Cognitive reserve, broadly conceived, encompasses aspects of brain structure and function that optimize individual performance in the presence of injury or pathology. Reserve is defined as a feature of brain structure and/or function that modifies the relationship between injury or pathology and performance on neuropsychological tasks or clinical outcomes. Reserve is challenging to study for two reasons. The first is: reserve is a hypothetical construct, and direct measures of reserve are not available. Proxy variables and latent variable models are used to attempt to operationalize reserve. The second is: in vivo measures of neuronal pathology are not widely available. It is challenging to develop and test models involving a risk factor (injury or pathology), a moderator (reserve) and an outcome (performance or clinical status) when neither the risk factor nor the moderator are measured directly. We discuss approaches for quantifying reserve with latent variable models, with emphasis on their application in the analysis of data from observational studies. Increasingly latent variable models are used to generate composites of cognitive reserve based on multiple proxies. We review the theoretical and ontological status of latent variable modeling approaches to cognitive reserve, and suggest research strategies for advancing the field. (JINS, 2011, 17, 593–601)

Schizophrenia is associated with executive dysfunction. Yet, the degree to which executive functions are impaired differentially, or above and beyond underlying basic cognitive processes is less clear. Participants included 145 matched pairs of individuals with schizophrenia (SCs) and normal comparison subjects (NCs). Executive functions were assessed with 10 tasks of the Delis-Kaplan Executive Function System (D-KEFS), in terms of “achievement scores” reflecting overall performance on the task. Five of these tasks (all measuring executive control) were further examined in terms of their basic component (e.g., processing speed) scores and contrast scores (reflecting residual higher order skills adjusted for basic component skills). Group differences were examined via multivariate analysis of variance. SCs had worse performance than NCs on all achievement scores, but the greatest SC-NC difference was that for the Trails Switching task. SCs also had worse performance than NCs on all basic component skills. Of the executive control tasks, only Trails Switching continued to be impaired after accounting for impairments in underlying basic component skills. Much of the impairment in executive functions in schizophrenia may reflect the underlying component skills rather than higher-order functions. However, the results from one task suggest that there might be additional impairment in some aspects of executive control. (JINS, 2010, 17, 000–000)

The performance of 65 patients with complicated mild–severe traumatic brain injury was evaluated on the Verbal and Design Fluency subtests of the Delis-Kaplan Executive Function System (D-KEFS), and compared with that of 65 demographically matched healthy controls. There were statistically significant group differences on Letter Fluency and Category Switching but not on any of the Design Fluency tasks. Combined, these two Verbal Fluency subtests had a classification accuracy of 65.39%, associated with a likelihood ratio of 1.87. The impact of length of coma on Letter Fluency performance but not Category Switching was mediated at least in part by processing speed. The findings suggest modest criterion validity of some of the D–KEFS Verbal Fluency subtests in the assessment of patients with complicated mild–severe traumatic brain injury. (JINS, 2011, 17, 230–237)

Poor functional status and high rates of anxiety and depression have been reported in individuals who have sustained a traumatic brain injury (TBI). However, it is unclear whether psychiatric disorders after TBI are a cause or a consequence of functional limitations. The current study aimed to investigate the temporal relationship between anxiety, depression and functional impairment following TBI. The study has a prospective, longitudinal single-group design. Anxiety and depression, assessed using the Structured Clinical Interview for DSM-IV, and functional changes, assessed with the Glasgow Outcome Scale—Extended, were measured six and 12 months post-injury in 122 individuals who had sustained a TBI (79% male, mean age 35 years, mean duration of post-traumatic amnesia 24 days, mean Glasgow Coma Scale score 9.2). Cross-lagged analyses were conducted within a structural equation modelling framework. Functional changes six months post-injury predicted depression and anxiety one year after the injury. Anxiety and depression, in turn, were not predictive of later functional status. This study adds to our understanding of the temporal relationship between depression, anxiety and functional status after TBI. The results indicate the importance of supporting brain injured individuals in coping with the functional consequences of their injury in order promote psychological well-being. (JINS, 2011, 17, 781–787)

