The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients’ quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832–842)

Objectives: White matter (WM) integrity within the mesial temporal lobe (MTL) is important for episodic memory (EM) functioning. The current study investigated the ability of diffusion tensor imaging (DTI) in MTL WM tracts to predict 3-year changes in EM performance in healthy elders at disproportionately higher genetic risk for Alzheimer’s disease (AD). Methods: Fifty-one cognitively intact elders (52% with family history (FH) of dementia and 33% possessing an Apolipoprotein E ε4 allelle) were administered the Rey Auditory Verbal Learning Test (RAVLT) at study entry and at 3-year follow-up. DTI scanning, conducted at study entry, examined fractional anisotropy and mean, radial and axial diffusion within three MTL WM tracts: uncinate fasciculus (UNC), cingulate-hippocampal (CHG), and fornix-stria terminalis (FxS). Correlations were performed between residualized change scores computed from RAVLT trials 1–5, immediate recall, and delayed recall scores and baseline DTI measures; MTL gray matter (GM) and WM volumes; demographics; and AD genetic and metabolic risk factors. Results: Higher MTL mean and axial diffusivity at baseline significantly predicted 3-year changes in EM, whereas baseline MTL GM and WM volumes, FH, and metabolic risk factors did not. Both ε4 status and DTI correlated with change in immediate recall. Conclusions: Longitudinal EM changes in cognitively intact, healthy elders can be predicted by disruption of the MTL WM microstructure. These results are derived from a sample with a disproportionately higher genetic risk for AD, suggesting that the observed WM disruption in MTL pathways may be related to early neuropathological changes associated with the preclinical stage of AD. (JINS, 2016, 22, 1005–1015)

Objectives: Connectionist theories of brain function took hold with the seminal contributions of Norman Geschwind a half century ago. Modern neuroimaging techniques have expanded the scientific interest in the study of brain connectivity to include the intact as well as disordered brain. Methods: In this review, we describe the most common techniques used to measure functional and structural connectivity, including resting state functional MRI, diffusion MRI, and electroencephalography and magnetoencephalography coherence. We also review the most common analytical approaches used for examining brain interconnectivity associated with these various imaging methods. Results: This review presents a critical analysis of the assumptions, as well as methodological limitations, of each imaging and analysis approach. Conclusions: The overall goal of this review is to provide the reader with an introduction to evaluating the scientific methods underlying investigations that probe the human connectome. (JINS, 2016, 22, 105–119)

To study the natural recovery from sports concussion, 12 concussed high school football athletes and 12 matched uninjured teammates were evaluated with symptom rating scales, tests of postural balance and cognition, and an event-related fMRI study during performance of a load-dependent working memory task at 13 h and 7 weeks following injury. Injured athletes showed the expected postconcussive symptoms and cognitive decline with decreased reaction time (RT) and increased RT variability on a working memory task during the acute period and an apparent full recovery 7 weeks later. Brain activation patterns showed decreased activation of right hemisphere attentional networks in injured athletes relative to controls during the acute period with a reversed pattern of activation (injured > controls) in the same networks at 7 weeks following injury. These changes coincided with a decrease in self-reported postconcussive symptoms and improved cognitive test performance in the injured athletes. Results from this exploratory study suggest that decreased activation of right hemisphere attentional networks mediate the cognitive changes and postconcussion symptoms observed during the acute period following concussion. Conversely, improvement in cognitive functioning and postconcussive symptoms during the subacute period may be mediated by compensatory increases in activation of this same attentional network. (JINS, 2013, 19, 1–10)

Previous studies suggest that task-activated functional magnetic resonance imaging (fMRI) can predict future cognitive decline among healthy older adults. The present fMRI study examined the relative sensitivity of semantic memory (SM) versus episodic memory (EM) activation tasks for predicting cognitive decline. Seventy-eight cognitively intact elders underwent neuropsychological testing at entry and after an 18-month interval, with participants classified as cognitively “Stable” or “Declining” based on ≥1.0 SD decline in performance. Baseline fMRI scanning involved SM (famous name discrimination) and EM (name recognition) tasks. SM and EM fMRI activation, along with Apolipoprotein E (APOE) ε4 status, served as predictors of cognitive outcome using a logistic regression analysis. Twenty-seven (34.6%) participants were classified as Declining and 51 (65.4%) as Stable. APOE ε4 status alone significantly predicted cognitive decline (R2 = .106; C index = .642). Addition of SM activation significantly improved prediction accuracy (R2 = .285; C index = .787), whereas the addition of EM did not (R2 = .212; C index = .711). In combination with APOE status, SM task activation predicts future cognitive decline better than EM activation. These results have implications for use of fMRI in prevention clinical trials involving the identification of persons at-risk for age-associated memory loss and Alzheimer's disease. (JINS, 2012, 18, 1–11)

We administered the Multiscale Depression Inventory (MDI) and the Beck Depression Inventory (BDI) to 84 multiple sclerosis (MS) patients, 101 patients diagnosed with major depression and 87 nonmedical, nonpsychiatric controls. The MDI consists of three separate depression scales measuring mood, vegetative, and evaluative symptoms. We found that: (a) MS patients did not significantly differ from the controls in mood symptoms, (b) the depression prevalence rate in MS patients was significantly lower when measured by the mood scale (17·7%) than by the BDI (30·5%) or MDI total score (26·6%), and (c) MS patients showed significantly less mood disturbance than a non-MS comparison group matched on BDI measured depression severity. We suggest that the inclusion of nonmood symptoms in self-report depression scales may artificially raise both prevalence rates and severity ratings of MS related depression and that the most valid measure of depression in MS is mood disturbance. (JINS, 1995, I, 291–296.)

Person identification represents a unique category of semantic knowledge that is commonly impaired in Alzheimer’s disease (AD), but has received relatively little investigation in patients with mild cognitive impairment (MCI). The current study examined the retrieval of semantic knowledge for famous names from three time epochs (recent, remote, and enduring) in two participant groups: 23 amnestic MCI (aMCI) patients and 23 healthy elderly controls. The aMCI group was less accurate and produced less semantic knowledge than controls for famous names. Names from the enduring period were recognized faster than both recent and remote names in both groups, and remote names were recognized more quickly than recent names. Episodic memory performance was correlated with greater semantic knowledge particularly for recent names. We suggest that the anterograde memory deficits in the aMCI group interferes with learning of recent famous names and as a result produces difficulties with updating and integrating new semantic information with previously stored information. The implications of these findings for characterizing semantic memory deficits in MCI are discussed. (JINS, 2009, 15, 9–18.)

Neuropsychological and neuroimaging changes have been observed in individuals with the Huntington's disease (HD) gene expansion prior to the onset of manifest HD. This cross-sectional fMRI study of preclinical HD (pre-HD) individuals was conducted to determine if functional brain changes precede deficits in behavioral performance and striatal atrophy. Twenty-six pre-HD and 13 demographically matched healthy participants performed a time reproduction task while undergoing fMRI scanning. Pre-HD participants were divided into two groups (n = 13 each): FAR (>12 years to estimated onset [YEO] of manifest HD) and CLOSE (<12 YEO). The CLOSE group demonstrated behavioral deficits, striatal atrophy, and reduced neural activation in the left putamen, SMA, left anterior insula and right inferior frontal gyrus. The FAR group showed reduced neural activation in the right anterior cingulate and right anterior insula. The FAR group also demonstrated increased neural activation in the left sensorimotor, left medial frontal gyrus, left precentral gyrus, bilateral superior temporal gyri and right cerebellum. The fMRI changes in the FAR group occurred in the relative absence of striatal atrophy and behavioral performance deficits. These results suggest that fMRI is sensitive to neural dysfunction occurring more than 12 years prior to the estimated onset of manifest HD. (JINS, 2007, 13, 758–769.)

Huntington's disease (HD) is a neurodegenerative disorder diagnosed clinically with the development of choreiform movements. However, neuropsychological studies have demonstrated cognitive and psychiatric changes during the preclinical phase (pre-HD) prior to formal diagnosis. Previous studies have demonstrated the sensitivity of time reproduction tasks to basal ganglia pathology, as seen in clinical HD and Parkinson's disease. In this study, 29 pre-HD participants, ranging from 3 to 39 years from estimated onset (YEO) of HD based on genetic testing and chronological age, were administered the paced finger-tapping task using target intervals of 600 and 1200 ms. Mean inter-response interval, a measure of timing accuracy, did not systematically deviate from the target interval as a function of YEO. In contrast, timing variability increased curvilinearly as a function of YEO, but not with chronological age alone. Motor timing variability, but not accuracy, may serve as a marker to define the earliest behavioral changes in HD. The present study is among the first to examine the relationship between behavioral measures and YEO in pre-HD. (JINS, 2007, 13, 539–543.)