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.

Brain network entropy, depression, and quality of life in people with traumatic brain injury and seizure disorders.

OBJECTIVE: Traumatic brain injury (TBI) often precedes the onset of epileptic (ES) or psychogenic nonepileptic seizures (PNES) with depression being a common comorbidity. The relationship between depression severity and quality of life (QOL) may be related to resting-state network complexity. We investigated these relationships in adults with TBI-only, TBI + ES, or TBI + PNES using Sample Entropy (SampEn), a measure of physiologic signals complexity. METHODS: Adults with TBI-only (n = 60), TBI + ES (n = 21), or TBI + PNES (n = 56) completed the Beck Depression Inventory-II (BDI-II; depression symptom severity) and QOL in Epilepsy (QOLIE-31) assessments and underwent resting-state functional magnetic resonance imaging (rs-fMRI). SampEn values derived from six resting state functional networks were calculated per participant. Effects of group, network, and group-by-network-interactions for SampEn were investigated with a mixed-effects model. We examined relationships between BDI-II, QOL, and SampEn of each of the networks. RESULTS: Groups did not differ in age, but there was a higher proportion of women with TBI + PNES (p = 0.040). TBI + ES and TBI-only groups did not differ in BDI-II or QOLIE-31 scores, while the TBI + PNES group scored worse on both measures. The fixed effects of the model revealed significant differences in SampEn values across networks (lower SampEn for the frontoparietal network compared to other networks). The likelihood ratio test for group-by-network-interactions was significant (p = 0.033). BDI-II was significantly negatively associated with Overall QOL scale scores in all groups, and significantly negatively associated with network SampEn values only in the TBI + PNES group. SIGNIFICANCE: Only TBI + PNES had significant relationships between depression symptom severity and network SampEn values indicating that the resting state network complexity is related to depression severity in this group but not in TBI + ES or TBI-only. PLAIN LANGUAGE SUMMARY: The brain has a complex network of internal connections. How well these connections work may be affected by TBI and seizures and may underlie mental health symptoms including depression; the worse the depression, the worse the quality of life. Our study compared brain organization in people with TBI, people with epilepsy after TBI, and people with nonepileptic seizures after TBI. Only people with nonepileptic seizures after TBI showed a relationship between how organized their brain connections were and how bad was their depression. We need to better understand these relationships to develop more impactful, effective treatments.

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.

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.

Repeatability of neurite orientation dispersion and density imaging in patients with traumatic brain injury.

BACKGROUND AND PURPOSE: The aim of this study was to assess the repeatability of neurite orientation dispersion and density imaging in healthy controls (HCs) and traumatic brain injury (TBI). METHODS: Seventeen HCs and 48 TBI patients were scanned twice over 18 weeks with diffusion imaging. Orientation dispersion (ODI), neurite density (NDI), and the fraction of isotropic diffusion (F-ISO) were quantified in regions of interest (ROIs) from a gray matter, subcortical, and white matter atlas and compared using the coefficient of variation for repeated measures (CVrep ), which quantifies the expected percent change on repeated measurement. We used a modified signed likelihood ratio test (M-SLRT) to compare the CVrep between groups in each ROI while correcting for multiple comparisons. RESULTS: NDI exhibited excellent repeatability in both groups; the only group difference was found in the fusiform gyrus, where HCs exhibited better repeatability (M-SLRT = 9.463, p = .0021). ODI also had excellent repeatability in both groups, although repeatability was significantly better in HCs in 16 cortical ROIs (p < .0022) and in the bilateral white matter and bilateral cortex (p < .0027). F-ISO exhibited relatively poor repeatability in both groups, with few group differences. CONCLUSION: Overall, the repeatability of the NDI, ODI, and F-ISO metrics over an 18-week period is acceptable for assessing the effects of behavioral or pharmacological interventions, though caution is advised when assessing F-ISO changes over time.

White Matter Changes after Neurobehavioral Therapy for Functional Seizures.

