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.

Decreased uncinate fasciculus integrity in functional seizures following traumatic brain injury.

OBJECTIVE: The uncinate fasciculus (UF) has been implicated previously in contributing to the pathophysiology of functional (nonepileptic) seizures (FS). FS are frequently preceded by adverse life events (ALEs) and present with comorbid psychiatric symptoms, yet neurobiological correlates of these factors remain unclear. To address this gap, using advanced diffusion magnetic resonance imaging (dMRI), UF tracts in a large cohort of patients with FS and pre-existing traumatic brain injury (TBI + FS) were compared to those in patients with TBI without FS (TBI-only). We hypothesized that dMRI measures in UF structural connectivity would reveal UF differences when controlling for TBI status. Partial correlation tests assessed the potential relationships with psychiatric symptom severity measures. METHODS: Participants with TBI-only (N = 46) and TBI + FS (N = 55) completed a series of symptom questionnaires and MRI scanning. Deterministic tractography via diffusion spectrum imaging (DSI) was implemented in DSI studio (https://dsi-studio.labsolver.org) with q-space diffeomorphic reconstruction (QSDR), streamline production, and manual segmentation to assess bilateral UF integrity. Fractional anisotropy (FA), radial diffusivity (RD), streamline counts, and their respective asymmetry indices (AIs) served as estimates of white matter integrity. RESULTS: Compared to TBI-only, TBI + FS participants demonstrated decreased left hemisphere FA and RD asymmetry index (AI) for UF tracts (both p < .05, false discovery rate [FDR] corrected). Additionally, TBI + FS reported higher symptom severity in depression, anxiety, and PTSD measures (all p < .01). Correlation tests comparing UF white matter integrity differences to psychiatric symptom severity failed to reach criteria for significance (all p > .05, FDR corrected). SIGNIFICANCE: In a large, well-characterized sample, participants with FS had decreased white matter health after controlling for the history of TBI. Planned follow-up analysis found no evidence to suggest that UF connectivity measures are a feature of group differences in mood or anxiety comorbidities for FS. These findings suggest that frontolimbic structural connectivity may play a role in FS symptomology, after accounting for prior ALEs and comorbid psychopathology severity.

Reduced Subjective Cognitive Concerns With Neurobehavioral Therapy in Functional Seizures and Traumatic Brain Injury.

OBJECTIVE: Functional seizures are common among people with traumatic brain injury (TBI). Subjective cognitive concerns refer to a person's own perception of problems with cognitive functioning in everyday life. The authors investigated the presence and correlates of subjective cognitive concerns and the response to neurobehavioral therapy among adults with TBI and functional seizures (TBI+FS group). METHODS: In this observational study, participants in the TBI+FS group (N=47) completed a 12-session neurobehavioral therapy protocol for seizures, while participants in the comparison group (TBI without seizures) (N=50) received usual treatment. Subjective cognitive concerns, objective cognition, mental health, and quality of life were assessed before and after treatment. Data collection occurred from 2018 to 2022. RESULTS: Baseline subjective cognitive concerns were reported for 37 (79%) participants in the TBI+FS group and 20 (40%) participants in the comparison group. In a multivariable regression model in the TBI+FS group, baseline global mental health (ß=-0.97) and obsessive-compulsive symptoms (ß=-1.01) were associated with subjective cognitive concerns at baseline. The TBI+FS group had fewer subjective cognitive concerns after treatment (η2=0.09), whereas the TBI comparison group showed a nonsignificant increase in subjective cognitive concerns. CONCLUSIONS: Subjective cognitive concerns are common among people with TBI and functional seizures and may be related to general mental health and obsessive-compulsive symptoms. Evidence-based neurobehavioral therapy for functional seizures is a reasonable treatment option to address such concerns in this population, although additional studies in culturally diverse samples are needed. In addition, people with functional seizures would likely benefit from rehabilitation specifically targeted toward cognitive functioning.

Altered fronto-limbic-motor response to stress differs between functional and epileptic seizures in a TBI model.

BACKGROUND AND OBJECTIVES: Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) with both often preceded by traumatic brain injury (TBI). FS and ES emergence and occurrence after TBI may be linked to aberrant neurobehavioral stress responses. We hypothesized that neural activity signatures in response to a psychosocial stress task would differ between TBI + FS and TBI + ES after controlling for TBI status (TBI-only). METHODS: In the current multicenter study, participants were recruited prospectively from Rhode Island Hospital, Providence Rhode Island Veterans Administration Medical Center, and the University of Alabama at Birmingham Medical Center. Previous diagnoses of TBI, ES, and FS were verified based on data collected from participants, medical chart and record review, and, where indicated, results of EEG and/or video-EEG confirmatory diagnosis. TBI + ES (N = 21) and TBI + FS (N = 21) were matched for age and sex and combined into an initial group (TBI + SZ; N = 42). A TBI-only group (N = 42) was age and sex matched to the TBI with seizures (TBI + SZ) group. All participants completed an fMRI control math task (CMT) and stress math task (SMT) based on the Montreal Imaging Stress Task (MIST). RESULTS: The TBI + SZ group (n = 24 female) did not differ in mood or anxiety severity compared to TBI-only group (n = 24 female). However, TBI + FS group (n = 11 female) reported greater severity of these symptoms compared to TBI + ES (n = 13 female). The linear mixed effects analysis identified neural responses that differed between TBI-only and TBI + SZ during math performance within the left premotor cortex and during auditory feedback within bilateral prefrontal cortex and hippocampus/amygdala regions. Additionally, neural responses differed between TBI + ES and TBI + FS during math performance within the right dorsolateral prefrontal cortex and bilateral amygdala during auditory feedback within the supplementary motor area. All tests comparing neural stress responses to psychiatric symptom severity failed to reach significance. DISCUSSION: Controlling for TBI and seizure status, these findings implicate specific nodes within frontal, limbic, and sensorimotor networks that may maintain functional neurological symptoms and possibly distinguish FS from ES. This study provides class II evidence of differences in neural responses to psychosocial stress between ES and FS after TBI.

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.

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.

Precentral gyrus and insula responses to stress vary with duration to diagnosis in functional seizures.

OBJECTIVE: This study was undertaken to determine whether undiagnosed illness duration (time between functional seizures [FS] onset and diagnosis) is linked to differences in neural response and functional connectivity during processing of stressful experiences. METHODS: Forty-nine participants with traumatic brain injury preceding the onset of FS confirmed by video-electroencephalography were recruited prospectively. Participants completed psychiatric symptom assessments before undergoing functional magnetic resonance imaging (fMRI) with an acute psychosocial stress task. Linear mixed effects (LME) analyses identified significant interactions between the factors of group (early vs. delayed diagnosis) and time lag to diagnosis on neural responses to stressful math performance and auditory feedback (corrected α = .05). Functional connectivity analysis utilized clusters from initial LME analyses as seed regions to determine significant interactions between these factors on network functional connectivity. RESULTS: Demographic and psychiatric symptom measures were similar between early (n = 25) and delayed (n = 24) groups. Responses to stressful math performance within the left anterior insula and functional connectivity between the anterior insula seed region and a precentral gyrus cluster were significantly negatively correlated with time lag to diagnosis for the early but not the delayed FS diagnosis group. There was no correlation between fMRI findings and psychiatric symptoms. SIGNIFICANCE: This study indicates that aberrant left anterior insula activation and its functional connectivity to the precentral gyrus underlie differences in processing of stressful experiences in patients with delayed FS diagnosis. Follow-up comparisons suggest changes are associated with undiagnosed illness duration rather than psychiatric comorbidities and indicate a potential mechanistic association between neuropathophysiology, response to stressful experiences, and functional neuroanatomy in FS.

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.

Diagnostic delay in functional seizures is associated with abnormal processing of facial emotions.

PURPOSE: In patients with functional seizures (FS), delay in diagnosis (DD) may negatively affect outcomes. Altered brain responses to emotional stimuli have been shown in adults with FS. We hypothesized that DD would be associated with differential fMRI activation in emotion processing circuits. METHODS: Fifty-two adults (38 females) with video-EEG confirmed FS prospectively completed assessments related to symptoms of depression (BDI-II), anxiety (BAI), post-traumatic stress disorder (PCL-S), a measure of how their symptoms affect day-to-day life (GAF), and fMRI at 3T with emotional faces task (EFT). During fMRI, subjects indicated "male" or "female" via button press while implicitly processing happy, sad, fearful, and neutral faces. Functional magnetic resonance imaging (FMRI) response to each emotion was modeled and group analyses were performed in AFNI within pre-specified regions-of-interest involved in emotion processing. A median split (507 days) defined short- (s-DD) and long-delay diagnosis (l-DD) groups. Voxelwise regression analyses were also performed to examine linear relationship between DD and emotion processing. FMRI signal was extracted from clusters showing group differences and Spearman's correlations assessed relationships with symptom scores. RESULTS: Groups did not differ in FS age of onset, sex distribution, years of education, TBI characteristics, EFT in-scanner or post-test performance, or scores on the GAF, BDI-II, BAI, and PCL-S measures. The s-DD group was younger than l-DD (mean age 32.6 vs. 40.1; p = 0.022) at the time of study participation. After correcting for age, compared to s-DD, the l-DD group showed greater fMRI activation to sad faces in the bilateral posterior cingulate cortex (PCC) and to neutral faces in the right anterior insula. Within-group linear regression revealed that with increasing DD, there was increased fMRI activation to sad faces in the PCC and to happy faces in the right anterior insula/inferior frontal gyrus (AI/IFG). There were positive correlations between PCC response to sad faces and BDI-II scores in the l-DD group (rho = 0.48, p = 0.012) and the combined sample (rho = 0.30, p = 0.029). Increased PCC activation to sad faces in those in the l-DD group was associated with worse symptoms of depression (i.e. higher BDI-II score). CONCLUSIONS: Delay in FS diagnosis is associated with fMRI changes in PCC and AI/IFG. As part of the default mode network, PCC is implicated in mood control, self-referencing, and other emotion-relevant processes. In our study, PCC changes are linked to depression. Future studies should assess the effects of interventions on these abnormalities.

Relationship between neural responses to stress and mental health symptoms in psychogenic nonepileptic seizures after traumatic brain injury.

OBJECTIVE: To utilize traumatic brain injury (TBI) as a model for investigating functioning during acute stress experiences in psychogenic nonepileptic seizures (PNES) and to identify neural mechanisms underlying the link between changes in processing of stressful experiences and mental health symptoms in PNES. METHODS: We recruited 94 participants: 50 with TBI only (TBI-only) and 44 with TBI and PNES (TBI + PNES). Participants completed mood (Beck Depression Inventory-II), anxiety (Beck Anxiety Inventory), and posttraumatic stress disorder (PTSD) symptom (PTSD Checklist-Specific Event) assessments before undergoing functional magnetic resonance imaging during an acute psychosocial stress task. Linear mixed-effects analyses identified clusters of significant interactions between group and neural responses to stressful math performance and stressful auditory feedback conditions within limbic brain regions (volume-corrected α = .05). Spearman rank correlation tests compared mean cluster signals to symptom assessments (false discovery rate-corrected α = .05). RESULTS: Demographic and TBI-related measures were similar between groups; TBI + PNES demonstrated worse clinical symptom severity compared to TBI-only. Stressful math performance induced relatively greater reactivity within dorsomedial prefrontal cortex (PFC) and right hippocampal regions and relatively reduced reactivity within left hippocampal and dorsolateral PFC regions for TBI + PNES compared to TBI-only. Stressful auditory feedback induced relatively reduced reactivity within ventral PFC, cingulate, hippocampal, and amygdala regions for TBI + PNES compared to TBI-only. Changes in responses to stressful math within hippocampal and dorsal PFC regions were correlated with increased mood, anxiety, and PTSD symptom severity. SIGNIFICANCE: Corticolimbic functions underlying processing of stressful experiences differ between patients with TBI + PNES and those with TBI-only. Relationships between these neural responses and symptom assessments suggest potential pathophysiologic mechanisms in PNES.

Endoscopic part-task training box scores correlate with endoscopic outcomes.

BACKGROUND: Competency in endoscopy has traditionally been based on number of procedures performed. With movement towards milestone-based accreditation, new standards of establishing competency are required. The Thompson Endoscopic Skills Trainer (TEST) is a training device previously shown to differentiate between novice and expert endoscopists. This study aims to correlate TEST scores to other markers of performance in endoscopy. METHODS: Trainees of a gastroenterology fellowship program were guided through the TEST. Their scores and sub-scores were correlated to their endoscopic metrics of performance, including adenoma detection rate, cecal intubation rate, cecal intubation time, withdrawal time, fentanyl usage, midazolam usage, pain score, overall procedure time, and performance on the ASGE Assessment of Competency in Endoscopy Tool (ACE Tool). RESULTS: The Overall Score positively correlated with the ACE Tool Total Score (r = 0.707, p = 0.010) and sub-scores (Cognitive Skills Score: r = 0.624, p = 0.030; Motor Skills Score: r = 0.756, p = 0.004), and negatively correlated with cecal intubation time (r = - 0.591, p = 0.043). The Gross Motor Score positively correlated with cecal intubation rate (r = 0.593, p = 0.042), ACE Tool Total Score (r = 0.594, p = 0.042) and Motor Skills Score (r = 0.623, p = 0.031), and negatively correlated with cecal intubation time (r = - 0.695, p = 0.012). The Fine Motor Score positively correlated with the ACE Tool Polypectomy Score (r = 0.601, p = 0.039), and negatively correlated with procedure time (r = - 0.640, p = 0.025), cecal intubation time (r = - 0.645, p = 0.024), and withdrawal time (r = - 0.629, p = 0.028). CONCLUSION: This study demonstrates that performance on the TEST correlate to endoscopic measures. Given these results, the TEST may be used in conjunction with existing assessment tools for demonstrating competency in endoscopy.

Violence exposure, affective style, and stress-induced changes in resting state functional connectivity.

Chronic childhood stress is linked to greater susceptibility to internalizing disorders in adulthood. Specifically, chronic stress leads to changes in brain connectivity patterns, and, in turn, affects psychological functioning. Violence exposure, a chronic stressor, increases stress reactivity and disrupts emotion regulation processes. However, it is unclear to what extent violence exposure affects the neural circuitry underlying emotion regulation. Individual differences in affective style also moderate the impact of stress on psychological function and can thus alter the relationship between violence exposure and brain function. Resting-state functional connectivity (rsFC) is an index of intrinsic brain activity. Stress-induced changes in rsFC between the amygdala, hippocampus, and prefrontal cortex (PFC) are associated with emotion dysregulation and may elucidate how affective style modulates the relationship between violence exposure and brain connectivity. Therefore, the present study examined the impact of violence exposure and affective style on stress-induced changes in rsFC. Participants (n = 233) completed two 6-minute resting-state functional magnetic resonance imaging scans, one before (pre-stress) and one after (post-stress) a psychosocial stress task. The bilateral amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) were used as seed regions for rsFC analyses. Significant stress-induced changes in the prefrontal, fronto-limbic, and parieto-limbic rsFC were observed. Further, pre-stress to post-stress differences in rsFC varied with violence exposure and affective style. These findings suggest that prefrontal, fronto-limbic, and parieto-limbic connectivity is associated with the emotional response to stress and provide new insight into the neural mechanisms through which affective style moderates the impact violence exposure has on the brain.

Negative life experiences contribute to racial differences in the neural response to threat.

Threat-related emotional function is supported by a neural circuit that includes the prefrontal cortex (PFC), hippocampus, and amygdala. The function of this neural circuit is altered by negative life experiences, which can potentially affect threat-related emotional processes. Notably, Black-American individuals disproportionately endure negative life experiences compared to White-American individuals. However, the relationships among negative life experiences, race, and the neural substrates that support threat-related emotional function remains unclear. Therefore, the current study investigated whether the brain function that supports threat-related emotional processes varies with racial differences in negative life experiences. In the present study, adolescent violence exposure, family income, and neighborhood disadvantage were measured prospectively (i.e., at 11-19 years of age) for Black-American and White-American volunteers. Participants then, as young adults (i.e., 18-23 years of age), completed a Pavlovian fear conditioning task during functional magnetic resonance imaging (fMRI). Cued and non-cued threats were presented during the conditioning task and behavioral (threat expectancy) and psychophysiological responses (skin conductance response; SCR) were recorded simultaneously with fMRI. Racial differences were observed in neural (fMRI activity), behavioral (threat expectancy), and psychophysiological (SCR) responses to threat. These threat-elicited responses also varied with negative life experiences (violence exposure, family income, and neighborhood disadvantage). Notably, racial differences in brain activity to threat were smaller after accounting for negative life experiences. The present findings suggest that racial differences in the neural and behavioral response to threat are due, in part, to exposure to negative life experiences and may provide new insight into the mechanisms underlying racial disparities in mental health.

Neural response to stress and perceived stress differ in patients with left temporal lobe epilepsy.

