Comparison of various treatment options for canine atopic dermatitis: a blinded, randomized, controlled study in a colony of research atopic beagle dogs.

BACKGROUND: No study has directly compared the various treatment options for canine atopic dermatitis and their effects on skin barrier. HYPOTHESIS/OBJECTIVES: To compare prednisone, oclacitinib, ciclosporin and lokivetmab treatment of atopic dermatitis. ANIMALS: Nineteen atopic beagle dogs. METHODS AND MATERIALS: Controlled, blinded study. Dogs were challenged with allergen twice weekly and randomized to oclacitinib, ciclosporin, lokivetmab, prednisone or no treatment for four weeks. Dermatitis and pruritus were assessed at baseline and after each challenge. Transepidermal water loss (TEWL) and hydration were measured at baseline, Day (D)14 and D28 (pinnae, axilla, groin). Area under the curve (AUC) was calculated for Canine Atopic Dermatitis Extent and Severity Index, 3rd iteration (CADESI-03), pruritus, TEWL and hydration. For CADESI, the AUC of the first two weeks was compared to that of the last two weeks. RESULTS: For CADESI, restricted maximum-likelihood ANOVA showed effect of time (P = 0034) and group x time interaction (P = 0.0169). In the first two weeks, prednisone and oclacitinib were significantly lower than controls (P = 0.019 and P = 0.015, respectively). Lokivetmab prevented flares. Due to variability, no significance differences in pruritus were observed among groups. The TEWL increased with time in controls (P = 0.0237) and ciclosporin (P = 0.04, axilla, D28 versus D0) but not in the oclacitinib and lokivetmab groups. CADESI-03 correlated with TEWL (P = 0.0043) and pruritus (P = 0.0283). Hydration did not correlate with any parameters. Hydration decreased in controls and prednisone group (axilla, D14 versus D0, P = 0.004 and P = 0.027, respectively). AUC for hydration, over time, was higher for lokivetmab and oclacitinib than controls (P = 0.014 and P = 0.04, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Lokivetmab prevented flares when given before challenge. Oclacitinib and lokivetmab have some positive effects on skin barrier parameters.

Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia.

The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic-sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow.

Clinicopathological correlations in behavioural variant frontotemporal dementia.

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia.

SEE SCABER AND TALBOT DOI101093/AWW264 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72 repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia-motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation.

Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion.

Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

Control of nucleus accumbens activity with neurofeedback.

The nucleus accumbens (NAcc) plays critical roles in healthy motivation and learning, as well as in psychiatric disorders (including schizophrenia and attention deficit hyperactivity disorder). Thus, techniques that confer control of NAcc activity might inspire new therapeutic interventions. By providing second-to-second temporal resolution of activity in small subcortical regions, functional magnetic resonance imaging (fMRI) can resolve online changes in NAcc activity, which can then be presented as "neurofeedback." In an fMRI-based neurofeedback experiment designed to elicit NAcc activity, we found that subjects could increase their own NAcc activity, and that display of neurofeedback significantly enhanced their ability to do so. Subjects were not as capable of decreasing their NAcc activity, however, and enhanced control did not persist after subsequent removal of neurofeedback. Further analyses suggested that individuals who recruited positive aroused affect were better able to increase NAcc activity in response to neurofeedback, and that NAcc neurofeedback also elicited functionally correlated activity in the medial prefrontal cortex. Together, these findings suggest that humans can modulate their own NAcc activity and that fMRI-based neurofeedback may augment their efforts. The observed association between positive arousal and effective NAcc control further supports an anticipatory affect account of NAcc function.

The functional oculomotor network and saccadic cognitive control in healthy elders.

Decline in executive function is the most common age-associated cognitive deficit and may be a risk factor for neurodegenerative disease. The antisaccade (AS) task involves inhibition of a prepotent visuomotor response and is a well-validated executive function test in aging and neurodegeneration. We investigated the functional connectivity of the cortical oculomotor network during successful AS performance in healthy elders. Elevated BOLD activity in the right lateral frontal eye field (rlatFEF), a region linked to volume loss in individuals with impaired AS performance, was associated with worse AS performance and weaker network efficiency. In contrast, hub integrity of the right dorsolateral prefrontal cortex (rDLPFC) and anterior cingulate cortex (rACC) was associated with better AS performance. These data suggest that while several right lateral frontal regions are central nodes in the oculomotor network, the rlatFEF demonstrates early neural aberrations and the rDLPFC and rACC continue to support inhibitory cognitive control in healthy elders. We conclude that alterations in AS task functional connectivity, quantified as hub and network efficiency, may be clinically-relevant biomarkers of cognitive decline in executive functioning.

Intrinsic connectivity network disruption in progressive supranuclear palsy.

OBJECTIVE: Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP. METHODS: Using task-free functional magnetic resonance imaging, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region that shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity. RESULTS: Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletomotor, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within corticosubcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores. INTERPRETATION: This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes.

