Few studies have examined functional connectivity (FC) patterns using functional magnetic resonance imaging (fMRI) to predict outcomes in late-life depression. We hypothesized that FC within and between frontal and limbic regions would be associated with 12-week depression outcome in older depressed adults. Seventy-one subjects with major depression were enrolled in the study. A study geriatric psychiatrist performed a clinical interview and completed a Montgomery-Åsberg Depression Rating Scale (MADRS). All study participants were free of medication at baseline and had a brain fMRI scan. Using a regions of interest (ROI) atlas (including 164 ROIs), we conducted ROI-to-ROI resting-state FC analyses for each participant. In terms of treatment participants were offered sertraline initially, although in this naturalistic study, other medications were also prescribed. Subjects were evaluated every 2 weeks up to 12 weeks by the study psychiatrist, who followed a flexible, clinically based medication dosing schedule. Multivariate regression analysis was used to examine correlation between change of MADRS score over 12 weeks and baseline FC between brain regions, controlling for age, gender, mean head motion, and baseline MADRS. We found greater FC between the left inferior frontal gyrus pars triangularis and the left frontal eye field and FC of these two regions with a number of brain regions related to reward, salience, and sensorimortor function were correlated with change in MADRS score over 12 weeks. Our results highlight the important role of between inner speech-reward, attention-salience, and attention-sensorimotor network synchronization in predicting acute treatment response in late-life depression.

Calhoun VD, Wu L, Kiehl KA, Eichele T, Pearlson GD. Aberrant processing of deviant stimuli in schizophrenia revealed by fusion of fMRI and EEG data.

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)

Regression-based normative techniques account for variability in test performance associated with multiple predictor variables and generate expected scores based on algebraic equations. Using this approach, we show that estimated IQ, based on oral word reading, accounts for 1–9% of the variability beyond that explained by individual differences in age, sex, race, and years of education for most cognitive measures. These results confirm that adding estimated “premorbid” IQ to demographic predictors in multiple regression models can incrementally improve the accuracy with which regression-based norms (RBNs) benchmark expected neuropsychological test performance in healthy adults. It remains to be seen whether the incremental variance in test performance explained by estimated “premorbid” IQ translates to improved diagnostic accuracy in patient samples. We describe these methods, and illustrate the step-by-step application of RBNs with two cases. We also discuss the rationale, assumptions, and caveats of this approach. More broadly, we note that adjusting test scores for age and other characteristics might actually decrease the accuracy with which test performance predicts absolute criteria, such as the ability to drive or live independently. (JINS, 2009, 15, 1012–1022.)

Synaptic development and elimination are normal neurodevelopmental processes, which if altered could contribute to various neuropsychiatric disorders. 31P-1H magnetic resonance spectroscopic imaging (MRSI) and structural magnetic resonance imaging (MRI) exams were conducted on 105 healthy children ages 6–18 years old to identify neuromolecular indices of synaptic development and elimination. Over the age range studied, age-related changes in high-energy phosphate (phosphocreatine), membrane phospholipid metabolism (precursors and breakdown products), and percent gray matter volume were found. These neuromolecular and structural indices of synaptic development and elimination are associated with development of several cognitive domains. Monitoring of these molecular markers is essential for devising treatment strategies for neurodevelopmental disorders. (JINS, 2009, 15, 671–683.)

Previous studies reveal significant relationships between some quantitative computed tomography (CT) measures and level of cognitive functioning in patients with Alzheimer's disease (AD). This study was designed to determine whether measurements from CT scans of AD patients could predict future rates of decline in cognitive function. Subjects were 8 men and 19 women diagnosed with probable AD. CT measures included bifrontal ratio, bicaudate ratio, and areas of lateral ventricles, third ventricle, and suprasellar cistern (SSC). Measures of cognitive and adaptive functioning were obtained at the time of the scan and on follow-up. Of the CT measures, the SSCR (SSC corrected for intracranial area) was the most highly correlated with Mini-Mental State Exam (MMSE) score and other cognitive measures at the time of the scan. Follow-up data were obtained for those 20 individuals who were mildly to moderately demented at the time of the scan (MMSE ≥ 10). Rate of change was calculated for each neuropsychological measure. The SSCR correlated significantly with rate of change for MMSE and other measures of cognitive and adaptive functioning. This study demonstrates that CT measurement of the SSC can predict the subsequent rate of neurocognitive decline in AD patients. (JINS, 1996, 2, 89–95.)

