Brain temperature and free water increases after mild COVID-19 infection.

The pathophysiology underlying the post-acute sequelae of COVID-19 remains understudied and poorly understood, particularly in healthy adults with a history of mild infection. Chronic neuroinflammation may underlie these enduring symptoms, but studying neuroinflammatory phenomena in vivo is challenging, especially without a comparable pre-COVID-19 dataset. In this study, we present a unique dataset of 10 otherwise healthy individuals scanned before and after experiencing mild COVID-19. Two emerging MR-based methods were used to map pre- to post-COVID-19 brain temperature and free water changes. Post-COVID-19 brain temperature and free water increases, which are indirect biomarkers of neuroinflammation, were found in structures functionally associated with olfactory, cognitive, and memory processing. The largest pre- to post-COVID brain temperature increase was observed in the left olfactory tubercle (p = 0.007, 95% CI [0.48, 3.01]), with a mean increase of 1.75 °C. Notably, the olfactory tubercle is also the region of the primary olfactory cortex where participants with chronic olfactory dysfunction showed the most pronounced increases as compared to those without lingering olfactory dysfunction (adjusted pFDR = 0.0189, 95% CI [1.42, 5.27]). These preliminary insights suggest a potential link between neuroinflammation and chronic cognitive and olfactory dysfunction following mild COVID-19, although further investigations are needed to improve our understanding of what underlies these phenomena.

The longitudinal effects of cannabidiol on brain temperature in patients with treatment-resistant epilepsy.

Neuroinflammation (NI) is a key pathophysiological contributor to treatment-resistant epilepsy (TRE) that remains challenging to observe in vivo. Magnetic resonance spectroscopic imaging and thermometry (MRSI-t) is an emerging technique that can be used to non-invasively map brain temperature, whereby brain temperature elevations serve as a surrogate for the cellular and biochemical processes associated with NI. In a previous multimodal imaging study of focal epilepsy patients, we observed MRSI-t-based brain temperature elevations ipsilateral to the seizure onset zone (SOZ) that were concordant with evidence of edema (Sharma et al., 2023). Despite its potential as tool, it is unclear if MRSI-t can monitor changes in brain temperature in response to treatment. We imaged 25 participants approximately 12-weeks apart. Eight patients with TRE were imaged before receiving highly-purified pharmaceutical grade cannabidiol (CBD; pre-CBD) and after 12-weeks of CBD (on-CBD) therapy. Seventeen healthy controls (HCs) were also imaged twice. Repeated measures t-tests computed changes in TRE patients' seizure symptoms, mood, and brain temperature within their respective SOZs. Repeated measures ANOVAs tested Group*Time changes in imaging data. Participants with TRE had abnormally high peak brain temperatures within their SOZs that decreased after CBD initiation (p < 0.0001). Seizure severity scores also improved after CBD initiation (p < 0.001). These findings provide insights into the possible neural effects of CBD, and further demonstrate MRSI-t's potential as a tool for delineating SOZ. Further investigations into MRSI-t as a longitudinal measure of therapy-induced changes in NI are warranted.

Neuromorphometric associations with mood, cognition, and self-reported exercise levels in epilepsy and healthy individuals.

Regular physical activity may promote beneficial neuroplasticity, e.g., increased hippocampus volume. However, it is unclear whether self-reported physical exercise in leisure (PEL) levels are associated with the brain structure features demonstrated by exercise interventions. This pilot study investigated the relationship between PEL, mood, cognition, and neuromorphometry in patients with idiopathic generalized epilepsy (IGEs) compared to healthy controls (HCs). Seventeen IGEs and 19 age- and sex-matched HCs underwent magnetic resonance imaging (MRI) at 3T. The Baecke Questionnaire of Habitual Physical Activity, Profile of Mood States, and Montreal Cognitive Assessment (MoCA) assessed PEL, mood, and cognition, respectively. Structural MRI data were analyzed by voxel- and surface-based morphometry. IGEs had significantly lower PEL (p < 0.001), poorer mood (p = 0.029), and lower MoCA scores (p = 0.027) than HCs. These group differences were associated with reduced volume, decreased gyrification, and altered surface topology (IGEs < HCs) in frontal, temporal and cerebellar regions involved in executive function, memory retrieval, and emotional regulation, respectively. These preliminary results support the notion that increased PEL may promote neuroplasticity in IGEs, thus emphasizing the role of physical activity in promoting brain health in people with epilepsy.

Peripheral and Central Nervous System Biomarkers of Inflammation in Functional Seizures: Assessment with Magnetic Resonance Spectroscopy.

Purpose: Inflammation may link trauma to clinical symptoms in functional seizures (FS). We compared brain temperature and metabolites in FS, psychiatric (PCs) and healthy controls (HCs) and quantified their associations with serum biomarkers of inflammation and clinical symptoms. Patients and Methods: Brain temperature and metabolites were measured with whole-brain magnetic resonance spectroscopic imaging (MRSI) and compared between groups in regions of interest and the whole brain. Relationships with inflammatory biomarkers and symptoms were assessed with Pearson correlations. Results: Brain temperature was higher in FS than HCs in the orbitofrontal cortex (OFC) and anterior cingulate gyrus (ACG) and lower in the occipital cortex and frontal lobe. PCs showed lower temperatures than HCs in the frontal lobe including precentral gyrus and in the cerebellum. Myo-inositol (MINO) was higher in FS than HCs in the precentral gyrus, posterior temporal gyrus, ACG and OFC, and choline (CHO) was higher in the occipital lobe. CHO was higher in PCs than HCs in the ACG and OFC, and N-acetylaspartate (NAA) was higher in the ACG. There were no significant correlations with the serum inflammatory biomarkers. In FS, brain temperature correlated with depression, quality of life, psychological symptoms, and disability, CHO correlated with disability, and MINO correlated with hostility, disability, and quality of life. Conclusion: Some of the previously identified neuroimaging abnormalities in FS may be related to comorbid psychiatric symptoms, while others, such as abnormalities in sensorimotor cortex, occipital regions, and the temporo-parietal junction may be specific to FS. Overlapping MINO and temperature increases in the ACG and OFC in FS suggest neuroinflammation.

An exploratory study of brain temperature and choline abnormalities in temporal lobe epilepsy patients with depressive symptoms.

OBJECTIVE: Epilepsy and depression share neurobiological origins, and evidence suggests a possible bidirectional relationship that remains poorly understood. This exploratory, cross-sectional study aimed to investigate this relationship by employing magnetic resonance spectroscopic imaging (MRSI) and thermometry (MRSI-t) in patients with temporal lobe epilepsy (TLE) with comorbid depressive symptoms and control participants. This is the first study to combine MRSI and MRSI-t to examine brain temperature and choline abnormalities in regions implicated in seizure onset and depression. METHODS: Twenty-six patients with TLE and 26 controls completed questionnaires and underwent imaging at 3T. Volumetric echo-planar MRSI/MRSI-t data were processed within the Metabolite Imaging and Data Analysis System (MIDAS). Choline (CHO) was quantified as a ratio over creatine (CRE; CHO/CRE). Brain temperature (TCRE ) was calculated based on the chemical shift difference of H2 O relative to CRE's stable location on the ppm spectrum. The Hospital Anxiety and Depression Scale measured anxiety and depressive symptoms. The Chalfont Seizure Severity Scale measured seizure severity in patients with TLE. Two sets of voxelwise independent sample t tests examined group differences in CHO/CRE and TCRE maps. Voxel-based multimodal canonical correlation analysis (mCCA) linked both datasets to investigate if, how, and where CHO/CRE and TCRE abnormalities were correlated in TLE participants and controls. RESULTS: Compared to controls, patients with TLE reported more depressive symptoms (P = 0.04) and showed CHO/CRE and TCRE elevations in left temporal and bilateral frontal regions implicated in seizure onset and depressive disorders (pFWE < 0.05). For the TLE group, CHO/CRE levels in temporal and frontal cortices were associated with elevated TCRE in bilateral frontal and temporal gyri (r = 0.96), and decreased TCRE in bilateral fronto-parietal regions (r = -0.95). SIGNIFICANCE: Abnormalities in TCRE and CHO/CRE were observed in seizure-producing areas and in regions implicated in depression. These preliminary findings suggest that common metabolic changes may underlie TLE and depression. Our results suggest further investigations into the proposed bidirectional mechanisms underlying this relationship are warranted.

Concordance between focal brain temperature elevations and focal edema in temporal lobe epilepsy.

OBJECTIVE: Neuroinflammation (NI) is a pathophysiological factor in many neurological disorders, including epilepsy. Because NI causes microstructural tissue damage that worsens with increasing brain temperature, abnormally elevated brain temperatures may be a surrogate measure of the biochemical consequences of NI. This study investigated whether patients with temporal lobe epilepsy (TLE) have abnormal brain temperature elevations (TCRE ) in seizure-producing regions that show evidence of edema and/or microstructural damage. METHODS: Twenty adults with TLE and 20 healthy controls (HCs) were scanned at 3-Tesla. TCRE in each voxel was calculated (TCRE  = -102.61(ΔH20-CRE) + 206.1°C) by non-invasive volumetric magnetic resonance spectroscopic imaging and thermometry (MRSI-t). Multi-shell diffusion images were processed by neurite orientation and density imaging (NODDI). Voxel wise two-sample t tests computed group differences in imaging data. Multimodal data fusion (joint independent component analysis [ICA]) determined the spatial coupling of TCRE with NODDI. RESULTS: TCRE analyses showed that, compared to HCs, TLEs had higher TCRE (p < .001). NODDI analyses showed increased extracellular free water (pFWE < 0.05) in the medial temporal lobes, with the most pronounced increases ipsilateral to seizure onset. TLEs also had increased angular dispersion of neurites (p < .001) and decreased neurite density (pFWE <0.05) in the ictal-onset medial temporal lobe, as well as more widespread, bilateral patterns of abnormalities. Focal increases in TCRE were spatially concordant with increased free water in the left inferior and middle temporal gyri and the associated cortex. In TLE, ICA loadings extracted from this region of overlap were associated with greater mood disturbance (r = .34, p = .02) and higher depression scores (r = .37, p = .009). SIGNIFICANCE: The spatial concordance between focal TCRE elevations and edema in TLE supports the notion that brain thermometry visualizes the correlates of focal NI. MRSI-t-based TCRE elevations may, therefore, be a useful biomarker for identifying seizure-producing tissue in patients with focal epilepsy caused by brain damage.

Regional brain atrophy and aberrant cortical folding relate to anxiety and depression in patients with traumatic brain injury and psychogenic nonepileptic seizures.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are characterized by multifocal and global abnormalities in brain function and connectivity. Only a few studies have examined neuroanatomic correlates of PNES. Traumatic brain injury (TBI) is reported in 83% of patients with PNES and may be a key component of PNES pathophysiology. In this study, we included patients with TBI preceding the onset of PNES (TBI-PNES) and TBI without PNES (TBI-only) to identify neuromorphometric abnormalities associated with PNES. METHODS: Adults diagnosed with TBI-PNES (n = 62) or TBI-only (n = 59) completed psychological questionnaires and underwent 3-T magnetic resonance imaging. Imaging data were analyzed by voxel- and surface-based morphometry. Voxelwise general linear models computed group differences in gray matter volume, cortical thickness, sulcal depth, fractal dimension (FDf), and gyrification. Statistical models were assessed with permutation-based testing at 5000 iterations with the Threshold-Free Cluster Enhancement toolbox. Logarithmically scaled p-values corrected for multiple comparisons using familywise error were considered significant at p < .05. Post hoc analyses determined the association between structural and psychological measures (p < .05). RESULTS: TBI-PNES participants demonstrated atrophy of the left inferior frontal gyrus and the right cerebellum VIII. Relative to TBI-only, TBI-PNES participants had decreased FDf in the right superior parietal gyrus and decreased sulcal depth in the left insular cortex. Significant clusters were positively correlated with global assessment of functioning scores, and demonstrated varying negative associations with measures of anxiety, depression, somatization, and global severity of symptoms. SIGNIFICANCE: The diagnosis of PNES was associated with brain atrophy and reduced cortical folding in regions implicated in emotion processing, regulation, and response inhibition. Cortical folds primarily develop during the third trimester of pregnancy and remain relatively constant throughout the remainder of one's life. Thus, the observed aberrations in FDf and sulcal depth could originate early in development. The convergence of environmental, developmental, and neurobiological factors may coalesce to reflect the neuropathophysiological substrate of PNES.

Corrigendum: Repeatability and Reproducibility of in-vivo Brain Temperature Measurements.

[This corrects the article DOI: 10.3389/fnhum.2020.598435.].

Neuroinflammation as a pathophysiological factor in the development and maintenance of functional seizures: A hypothesis.

The neurobiological underpinnings of functional seizure (FS) development and maintenance represent an active research area. Recent work has focused on hardware (brain structure) and software (brain function and connectivity). However, understanding whether FS are an adaptive consequence of changes in brain structure, function, and/or connectivity is important for identifying a causative mechanism and for FS treatment and prevention. Further, investigation must also uncover what causes these structural and functional phenomena. Pioneering work in the field of psychoneuroimmunology has established a strong, consistent link between psychopathology, immune dysfunction, and brain structure/function. Based on this and recent FS biomarker findings, we propose a new etiologic model of FS pathophysiology. We hypothesize that early-life stressors cause neuroinflammatory and neuroendocrine changes that prime the brain for later FS development following secondary trauma (e.g., traumatic brain injury or psychological trauma). This framework coalesces existing knowledge regarding brain aberrations underlying FS and established neurobiological theories on the pathophysiology of underlying psychiatric disorders. We also propose brain temperature mapping as a way of indirectly visualizing neuroinflammation in patients with FS, particularly in emotion regulation, fear processing, and sensory-motor integration circuits. We offer a foundation on which future research can be built, with clear recommendations for future studies.

In Vivo Imaging of Neuroinflammatory Targets in Treatment-Resistant Epilepsy.

PURPOSE OF REVIEW: Recent evidence indicates that chronic, low-level neuroinflammation underlies epileptogenesis. Targeted imaging of key neuroinflammatory cells, receptors, and tissues may enable localizing epileptogenic onset zone, especially in those patients who are treatment-resistant and considered MRI-negative. Finding a specific, sensitive neuroimaging-based biomarker could aid surgical planning and improve overall prognosis in eligible patients. This article reviews recent research on in vivo imaging of neuroinflammatory targets in patients with treatment-resistant, non-lesional epilepsy. RECENT FINDINGS: A number of advanced approaches based on imaging neuroinflammation are being implemented in order to assist localization of epileptogenic onset zone. The most exciting tools are based on radioligand-based nuclear imaging or revisiting of existing technology in novel ways. The greatest limitations stem from gaps in knowledge about the exact function of neuroinflammatory targets (e.g., neurotoxic or neuroprotective). Further, lingering questions about each approach's specificity, reliability, and sensitivity must be addressed, and clinical utility must be validated before any novel method is incorporated into mainstream clinical practice. Current applications of imaging neuroinflammation in humans are limited and underutilized, but offer hope for finding sensitive and specific neuroimaging-based biomarker(s). Future work necessitates appreciation of investigations to date, significant findings, and neuroinflammatory targets worth exploring further.

Repeatability and Reproducibility of in-vivo Brain Temperature Measurements.

Background: Magnetic resonance spectroscopic imaging (MRSI) is a neuroimaging technique that may be useful for non-invasive mapping of brain temperature (i.e., thermometry) over a large brain volume. To date, intra-subject reproducibility of MRSI-based brain temperature (MRSI-t) has not been investigated. The objective of this repeated measures MRSI-t study was to establish intra-subject reproducibility and repeatability of brain temperature, as well as typical brain temperature range. Methods: Healthy participants aged 23-46 years (N = 18; 7 females) were scanned at two time points ~12-weeks apart. Volumetric MRSI data were processed by reconstructing metabolite and water images using parametric spectral analysis. Brain temperature was derived using the frequency difference between water and creatine (TCRE) for 47 regions of interest (ROIs) delineated by the modified Automated Anatomical Labeling (AAL) atlas. Reproducibility was measured using the coefficient of variation for repeated measures (COVrep), and repeatability was determined using the standard error of measurement (SEM). For each region, the upper and lower bounds of Minimal Detectable Change (MDC) were established to characterize the typical range of TCRE values. Results: The mean global brain temperature over all subjects was 37.2°C with spatial variations across ROIs. There was a significant main effect for time [F (1, 1,591) = 37.0, p < 0.0001] and for brain region [F (46, 1,591) = 2.66, p < 0.0001]. The time*brain region interaction was not significant [F (46, 1,591) = 0.80, p = 0.83]. Participants' TCRE was stable for each ROI across both time points, with ROIs' COVrep ranging from 0.81 to 3.08% (mean COVrep = 1.92%); majority of ROIs had a COVrep <2.0%. Conclusions: Brain temperature measurements were highly consistent between both time points, indicating high reproducibility and repeatability of MRSI-t. MRSI-t may be a promising diagnostic, prognostic, and therapeutic tool for non-invasively monitoring brain temperature changes in health and disease. However, further studies of healthy participants with larger sample size(s) and numerous repeated acquisitions are imperative for establishing a reference range of typical brain TCRE, as well as the threshold above which TCRE is likely pathological.

Seizing the Neuroinflammatory Target: The Quest Continues.

[Box: see text].

A preliminary study of the effects of cannabidiol (CBD) on brain structure in patients with epilepsy.

Cannabis use is associated with changes in brain structure and function; its neurotoxic effects are largely attributed to Δ9-tetrahydrocannabidiol. Whether such effects are present in patients with epilepsy exposed to a highly-purified cannabidiol isolate (CBD; Epidiolex®; Greenwich Biosciences, Inc.) has not been investigated to date. This preliminary study examines whether daily CBD dose of 15-25 mg/kg produces cerebral macrostructure changes and, if present, how they relate to changes in seizure frequency. Twenty-seven patients with treatment-resistant epilepsy were recruited from the University of Alabama at Birmingham CBD Program. Participants provided seizure frequency diaries (SF), completed the Chalfont Seizure Severity Scale (CSSS) and Adverse Events Profile (AEP), and underwent MRI before CBD (baseline) and after achieving a stable CBD dosage (on-CBD). We examined T1-weighted structural images for gray matter volume (GMV) and cortical thickness changes from baseline to on-CBD in 18 participants. Repeated measures t-tests confirmed decreases in SF [t(17) = 3.08, p = 0.0069], CSSS [t(17) = 5.77, p < 0.001], and AEP [t(17) = 3.04, p = 0.0074] between the two time-points. Voxel-level paired samples t-tests did not identify significant changes in GMV or cortical thickness between these two time-points. In conclusion, short-term exposure to highly purified CBD may not affect cortical macrostructure.