We have recently reported (Saykin et al., 1999b) selective activation of left medial temporal lobe structures during processing of novel compared to familiar words using functional magnetic resonance imaging (fMRI). The current study describes the relationship between a widely used clinical test of verbal learning, the California Verbal Learning Test (CVLT), and the previously reported fMRI activations. Thirteen right-handed healthy adult participants were studied with whole brain echo-planar fMRI while listening to novel and recently learned (familiar) words intermixed pseudorandomly in an event-related design. These participants were also tested with the CVLT. Scores for CVLT Trial 1 (immediate encoding of novel words) and recognition discriminability (recognition of familiar vs. novel words) were correlated with fMRI signal change during processing of novel versus familiar words using a covariance model implemented in SPM96. For the novel words analysis, voxels in the right anterior hippocampus correlated significantly with Trial 1 (r = .76 at the maxima). For the recognition analysis, a significant cluster of voxels was found in the right dorsolateral prefrontal cortex (r = .88 at the maxima). Our prior results of separable left medial temporal activation to novel and familiar words, together with results of the covariance analyses reported here, suggest that in addition to the left medial temporal lobe (MTL) regions that are engaged during novel and familiar word processing, the right hippocampus and right frontal lobe are also involved, particularly in those participants with better memory ability. This positive relationship between fMRI activation and CVLT performance suggests a role for these right hemisphere regions in successful memory processing of verbal material, perhaps reflecting more efficient encoding and retrieval strategies that facilitate memory. (JINS, 2001, 7, 55–62.)

Blast injury is common in current warfare, but little is known about the effects of blast-related mild traumatic brain injury (mTBI). Profile analyses were conducted investigating differences in self-reported postconcussive (PC) symptoms in 339 veteran outpatients with mTBI histories reporting current symptoms based on mechanism of injury (blast only, nonblast only, or both blast and nonblast), number of blast injuries, and distance from the blast. Veterans with any blast-related mTBI history were younger and reported higher posttraumatic stress symptoms than veterans with nonblast-related mTBI histories, with a marginally significant difference in posttraumatic stress symptom report between veterans reporting blast-related mTBI only and those reporting nonblast-related mTBI. The groups did not differ in terms of PC symptom severity or PC symptom cluster profiles. Among veterans with blast-related mTBI histories, PC symptom report did not vary by number of blast-related mTBIs or proximity to blast. Overall, posttraumatic stress symptoms accounted for a substantial portion of variance in PC symptom report. In veteran outpatients with remote mTBI histories who have enduring symptom complaints related to the mTBI, mechanism of injury did not clearly contribute to differential PC symptom severity or PC symptom cluster profile. Proximal rather than distal factors may be important intervention targets in returning symptomatic veterans with mTBI histories. (JINS, 2010, 16, 856–866.)

Confrontation naming of 52 unilateral or bilateral brain-damaged Chinese patients were examined with a modified version of the Boston Naming Test (BNT). Chinese patients with left or right hemisphere lesions, contrary to studies on English speakers, demonstrated similar levels of naming impairments, supporting the notion that English and Chinese are mediated by different neuroprocessing systems. In addition, the psychometric properties of the BNT on Chinese population were examined. While the test demonstrated satisfactory internal consistency and discriminant validity, level of education was found to be a significant factor affecting participants' performance. A cut-off score of 24 in spontaneous naming yielded a sensitivity of 73.1% and specificity of 75.3% in differentiating normal from brain-damaged participants, suggesting that the modified BNT is applicable to the Chinese population. (JINS, 2004, 10, 46–53.)

Even though frontal lobe epilepsy (FLE) is a relatively common seizure type, no formal psychometric studies of children with FLE have been reported. We compared 12 children with FLE and 15 children with temporal lobe epilepsy (TLE) on neuropsychological tests of attention, memory, executive functioning, and adaptive functioning. The results of these tests indicated that the children with FLE had deficits in planning and executive functions, whereas their verbal and nonverbal memory was intact. The opposite pattern was observed in children with TLE. Measures of executive functioning and impulse control were the best predictors of adaptive functioning. The findings suggest that children with FLE have a pattern of cognitive deficits that differs markedly from the pattern seen in children with TLE. Children with FLE have prominent deficits in executive functioning that appear to be related to poor behavioral adaptation.

