Glenn R. Wylie

Intellectual Enrichment Is Linked to Cerebral Efficiency in Multiple Sclerosis: Functional Magnetic Resonance Imaging Evidence for Cognitive Reserve.

The cognitive reserve hypothesis helps to explain the incomplete relationship between brain disease and cognitive status in people with neurologic diseases, including Alzheimers; disease and multiple sclerosis. Lifetime intellectual enrichment (estimated with education or vocabulary knowledge) lessens the negative impact of brain disease on cognition, such that people with greater enrichment are able to withstand more severe neuropathology before suffering cognitive impairment or dementia. The current research is the first to investigate directly the relationship between intellectual enrichment and an index of cerebral activity (the blood oxygen level dependent signal) in a neurologic sample. Multiple sclerosis patients completed a vocabulary-based estimate of lifetime intellectual enrichment. Disease severity was estimated with brain atrophy. Cognitive status was measured with the Symbol Digit Modalities Test. Cerebral activity (functional magnetic resonance imaging blood oxygen level dependent signal) and behavioural performance (accuracy, reaction time) were recorded during the visual N-Back working memory task (three levels of demand: 0-, 1-, 2-Back). All patients produced perfect/nearly perfect accuracy during lower demands (0- and 1-Back), and reaction time was unrelated to intellectual enrichment; however, voxelwise partial correlations controlling for brain atrophy revealed strong positive correlations between intellectual enrichment and cerebral activity within the brains; default network (e.g. anterior and posterior cingulate corticies), indicating that patients with greater enrichment were able to maintain resting state activity during cognitive processing better. In turn, intellectual enrichment was negatively associated with prefrontal recruitment, suggesting that patients with lesser enrichment required more cerebral resources to perform the same cognitive task as patients with greater enrichment. This same pattern of enrichment-related cerebral activity was observed when cognitive demands increased (2-Back), and intellectual enrichment was negatively associated with reaction time. Principle components analysis revealed a single cognitive reserve network across tasks (greater default network, lesser prefrontal recruitment). Expression of this network almost fully mediated the positive relationship between intellectual enrichment and cognitive status (Symbol Digit Modalities Test). Also, expression of this network was positively associated with brain atrophy when controlling for cognitive status, indicating that patients with greater expression of this network can withstand more severe brain disease before exhibiting cognition similar to patients with lesser network expression. Of note, similar functional magnetic resonance imaging research with healthy adults has not found an association between intelligence and cerebral efficiency. The unique relationship between intellectual enrichment and cerebral efficiency in neurologic patients is consistent with the cognitive reserve hypothesis, which does not posit that enrichment leads to gains in neurocognitive functioning per se; rather, enrichment protects against neurocognitive decline secondarily to disease.

Cognitive reserve moderates the negative effect of brain atrophy on cognitive efficiency in multiple sclerosis

According to the cognitive reserve hypothesis, neuropsychological expression of brain disease is attenuated among persons with higher education or premorbid intelligence. The current research examined cognitive reserve in multiple sclerosis (MS) by investigating whether the negative effect of brain atrophy on information processing (IP) efficiency is moderated by premorbid intelligence. Thirty-eight persons with clinically definite MS completed a vocabulary-based estimate of premorbid intelligence (Wechsler Vocabulary) and a composite measure of IP efficiency (Symbol Digit Modalities Test and Paced Auditory Serial Addition Task). Brain atrophy was estimated from measurements of third ventricle width using high-resolution anatomical brain magnetic resonance imaging (magnetization-prepared rapid gradient echo). In a hierarchical regression analysis controlling for age and depressive symptomatology, brain atrophy predicted worse IP efficiency (R2 = .23, p = .003) and cognitive reserve predicted better IP efficiency (R2 = .13, p = .013), but these effects were moderated by an Atrophy x Cognitive Reserve interaction (R2 = .15, p = .004). The negative effect of brain atrophy on IP efficiency was attenuated at higher levels of reserve, such that MS subjects with higher reserve were better able to withstand MS neuropathology without suffering cognitive impairment. Results help explain the incomplete and inconsistent relationship between brain atrophy and IP efficiency in previous research.

The neural correlates of cognitive fatigue in traumatic brain injury using functional MRI

Primary objective: The present study used fMRI (functional magnetic resonance imaging) to objectively assess cognitive fatigue in persons with traumatic brain injury (TBI). It was hypothesized that while performing a cognitive task, TBI participants would show increased brain activity over time, indicative of increased cerebral ‘effort’ which might manifest as the subjective feeling of cognitive fatigue. Methods and procedures: Functional MRI was used to track brain activity across time while 11 TBI patients with moderate–severe injury and 11 age-matched healthy controls (HCs) performed a modified Symbol Digit Modalities Task (mSDMT). Cognitive fatigue was operationally defined as a relative increase in cerebral activation across time compared to that seen in HCs. ROIs were derived from the Chauduri and Behan model of cognitive fatigue. Main outcomes and results: While performing the mSDMT, participants with a TBI showed increased activity, while HCs subsequently showed decreased activity in several regions including the middle frontal gyrus, superior parietal cortex, basal ganglia and anterior cingulate. Conclusions: Increased brain activity exhibited by participants with a TBI might represent increased cerebral effort which may be manifested as cognitive fatigue. Functional MRI appears to be a potentially useful tool for understanding the neural mechanisms associated with cognitive fatigue in TBI.

