Collaboration between human neuropsychology and comparative neuroscience has generated invaluable contributions to our understanding of human brain evolution and function. Further cross-talk between these disciplines has the potential to continue to revolutionize these fields. Modern neuroimaging methods could be applied in a comparative context, yielding exciting new data with the potential of providing insight into brain evolution. Conversely, incorporating an evolutionary base into the theoretical perspectives from which we approach human neuropsychology could lead to novel hypotheses and testable predictions. In the spirit of these objectives, we present here a new theoretical proposal, the Inferential Brain Hypothesis, whereby the human brain is thought to be characterized by a shift from perceptual processing to inferential computation, particularly within the social realm. This shift is believed to be a driving force for the evolution of the large human cortex. (JINS, 2012, 18, 394–401)

Many neuroimaging studies interpret the commonly reported findings of age-related increases in frontal response and/or increased bilateral activation as suggestive of compensatory neural recruitment. However, it is often unclear whether differences are due to compensation or reflective of other cognitive or physiological processes. This study aimed to determine whether there are compensatory age-related changes in brain systems supporting successful associative encoding while taking into account potentially confounding factors including age-related differences in task performance, atrophy, and resting perfusion. Brain response during encoding of face-name pairs was measured using functional magnetic resonance imaging in 10 older and nine young adults and was correlated with memory performance. During successful encoding, older adults demonstrated increased frontal and decreased occipital activity as well as greater bilateral involvement relative to the young. Findings remained significant after controlling for age-related cortical atrophy and hypoperfusion. Among the older adults, greater response was associated with better memory performance. Cognitive aging may involve recruitment of compensatory mechanisms to improve performance or prevent impairment. Results extend previous findings by suggesting that age-related alterations in activation cannot be attributed to the commonly observed findings of poorer task performance, reduced resting perfusion, or cortical atrophy among older adults. (JINS, 2012, 18, 402–413)

Few studies have applied multiple imaging modalities to examine cognitive correlates of white matter. We examined the utility of T2-weighted magnetic resonance imaging (MRI) -derived white matter hyperintensities (WMH) and diffusion tensor imaging-derived fractional anisotropy (FA) to predict cognitive functioning among older adults. Quantitative MRI and neuropsychological evaluations were performed in 112 older participants from an ongoing study of the genetics of Alzheimer's disease (AD) in African Americans. Regional WMH volumes and FA were measured in multiple regions of interest. We examined the association of regional WMH and an FA summary score with cognitive test performance. Differences in WMH and FA were compared across diagnostic groups (i.e., normal controls, mild cognitive impairment, and probable AD). Increased WMH volume in frontal lobes was associated with poorer delayed memory performance. FA did not emerge as a significant predictor of cognition. White matter hyperintensity volume in the frontal and parietal lobes was increased in MCI participants and more so in AD patients relative to controls. These results highlight the importance of regionally distributed small vessel cerebrovascular disease in memory performance and AD among African American older adults. White matter microstructural changes, quantified with diffusion tensor imaging, appear to play a lesser role in our sample. (JINS, 2012, 18, 414–427)

Identification of preclinical Alzheimer's disease (AD) is an essential first step in developing interventions to prevent or delay disease onset. In this study, we examine the hypothesis that deeper analyses of traditional cognitive tests may be useful in identifying subtle but potentially important learning and memory differences in asymptomatic populations that differ in risk for developing Alzheimer's disease. Subjects included 879 asymptomatic higher-risk persons (middle-aged children of parents with AD) and 355 asymptotic lower-risk persons (middle-aged children of parents without AD). All were administered the Rey Auditory Verbal Learning Test at baseline. Using machine learning approaches, we constructed a new measure that exploited finer differences in memory strategy than previous work focused on serial position and subjective organization. The new measure, based on stochastic gradient descent, provides a greater degree of statistical separation (p = 1.44 × 10−5) than previously observed for asymptomatic family history and non-family history groups, while controlling for apolipoprotein epsilon 4, age, gender, and education level. The results of our machine learning approach support analyzing memory strategy in detail to probe potential disease onset. Such distinct differences may be exploited in asymptomatic middle-aged persons as a potential risk factor for AD. (JINS, 2012, 18, 428–439)