The frequency and determinants of abnormal test performance by normal individuals are critically important to clinical inference. Here we compare two approaches to predicting rates of abnormal test performance among healthy individuals with the rates actually shown by 327 neurologically normal adults aged 18–92 years. We counted how many participants produced abnormal scores, defined by three different cutoffs with test batteries of varied length, and the number of abnormal scores they produced. Observed rates generally were closer to predictions based on a series of Monte Carlo simulations than on the binomial model. They increased with the number of tests administered, decreased as more stringent cutoffs were used to identify abnormality, varied with the degree of correlation among test scores, and depended on individual differences in age, education, race, sex, and estimated premorbid IQ. Adjusting scores for demographic variables and premorbid IQ did not reduce rates of abnormal performance. However, it eliminated the contribution of these variables to rates of abnormal test performance. These findings raise fundamental questions about the nature and interpretation of abnormal test performance by normal, healthy adults. (JINS, 2008, 14, 436–445.)

Recency discrimination has been conceptualized as an executive ability by some investigators and as an aspect of episodic memory by others. We compared the performance of 261 neurologically healthy adults on a recency discrimination task (RDT) with their performance on measures of executive functioning and explicit memory. Mean z-transformed raw scores were used to construct indices of visual and verbal explicit memory, fluency, and executive functioning. Analyses revealed that RDT performance correlated more closely with visual (r = 0.32; p < 0.001) and verbal memory (r = 0.25; p < 0.001) than with fluency (r = 0.16; p < 0.05) and executive functioning (r = 0.13; p < 0.05). These findings suggest that recency discrimination might be better understood as an aspect of episodic memory that is subserved primarily by hippocampal and medial temporal structures than as an executive function that is subserved primarily by prefrontal cortex. (JINS, 2007, 13, 710–715.)

Diagnostic neuropsychological assessment requires the clinician to estimate a patient's premorbid abilities. Word reading tests, such as the National Adult Reading Test–Revised (NART–R), provide reasonably accurate estimates of premorbid IQ, but their capacity to benchmark other premorbid cognitive abilities remains unclear. In this extension of an earlier report, we administered the NART–R, an abbreviated Wechsler Adult Intelligence Scale (WAIS–R or WAIS–III), and 26 other cognitive measures to 322 reasonably healthy adults. While NART–R performance correlated robustly (rs ≥ .72) with concurrent Verbal and Full Scale IQ, its correlation with all other cognitive measures was significantly lower. Thus, while it is appealing to use word reading as a proxy for premorbid functioning in other cognitive domains, the NART–R has limited utility for this because it does not predict current performance on other cognitive tests as well as it predicts IQ in healthy adults. (JINS, 2005, 11, 784–787.)

The strength and nature of the association between IQ and performance on other cognitive tests has both practical and conceptual significance for clinical neuropsychology. In this study, 28 measures derived from 16 cognitive tests were analyzed as a function of IQ in 221 adults. Participants were grouped by their IQ scores as having below average (BA), average (A), or above average (AA) intelligence. Planned comparisons revealed that A adults performed significantly better than BA adults on 25 of the 28 cognitive measures, and that AA adults performed significantly better than A adults on 19 of 28 measures. Effect sizes averaged .74 for BA–A comparisons and .41 for A–AA comparisons. Linear, quadratic, and cubic functions described the relationships between IQ and cognitive test performance equally well for most individual test measures and for a composite index of test performance, whereas quadratic and cubic functions explained the proportion of abnormal performances better than a linear function. These findings confirm that IQ predicts concurrent neuropsychological performance across the entire spectrum of intelligence, but more so among persons of average IQ or less than among those with above average IQ. (JINS, 2004, 10, 82–90.)

