Ashley M. Stokes

Background/Objectives: Mild traumatic brain injury (mTBI) is frequently associated with persistent cognitive and neurobehavioral symptoms despite the absence of abnormalities on conventional structural imaging. Increasing evidence suggests that these symptoms arise from distributed functional and neurovascular alterations rather than focal damage. The goal of this pilot study was to investigate network-level functional alterations in subacute mTBI by evaluating resting-state functional MRI (rs-fMRI) combined with spin- and gradient-echo (SAGE) imaging to compare contrast-specific patterns across canonical resting-state networks. Methods: Rs-fMRI data from 20 subacute mTBI patients and 20 healthy controls were analyzed using independent component analysis across five canonical resting-state networks. SAGE-derived T2-weighted and T2*-weighted multi-echo contrasts were evaluated alongside conventional TE2 functional connectivity to differentiate microvascular from macrovascular contributions. Principal component analysis was applied within each network for dimensionality reduction, and multivariate patterns were compared across contrasts and networks to map group-level alterations. Results: The analysis revealed distinct, contrast-dependent spatial patterns of neurovascular alterations across multiple canonical networks. The T2-weighted contrast, reflecting microvascular weighting, identified pronounced differences in executive control, visual, and default mode networks, whereas conventional TE2 contrasts primarily highlighted alterations within sensorimotor and cerebellar circuits. Conclusions: This pilot study demonstrates the utility of evaluating SAGE-derived hemodynamic contrasts alongside canonical resting-state networks to characterize distinct spatial patterns of microvascular and macrovascular disruptions in subacute mTBI. These findings highlight the value of contrast-specific neuroimaging to disentangle complex neurovascular alterations following mild head injury.

Neuroinflammation is a critical pathological feature underlying neurodegenerative diseases. Spinocerebellar ataxia 13 (SCA13) is a heterogeneous ataxia with several allelic variations of differing phenotypes. All are neurodegenerative and currently without effective treatment. Our prior work identified human KCNC3 gene mutations as causative for SCA13, with the R423H allelic isoform specifically driving early-onset neurodegeneration. The precise nature of the inflammatory response and its link to neurodegeneration in SCA13 remains elusive. To address this, we engineered a single Kcnc3 R424H mutation (analogous to the human SCA13 KCNC3 R423H allele) into mice using CRISPR/Cas9. We performed thorough phenotypic analyses including motor function (gait, tremor, coordination, balance) and brain segmental /cerebellar volume at multiple timepoints. We then investigated both neurodegenerative Purkinje cell loss and inflammatory responses within the cerebellum (astroglia and microglia) and systemically (plasma cytokine levels). At 3 and 6 months of age, the R424H mice displayed profound neurological motor dysfunction, including high-frequency tremor, aberrant gait, and a decreased latency to fall. Electrophysiology revealed dysregulated spontaneous firing in Purkinje cells. Pathological examination confirmed progressive Purkinje cell degeneration and cerebellar atrophy. Critically, we observed a pronounced activation of microglia and astrocytes within the cerebella of R424H mice. Pearson correlation analyses highlighted a strong inverse correlation between the number of surviving Purkinje cells and markers of inflammatory activation. In conclusion, our transgenic R424H mice establish a novel model of brain hypoplasia and neurodegeneration caused by dysfunction of a voltage-gated potassium channel mimicking SCA13 ^R423H , exhibiting significant motor deficits, prominent Purkinje cell loss, cerebellar inflammation, and atrophy. This study strongly suggests that the aberrant activation of inflammatory immune cells, notably astroglia and microglia, is associated with Purkinje cell demise in the cerebellum. We propose that this observed neuroinflammation may play a significant and potentially aggressive role in driving the progression of neurodegeneration in SCA13.

