Lawrence Ver Hoef

Objective: This study investigated whether idiopathic generalized epilepsies (IGEs) are associated with neuroinflammation by measuring neurometabolite levels and brain temperature using whole‐brain magnetic resonance spectroscopy imaging (MRSI). We compared patients with IGEs to healthy controls (HCs), and in IGEs examined relationships with seizure control, MRSI markers, epilepsy duration, and cognitive performance. Methods: Seventeen patients with IGEs and 15 HCs underwent 3T‐MRI scans. IGEs were also administered the Montreal Cognitive Assessment (MoCA) and Flanker test. Whole‐brain ¹ H‐MRSI provided metabolite and water maps. Levels for myo‐inositol (MI; glial marker), glutamate‐glutamine complex (Glx), and N‐acetylaspartate (NAA) were normalized to creatine (Cr) levels. Brain temperature was obtained by frequency difference between water and Cr. IGEs were stratified into seizure‐free (IGE−) and treatment‐resistant (IGE+) groups. Group analyses were performed using permutation‐based threshold‐free cluster enhancement (TFCE) within bilateral regions of interest: anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), hippocampus, parietal cortex, and thalami. Results: Compared with HCs, IGEs showed higher MI/Cr in the parietal cortex, PCC, and thalamus; higher hippocampus Glx/Cr; and lower parietal cortex NAA/Cr. Brain temperature did not differ between groups. IGE− exhibited higher hippocampal NAA/Cr and better MoCA scores than IGE+. Longer epilepsy duration was associated with lower NAA/Cr in the ACC and PCC, and parietal cortex, as well as lower Glx/Cr in the ACC, PCC, parietal cortex, and hippocampus. Lower NAA/Cr in the ACC, PCC, hippocampus, and thalamus, together with higher thalamus MI/Cr, was associated with lower MoCA scores in IGEs. Lower NAA/Cr in the ACC, thalamus, and hippocampus was associated with poorer Flanker performance in IGEs. Significance: We provide novel evidence of neurometabolic abnormalities in IGEs. The associations between metabolite levels and clinical and cognitive variables suggest potential biomarkers for disease progression and treatment response. Furthermore, these results highlight the roles of abnormal glial activation, neuronal loss, and hyperexcitability in IGE pathophysiology. Plain Language Summary: We compared patients with idiopathic generalized epilepsies (IGEs) to healthy controls (HCs) to investigate brain chemistry and temperature differences and their relationships to seizure control, epilepsy duration, and cognitive performance. We found group differences in brain N‐acetylaspartate (NAA; neuronal marker), myo‐inositol (MI; glial cell marker), and glutamate/glutamine (Glx; excitatory neurotransmission) levels, but not in brain temperature. Longer epilepsy duration was associated with brain chemistry levels. In IGEs, lower NAA levels and higher MI levels were associated with worse cognitive performance. This study highlights the roles of abnormal glial activation, neuronal loss, and hyperexcitability in epilepsy duration and cognition in IGEs.

