Diagnostic performance of computed tomography features in detecting oropharyngeal squamous cell carcinoma extranodal extension.

OBJECTIVES: Accurate pre-treatment imaging determination of extranodal extension (ENE) could facilitate the selection of appropriate initial therapy for HPV-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). Small studies have associated 7 CT features with ENE with varied results and agreement. This article seeks to determine the replicable diagnostic performance of these CT features for ENE. METHODS: Five expert academic head/neck neuroradiologists from 5 institutions evaluate a single academic cancer center cohort of 75 consecutive HPV + OPSCC patients. In a web-based virtual laboratory for imaging research and education, the experts performed training on 7 published CT features associated with ENE and then independently identified the "single most (if any) suspicious" lymph node and presence/absence of each of the features. Inter-rater agreement was assessed using percentage agreement, Gwet's AC1, and Fleiss' kappa. Sensitivity, specificity, and positive and negative predictive values were calculated for each CT feature based on histologic ENE. RESULTS: All 5 raters identified the same node in 52 cases (69%). In 15 cases (20%), at least one rater selected a node and at least one rater did not. In 8 cases (11%), all raters selected a node, but at least one rater selected a different node. Percentage agreement and Gwet's AC1 coefficients were > 0.80 for lesion identification, matted/conglomerated nodes, and central necrosis. Fleiss' kappa was always < 0.6. CT sensitivity for histologically confirmed ENE ranged 0.18-0.94, specificity 0.41-0.88, PPV 0.26-0.36, and NPV 0.78-0.96. CONCLUSIONS: Previously described CT features appear to have poor reproducibility among expert head/neck neuroradiologists and poor predictive value for histologic ENE. KEY POINTS: • Previously described CT imaging features appear to have poor reproducibility among expert head and neck subspecialized neuroradiologists as well as poor predictive value for histologic ENE. • Although it may still be appropriate to comment on the presence or absence of these CT features in imaging reports, the evidence indicates that caution is warranted when incorporating these features into clinical decision-making regarding the likelihood of ENE.

Should Radiological Assessment be Part of Core General Surgery Competency? A Survey of the General Surgery Residents.

BACKGROUND: Radiological assessment is an important skill to develop in general surgery training. Therefore, we aimed to determine general surgery residents' points of view on receiving formal radiology didactics. METHODS: We performed an anonymous survey of general surgery residents throughout the USA. The survey queried the residents' postgraduate year, training program type, diagnostic radiology education in their training program, as well as the residents' comfort level in interpreting various imaging modalities, followed by a series of images to assess the residents' ability to interpret images showing various surgical disease processes. RESULTS: A total of 365 residents responded to the survey. In total, 76.6% of the respondent states that there is no structured didactic session in their program on radiological studies. However, 66.3% felt that interpretation of radiological images should be used to determine surgical competency and promotion to the next academic year. In terms of accurately reading images-68.7% of the residents were able to read an X-ray showing cecal volvulus correctly, 51.9% were able to read a cholangiogram correctly, and 95.3% were correctly read an X-ray showing free under the diaphragm. CONCLUSION: Most residents favored having radiological assessments as part of the competency evaluation. Furthermore, a curriculum and inbuilt training structure that aims to ensure residents develop competent clinical image interpretation abilities may enhance the development and retention of such skills, ultimately influencing patient outcomes.

Aquaporin 4 distribution in the brain and its relevance for the radiological appearance of neuromyelitis optica spectrum disease.

BACKGROUND AND PURPOSE: To determine the precise incidence of lesions at sites of high Aquaporin-4 expression (hAQP4) and their possible association with known neuromyelitis optica spectrum disease (NMOSD) lesions patterns. MATERIALS AND METHODS: A retrospective analysis of brain and, when available, spinal cord MRI scans of 54 NMOSD patients recruited among the French NMOSD cohort was performed. Brain lesions were annotated as MS-like, non-specific, or evocative of NMOSD. The topography of hAQP4 was reassessed by human brain atlas. The incidence of lesions in hAQP4 and their association with lesions evocative of NMOSD was estimated. RESULTS: Among those included (41/54 female, mean age: 45 years) 47/54 (87%) presented brain lesions. Twenty-six/47 (55%) had lesions in hAQP4. Thirty-two/54 patients (60%) had lesions considered evocative of NMOSD. The majority of them also presented lesions in hAQP4 (65%, 21/32). Patients with lesions in hAQP4 and lesions evocative of NMOSD demonstrated more extensive myelitis compared to the other patients (7 [6-10] versus 4 [3-5] vertebral segments, P=0.009). CONCLUSION: The coexistence of lesions evocative of NMOSD and in hAQP4 is associated with significantly more extensive myelitis, and might have pathophysiological and clinical significance.