Virtual reality (VR) assessment paradigms have the potential to address the limited ecological validity of pen and paper measures of executive function (EF) and the pragmatic and reliability issues associated with functional measures. To investigate the ecological validity and construct validity of a newly developed VR measure of EF, the Virtual Library Task (VLT); a real life analogous task—the Real Library Task (RLT); and five neuropsychological measures of EF were administered to 30 patients with traumatic brain injury (TBI) and 30 healthy Controls. Significant others for each participant also completed the Dysexecutive Questionnaire (DEX), which is a behavioral rating scale of everyday EF. Performances on the VLT and the RLT were significantly positively correlated indicating that VR performance is similar to real world performance. The TBI group performed significantly worse than the Control group on the VLT and the Modified Six Elements Test (MSET) but the other four neuropsychological measures of EF failed to differentiate the groups. Both the MSET and the VLT significantly predicted everyday EF suggesting that they are both ecologically valid tools for the assessment of EF. The VLT has the advantage over the MSET of providing objective measurement of individual components of EF. (JINS, 2012, 18, 440–450)

Mild traumatic brain injury (mild TBI) is often associated with postconcussive symptoms such as headache, memory problems, and irritability. However, high rates of similar symptoms in groups without a history of TBI raise questions about the clinical validity of the postconcussive syndrome. This study was conducted to address these issues through systematic examination of symptoms reported by those with and without a history of mild TBI or orthopedic injury. Responses to the Postconcussion Syndrome Checklist (PCSC), demographic information, and medical history were collected via online questionnaire from 3027 non-referred university students (2280 without a history of mild TBI or orthopedic injury, 491 with a history of orthopedic injury, and 256 with post-acute mild TBI). Although the mild TBI group reported higher mean levels of symptoms, confirmatory factor analyses demonstrated that symptoms clustered into parallel cognitive, somatic, affective, and sensory factors in all three groups. Despite modestly higher mean symptoms among those with a history of mild TBI, symptom clusters did not differ from non-TBI groups. These findings cast doubts about the clinical validity of the “postconcussive syndrome” and raise questions about pathways by which mild TBI and other factors may influence the expression of chronic symptoms. (JINS, 2012, 18, 451–460)

This study examined the relationship between cognitive function and sleep onset/maintenance difficulties (SO/MD) in nondemented older adults. We hypothesized that SO/MD negatively impacts cognition and that older adults with lower education would be especially vulnerable to its effects. The sample comprised 549 older adults from the Einstein Aging Study (EAS), a community-based cohort. Participants completed neuropsychological assessment and a sleep questionnaire. Univariate ANCOVAs were performed with cognitive performance as a dependent variable, SO/MD (present or absent) and education (lower: ⩽12 years; higher: >12 years) as between-subjects factors, and age, ethnicity, gender, depression, and cardiovascular comorbidies as covariates. Participants were an average age of 79.7 ± 5.0 years (range = 71–97 years). Fifty-seven percent (n = 314) of the sample met criteria for SO/MD. Among participants with SO/MD, those with lower education performed more poorly on a test of category fluency than participants with higher education (means: 35.2 vs. 41.0; p < .001); among older adults without SO/MD, educational attainment had no measurable effect on cognition (SO/MD × education interaction (F(1,536) = 14.5; p = .00)). Consistent with the cognitive reserve hypothesis, older adults with lower education appear selectively vulnerable to the negative effects of sleep onset/maintenance difficulties on tests of verbal fluency. (JINS, 2012, 18, 461–470)