Neuropsychologists often diagnose cerebral dysfunction based, in part, on marked variation in an individual's cognitive test performance. However, little is known about what constitutes the normal range of intraindividual variation. In this study, after excluding 54 individuals with significant health problems, we derived 32 z-transformed scores from 15 tests administered to 197 adult participants in a study of normal aging. The difference between each person's highest and lowest scores was computed to assess his or her maximum discrepancy (MD). The resulting MD values ranged from 1.6 to 6.1 meaning that the smallest MD shown by any person was 1.6 standard deviations (SDs) and the largest MD shown by any person was 6.1 SDs. Sixty-six percent of participants produced MD values that exceeded 3 SDs. Eliminating each person's highest and lowest test scores decreased their MDs, but 27% of the participants still produced MD values exceeding 3. Although MD values appeared to increase with age, adjusting test scores for age, which is standard in clinical practice, did not correct for this. These data reveal that marked intraindividual variability is very common in normal adults, and underscore the need to base diagnostic inferences on clinically recognizable patterns rather than psychometric variability alone. (JINS, 2003, 9, 864–870.)

One theory of normal cognitive aging asserts that decreases in simple processing speed mediate the age-related decline of fluid intelligence. Another possibility is that age-related atrophic changes in frontal brain structures undermine the functioning of executive abilities, thereby producing the same decline. In this study, we used principal components analysis to derive a measure of fluid–spatial intelligence in 197 normal adults between 20 and 92 years of age. Measures of perceptual comparison speed, working memory, and executive ability, as well as regional brain volumes based on high resolution magnetic resonance imaging were obtained from a subsample of 112 participants. We then conducted a series of hierarchical multiple regression analyses to test whether (1) the processing speed theory, (2) frontal–executive theory, or (3) some combination of these best accounted for age-related variation in fluid intelligence. The results showed that perceptual comparison speed, executive ability, and frontal lobe volume each made significant contributions to a regression equation that explained 57% of the variance in fluid intelligence. These findings suggest that both the processing speed and frontal–executive theory of cognitive aging are partially correct and complement one another. (JINS, 2000, 6, 52–61.)

Computerised tomography (CT) was used to assess the possible effects of substance abuse on brain morphology. Polydrug abusers had significantly wider third ventricles than normal controls, with a positive correlation between age and ventricle:brain ratio (VBR). Assuming no effect of age, estimated quantity of substance abuse was not significantly related to ventricular and sulcal measures, except that alcohol consumption correlated positively with VBR and severity of cocaine use correlated negatively with sulcal width. When age of the subjects was partialled out, alcohol use showed a tendency for association with VBR; however, severity of cocaine use did not remain a significant predictor of cortical sulcal width. The findings suggest that chronic use of alcohol, but not necessarily of other commonly abused substances, produces brain atrophy.

A standardized, reliable means of assessing CT attenuation numbers in the centrum semiovale and surrounding grey matter was developed. This was applied to cranial CT scans of 60 normal controls (36 aged > 60 years), 25 elderly patients with major depression (14 of whom had the dementia syndrome of depression), and 10 patients with Alzheimer's disease (AD). Subjects received neuropsychological evaluation.

Centrum semiovale (CSO) CT attenuation numbers decreased with increasing age for both white and grey matter. White matter attenuation values best discriminated elderly controls from the three patient groups. Both white and grey matter CSO attenuation values correlated with performance on a number of cognitive tasks.

Twenty-six elderly (> 60 yrs) patients with DSM-III major depression were compared to 13 patients with NINCDS/ADRDA probable Alzheimer's disease (AD), and to 31 screened normal controls. Subjects were matched on age and sex. Fifteen of the 26 depressed patients were cognitively impaired on the Mini-Mental State Examination (MMSE) upon admission, but after treatment returned to the normal range. These 15 patients were defined as having the dementia syndrome of depression (DOD). The remaining 11 depressed patients were termed depressed, cognitively normal (DCN). All subjects received standardized cranial CT scans for assessment of ventricular brain ratio (VBR) and CT attenuation numbers. Subjects also received neuropsychological evaluation.

CT values for the 26 depressed patients lay between those of AD patients and normal controls. CT values for the DOD subgroup clustered near those of AD patients. Patterns of cognitive deficits and correlations of CT attenuation values with cognitive measures were also similar in AD and DOD. Most patients were reassessed at a mean of two years after initial testing; of the 11 of the 15 DOD re-examined, only one had undergone cognitive decline. By contrast, all AD patients retested had declined significantly. Episodes of DOD and DCN tended to ‘breed true’. This study suggests that while patients with DOD may have underlying structural brain abnormalities, obvious short-term progression to AD does not commonly occur.