Mild traumatic brain injury (mTBI) frequently causes subtle brain changes that are difficult to detect with conventional diagnostic approaches. In this exploratory pilot study, we combined tri-exponential intravoxel incoherent motion (IVIM) and pseudocontinuous arterial spin labeling (pCASL) MRI with Multimodal Canonical Correlation Analysis and joint independent component analysis (mCCA+jICA) to identify imaging signatures distinguishing mTBI patients from healthy controls (HCs) and their associations with clinical function. Cerebral blood flow (CBF) and IVIM-derived metrics were extracted from 90 brain regions in 19 mTBI patients and 24 HCs, and multivariate components were identified using mCCA+jICA. Two independent components (IC2, IC15) showed group differences at the uncorrected level (p < 0.05) but did not survive false discovery rate (FDR) correction. IC2 correlated positively with CBF and perfusion fraction (F_p) and negatively with tissue diffusion fraction (F_s), consistent with reduced vascular integrity in mTBI, while IC15 showed similar trends. One component correlated with Glasgow Outcome Scale–Extended (GOS-E) scores (uncorrected p = 0.046). Although this study is preliminary and limited by a small sample size, our findings suggest that mTBI is associated with perfusion and microstructural alterations, particularly in subcortical regions, and demonstrate the potential value of combining IVIM and ASL within multivariate fusion frameworks to reveal patterns not captured by single-modality approaches.

Introduction: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. Levodopa remains the primary treatment, temporarily restoring dopamine levels and improving motor symptoms. Advanced diffusion MRI techniques, such as free-water corrected diffusion tensor imaging (fw-DTI) and neurite orientation dispersion and density imaging (NODDI), provide insights into PD-related microstructural changes beyond conventional DTI.Methods: This study investigates white matter alterations in PD using multi-shell fw-DTI and NODDI to compare voxel-wise differences between PD patients both OFF and ON levodopa, with comparison to healthy controls (HC). Effect sizes and receiver operating characteristic (ROC) analyses assessed the discriminative power of imaging metrics.Results: PD (OFF) exhibited increased free-water, reduced neurite density (NDI), and altered orientation dispersion (ODI) in key motor pathways in comparison to HC, while fw-FA offered robust group discrimination (AUC=0.956). Levodopa (ON state) increased NDI and NODDI-FWF, suggesting acute microstructural plasticity, though this finding contrasted with minimal fw-DTI FW changes. Additionally, voxel-based correlation analyses linked free-water and neurite integrity metrics with disease severity.Discussion: Our findings suggest that fw-DTI and NODDI provide complementary information on PD-related neurodegeneration and the transient effects of levodopa. These results underscore the potential of advanced diffusion MRI techniques as biomarkers for tracking PD progression and treatment response.

Introduction: Parkinson's Disease (PD), the second most common neurodegenerative disorder, is characterized by motor and non-motor symptoms linked to dopaminergic neuron degeneration. This study utilized the 6-hydroxydopamine (6-OHDA) rat model to replicate PD-like dopaminergic degeneration through targeted injections into the medial forebrain bundle and substantia nigra.Methods: Behavioral assessments revealed hallmark motor deficits, while MRI was performed to assess complementary functional connectivity and structural connectivity. Post-mortem tyrosine hydroxylase (TH) staining confirmed extensive dopaminergic neuron loss, validating the pathological relevance of the model and ensuring data integrity. MRI data were collected at 7T in 46 male Fischer F344 rats (23 6-OHDA, 23 sham) to characterize functional and structural connectivity differences between cohorts.Results: Functionally, decreased connectivity between the retrosplenial and endopiriform cortices in the 6-OHDA model suggests disrupted sensory processing, while increased connectivity between the hippocampus and retrosplenial cortex indicates possible compensatory mechanisms. Structurally, we observed reduced connectivity between the subcoeruleum and piriform cortex in the 6-OHDA model, which may reflect axonal degeneration, and increased connectivity between the ventral striatum and primary somatosensory cortex, which likely reflects compensatory changes to support motor-sensory integration. Diffusion MRI analysis further revealed changes in the white matter tracts connecting these regions, supporting these findings and highlighting adaptive responses to neurodegeneration in PD.Discussion: These findings demonstrate the utility of combining functional and structural connectivity analyses to capture PD-related network disruptions. These structural connectivity changes were further associated with microstructural alterations. The development of MRI biomarkers for understanding brain connectivity may enhance our understanding of PD pathology and advancing translation of these techniques to clinical applications.

