ASL MRI informs blood flow to chronic stroke lesions in patients with aphasia.

Introduction: Response to post-stroke aphasia language rehabilitation is difficult to anticipate, mainly because few predictors can help identify optimal, individualized treatment options. Imaging techniques, such as Voxel-based Lesion Symptom Mapping have been useful in linking specific brain areas to language behavior; however, further development is required to optimize the use of structural and physiological information in guiding individualized treatment for persons with aphasia (PWA). In this study, we will determine if cerebral blood flow (CBF) mapped in patients with chronic strokes can be further used to understand stroke-related factors and behavior. Methods: We collected perfusion MRI data using pseudo-Continuous Arterial Spin Labeling (pCASL) using a single post-labeling delay of 2,200 ms in 14 chronic PWA, along with high-resolution structural MRI to compute maps of tissue damage using Tissue Integrity Gradation via T2w T1w Ratio (TIGR). To quantify the CBF in chronic stroke lesions, we tested at what point spatial smoothing should be applied in the ASL analysis pipeline. We then related CBF to tissue damage, time since stroke, age, sex, and their respective cross-terms to further understand the variability in lesion CBF. Finally, we assessed the feasibility of computing multivariate brain-behavior maps using CBF and compared them to brain-behavior maps extracted with TIGR MRI. Results: We found that the CBF in chronic stroke lesions is significantly reduced compared to its homologue grey and white matter regions. However, a reliable CBF signal (although smaller than expected) was detected to reveal a negative relationship between CBF and increasing tissue damage. Further, the relationship between the lesion CBF and age, sex, time since stroke, and tissue damage and cross-terms suggested an aging-by-disease interaction. This relationship was strongest when smoothing was applied in the template space. Finally, we show that whole-brain CBF relates to domain-general visuospatial functioning in PWA. The CBF-based brain-behavior maps provide unique and complementary information to structural (lesion-based) brain-behavior maps. Discussion: Therefore, CBF can be detected in chronic stroke lesions using a standard pCASL MRI acquisition and is informative at the whole-brain level in identifying stroke rehabilitation targets in PWAs due to its relationship with demographic factors, stroke-related factors, and behavior.

Methodologies for task-fMRI based prognostic biomarkers in response to aphasia treatment.

With the diversity in aphasia coupled with diminished gains at the chronic phase, it is imperative to deliver effective rehabilitation plans. Treatment outcomes have therefore been predicted using lesion-to-symptom mapping, but this method lacks holistic functional information about the language-network. This study, therefore, aims to develop whole-brain task-fMRI multivariate analysis to neurobiologically inspect lesion impacts on the language-network and predict behavioral outcomes in persons with aphasia (PWA) undergoing language therapy. In 14 chronic PWA, semantic fluency task-fMRI and behavioral measures were collected to develop prediction methodologies for post-treatment outcomes. Then, a recently developed imaging-based multivariate method to predict behavior (i.e., LESYMAP) was optimized to intake whole-brain task-fMRI data, and systematically tested for reliability with mass univariate methods. We also accounted for lesion size in both methods. Results showed that both mass univariate and multivariate methods identified unique biomarkers for semantic fluency improvements from baseline to 2-weeks post-treatment. Additionally, both methods demonstrated reliable spatial overlap in task-specific areas including the right middle frontal gyrus when identifying biomarkers of language discourse. Thus whole-brain task-fMRI multivariate analysis has the potential to identify functionally meaningful prognostic biomarkers even for relatively small sample sizes. In sum, our task-fMRI based multivariate approach holistically estimates post-treatment response for both word and sentence production and may serve as a complementary tool to mass univariate analysis in developing brain-behavior relationships for improved personalization of aphasia rehabilitation regimens.

The association between language-based task-functional magnetic resonance imaging hemodynamics and baseline GABA+ and glutamate-glutamine measured in pre-supplementary motor area: A pilot study in an aging model.

