Sandra S. Kindermann

Analysis of fMRI Data by Blind Separation Into Independent Spatial Components

Current analytical techniques applied to functional magnetic resonance imaging (fMRI) data require a priori knowledge or specific assumptions about the time courses of processes contributing to the measured signals. Here we describe a new method for analyzing fMRI data based on the independent component analysis (ICA) algorithm of Bell and Sejnowski ([1995]: Neural Comput 7:1129–1159). We decomposed eight fMRI data sets from 4 normal subjects performing Stroop color‐naming, the Brown and Peterson word/number task, and control tasks into spatially independent components. Each component consisted of voxel values at fixed three‐dimensional locations (a component “map”), and a unique associated time course of activation. Given data from 144 time points collected during a 6‐min trial, ICA extracted an equal number of spatially independent components. In all eight trials, ICA derived one and only one component with a time course closely matching the time course of 40‐sec alternations between experimental and control tasks. The regions of maximum activity in these consistently task‐related components generally overlapped active regions detected by standard correlational analysis, but included frontal regions not detected by correlation. Time courses of other ICA components were transiently task‐related, quasiperiodic, or slowly varying. By utilizing higher‐order statistics to enforce successively stricter criteria for spatial independence between component maps, both the ICA algorithm and a related fourth‐order decomposition technique (Comon [1994]: Signal Processing 36:11–20) were superior to principal component analysis (PCA) in determining the spatial and temporal extent of task‐related activation. For each subject, the time courses and active regions of the task‐related ICA components were consistent across trials and were robust to the addition of simulated noise. Simulated movement artifact and simulated task‐related activations added to actual fMRI data were clearly separated by the algorithm. ICA can be used to distinguish between nontask‐related signal components, movements, and other artifacts, as well as consistently or transiently task‐related fMRI activations, based on only weak assumptions about their spatial distributions and without a priori assumptions about their time courses. ICA appears to be a highly promising method for the analysis of fMRI data from normal and clinical populations, especially for uncovering unpredictable transient patterns of brain activity associated with performance of psychomotor tasks. Hum. Brain Mapping 6:160–188, 1998.

Brain activation and pupil response during covert performance of the Stroop Color Word task.

Patterns of brain activation associated with covert performance of the Stroop Color-Word task were studied in young, healthy, adult volunteers using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Comparisons of the incongruous Stroop condition were made with both color naming and word reading baselines. Areas of the left and right anterior cingulate, the right precuneus, and the left pars opercularis displayed larger BOLD signal responses during the incongruous Stroop condition than during baseline conditions. Activation of BOLD signals in these areas was highly repeatable. In a second experiment, pupil diameter was used to assess cognitive load in 7 individuals studied during overt and covert performance of both Stroop and color naming conditions. Cognitive load was similar in overt and covert response conditions. Results from the BOLD study indicate that brain regions participating in selective visual attention and in the selection of motor programs involved in speech were activated more by the Stroop task than by the baseline tasks. The neural substrate involved in the resolution of the perceptual and motor conflicts elicited by the Stroop Color-Word task does not appear to be a single brain region. Rather, a network of brain regions is implicated, with separate regions within this system supporting distinct functions.

BOLD and perfusion response to finger-thumb apposition after acetazolamide administration: differential relationship to global perfusion.

The authors studied the effects of altering global cerebral blood flow on both blood oxygen level–dependent (BOLD) response and perfusion response to finger-thumb apposition. A PICORE/QUIPSS II protocol was used to collect interleaved BOLD-weighted and perfusion-weighted images on eight finger-thumb apposition trials. Subjects were studied on a drug-free day and on a day when acetazolamide was administered between the second and third trials. After acetazolamide administration, resting cortical perfusion increased an average of 20% from preadministration levels, whereas the BOLD response to finger-thumb apposition decreased by an average of 35% in the S1M1 hand area. Contrary to predictions from the exhausted cerebrovascular reserve hypothesis and the oxygen limitation model, an effect of acetazolamide on cerebral blood flow response in the S1M1 hand area was not observed. Across the acetazolamide trials, BOLD response was inversely correlated with resting cortical perfusion for individual subject data. These results suggest that resting perfusion affects the magnitude of the BOLD response and is thus an important confounding factor in fMRI studies, and that the physiologic systems that increase cerebral blood flow in response to acetazolamide administration and systems that increase cerebral blood flow in response to altered neural activity appear to have additive effects.

An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder

Structural neuroimaging studies have identified abnormalities in the basal ganglia in patients with bipolar disorder. Findings have been mixed with regard to affective state and have not elaborated on the role of medication on functional brain activity. The aims of the present study were to use functional magnetic resonance imaging (fMRI) to test whether depressed and manic bipolar disorder patients differ in terms of activity in cortical and subcortical brain areas and to examine the effects of psychotropic medication. Twenty-four bipolar disorder subjects and 13 healthy comparison subjects participated in an fMRI study of manual reaction time. Both manic and depressed subjects exhibited abnormally elevated blood oxygen level dependent BOLD responses in cortical and subcortical areas. Manic bipolar subjects had significantly higher BOLD responses in the left globus pallidus and significantly lower BOLD responses in the right globus pallidus compared with depressed bipolar patients. Correlational analyses revealed significant relationships between the severity of mania and activity within the globus pallidus and caudate. Patients off antipsychotic or mood-stabilizing medication exhibited significantly higher BOLD responses throughout the motor cortex, basal ganglia and thalamus compared with patients on these medications. These results suggest that affective state in bipolar disorder may be related to a disturbance of inhibitory regulation within the basal ganglia and that antipsychotics and/or mood stabilizers normalize cortical and subcortical hyperactivity.

Spatial working memory among middle-aged and older patients with schizophrenia and volunteers using fMRI

OBJECTIVE Goldman-Rakic and Selemon (Schizophr. Bull. 23 (1997)) hypothesized that many of the symptoms of schizophrenia can be explained by deficits of working memory (WM) that are, in turn, caused by dysfunction of dorsolateral prefrontal cortex (DLPFC). We examined whether older patients with schizophrenia would show an aberrant neural response in the DLPFC or other brain sites when performing a spatial working memory (WM) task adapted from McCarthy et al. (Proc. Natl. Acad. Sci. U. S. A. 91 (1994)). METHOD Middle-aged and older patients with schizophrenia or schizoaffective disorder and healthy volunteers performed a spatial WM task contrasted with two baselines, passive and active viewing (PV and AV, respectively), while blood oxygen level dependent (BOLD) images were acquired in a functional magnetic resonance study. RESULTS Patients did not perform significantly less well on the spatial tasks compared to the volunteers. Although we found no significant group effects in spatial WM activation of DLPFC, we did observe areas in medial frontal cortex including the left anterior cingulate gyrus, parietal areas of the both hemispheres, multiple sites within the basal ganglia of the left hemisphere, and the left superior temporal gyrus where healthy volunteers showed greater BOLD response to WM. In a second pattern, patients showed a greater BOLD response to WM in left fusiform gyrus [Brodmanns Area (BA) 19], peri-rolandic areas, medial frontal area; right anterior cerebellum (culmen), middle occipital lobe, and postcentral/supramarginal gyri (BA 2/40). CONCLUSIONS Middle-aged and older patients with schizophrenia display normal or near-normal spatial WM activation of DLPFC when the processing demands of the WM task are within their performance capacity. Nonetheless, even when patients perform nearly normally, they demonstrate an aberrant pattern of brain response.

Pharmacological treatment of psychosis and agitation in elderly patients with dementia: four decades of experience.

A number of studies, using different research designs and assessment instruments, have been conducted to elucidate the differential effects of drug treatments for psychosis, agitation and aggression in elderly patients with dementia. We have reviewed literature published from 1960 to 2000 on this topic; 48 studies that met our selection criteria were identified from Medline and Science Citation Index.Antipsychotic medication was generally effective for the treatment of psychosis and agitation in elderly patients with dementia. In double-blind, placebo-controlled trials in this population, mean improvement rates were 61% with antipsychotic s and 35% with placebo. Atypical antipsychotics appeared promising, but the number of well-designed studies has been small so far. Methodological limitations of the studies reviewed are discussed; future trials should ensure adequate sample size and duration and involve direct comparisons of individual medications.In conclusion, conventional antipsychotics are modestly effective for treatment of psychosis and agitation in elderly individuals with dementia, whereas newer treatments such as atypical antipsychotics appear to be at least as effective while having fewer adverse effects. Nonetheless, there is no currently available ideal pharmacotherapy, and psychosocial management is a necessary part of overall treatment. Additional large-scale, well-controlled studies are needed before conclusive statements regarding the value of treatment of psychosis and agitation with atypical antipsychotics and non-antipsychotic agents can be made.