Individuals suffering from Huntington's disease (HD) have been shown to present with poor self-awareness of a variety of symptoms. The aim of this study was to better assess the self-awareness of motor symptoms and activities of daily living (ADL) impairment in HD, in comparison to Parkinson's disease (PD) and cervical dystonia (CD). In particular, the anosognosia/anosodiaphoria of involuntary movements has been investigated. Self-awareness was tested in 23 patients with HD by comparing patient and caregiver ratings in reference to clinical control groups (25 PD with dyskinesias, PDdys; 21 PD without dyskinesias, PDndys; and 20 with CD). Patients were assessed neurologically by relevant rating scales. Self-awareness was tested using a scale based on 15 films demonstrating 3 types of motor symptoms (chorea/dyskinesias, parkinsonism, torticollis) as well as the Self-Assessment Parkinson's Disease Disability Scale. General cognitive status, verbal learning, cognitive control, and mood were also analyzed. Our results indicate that self-awareness of choreic movements was affected more severely in HD than in PDdys, despite comparable cognitive status. Patient–proxy agreement on ADL impairment was roughly similar in all clinical groups. The results are discussed in the context of orbitofrontal–limbic pathology as a potential trigger of anosognosia/anosodiaphoria in individuals with HD. (JINS, 2011, 17, 788–795)

We report the heritability of response inhibition, latency, and variability, which are potential markers of genetic risk in neuropsychiatric conditions. Genetic and environmental influences on cancellation and restraint, response latency, and variability measured in a novel variant of the stop signal task were studied in 139 eight-year-old twin pairs from a birth cohort. Cancellation (50%), restraint (27%), and response latency (41%) showed significant heritability, the balance being non-shared environmental influences and/or error. Response variability was not heritable, with 23% of the variance attributable to shared environmental influences and 77% to non-shared environmental risk or error. The phenotypic correlation between response cancellation and restraint was −.44 and between response latency and restraint was .21. These phenotypic correlations were entirely genetic in origin. The phenotypic correlation between response variability and % successful inhibition was .27, but was not genetic. Cancellation and restraint were heritable and shared genetic influences, indicating that they may be influenced by a common gene or genes. Response latency was moderately heritable and shared genetic influences with restraint, but was not correlated with cancellation. Response variability was not heritable. These results support the potential of response inhibition and latency as endophenotypes in genetic research. (JINS, 2011, 17, 238–247)

A growing number of schools have increasingly de-emphasized the importance of providing physical activity opportunities during the school day, despite emerging research that illustrates the deleterious relationship between low levels of aerobic fitness and neurocognition in children. Accordingly, a brief review of studies that link fitness-related differences in brain structure and brain function to cognitive abilities is provided herein. Overall, the extant literature suggests that childhood aerobic fitness is associated with higher levels of cognition and differences in regional brain structure and function. Indeed, it has recently been found that aerobic fitness level even predicts cognition over time. Given the paucity of work in this area, several avenues for future investigations are also highlighted. (JINS, 2011, 17, 975–985)

Traumatic axonal injury (TAI) is a common mechanism of traumatic brain injury not readily identified using conventional neuroimaging modalities. Novel imaging modalities such as diffusion tensor imaging (DTI) can detect microstructural compromise in white matter (WM) in various clinical populations including TAI. DTI-derived data can be analyzed using global methods (i.e., WM histogram or voxel-based approaches) or a regional approach (i.e., tractography). While each of these methods produce qualitatively comparable results, it is not clear which is most useful in clinical research and ultimately in clinical practice. This study compared three methods of analyzing DTI-derived data with regard to detection of WM injury and their association with clinical outcomes. Thirty patients with TAI and 19 demographically similar normal controls were scanned using a 3 Tesla magnet. Patients were scanned approximately eight months postinjury, and underwent an outcomes assessment at that time. Histogram analysis of fractional anisotropy (FA) and mean diffusivity showed global WM integrity differences between patients and controls. Voxel-based and tractography analyses showed significant decreases in FA within centroaxial structures involved in TAI. All three techniques were associated with functional and cognitive outcomes. DTI measures of microstructural integrity appear robust, as the three analysis techniques studied showed adequate utility for detecting WM injury. (JINS, 2011, 17, 000–000)

Studies of neuropathology-cognition associations are not common and have been limited by small sample sizes, long intervals between autopsy and cognitive testing, and lack of breadth of neuropathology and cognition variables. This study examined domain-specific effects of common neuropathologies on cognition using data (N = 652) from two large cohort studies of older adults. We first identified dimensions of a battery of 17 neuropsychological tests, and regional measures of Alzheimer’s disease (AD) neuropathology. We then evaluated how cognitive factors were related to dimensions of AD and additional measures of cerebrovascular and Lewy Body disease, and also examined independent effects of brain weight. All cognitive domains had multiple neuropathology determinants that differed by domain. Neocortical neurofibrillary tangles were the strongest predictors of most domains, while medial temporal tangles showed a weaker relationship with episodic memory. Neuritic plaques had relatively strong effects on multiple domains. Lewy bodies and macroscopic infarcts were associated with all domains, while microscopic infarcts had more limited associations. Brain weight was related to all domains independent of specific neuropathologies. Results show that cognition is complexly determined by multiple disease substrates. Neuropathological variables and brain weight contributed approximately a third to half of the explained variance in different cognitive domains. (JINS, 2011, 17, 602–614).