Objective: To investigate the relationship between cerebral blood flow (CBF), seizure control, and mood regulation in idiopathic generalized epilepsy (IGE), we hypothesized that higher CBF in mood‐regulating regions would be associated with greater mood disturbance, particularly in patients with poor seizure control.Methods: Twenty‐three patients with IGE (13 female) and 19 healthy controls (HCs; 9 female) completed 3T MRI. Patients with IGE were categorized into those with seizures controlled for >6 months (IGE−) and those with ≥1 seizure in the last 6 months (IGE+). Participants completed the Profile of Mood States, with the Total Mood Disturbance (TMD) score indexing the current overall mood state. A pulsed arterial spin labeling (PASL) MRI sequence was used to measure CBF. Average CBF within emotion‐related brain regions was estimated. One‐way ANOVA tests examined the main effect of group and seizure control on CBF and TMD. Pearson correlation analyses identified relationships between CBF and TMD in the combined sample and individual groups (significant at FDR‐corrected p < 0.05).Results: Compared to HCs, IGE exhibited significantly higher TMD (mean ± SD: IGE = 57.39 ± 32.32, HC = 2.05 ± 19.86; p < 0.001) and CBF (mean ± SD: IGE = 60.20 ± 10.88, HC = 53.45 ± 10.22; p = 0.046). However, no statistically significant differences in TMD were observed between IGE+ and IGE−, although both demonstrated significantly higher TMD than HCs (both p < 0.001). Additionally, no statistically significant effect of seizure control was found on CBF. In the combined groups, TMD and CBF showed a positive correlation (r = 0.36, p = 0.019).Significance: This is the first study to investigate the relationship between mood disturbance, seizure control, and CBF in IGE. Both neurobiological and mood state measures showed significant differences between IGE patients and HCs. The relationship between greater CBF and worse mood states (higher TMD) suggests changes in CBF may be a potential biomarker for mood disturbance in epilepsy. Larger studies investigating the effects of seizure control on CBF are needed to clarify this relationship in IGE.Plain Language Summary: Patients with idiopathic generalized epilepsy (IGE) often experience mood comorbidities, such as depression and anxiety. This study aimed to investigate whether cerebral blood flow (CBF) could serve as a potential biomarker for mood disturbance in IGE. We found that patients with IGE had higher CBF and greater mood disturbance compared to healthy individuals, and that higher CBF was associated with worse mood across all participants. Our findings suggest that CBF may be a useful biomarker for mood state, providing insights that could improve the mental health outcomes for patients with IGE. However, larger studies that better account for seizure frequency are needed to assess the effects of seizure control on CBF.

Temporal lobe epilepsy (TLE) is a type of focal epilepsy characterized by spontaneous recurrent seizures originating from the hippocampus. The epigenetic reprogramming hypothesis of epileptogenesis suggests that the development of TLE is associated with alterations in gene transcription changes resulting in a hyperexcitable network in TLE. DNA 5-methylcytosine (5-mC) is an epigenetic mechanism that has been associated with chronic epilepsy. However, the contribution of 5-hydroxymethylcytosine (5-hmC), a product of 5-mC demethylation by the Ten-Eleven Translocation (TET) family proteins in chronic TLE is poorly understood. 5-hmC is abundant in the brain and acts as a stable epigenetic mark altering gene expression through several mechanisms. Here, we found that the levels of bulk DNA 5-hmC but not 5-mC were significantly reduced in the hippocampus of human TLE patients and in the kainic acid (KA) TLE rat model. Using 5-hmC hMeDIP-sequencing, we characterized 5-hmC distribution across the genome and found bidirectional regulation of 5-hmC at intergenic regions within gene bodies. We found that hypohydroxymethylated 5-hmC intergenic regions were associated with several epilepsy-related genes, including Gal , SV2, and Kcnj11 and hyperdroxymethylation 5-hmC intergenic regions were associated with Gad65 , TLR4 , and Bdnf gene expression. Mechanistically, Tet1 knockdown in the hippocampus was sufficient to decrease 5-hmC levels and increase seizure susceptibility following KA administration. In contrast, Tet1 overexpression in the hippocampus resulted in increased 5-hmC levels associated with improved seizure resiliency in response to KA. These findings suggest an important role for 5-hmC as an epigenetic regulator of epilepsy that can be manipulated to influence seizure outcomes.

Cardiorespiratory fitness (CRF) mitigates age-related decline in cognition and brain volume. Little is known, however, about the effects of high-intensity interval training (HIIT) on cognitive aging and the relationship between HIIT, cognition, hippocampal subfield volumes, and cerebral oxygen extraction fraction (OEF). Older sedentary women participated in an 8-week HIIT intervention. We conducted cognitive assessments, fitness assessments (VO₂max), MRI scans: asymmetric spin echo oxygen extraction fraction (ASE-OEF), high-resolution multiple image co-registration and averaging (HR-MICRA) imaging, and transcranial Doppler ultrasonography before and after the intervention. VO₂max increased from baseline (M = 19.36, SD = 2.84) to follow-up (M = 23.25, SD = 3.61), Z = − 2.93, p < .001, r = 0.63. Composite cognitive (Z = − 2.05, p = 0.041), language (Z = − 2.19, p = 0.028), and visuospatial memory (Z = − 2.22, p = 0.026), z-scores increased significantly. Hippocampal subfield volumes CA1 and CA3 dentate gyrus and subiculum decreased non-significantly (all p > 0.05); whereas a significant decrease in CA2 (Z = − 2.045, p = 0.041, r = 0.436) from baseline (M = 29.51; SD = 24.50) to follow-up (M = 24.50; SD = 13.38) was observed. Right hemisphere gray matter was correlated with language z-scores (p = 0.025; r = 0.679). The subiculum was correlated with attention (p = 0.047; r = 0.618) and verbal memory (p = 0.020; r = 0.700). The OEF and CBF were unchanged at follow-up (all p > .05). Although we observed cognitive improvements following 8 weeks of our HIIT intervention, they were not explained by hippocampal, OEF, or CBF changes.