OBJECTIVE: We aimed to prospectively quantify changes in white matter morphology after neurobehavioral therapy (NBT) for functional seizures (FS) using neurite orientation dispersion and density imaging (NODDI). We hypothesized that patients with FS would exhibit white matter plasticity in the uncinate fasciculus, fornix/stria terminalis, cingulum, and corticospinal tract following NBT that would correlate with improvements in affective symptoms, postconcussive symptoms, and quality of life (QOL). METHODS: Forty-two patients with traumatic brain injury (TBI) and FS (TBI+FS) underwent NBT and provided pre-/postintervention neuroimaging and behavioral data; 47 controls with TBI without FS (TBI-only) completed the same measures but did not receive NBT. Changes in neurite density, orientation dispersion (orientation dispersion index [ODI]), and extracellular free water (FW) were compared between groups. RESULTS: Significant ODI increases in the left uncinate fasciculus in TBI+FS (mean difference = 0.017, p = 0.039) correlated with improvements in posttraumatic symptoms (r = -0.395, p = 0.013), QOL (r = 0.474, p = 0.002), emotional well-being (r = 0.524, p < 0.001), and energy (r = 0.474, p = 0.002). In TBI-only, ODI decreased (mean difference = -0.008, p = 0.047) and FW increased (mean difference = 0.011, p = 0.003) in the right cingulum. FW increases correlated with increased psychological problems (r = 0.383, p = 0.013). In TBI+FS, NBT resulted in FS decreases of 3.5 seizures per week. None of the imaging changes correlated with FS frequency. INTERPRETATION: We identified white matter changes after NBT in patients with FS that were associated with improved psychosocial functioning. NODDI could be incorporated into future mechanistic assessments of interventions in patients with FS. ANN NEUROL 2023;94:350-365.

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.

Relationship between intrinsic network connectivity and psychiatric symptom severity in functional seizures.

BACKGROUND: Traumatic brain injury (TBI) may precipitate the onset of functional seizures (FSs). Many patients with FS report at least one prior TBI, and these patients typically present with more severe psychiatric comorbidities. TBI and psychopathology are linked to changes in neural network connectivity, but their combined effects on these networks and relationship to the effects of FS remain unclear. We hypothesised that resting-state functional connectivity (rsFC) would differ between patients with FS and TBI (FS+TBI) compared with TBI without FS (TBI only), with variability only partially explained by the presence of psychopathology. METHODS: Patients with FS+TBI (n=52) and TBI only (n=54) were matched for age and sex. All participants completed psychiatric assessments prior to resting-state functional MRI at 3 T. Independent component analysis identified five canonical rsFC networks related to emotion and motor functions. RESULTS: Five linear mixed-effects analyses identified clusters of connectivity coefficients that differed between groups within the posterior cingulate of the default mode network, insula and supramarginal gyrus of the executive control network and bilateral anterior cingulate of the salience network (all α=0.05, corrected). Cluster signal extractions revealed decreased contributions to each network for FS+TBI compared to TBI only. Planned secondary analyses demonstrated correlations between signal and severity of mood, anxiety, somatisation and global functioning symptoms. CONCLUSIONS: These findings indicate the presence of aberrant connectivity in FS and extend the biopsychosocial network model by demonstrating that common aetiology is linked to both FS and comorbidities, but the overlap in affected networks varies by comorbid symptoms.

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

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

A Pilot Randomized Controlled Trial of Intermittent Theta Burst Stimulation as Stand-Alone Treatment for Post-Stroke Aphasia: Effects on Language and Verbal Functional Magnetic Resonance Imaging (fMRI).