This study characterized the relationship between apolipoprotein E (APOE) status and residual semantic abilities in amnestic mild cognitive impairment (MCI). APOE status (ε4 carrier/non ε4 carrier) was determined in 30 amnestic MCIs and in 22 healthy matched non ε4 carrier controls. The lexical characteristics (age of acquisition, typicality, familiarity) of words produced in a category fluency task were determined. MCIs produced fewer words than controls and these were also earlier acquired and more familiar. The words produced by MCI ε4 carriers were earlier acquired than those of non ε4 carriers. Analyses limited to the first 10 words produced by patients and controls showed similar findings and also revealed that MCI subgroups retrieved first more typical words than controls. Follow up showed higher conversion to Alzheimer's disease (AD) in MCI ε4 carriers than in non ε4 carriers. These findings show that a significant proportion of phenotype variability in performance on category fluency in people at increased AD risk is influenced by genetic factors. These findings explain why category fluency deficits, together with episodic memory deficits, are the only consistent early deficits in MCI patients who convert to AD. (JINS, 2011, 17, 423–430)

Individuals with schizophrenia demonstrate episodic memory (EM) deficits and abnormal EM-related brain activity. Experimental encoding manipulations significantly benefit memory performance in schizophrenia, suggesting that a strategic processing deficit may contribute to memory impairment. However, few studies have investigated the combined effects of encoding and retrieval strategies on EM in schizophrenia. The current study examined the impact of encoding and retrieval strategies on associative memory and brain activity in schizophrenia. We also assessed the role of verbal processing ability in response to strategic memory interventions in schizophrenia. Behavioral and functional neuroimaging data were collected from 23 participants with schizophrenia and 24 comparison subjects while performing associative memory encoding and recall tasks. Behaviorally, both schizophrenia participants and controls benefited from memory strategies and showed significant associations between verbal processing ability and recall. Additionally, among schizophrenia participants, encoding strategy use was associated with enhanced brain activity in multiple brain areas. Schizophrenia participants also demonstrated significant associations between verbal processing ability and encoding-related brain activity in prefrontal cortex. Findings suggest that memory performance and brain activity in schizophrenia can be enhanced via strategic manipulations, and individual differences in cognitive abilities in schizophrenia can affect behavioral and neurobiological responses to strategic memory interventions. (JINS, 2011, 17, 796–806)

Preschoolers with spina bifida (SB) were compared to typically developing (TD) children on tasks tapping mathematical knowledge at 36 months (n = 102) and 60 months of age (n = 98). The group with SB had difficulty compared to TD peers on all mathematical tasks except for transformation on quantities in the subitizable range. At 36 months, vocabulary knowledge, visual–spatial, and fine motor abilities predicted achievement on a measure of informal math knowledge in both groups. At 60 months of age, phonological awareness, visual–spatial ability, and fine motor skill were uniquely and differentially related to counting knowledge, oral counting, object-based arithmetic skills, and quantitative concepts. Importantly, the patterns of association between these predictors and mathematical performance were similar across the groups. A novel finding is that fine motor skill uniquely predicted object-based arithmetic abilities in both groups, suggesting developmental continuity in the neurocognitive correlates of early object-based and later symbolic arithmetic problem solving. Models combining 36-month mathematical ability and these language-based, visual–spatial, and fine motor abilities at 60 months accounted for considerable variance on 60-month informal mathematical outcomes. Results are discussed with reference to models of mathematical development and early identification of risk in preschoolers with neurodevelopmental disorder. (JINS, 2011, 17, 431–444)

Blast-related head injuries are one of the most prevalent injuries among military personnel deployed in service of Operation Iraqi Freedom. Although several studies have evaluated symptoms after blast injury in military personnel, few studies compared them to nonblast injuries or measured symptoms within the acute stage after traumatic brain injury (TBI). Knowledge of acute symptoms will help deployed clinicians make important decisions regarding recommendations for treatment and return to duty. Furthermore, differences more apparent during the acute stage might suggest important predictors of the long-term trajectory of recovery. This study evaluated concussive, psychological, and cognitive symptoms in military personnel and civilian contractors (N = 82) diagnosed with mild TBI (mTBI) at a combat support hospital in Iraq. Participants completed a clinical interview, the Automated Neuropsychological Assessment Metric (ANAM), PTSD Checklist-Military Version (PCL-M), Behavioral Health Measure (BHM), and Insomnia Severity Index (ISI) within 72 hr of injury. Results suggest that there are few differences in concussive symptoms, psychological symptoms, and neurocognitive performance between blast and nonblast mTBIs, although clinically significant impairment in cognitive reaction time for both blast and nonblast groups is observed. Reductions in ANAM accuracy were related to duration of loss of consciousness, not injury mechanism. (JINS, 2011, 17, 000–000)

