Investigating the link between regional oxygen metabolism and cognitive speed in multiple sclerosis: Implications for fatigue.

BACKGROUND: Most multiple sclerosis (MS) patients experience fatigue and cognitive decline but the underlying mechanisms remain unknown. Previous work has shown whole brain resting cerebral metabolic rate of oxygen (CMRO2) is associated with the extent of these symptoms. However, it is not known if the association between global CMRO2 and MS-related cognitive speed and fatigue can be localized to specific brain regions. Based upon previous research suggesting prefrontal involvement in MS-related changes in cognitive speed and fatigue, we hypothesized that oxygen metabolic changes within prefrontal cortex (PFC) might form the pathophysiologic basis of cognitive performance and fatigue in MS patients. OBJECTIVE: Investigate whether PFC ΔCMRO2 is associated with cognitive speed and fatigue in MS. METHODS: MS and healthy control (HC) participants were scanned using a dual--echo fMRI sequence and underwent a hypercapnia calibration experiment that permitted estimation of ΔCMRO2 while performing a scanner version of symbol-digit modalities task, a measure of information processing speed and utilized in the clinic as a reliable sentinel biomarker for global cognitive impairment in MS. Participants then completed the Modified Fatigue Impact Scale (MFIS) to measure fatigue. RESULTS: MS patients exhibited significant reductions in cognitive performance relative to HCs (p < 0.04). Prefrontal ΔCMRO2 explained significant variability (ΔR2 = 0.11) in cognitive speed, over and above disease and demographic variables, for the MS group only. Prefrontal ΔCMRO2 was not associated with fatigue across groups. ΔCMRO2 in visual and motor areas were not associated with cognitive performance or fatigue for either group. CONCLUSION: Prefrontal oxygen metabolism may be a sensitive measure of MS-related cognitive decline.

Altered task-induced cerebral blood flow and oxygen metabolism underlies motor impairment in multiple sclerosis.

The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural-vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO2), and flow-metabolism coupling (ΔCBF/ΔCMRO2), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO2 increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow-metabolism coupling (ΔCBF/ΔCMRO2) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO2 in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO2 responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural-vascular coupling.

Attentional flexibility and prioritization improves long-term memory.

Recent evidence suggests the focus of attention (FoA) is a flexible resource within working memory (WM) used to temporarily maintain some information in a highly accessible state. This flexibility comes at the expense of other representations, demonstrating a resource trade-off in WM maintenance. The present experiments evaluate how flexibility within the FoA impacts long-term memory (LTM) for semantically meaningful information. A WM probe-recognition task was used in which two items were presented in black and a single item was presented in red. To encourage the prioritization and uninterrupted preferential maintenance of specific items, a process we call online refreshing, the red item was associated with a greater point-reward value than were the black items. This WM task was followed by a surprise delayed LTM test. In Experiment 1, the FoA flexibly adjusted to maintain non-recent semantic information with evidence for a resource trade-off across list positions. Flexibility also directly improved LTM. In Experiment 2, reward value was equated across red and black items to evaluate whether an alternative explanation, distinctiveness of encoding, could account for the LTM findings. When reward value was equated, the cued item did not encourage flexible orienting of the FoA toward non-recent items and there was no benefit of the distinct red item on LTM performance. While supportive of past research, these data further demonstrate that semantic information can be flexibly prioritized at the expense of other list positions and that this is directly tied to improvements in LTM.

BOLD signal within and around white matter lesions distinguishes multiple sclerosis and non-specific white matter disease: a three-dimensional approach.

