory (the ability to remember visual images) and working memory (the ability to remember recent events; short-term memory). However, CCT had no significant effect on executive functions (cognitive processes involved in planning and judgment) or attention (selective concentration on one aspect of the environment). The design of CCT used in the different studies varied considerably, and “moderator” analyses revealed that home-based CCT was not effective, whereas center-based CCT was effective, and that training sessions undertaken more than three times a week were not effective. There was also some weak evidence suggesting that CCT sessions lasting less than 30 minutes may be ineffective. Finally, there was no evidence for the effectiveness of working memory training by itself (for example, programs that ask individuals to recall series of letters).
What Do These Findings Mean?
These findings suggest that CCT produces small improvements in cognitive performance in cognitively healthy older adults but that the efficacy of CCT varies across cognitive domains and is largely determined by design aspects of CCT. The most important result was that “do-it-yourself” CCT at home did not produce improvements. Rather, the small improvements seen were in individuals supervised by a trainer in a center and undergoing sessions 1–3 times a week. Because only cognitively healthy older adults were enrolled in the studies considered in this systematic review and meta-analysis, these findings do not necessarily apply to cognitively impaired individuals. Moreover, because all the included studies measured cognitive function immediately after CCT, these findings provide no information about the durability of the effects of CCT or about how the effects of CCT on cognitive function translate into real-life outcomes for individuals such as independence and the long-term risk of dementia. The researchers call, therefore, for additional research into CCT, an intervention that might help to attenuate age-related cognitive decline and improve the quality of life for older individuals.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001756.
This study is further discussed in a PLOS Medicine Perspective by Druin Burch
The US National Institute on Aging provides information for patients and carers about age-related forgetfulness, about memory and cognitive health, and about dementia (in English and Spanish)
The UK National Health Service Choices website also provides information about dementia and about memory loss
MedlinePlus provides links to additional resources about memory, mild cognitive impairment, and dementia (in English and Spanish)
doi:10.1371/journal.pmed.1001756
PMCID: PMC4236015  PMID: 25405755
2.  A Common Cortical Circuit Mechanism for Perceptual Categorical Discrimination and Veridical Judgment 
PLoS Computational Biology  2008;4(12):e1000253.
Perception involves two types of decisions about the sensory world: identification of stimulus features as analog quantities, or discrimination of the same stimulus features among a set of discrete alternatives. Veridical judgment and categorical discrimination have traditionally been conceptualized as two distinct computational problems. Here, we found that these two types of decision making can be subserved by a shared cortical circuit mechanism. We used a continuous recurrent network model to simulate two monkey experiments in which subjects were required to make either a two-alternative forced choice or a veridical judgment about the direction of random-dot motion. The model network is endowed with a continuum of bell-shaped population activity patterns, each representing a possible motion direction. Slow recurrent excitation underlies accumulation of sensory evidence, and its interplay with strong recurrent inhibition leads to decision behaviors. The model reproduced the monkey's performance as well as single-neuron activity in the categorical discrimination task. Furthermore, we examined how direction identification is determined by a combination of sensory stimulation and microstimulation. Using a population-vector measure, we found that direction judgments instantiate winner-take-all (with the population vector coinciding with either the coherent motion direction or the electrically elicited motion direction) when two stimuli are far apart, or vector averaging (with the population vector falling between the two directions) when two stimuli are close to each other. Interestingly, for a broad range of intermediate angular distances between the two stimuli, the network displays a mixed strategy in the sense that direction estimates are stochastically produced by winner-take-all on some trials and by vector averaging on the other trials, a model prediction that is experimentally testable. This work thus lends support to a common neurodynamic framework for both veridical judgment and categorical discrimination in perceptual decision making.
Author Summary
In daily life, we constantly face two types of perceptual decisions: to identify an object feature (what is the speed of that car?) or to discriminate the same feature among two or more possible categories (is that car going faster than the speed limit?). These decision processes appear to involve very different computations: while identification relies on an analog judgment, categorical discrimination is based on a comparison of the object feature with discrete options. Do they engage entirely separate brain mechanisms? In this work, we showed that these two types of decision making can be instantiated by a single cortical circuit. We used a continuous recurrent network model to simulate two monkey experiments in which subjects were required to make either a two-alternative choice or a veridical judgment about the direction of random-dot motion. The model reproduced salient experimental observations and makes testable predictions. The results demonstrate that a common cortical circuit can perform both categorical discrimination and veridical judgment. Conceptually, this work supports the notion that a cortical circuit endowed with reverberatory dynamics can fulfill multiple cognitive functions such as working memory and decision making.
doi:10.1371/journal.pcbi.1000253
PMCID: PMC2596311  PMID: 19112487
3.  Better assessment of physical function: item improvement is neglected but essential 
Arthritis Research & Therapy  2009;11(6):R191.
Introduction
Physical function is a key component of patient-reported outcome (PRO) assessment in rheumatology. Modern psychometric methods, such as Item Response Theory (IRT) and Computerized Adaptive Testing, can materially improve measurement precision at the item level. We present the qualitative and quantitative item-evaluation process for developing the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function item bank.
Methods
The process was stepwise: we searched extensively to identify extant Physical Function items and then classified and selectively reduced the item pool. We evaluated retained items for content, clarity, relevance and comprehension, reading level, and translation ease by experts and patient surveys, focus groups, and cognitive interviews. We then assessed items by using classic test theory and IRT, used confirmatory factor analyses to estimate item parameters, and graded response modeling for parameter estimation. We retained the 20 Legacy (original) Health Assessment Questionnaire Disability Index (HAQ-DI) and the 10 SF-36's PF-10 items for comparison. Subjects were from rheumatoid arthritis, osteoarthritis, and healthy aging cohorts (n = 1,100) and a national Internet sample of 21,133 subjects.
Results
We identified 1,860 items. After qualitative and quantitative evaluation, 124 newly developed PROMIS items composed the PROMIS item bank, which included revised Legacy items with good fit that met IRT model assumptions. Results showed that the clearest and best-understood items were simple, in the present tense, and straightforward. Basic tasks (like dressing) were more relevant and important versus complex ones (like dancing). Revised HAQ-DI and PF-10 items with five response options had higher item-information content than did comparable original Legacy items with fewer response options. IRT analyses showed that the Physical Function domain satisfied general criteria for unidimensionality with one-, two-, three-, and four-factor models having comparable model fits. Correlations between factors in the test data sets were > 0.90.
Conclusions
Item improvement must underlie attempts to improve outcome assessment. The clear, personally important and relevant, ability-framed items in the PROMIS Physical Function item bank perform well in PRO assessment. They will benefit from further study and application in a wider variety of rheumatic diseases in diverse clinical groups, including those at the extremes of physical functioning, and in different administration modes.
doi:10.1186/ar2890
PMCID: PMC3003539  PMID: 20015354
4.  A Model for Integrating Elementary Neural Functions into Delayed-Response Behavior 
PLoS Computational Biology  2006;2(4):e25.
It is well established that various cortical regions can implement a wide array of neural processes, yet the mechanisms which integrate these processes into behavior-producing, brain-scale activity remain elusive. We propose that an important role in this respect might be played by executive structures controlling the traffic of information between the cortical regions involved. To illustrate this hypothesis, we present a neural network model comprising a set of interconnected structures harboring stimulus-related activity (visual representation, working memory, and planning), and a group of executive units with task-related activity patterns that manage the information flowing between them. The resulting dynamics allows the network to perform the dual task of either retaining an image during a delay (delayed-matching to sample task), or recalling from this image another one that has been associated with it during training (delayed-pair association task). The model reproduces behavioral and electrophysiological data gathered on the inferior temporal and prefrontal cortices of primates performing these same tasks. It also makes predictions on how neural activity coding for the recall of the image associated with the sample emerges and becomes prospective during the training phase. The network dynamics proves to be very stable against perturbations, and it exhibits signs of scale-invariant organization and cooperativity. The present network represents a possible neural implementation for active, top-down, prospective memory retrieval in primates. The model suggests that brain activity leading to performance of cognitive tasks might be organized in modular fashion, simple neural functions becoming integrated into more complex behavior by executive structures harbored in prefrontal cortex and/or basal ganglia.