Brain anatomical correlates of fatigue in multiple sclerosis.

Fatigue is one of the most debilitating symptoms in patients with multiple sclerosis (MS). Despite its clinical significance, the aetiology and pathophysiology of MS-related fatigue are not well understood. Current evidence and understanding of the neuroanatomical underpinnings of MS-related fatigue are reviewed in this article. The aims of this paper are to (1) review the findings of previous structural neuroimaging studies on MS-related fatigue and summarize consistent findings regarding brain circuitry associated with fatigue in MS, (2) contextualize these findings with the neurochemistry of the relevant circuits and (3) discuss future perspectives with regard to impact on fatigue management of MS patients and methodological challenges towards improved understanding of fatigue pathogenesis. The detailed understanding of the neuroanatomical underpinnings of fatigue might contribute to the identification of novel treatment targets and factors determining treatment resistance to drugs used in current clinical practice.

A novel classification of fatigue in multiple sclerosis based on longitudinal assessments.

BACKGROUND: Magnetic resonance imaging (MRI) studies of multiple sclerosis-related fatigue had limited reproducibility. Temporal fatigue fluctuations have not been considered. OBJECTIVE: To investigate whether a novel group allocation that reflects temporal dynamics of fatigue improves our ability to detect fatigue-associated structural brain abnormalities. METHODS: Patient stratification based on biennial fatigue assessments: sustained fatigue (SF, n = 29, fatigued at the latest ⩾2 assessments), one time-point fatigue (1F, n = 15, fatigued at the latest, but non-fatigued at the penultimate assessment), reversible fatigue (RF, n = 31, non-fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 54). Brain parenchymal fraction (BPF) and T2 lesion volume (T2LV) were compared between these groups and were derived using a conventional, single time-point fatigued versus non-fatigued stratification. RESULTS: The SF versus NF stratification yielded improved power. SF (p = 0.005) and RF (p = 0.043) showed significantly higher T2LV than NF. T2LV showed no significant differences in SF versus 1F, SF versus RF, or 1F versus RF. Fatigued versus non-fatigued patients showed significantly higher T2LV (p = 0.030). We found no significant differences in BPF between the groups. CONCLUSION: Taking into account temporal fatigue dynamics increases the statistical power with respect to T2LV and may improve characterization of brain pathological correlates of MS-related fatigue.

Microstructural fronto-striatal and temporo-insular alterations are associated with fatigue in patients with multiple sclerosis independent of white matter lesion load and depression.

BACKGROUND: Fatigue in multiple sclerosis (MS) has been inconsistently associated with disruption of specific brain circuitries. Temporal fluctuations of fatigue have not been considered. OBJECTIVE: The aim of this study was to investigate the association of fatigue with brain diffusion abnormalities, using robust criteria for patient stratification based on longitudinal patterns of fatigue. METHODS: Patient stratification: (1) sustained fatigue (SF, n = 26): latest two Modified Fatigue Impact Scale (MFIS) ⩾ 38; (2) reversible fatigue (RF, n = 25): latest MFIS < 38 and minimum one previous MFIS ⩾ 38; and (3) never fatigued (NF, n = 42): MFIS always < 38 (five assessments minimum). 3T brain magnetic resonance imaging (MRI) was used to perform voxel-wise comparison of fractional anisotropy (FA) between the groups controlling for age, sex, disease duration, physical disability, white matter lesion load (T2LV), and depression. RESULTS: SF and, to a lesser extent, RF patients showed lower FA in multiple brain regions compared to NF patients, independent of age, sex, disease duration, and physical disability. In cingulo-postcommissural-striato-thalamic regions, the differences in FA between SF and NF (but not between RF and NF or SF) patients were independent of T2LV, and in ventromedial prefronto-precommissuro-striatal and temporo-insular areas, independent of T2LV and depression. CONCLUSION: Damage to ventromedial prefronto-precommissuro-striatal and temporo-insular pathways appears to be a specific substrate of SF in MS.