Forty-one boys diagnosed with Duchenne muscular dystrophy (DMD) were each compared to an unaffected sibling on a battery of neuropsychological tests. Verbal, visuospatial, attention/memory, abstract thinking, and academic achievement skills were tested. Results indicated the boys with DMD performed similarly to their siblings on the majority of measures, indicating intact verbal, visuospatial, long-term memory, and abstract skills. However, the DMD group did significantly more poorly than their siblings on specific measures of story recall, digit span, and auditory comprehension, as well as in all areas of academic achievement (reading, writing, and math). This profile indicates that verbal working memory skills are selectively impaired in DMD, and that that likely contributes to limited academic achievement. The association between the known impact of the genetic mutation on the development of the central nervous system and boys' cognitive profile is discussed. (JINS, 2001, 7, 45–54.)

Previous studies have documented weaknesses in cognitive ability and early academic readiness in young children with traumatic brain injury (TBI). However, few of these studies have rigorously controlled for demographic characteristics, examined the effects of TBI severity on a wide range of skills, or explored moderating influences of environmental factors on outcomes. To meet these objectives, each of three groups of children with TBI (20 with severe, 64 with moderate, and 15 with mild) were compared with a group of 117 children with orthopedic injuries (OI group). The children were hospitalized for their injuries between 3 and 6 years of age and were assessed an average of 1½ months post injury. Analysis revealed generalized weaknesses in cognitive and school readiness skills in the severe TBI group and less pervasive effects of moderate TBI. Indices of TBI severity predicted outcomes within the TBI sample and environmental factors moderated the effects of TBI on some measures. The findings document adverse effects of TBI in early childhood on postacute cognitive and school readiness skills and indicate that these effects are related to both injury severity and the family environment. (JINS, 2008, 14, 734–745.)

Repeated neuropsychological testing gives rise to practice effects in that patients become familiar with test material as well as test-taking procedures. Using alternate forms prevents the learning of specific test stimuli, potentially mitigating practice effects. However, changing forms could diminish test-retest reliability coefficients. Our objective was to examine test-retest effects in multiple sclerosis (MS) patients randomly assigned to same- (SF) or alternate-form (AF) conditions. Thirty-four MS patients underwent neuropsychological evaluation. The battery included the California Verbal Learning Test II (CVLT-II) and the Brief Visuospatial Memory Test–Revised (BVMT-R), memory tests recommended by a recently convened consensus panel. Patients were randomly assigned to SF or AF groups and then tested at baseline and follow-up examination 1 week later. Analysis of variance tests (ANOVAs) revealed significant group × time interactions, with SF patients showing greater gain than AF patients. SF practice effects were often large, compromising test validity. Reliability coefficients were either equivalent or higher in the AF group, a finding attributed to ceiling effects and reduced variance in the SF group at retest. The generalizability of the findings may be limited to short test-retest intervals and the MS population. Nevertheless, I conclude that the use of CVLT-II and BVMT-R alternate forms likely helps preserve test validity without compromising test-retest reliability. (JINS, 2005, 11, 727–736.)

Verbal fluency tasks are frequently used in clinical neuropsychology. Clustering (the production of words within semantic subcategories) and switching (the ability to shift between clusters) have been described as 2 components underlying fluency performance. We compared the use of clustering and switching in schizophrenic patients and healthy subjects. Seventy-eight schizophrenic subjects (DSM–IV criteria) and 64 control participants matched for age and educational level were recruited. Negative, disorganized, and productive clinical dimensions were evaluated using the SANS and SAPS scales. The number of words generated per semantic–phonemic cluster and the number of switches were evaluated during 2 verbal fluency tasks (phonemic and semantic). In the healthy controls switching and clustering were closely related to the total number of words generated in the verbal fluency tests. The role of the 2 components was partly dependent on the specific task. Switching was prevalent in formal fluency, while both switching and clustering contributed to semantic fluency. In comparison to the healthy controls, the overall group of schizophrenic patients showed a significant impairment of switching in the formal fluency task and of both switching and clustering in the semantic fluency task, and both the negative and disorganized dimensions correlated with verbal fluency performance, the number of switches during the phonemic fluency task, and the clustering during semantic fluency task. (JINS, 1998, 4, 539–546.)