Synopsis
Before we do anything, our brain must construct neural representations of the operations required. Imaging and recording techniques are indeed providing ever more detailed insight into how different regions of the brain contribute to behavior. However, it has remained elusive exactly how these various regions then come to cooperate with each other, thus organizing the brain-scale activity patterns needed for even the simplest planned tasks. In the present work, the authors propose a neural network model built around the hypothesis of a modular organization of brain activity, where relatively autonomous basic neural functions useful at a given moment are recruited and integrated into actual behavior. At the heart of the model are regulating structures that restrain information from flowing freely between the different cortical areas involved, releasing it instead in a controlled fashion able to produce the appropriate response. The dynamics of the network, simulated on a computer, enables it to pass simple cognitive tests while reproducing data gathered on primates carrying out these same tasks. This suggests that the model might constitute an appropriate framework for studying the neural basis of more general behavior.
doi:10.1371/journal.pcbi.0020025
PMCID: PMC1428791  PMID: 16604158
5.  Deciding Not to Decide: Computational and Neural Evidence for Hidden Behavior in Sequential Choice 
PLoS Computational Biology  2013;9(10):e1003309.
Understanding the cognitive and neural processes that underlie human decision making requires the successful prediction of how, but also of when, people choose. Sequential sampling models (SSMs) have greatly advanced the decision sciences by assuming decisions to emerge from a bounded evidence accumulation process so that response times (RTs) become predictable. Here, we demonstrate a difficulty of SSMs that occurs when people are not forced to respond at once but are allowed to sample information sequentially: The decision maker might decide to delay the choice and terminate the accumulation process temporarily, a scenario not accounted for by the standard SSM approach. We developed several SSMs for predicting RTs from two independent samples of an electroencephalography (EEG) and a functional magnetic resonance imaging (fMRI) study. In these studies, participants bought or rejected fictitious stocks based on sequentially presented cues and were free to respond at any time. Standard SSM implementations did not describe RT distributions adequately. However, by adding a mechanism for postponing decisions to the model we obtained an accurate fit to the data. Time-frequency analysis of EEG data revealed alternating states of de- and increasing oscillatory power in beta-band frequencies (14–30 Hz), indicating that responses were repeatedly prepared and inhibited and thus lending further support for the existence of a decision not to decide. Finally, the extended model accounted for the results of an adapted version of our paradigm in which participants had to press a button for sampling more information. Our results show how computational modeling of decisions and RTs support a deeper understanding of the hidden dynamics in cognition.
Author Summary
When decisions are made under uncertainty, we often decide not to choose immediately but to search for more information that reduces the uncertainty. In most psychological experiments, however, participants are forced to choose at once and cognitive models do not account for the possibility of deliberately delaying decisions. By modeling RT distributions in a sequential choice paradigm, we demonstrate that people decide not to decide when given the opportunity to sample more information. Importantly, this explicit decision to wait is distinguishable from an implicit delay in ongoing decisions as it actively inhibits this ongoing process. We then looked at EEG spectral power in the beta-band (frequencies from 14 to 30 Hz), which is known to reflect both the preparation and inhibition of responses. The obtained pattern is consistent with our proposal that participants repeatedly alternated between considering and postponing their decision in the sequential task. In an additional behavioral experiment, we show that our model also predicts RTs of the decision to sample more information. Hence, our combination of cognitive modeling and EEG provides converging evidence for the existence of a decision that is usually not directly observable.
doi:10.1371/journal.pcbi.1003309
PMCID: PMC3814623  PMID: 24204242
6.  Robot Cognitive Control with a Neurophysiologically Inspired Reinforcement Learning Model 
A major challenge in modern robotics is to liberate robots from controlled industrial settings, and allow them to interact with humans and changing environments in the real-world. The current research attempts to determine if a neurophysiologically motivated model of cortical function in the primate can help to address this challenge. Primates are endowed with cognitive systems that allow them to maximize the feedback from their environment by learning the values of actions in diverse situations and by adjusting their behavioral parameters (i.e., cognitive control) to accommodate unexpected events. In such contexts uncertainty can arise from at least two distinct sources – expected uncertainty resulting from noise during sensory-motor interaction in a known context, and unexpected uncertainty resulting from the changing probabilistic structure of the environment. However, it is not clear how neurophysiological mechanisms of reinforcement learning and cognitive control integrate in the brain to produce efficient behavior. Based on primate neuroanatomy and neurophysiology, we propose a novel computational model for the interaction between lateral prefrontal and anterior cingulate cortex reconciling previous models dedicated to these two functions. We deployed the model in two robots and demonstrate that, based on adaptive regulation of a meta-parameter β that controls the exploration rate, the model can robustly deal with the two kinds of uncertainties in the real-world. In addition the model could reproduce monkey behavioral performance and neurophysiological data in two problem-solving tasks. A last experiment extends this to human–robot interaction with the iCub humanoid, and novel sources of uncertainty corresponding to “cheating” by the human. The combined results provide concrete evidence for the ability of neurophysiologically inspired cognitive systems to control advanced robots in the real-world.
doi:10.3389/fnbot.2011.00001
PMCID: PMC3136731  PMID: 21808619
iCub; humanoid robot; reinforcement learning; meta-learning; bio-inspiration; prefrontal cortex
7.  Forward and Backward Inference in Spatial Cognition 
PLoS Computational Biology  2013;9(12):e1003383.
This paper shows that the various computations underlying spatial cognition can be implemented using statistical inference in a single probabilistic model. Inference is implemented using a common set of ‘lower-level’ computations involving forward and backward inference over time. For example, to estimate where you are in a known environment, forward inference is used to optimally combine location estimates from path integration with those from sensory input. To decide which way to turn to reach a goal, forward inference is used to compute the likelihood of reaching that goal under each option. To work out which environment you are in, forward inference is used to compute the likelihood of sensory observations under the different hypotheses. For reaching sensory goals that require a chaining together of decisions, forward inference can be used to compute a state trajectory that will lead to that goal, and backward inference to refine the route and estimate control signals that produce the required trajectory. We propose that these computations are reflected in recent findings of pattern replay in the mammalian brain. Specifically, that theta sequences reflect decision making, theta flickering reflects model selection, and remote replay reflects route and motor planning. We also propose a mapping of the above computational processes onto lateral and medial entorhinal cortex and hippocampus.
Author Summary
The ability of mammals to navigate is well studied, both behaviourally and in terms on the underlying neurophysiology. Navigation is a well studied topic in computational fields such as machine learning and signal processing. However, studies in computational neuroscience, which draw together these findings, have mainly focused on specific navigation tasks such as spatial localisation. In this paper, we propose a single probabilistic model which can support multiple tasks, from working out which environment you are in, to computing a sequence of motor commands that will take you to a sensory goal, such as being warm or viewing a particular object. We describe how these tasks can be implemented using a common set of lower level algorithms that implement ‘forward and backward inference over time’. We relate these algorithms to recent findings in animal electrophysiology, where sequences of hippocampal cell activations are observed before, during or after a navigation task, and these sequences are played either forwards or backwards. Additionally, one function of the hippocampus that is preserved across mammals is that it integrates spatial and non-spatial information, and we propose how the forward and backward inference algorithms naturally map onto this architecture.
doi:10.1371/journal.pcbi.1003383
PMCID: PMC3861045  PMID: 24348230
8.  The Value of Various Assessment Techniques in Detecting the Effects of Concussion on Cognition, Symptoms, and Postural Control 
Journal of Athletic Training  2009;44(6):663-665.
Abstract
Reference/Citation:
Broglio SP, Puetz TW. The effect of sport concussion on neurocognitive function, self-report symptoms, and postural control: a meta-analysis. Sports Med. 2008;38(1):53–67.
Clinical Question:
How effective are various concussion assessment techniques in detecting the effects of concussion on cognition, balance, and symptoms in athletes?
Data Sources:
Studies published between January 1970 and June 2006 were identified from the PubMed and PsycINFO databases. Search terms included concussion, mild traumatic brain injury, sport, athlete, football, soccer, hockey, boxing, cognition, cognitive impairment, symptoms, balance, and postural control. The authors also handsearched the reference list of retrieved articles and sought the opinions of experts in the field for additional studies.
Study Selection:
Studies were included if they were published in English; described a sample of athletes concussed during athletic participation; reported outcome measures of neurocognitive function, postural stability, or self-report symptoms; compared the postconcussion assessments with preseason (healthy) baseline scores or a control group; completed at least 1 postinjury assessment within the first 14 days after the concussion (to reflect neurometabolic recovery); and provided enough information for the authors to calculate effect sizes (means and SDs at baseline and postinjury time points). Selected studies were grouped according to their outcome measure (neurocognitive function, symptoms, or postural control) at initial and follow-up (if applicable) time points. Excluded articles included review articles, abstracts, case studies, editorials, articles without baseline data, and articles with data extending beyond the 14-day postinjury time frame.