BACKGROUND There is an ongoing need for facilitating language recovery in chronic post-stroke aphasia. The primary aim of this study (NCT01512264) was to examine if noninvasive intermittent theta burst stimulation (iTBS) applied to the injured left-hemispheric cortex promotes language improvements and fMRI changes in post-stroke aphasia. MATERIAL AND METHODS Participants were randomized to 3 weeks of sham (Tx0) or 1-3 weeks of iTBS (Tx123). We assessed participants who completed the first 2 functional MRI (fMRI) sessions (T1, T2) where they performed 2 overt language fMRI tasks, and examined longitudinal response after 3 months (T3). Language performance and fMRI activation changes, and relationships between these changes were assessed. RESULTS From T1 to T2, both groups showed improvements on the Boston Naming Test (BNT). From T1 to T3, Tx123 improved on the Aphasia Quotient, post-scan word recognition on the verbal paired associates task (VPAT), and perceived communicative ability. Each group exhibited significant activation changes between T1 and T2 for both tasks. Only the Tx123 group exhibited fMRI activation changes between T2 to T3 on the verb-generation task and between T1 and T3 on VPAT. Delayed aphasia symptom improvement for Tx123 was associated with increased left ventral visual stream activation from T1 to T3 (rho=0.74, P=0.0058), and with decreased bilateral supplementary motor area activation related to VPAT encoding from T2 to T3 (rho=-0.80, P=0.0016). CONCLUSIONS Observed iTBS-induced language improvements and associations between delayed fMRI changes and aphasia improvements support the therapeutic and neurorehabilitative potential of iTBS in post-stroke aphasia recovery.

Intermittent Theta Burst Stimulation (iTBS) for Treatment of Chronic Post-Stroke Aphasia: Results of a Pilot Randomized, Double-Blind, Sham-Controlled Trial.

BACKGROUND Research indicates intermittent theta burst stimulation (iTBS) is a potential treatment of post-stroke aphasia. MATERIAL AND METHODS In this double-blind, sham-controlled trial (NCT01512264) participants were randomized to receive 3 weeks of sham (G0), 1 week of iTBS/2 weeks of sham (G1), 2 weeks of iTBS/1 week of sham (G2), or 3 weeks of iTBS (G3). FMRI localized residual language function in the left hemisphere; iTBS was applied to the maximum fMRI activation in the residual language cortex in the left frontal lobe. FMRI and aphasia testing were conducted pre-treatment, at ≤1 week after completing treatment, and at 3 months follow-up. RESULTS 27/36 participants completed the trial. We compared G0 to each of the individual treatment group and to all iTBS treatment groups combined (G1₋3). In individual groups, participants gained (of moderate or large effect sizes; some significant at P<0.05) on the Boston Naming Test (BNT), the Semantic Fluency Test (SFT), and the Aphasia Quotient of the Western Aphasia Battery-Revised (WAB-R AQ). In G1₋3, BNT, and SFT improved immediately after treatment, while the WAB-R AQ improved at 3 months. Compared to G0, the other groups showed greater fMRI activation in both hemispheres and non-significant increases in language lateralization to the left hemisphere. Changes in IFG connectivity were noted with iTBS, showing differences between time-points, with some of them correlating with the behavioral measures. CONCLUSIONS The results of this pilot trial support the hypothesis that iTBS applied to the ipsilesional hemisphere can improve aphasia and result in cortical plasticity.

Functional Magnetic Resonance Imaging of Language Following Constraint-Induced Aphasia Therapy Primed with Intermittent Theta Burst Stimulation in 13 Patients with Post-Stroke Aphasia.