Characterization of glioblastoma in an orthotopic mouse model with magnetic resonance elastography.

Glioblastoma (GBM) is the most common primary brain tumor. It is highly malignant and has a correspondingly poor prognosis. Diagnosis and monitoring are mainly accomplished with MRI, but remain challenging in some cases. Therefore, complementary methods for tumor detection and characterization would be beneficial. Using magnetic resonance elastography (MRE), we performed a longitudinal study of the biomechanical properties of intracranially implanted GBM in mice and compared the results to histopathology. The biomechanical parameters of viscoelastic modulus, shear wave speed and phase angle were significantly lower in tumors compared with healthy brain tissue and decreased over time with tumor progression. Moreover, some MRE parameters revealed sub-regions at later tumor stages, which were not easily detectable on anatomical MRI images. Comparison with histopathology showed that softer tumor regions contained necrosis and patches of viable tumor cells. In contrast, areas of densely packed tumor cells and blood vessels identified with histology coincided with higher values of viscoelastic modulus and shear wave speed. Interestingly, the phase angle was independent from these anatomical variations. In summary, MRE depicted longitudinal and morphological changes in GBM and may prove valuable for tumor characterization in patients.

Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis.

BACKGROUND: Reports on the relationships between white matter lesion load (WMLL) and fatigue and anxiety in multiple sclerosis (MS) are inconsistent. OBJECTIVE: To investigate the association of total and tract-specific WMLL with fatigue and anxiety. METHODS: Total and regional T2 WMLL was assessed for 19 tracts in 48 MS patients (30 females). ICBM-DTI-81 Atlas-based parcellation was combined with WMLL segmentation of T2-weighted magnetic resonance imaging (MRI). Fatigue, anxiety, and depression were assessed using Fatigue Impact Scale, State Trait Anxiety Inventory, and Beck Depression Inventory, respectively. RESULTS: Fatigue, anxiety, and depression showed significant inter-correlation. We found no association between fatigue and total or regional WMLLs, whereas anxiety was associated with total and regional WMLLs in nine tracts. After adjusting for total WMLL, age, and depression, only the column and body of the fornix (CBF) remained significantly associated with anxiety. Post hoc analyses showed no CBF lesions on T1-weighted MRI and suggested, but could not confirm, that the septum pellucidum might play a role in the pathogenesis of anxiety. CONCLUSION: Our results suggest that anxiety in MS patients may have a neuropathological substrate in the septo-fornical area, which requires further validation using larger sample size and ultra-high-field MRI in targeted prospective studies.

The action of neuropeptide AF on passive avoidance learning. Involvement of neurotransmitters.

Neuropeptide AF (NPAF) is an amidated octadecapeptide, which is member of the RFamide peptide family. NPAF is encoded by the farp-1 gene and acts through the G protein coupled NPFF-1 and NPFF-2 receptors. NPAF is involved in several physiological functions of the central nervous system, however we have little evidence about the involvement of NPAF in learning and memory. Therefore, the aim of the present study was to investigate the action of NPAF on consolidation of memory in a passive avoidance learning paradigm in mice. We have also investigated the underlying neurotransmissions and the action of NPAF on ß-amyloid-induced memory impairment. Accordingly, mice were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a non-selective opioid receptor antagonist, naloxone, a nitric oxide synthase inhibitor, nitro-l-arginine, a α1/α2ß-adrenergic receptor antagonist, prazosin, a nonselective ß-adrenergic receptor antagonist, propranolol or ß-amyloid 25-35 in combination with NPAF administration. Our results demonstrate for the first time that NPAF improves the consolidation of passive avoidance learning. This effect is mediated through muscarinic cholinergic, 5HT1- and 5HT2-serotoninergic, dopaminergic, nitrergic and α- and ß-adrenergic neurotransmissions, but not by opioid transmission, since atropine, cyproheptadine, methysergide, haloperidol, nitro-l-arginine, prazosin and propranolol reversed the action of NPAF, whereas naloxone was ineffective. The present study also shows that NPAF reverses the ß-amyloid 25-35-induced memory impairment.

Fatigue predicts disease worsening in relapsing-remitting multiple sclerosis patients.