Studies in adults with multiple sclerosis (MS) have associated regional brain abnormalities with memory impairment. While memory problems in children with MS are often reported, little is known about the neural correlates that may contribute to these difficulties. We measured verbal and nonverbal memory using the Test of Memory and Learning (TOMAL-2) in 32 children and adolescents with MS and 26 age- and sex-matched healthy controls. Memory performance was correlated with volumetric measures of the whole brain, hippocampus, amygdala, and thalamus. Brain volumes were normalized for age and sex using magnetic resonance imaging (MRI) data from the National Institutes of Health MRI Study of Normal Brain development. With the exception of story recall, performance on memory tests was similar to that of the control group. Relative to controls, patient with MS showed reduced volume in the whole brain (p < .001), amygdala (p < .005), and thalamus (p < .001), but not the hippocampus. In the patient group, word-list learning correlated with whole brain volume (r = .53) and hippocampal volume (r = .43), whereas visual recognition memory correlated with thalamic volume (r = .48). Findings are consistent with the well-established role of the hippocampus in learning and consolidation and also highlight the importance of diffuse brain pathology on memory function. (JINS, 2012, 18, 471–480)

Obstructive sleep apnea (OSA) is a nocturnal respiratory disorder associated with cognitive and behavioral sequelae, including impairments in executive functioning (EF). Previous literature has focused on “cool” EF, meaning abilities such as working memory and planning that do not involve affective control requirements. Little is known about the impact OSA may have on “hot” EF that involves regulation of affect and risk-related decision-making, and that may be particularly salient during adolescence, when these skills are rapidly developing. This study examined performance on the Iowa Gambling Task (IGT), a task believed to assess aspects of “hot” EF, in overweight adolescents at risk for OSA. Consistent with hypotheses, individuals without OSA made more beneficial decisions on the IGT over time, but participants with OSA did not benefit from feedback and continued to make choices associated with higher initial rewards, but greater long-term losses. The relationship between developmental level and IGT performance was moderated by OSA status. Individuals with OSA did not demonstrate the expected developmental gains in performance during the IGT. This finding suggests that OSA may impact the development of critical aspects of EF, or at least the expression of these skills during the developmentally important period of adolescence. (JINS, 2012, 18, 481–489)

Whereas patients with Alzheimer's disease (AD) experience difficulties forming and retrieving memories, their memory impairments may also partially reflect an unrecognized dysfunction in sleep-dependent consolidation that normally stabilizes declarative memory storage across cortical areas. Patients with amnestic mild cognitive impairment (aMCI) exhibit circumscribed declarative memory deficits, and many eventually progress to an AD diagnosis. Whether sleep is disrupted in aMCI and whether sleep disruptions contribute to memory impairment is unknown. We measured sleep physiology and memory for two nights and found that aMCI patients had fewer stage-2 spindles than age-matched healthy adults. Furthermore, aMCI patients spent less time in slow-wave sleep and showed lower delta and theta power during sleep compared to controls. Slow-wave and theta activity during sleep appear to reflect important aspects of memory processing, as evening-to-morning change in declarative memory correlated with delta and theta power during intervening sleep in both groups. These results suggest that sleep changes in aMCI patients contribute to memory impairments by interfering with sleep-dependent memory consolidation. (JINS, 2012, 18, 490–500)

Many studies have assessed visual short-term memory (VSTM) abilities in children with specific language impairment (SLI), with contrasting results: some studies observed preserved VSTM capacities, while others reported impaired VSTM. The present study explores the hypothesis that the complexity of the visual information to be encoded and stored might underlie these discrepancies. Four VSTM conditions were administered to a group of 15 children with SLI, as well as to two groups of typically developing children, matched for chronological age and for VSTM capacity for visually simple stimuli, respectively. The stimuli to be remembered varied in their visual similarity and in the number of their visual features. Across the four VSTM conditions, children with SLI showed significantly reduced performance relative to an age-matched control group, and they were more strongly affected by visual similarity and number of features when compared to a control group matched for VSTM capacity for visually simple stimuli. The present results support the hypothesis that stimulus complexity is a determining factor of the poor VSTM performances in children with SLI. (JINS, 2012, 18, 501–510)