Data Extraction:
From each study, the following information was extracted by one author and checked by the second author: participant demographics (sport, injury severity, incidence of loss of consciousness, and postconcussion assessment times), sample sizes, and baseline and postconcussion means and SDs for all groups. All effect sizes (the Hedge g) were computed so that decreases in neurocognitive function and postural control or increases in symptom reports resulted in negative effect sizes, demonstrating deficits in these domains after concussion. The authors also extracted the following moderators: study design (with or without control group), type of neurocognitive technique (Standardized Assessment of Concussion, computerized test, or pencil-and-paper test), postconcussion assessment time, and number of postconcussion assessments.
Main Results:
The search identified 3364 possible abstracts, which were then screened by the authors, with 89 articles being further reviewed for relevancy. Fifty articles were excluded because of insufficient data to calculate effect sizes, lack of a baseline assessment or control group, or because the data had been published in more than one study. The remaining 39 studies met all of the inclusion criteria and were used in the meta-analysis; 34 reported neurocognitive outcome measures, 14 provided self-report symptom outcomes, and 6 presented postural control as the dependent variable. The analyzed studies included 4145 total participants (concussed and control) with a mean age of 19.0 ± 0.4 years. The quality of each included study was also evaluated by each of the 2 authors independently using a previously published 15-item scale; the results demonstrated excellent agreement between the raters (intraclass correlation coefficient  =  0.91, 95% confidence interval [CI]  =  0.83, 0.95). The quality appraisal addressed randomization, sample selection, outcome measures, and statistical analysis, among other methodologic considerations. Quality scores of the included studies ranged from 5.25 to 9.00 (scored from 0–15).
The initial assessment demonstrated a deficit in neurocognitive function (Z  =  7.73, P < .001, g  =  −0.81 [95% CI  =  −1.01, −0.60]), increase in self-report symptoms (Z  =  2.13, P  =  .03, g  =  −3.31 [95% CI  =  −6.35, −0.27]), and a nonsignificant decrease in postural control (Z  =  1.29, P  =  .19, g  =  −2.56 [95% CI  =  −6.44, 1.32]).
For the follow-up assessment analyses, a decrease in cognitive function (Z  =  2.59, P  =  .001, g  =  −26 [95% CI  =  −0.46, −0.06]), an increase in self-report symptoms (Z  =  2.17, P  =  .03, g  =  −1.09 [95% CI  =  −2.07, −0.11]), and a nonsignificant decrease in postural control (Z  =  1.59, P  =  0.11, g  =  −1.16 [95% CI  =  −2.59, 0.27]) were found.
Neurocognitive and symptom outcomes variables were reported in 10 studies, and the authors were able to compare changes from baseline in these measures during the initial assessment time point. A difference in effect sizes was noted (QB(1)  =  5.28, P  =  .02), with the increases in self-report symptoms being greater than the associated deficits in neurocognitive function.
Conclusions:
Sport-related concussion had a large negative effect on cognitive function during the initial assessment and a small negative effect during the first 14 days postinjury. The largest neurocognitive effects were found with the Standardized Assessment of Concussion during the immediate assessment and with pencil-and-paper neurocognitive tests at the follow-up assessment. Large negative effects were noted at both assessment points for postural control measures. Self-report symptoms demonstrated the greatest changes of all outcomes variables, with large negative effects noted both immediately after concussion and during the follow-up assessment. These findings reiterate the recommendations made to include neurocognitive measures, postural control tests, and symptom reports into a multifaceted concussion battery to best assess these injuries.
doi:10.4085/1062-6050-44.6.663
PMCID: PMC2775369  PMID: 19911094
patient-oriented evidence; POEM; clinical outcomes; children
9.  PhyloGibbs: A Gibbs Sampling Motif Finder That Incorporates Phylogeny 
PLoS Computational Biology  2005;1(7):e67.
A central problem in the bioinformatics of gene regulation is to find the binding sites for regulatory proteins. One of the most promising approaches toward identifying these short and fuzzy sequence patterns is the comparative analysis of orthologous intergenic regions of related species. This analysis is complicated by various factors. First, one needs to take the phylogenetic relationship between the species into account in order to distinguish conservation that is due to the occurrence of functional sites from spurious conservation that is due to evolutionary proximity. Second, one has to deal with the complexities of multiple alignments of orthologous intergenic regions, and one has to consider the possibility that functional sites may occur outside of conserved segments. Here we present a new motif sampling algorithm, PhyloGibbs, that runs on arbitrary collections of multiple local sequence alignments of orthologous sequences. The algorithm searches over all ways in which an arbitrary number of binding sites for an arbitrary number of transcription factors (TFs) can be assigned to the multiple sequence alignments. These binding site configurations are scored by a Bayesian probabilistic model that treats aligned sequences by a model for the evolution of binding sites and “background” intergenic DNA. This model takes the phylogenetic relationship between the species in the alignment explicitly into account. The algorithm uses simulated annealing and Monte Carlo Markov-chain sampling to rigorously assign posterior probabilities to all the binding sites that it reports. In tests on synthetic data and real data from five Saccharomyces species our algorithm performs significantly better than four other motif-finding algorithms, including algorithms that also take phylogeny into account. Our results also show that, in contrast to the other algorithms, PhyloGibbs can make realistic estimates of the reliability of its predictions. Our tests suggest that, running on the five-species multiple alignment of a single gene's upstream region, PhyloGibbs on average recovers over 50% of all binding sites in S. cerevisiae at a specificity of about 50%, and 33% of all binding sites at a specificity of about 85%. We also tested PhyloGibbs on collections of multiple alignments of intergenic regions that were recently annotated, based on ChIP-on-chip data, to contain binding sites for the same TF. We compared PhyloGibbs's results with the previous analysis of these data using six other motif-finding algorithms. For 16 of 21 TFs for which all other motif-finding methods failed to find a significant motif, PhyloGibbs did recover a motif that matches the literature consensus. In 11 cases where there was disagreement in the results we compiled lists of known target genes from the literature, and found that running PhyloGibbs on their regulatory regions yielded a binding motif matching the literature consensus in all but one of the cases. Interestingly, these literature gene lists had little overlap with the targets annotated based on the ChIP-on-chip data. The PhyloGibbs code can be downloaded from http://www.biozentrum.unibas.ch/~nimwegen/cgi-bin/phylogibbs.cgi or http://www.imsc.res.in/~rsidd/phylogibbs. The full set of predicted sites from our tests on yeast are available at http://www.swissregulon.unibas.ch.
Synopsis
Computational discovery of regulatory sites in intergenic DNA is one of the central problems in bioinformatics. Up until recently motif finders would typically take one of the following two general approaches. Given a known set of co-regulated genes, one searches their promoter regions for significantly overrepresented sequence motifs. Alternatively, in a “phylogenetic footprinting” approach one searches multiple alignments of orthologous intergenic regions for short segments that are significantly more conserved than expected based on the phylogeny of the species.
In this work the authors present an algorithm, PhyloGibbs, that combines these two approaches into one integrated Bayesian framework. The algorithm searches over all ways in which an arbitrary number of binding sites for an arbitrary number of transcription factors can be assigned to arbitrary collections of multiple sequence alignments while taking into account the phylogenetic relations between the sequences.
The authors perform a number of tests on synthetic data and real data from Saccharomyces genomes in which PhyloGibbs significantly outperforms other existing methods. Finally, a novel anneal-and-track strategy allows PhyloGibbs to make accurate estimates of the reliability of its predictions.
doi:10.1371/journal.pcbi.0010067
PMCID: PMC1309704  PMID: 16477324
10.  Inefficient cognitive control in adult ADHD: evidence from trial-by-trial Stroop test and cued task switching performance 
Background
Contemporary neuropsychological models of ADHD implicate impaired cognitive control as contributing to disorder characteristic behavioral deficiencies and excesses; albeit to varying degrees. While the traditional view of ADHD postulates a core deficiency in cognitive control processes, alternative dual-process models emphasize the dynamic interplay of bottom-up driven factors such as activation, arousal, alerting, motivation, reward and temporal processing with top-down cognitive control. However, neuropsychological models of ADHD are child-based and have yet to undergo extensive empirical scrutiny with respect to their application to individuals with persistent symptoms in adulthood. Furthermore, few studies of adult ADHD samples have investigated two central cognitive control processes: interference control and task-set coordination. The current study employed experimental chronometric Stroop and task switching paradigms to investigate the efficiency of processes involved in interference control and task-set coordination in ADHD adults.
Methods
22 adults diagnosed with persistent ADHD (17 males) and 22 matched healthy control subjects performed a manual trial-by-trial Stroop color-word test and a blocked explicitly cued task switching paradigm. Performance differences between neutral and incongruent trials of the Stroop task measured interference control. Task switching paradigm manipulations allowed for measurement of transient task-set updating, sustained task-set maintenance, preparatory mechanisms and interference control. Control analyses tested for the specificity of group × condition interactions.