BACKGROUND: It is unclear whether fatigue is a consequence or a predictive trait of disease worsening. OBJECTIVE: To investigate the predictive value of fatigue toward conversion to confirmed moderate-severe disability in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women's Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (⩾2 years) Expanded Disability Status Scale (EDSS) score ⩾3 within a follow-up period ⩾3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS ⩾3, with that of 33 non-converter RRMS patients matched for baseline characteristics. RESULTS: Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS ⩾3. CONCLUSION: Fatigue is a promising indicator of risk for conversion to confirmed moderate-severe disability in RRMS patients.

Involvement of neurotransmitters in the action of the nociceptin/orphanin FQ peptide-receptor system on passive avoidance learning in rats.

The nociceptin/orphanin FQ peptide (NOP) receptor and its endogenous ligand plays role in several physiologic functions of the central nervous system, including pain, locomotion, anxiety and depression, reward and drug addiction, learning and memory. Previous studies demonstrated that the NOP-receptor system induces impairment in memory and learning. However, we have little evidence about the underlying neuromodulation. The aim of the present study was to investigate the involvement of distinct neurotransmitters in the action of the selective NOP receptor agonist orphan G protein-coupled receptor (GPCR) SP9155 P550 on memory consolidation in a passive avoidance learning test in rats. Accordingly, rats were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective opioid receptor antagonist, naloxone, a non-specific nitric oxide synthase inhibitor, nitro-L-arginine, a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a ß-adrenergic receptor antagonist, propranolol. Atropine, bicuculline, naloxone and phenoxybenzamine reversed the orphan GPCR SP9155 P550-induced memory impairment, whereas propranolol, haloperidol and nitro-L-arginine were ineffective. Our results suggest that the NOP system-induced impairment of memory consolidation is mediated through muscarinic cholinergic, GABA-A-ergic, opioid and α-adrenergic receptors, whereas ß-adrenergic, D2, D3, D4-dopaminergic and nitrergic mechanisms are not be implicated.

Interleukin-1ß (187-207)-induced hyperthermia is inhibited by interleukin-1ß (193-195) in rats.

Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine, which plays an important role in the immune response and signal transduction both in the periphery and the central nervous system (CNS). Various diseases of the CNS, including neurodegenerative disorders, vascular lesions, meningo-encephalitis or status epilepticus are accompanied by elevated levels of IL-1ß. Different domains within the IL-lß protein are responsible for distinct functions. The IL-lß domain in position 208-240 has pyrogenic properties, while the domain in position 193-195 exerts anti-inflammatory effects. Previous studies provide little evidence about the effect of the domain in position 187-207 on the body temperature. Therefore, the aim of the present study was to investigate the action of IL-1ß (187-207) and its interaction with IL-1ß (193-195) on the body temperature. IL fragments were administered intracerebroventricularly and the body temperature was measured rectally in male Wistar rats. IL-1ß (187-207) induced hyperthermia, while IL-1ß (193-195) did not influence the core temperature considerably. In co-administration, IL-1ß (193-195) completely abolished the IL-1ß (187-207)-induced hyperthermia. The non-steroid anti-inflammatory drug metamizole also reversed completely the action of IL-1ß (187-207). Our results provide evidence that the IL-lß domain in position 187-207 has hyperthermic effect. This effect is mediated through prostaglandin E2 stimulation and other mechanisms may also be involved in the action of IL-1ß (187-207). It also suggests that IL-lß domain in position 187-207 and IL-1ß (193-195) fragment may serve as novel target for treatment of disorders accompanied with hyperthermia.

Ghrelin and nicotine stimulate equally the dopamine release in the rat amygdala.

The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward processes and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Ghrelin and nicotine activates the mesolimbicocortical dopaminergic pathways via growth hormone secretagogue receptors (GHS-R1A) and nicotinic acetylcholine receptors (nAchR), respectively, resulting in the release of dopamine in the nucleus accumbens, the amygdala and the prefrontal cortex. In the present study an in vitro superfusion of rat amygdalar slices was performed in order to investigate the direct action of ghrelin and nicotine on the amygdalar dopamine release. Ghrelin increased significantly the dopamine release from the rat amygdala following electrical stimulation. This effect was inhibited by both the selective GHS-R1A antagonist GHRP-6 and the selective nAchR antagonist mecamylamine. Under the same conditions, nicotine also increased significantly the dopamine release from the rat amygdala. This effect was antagonized by mecamylamine, but not by GHRP-6. Co-administration of ghrelin and nicotine induced a similar increase of amygdalar dopamine release. This stimulatory effect was partially reversed by both GHRP-6 and mecamylamine. The present results demonstrate that both ghrelin and nicotine stimulates directly the dopamine release in the amygdala, an important dopaminergic target area of the mesolimbicocortical pathway.