Difficulty with selective attention is a frequent complaint of adult patients with ADHD, but selective attention tasks have not provided robust evidence of attentional dysfunction in this group. Two experiments examine this puzzle by distinguishing between failures of spatial selection and problems due to sensitivity to perceptual interference. In Experiment 1, we measured the level of perceptual interference generated by targets in crowded displays with nearby distractors by comparing luminance thresholds in both distractor-present (noise) and distractor-absent (clean) displays. ADHD and control participants had comparable thresholds for clean displays, but ADHD individuals had elevated thresholds to crowded displays. These effects could be explained in two distinct ways. Deficits may have arisen from amplified visual interference in the noise condition, or from abnormalities in top-down attentional processes that reduce visual interference. Experiment 2 adjusted for individual perceptual differences with clean and noise displays, before measuring visual interference resolution at attended versus unattended locations. ADHD and control groups had comparable interference resolution at attended locations. These results suggest that perceptual interference rather than spatial attention deficits may account for some deficits in ADHD. This putative deficit in sensory function highlights a potential early-stage perceptual processing deficit in ADHD distinct from selective attention. (JINS, 2012, 18, 511–520)

Corpus callosum malformation and dysfunction are increasingly recognized causes of cognitive and behavioral disability. Individuals with agenesis of the corpus callosum (AgCC) offer unique insights regarding the cognitive skills that depend specifically upon callosal connectivity. We examined the impact of AgCC on cognitive inhibition, flexibility, and processing speed using the Color-Word Interference Test (CWIT) and Trail Making Test (TMT) from the Delis-Kaplan Executive Function System. We compared 36 individuals with AgCC and IQs within the normal range to 56 matched controls. The AgCC cohort was impaired on timed measures of inhibition and flexibility; however, group differences on CWIT Inhibition, CWIT Inhibition/Switching and TMT Number-Letter Switching appear to be largely explained by slow performance in basic operations such as color naming and letter sequencing. On CWIT Inhibition/Switching, the AgCC group was found to commit significantly more errors which suggests that slow performance is not secondary to a cautious strategy. Therefore, while individuals with agenesis of the corpus callosum show real deficits on tasks of executive function, this impairment appears to be primarily a consequence of slow cognitive processing. Additional studies are needed to investigate the impact of AgCC on other aspects of higher order cortical function. (JINS, 2012, 18, 521–529)

Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are chronic immunologic diseases that can cause cognitive dysfunction. MS is a central nervous system (CNS) disease characterized by demyelination and progressive brain atrophy. SLE is an autoimmune disease capable of damaging multiple organ systems, including the CNS. Cognitive disturbances are seen in both SLE and MS. The present study is concerned with understanding the similarities and differences between the cognitive profiles of SLE and MS as well as the relationship between cognitive impairment and vocational disability in these patients. We examined 47 SLE patients, 47 MS patients, and 44 healthy controls. The groups were well matched on demographics and the patient groups were also matched on disease duration and severity. Group comparisons revealed that generative verbal fluency and visual-spatial memory are more profoundly affected in MS than SLE; whereas depression, fatigue, and working memory deficits are similarly involved in both diseases. Logistic regression analysis revealed that executive function, in particular, was predictive of vocational outcomes in SLE and MS patients. (JINS, 2012, 18, 530–540)

Amnestic mild cognitive impairment (aMCI) represents a group of individuals who are highly likely to develop Alzheimer's disease (AD). Although aMCI is typically conceptualized as involving predominantly deficits in episodic memory, recent studies have demonstrated that deficits in executive functioning may also be present, and thorough categorization of cognitive functioning in MCI may improve early diagnosis and treatment of AD. We first provide an extensive review of neuropsychology studies that examined executive functioning in MCI. We then present data on executive functioning across multiple sub-domains (divided attention, working memory, inhibitory control, verbal fluency, and planning) in 40 aMCI patients (single or multiple domain) and 32 normal elderly controls (NECs). MCI patients performed significantly worse than NECs in all 5 sub-domains, and there was impairment (>1.0 SD below the mean of NECs) in all sub-domains. Impairment on each test was frequent, with 100% of MCI patients exhibiting a deficit in at least one sub-domain of executive functioning. Inhibitory control was the most frequently and severely impaired. These results indicate that executive dysfunction in multiple sub-domains is common in aMCI and highlights the importance of a comprehensive neuropsychological evaluation for fully characterizing the nature and extent of cognitive deficits in MCI. (JINS, 2012, 18, 541–555)