Results
Abnormal processing of task-irrelevant stimulus features was evident in ADHD group performance on both tasks. ADHD group interference effects on the task switching paradigm were found to be dependent on the time allotted to prepare for an upcoming task. Group differences in sustained task-set maintenance and transient task-set updating were also found to be dependent on experimental manipulation of task preparation processes. With the exception of Stroop task error rates, all analyses revealed generally slower and less accurate ADHD group response patterns.
Conclusion
The current data obtained with experimental paradigms deliver novel evidence of inefficient interference control and task-set coordination in adults with persistent ADHD. However, all group differences observed in these central cognitive control processes were found to be partially dependent on atypical ADHD group task preparation mechanisms and/or response inconsistency. These deficiences may have contributed not only to inefficient cognitive control, but also generally slower and less accurate ADHD group performance. Given the inability to dissociate these impairments with the current data, it remains inconclusive as to whether ineffecient cognitive control in the clinical sample was due to top-down failure or bottom-up engagement thereof. To clarify this issue, future neuropsychological investigations are encouraged to employ tasks with significantly more trials and direct manipulations of bottom-up mechanisms with larger samples.
doi:10.1186/1744-9081-3-42
PMCID: PMC1988818  PMID: 17708762
11.  Cholinesterase Inhibitors in Mild Cognitive Impairment: A Systematic Review of Randomised Trials 
PLoS Medicine  2007;4(11):e338.
Background
Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.
Methods and Findings
The terms “donepezil”, “rivastigmine”, “galantamine”, and “mild cognitive impairment” and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64–1.12), and 0.84 (0.57–1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).
Conclusions
The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.
A systematic review of trials of cholinesterase inhibitors for preventing transition of mild cognitive impairment (MCI) to dementia, conducted by Roberto Raschetti and colleagues, found no difference between treatment and control groups and concluded that uncertainty regarding the definition of MCI casts doubts on the validity of such trials.
Editors' Summary
Background.
Worldwide, more than 24 million people have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. The commonest form of dementia is Alzheimer disease (AD). The risk of developing AD increases with age—AD is rare in people younger than 65 but about half of people over 85 years old have it. The earliest symptom of AD is usually difficulty in remembering new information. As the disease progresses, patients may become confused and have problems expressing themselves. Their behavior and personality can also change. In advanced AD, patients need help with daily activities like dressing and eating, and eventually lose their ability to recognize relatives and to communicate. There is no cure for AD but a class of drugs called “cholinesterase inhibitors” can sometimes temporarily slow the worsening of symptoms. Three cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—are currently approved for use in mild-to-moderate AD.
Why Was This Study Done?
Some experts have questioned the efficacy of cholinesterase inhibitors in AD, but other experts and patient support groups have called for these drugs to be given to patients with a condition called mild cognitive impairment (MCI) as well as to those with mild AD. People with MCI have memory problems that are more severe than those normally seen in people of their age but no other symptoms of dementia. They are thought to have an increased risk of developing AD, but it is not known whether everyone with MCI eventually develops AD, and there is no standardized way to diagnose MCI. Despite these uncertainties, several clinical trials have investigated whether cholinesterase inhibitors prevent progression from MCI to AD. In this study, the researchers have assessed whether the results of these trials provide any evidence that cholinesterase inhibitors can prevent MCI progressing to AD.
What Did the Researchers Do and Find?
The researchers conducted a systematic review of the medical literature to find trials that had addressed this issue, which met criteria that they had defined clearly in advance of their search. They identified three published and five unpublished randomized controlled trials (studies in which patients randomly receive the test drug or an inactive placebo) that investigated the effect of cholinesterase inhibitors on the progression of MCI. The researchers obtained the results of six of these trials—four examined the effect of cholinesterase inhibitors on the conversion of MCI to clinically diagnosed AD or dementia (the primary end point); all six examined the effect of the drugs on several secondary end points (for example, individual aspects of cognitive function). None of the drugs produced a statistically significant difference (a difference that is unlikely to have happened by chance) in the probability of progression from MCI to AD. The only statistically significant secondary end point after adjustment for multiple comparisons (when many outcomes are considered, false positive results can occur unless specific mathematical techniques are used to prevent this problem) was a decrease in the rate of brain shrinkage associated with galantamine treatment. More patients treated with cholinesterase inhibitors dropped out of trials because of adverse effects than patients given placebo. Finally, in the one trial that reported all causes of deaths, one participant who received placebo and six who received galantamine died.
What Do These Findings Mean?
These findings suggest that the use of cholinesterase inhibitors is not associated with any delay in the onset of clinically diagnosed AD or dementia in people with MCI. They also show that the use of these drugs has no effect on most surrogate (substitute) indicators of AD but that the risks associated with their use are not negligible. However, because MCI has not yet been clearly defined as a clinical condition that precedes dementia, some (even many) of the patients enrolled into the trials that the researchers assessed may not actually have had MCI. Thus, further clinical trials are needed to clarify whether cholinesterase inhibitors can delay the progression of MCI to dementia, but these additional trials should not be done until the diagnosis of MCI has been standardized.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040338.
An essay by Matthews and colleagues, in the October 2007 issue of PLoS Medicine, discusses how mild cognitive impairment is currently diagnosed
The US Alzheimer's Association provides information about all aspects of Alzheimer disease, including fact sheets on treatments for Alzheimer disease and on mild cognitive impairment
The UK Alzheimer's Society provides information for patients and caregivers on all aspects of dementia, including drug treatments and mild cognitive impairment
The UK charity DIPEx provides short video clips of personal experiences of care givers of people with dementia
doi:10.1371/journal.pmed.0040338
PMCID: PMC2082649  PMID: 18044984
12.  A model of yeast cell-cycle regulation based on multisite phosphorylation 
Multisite phosphorylation of CDK target proteins provides the requisite nonlinearity for cell cycle modeling using elementary reaction mechanisms.Stochastic simulations, based on Gillespie's algorithm and using realistic numbers of protein and mRNA molecules, compare favorably with single-cell measurements in budding yeast.The role of transcription–translation coupling is critical in the robust operation of protein regulatory networks in yeast cells.
Progression through the eukaryotic cell cycle is governed by the activation and inactivation of a family of cyclin-dependent kinases (CDKs) and auxiliary proteins that regulate CDK activities (Morgan, 2007). The many components of this protein regulatory network are interconnected by positive and negative feedback loops that create bistable switches and transient pulses (Tyson and Novak, 2008). The network must ensure that cell-cycle events proceed in the correct order, that cell division is balanced with respect to cell growth, and that any problems encountered (in replicating the genome or partitioning chromosomes to daughter cells) are corrected before the cell proceeds to the next phase of the cycle. The network must operate robustly in the context of unavoidable molecular fluctuations in a yeast-sized cell. With a volume of only 5×10−14 l, a yeast cell contains one copy of the gene for each component of the network, a handful of mRNA transcripts of each gene, and a few hundreds to thousands of protein molecules carrying out each gene's function. How large are the molecular fluctuations implied by these numbers, and what effects do they have on the functioning of the cell-cycle control system?
To answer these questions, we have built a new model (Figure 1) of the CDK regulatory network in budding yeast, based on the fact that the targets of CDK activity are typically phosphorylated on multiple sites. The activity of each target protein depends on how many sites are phosphorylated. The target proteins feedback on CDK activity by controlling cyclin synthesis (SBF's role) and degradation (Cdh1's role) and by releasing a CDK-counteracting phosphatase (Cdc14). Every reaction in Figure 1 can be described by a mass-action rate law, with an accompanying rate constant that must be estimated from experimental data. As the transcription and translation of mRNA molecules have major effects on fluctuating numbers of protein molecules (Pedraza and Paulsson, 2008), we have included mRNA transcripts for each protein in the model.
To create a deterministic model, the rate laws are combined, according to standard principles of chemical kinetics, into a set of 60 differential equations that govern the temporal dynamics of the control system. In the stochastic version of the model, the rate law for each reaction determines the probability per unit time that a particular reaction occurs, and we use Gillespie's stochastic simulation algorithm (Gillespie, 1976) to compute possible temporal sequences of reaction events. Accurate stochastic simulations require knowledge of the expected numbers of mRNA and protein molecules in a single yeast cell. Fortunately, these numbers are available from several sources (Ghaemmaghami et al, 2003; Zenklusen et al, 2008). Although the experimental estimates are not always in good agreement with each other, they are sufficiently reliable to populate a stochastic model with realistic numbers of molecules.