Anterior temporal lobe degeneration produces widespread network-driven dysfunction.

The neural organization of semantic memory remains much debated. A 'distributed-only' view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality-selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain-specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.

Rivastigmine is associated with restoration of left frontal brain activity in Parkinson's disease.

The objective of this study was to investigate how acetylcholinesterase inhibitor (ChEI) treatment affects brain function in Parkinson's disease (PD). Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after 3 months of ChEI treatment and were compared with 15 age- and sex-matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low-frequency fluctuations. At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (eg, caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (eg, lateral prefrontal cortex), and episodic memory (eg, precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased posttreatment compared with baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared with controls, and rivastigmine is associated with performance-related normalization in the left frontal cortex function.

Transcription of interleukin 31 and its receptor by leukocytes after Culicoides sp stimulation is dose dependent but is not exaggerated in allergic horses or correlated with pruritus.

OBJECTIVE: Preliminary evidence supports a role for IL-31 in equine insect bite hypersensitivity (IBH) and pruritus. Our studies investigated IL-31 and IL-31 receptor-α (IL-31RA) transcription in leukocytes from normal and IBH horses in response to Culicoides nubeculosus. ANIMALS: 19 normal and 15 IBH horses were recruited in the summer of 2019 (low-dose study) and 8 normal and 10 IBH horses in the winter of 2022 to 2023 (high-dose study). Normal horses had no history or signs of allergic skin disease, while IBH horses had a history and clinical signs compatible with IBH. Pruritus was scored using a visual analog score or a 1 to 6 grading system. PROCEDURES: Whole blood leukocytes were incubated with saline (0.9% NaCl) solution or C nubeculosus (0.26 µg/mL [low dose]; 5 µg/mL [high dose]). Transcription of IL-31 and IL-31RA was measured by quantitative RT-PCR. RESULTS: Transcription of IL-31 and IL-31RA significantly increased in leukocytes from normal and IBH horses following high-dose C nubeculosus, and no differences were found between populations. Following low-dose C nubeculosus IL-31RA, transcription was increased in both normal and IBH horses, but IL-31 transcription was reduced in normal horses. No positive correlation was found between pruritus scores and IL-31 transcription after low- or high-dose C nubeculosus stimulation. CLINICAL RELEVANCE: Exaggerated IL-31 transcription was not identified in IBH horses, suggesting that dysregulation in IL-31 signaling occurs downstream or in localized tissues or involves regulation by yet unidentified receptor splice variants or IL-31-induced increased sensitivity to other pruritogens. Further studies to understand IL-31 signaling in equine allergic skin disease are needed.

Brain Modulyzer: Interactive Visual Analysis of Functional Brain Connectivity.

We present Brain Modulyzer, an interactive visual exploration tool for functional magnetic resonance imaging (fMRI) brain scans, aimed at analyzing the correlation between different brain regions when resting or when performing mental tasks. Brain Modulyzer combines multiple coordinated views-such as heat maps, node link diagrams and anatomical views-using brushing and linking to provide an anatomical context for brain connectivity data. Integrating methods from graph theory and analysis, e.g., community detection and derived graph measures, makes it possible to explore the modular and hierarchical organization of functional brain networks. Providing immediate feedback by displaying analysis results instantaneously while changing parameters gives neuroscientists a powerful means to comprehend complex brain structure more effectively and efficiently and supports forming hypotheses that can then be validated via statistical analysis. To demonstrate the utility of our tool, we present two case studies-exploring progressive supranuclear palsy, as well as memory encoding and retrieval.

The anterior insula shows heightened interictal intrinsic connectivity in migraine without aura.

OBJECTIVE: We sought to explore whether patients with migraine show heightened interictal intrinsic connectivity within primary sensory networks, the salience network, and a network anchored by the dorsal pons, a region known to be active during migraine attacks. METHODS: Using task-free fMRI and a region-of-interest analysis, we compared intrinsic connectivity patterns in 15 migraineurs without aura to 15 age- and sex-matched healthy controls, focusing on networks anchored by the calcarine cortex, Heschl gyrus, right anterior insula, and dorsal pons, a region active during migraine attacks. We also examined the relationship between network connectivity, migraine frequency, and sensory sensitivity symptoms. RESULTS: Migraineurs showed increased connectivity between primary visual and auditory cortices and the right dorsal anterior insula, between the dorsal pons and the bilateral anterior insulae, and between the right and left ventral anterior insulae. Increased connectivity showed no clinical correlation with migraine frequency or sensory sensitivity. CONCLUSIONS: Patients with migraine display interictal changes in the topology of intrinsic connections, with greater connectivity between primary sensory cortices, the pons, and the anterior insula, a region involved in representing and coordinating responses to emotional salience.