In addition to having difficulties with social communications, individuals with an autism spectrum disorder (ASD) often also experience impairment in higher-order, executive skills. The present study examined the effects of pharmacological modulation of the norepinephrine system on the severity of such impairments. A sample of 14 high-functioning adults with ASD and a demographically-matched comparison group of 13 typically developing individuals participated. An AX continuous performance test (AX-CPT) was used to evaluate working memory and inhibitory control. AX-CPT performance was assessed following administration of a single dose of propranolol (a beta adrenergic antagonist) and following placebo (sugar pill) administration. Individuals with ASD performed more poorly than non-ASD individuals in the working memory condition (BX trials). Importantly, administration of propranolol attenuated this impairment, with the ASD group performing significantly better in the propranolol condition than the placebo condition. Working memory performance of the non-ASD group was unaffected by propranolol/placebo administration. No group or medication effects were observed for the inhibition condition (AY trials). The present findings suggest that norepinephrine may play a role in some, but not necessarily all, cognitive impairments associated with ASD. Additional research is needed to fully understand whether this role is primarily causal or compensatory in nature. (JINS, 2012, 18, 556–564)

Decreased productivity on verbal fluency tasks by persons with schizophrenia has been attributed to semantic system abnormalities. Semantic structure is often assessed using multidimensional scaling (MDS) to detect normal and aberrant semantic clustering. However, MDS has limitations that may be particularly problematic for such assessments. Here, we introduce a different clustering technique, singular value decomposition (SVD), to elucidate abnormalities of the semantic system in schizophrenia. We compared 102 treated outpatients with schizophrenia to 109 healthy adults on two category-cued word fluency tasks. Patients with schizophrenia showed semantic clustering patterns that differ markedly from those of healthy adults. However, SVD revealed more detailed and critical semantic system abnormalities than previously appreciated using MDS. Patients with schizophrenia showed less coherent semantic clustering of both low- and high-frequency category exemplars than healthy adults. These results suggest the intriguing possibility that impaired automatic activation of semantic information is a key deficit in schizophrenia. (JINS, 2012, 18, 565–575)

Mild traumatic brain injury (mTBI) affects a significant number of combat veterans returning from Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF). Although resolution of mTBI symptoms is expected over time, some individuals continue to report lingering cognitive difficulties. This study examined the contributions of self-reported mTBI injury characteristics (e.g., loss of consciousness, post-traumatic amnesia) and psychiatric symptoms to both subjective and objective cognitive functioning in a sample of 167 OEF/OIF veterans seen in a TBI clinic. Injury characteristics were not associated with performance on neuropsychological tests but were variably related to subjective ratings of cognitive functioning. Psychiatric symptoms were highly prevalent and fully mediated most of the relationships between injury characteristics and cognitive ratings. This indicates that mTBI characteristics such as longer time since injury and loss of consciousness or post-traumatic amnesia can lead to increased perceived cognitive deficits despite having no objective effects on cognitive performance. Psychiatric symptoms were associated with both cognitive ratings and neuropsychological performance, illustrating the important role that psychiatric treatment can potentially play in optimizing functioning. Finally, subjective cognitive ratings were not predictive of neuropsychological performance once psychiatric functioning was statistically controlled, suggesting that neuropsychological assessment provides valuable information that cannot be gleaned from self-report alone. (JINS, 2012, 18, 576–584)