By simulating thousands of cells (as in Figure 5), we can build up representative samples for computing the mean and s.d. of any measurable cell-cycle property (e.g. interdivision time, size at division, duration of G1 phase). The excellent fit of simulated statistics to observations of cell-cycle variability is documented in the main text and Supplementary Information.
Of particular interest to us are observations of Di Talia et al (2007) of the timing of a crucial G1 event (export of Whi5 protein from the nucleus) in a population of budding yeast cells growing at a specific growth rate α=ln2/(mass-doubling time). Whi5 export is a consequence of Whi5 phosphorylation, and it occurs simultaneously with the release (activation) of SBF (see Figure 1). Using fluorescently labeled Whi5, Di Talia et al could easily measure (in individual yeast cells) the time, T1, from cell birth to the abrupt loss of Whi5 from the nucleus. Correlating T1 to the size of the cell at birth, Vbirth, they found that, for a sample of daughter cells, αT1 versus ln(Vbirth) could be fit with two straight lines of slope −0.7 and −0.3. Our simulation of this experiment (Figure 7 of the main text) compares favorably with Figure 3d and e in Di Talia et al (2007).
The major sources of noise in our model (and in protein regulatory networks in yeast cells, in general) are related to gene transcription and the small number of unique mRNA transcripts. As each mRNA molecule may instruct the synthesis of dozens of protein molecules, the coefficient of variation of molecular fluctuations at the protein level (CVP) may be dominated by fluctuations at the mRNA level, as expressed in the formula (Pedraza and Paulsson, 2008) where NM, NP denote the number of mRNA and protein molecules, respectively, and ρ=τM/τP is the ratio of half-lives of mRNA and protein molecules. For a yeast cell, typical values of NM and NP are 8 and 800, respectively (Ghaemmaghami et al, 2003; Zenklusen et al, 2008). If ρ=1, then CVP≈25%. Such large fluctuations in protein levels are inconsistent with the observed variability of size and age at division in yeast cells, as shown in the simplified cell-cycle model of Kar et al (2009) and as we have confirmed with our more realistic model. The size of these fluctuations can be reduced to a more acceptable level by assuming a shorter half-life for mRNA (say, ρ=0.1).
There must be some mechanisms whereby yeast cells lessen the protein fluctuations implied by transcription–translation coupling. Following Pedraza and Paulsson (2008), we suggest that mRNA gestation and senescence may resolve this problem. Equation (3) is based on a simple, one-stage, birth–death model of mRNA turnover. In Supplementary Appendix 1, we show that a model of mRNA processing, with 10 stages each of mRNA gestation and senescence, gives reasonable fluctuations at the protein level (CVP≈5%), even if the effective half-life of mRNA is 10 min. A one-stage model with τM=1 min gives comparable fluctuations (CVP≈5%). In the main text, we use a simple birth–death model of mRNA turnover with an ‘effective' half-life of 1 min, in order to limit the computational complexity of the full cell-cycle model.
In order for the cell's genome to be passed intact from one generation to the next, the events of the cell cycle (DNA replication, mitosis, cell division) must be executed in the correct order, despite the considerable molecular noise inherent in any protein-based regulatory system residing in the small confines of a eukaryotic cell. To assess the effects of molecular fluctuations on cell-cycle progression in budding yeast cells, we have constructed a new model of the regulation of Cln- and Clb-dependent kinases, based on multisite phosphorylation of their target proteins and on positive and negative feedback loops involving the kinases themselves. To account for the significant role of noise in the transcription and translation steps of gene expression, the model includes mRNAs as well as proteins. The model equations are simulated deterministically and stochastically to reveal the bistable switching behavior on which proper cell-cycle progression depends and to show that this behavior is robust to the level of molecular noise expected in yeast-sized cells (∼50 fL volume). The model gives a quantitatively accurate account of the variability observed in the G1-S transition in budding yeast, which is governed by an underlying sizer+timer control system.
doi:10.1038/msb.2010.55
PMCID: PMC2947364  PMID: 20739927
bistability; cell-cycle variability; size control; stochastic model; transcription–translation coupling
13.  Brain Systems for Probabilistic and Dynamic Prediction: Computational Specificity and Integration 
PLoS Biology  2013;11(9):e1001662.
Using computational modelling and neuroimaging, two distinct brain systems are shown to use distinct algorithms to make parallel predictions about the environment. The predictions are then optimally combined to control behavior.
A computational approach to functional specialization suggests that brain systems can be characterized in terms of the types of computations they perform, rather than their sensory or behavioral domains. We contrasted the neural systems associated with two computationally distinct forms of predictive model: a reinforcement-learning model of the environment obtained through experience with discrete events, and continuous dynamic forward modeling. By manipulating the precision with which each type of prediction could be used, we caused participants to shift computational strategies within a single spatial prediction task. Hence (using fMRI) we showed that activity in two brain systems (typically associated with reward learning and motor control) could be dissociated in terms of the forms of computations that were performed there, even when both systems were used to make parallel predictions of the same event. A region in parietal cortex, which was sensitive to the divergence between the predictions of the models and anatomically connected to both computational networks, is proposed to mediate integration of the two predictive modes to produce a single behavioral output.
Author Summary
To interact effectively with the environment, brains must predict future events based on past and current experience. Predictions associated with different behavioural domains of the brain are often associated with different algorithmic forms. For example, whereas the motor system makes dynamic moment-by-moment predictions based on physical world models, the reward system is more typically associated with statistical predictions learned over discrete events. However, in perceptually rich natural environments, behaviour is not neatly segmented into tasks like “reward learning” and “motor control.” Instead, many different types of information are available in parallel. The brain must both select behaviourally relevant information and arbitrate between conflicting predictions. To investigate how the brain balances and integrates different types of predictive information, we set up a task in which humans predicted an object's flight trajectory by using one of two strategies: either a statistical model (based on where objects had often landed in the past) or dynamic calculation of the current flight trajectory. Using fMRI, we show that brain activity switches between different regions of the brain, depending on which predictive strategy was used, even though behavioural output remained the same. Furthermore, we found that brain regions involved in selecting actions took into account the predictions from both competing algorithms, weighting each algorithm optimally in terms of the precision with which it could predict the event of interest. Thus, these distinct brain systems compete to control predictive behaviour.
doi:10.1371/journal.pbio.1001662
PMCID: PMC3782423  PMID: 24086106
14.  Searching for the Majority: Algorithms of Voluntary Control 
PLoS ONE  2008;3(10):e3522.
Voluntary control of information processing is crucial to allocate resources and prioritize the processes that are most important under a given situation; the algorithms underlying such control, however, are often not clear. We investigated possible algorithms of control for the performance of the majority function, in which participants searched for and identified one of two alternative categories (left or right pointing arrows) as composing the majority in each stimulus set. We manipulated the amount (set size of 1, 3, and 5) and content (ratio of left and right pointing arrows within a set) of the inputs to test competing hypotheses regarding mental operations for information processing. Using a novel measure based on computational load, we found that reaction time was best predicted by a grouping search algorithm as compared to alternative algorithms (i.e., exhaustive or self-terminating search). The grouping search algorithm involves sampling and resampling of the inputs before a decision is reached. These findings highlight the importance of investigating the implications of voluntary control via algorithms of mental operations.
doi:10.1371/journal.pone.0003522
PMCID: PMC2567037  PMID: 18949039
15.  Autism spectrum disorder, but not amygdala lesions, impairs social attention in visual search 
Neuropsychologia  2014;63:259-274.
