The deleterious effect of crossfostering in rat pups on hypoxic-ischemic injury tolerance and hypothermic neuroprotection

We study the effect of hypothermia (HT) following hypoxic-ischemic (HI) brain injury in postnatal day 7 (P7) rats. In 2015, new European Union animal transport regulations prompted a change in practice at the breeding facility, which henceforth crossfostered P3 litters to P8 older lactating dam prior to transportation. It is generally assumed that crossfostering does not significantly affect the experimental results. The aim of this study was to examine whether crossfostering affects our model consistency by modifying injury susceptibility and hypothermic neuroprotection. We analysed 219 pups (56 litters) from 11 experiments conducted between 2013 and 2015: 73 non-crossfostered and 146 crossfostered pups. At P7, all pups underwent unilateral common carotid artery ligation followed by 50min of hypoxia (8% O2, 36°C). Immediately after this mild insult, the pups were randomised to post-insult normothermia (NT) or HT treatment. Pups were culled at P14. Injury was assessed by area loss of the ipsilateral hemisphere and histopathology scoring of hippocampus, cortex, thalamus, and basal ganglia. Crossfostered pups had double the injury compared to non-crossfostered pups irrespective of treatment group. Hypothermic neuroprotection was statistically significant, but with a smaller and less consistent effect in crossfostered pups (relative neuroprotection 16% vs. 31% in non-crossfostered). These results demonstrate hypothermic neuroprotection following a mild HI insult. A representative subset of 41 animals were also assessed for evidence of microglial reactivity, however no detectable difference in microglial reactivity was observed between any of the groups. In conclusion, crossfostering alters outcomes in our established model through reduced insult tolerance and variable neuroprotection. Crossfostering as a common breeding practice is a largely unexplored variable in animal research that may result in invalid research conclusions if inadequately adjusted for by larger group sizes. As a result, crossfostering is likely to be inconsistent with the principles of replacement, reduction, and refinement.

A Systematic Review of Case Reports on the Neck-Tongue Syndrome

Background and Objectives: Neck-tongue syndrome (NTS) is rare, and characterized by unilateral upper neck or occipital pain and paresthesia in the ipsilateral hemisphere of the tongue due to neck movement. Treatment for NTS is mainly conservative, but the symptoms, causes, and rationale for treatment remain controversial. This study aimed to provide a framework for NTS treatment in clinical practice based on recent treatment directions. Materials and Methods: Case reports published from the past 20 years to August 2021 were searched through MEDLINE, EMBASE, and PEDro databases. Since there is no established management for NTS, the search terms were neck-tongue syndrome and case reports. The Critical Appraisal Checklist for Case Reports was used for the quality assessment of case reports. Through descriptive analysis, NTS symptoms, interventions, and results were reviewed. Results: Among the 16 studies searched, six case reports were selected and analyzed based on eight criteria. Symptoms included neck pain and ipsilateral tongue paralysis when the head was turned. As an intervention, six and four studies showed immediate symptom relief through manual therapy and exercise, respectively. Conclusions: Based on the reviewed evidence, management through physical therapy and chiropractic therapy with conservative methods such as manual therapy and exercise for patients with neck-tongue syndrome is recommended.

Intrinsic Thalamic Network in Temporal Lobe Epilepsy With Hippocampal Sclerosis According to Surgical Outcomes

Background: The aim of this study was to identify the differences of intrinsic amygdala, hippocampal, or thalamic networks according to surgical outcomes in temporal lobe epilepsy (TLE) patients with hippocampal sclerosis (HS).Methods: We enrolled 69 pathologically confirmed TLE patients with HS. All patients had pre-operative three-dimensional T1-weighted MRI using a 3.0 T scanner. We obtained the structural volumes of the amygdala nuclei, hippocampal subfields, and thalamic nuclei. Then, we investigated the intrinsic networks based on volumes of these structures using structural covariance and graph theoretical analysis.Results: Of the 69 TLE patients with HS, 21 patients (42.1%) had poor surgical outcomes, whereas 40 patients (57.9%) had good surgical outcomes. The volumes in the amygdala nuclei, hippocampal subfields, and thalamic nuclei were not different according to surgical outcome. In addition, the intrinsic amygdala and hippocampal networks were not different between the patients with poor and good surgical outcomes. However, there was a significant difference in the intrinsic thalamic network in the ipsilateral hemisphere between them. The eccentricity and small-worldness index were significantly increased, whereas the characteristic path length was decreased in the patients with poor surgical outcomes compared to those with good surgical outcomes.Conclusion: We successfully demonstrated significant differences in the intrinsic thalamic network in the ipsilateral hemisphere between TLE patients with HS with poor and good surgical outcomes. This result suggests that the pre-operative intrinsic thalamic network can be related with surgical outcomes in TLE patients with HS.