Intellectual enrichment lessens the effect of brain atrophy on learning and memory in multiple sclerosis

Objective: Learning and memory impairments are prevalent among persons with multiple sclerosis (MS); however, such deficits are only weakly associated with MS disease severity (brain atrophy). The cognitive reserve hypothesis states that greater lifetime intellectual enrichment lessens the negative impact of brain disease on cognition, thereby helping to explain the incomplete relationship between brain disease and cognitive status in neurologic populations. The literature on cognitive reserve has focused mainly on Alzheimer disease. The current research examines whether greater intellectual enrichment lessens the negative effect of brain atrophy on learning and memory in patients with MS. Methods: Forty-four persons with MS completed neuropsychological measures of verbal learning and memory, and a vocabulary-based estimate of lifetime intellectual enrichment. Brain atrophy was estimated with third ventricle width measured from 3-T magnetization-prepared rapid gradient echo MRIs. Hierarchical regression was used to predict learning and memory with brain atrophy, intellectual enrichment, and the interaction between brain atrophy and intellectual enrichment. Results: Brain atrophy predicted worse learning and memory, and intellectual enrichment predicted better learning; however, these effects were moderated by interactions between brain atrophy and intellectual enrichment. Specifically, higher intellectual enrichment lessened the negative impact of brain atrophy on both learning and memory. Conclusion: These findings help to explain the incomplete relationship between multiple sclerosis disease severity and cognition, as the effect of disease on cognition is attenuated among patients with higher intellectual enrichment. As such, intellectual enrichment is supported as a protective factor against disease-related cognitive impairment in persons with multiple sclerosis.

Examination of processing speed deficits in multiple sclerosis using functional magnetic resonance imaging.

Although it is known that processing speed deficits are one of the primary cognitive impairments in multiple sclerosis (MS), the underlying neural mechanisms responsible for impaired processing speed remain undetermined. Using BOLD functional magnetic resonance imaging, the current study compared the brain activity of 16 individuals with MS to 17 healthy controls (HCs) during performance of a processing speed task, a modified version of the Symbol Digit Modalities Task. Although there were no differences in performance accuracy, the MS group was significantly slower than HCs. Although both groups showed similar activation involving the precentral gyrus and occipital cortex, the MS showed significantly less cerebral activity than HCs in bilateral frontal and parietal regions, similar to what has been reported in aging samples during speeded tasks. In the HC group, processing speed was mediated by frontal and parietal regions, as well as the cerebellum and thalamus. In the MS group, processing speed was mediated by insula, thalamus and anterior cingulate. It therefore appears that neural networks involved in processing speed differ between MS and HCs, and our findings are similar to what has been reported in aging, where damage to both white and gray matter is linked to processing speed impairments.

The brain uses single-trial multisensory memories to discriminate without awareness.

Multisensory experiences enhance perceptions and facilitate memory retrieval processes, even when only unisensory information is available for accessing such memories. Using fMRI, we identified human brain regions involved in discriminating visual stimuli according to past multisensory vs. unisensory experiences. Subjects performed a completely orthogonal task, discriminating repeated from initial image presentations intermixed within a continuous recognition task. Half of initial presentations were multisensory, and all repetitions were exclusively visual. Despite only single-trial exposures to initial image presentations, accuracy in indicating image repetitions was significantly improved by past auditory-visual multisensory experiences over images only encountered visually. Similarly, regions within the lateral-occipital complex-areas typically associated with visual object recognition processes-were more active to visual stimuli with multisensory than unisensory pasts. Additional differential responses were observed in the anterior cingulate and frontal cortices. Multisensory experiences are registered by the brain even when of no immediate behavioral relevance and can be used to categorize memories. These data reveal the functional efficacy of multisensory processing.

Examination of Cognitive Fatigue in Multiple Sclerosis using Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging

The present study investigated the neural correlates of cognitive fatigue in Multiple Sclerosis (MS), looking specifically at the relationship between self-reported fatigue and objective measures of cognitive fatigue. In Experiment 1, functional magnetic resonance imaging (fMRI) was used to examine where in the brain BOLD activity covaried with “state” fatigue, assessed during performance of a task designed to induce cognitive fatigue while in the scanner. In Experiment 2, diffusion tensor imaging (DTI) was used to examine where in the brain white matter damage correlated with increased “trait” fatigue in individuals with MS, assessed by the Fatigue Severity Scale (FSS) completed outside the scanning session. During the cognitively fatiguing task, the MS group had increased brain activity associated with fatigue in the caudate as compared with HCs. DTI findings revealed that reduced fractional anisotropy in the anterior internal capsule was associated with increased self-reported fatigue on the FSS. Results are discussed in terms of identifying a “fatigue-network” in MS.

Don't think of a white bear: An fMRI investigation of the effects of sequential instructional sets on cortical activity in a task‐switching paradigm

Using functional magnetic resonance imaging (fMRI), we investigated processes involved in switching between two ongoing tasks, thought to be paradigmatic of executive control processes. Subjects were considerably slower and less accurate when switching between two tasks than when repeatedly carrying out one task, so‐called “switch costs.” Switch costs, however, generally occur only when more than one task is associated with each stimulus type. This has led to the surmise that switch costs may be due largely to ongoing interference from previously learned stimulus‐response (S‐R) associations, which are no longer relevant for the task at hand. We used a paradigm that specifically assessed this hypothesis and investigated three stages. In Stage 1, a single task was carried out with each stimulus type; in Stage 2, a second novel task was introduced for each stimulus type; and in Stage 3, subjects reverted to carrying out solely the original tasks (as in Stage 1). In Stage 1, only one task was associated with each stimulus type, whereas two tasks were associated with each stimulus type in Stages 2 and 3. We compared images obtained during Stage 3 to those obtained during Stage 1 and show that during Stage 3, there was robust activation in the network of areas associated with the Stage 2 tasks, even though these tasks were no longer relevant. Our data strongly suggest that switch costs may derive largely from continued activation of areas associated with carrying out the now‐irrelevant task(s). We posit that a large component of executive control processes involves resolution of competition between potentially relevant tasks. Our data also revealed widespread activation of a frontoparietal network of areas, and we discuss how this network might be involved in mediating this competition. Hum. Brain Mapping 21:279–297, 2004.

Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: Preliminary findings

Multiple sclerosis leads to prominent hippocampal atrophy, which is linked to memory deficits. Indeed, 50% of multiple sclerosis patients suffer memory impairment, with negative consequences for quality of life. There are currently no effective memory treatments for multiple sclerosis either pharmacological or behavioral. Aerobic exercise improves memory and promotes hippocampal neurogenesis in nonhuman animals. Here, we investigate the benefits of aerobic exercise in memory-impaired multiple sclerosis patients. Pilot data were collected from two ambulatory, memory-impaired multiple sclerosis participants randomized to non-aerobic (stretching) and aerobic (stationary cycling) conditions. The following baseline/follow-up measurements were taken: high-resolution MRI (neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Intervention was 30-minute sessions 3 times per week for 3 months. Aerobic exercise resulted in 16.5% increase in hippocampal volume and 53.7% increase in memory, as well as increased hippocampal resting-state functional connectivity. Improvements were specific, with no comparable changes in overall cerebral gray matter (+2.4%), non-hippocampal deep gray matter structures (thalamus, caudate: −4.0%), or in non-memory cognitive functioning (executive functions, processing speed, working memory: changes ranged from −11% to +4%). Non-aerobic exercise resulted in relatively no change in hippocampal volume (2.8%) or memory (0.0%), and no changes in hippocampal functional connectivity. This is the first evidence for aerobic exercise to increase hippocampal volume and connectivity and improve memory in multiple sclerosis. Aerobic exercise represents a cost-effective, widely available, natural, and self-administered treatment with no adverse side effects that may be the first effective memory treatment for multiple sclerosis patients.

Premorbid cognitive leisure independently contributes to cognitive reserve in multiple sclerosis

Objective: Consistent with the cognitive reserve hypothesis, higher education and vocabulary help persons with Alzheimer disease (AD) and multiple sclerosis (MS) better withstand neuropathology before developing cognitive impairment. Also, premorbid cognitive leisure (e.g., reading, hobbies) is an independent source of cognitive reserve for elders with AD, but there is no research on the contribution of leisure activity to cognition in MS. We investigated whether premorbid cognitive leisure protects patients with MS from cognitive impairment. Methods: Premorbid cognitive leisure was surveyed in 36 patients with MS. Neurologic disease severity was estimated with brain atrophy, measured as third ventricle width on high-resolution MRI. Cognitive status was measured with a composite score of processing speed and memory. Results: Controlling for brain atrophy, premorbid cognitive leisure was positively associated with current cognitive status (rp = 0.49, p < 0.01), even when controlling for vocabulary (rp = 0.39, p < 0.05) and education (rp = 0.47, p < 0.01). Also, premorbid cognitive leisure was unrelated to brain atrophy (r = 0.03, p > 0.5), but a positive partial correlation between leisure and atrophy emerged when controlling for cognitive status (rp = 0.37, p < 0.05), which remained when also controlling for vocabulary (rp = 0.34, p < 0.05) and education (rp = 0.35, p < 0.05). Conclusions: Premorbid cognitive leisure contributes to cognitive status in patients with MS independently of vocabulary and education. Also, patients with MS who engaged in more cognitive leisure were able to withstand more severe brain atrophy at a given cognitive status. Premorbid cognitive leisure is supported as an independent source of cognitive reserve in patients with MS.