People with autism spectrum disorders (ASD) have pervasive impairments in social interactions, a diagnostic component that may have its roots in atypical social motivation and attention. One of the brain structures implicated in the social abnormalities seen in ASD is the amygdala. To further characterize the impairment of people with ASD in social attention, and to explore the possible role of the amygdala, we employed a series of visual search tasks with both social (faces and people with different postures, emotions, ages, and genders) and non-social stimuli (e.g., electronics, food, and utensils). We first conducted trial-wise analyses of fixation properties and elucidated visual search mechanisms. We found that an attentional mechanism of initial orientation could explain the detection advantage of non-social targets. We then zoomed into fixation-wise analyses. We defined target-relevant effects as the difference in the percentage of fixations that fell on target-congruent vs. target-incongruent items in the array. In Experiment 1, we tested 8 high-functioning adults with ASD, 3 adults with focal bilateral amygdala lesions, and 19 controls. Controls rapidly oriented to target-congruent items and showed a strong and sustained preference for fixating them. Strikingly, people with ASD oriented significantly less and more slowly to target-congruent items, an attentional deficit especially with social targets. By contrast, patients with amygdala lesions performed indistinguishably from controls. In Experiment 2, we recruited a different sample of 13 people with ASD and 8 healthy controls, and tested them on the same search arrays but with all array items equalized for low-level saliency. The results replicated those of Experiment 1. In Experiment 3, we recruited 13 people with ASD, 8 healthy controls, 3 amygdala lesion patients and another group of 11 controls and tested them on a simpler array. Here our group effect for ASD strongly diminished and all four subject groups showed similar target-relevant effects. These findings argue for an attentional deficit in ASD that is disproportionate for social stimuli, cannot be explained by low-level visual properties of the stimuli, and is more severe with high-load top-down task demands. Furthermore, this deficit appears to be independent of the amygdala, and not evident from general social bias independent of the target-directed search.
doi:10.1016/j.neuropsychologia.2014.09.002
PMCID: PMC4317264  PMID: 25218953
Visual search; Autism; Amygdala; Saliency; Social
16.  A search model and figure of merit for observer data acquired according to the free-response paradigm 
Physics in medicine and biology  2006;51(14):3449-3462.
Search is a basic activity that is performed routinely in many different tasks. In the context of medical imaging it involves locating lesions in images under conditions of uncertainty regarding the number and locations of lesions that may be present. A model of search is presented that applies to situations, as in the free-response paradigm, where on each image the number of normal regions that could be mistaken for lesions is unknown, and the number of observer generated localizations of suspicious regions (marks) is unpredictable. The search model is based on a two-stage model that has been proposed in the literature according to which at the first stage (the preattentive stage) the observer uses mainly peripheral vision to identify likely lesion candidates, and at the second stage the observer decides (i.e., cognitively evaluates) whether or not to report the candidates. The search model regards the unpredictable numbers of lesion and non-lesion localizations as random variables and models them via appropriate statistical distributions. The model has three parameters quantifying the lesion signal-to-noise ratio, the observer's expertise at rejecting non-lesion locations, and the observer's expertise at finding lesions. A figure-of-merit quantifying the observer's search performance is described. The search model bears a close resemblance to the initial detection and candidate analysis (IDCA) model that has been recently proposed for analyzing computer aided detection (CAD) algorithms. The ability to analytically model and quantify the search process would enable more powerful assessment and optimization of performance in these activities, which could be highly significant.
doi:10.1088/0031-9155/51/14/012
PMCID: PMC2230665  PMID: 16825742
search model; lesion localization; free-response paradigm; statistical modeling; observer performance; figure of merit
17.  Developmental Maturation of Dynamic Causal Control Signals in Higher-Order Cognition: A Neurocognitive Network Model 
PLoS Computational Biology  2012;8(2):e1002374.
Cognitive skills undergo protracted developmental changes resulting in proficiencies that are a hallmark of human cognition. One skill that develops over time is the ability to problem solve, which in turn relies on cognitive control and attention abilities. Here we use a novel multimodal neurocognitive network-based approach combining task-related fMRI, resting-state fMRI and diffusion tensor imaging (DTI) to investigate the maturation of control processes underlying problem solving skills in 7–9 year-old children. Our analysis focused on two key neurocognitive networks implicated in a wide range of cognitive tasks including control: the insula-cingulate salience network, anchored in anterior insula (AI), ventrolateral prefrontal cortex and anterior cingulate cortex, and the fronto-parietal central executive network, anchored in dorsolateral prefrontal cortex and posterior parietal cortex (PPC). We found that, by age 9, the AI node of the salience network is a major causal hub initiating control signals during problem solving. Critically, despite stronger AI activation, the strength of causal regulatory influences from AI to the PPC node of the central executive network was significantly weaker and contributed to lower levels of behavioral performance in children compared to adults. These results were validated using two different analytic methods for estimating causal interactions in fMRI data. In parallel, DTI-based tractography revealed weaker AI-PPC structural connectivity in children. Our findings point to a crucial role of AI connectivity, and its causal cross-network influences, in the maturation of dynamic top-down control signals underlying cognitive development. Overall, our study demonstrates how a unified neurocognitive network model when combined with multimodal imaging enhances our ability to generalize beyond individual task-activated foci and provides a common framework for elucidating key features of brain and cognitive development. The quantitative approach developed is likely to be useful in investigating neurodevelopmental disorders, in which control processes are impaired, such as autism and ADHD.
Author Summary
The human brain undergoes significant maturational changes between childhood and adulthood that are thought to enable increasingly sophisticated thoughts and behaviors. One of the skills that we develop over time is the ability to problem solve, which relies in turn on the ability to control our attention and successfully direct our cognitive efforts. Using a novel multi-pronged neuroimaging approach, we identify for the first time the dynamic brain systems underlying the maturation of problem solving abilities. We find that the anterior insula, part of a larger network of regions previously shown to be important for salience processing and generating influential control signals, shows weaker influences over other key brain regions important for task performance in children compared to adults. In addition, structural connections between the anterior insula and other key regions were found to be weaker in children compared to adults. Importantly, measures of causal influences between key regions could be used to predict individual differences in behavioral performance. Our study is the first to show that the anterior insula, by virtue of its dynamic influences on other key brain regions, shows developmental differences in both structural and functional connectivity, which may contribute to more mature cognitive abilities in adulthood compared to childhood.
doi:10.1371/journal.pcbi.1002374
PMCID: PMC3271018  PMID: 22319436
18.  Dynamics of the Central Bottleneck: Dual-Task and Task Uncertainty 
PLoS Biology  2006;4(7):e220.
Why is the human brain fundamentally limited when attempting to execute two tasks at the same time or in close succession? Two classical paradigms, psychological refractory period (PRP) and task switching, have independently approached this issue, making significant advances in our understanding of the architecture of cognition. Yet, there is an apparent contradiction between the conclusions derived from these two paradigms. The PRP paradigm, on the one hand, suggests that the simultaneous execution of two tasks is limited solely by a passive structural bottleneck in which the tasks are executed on a first-come, first-served basis. The task-switching paradigm, on the other hand, argues that switching back and forth between task configurations must be actively controlled by a central executive system (the system controlling voluntary, planned, and flexible action). Here we have explicitly designed an experiment mixing the essential ingredients of both paradigms: task uncertainty and task simultaneity. In addition to a central bottleneck, we obtain evidence for active processes of task setting (planning of the appropriate sequence of actions) and task disengaging (suppression of the plan set for the first task in order to proceed with the next one). Our results clarify the chronometric relations between these central components of dual-task processing, and in particular whether they operate serially or in parallel. On this basis, we propose a hierarchical model of cognitive architecture that provides a synthesis of task-switching and PRP paradigms.
The authors investigate the cognitive processes that constrain our ability to perform multiple mental tasks by clarifying the relationship between task chronometry and the dynamics of task selection.
doi:10.1371/journal.pbio.0040220
PMCID: PMC1481521  PMID: 16787105
19.  Cognitive and cognitive-motor interventions affecting physical functioning: A systematic review 
BMC Geriatrics  2011;11:29.
Background
Several types of cognitive or combined cognitive-motor intervention types that might influence physical functions have been proposed in the past: training of dual-tasking abilities, and improving cognitive function through behavioral interventions or the use of computer games. The objective of this systematic review was to examine the literature regarding the use of cognitive and cognitive-motor interventions to improve physical functioning in older adults or people with neurological impairments that are similar to cognitive impairments seen in aging. The aim was to identify potentially promising methods that might be used in future intervention type studies for older adults.
Methods
A systematic search was conducted for the Medline/Premedline, PsycINFO, CINAHL and EMBASE databases. The search was focused on older adults over the age of 65. To increase the number of articles for review, we also included those discussing adult patients with neurological impairments due to trauma, as these cognitive impairments are similar to those seen in the aging population. The search was restricted to English, German and French language literature without any limitation of publication date or restriction by study design. Cognitive or cognitive-motor interventions were defined as dual-tasking, virtual reality exercise, cognitive exercise, or a combination of these.
Results
28 articles met our inclusion criteria. Three articles used an isolated cognitive rehabilitation intervention, seven articles used a dual-task intervention and 19 applied a computerized intervention. There is evidence to suggest that cognitive or motor-cognitive methods positively affects physical functioning, such as postural control, walking abilities and general functions of the upper and lower extremities, respectively. The majority of the included studies resulted in improvements of the assessed functional outcome measures.
Conclusions
The current evidence on the effectiveness of cognitive or motor-cognitive interventions to improve physical functioning in older adults or people with neurological impairments is limited. The heterogeneity of the studies published so far does not allow defining the training methodology with the greatest effectiveness. This review nevertheless provides important foundational information in order to encourage further development of novel cognitive or cognitive-motor interventions, preferably with a randomized control design. Future research that aims to examine the relation between improvements in cognitive skills and the translation to better performance on selected physical tasks should explicitly take the relation between the cognitive and physical skills into account.
doi:10.1186/1471-2318-11-29
PMCID: PMC3147016  PMID: 21651800
20.  BRAIN ABNORMALITIES IN YOUNG ADULTS AT GENETIC RISK FOR AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: A CROSS-SECTIONAL STUDY 
The Lancet. Neurology  2012;11(12):1048-1056.
Summary
Background
We previously detected functional brain imaging abnormalities in young adults at genetic risk for late-onset Alzheimer’s disease (AD). Here, we sought to characterize structural and functional magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma biomarker abnormalities in young adults at risk for autosomal dominant early-onset AD. Biomarker measurements were characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the world’s largest known autosomal dominant early-onset AD kindred, more than two decades before the carriers’ estimated median age of 44 at the onset of mild cognitive impairment (MCI) and before their estimated age of 28 at the onset of amyloid-β (Aβ) plaque deposition.
Methods
Biomarker data for this cross-sectional study were acquired in Antioquia, Colombia between July and August, 2010. Forty-four participants from the Colombian Alzheimer’s Prevention Initiative (API) Registry had structural MRIs, functional MRIs during associative memory encoding/novel viewing and control tasks, and cognitive assessments. They included 20 mutation carriers and 24 non-carriers, who were cognitively normal, 18-26 years old and matched for their gender, age, and educational level. Twenty of the participants, including 10 mutation carriers and 10 non-carriers, had lumbar punctures and venipunctures. Primary outcome measures included task-dependent hippocampal/parahippocampal activations and precuneus/posterior cingulate deactivations, regional gray matter reductions, CSF Aβ1-42, total tau and phospho-tau181 levels, and plasma Aβ1-42 levels and Aβ1-42/Aβ1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and AD-related search regions. Cognitive and fluid biomarkers were compared using Mann-Whitney tests.
Findings
The mutation carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ε4 carriers. Compared to the non-carriers, carriers had higher CSF Aβ1-42 levels (p=0·008), plasma Aβ1-42 levels (p=0·01), and plasma Aβ1-42/Aβ1-40 ratios (p=0·001), consistent with Aβ1-42 overproduction. They also had greater hippocampal/parahippocampal activations (as low as p=0·008, after correction for multiple comparisons), less precuneus/posterior cingulate deactivations (as low as p=0·001, after correction), less gray matter in several regions (p-values <0·005, uncorrected, and corrected p=0·008 in the parietal search region), similar to findings in the later preclinical and clinical stages of autosomal dominant and late-onset AD.
Interpretation
Young adults at genetic risk for autosomal dominant AD have functional and structural MRI abnormalities, along with CSF and plasma biomarker findings consistent with Aβ1-42 over-production. While the extent to which the underlying brain changes are progressive or developmental remain to be determined, this study demonstrates the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant AD.
Funding
Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias (1115-408-20512, 1115-545-31651), National Institute on Aging (R01 AG031581, P30 AG19610, UO1 AG024904, RO1 AG025526, RF1AG041705), National Institute of Neurological Disorders and Stroke (F31-NS078786) and state of Arizona.
doi:10.1016/S1474-4422(12)70228-4
PMCID: PMC4181671  PMID: 23137948
Alzheimer’s disease; biomarkers; preclinical; early-onset; dominantly inherited; MRI; functional MRI; cerebrospinal fluid; plasma; presenilin E280A mutation; amyloid; tau; genetics; prevention
21.  Interindividual Differences in Mid-Adolescents in Error Monitoring and Post-Error Adjustment 
PLoS ONE  2014;9(2):e88957.
A number of studies have concluded that cognitive control is not fully established until late adolescence. The precise differences in brain function between adults and adolescents with respect to cognitive control, however, remain unclear. To address this issue, we conducted a study in which 185 adolescents (mean age (SD) 14.6 (0.3) years) and 28 adults (mean age (SD) 25.2 (6.3) years) performed a single task that included both a stimulus-response (S-R) interference component and a task-switching component. Behavioural responses (i.e. reaction time, RT; error rate, ER) and brain activity during correct, error and post-error trials, detected by functional magnetic resonance imaging (fMRI), were measured. Behaviourally, RT and ER were significantly higher in incongruent than in congruent trials and in switch than in repeat trials. The two groups did not differ in RT during correct trials, but adolescents had a significantly higher ER than adults. In line with similar RTs, brain responses during correct trials did not differ between groups, indicating that adolescents and adults engage the same cognitive control network to successfully overcome S-R interference or task switches. Interestingly, adolescents with stronger brain activation in the bilateral insulae during error trials and in fronto-parietal regions of the cognitive control network during post-error trials did have lower ERs. This indicates that those mid-adolescents who commit fewer errors are better at monitoring their performance, and after detecting errors are more capable of flexibly allocating further cognitive control resources. Although we did not detect a convincing neural correlate of the observed behavioural differences between adolescents and adults, the revealed interindividual differences in adolescents might at least in part be due to brain development.
doi:10.1371/journal.pone.0088957
PMCID: PMC3928333  PMID: 24558455
22.  Spatial navigation, episodic memory, episodic future thinking, and theory of mind in children with autism spectrum disorder: evidence for impairments in mental simulation? 
Frontiers in Psychology  2014;5:1411.
This study explored spatial navigation alongside several other cognitive abilities that are thought to share common underlying neurocognitive mechanisms (e.g., the capacity for self-projection, scene construction, or mental simulation), and which we hypothesized may be impaired in autism spectrum disorder (ASD). Twenty intellectually high-functioning children with ASD (with a mean age of ~8 years) were compared to 20 sex, age, IQ, and language ability matched typically developing children on a series of tasks to assess spatial navigation, episodic memory, episodic future thinking (also known as episodic foresight or prospection), theory of mind (ToM), relational memory, and central coherence. This is the first study to explore these abilities concurrently within the same sample. Spatial navigation was assessed using the “memory island” task, which involves finding objects within a realistic, computer simulated, three-dimensional environment. Episodic memory and episodic future thinking were assessed using a past and future event description task. ToM was assessed using the “animations” task, in which children were asked to describe the interactions between two animated triangles. Relational memory was assessed using a recognition task involving memory for items (line drawings), patterned backgrounds, or combinations of items and backgrounds. Central coherence was assessed by exploring differences in performance across segmented and unsegmented versions of block design. Children with ASD were found to show impairments in spatial navigation, episodic memory, episodic future thinking, and central coherence, but not ToM or relational memory. Among children with ASD, spatial navigation was found to be significantly negatively related to the number of repetitive behaviors. In other words, children who showed more repetitive behaviors showed poorer spatial navigation. The theoretical and practical implications of the results are discussed.
doi:10.3389/fpsyg.2014.01411
PMCID: PMC4256988  PMID: 25538661
autism spectrum disorder; episodic future thinking; episodic memory; mental simulation; scene construction; self-projection; spatial navigation; theory of mind
23.  Home Telemonitoring for Type 2 Diabetes 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this report is to determine whether home telemonitoring and management of blood glucose is effective for improving glycemic control in adults with type 2 diabetes.
Background
An aging population coupled with a shortage of nurses and physicians in Ontario is increasing the demand for home care services for chronic diseases, including diabetes. In recent years, there has also been a concurrent rise in the number of blood glucose home telemonitoring technologies available for diabetes management. The Canadian Diabetes Association (CDA) currently recommends self-monitoring of blood glucose for patients with type 2 diabetes, particularly for individuals using insulin. With the emergence of home telemonitoring, there is potential for improving the impact of self-monitoring by linking patients with health care professionals who can monitor blood glucose values and then provide guided recommendations remotely. The MAS has, therefore, conducted a review of the available evidence on blood glucose home telemonitoring and management technologies for type 2 diabetes.
Evidence-Based Analysis of Effectiveness
Research Question
Is home telemonitoring of blood glucose for adults with type 2 diabetes more efficacious in improving glycemic control (i.e. can it reduce HbA1c levels) in comparison to usual care?
Literature Search
Inclusion Criteria
Intervention: Must involve the frequent transmission of remotely-collected blood glucose measurements by patients to health care professionals for routine monitoring through the use of home telemonitoring technology.
Intervention: Monitoring must be combined with a coordinated management and feedback system based on transmitted data.
Control: Usual diabetes care as provided by the usual care provider (usual care largely varies by jurisdiction and study).
