David J. Schretlen

A quantitative review of the effects of traumatic brain injury on cognitive functioning

Changes in cognitive functioning often result from traumatic brain injury (TBI) and predict other important aspects of psychosocial recovery. Despite this pivotal role, no quantitative review of cognitive functioning across the spectrum of TBI severity has been reported. We therefore conducted a meta-analysis of 39 mostly cross-sectional studies of the cognitive effects of mild head injury (MHI) and moderate–severe TBI from the acute phase through long-term follow-up. The studies reported 48 comparisons of patients (n = 1716) and control subjects (n = 1164). Averaged across all follow-up periods, the effect of moderate–severe TBI (weighted mean Cohen‘s d = −0.74) was more than three times the effect of MHI (weighted mean d = −0.24) on overall cognitive functioning. Further, the natural logarithm of the follow-up interval correlated very strongly with estimates of d among patients with MHI, but less so among those with moderate–severe TBI. In short, findings from published research suggest that overall cognitive functioning recovers most rapidly during the first few weeks following MHI, and essentially returns to baseline within 1–3 months. Cognitive functioning also improves during the first two years after moderate–severe TBI, but remains markedly impaired even among patients tested > 2 years post-injury.

Revision of the Brief Visuospatial Memory Test: Studies of normal performance, reliability, and validity.

There is an increasing demand for alternate-form neuropsychological tests that can be used in clinical trials with little risk of direct practice effect. Although the Brief Visuospatial Memory Test (BVMT) includes six equivalent alternate forms, its administration is limited to an immediate and 25-min delayed free-recall trial. We now present a revised version of the BVMT called the Brief Visuospatial Memory Test-Revised (BVMT-R) that includes three learning trials, a 25-min delayed recall trial, and a delayed yes/no recognition task. A new scoring system, which accounts for the location of test stimuli as well as the accuracy of recall, is also introduced. Using these new administration and scoring procedures, we administered the BVMT-R to 261 neuropsychiatric patients and 456 normal healthy adults. The results indicated that the test has excellent interform reliability, and the construct and criterion-related validity of the test were supported in studies using clinical samples. Although the BVMT-R is not without its limitations, the tests brevity and alternate-form capacity make it a valuable instrument for serial neuropsychological assessments.

Increased Occupancy of Dopamine Receptors in Human Striatum during Cue-Elicited Cocaine Craving

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [11C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Neuropsychological Functioning in Bipolar Disorder and Schizophrenia

BACKGROUND Some patients with bipolar disorder (BD) demonstrate neuropsychological deficits even when stable. However, it remains unclear whether these differ qualitatively from those seen in schizophrenia (SZ). METHODS We compared the nature and severity of cognitive deficits shown by 106 patients with SZ and 66 patients with BD to 316 healthy adults (NC). All participants completed a cognitive battery with 19 individual measures. After adjusting their test performance for age, sex, race, education, and estimated premorbid IQ, we derived regression-based T-scores for each measure and the six cognitive domains. RESULTS Both patient groups performed significantly worse than NCs on most (BD) or all (SZ) cognitive tests and domains. The resulting effect sizes ranged from .37 to 1.32 (mean=.97) across tests for SZ patients and from .23 to .87 (mean=.59) for BD patients. The Pearson correlation of these effect sizes was .71 (p<.001). CONCLUSIONS Patients with bipolar disorder suffer from cognitive deficits that are milder but qualitatively similar to those of patients with schizophrenia. These findings support the notion that schizophrenia and bipolar disorder show greater phenotypic similarity in terms of the nature than severity of their neuropsychological deficits.

Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: A pilot study

BACKGROUND Previous reports of ventricular and hippocampal volumes in patients with bipolar disorder (BP) have been inconsistent in their findings. One possibility is that volumetric abnormalities are determined by disease subtype. Prior evidence suggests that psychotic (PBP) and nonpsychotic (NPBP) forms of BP are two subtypes that might differ in pathophysiology. METHODS We investigated ventricular and hippocampal volumes in 38 adults with clearly defined PBP (n = 23) and NPBP subtypes, compared with 33 persons with schizophrenia (SZ) and 44 healthy community control subjects (HC). Ventricular and hippocampal volumes were reliably measured on high-resolution anatomic magnetic resonance imaging scans. We used a multivariate analysis of covariance to compare volumes across groups, covarying for total brain volume. Potential effects of BP illness features were explored, contrasting PBP and NPBP. RESULTS For ventricular but not hippocampal regions, we found significant volume difference in PBP but not NPBP compared with HC (p < .005). We also observed nonsignificantly smaller left hippocampal volumes in PBP versus HC. Schizophrenic subjects had significantly larger ventricular and smaller left hippocampal volumes than HC. CONCLUSIONS These results suggest that PBP but not NPBP is associated with increased ventricle volumes and a trend toward smaller left hippocampal volumes, as observed in SZ.

