Pathological manifestation of human endogenous retrovirus K in frontotemporal dementia

Background Behavioral variant frontotemporal dementia (bvFTD) is a common form of younger-onset dementia with a proportion of cases overlapping pathologically and genetically with amyotrophic lateral sclerosis (ALS). Previous studies have identified that the human endogenous retrovirus K (HERV-K) is elevated in ALS serum and is associated with ALS TDP-43 pathology. In contrast, little is known about HERV-K changes in bvFTD. Here, we investigated the possible role of HERV-K in bvFTD. Methods We measured the HERV-K env gene in sporadic bvFTD (N = 63), sporadic ALS (N = 89), and control (N = 21) serum by ddPCR. We also analyzed HERV-K env, by qPCR, and the HERV-K reverse transcriptase protein, by confocal immunofluorescence microscopy, in the disease-affected superior frontal cortex of bvFTD with TDP-43 pathology. Results Here, we show that HERV-K env levels are significantly elevated (P = 3.5 × 10−6) in bvFTD compared to control serum, differentiating cases with an AUC value of 0.867. HERV-K env levels are also specifically elevated in the superior frontal cortex of bvFTD with TDP-43 pathology, with the HERV-K reverse transcriptase protein and TDP-43 deposit localized to the neuronal cytoplasm. Furthermore, in a neuronal cell line overexpression of TDP-43 induces HERV-K env transcription. Conclusions These results suggest that manifestation of HERV-K is associated with bvFTD TDP-43 pathology. Analysis of HERV-K in bvFTD may provide insight into an unrecognized but targetable perturbed pathology.

Cortical thickness, gyrification and sulcal depth in trigeminal neuralgia

Neuroimaging studies have documented brain structural alterations induced by chronic pain, particularly in gray matter volume. However, the effects of trigeminal neuralgia (TN), a severe paroxysmal pain disorder, on cortical morphology are not yet known. In this study, we recruited 30 TN patients and 30 age-, and gender-matched healthy controls (HCs). Using Computational Anatomy Toolbox (CAT12), we calculated and compared group differences in cortical thickness, gyrification, and sulcal depth with two-sample t tests (p < 0.05, multiple comparison corrected). Relationships between altered cortical characteristics and pain intensity were investigated with correlation analysis. Compared to HCs, TN patients exhibited significantly decreased cortical thickness in the left inferior frontal, and left medial orbitofrontal cortex; decreased gyrification in the left superior frontal cortex; and decreased sulcal depth in the bilateral superior frontal (extending to anterior cingulate) cortex. In addition, we found significantly negative correlations between the mean cortical thickness in left medial orbitofrontal cortex and pain intensity, and between the mean gyrification in left superior frontal cortex and pain intensity. Chronic pain may be associated with abnormal cortical thickness, gyrification and sulcal depth in trigeminal neuralgia. These morphological changes might contribute to understand the underlying neurobiological mechanism of trigeminal neuralgia.

Recurrent Facial Focal Seizures With Chronic Striatopathy and Caudate Atrophy—A Double Whammy in an Elderly Woman With Diabetes Mellitus

Seizures and involuntary movements are relatively rare, but well-known neurological complications of non-ketotic hyperglycemia. While hemichorea-hemiballism secondary to diabetic striatopathy is increasingly being reported, unilateral caudate atrophy resulting from chronic vascular insufficiency/insult in a backdrop of poorly controlled diabetes mellitus is sparsely described in literature. We herein report a 75-year-old woman with poorly controlled diabetes mellitus who presented with concurrent epilepsia partialis continua involving left side of her face and hemichorea on the right side in the context of non-ketotic hyperglycemia. Neuroimaging revealed a space-occupying lesion suggestive of low-grade glioma in the right superior frontal cortex and left-sided caudate atrophy as well. Possibly, space-occupying lesion in motor cortex acted as an inciting factor for seizures and non-ketotic hyperglycemia further lowered the seizures threshold. On the other hand, atrophied left caudate had led to persistent choreiform movements secondary to chronic uncontrolled hyperglycemia. The simultaneous presence of acute and chronic neurological complications of diabetes mellitus makes this case unique. It also highlights the need for strict control of blood glucose and utility of appropriate neuroimaging to rapidly diagnose and prevent further complications.

GPT-2’s activations predict the degree of semantic comprehension in the human brain

Language transformers, like GPT-2, have demonstrated remarkable abilities to process text, and now constitute the backbone of deep translation, summarization and dialogue algorithms. However, whether these models actually understand language is highly controversial. Here, we show that the representations of GPT-2 not only map onto the brain responses to spoken stories, but also predict the extent to which subjects understand the narratives. To this end, we analyze 101 subjects recorded with functional Magnetic Resonance Imaging while listening to 70 min of short stories. We then fit a linear model to predict brain activity from GPT-2 activations, and correlate this mapping with subjects’ comprehension scores as assessed for each story. The results show that GPT-2’s brain predictions significantly correlate with semantic comprehension. These effects are bilaterally distributed in the language network and peak with a correlation above 30% in the infero-frontal and medio-temporal gyri as well as in the superior frontal cortex, the planum temporale and the precuneus. Overall, this study provides an empirical framework to probe and dissect semantic comprehension in brains and deep learning algorithms.