BACKGROUND Aphasia is a debilitating consequence of stroke. This study aimed to investigate the role of functional magnetic resonance imaging (fMRI) activation changes during overt language tasks in promoting language improvements following constraint-induced aphasia therapy (CIAT) primed with intermittent theta burst stimulation (iTBS) in 13 patients with aphasia following ischemic stroke. MATERIAL AND METHODS Participants with post-stroke aphasia participated in CIAT primed with iTBS on 10 consecutive weekdays. They also underwent language testing and fMRI while performing overt language tasks at baseline (N=13), immediately post-treatment (N=13), and after 3 months (N=12). Outcome measures were compared between time points, and relationships between changes in language ability and fMRI activation were examined. RESULTS We observed improvements in naming (p<0.001), aphasia symptoms (p=0.038), apraxia of speech symptoms (p=0.040), perception of everyday communicative ability (p=0.001), and the number of spoken words produced during fMRI (p=0.028). Pre- to post-treatment change in naming was negatively correlated with change in right postcentral gyrus activation related to noun-verb associations (rho=-0.554, p=0.0497). Change in aphasia symptoms from immediately after to 3 months post-treatment was negatively correlated with change in bilateral supplementary motor area activation related to verbal encoding (rho=-0.790, p=0.0022). CONCLUSIONS Aphasia improvements coupled with fMRI activation changes over time provide support for treatment-induced neuroplasticity with CIAT primed with iTBS. However, a larger randomized sham-controlled study is warranted to confirm our findings and further our understanding of how iTBS can potentiate beneficial effects of language therapy in post-stroke aphasia.

Cannabidiol normalizes resting-state functional connectivity in treatment-resistant epilepsy.

OBJECTIVE: Resting-state (rs) network dysfunction is a contributing factor to treatment resistance in epilepsy. In treatment-resistant epilepsy (TRE), pharmacological and nonpharmacological therapies have been shown to improve such dysfunction. In this study, our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol (CBD; Epidiolex®) on rs functional magnetic resonance imaging (fMRI) functional connectivity (rs-FC). We hypothesized that CBD would change and potentially normalize the rs-FC in TRE. METHODS: Twenty-two of 27 participants with TRE completed all study procedures including longitudinal pre-/on-CBD rs-fMRI (8M/14F, mean age = 36.2 ±â€¯15.9 years, TRE duration = 18.3 ±â€¯12.6 years); there were no differences in age (p = 0.99) or sex (p = 0.15) between groups. Assessments collected included seizure frequency (SF), Chalfont Seizure Severity Scale (CSSS), Columbia Suicide Severity Rating Scale (C-SSRS), Adverse Events Profile (AEP), and Profile of Mood States (POMS). Twenty-three healthy controls (HCs) received rs-fMRI and POMS once. RESULTS: Participants with TRE showed average decrease of 71.7% in SF (p < 0.0001) and improved CSSS, AEP, and POMS confusion, depression, and fatigue subscores (all p < 0.05) on-CBD with POMS scores becoming similar to those of HCs. Paired t-tests showed significant pre-/on-CBD changes in rs-FC in cerebellum, frontal areas, temporal areas, hippocampus, and amygdala with some of them correlating with improvement in behavioral measures. Significant differences in rs-FC between pre-CBD and HCs were found in cerebellum, frontal, and occipital regions. After controlling for changes in SF with CBD, these differences were no longer present when comparing on-CBD to HCs. SIGNIFICANCE: This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain. This effect may underlie its efficacy. This study provides Class III evidence for CBD's normalizing effect on rs-FC in TRE.

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.

Sex, Age, and Handedness Modulate the Neural Correlates of Active Learning.

BACKGROUND: Self-generation of material compared to passive learning results in mproved memory performance; this may be related to recruitment of a fronto-temporal encoding network. Using a verbal paired-associate learning fMRI task, we examined the effects of sex, age, and handedness on the neural correlates of self-generation. METHODS: Data from 174 healthy English-speaking participants (78M, 56 atypically handed; ages 19-76) were preprocessed using AFNI and FSL. Independent component analysis was conducted using GIFT (Group ICA fMRI Toolbox). Forty-one independent components were temporally sorted by task time series. Retaining correlations (r > 0.25) resulted in three task-positive ("generate") and three task-negative ("read") components. Using participants' back-projected components, we evaluated the effects of sex, handedness, and aging on activation lateralization and localization in task-relevant networks with two-sample t-tests. Further, we examined the linear relationship between sex and neuroimaging data with multiple regression, covarying for scanner, age, and handedness. RESULTS: Task-positive components identified using ICA revealed a fronto-parietal network involved with self-generation, while task-negative components reflecting passive reading showed temporo-occipital involvement. Compared to older adults, younger adults exhibited greater task-positive involvement of the left inferior frontal gyrus and insula, whereas older adults exhibited reduced prefrontal lateralization. Greater involvement of the left angular gyrus in task-positive encoding networks among right-handed individuals suggests the reliance on left dominant semantic processing areas may be modulated by handedness. Sex effects on task-related encoding networks while controlling for age and handedness suggest increased right hemisphere recruitment among males compared to females, specifically in the paracentral lobe during self-generation and the suparmarginal gyrus during passive reading. IMPLICATIONS: Identified neuroimaging differences suggest that sex, age, and handedness are factors in the differential recruitment of encoding network regions for both passive and active learning.