Hippocampal dentation (HD) refers to a series of ridges (dentes) seen on the inferior aspect of the hippocampus. The degree of HD varies dramatically across healthy individuals, and hippocampal pathology may result in loss of HD. Existing studies show associations between HD and memory performance in healthy adults as well as temporal lobe epilepsy (TLE) patients. However, until now studies relied on visual assessment of HD as no objective methods to quantify HD have been described. In this work, we describe a method to objectively quantify HD by transforming the characteristic 3D surface morphology of HD into a simplified 2D plot for which area under the curve (AUC) was calculated. This was applied to T1w scans of 59 TLE subjects, each with one epileptic hippocampus and one normal appearing hippocampus. Results showed that AUC significantly correlated with the number of dentes based on visual inspection (p < .05) and correctly sorted a set of hippocampi from least to most prominently dentated. Intra‐ and inter‐rater reliability was nearly perfect (ICC ≥ 0.99). AUC values were significantly lower in epileptic hippocampi compared to contralateral hippocampi (p = .00019), consistent with previously published findings. In the left TLE group, the AUC values from the contralateral hippocampi showed a positive trend (p = .07) with verbal memory acquisition scores but was not statistically significant. The proposed approach is the first objective, quantitative measurement of dentation described in the literature. The AUC values numerically capture the complex surface contour information of HD and will enable future study of this interesting morphologic feature.

The degree of hippocampal dentation, a morphologic feature of the inferior surface of the human hippocampus, has been positively associated with episodic memory performance in healthy adults. This study examined hippocampal dentation in healthy children and adolescents. The Cincinnati MR Imaging of NeuroDevelopment (C-MIND) dataset was used to examine the relationship between age and hippocampal dentation in 90 healthy children, age < 1 to 18 years old, using T1-weighted MPRAGE scans. Hippocampal dentation was assessed by counting the number of dentes for the left and right hippocampi. Participants had slightly more left than right hippocampal dentes, on average. Dentation did not differ significantly between males and females. Correlational analyses revealed that the numbers of left, right, and total dentes were positively associated with age in this sample. Interestingly, these data highlight the wide variability of dentation in older age groups. While younger children tended to have absent or few dentes, a range of dentation was present in older children and adolescents (ranging from absent to numerous, bilaterally). This is consistent with previous research in a healthy adult cohort, where a range of dentation was also observed. This study is the first to examine hippocampal dentation in children.

Summary: Objective: Hippocampal dentation (HD) is a “toothlike” morphological feature observed on the inferior aspect of the human hippocampus. It has been found that HD varies dramatically in healthy adults and is positively associated with verbal and visual memory. In this work, we evaluate the loss of HD and its association with memory dysfunction in patients with temporal lobe epilepsy (TLE) who have hippocampal sclerosis (HS).Methods: Fifty‐eight unilateral HS patients with neuropsychological data were identified from a retrospective database. T1‐weighted magnetization‐prepared rapid acquisition gradient echo images (~1 mm resolution) were upsampled to .25 mm and were processed using ASHS software to obtain ultra‐high‐resolution segmentations and three‐dimensional renderings. Dentes were counted on the epileptic and contralateral sides, and associations were tested between dentation on the epileptic versus contralateral sides and measures of verbal and visuospatial memory with respect to the dominant versus nondominant hemisphere.Results: The median number of dentes in epileptic hippocampi was significantly lower than in contralateral hippocampi (p < .0001). Among cases with HS in the dominant hemisphere, verbal memory was significantly correlated with contralateral nondominant hemisphere dentation (r = .43, p = .04). Similarly, among cases of HS in the nondominant hemisphere, visual memory was significantly correlated with contralateral dominant hemisphere dentation (r = .48, p = .04). All other analyses were not significant.Significance: This is the first study characterizing dentation in TLE patients with HS and its memory correlates. There is marked loss of dentation in sclerotic hippocampi compared to the unaffected contralateral hippocampi. Material‐specific measures of memory performance are paradoxically correlated with dentation contralateral to the side with HS, suggesting that contralateral functional capacity explains some of the variation in memory across TLE patients. HD is an important variable to consider in understanding memory loss in TLE.

Magnetic resonance imaging of hippocampal internal architecture (HIA) at 3T is challenging. HIA is defined by layers of gray and white matter that are less than 1 mm thick in the coronal plane. To visualize HIA, conventional MRI approaches have relied on sequences with high in-plane resolution (≤0.5 mm) but comparatively thick slices (2–5 mm). However, thicker slices are prone to volume averaging effects that result in loss of HIA clarity and blurring of the borders of the hippocampal subfields in up to 61% of slices as has been reported. In this work we describe an approach to hippocampal imaging that provides consistently high HIA clarity using a commonly available sequence and post-processing techniques that is flexible and may be applicable to any MRI platform. We refer to this approach as High Resolution Multiple Image Co-registration and Averaging (HR-MICRA). This approach uses a variable flip angle turbo spin echo sequence to repeatedly acquire a whole brain T2w image volume with high resolution in three dimensions in a relatively short amount of time, and then co-register the volumes to correct for movement and average the repeated scans to improve SNR. We compared the averages of 4, 9, and 16 individual scans in 20 healthy controls using a published HIA clarity rating scale. In the body of the hippocampus, the proportion of slices with good or excellent HIA clarity was 90%, 83%, and 67% for the 16x, 9x, and 4x HR-MICRA images, respectively. Using the 4x HR-MICRA images as a baseline, the 9x HR-MICRA images were 2.6 times and 16x HR-MICRA images were 3.2 times more likely to have high HIA ratings (p < 0.001) across all hippocampal segments (head, body, and tail). The thin slices of the HR-MICRA images allow reformatting in any plane with clear visualization of hippocampal dentation in the sagittal plane. Clear and consistent visualization of HIA will allow application of this technique to future hippocampal structure research, as well as more precise manual or automated segmentation.

Objective: To further evaluate the relationship between the clinical profiles and limbic and motor brain regions and their connecting pathways in psychogenic nonepileptic seizures (PNES). Neurite Orientation Dispersion and Density Indices (NODDI) multicompartment modeling was used to test the relationships between tissue alterations in patients with traumatic brain injury (TBI) and multiple psychiatric symptoms.Methods: The sample included participants with prior TBI (TBI; N = 37) but no PNES, and with TBI and PNES (TBI + PNES; N = 34). Participants completed 3T Siemens Prisma MRI high angular resolution imaging diffusion protocol. Statistical maps, including fractional anisotropy (FA), mean diffusivity (MD), neurite dispersion [orientation dispersion index (ODI)] and density [intracellular volume fraction (ICVF), and free water (i.e., isotropic) volume fraction (V‐ISO)] signal intensity, were generated for each participant. Linear mixed‐effects models identified clusters of between‐group differences in indices of white matter changes. Pearson’s r correlation tests assessed any relationship between signal intensity and psychiatric symptoms.Results: Compared to TBI, TBI + PNES revealed decreases in FA, ICVF, and V‐ISO and increases in MD for clusters within cingulum bundle, uncinate fasciculus, fornix/stria terminalis, and corticospinal tract pathways (cluster threshold α = 0.05). Indices of white matter changes for these clusters correlated with depressive, anxiety, PTSD, psychoticism, and somatization symptom severity (FDR threshold α = 0.05). A follow‐up within‐group analysis revealed that these correlations failed to reach the criteria for significance in the TBI + PNES group alone.Interpretation: The results expand support for the hypothesis that alterations in pathways comprising the specific PNES network correspond to patient profiles. These findings implicate myelin‐specific changes as possible contributors to PNES, thus introducing novel potential treatment targets.