Behavioral, Anatomical and Genetic Convergence of Affect and Cognition in Superior Frontal Cortex

Affective experience and cognition are key human traits that are proposed to be inherently coupled in the human brain. Here we studied shared genetic basis of cognitive and affective traits in behavior and brain structure in the twin-based Human Connectome Project sample (n=1087). Both affective and cognitive trait scores were highly heritable and showed significant phenotypic correlation on the behavioral level. We further evaluated the correlation of affect and cognition, respectively, with local brain structure (cortical thickness, subcortical volumes, and surface area). Cortical thickness in the left superior frontal cortex showed a phenotypic association with both affect and cognition, which was driven by shared genetic effects. Quantitative functional decoding of this region yielded associations with cognitive and emotional functioning. This study provides a multi-level approach to study the association between affect and cognition and suggests a convergence of both in superior frontal anatomy.

Functional Dysconnectivity of Frontal Cortex to Striatum Predicts Ketamine Infusion Response in Treatment-Resistant Depression

Background Frontostriatal disconnectivity plays a crucial role in the pathophysiology of major depressive disorder. However, whether the baseline functional connectivity of the frontostriatal network could predict the treatment outcome of low-dose ketamine infusion remains unknown. Methods In total, 48 patients with treatment-resistant depression were randomly divided into 3 treatment groups (a single-dose 40-minute i.v. infusion) as follows: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and saline placebo infusion. Patients were subsequently followed-up for 2 weeks. Resting-state functional magnetic resonance imaging was performed for each patient before infusion administration. In addition, the baseline frontostriatal functional connectivity of patients with treatment-resistant depression was also compared with that of healthy controls. Results Compared with the healthy controls, patients with treatment-resistant depression had a decreased functional connectivity in the frontostriatal circuits, especially between the right superior frontal cortex and executive region of the striatum and between the right paracingulate cortex and rostral-motor region of the striatum. The baseline hypoconnectivity of the bilateral superior frontal cortex to the executive region of the striatum was associated with a greater reduction of depression symptoms after a single 0.2-mg/kg ketamine infusion. Conclusion Reduced connectivity of the superior frontal cortex to the striatum predicted the response to ketamine infusion among patients with treatment-resistant depression.

M154. INTRA- AND INTER-SCANNER RELIABILITY OF GRAY MATTER VOLUME AND CORTICAL THICKNESS ESTIMATES: IMPLICATIONS FOR MULTICENTRE IMAGING STUDIES IN PSYCHOSIS

Background High-resolution structural MRI has been widely used in clinical research to detect and quantify subtle brain changes in patient populations. Findings from prospective, longitudinal studies show structural brain abnormalities as well as progressive gray matter changes over time in individuals at clinical high risk for psychosis compared to healthy subjects. In recent years, research in this field has seen an increase in multicentre neuroimaging projects, such as EU-GEI, PSYSCAN, PRONIA and NAPLS. Additional sources of variance, alongside known technological and biological factors, may be introduced when MRI images are acquired and combined from different sites. It is imperative for longitudinal multicentre studies to determine the accuracy of quantitative MRI measurements and account for systematic differences both between scanners and across scanning sessions. This is particularly true within psychosis research where morphometric changes as small as 3% or less are expected. Methods Six healthy participants were scanned on four separate occasions over a two-month period at King’s College London; twice on a GE SIGNA HDx 3T scanner used locally in the EU-GEI High Risk Study and twice on a GE MR750 3T scanner used locally in the PSYSCAN study. Both scanners implemented the ADNI-2 T1 protocol which is used globally across the EU-GEI and PSYSCAN consortia. Structural imaging data was segmented using the FreeSurfer 6.0 longitudinal pipeline. Intraclass correlation coefficients (ICCs) with a two-way mixed effects model of absolute agreement were calculated to assess intra- and inter-scanner reliability of brain morphometry. For volumetric studies, ICC values greater than 0.9 indicate ‘excellent’ reliability. Reliability analyses of key regions implicated in psychosis included gray matter volume estimates of the hippocampus, insula, lateral ventricle, orbitofrontal cortex and anterior cingulate cortex, and average cortical thickness measurements of the whole brain, parahippocampus and superior frontal cortex. Results Gray matter volume estimates of all structures yielded ‘excellent’ reliability for both intra-scanner (ICCs of 0.979 – 0.998) and inter-scanner analyses (ICCs of 0.976 – 0.999). Intra-scanner reliability for mean cortical thickness measurements was ‘excellent’ for right total cortex, resulting in an ICC of 0.901, but otherwise ‘good’ for left and total cortex, parahippocampus, superior frontal cortex (ICCs of 0.754 – 0.875). Inter-scanner reliability for mean cortical thickness estimates were most variable across the brain structures. Here, results demonstrated ‘excellent’ reliability for the parahippocampus and left total cortex (ICCs of 0.907 – 0.965), ‘good’ for total cortex (ICC of 0.835), ‘moderate’ for right total cortex, right and total superior frontal cortex (ICCs of 0.520 – 0.676), and ‘poor’ for the left superior frontal cortex which produced an ICC of 0.470. Overall, mean cortical thickness estimates of the superior frontal cortex from two different MR scanners showed the least reliability. Discussion Results confirmed highly reliable estimates for gray matter volumes in all brain structures, both from images acquired within the same scanner and across two different scanners. However, the findings indicated increased variability of mean cortical thickness estimates, particularly between scanners, which should be considered when interpreting study findings. Multicentre structural neuroimaging within the field of psychosis is becoming more common and it must be acknowledged that combining MRI data in multicentre studies will contribute additional sources of variance and potential bias with certain brain regions affected more than others.