FMRI response to acute psychological stress differentiates patients with psychogenic non-epileptic seizures from healthy controls - A biochemical and neuroimaging biomarker study.

We investigated psychological stress response in the brain regions involved in emotion-motor-executive control in psychogenic non-epileptic seizures (PNES). 12 PNES patients and 12 healthy controls (HCs) underwent stress task and resting state functional MRI (fMRI), mood and quality of life (QOL) assessments, and measurements of salivary cortisol, alpha-amylase, and heart rate. Group differences were assessed, and we correlated beta values from a priori selected brain regions showing stress task fMRI group differences with other stress response measures. We also used the regions showing stress task fMRI group differences as seeds for resting state functional connectivity (rs-FC) analysis. Mood and QOL were worse in PNES versus HCs. Physiological and assessment measures were similar except 'Planful Problem Solving' coping that was greater for HCs (p = .043). Perceived stress associated negatively with heart rate change (rs = -0.74, p = .0063). There was stress fMRI hyporeactivity in left/right amygdala and left hippocampus in PNES versus HCs (corrected p < .05). PNES exhibited a positive association between alpha-amylase change and right amygdala activation (rs = 0.71, p = .010). PNES versus HCs exhibited greater right amygdala rs-FC to left precentral and inferior/middle frontal gyri (corrected p < .05). Our findings of fMRI hyporeactivity to psychological stress, along with greater emotion-motor-executive control network rs-FC in PNES when compared to HCs suggest a dysregulation in stress response circuitry in PNES.

A pilot study of combined endurance and resistance exercise rehabilitation for verbal memory and functional connectivity improvement in epilepsy.

Memory impairment is common in persons with epilepsy (PWE), and exercise may be a strategy for its improvement. In this pilot study, we hypothesized that exercise rehabilitation would improve physical fitness and verbal memory and induce changes in brain networks involved in memory processes. We examined the effects of combined endurance and resistance exercise rehabilitation on memory and resting state functional connectivity (rsFC). Participants were randomized to exercise (PWE-E) or control (PWE-noE). The exercise intervention consisted of 18 supervised sessions on nonconsecutive days over 6 weeks. Before and after the intervention period, both groups completed self-report assessments (Short Form-36 (SF-36), Baecke Questionnaire (BQ) of habitual physical activity, and Profile of Mood States (POMS)), cognitive testing (California Verbal Learning Test-II (CVLT-II)), and magnetic resonance imaging (MRI); PWE-E also completed exercise performance tests. After completing the study, PWE-noE were offered cross-over to the exercise arm. There were no differences in baseline demographic, clinical, or assessment variables between 8 PWE-noE and 9 PWE-E. Persons with epilepsy that participated in exercise intervention increased maximum voluntary strength (all strength tests p < 0.05) and exhibited nonsignificant improvement in cardiorespiratory fitness (p = 0.15). Groups did not show significant changes in quality of life (QOL) or habitual physical activity between visits. However, there was an effect of visit on POMS total mood disturbance (TMD) measure showing improvement from baseline to visit 2 (p = 0.023). There were significant group by visit interactions on CVLT-II learning score (p = 0.044) and total recognition discriminability (d') (p = 0.007). Persons with epilepsy that participated in exercise intervention had significant reductions in paracingulate rsFC with the anterior cingulate and increases in rsFC for the cerebellum, thalamus, posterior cingulate cortex (PCC), and left and right inferior parietal lobule (IPL) (corrected p < 0.05). Change in CVLT-II learning score was associated with rsFC changes for the paracingulate cortex (rS = -0.67; p = 0.0033), left IPL (rS = 0.70; p = 0.0019), and right IPL (rS = 0.71; p = 0.0015) while change in d' was associated with change in cerebellum rsFC to angular/middle occipital gyrus (rS = 0.68; p = 0.0025). Our conclusion is that exercise rehabilitation may facilitate verbal memory improvement and brain network functional connectivity changes in PWE and that improved memory performance is associated with changes in rsFC. A larger randomized controlled trial of exercise rehabilitation for cognitive improvement in PWE is warranted.