Patients with epilepsy are often able to predict seizure occurrence subsequent to an acute stress experience. However, neuroimaging investigations into the neural basis of this relationship or the potential influence of perceived life stress are limited. The current study assessed the relationship between perceived stress and the neurobehavioral response to stress in patients with left temporal lobe epilepsy (LTLE) and healthy controls (HCs) using heart rate, salivary cortisol level, and functional magnetic resonance imaging and compared these effects between HCs and LTLE. Matched on perceived stress levels, groups of 36 patients with LTLE and 36 HCs completed the Montreal Imaging Stress Task, with control and stress math task conditions. Among LTLEs, 27 reported that prior (acute) stress affected their seizures (LTLES+), while nine did not (LTLES-). The results revealed that increased perceived stress was associated with seizure frequency in LTLE. Further, cortisol secretion was greater in LTLE, but did not vary with perceived stress as observed in HCs. A linear mixed-effects analysis revealed that as perceived stress increased, activation in the hippocampal complex (parahippocampal gyrus and hippocampus) decreased during stressful math in the LTLES+, increased in HCs, but did not vary in the LTLES-. Task-based functional connectivity analyses revealed LTLE differences in hippocampal functional connectivity with sensory cortex specific to stressor modalities. We argue that the current study demonstrates an inhibitory hippocampal mechanism underlying differences in resilience to stress between HCs and LTLE, as well as LTLE patients who report stress as a precipitant of seizures.

Endoscopic simulators.

BACKGROUND AND AIMS: Simulation refers to educational tools that allow for repetitive instruction in a nonpatient care environment that is risk-free. In GI endoscopy, simulators include ex vivo animal tissue models, live animal models, mechanical models, and virtual reality (VR) computer simulators. METHODS: After a structured search of the peer-reviewed medical literature, this document reviews commercially available GI endoscopy simulation systems and clinical outcomes of simulation in endoscopy. RESULTS: Mechanical simulators and VR simulators are frequently used early in training, whereas ex vivo and in vivo animal models are more commonly used for advanced endoscopy training. Multiple studies and systematic reviews show that simulation-based training appears to provide novice endoscopists with some advantage over untrained peers with regard to endpoints such as independent procedure completion and performance time, among others. Data also suggest that simulation training may accelerate the acquisition of specific technical skills in colonoscopy and upper endoscopy early in training. However, the available literature suggests that the benefits of simulator training appear to attenuate and cease after a finite period. Further studies are needed to determine if meeting competency metrics using simulation will predict actual clinical competency. CONCLUSIONS: Simulation training is a promising modality that may aid in endoscopic education. However, for widespread incorporation of simulators into gastroenterology training programs to occur, simulators must show a sustained advantage over traditional mentored teaching in a cost-effective manner. Because most studies evaluating simulation have focused on novice learners, the role of simulation training in helping practicing endoscopists gain proficiency using new techniques and devices should be further explored.

Effects of set size on identity and oddity abstract-concept learning in rats.

Match (MTS) and non-match-to-sample (NMTS) procedures are used to assess concepts of identity and oddity across species and are measured by transfer performance to novel stimuli. The number of exemplars used in training (set size) has been shown to affect learning with evidence of larger set sizes promoting concept learning in several species. The present study explored the effects of set size and procedure on concept learning in rats using olfactory stimuli. Concept learning was assessed for 20 rats via transfer tests consisting of novel stimuli after rats were initially trained to either MTS or NMTS with two or ten stimuli as exemplars. No difference was found in acquisition or transfer between MTS and NMTS, but rats trained with ten stimuli performed better on novel transfer tests than rats trained with two. When set size was expanded for rats originally trained with two stimuli and rats were re-tested with ten novel stimuli, performance showed full transfer demonstrating that training with multiple exemplars facilitates concept learning.

Anticipatory prefrontal cortex activity underlies stress-induced changes in Pavlovian fear conditioning.

Excessive stress exposure often leads to emotional dysfunction, characterized by disruptions in healthy emotional learning, expression, and regulation processes. A prefrontal cortex (PFC)-amygdala circuit appears to underlie these important emotional processes. However, limited human neuroimaging research has investigated whether these brain regions underlie the altered emotional function that develops with stress. Therefore, the present study used functional magnetic resonance imaging (fMRI) to investigate stress-induced changes in PFC-amygdala function during Pavlovian fear conditioning. Participants completed a variant of the Montreal Imaging Stress Task (MIST) followed (25 min later) by a Pavlovian fear conditioning task during fMRI. Self-reported stress to the MIST was used to identify three stress-reactivity groups (Low, Medium, and High). Psychophysiological, behavioral, and fMRI signal responses were compared between the three stress-reactivity groups during fear conditioning. Fear learning, indexed via participant expectation of the unconditioned stimulus during conditioning, increased with stress reactivity. Further, the High stress-reactivity group demonstrated greater autonomic arousal (i.e., skin conductance response, SCR) to both conditioned and unconditioned stimuli compared to the Low and Medium stress-reactivity groups. Finally, the High stress group did not regulate the emotional response to threat. More specifically, the High stress-reactivity group did not show a negative relationship between conditioned and unconditioned SCRs. Stress-induced changes in these emotional processes paralleled changes in dorsolateral, dorsomedial, and ventromedial PFC function. These findings demonstrate that acute stress facilitates fear learning, enhances autonomic arousal, and impairs emotion regulation, and suggests these stress-induced changes in emotional function are mediated by the PFC.