Ghrelin Amplifies the Nicotine-Induced Release of Dopamine in the Bed Nucleus of Stria Terminalis (BNST).

Ghrelin is an orexigenic neuropeptide that is known for stimulating the release of growth hormone (GH) and appetite. In addition, ghrelin has been implicated in addiction to drugs such as nicotine. Nicotine is the principal psychoactive component in tobacco and is responsible for the reward sensation produced by smoking. In our previous in vitro superfusion studies, it was demonstrated that ghrelin and nicotine stimulate equally the dopamine release in the rat amygdala, and ghrelin amplifies the nicotine-induced dopamine release in the rat striatum. However, less attention was paid to the actions of ghrelin and nicotine in the bed nucleus of the stria terminalis (BNST). Therefore, in the present study, nicotine and ghrelin were superfused to the BNST of male Wistar rats, and the dopamine release from the BNST was measured in vitro. In order to determine which receptors mediate these effects, mecamylamine, a non-selective nicotinic acetylcholine receptor (nAchR) antagonist, and GHRP-6, a selective growth hormone secretagogue receptor (GHS-R1A) antagonist, were also superfused to the rat BNST. Nicotine significantly increased the release of dopamine, and this effect was significantly inhibited by mecamylamine. Ghrelin increased dopamine release even more significantly than nicotine did, and this effect was significantly inhibited by GHRP-6. Moreover, when administered together, ghrelin significantly amplified the nicotine-induced release of dopamine in the BNST, and this additive effect was reversed partly by mecamylamine and partly by GHRP-6. Therefore, the present study provides a new base of evidence for the involvement of ghrelin in dopamine signaling implicated in nicotine addiction.

Fronto-striatal damage may contribute to resistance to fatigue-lowering medications in multiple sclerosis.

BACKGROUND AND PURPOSE: Commonly used fatigue-lowering medications have not been proven effective in treating multiple sclerosis (MS)-related fatigue. A neuroanatomical basis for treatment-resistant fatigue in MS has not been explored. The aim of this study was to investigate the association between brain diffusion abnormality patterns and resistance to fatigue-lowering treatment. METHODS: Retrospective patient stratification: 1. treatment-resistant (n = 22) received anti-fatigue and/or anti-depressant and/or anxiolytic medication and the latest two Modified Fatigue Impact Scale (MFIS) score≥38; 2. responder (n = 16): received anti-fatigue and/or antidepressant and/or anxiolytic medication while the latest MFIS was <38, and minimum one previous MFIS was ≥38; 3. non-treated never-fatigued (n = 26): received none of the above-mentioned medications and MFIS was always<38 (over minimum four years assessed with MFIS every 1-2 years). 3T brain MRI was used to perform a cross-sectional voxel-wise comparison of fractional anisotropy (FA) between the groups. RESULTS: Treatment-resistant versus responder patients showed more extensive brain damage (ie, lower FA) favoring the fronto-striatal pathways. Both groups showed more widespread brain damage than non-treated never-fatigued patients. A mean fronto-striatal FA value of 0.26 could perfectly predict response to modafinil/armodafinil. CONCLUSION: Fronto-striatal damage may play a role in the development of resistance to fatigue-lowering treatment. Fronto-striatal FA may serve as a biomarker to predict response to fatigue-lowering medications in MS.

Multiple sclerosis lesions that impair memory map to a connected memory circuit.

BACKGROUND: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit. METHODS: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes. RESULTS: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit. CONCLUSIONS: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.

Magnetic resonance elastography to study the effect of amyloid plaque accumulation in a mouse model.