fMRI study of cannabidiol-induced changes in attention control in treatment-resistant epilepsy.

Patients with treatment-resistant epilepsy (TRE) frequently exhibit memory and attention deficits that contribute to their poor personal and societal outcomes. We studied the effects of adjunct treatment with pharmaceutical grade cannabidiol (CBD) oral solution (Epidiolex®; Greenwich Biosciences, Inc.) on attention control processes related to stimulus conflict resolution in patients with TRE. Twenty-two patients with TRE underwent 3 T magnetic resonance imaging (MRI) before receiving (PRE) and after achieving a stable dose of CBD (ON). Functional MRI (fMRI) data were collected while patients performed 2 runs of a flanker task (FT). Patients were instructed to indicate via button press the congruent (CON) and incongruent (INC) conditions. We performed t-tests to examine with FT attention control processes at PRE and ON visits and to compare the 2 visits using derived general linear model (GLM) data (INC - CON). We performed generalized psychophysiological interaction (gPPI) analyses to assess changes in condition-based functional connectivity on FT. Median time between fMRI visits was 10 weeks, and median CBD dose at follow-up was 25 mg/kg/d. From PRE to ON, participants experienced improvements in seizure frequency (SF) (p = 0.0009), seizure severity (Chalfont Seizure Severity Scale (CSSS); p < 0.0001), and mood (Total Mood Disturbance (TMD) score from Profile of Mood States (POMS); p = 0.0026). Repeated measures analysis of variance showed nonsignificant improvements in executive function from 34.6 (23.5)% to 41.9 (22.4)% CON accuracy and from 34.2 (25.7)% to 37.6 (24.4)% INC accuracy (p = 0.199). Change in CON accuracy was associated with change in INC accuracy (rS = 0.81, p = 0.0005). Participants exhibited CBD-induced increases in fMRI activation in the right superior frontal gyrus (SFG) and right insula/middle frontal gyrus (MFG) and decrease in activation for both regions at ON relative to PRE (corrected p = 0.05). The subset of patients who improved in FT accuracy with CBD showed a negative association between change in right insula/MFG activation and change in accuracy for the INC condition (rS = -0.893, p = 0.0068). The gPPI analysis revealed a CBD-induced decrease in condition-based functional connectivity differences for the right SFG seed region (corrected p = 0.05). Whole-brain regression analysis documented a negative association of change in right insula/MFG condition-based connectivity with change in INC accuracy (corrected p = 0.005). Our results suggest that CBD modulates attention control processing in patients with TRE by reducing right SFG and right insula/MFG activation related to stimulus conflict resolution and by dampening differences in condition-based functional connectivity of the right SFG. Our study is the first to provide insight into how CBD affects the neural substrates involved in attention processing and how modulation of the activity and functional connectivity related to attentional control processes in the right insula/MFG may be working to improve cognitive performance in TRE.

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.

Cortical excitability affects mood state in patients with idiopathic generalized epilepsies (IGEs).

Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = -2.12; T (50) = -2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = -2.12; T (50) = -2.47, p = 0.04) and Fatigue (MD = -3.42; T (50) = -2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted.