Dominic A. Carone

Correlating brain atrophy with cognitive dysfunction, mood disturbances, and personality disorder in multiple sclerosis.

Neuropsychological impairment is a common feature of multiple sclerosis. Affected patients often have deficits in informationprocessing speed and memory and exhibit psychopathological states such as depression. A minority of patients have rarer affect/mood disorders such as euphoria sclerotica and pathological laughter/crying. Neuropsychological impairment is a major predictor of low quality of life, unemployment, and caregiver distress. Studies evaluating correlations between neuropsychological impairment and findings on magnetic resonance imaging show that neuropsychological dysfunction is associated with lesion burden and diffuse disease in normalappearing brain tissue. However, measures of tissue atrophy including whole‐brain and central atrophy are especially well correlated with and predictive of cognitive impairment. Moreover, recent studies have shown that conventional measures of brain atrophy explain more variance in neuropsychological dysfunction than do measures of lesion burden. In particular, neuropsychological outcomes correspond highly with linear measures of subcortical atrophy such as ventricle enlargement. Within the domain of emotional dysfunction, both lesion burden and atrophy are related to major depressive disorder. Brain atrophy also predicts euphoria and disinhibition. The preliminary data suggest that although lesion burden primarily predicts depressive disorder, both lesion burden and atrophy predict the presence of euphoria. Euphoria and disinhibition likely represent personality change associated with worsening cognition as the disease progresses. Taken together, this growing body of data on magnetic resonance imaging to neuropsychological correlations supports the clinical relevance and validity of brain atrophy as a measure of disease progression in multiple sclerosis. Continuing research focuses on the possible relationship between measures of regional brain atrophy and cognitive and emotional impairment.

Independent contributions of cortical gray matter atrophy and ventricle enlargement for predicting neuropsychological impairment in multiple sclerosis

The primary goal of this study was to investigate associations between regional gray matter (GM) atrophy and neuropsychological function in multiple sclerosis (MS), while accounting for the influence of central brain atrophy (i.e. third ventricle enlargement). Using a cross-sectional design, we studied 59 MS patients with brain MRI and neuropsychological testing. Regional gray matter fractions (rGMFs) were calculated from MRI images for 11 homologous brain areas using the semiautomatic brain region extraction (SABRE) technique. Neuropsychological testing followed consensus panel guidelines and included tests emphasizing episodic memory, working memory and processing speed. The analytic approach was stepwise linear regression, with forward selection and p<0.05 threshold for significance. Consistent with previous research, there were significant correlations between third ventricle width and neuropsychological tests. Stepwise linear regression analyses controlling for third ventricle width retained rGMFs obtained from specific regions within the prefrontal cortex. Left frontal atrophy was associated with tests emphasizing auditory/verbal memory. Right frontal atrophy was associated with impairment in visual episodic and working memory. For the first time, we show an independent relationship between cortical atrophy and cognitive impairment after accounting for the effects of central atrophy.

Children with moderate/severe brain damage/dysfunction outperform adults with mild-to-no brain damage on the Medical Symptom Validity Test

Primary objective: This study sought independent confirmation that the English computerized Medical Symptom Validity Test can be easily passed by children with moderate-to-severe brain injury/dysfunction (e.g. traumatic brain injury, stroke) and/or developmental disabilities. In addition, it was hypothesized that a higher percentage of such children would pass the MSVT compared to adults with mild traumatic brain injury or head injury (MTBI/HI) and would rate the task as easier. Methods: Thirty-eight children and 67 adults were administered the MSVT during an outpatient neuropsychological evaluation. Results: Two children (5%) failed the MSVT, whereas 14 (21%) of adults failed. Children performed significantly better on the MSVT and rated it as significantly easier compared to adults who failed the MSVT. There were no such differences when children were compared to adults who passed the MSVT. Conclusions: Findings independently validate the use of the MSVT with children and demonstrate symptom exaggeration in a sub-set of adult MTBI/HI patients.

Interpreting patient/informant discrepancies of reported cognitive symptoms in MS

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.

Semi-automatic brain region extraction (SABRE) reveals superior cortical and deep gray matter atrophy in MS.

In multiple sclerosis (MS), atrophy occurs in various cortical and subcortical regions. However, it is unclear whether this is mostly due to gray (GM) or white matter (WM) loss. Recently, a new semi-automatic brain region extraction (SABRE) technique was developed to quantify parenchyma volume in 13 hemispheric regions. This study utilized SABRE and tissue segmentation to examine whether regional brain atrophy in MS is mostly due to GM or WM loss, correlated with disease duration, and moderated by disease course. We studied 68 MS patients and 39 normal controls with 1.5 T brain MRI. As expected, MS diagnosis was associated with significantly lower (P < 0.001) regional brain parenchymal fractions (RBPFs). While significant findings emerged in 11 GM comparisons, only four WM comparisons were significant. The largest mean RBPF percent differences between groups (MS < NC) were in the posterior basal ganglia/thalamus region (-19.3%), superior frontal (-15.7%), and superior parietal (-14.3%) regions. Logistic regression analyses showed GM regions were more predictive of MS diagnosis than WM regions. Eight GM RBPFs were significantly correlated (P < 0.001) with disease duration compared to only one WM region. Significant trends emerged for differences in GM, but not WM between secondary progressive (SP) and relapsing-remitting MS patients. Percent differences in GM between the two groups were largest in superior frontal (-9.9%), medial superior frontal (-6.5%), and superior parietal (-6.1%) regions, with SP patients having lower volumes. Overall, atrophy in MS is diffuse and mostly related to GM loss particularly in deep GM and superior frontal-parietal regions.

Assessment of effort in children: A systematic review

The assessment of response validity is now considered an important and necessary component of neuropsychological evaluations. One way for assessing response validity is with performance validity tests (PVTs), which measure the degree of effort applied to testing to achieve optimal performance. Numerous studies have shown that normal and neurologically impaired children are capable of passing certain free-standing PVTs using adult cutoffs. Despite this, PVT use appears to be more common in adults compared to children. The overall purpose of this systematic review is to provide the reader with a general overview of the existing literature on PVTs in children. As part of this review, goals are to inform the reader why PVT use is not as prevalent in children compared to adults, to discuss why PVTs and related methods are important in pediatric cognitive evaluations, and to discuss practical limitations and future directions.

Test Review of the Medical Symptom Validity Test

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Young Child With Severe Brain Volume Loss Easily Passes the Word Memory Test and Medical Symptom Validity Test: Implications for Mild TBI

The Word Memory Test (WMT) and Medical Symptom Validity Test (MSVT) are two commonly used free-standing measures of test-taking effort. The use of any test as a measure of effort is enhanced when evidence shows that it can be easily passed by patients with severe neurological conditions. The opportunity arose to administer the WMT and MSVT to a 9-year-old girl (referred to as CJ) with severe congenital bilateral brain tissue loss (shown via a compelling brain MRI image), chronic epilepsy, an extremely low Full Scale IQ, extremely low adaptive functioning, developmental delays, numerous severe cognitive impairments, and treatment with multiple high-dose benzodiazepines. She received extensive early intervention services and numerous academic accommodations. Despite this set of problems, CJ passed the WMT and MSVT at perfect to near perfect levels. Implications for failure on these tests among patients with known or alleged mild traumatic brain injury are discussed.

Word Memory Test Profiles in Two Cases with Surgical Removal of the Left Anterior Hippocampus and Parahippocampal Gyrus

One principle underlying the use of the Word Memory Test (WMT) as an effort test is that with good effort, recognition scores above the cutoffs will be observed. However, to understand the limits of effort testing, it is necessary to study people known to have severe impairment and significant neuropathology involving memory structures. Goodrich-Hunsaker and Hopkins (2009) reported that three amnesic patients with bilateral hippocampal damage had severely impaired free recall of the WMT word list but passed the recognition subtests of the WMT, which are often called effort subtests. We tested two patients with surgical resections in the left anterior temporal region to treat chronic intractable epilepsy; both patients had suffered postoperative strokes. Patient A was a 15-year-old boy and Patient B was a 58-year-old woman. Despite destruction of the left anterior hippocampus and the parahippocampal gyrus and despite impairment of free recall, both cases passed the easy WMT effort subtests. These data reinforce previous findings that people with severe impairment of free recall will score much higher on the verbal recognition memory subtests than on the more difficult memory subtests. Even severe memory impairment and/or removal of hippocampal areas do not necessarily lead to failure on the easy WMT recognition subtests.

Regionally Distinct White Matter Lesions Do Not Contribute to Regional Gray Matter Atrophy in Patients with Multiple Sclerosis

To determine to what extent T1‐ and T2‐regional lesion volumes (RLVs) contribute to total and/or regional gray matter (GM) atrophy in multiple sclerosis (MS).