Comparison of Endoscopic Ultrasound-Fine-Needle Aspiration and Endoscopic Ultrasound-Fine-Needle Biopsy for Solid Lesions in a Multicenter, Randomized Trial.

BACKGROUND & AIMS: Endoscopic ultrasound with fine-needle aspiration (FNA) is the standard of care for tissue sampling of solid lesions adjacent to the gastrointestinal tract. Fine-needle biopsy (FNB) may provide higher diagnostic yield with fewer needle passes. The aim of this study was to assess the difference in diagnostic yield between FNA and FNB. METHODS: This is a multicenter, prospective randomized clinical trial from 6 large tertiary care centers. Patients referred for tissue sampling of solid lesions were randomized to either FNA or FNB of the target lesion. Demographics, size, location, number of needle passes, and final diagnosis were recorded. RESULTS: After enrollment, 135 patients were randomized to FNA (49.3%), and 139 patients were randomized to FNB (50.7%).The following lesions were sampled: mass (n = 210, 76.6%), lymph nodes (n = 46, 16.8%), and submucosal tumors (n = 18, 6.6%). Final diagnosis was malignancy (n = 192, 70.1%), reactive lymphadenopathy (n = 30, 11.0%), and spindle cell tumors (n = 24, 8.8%). FNA had a diagnostic yield of 91.1% compared with 88.5% for FNB (P = .48). There was no difference between FNA and FNB when stratified by the presence of on-site cytopathology or by type of lesion sampled. A median of 1 needle pass was needed to obtain a diagnostic sample for both needles. CONCLUSIONS: FNA and FNB obtained a similar diagnostic yield with a comparable number of needle passes. On the basis of these results, there is no significant difference in the performance of FNA compared with FNB in the cytologic diagnosis of solid lesions adjacent to the gastrointestinal tract. ClinicalTrials.gov identifier: NCT01698190.

Compromised hippocampus-striatum pathway as a potential imaging biomarker of mild-traumatic brain injury and posttraumatic stress disorder.

OBJECTIVES: Military service members risk acquiring posttraumatic stress disorder (PTSD) and mild-traumatic brain injury (mTBI), with high comorbidity. Owing to overlapping symptomatology in chronic mTBI or postconcussion syndrome (PCS) and PTSD, it is difficult to assess the etiology of a patient's condition without objective measures. Using resting-state functional MRI in a novel framework, we tested the hypothesis that their neural signatures are characterized by functionally hyperconnected brain regions which are less variable over time. Additionally, we predicted that such connectivities possessed the highest ability in predicting the diagnostic membership of a novel subject (top-predictors) in addition to being statistically significant. METHODS: U.S. Army Soldiers (N = 87) with PTSD and comorbid PCS + PTSD were recruited along with combat controls. Static and dynamic functional connectivities were evaluated. Group differences were obtained in accordance with our hypothesis. Machine learning classification (MLC) was employed to determine top predictors. RESULTS: From whole-brain connectivity, we identified the hippocampus-striatum connectivity to be significantly altered in accordance with our hypothesis. Diffusion tractography revealed compromised white-matter integrity between aforementioned regions only in the PCS + PTSD group, suggesting a structural etiology for the PCS + PTSD group rather than being an extreme subset of PTSD. Employing MLC, connectivities provided worst-case accuracy of 84% (9% more than psychological measures). Additionally, the hippocampus-striatum connectivities were found to be top predictors and thus a potential biomarker of PTSD/mTBI. CONCLUSIONS: PTSD/mTBI are associated with hippocampal-striatal hyperconnectivity from which it is difficult to disengage, leading to a habit-like response toward episodic traumatic memories, which fits well with behavioral manifestations of combat-related PTSD/mTBI. Hum Brain Mapp 38:2843-2864, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.