Biology subjects

Kennerley, A. J.

Publications and source records attributed to Kennerley, A. J..

5 recordsLinked to original sources

bioRxiv2026

Continuous sumatriptan exposure induces persistent trigeminovascular sensitisation and brain perfusion changes in a rat model of medication overuse headache.

BackgroundRepeated exposure to acute antimigraine medication can promote medication overuse headache, but the mechanisms underlying this transition remain incompletely understood. We used a clinically relevant rat model of continuous sumatriptan exposure to investigate whether medication overuse is associated with persistent sensitisation of the trigeminovascular system and longer-lasting changes in brain perfusion. MethodsAdult male Sprague Dawley rats received continuous subcutaneous sumatriptan (0.6 mg/kg/day) or saline infusion for 6 days via osmotic minipumps. Periorbital and hindpaw mechanical thresholds were measured over 20 days. On day 6 and day 20, trigeminal ganglia and trigeminal nucleus caudalis were processed for immunohistochemistry for pERK, pp38, Iba-1, GFAP and NeuN. On day 20, a subgroup received sodium nitroprusside (SNP, 3 mg/kg, i.p.) to unmask latent sensitisation. Cerebral blood flow was assessed by MRI. ResultsSumatriptan induced reversible cephalic and extracephalic allodynia. Previously exposed rats showed evidence of persistent sensitisation, including enhanced biomarker and glial responses after withdrawal and following SNP challenge. pERK and pp38 expression increased in both the trigeminal ganglion and trigeminal nucleus caudalis. In the TNC, marker association shifted over time from predominantly neuronal at day 6 to greater apparent glial association at day 20. Iba-1 and GFAP expression increased after withdrawal of sumatriptan and was further enhanced by SNP challenge. Within the TNC, neuronal marker expression was greatest in the ophthalmic representation. Sumatriptan exposure also produced a persistent reduction in cerebral blood flow that remained evident after behavioural recovery. ConclusionContinuous sumatriptan exposure produces prolonged trigeminovascular neuronal and glial alterations together with persistent changes in brain perfusion. These data support a state of latent sensitisation after repeated triptan exposure and provide mechanistic insight into medication overuse headache. HIGHLIGHTSO_LIRepeated sumatriptan exposure induces reversible cephalic and extracephalic allodynia but leaves persistent trigeminovascular sensitisation after drug withdrawal. C_LIO_LIpERK and pp38 expression increase in the trigeminal ganglion and trigeminal nucleus caudalis, with the strongest regional changes seen in the ophthalmic representation of the TNC. C_LIO_LIDelayed increases in Iba-1 and GFAP in the TNC suggest that glial activation may contribute to maintenance of latent sensitisation, although the colocalisation findings are qualitative and should be interpreted cautiously. C_LIO_LIRepeated sumatriptan exposure is also associated with a persistent reduction in cerebral blood flow, indicating longer-lasting changes in brain perfusion beyond the period of overt allodynia. C_LI

neuroscience↗

bioRxiv2021

Sodium accumulation in breast cancer predicts malignancy and treatment response

Breast cancer is the leading cause of cancer-related death in women worldwide. Development of novel noninvasive diagnostic and predictive pathophysiological biomarkers would represent a significant clinical improvement. Here, we explored the utility of non-invasive 23Na MRI to profile tumour physiology using preclinical mouse models of breast cancer. We establish that tissue Na+ concentration ([Na+]) is elevated vs non-tumour regions across multiple different tumour models. Ex vivo SBFI fluorescence imaging corroborated that this elevation in tumour [Na+] is due to increased intracellular [Na+]. Effective treatment with cytotoxic chemotherapy reduced tumour tissue [Na+], but was not detected by 1H diffusion-weighted imaging (DWI). Moreover, combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared to either parameter alone. Quantification of breast tumour tissue [Na+] using 23Na MRI thus represents a novel, accurate, non-invasive diagnostic and predictive imaging biomarker.