Cerebrovascular reactivity (CVR) shows promise as a biomarker of vascular integrity and may benefit from a repeatable, reliable, and microvasculature-sensitive acquisition. A combined spin- and gradient-echo (SAGE) functional MRI (fMRI) acquisition may improve repeatability and reliability compared to single spin- (SE) and gradient-echo (GRE) fMRI and provide a microvascular-weighted analysis. The most repeatable and reliable MRI acquisition CVR maps were compared across three CVR paradigms: a breath-hold task, a breath modulation task, and a resting state acquisition. SAGE-fMRI data was acquired in fifteen young adults at two timepoints. Mean gray matter (GM) within-subject coefficient of variation (wCV) and intraclass correlation coefficient (ICC) were compared within the quantitative and weighted SAGE-fMRI CVR maps and single GRE- and SE-fMRI CVR. Total and microvascular MRI inputs with lowest wCV and highest ICC were used to compare three CVR paradigms. Total and microvascular weighted SAGE-fMRI CVR had the lowest wCV and highest ICC across paradigms. The breath-hold paradigm produced significantly higher GM CVR estimates. SAGE repeatably and reliably measures CVR and offers a simultaneous, complementary analysis on total and microvascular scales. The breath-hold paradigm showed significantly higher CVR estimates, but less compliance-dependent protocols may be ideal for applications in patient populations.

Mild Cognitive Impairment (MCI) is a transitional stage between normal aging and Alzheimer’s disease. Differentiating early MCI (EMCI) from late MCI (LMCI) is crucial for early diagnosis and intervention. This study used free-water diffusion tensor imaging (fw-DTI) to investigate white matter differences and voxel-based correlations with Mini–Mental State Examination (MMSE) scores. Data from the Alzheimer’s Disease Neuroimaging Initiative included 476 healthy controls (CN), 137 EMCI participants, and 62 LMCI participants. Significant MMSE differences were found between the CN and MCI groups, but not between EMCI and LMCI. However, distinct white matter changes were observed: LMCI showed a higher f-index and lower fw-fractional anisotropy (fw-FA) compared to EMCI in several white matter regions. These findings indicate specific white matter tracts involved in MCI progression. Voxel-based correlations between fw-DTI metrics and MMSE scores further supported these results. In conclusion, this study provides crucial insights into white matter changes associated with EMCI and LMCI, offering significant implications for future research and clinical practice.

Background: White matter hyperintensities (WMHs) are common in older adults and appear as abnormal signal on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). They are often linked to demyelination, axonal damage, and gliosis, as well as vascular changes. WMHs occur in both normal aging and mild cognitive impairment (MCI), where they may contribute to cognitive decline. Objective: The study objectives were to determine whether advanced diffusion MRI (dMRI) techniques can detect distinct microstructural changes within WMHs in individuals with MCI compared to healthy controls and to evaluate relationships between these measures and cognitive performance. Methods: Advanced dMRI techniques were used to assess WMH microstructural changes in normal aging (n = 55) and MCI (n = 46) participants from the ADNI database. WMHs and their surrounding penumbra were identified using an automated approach. Microstructural characteristics, derived from free-water (FW) diffusion tensor imaging and diffusion kurtosis imaging, were evaluated between groups and white matter regions. Associations between these measures and cognitive performance (assessed by the Mini-Mental State Exam) were examined. Results: Across both groups, WMHs showed higher FW and lower FW-fractional anisotropy and kurtosis metrics compared to normal-appearing white matter, indicating widespread microstructural alterations. No groupwise microstructural differences were observed within corresponding tissue types. In the MCI group, kurtosis metrics within WMHs correlated with cognitive performance. Conclusions: These findings highlight the complexity of WMH-related microstructural changes and suggest that advanced dMRI biomarkers may offer valuable insights into the role of white matter changes in aging and cognitive decline.