Multiple sclerosis (MS) diagnostic criteria are based upon clinical presentation and presence of white matter hyperintensities on two-dimensional magnetic resonance imaging (MRI) views. Such criteria, however, are prone to false-positive interpretations due to the presence of similar MRI findings in non-specific white matter disease (NSWMD) states such as migraine and microvascular disease. The coexistence of age-related changes has also been recognized in MS patients, and this comorbidity further poses a diagnostic challenge. In this study, we investigated the physiologic profiles within and around MS and NSWMD lesions and their ability to distinguish the two disease states. MS and NSWMD lesions were identified using three-dimensional (3D) T2-FLAIR images and segmented using geodesic active contouring. A dual-echo functional MRI sequence permitted near-simultaneous measurement of blood-oxygen-level-dependent signal (BOLD) and cerebral blood flow (CBF). BOLD and CBF were calculated within lesions and in 3D concentric layers surrounding each lesion. BOLD slope, an indicator of lesion metabolic capacity, was calculated as the change in BOLD from a lesion through its surrounding perimeters. We observed sequential BOLD signal reductions from the lesion towards the perimeters for MS, while no such decreases were observed for NSWMD lesions. BOLD slope was significantly lower in MS compared to NSWM lesions, suggesting decreased metabolic activity in MS lesions. Furthermore, BOLD signal within and around lesions significantly distinguished MS and NSWMD lesions. These results suggest that this technique shows promise for clinical utility in distinguishing NSWMD or MS disease states and identifying NSWMD lesions occurring in MS patients.

The neurovascular basis of processing speed differences in humans: A model-systems approach using multiple sclerosis.

Behavioral studies investigating fundamental cognitive abilities provide evidence that processing speed accounts for large proportions of performance variability between individuals. Processing speed decline is a hallmark feature of the cognitive disruption observed in healthy aging and in demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica, and Wilson's disease. Despite the wealth of evidence suggesting a central role for processing speed in cognitive decline, the neural mechanisms of this fundamental ability remain unknown. Intact neurovascular coupling, acute localized blood flow increases following neural activity, is essential for optimal neural function. We hypothesized that efficient coupling forms the neural basis of processing speed. Because MS features neural-glial-vascular system disruption, we used it as a model to test this hypothesis. To assess the integrity of the coupling system, we measured blood-oxygen-level-dependent (BOLD) signal in healthy controls (HCs) and MS patients using a 3T MRI scanner while they viewed radial checkerboards that flickered periodically at 8 â€‹Hz. To assess processing speed and cognitive function, we administered a battery of neuropsychological tests. While MS patients exhibited reduced ΔBOLD with reductions in processing speed, no such relationships were observed in HCs. To further investigate the mechanisms that underlie ΔBOLD-processing speed relationships, we assessed the physiologic components that constitute ΔBOLD signal (i.e., cerebral blood flow, ΔCBF; cerebral metabolic rate of oxygen, ΔCMRO2; neurovascular coupling ratio) in speed-preserved and -impaired MS patients. While ΔCBF and ΔCMRO2 showed no group-differences, the neurovascular coupling ratio was significantly reduced in speed-impaired MS patients compared to speed-preserved MS patients. Together, these results suggest that neurovascular uncoupling might underlie cognitive slowing in MS and might be the central pathogenic mechanism governing processing speed decline.

Reduced arterial compliance along the cerebrovascular tree predicts cognitive slowing in multiple sclerosis: Evidence for a neurovascular uncoupling hypothesis.

BACKGROUND: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. OBJECTIVE: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. METHODS: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. RESULTS: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects' reaction time and predicted reaction time after controlling for disease processes. CONCLUSION: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS.

Poor Encoding and Weak Early Consolidation Underlie Memory Acquisition Deficits in Multiple Sclerosis: Retroactive Interference, Processing Speed, or Working Memory?