Population: Adults ≥18 years of age with type 2 diabetes.
Follow-up: ≥6 months.
Sample size: ≥30 patients total.
Publication type: Randomized controlled trials (RCTs), systematic reviews, and/or meta-analyses.
Publication date range: January 1, 1998 to January 31, 2009.
Exclusion Criteria
Studies with a control group other than usual care.
Studies published in a language other than English.
Studies in which there is indication that the monitoring of patients’ diabetic measurements by a health care professional(s) was not occurring more frequently in intervention patients than in control patients receiving usual care.
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and INAHTA for studies published between January 1, 2007 and January 31, 2009. The search was designed as a continuation of a search undertaken for a systematic review by the Canadian Agency for Drugs and Technologies in Health, originally encompassing studies published from 1950 up until July of 2008 and which reviewed home telemonitoring in comparison to usual care for the management of type 1 and type 2 diabetes.
Summary of Findings
A total of eight studies identified by the literature search were eligible for inclusion (one was excluded post-hoc from analysis). Studies varied considerably on characteristics of design, population, and intervention/control. Of note, few trials limited populations to type 2 diabetics only, thus trials with mixed populations (type 1 and type 2) were included, though in such cases, the majority of patients (>60%) had type 2 diabetes. No studies restricted inclusion or analyses by diabetes treatment type (i.e. populations were mixed with respect to those on insulin therapy vs. not) and studies further varied on whether intervention was provided in addition to usual care or as a replacement. Lastly, trials often included blood glucose home telemonitoring as an adjunct to other telemedicine components and thus the incremental value of adding home telemonitoring remains unclear. The overall grading of the quality of evidence was low, indicating that there is uncertainty in the findings.
Meta-analysis of the seven trials identified a moderate but significant reduction in HbA1c levels (~0.5% reduction) in favour blood glucose home telemonitoring compared to usual care for adults with type 2 diabetes). Subgroup analyses suggested differences in effect size depending on the type of intervention, however, these findings should be held under caution as the analyses were exploratory in nature and intervention components overlapped between subgroups.
Meta-Analyses of Reduction in HbA1c Values for Analyzed Studies
Conclusions
Based on low quality evidence, blood glucose home telemonitoring technologies confer a statistically significant reduction in HbA1c of ~0.50% in comparison to usual care when used adjunctively to a broader telemedicine initiative for adults with type 2 diabetes.
Exploratory analysis suggests differences in effect sizes for the primary outcome when analyzing by subgroup; however, this should only be viewed as exploratory or hypothesis-generating only.
Significant limitations and/or sources of clinical heterogeneity are present in the available literature, generating great uncertainty in conclusions.
More robust trials in type 2 diabetics only, utilizing more modern technologies, preferably performed in an Ontario or a similar setting (given the infrastructure demands and that the standard comparator is usual care), while separating out the effects of other telemedicine intervention components, are needed to clarify the effect of emerging remote blood glucose monitoring technologies.
PMCID: PMC3377533  PMID: 23074529
24.  Asenapine Effects on Cognitive and Monoamine Dysfunction Elicited by Subchronic Phencyclidine Administration 
Neuropharmacology  2011;62(3):1442-1452.
Purpose
Repeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive functions, modeling important sequelae of schizophrenia; these effects are thought to be due to a dysregulation of neurotransmission within the prefrontal cortex. Atypical antipsychotic drugs have been reported to have measurable, if incomplete, effects on cognitive dysfunction in this model, and these effects may be due to their ability to normalize a subset of the physiological deficits occurring within the prefrontal cortex. Asenapine is an atypical antipsychotic approved in the US for the treatment of schizophrenia and for the treatment, as monotherapy or adjunctive therapy to lithium or valproate, of acute manic or mixed episodes associated bipolar I disorder. To understand its cognitive and neurochemical actions more fully, we explored the effects of short- and long-term dosing with asenapine on measures of cognitive and motor function in normal monkeys and in those previously exposed for 2 weeks to PCP; we further studied the impact of treatment with asenapine on dopamine and serotonin turnover in discrete brain regions from the same cohort.
Methods
Monkeys were trained to perform reversal learning and object retrieval procedures before twice-daily administration of PCP (0.3 mg/kg intramuscular) or saline for 14 days. Tests confirmed cognitive deficits in PCP-exposed animals before beginning twice-daily administration of saline (control) or asenapine (50, 100, or 150 μg/kg, intramuscular). Dopamine and serotonin turnover were assessed in 15 specific brain regions by high-pressure liquid chromatography measures of the ratio of parent amine to its major metabolite.
Results
On average, PCP-treated monkeys made twice as many errors in the reversal task as did control monkeys. Asenapine facilitated reversal learning performance in PCP-exposed monkeys, with improvements at trend level after 1 week of administration and reaching significance after 2–4 weeks of dosing. In week 4, the improvement with asenapine 150 μg/kg (p=0.01) rendered the performance of PCP-exposed monkeys indistinguishable from that of normal monkeys without compromising fine motor function. Asenapine administration (150 μg/kg twice daily) produced an increase in dopamine and serotonin turnover in most brain regions of control monkeys and asenapine (50–150 μg/kg) increased dopamine and serotonin turnover in several brain regions of subchronic PCP-treated monkeys. No significant changes in the steady-state levels of dopamine or serotonin were observed in any brain region except for the central amygdala, in which a significant depletion of dopamine was observed in PCP-treated control monkeys; asenapine treatment reversed this dopamine depletion. A significant decrease in serotonin utilization was observed in the orbitofrontal cortex and nucleus accumbens in PCP monkeys, which may underlie poor reversal learning. In the same brain regions, dopamine utilization was not affected. Asenapine ameliorated this serotonin deficit in a dose-related manner that matched its efficacy for reversing the cognitive deficit.
Conclusions
In this model of cognitive dysfunction, asenapine produced substantial gains in executive functions that were maintained with long-term administration. The cognition-enhancing effects of asenapine and the neurochemical changes in serotonin and dopamine turnover seen in this study are hypothesized to be primarily related to its potent serotonergic and noradrenergic receptor binding properties, and support the potential for asenapine to reduce cognitive dysfunction in patients with schizophrenia and bipolar disorder.
doi:10.1016/j.neuropharm.2011.08.026
PMCID: PMC3711239  PMID: 21875607
asenapine; cognitive function; phencyclidine; primate; schizophrenia; serotonin
25.  Different impairments of semantic cognition in semantic dementia and semantic aphasia: evidence from the non-verbal domain 
Brain  2009;132(9):2593-2608.
Disorders of semantic cognition in different neuropsychological conditions result from diverse areas of brain damage and may have different underlying causes. This study used a comparative case-series design to examine the hypothesis that relatively circumscribed bilateral atrophy of the anterior temporal lobe in semantic dementia (SD) produces a gradual degradation of core semantic representations, whilst a deficit of cognitive control produces multi-modal semantic impairment in a subset of patients with stroke aphasia following damage involving the left prefrontal cortex or regions in and around the temporoparietal area; this condition, which transcends traditional aphasia classifications, is referred to as ‘semantic aphasia’ (SA). There have been very few direct comparisons of these patient groups to date and these previous studies have focussed on verbal comprehension. This study used a battery of object-use tasks to extend this line of enquiry into the non-verbal domain for the first time. A group of seven SA patients were identified who failed both word and picture versions of a semantic association task. These patients were compared with eight SD cases. Both groups showed significant deficits in object use but these impairments were qualitatively different. Item familiarity correlated with performance on object-use tasks for the SD group, consistent with the view that core semantic representations are degrading in this condition. In contrast, the SA participants were insensitive to the familiarity of the objects. Further, while the SD patients performed consistently across tasks that tapped different aspects of knowledge and object use for the same items, the performance of the SA participants reflected the control requirements of the tasks. Single object use was relatively preserved in SA but performance on complex mechanical puzzles was substantially impaired. Similarly, the SA patients were able to complete straightforward item matching tasks, such as word-picture matching, but performed more poorly on associative picture-matching tasks, even when the tests involved the same items. The two groups of patients also showed a different pattern of errors in object use. SA patients made substantial numbers of erroneous intrusions in their demonstrations, such as inappropriate object movements. In contrast, response omissions were more common in SD. This study provides converging evidence for qualitatively different impairments of semantic cognition in SD and SA, and uniquely demonstrates this pattern in a non-verbal expressive domain—object use.
doi:10.1093/brain/awp146
PMCID: PMC2766180  PMID: 19506072
semantic dementia; stroke aphasia; semantic memory; semantic cognition; non-verbal; object use

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