BACKGROUND AND PURPOSE: Biomechanical changes in the brain have not been fully elucidated in Alzheimer's disease (AD). We aimed to investigate the effect of ß-amyloid accumulation on mouse brain viscoelasticity. METHODS: Magnetic resonance elastography was used to calculate magnitude of the viscoelastic modulus (|G*|), elasticity (Gd ), and viscosity (Gl ) in the whole brain parenchyma (WB) and bilateral hippocampi of 9 transgenic J20 (AD) mice (5 males/4 females) and 10 wild-type (WT) C57BL/6 mice (5 males/5 females) at 11 and 14 months of age. RESULTS: Cross-sectional analyses showed no significant difference between AD and WT mice at either timepoints. No sex-specific differences were observed at 11 months of age, but AD females showed significantly higher hippocampal |G*| and Gl and WB |G*|, Gd , and Gl compared to both AD and WT males at 14 months of age. Similar trending differences were found between female AD and female WT animals but did not reach significance. Longitudinal analyses showed significant increases in hippocampal |G*|, Gd , and Gl , and significant decreases in WB |G*|, Gd , and Gl between 11 and 14 months in both AD and WT mice. Each subgroup showed significant increases in all hippocampal and significant decreases in all WB measures, with the exception of AD females, which showed no significant changes in WB |G*|, Gd , or Gl . CONCLUSION: Aging had region-specific effects on cerebral viscoelasticity, namely, WB softening and hippocampal stiffening. Amyloid plaque deposition may have sex-specific effects, which require further scrutiny.

Usability of a Mobile App for Real-Time Assessment of Fatigue and Related Symptoms in Patients With Multiple Sclerosis: Observational Study.

BACKGROUND: Although fatigue is one of the most debilitating symptoms in patients with multiple sclerosis (MS), its pathogenesis is not well understood. Neurogenic, inflammatory, endocrine, and metabolic mechanisms have been proposed. Taking into account the temporal dynamics and comorbid mood symptoms of fatigue may help differentiate fatigue phenotypes. These phenotypes may reflect different pathogeneses and may respond to different mechanism-specific treatments. Although several tools have been developed to assess various symptoms (including fatigue), monitor clinical status, or improve the perceived level of fatigue in patients with MS, options for a detailed, real-time assessment of MS-related fatigue and relevant comorbidities are still limited. OBJECTIVE: This study aims to present a novel mobile app specifically designed to differentiate fatigue phenotypes using circadian symptom monitoring and state-of-the-art characterization of MS-related fatigue and its related symptoms. We also aim to report the first findings regarding patient compliance and the relationship between compliance and patient characteristics, including MS disease severity. METHODS: After developing the app, we used it in a prospective study designed to investigate the brain magnetic resonance imaging correlates of MS-related fatigue. In total, 64 patients with MS were recruited into this study and asked to use the app over a 2-week period. The app features the following modules: Visual Analogue Scales (VASs) to assess circadian changes in fatigue, depression, anxiety, and pain; daily sleep diaries (SLDs) to assess sleep habits and quality; and 10 one-time questionnaires to assess fatigue, depression, anxiety, sleepiness, physical activity, and motivation, as well as several other one-time questionnaires that were created to assess those relevant aspects of fatigue that were not captured by existing fatigue questionnaires. The app prompts subjects to assess their symptoms multiple times a day and enables real-time symptom monitoring through a web-accessible portal. RESULTS: Of 64 patients, 56 (88%) used the app, of which 51 (91%) completed all one-time questionnaires and 47 (84%) completed all one-time questionnaires, VASs, and SLDs. Patients reported no issues with the usage of the app, and there were no technical issues with our web-based data collection system. The relapsing-remitting MS to secondary-progressive MS ratio was significantly higher in patients who completed all one-time questionnaires, VASs, and SLDs than in those who completed all one-time questionnaires but not all VASs and SLDs (P=.01). No other significant differences in demographics, fatigue, or disease severity were observed between the degrees of compliance. CONCLUSIONS: The app can be used with reasonable compliance across patients with relapsing-remitting and secondary-progressive MS irrespective of demographics, fatigue, or disease severity.

The effects of CRF and the urocortins on the hippocampal acetylcholine release in rats.