cancer biology↗

bioRxiv2020

Validating layer-specific VASO across species

Cerebral blood volume (CBV) has been shown to be a robust and important physiological parameter for quantitative interpretation of functional (f)MRI, capable of delivering highly localized mapping of neural activity. Indeed, with recent advances in ultra-high-field (>=7T) MRI hardware and associated sequence libraries, it has become possible to capture non-invasive CBV weighted fMRI signals across cortical layers. One of the most widely used approaches to achieve this (in humans) is through vascular-space-occupancy (VASO) fMRI. Unfortunately, the exact contrast mechanisms of layer-dependent VASO fMRI have not been validated and thus interpretation of such data is confounded. Here we cross-validate layer-dependent VASO fMRI contrast in a preclinical rat model using well established (but invasive) imaging methods in response to neuronal activation (somatosensory cortex) and respiratory challenge (hypercapnia). In particular VASO derived CBV measures are directly compared to concurrent measures of total haemoglobin changes from high resolution intrinsic optical imaging spectroscopy (OIS). Through direct comparison of response magnitude, across time, negligible changes in hematocrit ratio during activation (neuronal or vascular) are inferred. Quantified cortical layer profiling is demonstrated and in agreement between both VASO and contrast enhanced fMRI (using monocrystalline iron oxide nanoparticles, MION). Responses show high spatial localisation to layers of cortical excitatory and inhibitory processing independent of confounding large draining veins which hamper BOLD fMRI studies. While we find increased VASO based CBV reactivity (3.1 {+/-} 1.2 fold increase) in humans compared to rats it is demonstrated that this reflects differences in stimulus design rather than confounds of the VASO signal source. Together, our findings confirm that the VASO contrast is indeed a reliable estimate of layer-specific CBV changes. This validation study increases the neuronal interpretability of human layer-dependent fMRI results and should supersede BOLD fMRI as the method of choice in neuroscience application studies. HighlightsO_LIOur goal is to validate layer-specific VASO fMRI with gold standard methods C_LIO_LILayer-specific VASO sequences are implemented for 7T imaging in humans and rats C_LIO_LIComparisons of VASO, optical imaging, and MION confirm the expected contrast origin C_LIO_LISomatosensory stimulation in humans and rats reveal the same layer-fMRI signatures C_LIO_LIWe confirm that VASO is a valid measure to estimate layer-specific neural activity C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/219378v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@4f9733org.highwire.dtl.DTLVardef@14fccd2org.highwire.dtl.DTLVardef@101edaorg.highwire.dtl.DTLVardef@598bae_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2017

Physiological and pathological brain activation in the anesthetized rat produces hemodynamic-dependent cortical temperature increases that can confound the BOLD fMRI signal.

Anesthetized rodent models are ubiquitous in pre-clinical neuroimaging studies. However, because the associated cerebral morphology and experimental methodology results in a profound negative brain-core temperature differential, cerebral temperature changes during functional activation are likely to be principally driven by local inflow of fresh, core-temperature, blood. This presents a confound to the interpretation of blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) data acquired from such models, since this signal is also critically temperature-dependent. Nevertheless, previous investigation on the subject is surprisingly sparse. Here, we address this issue through use of a novel multi-modal methodology in the urethane anesthetized rat. We reveal that sensory stimulation, hypercapnia and recurrent acute seizures induce significant increases in cortical temperature that are preferentially correlated to changes in total hemoglobin concentration, relative to cerebral blood flow and oxidative metabolism. Furthermore, using a phantom-based evaluation of the effect of such temperature changes on the BOLD fMRI signal, we demonstrate a robust inverse relationship between the two. These findings indicate that temperature increases, due to functional hyperemia, should be accounted for to ensure accurate interpretation of BOLD fMRI signals in pre-clinical neuroimaging studies.

neuroscience↗

bioRxiv2017

Seizure epicenter depth and translaminar field potential synchrony underlie complex variations in tissue oxygenation during ictal initiation.

Whether functional hyperemia during epileptic activity is adequate to meet the heightened metabolic demand of such events is controversial. Whereas some studies have demonstrated hyperoxia during ictal onsets, other work has reported transient hypoxic episodes that are spatially dependent on local surface microvasculature. Crucially, how laminar differences in ictal evolution can affect subsequent cerebrovascular responses has not been thus far investigated, and is likely significant in view of possible laminar-dependent neurovascular mechanisms and angioarchitecture. We addressed this open question using a novel multi-modal methodology enabling concurrent measurement of cortical tissue oxygenation, blood flow and hemoglobin concentration, alongside laminar recordings of neural activity, in a urethane anesthetized rat model of recurrent seizures induced by 4-aminopyridine. We reveal there to be a close relationship between seizure epicenter depth, translaminar LFP synchrony and tissue oxygenation during the early stages of recurrent seizures, whereby deep layer seizures are associated with decreased cross laminar synchrony and prolonged periods of hypoxia, and middle layer seizures are accompanied by increased cross-laminar synchrony and hyperoxia. Through comparison with functional activation by somatosensory stimulation and graded hypercapnia, we show that these seizure-related cerebrovascular responses occur in the presence of conserved neural-hemodynamic and blood flow-volume coupling. Our data provide new insights into the laminar dependency of seizure-related neurovascular responses, which may reconcile inconsistent observations of seizure-related hypoxia in the literature, and highlight a potential layer-dependent vulnerability that may contribute to the harmful effects of clinical recurrent seizures. The relevance of our findings to perfusion-related functional neuroimaging techniques in epilepsy are also discussed.

neuroscience↗