Review of functional magnetic resonance imaging in schizophrenia

Functional magnetic resonance imaging (fMRI) holds great promise for assessing temporal changes in brain activity using various challenge paradigms. In this report, we review the 14 studies (eight of them abstracts) that comprise the fMRI literature available to date relating to schizophrenia. Twelve of the 14 investigations examined changes in blood-oxygen-level-dependent (BOLD) contrast: two examined blood volume. Eight of the 12 BOLD studies relied on lower-order cognitive processing to measure activation (involving sensory or motor areas), whereas four used higher-order tasks (word production, auditory processing, and subspan word recall involving multiple brain areas). Although the variability in tasks used, brain regions studied, imaging methods used, patient characteristics reported, and methods of reporting significance precluded a full meta-analysis, we re-analyzed these published data to compute effect sizes. In most studies, resting blood volume and BOLD changes, regardless of the complexity of the cognitive task, appeared to differ between patients with schizophrenia and control subjects.

Functional Brain Asymmetries During Visuomotor Tracking

This study examined brain asymmetries elicited during visuomotor tracking. Thirty-two healthy participants performed a fixed gaze, dynamic, pinch force, visuomotor tracking task during a functional magnetic resonance imaging study. The dynamic task required the subject to press a rubber bulb with the thumb to trace a cosine square wave varying in force amplitude from 0-500 cN and having a frequency of 1.5 Hz. Response hand order and direction of the stimulus presentation (right-to-left or left-to-right) were permuted across participants. Two forms of functional cerebral asymmetry were observed, hemispheric specialization and homologous lateralized response. The superior portion of the right middle frontal gyrus and the left supplementary motor area appeared specialized for VM tracking regardless of response hand used or stimulus movement direction. Lateralized effects appeared in the primary sensorimotor hand area, putamen, parietal operculum/posterior insula, dentate nucleus of the cerebellum, precuneus, and middle occipital gyrus. These lateralized areas of activation surfaced when either response hand or direction of stimulus movement was manipulated. The VM task used in this study activated asymmetrical neural activity in the vertically organized skelotomotor system and in sensory systems involving visual attention or proprioception.

Effects of task structure on category priming in patients with Parkinson's disease and in healthy individuals

Lexical decision tasks have been used to study both shifts of attention and semantic processing in Parkinsons Disease (PD). Whereas other laboratories have reported normal levels of semantic priming among PD patients, our laboratory has reported abnormally large levels. In this study, two experiments were performed to determine the influence of task structure on the extent of semantic priming during lexical decision-making and pronunciation tasks among PD patients and neurologically healthy controls. In Experiment 1, the effect of Prime Dominance (the ratio of category to neutral trials) on lexical decision-making was studied. Although equal numbers of word and nonword trials were presented, half of the PD patients and controls were studied under Category Prime Dominance (category : neutral prime ratio of 2:1) and half were studied under Neutral Prime Dominance (category : neutral prime ratio of 1:2). In Experiment 2, PD and control participants were studied on lexical decision-making and pronunciation tasks where twice as many words as nonword trials were presented, consistent with other studies from our laboratory. In Experiment 1, we found no group differences in the magnitude of priming and no effect of Prime Dominance. Moreover, the findings were similar in pattern and magnitude to results published by Neely (1977). In Experiment 2, we observed larger priming effects among PD patients than among controls, but only on the lexical decision (LD) task. These results support the hypothesis that abnormally large category-priming effects appear in LD studies of PD patients when the number of word trials exceeds the number of nonword trials. Furthermore, increased lexical priming in PD appears to be due to processes operating during the decision-making period that follows presentation of the lexical target.

Neuropsychological Aspects of Stroke

This chapter discusses neuropsychological aspects of stroke. Neuropsychological measures are sensitive to brain changes associated with stroke and have implications for adaptive behavior outside clinical settings. Neuropsychological assessment can provide unique information about stroke disability. The evidence for focal or lateralized neuropsychological deficits following brain hemorrhage is less consistent than following ischemic stroke. Patients with aneurysmal subarachnoid hemorrhage often display a broad range of neuropsychological deficits that frequently cannot be correlated with the site of the aneurysm. Arteriovenous malformations (AVMs) often produce impairments of general adaptive abilities; they less consistently produce lateralized or focal neuropsychological deficits than ischemic stroke. When neuropsychological signs of asymmetry are clearly present; the laterality of AVMs can be predicted as accurately as the laterality of thrombotic-embolic strokes. The integration of neuropsychological and pathophysiological data requires more basic research relating improved neuropsychological functioning during recovery to changes in regional cerebral blood flow, cerebral metabolism, neurotransmitter levels, structural damage, and edema.