Baseline cerebral metabolism predicts fatigue and cognition in Multiple Sclerosis patients.

BACKGROUND: Cerebral metabolic rate of oxygen (CMRO2), a measure of global oxygen metabolism, reflects resting cellular activity. The mechanisms underlying fatigue and cognitive dysfunction in multiple sclerosis (MS) remain unknown. If fatigue indeed reflects ongoing autoimmune activity and cortical reorganization, and cognitive decline is the result of gray matter atrophy and white matter degeneration, we postulate that changes in CMRO2 should reflect disease activity and predict these symptoms. OBJECTIVE: We sought to utilize T2-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI to measure global CMRO2 to understand its relationships to white matter microstructure, fatigue and cognitive dysfunction. METHODS: We measured venous oxygenation (TRUST) and cerebral blood flow (PC-MRI) in superior sagittal sinus to calculate global CMRO2 and diffusion tensor imaging (DTI) to evaluate white matter microstructure in healthy controls (HC) and MS patients. Participants underwent neuropsychological examinations including Modified Fatigue Impact Scale (MFIS) and Symbol-Digit-Modalities Test (SDMT). RESULTS: We observed lower CMRO2 in MS patients compared to HC. After controlling for demographic and disease characteristics (i.e., age, education, disability, lesion volume), CMRO2 predicted increased fatigue (MFIS) and reduced cognitive performance (SDMT) in MS patients. Finally, MS patients with higher CMRO2 have reduced FA in normal-appearing white-matter. CONCLUSION: Altogether, these results suggest that increased CMRO2 reflects ongoing demyelination and autoimmune activity which plays an important role in both fatigue and cognitive dysfunction.

Factors controlling neural activity during delayed-response task performance: testing a memory organization hypothesis of prefrontal function.

Understanding the role of prefrontal cortex in delayed-response task performance has been a central focus of neuroimaging research. The first part of this review will emphasize consistent observations of memory-load-related effects on prefrontal cortex activity that have led me and my colleagues to propose a "memory-organization hypothesis" of prefrontal cortex function. The second part examines how predictions of this hypothesis have borne up to empirical testing. The final part of this review suggests that there is important information contained in between-study variance in the anatomical locus and temporal sequence of neural activity. I will examine how subtle variations in task-structure affect subjects' strategies, producing meaningful variability in neuroimaging data. Systematic manipulation of these variables in future research can assist in elucidating the role of prefrontal cortex in delayed response task performance.

Age differences in prefrontal cortical activity in working memory.

Working memory (WM) declines with advancing age. Brain imaging studies indicate that ventral prefrontal cortex (PFC) is active when information is retained in WM and that dorsal PFC is further activated for retention of large amounts of information. The authors examined the effect of aging on activation in specific PFC regions during WM performance. Six younger and 6 older adults performed a task in which, on each trial, they (a) encoded a 1- or 6-letter memory set, (b) maintained these letters over 5-s. and (c) determined whether or not a probe letter was part of the memory set. Comparisons of activation between the 1- and 6-letter conditions indicated age-equivalent ventral PFC activation. Younger adults showed greater dorsal PFC activation than older adults. Older adults showed greater rostral PFC activation than younger adults. Aging may affect dorsal PFC brain regions that are important for WM executive components.

Neural substrates of mathematical reasoning: a functional magnetic resonance imaging study of neocortical activation during performance of the necessary arithmetic operations test.

Brain activation was examined using functional magnetic resonance imaging during mathematical problem solving in 7 young healthy participants. Problems were selected from the Necessary Arithmetic Operations Test (NAOT; R. B. Ekstrom, J. W. French, H. H. Harman, & D. Dermen, 1976). Participants solved 3 types of problems: 2-operation problems requiring mathematical reasoning and text processing, 1-operation problems requiring text processing but minimal mathematical reasoning, and 0-operation problems requiring minimal text processing and controlling sensorimotor demands of the NAOT problems. Two-operation problems yielded major activations in bilateral frontal regions similar to those found in other problem-solving tasks, indicating that the processes mediated by these regions subserve many forms of reasoning. Findings suggest a dissociation in mathematical problem solving between reasoning, mediated by frontal cortex, and text processing, mediated by temporal cortex.

Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies.

Working memory refers to the short-term retention of information that is no longer accessible in the environment, and the manipulation of this information, for subsequent use in guiding behavior. In this review, we will present data from a series of event-related functional magnetic-resonance-imaging (fMRI) studies of delayed-response tasks that were designed to investigate the role of different regions of the prefrontal cortex (PFC) during different working-memory component processes. From these data, we conclude that: (1) lateral PFC is anatomically organized according to the types of cognitive operations that one performs when attempting to temporarily maintain and manipulate information; and (2) consistent with the picture that has emerged from the monkey electrophysiological literature, human lateral PFC is involved in several encoding- and response-related processes as well as mnemonic and nonmnemonic processes that are engaged during the temporary maintenance of information. Thus, lateral PFC activity cannot be ascribed to the function of a single, unitary cognitive operation.

Isolating the neural mechanisms of age-related changes in human working memory.

Working memory (WM), the process by which information is coded into memory, actively maintained and subsequently retrieved, declines with age. To test the hypothesis that age-related changes in prefrontal cortex (PFC) may mediate this WM decline, we used functional MRI to investigate age differences in PFC activity during separate WM task components (encoding, maintenance, retrieval). We found greater PFC activity in younger than older adults only in dorsolateral PFC during memory retrieval. Fast younger subjects showed less dorsolateral PFC activation during retrieval than slow younger subjects, whereas older adults showed the opposite pattern. Thus age-related changes in dorsolateral PFC and not ventrolateral PFC account for WM decline with normal aging.

Imagined transformations of bodies: an fMRI investigation.

A number of spatial reasoning problems can be solved by performing an imagined transformation of one's egocentric perspective. A series of experiments were carried out to characterize this process behaviorally and in terms of its brain basis, using functional magnetic resonance imaging (tMRI). In a task contrast designed to isolate egocentric perspective transformations, participants were slower to make left-right judgments about a human figure from the figure's perspective than from their own. This transformation led to increased cortical activity around the left parietal-temporal-occipital junction, as well as in other areas including left frontal cortex. In a second task contrast comparing judgments about inverted figures to judgments about upright figures (always from the figure's perspective), participants were slower to make left-right judgments about inverted figures than upright ones. This transformation led to activation in posterior areas near those active in the first experiment, but weaker in the left hemisphere and stronger in the right, and also to substantial left frontal activation. Together, the data support the specialization of areas near the parietal-temporal-occipital junction for egocentric perspective transformations. These results are also suggestive of a dissociation between egocentric perspective transformations and object-based spatial transformations such as mental rotation.

The effect of normal aging on the coupling of neural activity to the bold hemodynamic response.

The use of functional neuroimaging to test hypotheses regarding age-related changes in the neural substrates of cognitive processes relies on assumptions regarding the coupling of neural activity to neuroimaging signal. Differences in neuroimaging signal response between young and elderly subjects can be mapped directly to differences in neural response only if such coupling does not change with age. Here we examined spatial and temporal characteristics of the BOLD fMRI hemodynamic response in primary sensorimotor cortex in young and elderly subjects during the performance of a simple reaction time task. We found that 75% of elderly subjects (n = 20) exhibited a detectable voxel-wise relationship with the behavioral paradigm in this region as compared to 100% young subjects (n = 32). The median number of suprathreshold voxels in the young subjects was greater than four times that of the elderly subjects. Young subjects had a slightly greater signal:noise per voxel than the elderly subjects that was attributed to a greater level of noise per voxel in the elderly subjects. The evidence did not support the idea that the greater head motion observed in the elderly was the cause of this greater voxel-wise noise. There were no significant differences between groups in either the shape of the hemodynamic response or in its the within-group variability, although the former evidenced a near significant trend. The overall finding that some aspects of the hemodynamic coupling between neural activity and BOLD fMRI signal change with age cautions against simple interpretations of the results of imaging studies that compare young and elderly subjects.

The roles of prefrontal brain regions in components of working memory: effects of memory load and individual differences.

Using an event-related functional MRI design, we explored the relative roles of dorsal and ventral prefrontal cortex (PFC) regions during specific components (Encoding, Delay, Response) of a working memory task under different memory-load conditions. In a group analysis, effects of increased memory load were observed only in dorsal PFC in the encoding period. Activity was lateralized to the right hemisphere in the high but not the low memory-load condition. Individual analyses revealed variability in activation patterns across subjects. Regression analyses indicated that one source of variability was subjects' memory retrieval rate. It was observed that dorsal PFC plays a differentially greater role in information retrieval for slower subjects, possibly because of inefficient retrieval processes or a reduced quality of mnemonic representations. This study supports the idea that dorsal and ventral PFC play different roles in component processes of working memory.

Autonomic physiological activity in mental rotation tasks.

The electrodermal response (EDR) during a mental rotation (MR) task performance was investigated. For 6 males and 8 females (16-25 years old) there was a progressive increase in the number of EDRs as the angle of rotation (complexity) of the task was increased. These results support previous findings that autonomic physiological activity varies with the amount of information processing or its difficulty.

Load-dependent roles of frontal brain regions in the maintenance of working memory.

Brain imaging studies have suggested a critical role for prefrontal cortex in working memory (WM) tasks that require both maintainenance and manipulation of information over time in delayed-response WM tasks. In the present study, functional magnetic resonance imaging (fMRI) was used to examine whether prefrontal areas are activated when only maintenance is required in a delayed-response WM task, without the overt requirement to manipulate the stored information. In two scans, six subjects performed WM tasks in which, on each trial, they (1) encoded 1, 3, or 6 to-be-remembered letters, (2) maintained these letters across a 5-second unfilled delay, and (3) determined whether a single probe letter was or was not part of the memory set. Activation of left caudal inferior frontal gyrus was observed, relative to the 1-letter task, when subjects were required to maintain 3 letters in WM. When subjects were required to maintain 6 letters in WM, additional prefrontal areas, most notably middle and superior frontal gyri, were activated bilaterally. Thus, increasing the amount of to-be-maintained information, without any overt manipulation requirement, resulted in the recruitment of wide-spread frontal-lobe regions. Inferior frontal gyrus activation was left-hemisphere dominant in both the 3- and 6-letter conditions, suggesting that such activation reflected material-specific verbal processes. Activation in middle and superior frontal gyri appeared only in the 6-letter condition and was right-hemisphere dominant, suggesting that such activation reflected material-independent executive processes.

Age differences in mental rotation task performance: the influence of speed/accuracy tradeoffs.

Young and old subjects performed a mental rotation task with a within-subject instructional manipulation of speed/accuracy criteria. The three sets of instructions emphasized speed, accuracy, or both speed and accuracy equally. Both age groups changed reaction time (RT) in response to instructions, but there was no Age x Instruction interaction. Whereas young subjects showed decreases in accuracy with decreasing RT, older adults showed relatively stable levels of accuracy with decreasing RT, suggesting that young subjects were more willing to sacrifice accuracy for improvement in speed. Speed/accuracy operating characteristics for the two groups did not overlap, suggesting that age differences in response criteria cannot completely account for age differences in mental rotation performance.

Age and inhibition.

Two experiments assess adult age differences in the extent of inhibition or negative priming generated in a selective-attention task. Younger adults consistently demonstrated negative priming effects; they were slower to name a letter on a current trial that had served as a distractor on the previous trial relative to one that had not occurred on the previous trial. Whether or not inhibition dissipated when the response to stimulus interval was lengthened from 500 ms in Experiment 1 to 1,200 ms in Experiment 2 depended upon whether young subjects were aware of the patterns across trial types. Older adults did not show inhibition at either interval. The age effects are interpreted within the Hasher-Zacks (1988) framework, which proposes inhibition as a central mechanism determining the contents of working memory and consequently influencing a wide array of cognitive functions.

Clinical stages of dementia and the dexamethasone suppression test.

1. This study was undertaken to evaluate the relationship between clinical aspects of primary degenerative dementia and suppression or non-suppression in the dexamethasone suppression test. 2. We studied 34 male patients with primary degenerative dementia (as diagnosed by DSM-III criteria). Dexamethasone 1 mg p.o. was administered at 11:00 PM and blood was drawn for cortisol determination at 4:00 PM the next day. 3. CLINICAL FACTORS INCLUDED: age, age at onset, duration of dementia, history of psychiatric illness, severity as measured by Global Deterioration Scale (GDS) score, and "malignancy" of dementia (rated by years of onset to institutionalization and as a ratio of Global Deterioration Scale to duration of primary degenerative dementia). 4. RESULTS: 56% of primary degenerative dementia patients failed to suppress. The highest degree of non-suppression was seen in Global Deterioration Scale 5 and 6 subjects (Table). 5. An unexpected finding was that a large number of Global Deterioration Scale 7 patients demonstrated normal post-dexamethasone suppression of the hypothalamic-pituitary-adrenal axis. 6. Some contradictions in previously reported studies may be explained by this pattern.