Cognitive reserve is thought to reflect life experiences. Which experiences contribute to reserve and their relative importance is not understood. Subjects were 652 autopsied cases from the Rush Memory and Aging Project and the Religious Orders Study. Reserve was defined as the residual variance of the regressions of cognitive factors on brain pathology and was captured in a latent variable that was regressed on potential determinants of reserve. Neuropathology variables included Alzheimer's disease markers, Lewy bodies, infarcts, microinfarcts, and brain weight. Cognition was measured with six cognitive domain scores. Determinants of reserve were socioeconomic status (SES), education, leisure cognitive activities at age 40 (CA40) and at study enrollment (CAbaseline) in late life. The four exogenous predictors of reserve were weakly to moderately inter-correlated. In a multivariate model, all except SES had statistically significant effects on Reserve, the strongest of which were CA40 (β = .31) and CAbaseline (β = .28). The Education effect was negative in the full model (β = –.25). Results suggest that leisure cognitive activities throughout adulthood are more important than education in determining reserve. Discrepancies between cognitive activity and education may be informative in estimating late life reserve. (JINS, 2011, 17, 615–624)

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, resulting in physical, cognitive and affective disturbances, with notable declines in the ability to learn and retain new information. In this study, we examined if higher levels of physical activity in MS individuals were associated with an increased resting-state connectivity of the hippocampus and cortex, resulting in better performance on a task of episodic memory. Forty-five individuals with a clinically definite diagnosis of MS were recruited for the study. Consistent with previous reports, hippocampus was functionally connected to the posteromedial cortex, parahippocampal gyrus, superior frontal gyrus, and the medial frontal cortex. Higher levels of physical activity in MS patients were associated with an increased coherence between the hippocampus and the posteromedial cortex (PMC). The increased connectivity between these two regions, in turn, was predictive of better relational memory, such that MS patients who showed an increased coherence between the left (not right) hippocampus and the PMC also showed better relational memory. Results of the study are interpreted in light of the challenge of disentangling effects of physical activity from effects of disease severity and its neuropathological correlates. (JINS, 2011, 17, 986–997)

Many people who sustain traumatic brain injuries (TBI) have poor psychosocial outcomes that have been related to the use of avoidant coping. A major obstacle to understanding the mechanisms of this relationship are the self-report measures by which coping has been traditionally evaluated. The purpose of the present study was to compare coping behavior during a simulated real-world stress test with self-reported coping. People with moderate-to-severe TBI and matched controls completed the Baycrest Psychosocial Stress Test (BPST) where coping behavior was evaluated, and also completed the Ways of Coping Questionnaire (WOC). While there were no group differences in self- or significant-other-reported behavior on the WOC, the TBI group engaged in more avoidant than planful behavior on the BPST, while the control group displayed the opposite pattern of behavior. Moreover, in the control group there were positive relations between behavior on the BPST and self-reported coping on the WOC, but no such relation within the TBI group. Secondary analyses allowed for TBI participants to be characterized as “planners” or “avoiders.” This is the first study, to our knowledge, to report behavioral differences in coping post-TBI. Future work investigating the moderators of these differences may have significant implications for rehabilitative intervention. (JINS, 2011, 17, 248–255)

This study investigated the specific patient factors that predict responsiveness to a cognitive rehabilitation program. The program has previously been demonstrated to be successful at the group level in patients with gliomas, but it is unclear which patient characteristics optimized the effect of the intervention at the individual level. Four categories of possible predictors of improvement were selected for evaluation: sociodemographic and clinical variables, self-reported cognitive symptoms, and objective neuropsychological test performance. Hierarchical logistic regression analyses were conducted, beginning with the most accessible (sociodemographic) variables and ending with the most difficult (baseline neuropsychological) to identify in clinical practice. Nearly 60% of the participants of the intervention were classified as reliably improved. Reliable improvement was predicted by age (p = .003) and education (p = .011). Additional results suggested that younger patients were more likely to benefit specifically from the cognitive rehabilitation program (p = .001), and that higher education was also associated with improvement in the control group (p = .024). The findings are discussed in light of brain reserve theory. A practical implication is that cognitive rehabilitation programs should take the patients’ age into account and, if possible, adapt programs to increase the likelihood of improvement among older participants. (JINS, 2011, 17, 256–266)