Corticotropin-releasing factor (CRF) and the urocortins (Ucn1, Ucn2 and Ucn3) are structurally related neuropeptides which act via two distinct CRF receptors, CRF1 and CRF2, with putatively antagonistic effects in the brain. CRF and Ucn1 activate both CRF1 and CRF2, while Ucn2 and Ucn3 activate selectively CRF2. The aim of the present study was to investigate the effects of CRF, Ucn1, Ucn2 and Ucn3 on the hippocampal acetylcholine release through which they may modulate cognitive functions, including attention, learning and memory. In this purpose male Wistar rats were used, their hippocampus was isolated, dissected, incubated, superfused and stimulated electrically. The hippocampal slices were first pretreated with selective CRF1 antagonist antalarmin or selective CRF2 antagonist astressin2B, and then treated with non-selective CRF1 agonists, CRF or Ucn1, and selective CRF2 agonists, Ucn2 or Ucn3. The hippocampal acetylcholine release was increased significantly by CRF and Ucn1 and decreased significantly by Ucn2 and Ucn3. The increasing effect of CRF and Ucn1 was reduced significantly by antalarmin, but not astressin2B. In contrast, the decreasing effect of Ucn2 and Ucn3 was reversed significantly by the selective CRF2, but not the selective CRF1 antagonist. Our results demonstrate that CRF and Ucn1 stimulate the hippocampal acetylcholine release through CRF1, whereas Ucn2 and Ucn3 inhibit the hippocampal acetylcholine release through CRF2. Therefore, the present study suggests the existence of two apparently opposing CRF systems in the hippocampus, through which CRF and the urocortins might modulate cholinergic activity and thereby cognitive functions.

Targeted Blood Brain Barrier Opening With Focused Ultrasound Induces Focal Macrophage/Microglial Activation in Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis (MS). EAE reflects important histopathological hallmarks, dissemination, and diversity of the disease, but has only moderate reproducibility of clinical and histopathological features. Focal lesions are less frequently observed in EAE than in MS, and can neither be constrained to specific locations nor timed to occur at a pre-specified moment. This renders difficult any experimental assessment of the pathogenesis of lesion evolution, including its inflammatory, degenerative (demyelination and axonal degeneration), and reparatory (remyelination, axonal sprouting, gliosis) component processes. We sought to develop a controlled model of inflammatory, focal brain lesions in EAE using focused ultrasound (FUS). We hypothesized that FUS induced focal blood brain barrier disruption (BBBD) will increase the likelihood of transmigration of effector cells and subsequent lesion occurrence at the sonicated location. Lesion development was monitored with conventional magnetic resonance imaging (MRI) as well as with magnetic resonance elastography (MRE) and further analyzed by histopathological means. EAE was induced in 12 6-8 weeks old female C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide. FUS-induced BBBD was performed 6, 7, and 9 days after immunization in subgroups of four animals and in an additional control group. MRI and MRE were performed on a 7T horizontal bore small animal MRI scanner. Imaging was conducted longitudinally 2 and 3 weeks after disease induction and 1 week after sonication in control animals, respectively. The scan protocol comprised contrast-enhanced T1-weighted and T2-weighted sequences as well as MRE with a vibration frequency of 1 kHz. Animals were sacrificed for histopathology after the last imaging time point. The overall clinical course of EAE was mild. A total of seven EAE animals presented with focal T2w hyperintense signal alterations in the sonicated hemisphere. These were most frequent in the group of animals sonicated 9 days after immunization. Histopathology revealed foci of activated microglia/macrophages in the sonicated right hemisphere of seven EAE animals. Larger cellular infiltrates or apparent demyelination were not seen. Control animals showed no abnormalities on MRI and did not have clusters of activated microglia/macrophages at the sites targeted with FUS. None of the animals had hemorrhages or gross tissue damage as potential side effects of FUS. EAE-animals tended to have lower values of viscoelasticity and elasticity in the sonicated compared to the contralateral parenchyma. This trend was significant when comparing the right sonicated to the left normal hemisphere and specifically the right sonicated compared to the left normal cortex in animals that underwent FUS-BBBD 9 days after immunization (right vs. left hemisphere: mean viscoelasticity 6.1 vs. 7.2 kPa; p = 0.003 and mean elasticity 4.9 vs. 5.7 kPa, p = 0.024; right vs. left cortex: mean viscoelasticity 5.8 vs. 7.5 kPa; p = 0.004 and mean elasticity 5 vs. 6.5 kPa; p = 0.008). A direct comparison of the biomechanical properties of focal T2w hyperintensities with normal appearing brain tissue did not yield significant results. Control animals showed no differences in viscoelasticity between sonicated and contralateral brain parenchyma. We here provide first evidence for a controlled lesion induction model in EAE using FUS-induced BBBD. The observed lesions in EAE are consistent with foci of activated microglia that may be interpreted as targeted initial inflammatory activity and which have been described as pre-active lesions in MS. Such foci can be identified and monitored with MRI. Moreover, the increased inflammatory activity in the sonicated brain parenchyma seems to have an effect on overall tissue matrix structure as reflected by changes of biomechanical parameters.