[Show abstract][Hide abstract] ABSTRACT: Individuals with schizophrenia display substantial neurocognitive deficits for which available treatments offer only limited
benefits. Yet, findings from studies of animals, clinical and nonclinical populations have linked neurocognitive improvements
to increases in aerobic fitness (AF) via aerobic exercise training (AE). Such improvements have been attributed to up-regulation
of brain-derived neurotrophic factor (BDNF). However, the impact of AE on neurocognition, and the putative role of BDNF, have
not been investigated in schizophrenia. Employing a proof-of-concept, single-blind, randomized clinical trial design, 33 individuals
with schizophrenia were randomized to receive standard psychiatric treatment (n = 17; “treatment as usual”; TAU) or attend a 12-week AE program (n = 16) utilizing active-play video games (Xbox 360 Kinect) and traditional AE equipment. Participants completed assessments
of AF (indexed by VO2 peak ml/kg/min), neurocognition (MATRICS Consensus Cognitive Battery), and serum-BDNF before and after and 12-week period.
Twenty-six participants (79%) completed the study. At follow-up, the AE participants improved their AF by 18.0% vs a −0.5%
decline in the TAU group (P = .002) and improved their neurocognition by 15.1% vs −2.0% decline in the TAU group (P = .031). Hierarchical multiple regression analyses indicated that enhancement in AF and increases in BDNF predicted 25.4%
and 14.6% of the neurocognitive improvement variance, respectively. The results indicate AE is effective in enhancing neurocognitive
functioning in people with schizophrenia and provide preliminary support for the impact of AE-related BDNF up-regulation on
neurocognition in this population. Poor AF represents a modifiable risk factor for neurocognitive dysfunction in schizophrenia
for which AE training offer a safe, nonstigmatizing, and side-effect-free intervention.
[Show abstract][Hide abstract] ABSTRACT: Previous reports indicate that among healthy individuals low aerobic fitness (AF) and high body-mass index (BMI) predict poor neurocognition and daily-functioning. It is unknown whether these associations extend to disorders characterized by poor neurocognition, such as schizophrenia. Therefore, we compared AF and BMI in individuals with schizophrenia and non-clinical controls, and then within the schizophrenia group we examined the links between AF, BMI, neurocognition and daily-functioning. Thirty-two individuals with schizophrenia and 64 gender- and age-matched controls completed assessments of AF (indexed by VO2max) and BMI. The former also completed measures of neurocognition, daily-functioning and physical activity. The schizophrenia group displayed significantly lower AF and higher BMI. In the schizophrenia group, AF was significantly correlated with overall neurocognition (r=0.57), along with executive functioning, working memory, social cognition, and processing speed. A hierarchical regression analysis indicated that AF accounted for 22% of the neurocognition variance. Furthermore, AF was significantly correlated with overall daily-functioning (r=0.46). In contrast, BMI displayed significant inverse correlations with neurocognition, but no associations to daily-functioning. AF was significantly correlated physical activity. The authors discuss the potential use of AF-enhancing interventions to improve neurocognitive and daily-functioning in schizophrenia, along with putative neurobiological mechanisms underlying these links, including Brain-Derived Neurotrophic Factor.
Psychiatry Research 12/2014; 220(3):784-791. DOI:10.1016/j.psychres.2014.08.052 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been challenging to identify core neurocognitive deficits that are consistent across multiple studies in patients with Obsessive Compulsive Disorder (OCD). In turn, this leads to difficulty in translating findings from human studies into animal models to dissect pathophysiology. In this article, we use primary data from a working memory task in OCD patients to illustrate this issue. Working memory deficiencies have been proposed as an explanatory model for the evolution of checking compulsions in a subset of OCD patients. However, findings have been mixed due to variability in task design, examination of spatial vs. verbal working memory, and heterogeneity in patient populations. Two major questions therefore remain: First, do OCD patients have disturbances in working memory? Second, if there are working memory deficits in OCD, do they cause checking compulsions? In order to investigate these questions, we tested 19 unmedicated OCD patients and 23 matched healthy controls using a verbal working memory task that has increased difficulty/ task-load compared to classic digit-span tasks. OCD patients did not significantly differ in their performance on this task compared to healthy controls, regardless of the outcome measure used (i.e. reaction time or accuracy). Exploratory analyses suggest that a subset of patients with predominant doubt/ checking symptoms may have decreased memory confidence despite normal performance on trials with the highest working memory load. These results suggest that other etiologic factors for checking compulsions should be considered. In addition, they serve a touchstone for discussion, and therefore help us to generate a roadmap for increasing consensus in the assessment of neurocognitive function in psychiatric disorders.
Neurobiology of Learning and Memory 06/2014; 115. DOI:10.1016/j.nlm.2014.06.011 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is characterized by an abnormal dopamine system, and dopamine blockade is the primary mechanism of antipsychotic treatment. Consistent with the known role of dopamine in reward processing, prior research has demonstrated that patients with schizophrenia exhibit impairments in reward-based learning. However, it remains unknown how treatment with antipsychotic medication impacts the behavioral and neural signatures of reinforcement learning in schizophrenia. The goal of this study was to examine whether antipsychotic medication modulates behavioral and neural responses to prediction error coding during reinforcement learning. Patients with schizophrenia completed a reinforcement learning task while undergoing functional magnetic resonance imaging. The task consisted of two separate conditions in which participants accumulated monetary gain or avoided monetary loss. Behavioral results indicated that antipsychotic medication dose was associated with altered behavioral approaches to learning, such that patients taking higher doses of medication showed increased sensitivity to negative reinforcement. Higher doses of antipsychotic medication were also associated with higher learning rates (LRs), suggesting that medication enhanced sensitivity to trial-by-trial feedback. Neuroimaging data demonstrated that antipsychotic dose was related to differences in neural signatures of feedback prediction error during the loss condition. Specifically, patients taking higher doses of medication showed attenuated prediction error responses in the striatum and the medial prefrontal cortex. These findings indicate that antipsychotic medication treatment may influence motivational processes in patients with schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: We hypothesized that semantic memory for object concepts involves both representations of visual feature knowledge in modality-specific association cortex and heteromodal regions that are important for integrating and organizing this semantic knowledge so that it can be used in a flexible, contextually appropriate manner. We examined this hypothesis in an fMRI study of mild Alzheimer's disease (AD). Participants were presented with pairs of printed words and asked whether the words matched on a given visual-perceptual feature (e.g., guitar, violin: SHAPE). The stimuli probed natural kinds and manufactured objects, and the judgments involved shape or color. We found activation of bilateral ventral temporal cortex and left dorsolateral prefrontal cortex during semantic judgments, with AD patients showing less activation of these regions than healthy seniors. Moreover, AD patients showed less ventral temporal activation than did healthy seniors for manufactured objects, but not for natural kinds. We also used diffusion-weighted MRI of white matter to examine fractional anisotropy (FA). Patients with AD showed significantly reduced FA in the superior longitudinal fasciculus and inferior frontal-occipital fasciculus, which carry projections linking temporal and frontal regions of this semantic network. Our results are consistent with the hypothesis that semantic memory is supported in part by a large-scale neural network involving modality-specific association cortex, heteromodal association cortex, and projections between these regions. The semantic deficit in AD thus arises from gray matter disease that affects the representation of feature knowledge and processing its content, as well as white matter disease that interrupts the integrated functioning of this large-scale network.
[Show abstract][Hide abstract] ABSTRACT: The concept of capacity has become increasingly important in discussions of working memory (WM), in so far as most models of WM conceptualize it as a limited-capacity mechanism for maintaining information in an active state, and as capacity estimates from at least one type of WM task-complex span-are valid predictors of real-world cognitive performance. However, the term capacity is also often used in the context of a distinct set of WM tasks, change detection, and may or may not refer to the same cognitive capability. We here develop maximum-likelihood models of capacity from each of these tasks-as well as from a third WM task that places heavy demands on cognitive control, the self-ordered WM task (SOT)-and show that the capacity estimates from change detection and complex span tasks are not correlated with each other, although capacity estimates from change detection tasks do correlate with those from the SOT. Furthermore, exploratory factor analysis confirmed that performance on the SOT and change detection load on the same factor, with performance on our complex span task loading on its own factor. These findings suggest that at least two distinct cognitive capabilities underlie the concept of WM capacity as it applies to each of these three tasks.
[Show abstract][Hide abstract] ABSTRACT: A major difference between humans and other animals is our capacity to maintain information in working memory (WM) while performing secondary tasks, which enables sustained, complex cognition. A common assumption is that the lateral prefrontal cortex (PFC) is critical for WM performance in the presence of distracters, but direct evidence is scarce. We assessed the relationship between fMRI activity and WM performance within subjects, with performance matched across distracter and no-distracter conditions. Activity in the ventrolateral PFC during WM encoding and maintenance positively predicted performance in both conditions, whereas activity in the presupplementary motor area (pre-SMA) predicted performance only under distraction. Other parts of the dorsolateral and ventrolateral PFCs predicted performance only in the no-distracter condition. These findings challenge a lateral-PFC-centered view of distracter resistance, and suggest that the lateral PFC supports a type of WM representation that is efficient for dealing with task-irrelevant input but is, nonetheless, easily disrupted by dual-task demands.
[Show abstract][Hide abstract] ABSTRACT: Orienting toward emotionally salient information can be adaptive, as when danger needs to be avoided. Consistent with this idea, research has shown that emotionally valenced information draws attention more so than does neutral information in healthy individuals. However, at times this tendency is not adaptive, and it may distract the individual from goals. People with schizophrenia (PSZ), though they frequently show deficits in attentional control, have also been shown to exhibit diminished recognition of and attention to emotional information. In the present study, we investigated how the presentation of emotionally salient information affected performance on a working memory task for PSZ and healthy controls (HC). We found that although hit rates were equal to those of HCs for PSZ, the PSZ made fewer false alarms-resulting in overall better performance-than did the HCs. Deficits in emotional processing in PSZ appear to provide an advantage to them in situations in which salient emotional information competes with active cognitive goals.
[Show abstract][Hide abstract] ABSTRACT: One of the most common deficits in patients with schizophrenia (SZ) is in working memory (WM), which has wide-reaching impacts across cognition. However, previous approaches to studying WM in SZ have used tasks that require multiple cognitive-control processes, making it difficult to determine which specific cognitive and neural processes underlie the WM impairment.
We used functional magnetic resonance imaging to investigate component processes of WM in SZ. Eighteen healthy controls (HCs) and 18 patients with SZ performed an item-recognition task that permitted separate neural assessments of 1) WM maintenance, 2) inhibition, and 3) interference control in response to recognition probes.
Before inhibitory demands, posterior ventrolateral prefrontal cortex (VLPFC), an area involved in WM maintenance, was activated to a similar degree in both HCs and patients, indicating preserved maintenance operations in SZ. When cued to inhibit items from WM, HCs showed reduced activation in posterior VLPFC, commensurate with appropriately inhibiting items from WM. However, these inhibition-related reductions were absent in patients. When later probed with items that should have been inhibited, patients showed reduced behavioral performance and increased activation in mid-VLPFC, an area implicated in interference control. A mediation analysis indicated that impaired inhibition led to increased reliance on interference control and reduced behavioral performance.
In SZ, impaired control over memory, manifested through proactive inhibitory deficits, leads to increased reliance on reactive interference-control processes. The strain on interference-control processes results in reduced behavioral performance. Thus, inhibitory deficits in SZ may underlie widespread impairments in WM and cognition.
[Show abstract][Hide abstract] ABSTRACT: Our ability to form abstract representations of objects in semantic memory is crucial to language and thought. The utility of this information relies both on the representations of sensory-motor feature knowledge stored in long-term memory and the executive processes required to retrieve, manipulate, and evaluate this semantic knowledge in a task-relevant manner. These complementary components of semantic memory can be differentially impacted by aging. We investigated semantic processing in normal aging using functional magnetic resonance imaging (fMRI). Young and older adults were asked to judge whether two printed object names match on a particular feature (for example, whether a tomato and strawberry have the same color). The task thus required both retrieval of relevant visual feature knowledge of object concepts and evaluating this information. Objects were drawn from either natural kinds or manufactured objects, and were queried on either color or shape in a factorial design. Behaviorally, all subjects performed well, but older adults could be divided into those whose performance matched that of young adults (better performers) and those whose performance was worse (poorer performers). All subjects activated several cortical regions while performing this task, including bilateral inferior and lateral temporal cortex and left frontal and prefrontal cortex. Better performing older adults showed increased overall activity in bilateral premotor cortex and left lateral occipital cortex compared to young adults, and increased activity in these brain regions relative to poorer performing older adults who also showed gray matter atrophy in premotor cortex. These findings highlight the contribution of domain-general executive processing brain regions to semantic memory, and illustrate differences in how these regions are recruited in healthy older adults.
[Show abstract][Hide abstract] ABSTRACT: Patients with Alzheimer's disease have category-specific semantic memory difficulty for natural relative to manufactured objects. We assessed the basis for this deficit by asking healthy adults and patients to judge whether pairs of words share a feature (e.g. "banana:lemon - COLOR"). In an fMRI study, healthy adults showed gray matter (GM) activation of temporal-occipital cortex (TOC) where visual-perceptual features may be represented, and prefrontal cortex (PFC) which may contribute to feature selection. Tractography revealed dorsal and ventral stream white matter (WM) projections between PFC and TOC. Patients had greater difficulty with natural than manufactured objects. This was associated with greater overlap between diseased GM areas correlated with natural kinds in patients and fMRI activation in healthy adults for natural than manufactured artifacts, and the dorsal WM projection between PFC and TOC in patients correlated only with judgments of natural kinds. Patients thus remained dependent on the same neural network as controls during judgments of natural kinds, despite disease in these areas. For manufactured objects, patients' judgments showed limited correlations with PFC and TOC GM areas activated by controls, and did not correlate with the PFC-TOC dorsal WM tract. Regions outside of the PFC-TOC network thus may help support patients' judgments of manufactured objects. We conclude that a large-scale neural network for semantic memory implicates both feature knowledge representations in modality-specific association cortex and heteromodal regions important for accessing this knowledge, and that patients' relative deficit for natural kinds is due in part to their dependence on this network despite disease in these areas.
[Show abstract][Hide abstract] ABSTRACT: Many neuroimaging studies of semantic memory have argued that knowledge of an object's perceptual properties are represented in a modality-specific manner. These studies often base their argument on finding activation in the left-hemisphere fusiform gyrus-a region assumed to be involved in perceptual processing-when the participant is verifying verbal statements about objects and properties. In this paper, we report an extension of one of these influential papers-Kan, Barsalou, Solomon, Minor, and Thompson-Schill ( 2003 )-and present evidence for an amodal component in the representation and processing of perceptual knowledge. Participants were required to verify object-property statements (e.g., "cat-whiskers?"; "bear-wings?") while they were being scanned by functional magnetic resonance imaging (fMRI). We replicated Kan et al.'s activation in the left fusiform gyrus, but also found activation in regions of left inferior frontal gyrus (IFG) and middle-temporal gyrus, areas known to reflect amodal processes or representations. Further, only activations in the left IFG, an amodal area, were correlated with measures of behavioural performance.
[Show abstract][Hide abstract] ABSTRACT: In 1918, the American philosopher and psychologist William James wrote: “Nature in her unfathomable designs had mixed us of clay and flame, of brain and mind, that the two things hang indubitably together and determine each other’s being but how or why, no mortal may ever know” (Principles of Psychology, 1918, p. 200). The study of how the brain produces thoughts and behaviors is referred to as cognitive neuroscience (CNS). CNS is defined as an interdisciplinary field that combines neuroscience and cognitive psychology. Neuroscience is the scientific study of the central nervous system. Cognitive psychology is a branch of psychology that explores human cognition (Latin cognitiōn-em, a getting to know, acquaintance, notion, knowledge [Oxford English Dictionary]), or the internal mental processes, including learning, memory (including long term and short term), perception, attention, cognitive control, language, motor control, decision making, and social cognition. CNS is devoted to understanding how the human brain supports, through neural mechanisms, these cognitive processes. For example, the “primacy effect” in memory is a cognitive phenomenon in which memory for items that appear at the beginning of a list will be better remembered than items that appear toward the middle of the list. Cognitive psychology helps us to understand why and when this phenomenon occurs: the first items are rehearsed more than the middle items because there are fewer interfering items at the beginning, and therefore the first items are encoded more strongly into long-term memory. CNS would help us to understand what brain mechanisms contribute to this phenomenon: The medial temporal lobe (an area long known to be involved in the formation of memories) is activated only for items from the beginning of the list. Thus, rather than trying to simply understand how and when a memory is formed, CNS attempts to discover how the brain allows for the formation of memories. The methods and technologies used to study these aspects of human cognition are diverse. Cognitive neuroscientists perform behavioral tests on both animals and humans inside and outside of the laboratory. Numerous types of structural brain imaging and functional brain-imaging technologies are used in CNS (for example, MRI, fMRI, EEG, PET, CAT, MEG), and researchers also employ computational modeling, genetic and candidate gene studies, and pharmacologic manipulations to better understand how the brain underlies cognitive processes. Research from numerous scientific disciplines in addition to neuroscience and cognitive psychology are also integrated into the study of CNS, including social and affective neuroscience, neurology, pharmacology, and computational neuroscience.
[Show abstract][Hide abstract] ABSTRACT: The prevailing view is that recreational methamphetamine use causes a broad range of severe cognitive deficits, despite the fact that concerns have been raised about interpretations drawn from the published literature. This article addresses an important gap in our knowledge by providing a critical review of findings from recent research investigating the impact of recreational methamphetamine use on human cognition. Included in the discussion are findings from studies that have assessed the acute and long-term effects of methamphetamine on several domains of cognition, including visuospatial perception, attention, inhibition, working memory, long-term memory, and learning. In addition, relevant neuroimaging data are reviewed in an effort to better understand neural mechanisms underlying methamphetamine-related effects on cognitive functioning. In general, the data on acute effects show that methamphetamine improves cognitive performance in selected domains, that is, visuospatial perception, attention, and inhibition. Regarding long-term effects on cognitive performance and brain-imaging measures, statistically significant differences between methamphetamine users and control participants have been observed on a minority of measures. More importantly, however, the clinical significance of these findings may be limited because cognitive functioning overwhelmingly falls within the normal range when compared against normative data. In spite of these observations, there seems to be a propensity to interpret any cognitive and/or brain difference(s) as a clinically significant abnormality. The implications of this situation are multiple, with consequences for scientific research, substance-abuse treatment, and public policy.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2011; 37(3):586-608. DOI:10.1038/npp.2011.276 · 7.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative, funded by an R13 from the National Institute of Mental Health, seeks to enhance translational research in treatment development for impaired cognition in schizophrenia by developing tools from cognitive neuroscience into useful measures of treatment effects on behavior and brain function. An initial series of meetings focused on the selection of a new set of tasks from cognitive neuroscience for the measurement of treatment effects on specific cognitive and neural systems. Subsequent validation and optimization studies are underway and a subset of validated measures with well-characterized psychometric properties will be generally available in 2011. This article describes results of the first meeting of the second phase of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia, which seeks to develop imaging biomarkers and improved animal models to enhance translational research. In this meeting, we considered issues related to the use of methods such as functional magnetic resonance imaging, electroencephalography, magnetoencephalography, and transcranial magnetic simulation as biomarkers for treatment development. We explored the biological nature of the signals measured by each method, their validity and reliability as measures of cognition-related neural activity, potential confounds related to drug effects on the signal of interest, and conceptual, methodological, and pragmatic issues related to their use in preclinical, first into human, and multicenter phase II and III studies. This overview article describes the background and goals of the meeting together with a summary of the major issues discussed in more detail in the accompanying articles appearing in this issue of Biological Psychiatry.
[Show abstract][Hide abstract] ABSTRACT: How similar are the experiences of social rejection and physical pain? Extant research suggests that a network of brain regions that support the affective but not the sensory components of physical pain underlie both experiences. Here we demonstrate that when rejection is powerfully elicited--by having people who recently experienced an unwanted break-up view a photograph of their ex-partner as they think about being rejected--areas that support the sensory components of physical pain (secondary somatosensory cortex; dorsal posterior insula) become active. We demonstrate the overlap between social rejection and physical pain in these areas by comparing both conditions in the same individuals using functional MRI. We further demonstrate the specificity of the secondary somatosensory cortex and dorsal posterior insula activity to physical pain by comparing activated locations in our study with a database of over 500 published studies. Activation in these regions was highly diagnostic of physical pain, with positive predictive values up to 88%. These results give new meaning to the idea that rejection "hurts." They demonstrate that rejection and physical pain are similar not only in that they are both distressing--they share a common somatosensory representation as well.
Proceedings of the National Academy of Sciences 03/2011; 108(15):6270-5. DOI:10.1073/pnas.1102693108 · 9.67 Impact Factor