Aging is a natural phenomenon that elicits slow and progressive cerebrovascular and neurophysiological changes that eventually lead to cognitive decline. The objective of this pilot study is to examine the association of GABA+ and glutamate-glutamine (Glx) complex with language-based blood oxygen level dependent (BOLD) hemodynamics in an aging model. More specifically, using standard BOLD we will first attempt to validate whether previously reported findings for BOLD amplitude and resting neurochemical relationships hold in an aging model. Secondly, we will investigate how our recently established neurosensitized task-BOLD energetics relate to resting GABA+ and Glx, especially accounting for titration of task difficulty. To support the above endeavors, we optimize the baseline fitting for edited magnetic resonance spectroscopy (MRS) difference spectra to sensitize GABA+ and Glx concentrations to aging-related differences. We identify a spline-knot spacing of 0.6ppm to yield the optimal aging-related differences in GABA+ and Glx. The optimized MRS values were then graduated to relate to task-BOLD hemodynamics. Our results did not replicate previous findings that relate task-BOLD amplitude and resting GABA+ and Glx. However, we did identify neurochemistry relationships with the vascularly-driven dispersion component of the hemodynamic response function, specifically in older participants. In terms of neuro-sensitized BOLD energetics and the underlying role of GABA+ and Glx, our data suggests that the task demands are supported by both neurometabolites depending on the difficulty of the task stimuli. Another novelty is that we developed task-based functional parcellation of pre-SMA using both groups. In sum, we are the first to demonstrate that multimodal task-fMRI and MRS studies are beneficial to improve our understanding of the aging brain physiology, and to set the platform to better inform approaches for clinical care in aging-related neurovascular diseases. We also urge future studies to replicate our findings in a larger population incorporating a lifespan framework.

The Relationship Between Resting Cerebral Blood Flow, Neurometabolites, Cardio-Respiratory Fitness and Aging-Related Cognitive Decline.

Older adults typically experience a decline in cognitive function, but improvements in physical health and lifestyle can be neuroprotective across the human lifespan. The primary objective of this study is to advance our basic understanding of how cardiorespiratory fitness and neurophysiological attributes relate to cognitive decline. While cerebral blood flow (CBF) is critical for the supply of nutrients to the tissue, the brain's major neurotransmitters (i.e., gamma-aminobutyric acid, GABA, and glutamate-glutamine complex, Glx) are closely linked to oxidative metabolism. Within the context of flow-metabolism coupling, the critical question is how these neurophysiological parameters interplay, resulting in cognitive decline. Further, how cardiorespiratory fitness may impact aging neurophysiology and cognition is not well understood. To address these questions, we recruited 10 younger and 12 older cognitively intact participants to collect GABA and Glx using magnetic resonance spectroscopy (MRS), CBF using pseudo-continuous arterial spin labeling Magnetic Resonance Imaging (MRI), VO2max as a measure of cardiorespiratory fitness using the YMCA submax test, and cognitive and motor-cognitive measures using a battery of behavioral assessments. We observed expected differences in GABA+, Glx, and CBF between younger and older participants in pre-SMA, a frontal domain-general region. When GABA+ and Glx were related to CBF via multiple linear regression, Glx was identified as the main contributor to the model. For higher-order executive function (i.e., inhibition versus color naming), GABA*Glx*CBF interaction was critical in younger, while only Glx was involved in older participants. For unimanual motor dexterity, GABA*Glx interaction was the common denominator across both groups, but younger participants' brain also engages CBF. In terms of selective motor inhibition, CBF from younger participants was the only major neurophysiological factor. In terms of fitness, cardiorespiratory fitness was significantly related to GABA, Glx, and motor performance when combining cohorts, but no group-specific relationships were observed. Taken together, our results indicate that Glx and CBF coupling decreases with aging, perhaps due to altered glial oxidative metabolism. Our data suggest that GABA, Glx, and CBF are engaged and weighted differently for different cognitive measures sensitized to aging, and higher fitness allows for a more efficient metabolic shift that facilitates improved performance on cognitive-motor tasks.

Not All Lesioned Tissue Is Equal: Identifying Pericavitational Areas in Chronic Stroke With Tissue Integrity Gradation via T2w T1w Ratio.