OBJECTIVE: Learning and memory impairments are common in multiple sclerosis (MS) and may be related to difficulty acquiring (encoding or consolidating) new information. We evaluate the role of retroactive interference and investigate whether minimizing interference immediately following encoding (early during consolidation) will improve MS participants' ability to remember new verbal information. Additionally, we investigate processing speed differences between memory-impaired and unimpaired participants and present an exploratory analysis of how the dual-components of working memory (capacity vs. processing) relate to memory impairment. METHOD: MS memory-unimpaired (N = 12) and MS memory-impaired participants (N = 12) were compared to healthy controls (N = 15). Interference onset following encoding (early, mid, late, no interference) was manipulated over the retention interval of a verbal learning and memory task. Response times (RT) were recorded during interference trials. RESULTS: MS memory-impaired participants encoded less information and lost proportionally more information over the retention interval (weak consolidation). Lengthening the onset of interference did not benefit memory performance in this sample. Memory performance was unrelated to RT but was related to performance on the Symbol Digit Modalities Test. Primary capacity of working memory did not differ across groups; however, secondary memory processing was reduced for MS memory-impaired participants. CONCLUSION: Minimizing interference following encoding did not improve memory in this sample. Both initial encoding and early consolidation were reduced for memory-impaired MS participants. Evidence for a relationship between processing speed and memory was mixed and depended on the processing speed assessment used. Memory impairment in MS may be partially due to inefficient processing within working memory.

BOLD hemodynamic response function changes significantly with healthy aging.

Functional magnetic resonance imaging (fMRI) has been used to infer age-differences in neural activity from the hemodynamic response function (HRF) that characterizes the blood-oxygen-level-dependent (BOLD) signal over time. BOLD literature in healthy aging lacks consensus in age-related HRF changes, the nature of those changes, and their implications for measurement of age differences in brain function. Between-study discrepancies could be due to small sample sizes, analysis techniques, and/or physiologic mechanisms. We hypothesize that, with large sample sizes and minimal analysis assumptions, age-related changes in HRF parameters could reflect alterations in one or more components of the neural-vascular coupling system. To assess HRF changes in healthy aging, we analyzed the large population-derived dataset from the Cambridge Center for Aging and Neuroscience (CamCAN) study (Shafto et al., 2014). During scanning, 74 younger (18-30 years of age) and 173 older participants (54-74 years of age) viewed two checkerboards to the left and right of a central fixation point, simultaneously heard a binaural tone, and responded via right index finger button-press. To assess differences in the shape of the HRF between younger and older groups, HRFs were estimated using FMRIB's Linear Optimal Basis Sets (FLOBS) to minimize a priori shape assumptions. Group mean HRFs were different between younger and older groups in auditory, visual, and motor cortices. Specifically, we observed increased time-to-peak and decreased peak amplitude in older compared to younger adults in auditory, visual, and motor cortices. Changes in the shape and timing of the HRF in healthy aging, in the absence of performance differences, support our hypothesis of age-related changes in the neural-vascular coupling system beyond neural activity alone. More precise interpretations of HRF age-differences can be formulated once these physiologic factors are disentangled and measured separately.

Pilot investigation of the relationship between hippocampal volume and pattern separation deficits in multiple sclerosis.

Memory impairment and hippocampal atrophy are common in multiple sclerosis (MS). In the present pilot study, we investigate whether the mnemonic process of pattern separation is impaired and a predictor of hippocampal volume in relapsing remitting MS. MS participants and healthy controls completed the Mnemonic Similarities Task (MST) along with traditional neurocognitive assessments of memory. 3T structural magnetic resonance imaging was used to estimate whole hippocampal volumes (main aim) and hippocampal subfield volumes (exploratory aim). Results revealed that pattern separation performance was worse for MS participants compared to healthy controls (Cohen's d = 0.96). For MS participants, hippocampal volume was more strongly related to pattern separation performance (r = 0.83) than a traditional neurocognitive measure of visual memory (r = 0.65); hippocampal volume was not related to a traditional neurocognitive measure of verbal memory in this sample. No brain-behavior correlations were significant in the healthy control group. Results of the exploratory analysis revealed relationships between pattern separation performance and subiculum, molecular layer, and CA1 hippocampal subfield volumes for MS participants only. Pattern separation assessed using the MST may be a sensitive cognitive-biomarker of memory dysfunction and changes in hippocampal volume in relapsing-remitting MS.