Prenatal alcohol exposure is associated with widespread and devastating neurodevelopmental deficits. Numerous reports have suggested memory deficits in both humans and animals exposed prenatally to alcohol. However, the nature of these memory deficits remains to be characterized. Recently children with fetal alcohol syndrome were shown to have learning and memory deficits on a verbal learning and memory measure that involved free recall and recognition memory. The current study seeks to further characterize memory functioning in children with heavy prenatal alcohol exposure by evaluating priming performance. The choice of task is also relevant given previous studies of memory performance in patient groups with and without involvement of the basal ganglia, a group of structures known to be affected in fetal alcohol syndrome. Three groups were evaluated for lexical priming, free recall, recognition memory, and verbal fluency: (1) children with heavy prenatal alcohol exposure; (2) children with Down syndrome; and (3) nonexposed controls. The children with Down syndrome showed significantly less priming than alcohol-exposed children, who did not differ from controls. In addition, the alcohol-exposed children were impaired on the free recall task but not on the recognition memory task, whereas the children with Down syndrome performed significantly worse than the alcohol-exposed group on both tasks. Finally, on the verbal fluency task, children with heavy prenatal alcohol exposure were impaired on both category and letter fluency, but the degree of impairment was greater for letter fluency. These results further characterize the memory deficits in children with heavy prenatal alcohol exposure suggesting that in spite of learning and memory deficits, they are able to benefit from priming of verbal information. (JINS, 1999, 5, 462–471.)

Previous studies have documented poor family functioning, anxiety, and depression in relatives of individuals with traumatic brain injury (TBI). However, few studies have examined family functioning over extended periods after injury. The present study aimed to investigate family functioning and relatives’ emotional state 2 and 5 years following TBI, predictive factors, and their interrelationships. Participants were individuals with TBI and their relatives, with 301 seen at 2 years and 266 at 5 years post-injury. Measures included a Structured Outcome Questionnaire, Family Assessment Device (FAD), Hospital Anxiety and Depression Scale, and the Craig Handicap Assessment and Reporting Technique. Results showed that while the group did not differ greatly in family functioning from a normative group, a significant proportion showed unhealthy functioning across most FAD subscales. Both TBI participants and their relatives showed elevated rates of anxiety and depression. There was little difference between family functioning or relatives’ anxiety or depression levels at 2 and 5 years post-injury. Path analysis indicated that neurobehavioral changes in the injured individual have an impact on family functioning and distress in relatives even at 5 years post-injury. These findings indicate the need for long-term support of families with a brain-injured member. (JINS, 2010, 16, 306–317.)

The study investigated longitudinal change in cognitive function in 87 patients with Huntington's disease (HD), using a range of neuropsychological tests, which tap mental manipulative abilities, memory, and frontal executive skills. Over a 1-year period the largest changes were noted in letter fluency, object recall, and Stroop Test performance, whereas no changes were noted over more than 3 years on the modified Wisconsin Card Sorting Test. Contrary to expectation, greater change was evident over 1 year for tasks with low compared to high cognitive demands. The differential sensitivity of tasks was attributed in part to inherent characteristics of the tests themselves: their capacity to detect minor gradations of change and their vulnerability to practice effects. However, the greater change for relatively automatic, speed-based tasks with low cognitive demands was interpreted as reflecting the evolution of HD, with a greater magnitude of change occurring in basal ganglia than cortical function. One purpose of the study was to identify tasks sensitive to the progression of HD and hence most suitable for the evaluation of therapies. Despite reaching statistical significance by virtue of the large group size, numerical differences in test scores over 1 year were very small, suggesting that the use of such tests to evaluate change in individuals or small groups of subjects would be problematic. The data highlight the slow progression of HD, the limitations of standard cognitive tests in detecting change over short periods, and the need for therapeutic studies that encompass a relatively prolonged time frame. (JINS, 2001, 7, 33–44.)

The prevalence and nature of post-traumatic stress disorder (PTSD) following mild traumatic brain injury (MTBI) is controversial because of the apparent paradox of suffering PTSD with impaired memory for the traumatic event. In this study, 1167 survivors of traumatic injury (MTBI: 459, No TBI: 708) were assessed for PTSD symptoms and post-traumatic amnesia during hospitalization, and were subsequently assessed for PTSD 3 months later (N = 920). At the follow-up assessment, 90 (9.4%) patients met criteria for PTSD (MTBI: 50, 11.8%; No-TBI: 40, 7.5%); MTBI patients were more likely to develop PTSD than no-TBI patients, after controlling for injury severity (adjusted odds ratio: 1.86; 95% confidence interval, 1.78–2.94). Longer post-traumatic amnesia was associated with less severe intrusive memories at the acute assessment. These findings indicate that PTSD may be more likely following MTBI, however, longer post-traumatic amnesia appears to be protective against selected re-experiencing symptoms. (JINS, 2009, 15, 862–867.)

In this study, verbal learning and memory following pediatric closed-head injuries (CHI) using the children's version of the California Verbal Learning Test (CVLT). Participants included 47 children, ages 5–16 yr, with a history of CHI, and 47 matched, noninjured controls. Children with CHI performed more poorly than controls on the CVLT, although their deficits varied qualitatively as a function of injury severity. Those with mild/moderate injuries performed as well as controls on learning trials, but they recalled proportionally fewer words after a delay (although their recognition was intact). Severely injured children demonstrated deficits in learning, delayed recall, and recognition, compared to controls. The groups did not differ in learning characteristics, but children with severe CHI exhibited more intrusions than controls. Pediatric CHI are associated with specific disturbances in verbal learning and memory similar to those of adults with CHI but different from those of children with other developmental and neurological disorders. JINS, 1995, I, 78–87.)

Although numerous studies have shown that brain-damaged patients tend to underestimate neuropsychological (NP) impairment when self-ratings are compared to informant ratings, the meaning of such discrepancies is not well studied in multiple sclerosis (MS). We compared patient self- and informant-report questionnaire ratings of NP functioning in 122 MS patients and 37 age- and education-matched normal controls. In addition to completing the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), participants underwent NP testing and assessment of depression, personality, and neuropsychiatric symptoms. Based on the normal distribution of discrepancy scores, patients were classified according to whether they overestimated or underestimated their cognitive ability, relative to informant ratings. ANOVAs comparing test scores derived from overestimators, underestimators, and accurate estimators were significant for multiple measures of cognitive function, depression, personality, and neuropsychiatric symptoms. Overestimators were characterized by less depression and conscientiousness, and greater degrees of cognitive impairment, euphoric behavioral disinhibition, and unemployment as compared to underestimators. We conclude that patient/informant discrepancy scores on the MSNQ are associated with the aforementioned neuropsychiatric features, and that the MSNQ has potential utility for predicting euphoria and disinhibition syndromes in MS. (JINS, 2005, 11, 574–583.)All authors are from the State University of New York (SUNY) at Buffalo School of Medicine, Department of Neurology, Division of Departmental and Behavioral Neurosciences, and the Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY.

The current review was conducted to address the ongoing debate regarding the presence or absence of neuropsychological impairment in asymptomatic HIV-Type 1 (HIV-1) seropositive individuals. Results were summarized from 57 studies that compared the performances of seropositive asymptomatic and seronegative individuals. Overall, the differences observed between median rates of impairment for asymptomatic (35%) and seronegative (12%) groups provided the clearest indication of deficits in asymptomatics. In addition, five variables were examined as possible contributors to inconsistencies found in the literature: mode of infection, test battery type, test battery size, sample size, and method of data analysis. Of these variables, only mode of infection and test battery size appeared to substantially influence the outcome of the studies reviewed with regard to identifying neuropsychological impairment in asymptomatics. (JINS, 1995, I, 304–315.)

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)

We examined whether conversion to dementia can be predicted by self-reported olfactory impairment and/or by an inability to identify odors. Common forms of dementia involve an impaired sense of smell, and poor olfactory performance predicts cognitive decline among the elderly. We followed a sample of 1529 participants, who were within a normal range of overall cognitive function at baseline, over a 10-year period during which 159 were classified as having a dementia disorder. Dementia conversion was predicted from demographic variables, Mini-Mental State Examination score, and olfactory assessments. Self-reported olfactory impairment emerged as an independent predictor of dementia. After adjusting for effects of other predictors, individuals who rated their olfactory sensitivity as “worse than normal” were more likely to convert to dementia than those who reported normal olfactory sensitivity (odds ratio [OR] = 2.17; 95% confidence interval [CI] [1.40, 3.37]). Additionally, low scores on an odor identification test also predicted conversion to dementia (OR per 1 point increase = 0.89; 95% CI [0.81, 0.98]), but these two effects were additive. We suggest that assessing subjective olfactory complaints might supplement other assessments when evaluating the risk of conversion to dementia. Future studies should investigate which combination of olfactory assessments is most useful in predicting dementia conversion. (JINS, 2014, 20, 1–9)

Very few empirically validated interventions for improving metacognitive skills (i.e., self-awareness and self-regulation) and functional outcomes have been reported. This single-case experimental study presents JM, a 36-year-old man with a very severe traumatic brain injury (TBI) who demonstrated long-term awareness deficits. Treatment at four years post-injury involved a metacognitive contextual intervention based on a conceptualization of neuro-cognitive, psychological, and socio-environmental factors contributing to his awareness deficits. The 16-week intervention targeted error awareness and self-correction in two real life settings: (a) cooking at home; and (b) volunteer work. Outcome measures included behavioral observation of error behavior and standardized awareness measures. Relative to baseline performance in the cooking setting, JM demonstrated a 44% reduction in error frequency and increased self-correction. Although no spontaneous generalization was evident in the volunteer work setting, specific training in this environment led to a 39% decrease in errors. JM later gained paid employment and received brief metacognitive training in his work environment. JM's global self-knowledge of deficits assessed by self-report was unchanged after the program. Overall, the study provides preliminary support for a metacognitive contextual approach to improve error awareness and functional outcome in real life settings. (JINS, 2006, 12, 54–63.)

We determined the rates of cognitive change associated with twenty individual measures. Participants included 547 noninstitutionalized septuagenarians and octogenarian residents of a comprehensive care retirement community who were studied over three years. Latent growth curves (LGC) of multiple cognitive measures were compared to a LGC model of the rates of change in Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). All curves were standardized relative to each variable's baseline distribution. Baseline scores were within their expected normal age-specific ranges. Most measures showed significant rates of change over time. There was also significant variability about those rates, suggesting clinical heterogeneity. Many deteriorated over time, as did ADLs and IADLs. However, performance on some measures improved, consistent with learning effects. The rates of change in two measures, the Executive Interview and the Trail Making Test, were closely related to decline in IADLs. These results suggest that age-related cognitive decline is a dynamic longitudinal process affecting multiple cognitive domains. Heterogeneity in the rates of cognitive change may reflect the summed effects of age and comorbid conditions affecting cognition. Some measures may be ill-suited for measuring age-related changes in cognition, either because they are insensitive to change, or hindered by learning effects. Nonverbal measures appear to be particularly well suited for the prediction of age-related functional decline. These observations are relevant to the definition and diagnosis of “dementing” conditions. (JINS, 2005, 11, 899–909.)

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer's disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants' activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD. (JINS, 2007, 13, 450–461.)