Stroke-related tissue damage within lesioned brain areas is topologically non-uniform and has underlying tissue composition changes that may have important implications for rehabilitation. However, we know of no uniformly accepted, objective non-invasive methodology to identify pericavitational areas within the chronic stroke lesion. To fill this gap, we propose a novel magnetic resonance imaging (MRI) methodology to objectively quantify the lesion core and surrounding pericavitational perimeter, which we call tissue integrity gradation via T2w T1w ratio (TIGR). TIGR uses standard T1-weighted (T1w) and T2-weighted (T2w) anatomical images routinely collected in the clinical setting. TIGR maps are analyzed with relation to subject-specific gray matter and cerebrospinal fluid thresholds and binned to create a false colormap of tissue damage within the stroke lesion, and these are further categorized into low-, medium-, and high-damage areas. We validate TIGR by showing that the cerebral blood flow within the lesion reduces with greater tissue damage (p = 0.005). We further show that a significant task activity can be detected in pericavitational areas and that medium-damage areas contain a significantly lower magnitude of hemodynamic response function than the adjacent damaged areas (p < 0.0001). We also demonstrate the feasibility of using TIGR maps to extract multivariate brain-behavior relationships (p < 0.05) and show general agreement in location compared to binary lesion, T1w-only, and T2w-only maps but that the extent of brain behavior maps may depend on signal sensitivity as denoted by the sparseness coefficient (p < 0.0001). Finally, we show the feasibility of quantifying TIGR in early and late subacute stroke phases, where higher-damage areas were smaller in size (p = 0.002) and that lesioned voxels transition from lower to higher damage with increasing time post-stroke (p = 0.004). We conclude that TIGR is able to (1) identify tissue damage gradient within the stroke lesion across different post-stroke timepoints and (2) more objectively delineate lesion core from pericavitational areas wherein such areas demonstrate reasonable and expected physiological and functional impairments. Importantly, because T1w and T2w scans are routinely collected in the clinic, TIGR maps can be readily incorporated in clinical settings without additional imaging costs or patient burden to facilitate decision processes related to rehabilitation planning.

The effect of time since stroke, gender, age, and lesion size on thalamus volume in chronic stroke: a pilot study.

Recent stroke studies have shown that the ipsi-lesional thalamus longitudinally and significantly decreases after stroke in the acute and subacute stages. However, additional considerations in the chronic stages of stroke require exploration including time since stroke, gender, intracortical volume, aging, and lesion volume to better characterize thalamic differences after cortical infarct. This cross-sectional retrospective study quantified the ipsilesional and contralesional thalamus volume from 69 chronic stroke subjects' anatomical MRI data (age 35-92) and related the thalamus volume to time since stroke, gender, intracortical volume, age, and lesion volume. The ipsi-lesional thalamus volume was significantly smaller than the contra-lesional thalamus volume (t(68) = 13.89, p < 0.0001). In the ipsilesional thalamus, significant effect for intracortical volume (t(68) = 2.76, p = 0.008), age (t(68) = 2.47, p = 0.02), lesion volume (t(68) = - 3.54, p = 0.0008), and age*time since stroke (t(68) = 2.46, p = 0.02) were identified. In the contralesional thalamus, significant effect for intracortical volume (t(68) = 3.2, p = 0.002) and age (t = - 3.17, p = 0.002) were identified. Clinical factors age and intracortical volume influence both ipsi- and contralesional thalamus volume and lesion volume influences the ipsilesional thalamus. Due to the cross-sectional nature of this study, additional research is warranted to understand differences in the neural circuitry and subsequent influence on volumetrics after stroke.

Exploring brain mechanisms underlying Gulf War Illness with group ICA based analysis of fMRI resting state networks.

Around 200,000 veterans (up to 32% of those deployed) of the 1991 Gulf War (GW) suffer from GW illness (GWI), which is characterized by multiple deficits in cognitive, affective, sensory and nociception domains. In this study we employed resting state fMRI (rsfMRI) to map impairments in brain function in GWI with advanced network analysis. RsfMRI data was obtained from 60 GWI veterans and 30 age-matched military controls. Group independent component analysis (GICA) was conducted to probe the functional connectivity networks in all 90 subjects. GICA revealed impaired functional connectivity (FC) in GWI veterans between a number of brain function networks consistent with their self-reported symptoms. GWI veterans exhibited impaired FC between language networks, and sensory input networks of all modalities as well as motor output networks. GWI veterans also exhibited impaired FC between different sensory perception and motor networks, and between different networks in the sensorimotor domain. These FC impairments provide putative mechanism of central nervous system dysfunction in GWI.

Hubs of Anticorrelation in High-Resolution Resting-State Functional Connectivity Network Architecture.

A major focus of brain research recently has been to map the resting-state functional connectivity (rsFC) network architecture of the normal brain and pathology through functional magnetic resonance imaging. However, the phenomenon of anticorrelations in resting-state signals between different brain regions has not been adequately examined. The preponderance of studies on resting-state fMRI (rsFMRI) have either ignored anticorrelations in rsFC networks or adopted methods in data analysis, which have rendered anticorrelations in rsFC networks uninterpretable. The few studies that have examined anticorrelations in rsFC networks using conventional methods have found anticorrelations to be weak in strength and not very reproducible across subjects. Anticorrelations in rsFC network architecture could reflect mechanisms that subserve a number of important brain processes. In this preliminary study, we examined the properties of anticorrelated rsFC networks by systematically focusing on negative cross-correlation coefficients (CCs) among rsFMRI voxel time series across the brain with graph theory-based network analysis. A number of methods were implemented to enhance the neuronal specificity of resting-state functional connections that yield negative CCs, although at the cost of decreased sensitivity. Hubs of anticorrelation were seen in a number of cortical and subcortical brain regions. Examination of the anticorrelation maps of these hubs indicated that negative CCs in rsFC network architecture highlight a number of regulatory interactions between brain networks and regions, including reciprocal modulations, suppression, inhibition, and neurofeedback.

Delayed diagnosis of intracerebral foreign body from the Vietnam War.

We report on a 22-year-old infantryman who sustained a right frontal wound to his head. He was treated and returned to duty immediately. During a computed tomography scan, 38 years after the incident, a metallic foreign body and disruption of the brain consistent with a projectile track were discovered in his brain. In this report, we review similar cases of delayed discovery of unsuspected foreign bodies and the probable nature of the wound.

Diffusion weighted imaging and neuropsychological correlates in adults with mild traumatic brain injury.

Diffusion Tensor Imaging (DTI) is increasingly being used as a research tool in mild Traumatic Brain Injury (mTBI). This article reviews the concepts of diffusion tensor imaging, neuropsychological testing and results to date when applied to mTBI in adults. DTI is being used in conjunction with neuropsychological and electrophysiological measures to provide improved structural/functional correlations of mTBI. Future directions and applications of DTI in mTBI research are suggested.

Functional magnetic resonance imaging before and after aphasia therapy: shifts in hemodynamic time to peak during an overt language task.

BACKGROUND AND PURPOSE: Comparing the temporal characteristics of hemodynamic responses in activated cortical regions of aphasic patients before and after therapy would provide insight into the relationship between improved task performance and changes in blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal. This study investigated differences in the time to peak (TTP) of hemodynamic responses in activated regions of interest (ROIs), before and after therapy, and related them to changes in task performance. METHODS: Three aphasic patients and 3 controls overtly generated a single exemplar in response to a category. For the patients, TTP of hemodynamic responses in selected ROIs was compared before and after language therapy. The timing differences between auditory cues and verbal responses were compared with TTP differences between auditory and motor cortices. RESULTS: The selected ROIs were significantly activated in both aphasic patients and controls during overt word generation. In the aphasic patients, both the timing difference from auditory cues to verbal responses and the TTP difference between auditory and motor cortices decreased after rehabilitation, becoming similar to the values found in controls. CONCLUSIONS: Findings indicate that (1) rehabilitation increased the speed of word-finding processes; (2) TTP analysis was sensitive to this functional change and can be used to represent improvement in behavior; and (3) it is important to monitor the behavioral performance that might correlate with the temporal pattern of the hemodynamic response.