Al-Fakih, A., A. Shazly, A. Mohammed, M. Elbushnaq, K. Ryu, Y. H. Gu, M. A. Al-masni, and M. M. Makary, "FLAIR MRI sequence synthesis using squeeze attention generative model for reliable brain tumor segmentation", Alexandria Engineering Journal, vol. 99, pp. 108-123, 2024.
Zaninotto, A. L., M. M. Makary, H. P. Rowe, M. Eshghi, C. - E. J. Tseng, J. Chan, N. R. Zürcher, J. Hooker, A. Lewis, M. Keegan, et al., "Speech motor impairment in ALS is associated with multiregional cortical thinning beyond primary motor cortex.", Frontiers in neurology, vol. 15, pp. 1451177, 2024. Abstract

INTRODUCTION: Cortical thinning is well-documented in individuals with amyotrophic lateral sclerosis (ALS), yet its association with speech deterioration remains understudied. This study characterizes anatomical changes in the brain within the context of speech impairment patterns in individuals with ALS, providing insight into the disease's multiregional spread and biology.

METHODS: To evaluate patterns of cortical thickness in speakers with ALS with and without functional speech changes compared to healthy controls (HCs) using whole-brain and region of interest (ROI) analyses. Forty individuals with ALS and 22 HCs underwent a T1-weighted 3-Tesla magnetic resonance imaging (MRI). Individuals with ALS were divided into two groups based on the preserved speech [ps-ALS] ( = 18) or deteriorated speech [ds-ALS] ( = 22) as measured by the ALSFRSF-R speech subscore (=4 or <4 points, respectively). Sixteen a priori-defined and automatically segmented cortical and subcortical brain ROIs were selected based on their previously documented roles in speech production. Two cortical thickness analyses were performed: (1) group-level whole-brain surface-based analyses and (2) group-level ROI analyses. A case study of 6 ALS individuals examined the cortical thickness, and their speech was characterized using quantitative and qualitative measures.

RESULTS: Based on the group-level whole-brain surface-based analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in the left primary motor and somatosensory cortices and the right inferior parietal lobe with its adjacent lateral occipital cortical regions. The ps-ALS group demonstrated no significant cortical thinning compared to HCs. Based on the group-level ROI analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in bilateral middle motor cortices, right posterior dorsal premotor cortex, and left anterior cingulate cortex. The case study analysis revealed that ALS speakers with speech features characteristic of spastic dysarthria exhibited cortical thinning, while those with speech features characteristic of flaccid dysarthria did not.

DISCUSSION: Individuals with ALS have anatomical changes involving multiregional neocortical areas beyond the primary motor cortex that may manifest as subjective (i.e., clinical judgment) and objective (i.e., speaking rate) changes in speech production. Further longitudinal work in ALS is needed to better understand the link between MRI cortical thickness changes and bulbar dysfunction.

Herranz, E., C. A. Treaba, V. T. Barletta, A. Mehndiratta, R. Ouellette, J. A. Sloane, C. Ionete, S. Babu, M. Mastantuono, S. Magon, et al., "Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.", Brain : a journal of neurology, vol. 147, issue 7, pp. 2566-2578, 2024. Abstract

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18 kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratios sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

Tseng, C. - E. J., C. Canales, R. E. Marcus, A. J. Parmar, B. G. Hightower, J. E. Mullett, M. M. Makary, A. U. Tassone, H. K. Saro, P. H. Townsend, et al., "In vivo translocator protein in females with autism spectrum disorder: a pilot study.", Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 49, issue 7, pp. 1193-1201, 2024. Abstract

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [C]PBR28 SUVR across time in both groups. Elevated regional [C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

Housman, H., L. Brusaferri, M. Datko, S. Tohyama, K. Round, R. G. G. Gomez, R. L. Gollub, R. R. Edwards, M. Makary, B. R. Rosen, et al., "In Vivo Molecular Imaging of Neuroinflammation in Patients with Migraine", The Journal of Pain, vol. 23, issue 5, pp. 44, 2022.
Gilman, J. M., W. A. Schmitt, K. Potter, B. Kendzior, G. N. Pachas, S. Hickey, M. Makary, M. A. Huestis, and E. A. Evins, "Correction to: Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging.", Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 47, issue 6, pp. 1282, 2022.
Gilman, J. M., W. A. Schmitt, K. Potter, B. Kendzior, G. N. Pachas, S. Hickey, M. Makary, M. A. Huestis, and E. A. Evins, "Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging.", Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 47, issue 4, pp. 944-952, 2022. Abstract

The primary cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC), causes intoxication and impaired function, with implications for traffic, workplace, and other situational safety risks. There are currently no evidence-based methods to detect cannabis-impaired driving, and current field sobriety tests with gold-standard, drug recognition evaluations are resource-intensive and may be prone to bias. This study evaluated the capability of a simple, portable imaging method to accurately detect individuals with THC impairment. In this double-blind, randomized, cross-over study, 169 cannabis users, aged 18-55 years, underwent functional near-infrared spectroscopy (fNIRS) before and after receiving oral THC and placebo, at study visits one week apart. Impairment was defined by convergent classification by consensus clinical ratings and an algorithm based on post-dose tachycardia and self-rated "high." Our primary outcome, prefrontal cortex (PFC) oxygenated hemoglobin concentration (HbO), was increased after THC only in participants operationalized as impaired, independent of THC dose. ML models using fNIRS time course features and connectivity matrices identified impairment with 76.4% accuracy, 69.8% positive predictive value (PPV), and 10% false-positive rate using convergent classification as ground truth, which exceeded Drug Recognition Evaluator-conducted expanded field sobriety examination (67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate). These findings demonstrate that PFC response activation patterns and connectivity produce a neural signature of impairment, and that PFC signal, measured with fNIRS, can be used as a sole input to ML models to objectively determine impairment from THC intoxication at the individual level. Future work is warranted to determine the specificity of this classifier to acute THC impairment.ClinicalTrials.gov Identifier: NCT03655717.

Brusaferri, L., Z. Alshelh, D. Martins, M. Kim, A. Weerasekera, H. Housman, E. J. Morrissey, P. C. Knight, K. A. Castro-Blanco, D. S. Albrecht, et al., "The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic.", Brain, behavior, and immunity, vol. 102, pp. 89-97, 2022. Abstract

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

Murray, K., Y. Lin, M. M. Makary, P. G. Whang, and P. Geha, "Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.", Molecular pain, vol. 17, pp. 1744806921990938, 2021. Abstract

Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.

Makary, M. M., A. Weerasekara, H. Rodham, B. G. Hightower, C. - E. J. Tseng, J. Chan, S. Chew, S. Paganoni, E. - M. Ratai, N. R. Zürcher, et al., "Comparison of Two Clinical Upper Motor Neuron Burden Rating Scales in ALS Using Quantitative Brain Imaging.", ACS chemical neuroscience, vol. 12, issue 5, pp. 906-916, 2021. Abstract

Several clinical upper motor neuron burden scales (UMNSs) variably measure brain dysfunction in amyotrophic lateral sclerosis (ALS). Here, we compare relationship of two widely used clinical UMNSs in ALS (Penn and MGH UMNSs) with (a) neuroimaging markers of brain dysfunction and (b) neurological impairment status using the gold-standard functional measure, the revised ALS Functional Rating Scale (ALSFRS-R). MGH UMNS measures hyperreflexia alone, and Penn UMNS measures hyperreflexia, spasticity, and pseudobulbar affect. Twenty-eight ALS participants underwent both Penn and MGH UMNSs, at a matching time-point as a simultaneous [C]PBR28 positron emission tomography (PBR28-PET)/Magnetic Resonance scan and ALSFRS-R. The two UMNSs were compared for localization and strength of association with neuroimaging markers of: (a) neuroinflammation, PBR28-PET and MR Spectroscopy metabolites (myo-inositol and choline) and (b) corticospinal axonal loss, fractional anisotropy (FA), and MR Spectroscopy metabolite (-acetylaspartate). Among clinical UMN manifestations, segmental hyperreflexia, spasticity, and pseudobulbar affect occurred in 100, 43, and 18% ALS participants, respectively. Pseudobulbar affect did not map to any specific brain regional dysfunction, while hyperreflexia and spasticity subdomains significantly correlated and colocalized neurobiological changes to corticospinal pathways on whole brain voxel-wise analyses. Both UMNS total scores showed significant and similar strength of association with (a) neuroimaging changes (PBR28-PET, FA, MR Spectroscopy metabolites) in primary motor cortices and (b) severity of functional decline (ALSFRS-R). Hyperreflexia is the most frequent clinical UMN manifestation and correlates best with UMN molecular imaging changes in ALS. Among Penn UMNS's subdomains, hyperreflexia carries the weight of association with neuroimaging markers of biological changes in ALS. A clinical UMN scale comprising hyperreflexia items alone is clinically relevant and sufficient to predict the highest yield of molecular neuroimaging abnormalities in ALS.

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