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-Rs), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DArel) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DArel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D2-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS-OCD). In three subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DArel and 5-HT2A BP, when compared with TS–OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DArel is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT2AR in individuals with TS who had increased DArel, suggest a condition of increased phasic DArel modulated by low 5-HT in concomitant OCD.

Elucidating the contributions of processing speed, executive ability, and frontal lobe volume to normal age-related differences in fluid intelligence.

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.

Source-based morphometry: The use of independent component analysis to identify gray matter differences with application to schizophrenia

We present a multivariate alternative to the voxel‐based morphometry (VBM) approach called source‐based morphometry (SBM), to study gray matter differences between patients and healthy controls. The SBM approach begins with the same preprocessing procedures as VBM. Next, independent component analysis is used to identify naturally grouping, maximally independent sources. Finally, statistical analyses are used to determine the significant sources and their relationship to other variables. The identified “source networks,” groups of spatially distinct regions with common covariation among subjects, provide information about localization of gray matter changes and their variation among individuals. In this study, we first compared VBM and SBM via a simulation and then applied both methods to real data obtained from 120 chronic schizophrenia patients and 120 healthy controls. SBM identified five gray matter sources as significantly associated with schizophrenia. These included sources in the bilateral temporal lobes, thalamus, basal ganglia, parietal lobe, and frontotemporal regions. None of these showed an effect of sex. Two sources in the bilateral temporal and parietal lobes showed age‐related reductions. The most significant source of schizophrenia‐related gray matter changes identified by SBM occurred in the bilateral temporal lobe, while the most significant change found by VBM occurred in the thalamus. The SBM approach found changes not identified by VBM in basal ganglia, parietal, and occipital lobe. These findings show that SBM is a multivariate alternative to VBM, with wide applicability to studying changes in brain structure. Hum Brain Mapp, 2009.

Is Aberrant Functional Connectivity A Psychosis Endophenotype? A Resting State Functional Magnetic Resonance Imaging Study

BACKGROUND Schizophrenia and bipolar disorder share overlapping symptoms and risk genes. Shared aberrant functional connectivity is hypothesized in both disorders and in relatives. METHODS We investigated resting state functional magnetic resonance imaging in 70 schizophrenia and 64 psychotic bipolar probands, their respective first-degree relatives (n = 70 and 52), and 118 healthy subjects. We used independent component analysis to identify components representing various resting state networks and assessed spatial aspects of functional connectivity within all networks. We first investigated group differences using five-level, one-way analysis of covariance (ANCOVA), followed by post hoc t tests within regions displaying ANCOVA group differences and correlation of such functional connectivity measures with symptom ratings to examine clinical relationships. RESULTS Seven networks revealed abnormalities (five-level one-way ANCOVA, family-wise error correction p < .05): A) fronto-occipital, B) midbrain/cerebellum, C) frontal/thalamic/basal ganglia, D) meso/paralimbic, E) posterior default mode network, F) fronto-temporal/paralimbic and G) sensorimotor networks. Abnormalities in networks B and F were unique to schizophrenia probands. Furthermore, abnormalities in networks D and E were common to both patient groups. Finally, networks A, C, and G showed abnormalities shared by probands and their relative groups. Negative correlation with Positive and Negative Syndrome Scale negative and positive scores were found in regions within network C and F respectively, and positive correlation with Positive and Negative Syndrome Scale negative scores was found in regions in network D among schizophrenia probands only. CONCLUSIONS Schizophrenia, psychotic bipolar probands, and their relatives share both unique and overlapping within-network brain connectivity abnormalities, revealing potential psychosis endophenotypes.

Frequency and bases of abnormal performance by healthy adults on neuropsychological testing

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.