Spatial Analysis of Neural Cell Proteomic Profiles following Ischemic Stroke in Mice using High-Plex Digital Spatial Profiling

Stroke is ranked as the fifth leading cause of death and the leading cause of adult disability. The progression of neuronal damage after stroke is recognized to be a complex integration of glia, neurons, and the surrounding extracellular matrix, therefore potential treatments must target the detrimental effects created by these interactions. In this study, we examined the spatial cellular and neuroinflammatory mechanisms occurring early after ischemic stroke utilizing Nanostring Digital Spatial Profiling (DSP) technology. Male C57bl/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and sacrificed at three-days post-ischemia. Spatial distinction of the ipsilateral hemisphere was studied according to the regions of interest: the ischemic core, peri-infarct tissues, and peri-infarct normal tissue (PiNT) in comparison to the contralateral hemisphere. We demonstrated that the ipsilateral hemisphere initiates distinct spatial regulatory proteomic profiles with DSP technology that can be identified consistently with the immunohistochemical markers, FJB, GFAP, and Iba-1. The core border profile demonstrated an induction of neuronal death, apoptosis, autophagy, immunoreactivity, and early degenerative proteins. Most notably, the core border resulted in a decrease of the neuronal proteins Map2 and NeuN, an increase in the autophagy proteins BAG3 and CTSD, an increase in the microglial and peripheral immune invasion proteins Iba1, CD45, CD11b, and CD39, and an increase in the neurodegenerative proteins BACE1, APP, αβ 1-42, ApoE, and hyperphosphorylated tau protein S-199. The peri-infarct region demonstrated increased astrocytic immunoreactivity, apoptotic, and neurodegenerative proteomic profile, with an increase in BAG3, GFAP, and hyperphosphorylated tau protein S-199. The PiNT region displayed minimal changes compared to the contralateral cortex with only an increase in GFAP. Overall, our data highlight the importance of identifying ischemic mechanisms in a spatial manner to understand the complex, dynamic interactions throughout ischemic progression and repair as well to introduce potential targets for successful therapeutic interventions.

Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.

Leptomeningeal collateral activation indicates severely impaired cerebrovascular reserve capacity in patients with symptomatic unilateral carotid artery occlusion

For patients with symptomatic unilateral internal carotid artery (ICA) occlusion, impaired cerebrovascular reactivity (CVR) indicates increased stroke risk. Here, the role of collateral activation remains a matter of debate, whereas angio-anatomical collateral abundancy does not necessarily imply sufficient compensatory flow provided. We aimed to further elucidate the role of collateral activation in the presence of impaired CVR. From a prospective database, 62 patients with symptomatic unilateral ICA occlusion underwent blood oxygenation-level dependent (BOLD) fMRI CVR imaging and a transcranial Doppler (TCD) investigation for primary and secondary collateral activation. Descriptive statistic and multivariate analysis were used to evaluate the relationship between BOLD-CVR values and collateral activation. Patients with activated secondary collaterals exhibited more impaired BOLD-CVR values of the ipsilateral hemisphere (p = 0.02). Specifically, activation of leptomeningeal collaterals showed severely impaired ipsilateral hemisphere BOLD-CVR values when compared to activation of ophthalmic collaterals (0.05 ± 0.09 vs. 0.12 ± 0.04, p = 0.005). Moreover, the prediction analysis showed leptomeningeal collateral activation as a strong independent predictor for ipsilateral hemispheric BOLD-CVR. In our study, ipsilateral leptomeningeal collateral activation is the sole collateral pathway associated with severely impaired BOLD-CVR in patients with symptomatic unilateral ICA occlusion.

Left Hemisphere Dominance for Bilateral Kinematic Encoding in the Human Brain

Neurophysiological studies in humans and non-human primates have revealed movement representations in both the contralateral and ipsilateral hemisphere. Inspired by clinical observations, we ask if this bilateral representation differs for the left and right hemispheres. Electrocorticography (ECoG) was recorded in human participants during an instructed-delay reaching task, with movements produced with either the contralateral or ipsilateral arm. Using a cross-validated kinematic encoding model, we found stronger bilateral encoding in the left hemisphere, an effect that was present during preparation and was amplified during execution. Consistent with this asymmetry, we also observed better across-arm generalization in the left hemisphere, indicating similar neural representations for right and left arm movements. Notably, these left hemisphere electrodes were largely located over premotor and parietal regions. The more extensive bilateral encoding in the left hemisphere adds a new perspective to the pervasive neuropsychological finding that the left hemisphere plays a dominant role in praxis.

Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery

ABSTRACTThe aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis, and had higher levels of glutamate, serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nesting test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery.SIGNIFICANCE STATEMENTThe findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer’s disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

Diffusion Tensor Imaging Detects Acute Pathology-Specific Changes in the P301L Tauopathy Mouse Model Following Traumatic Brain Injury

Traumatic brain injury (TBI) has been linked with tauopathy. However, imaging methods that can non-invasively detect tau-protein abnormalities following TBI need further investigation. This study aimed to investigate the potential of diffusion tensor imaging (DTI) to detect tauopathy following TBI in P301L mutant-tau-transgenic-pR5-mice. A total of 24 9-month-old pR5 mice were randomly assigned to sham and TBI groups. Controlled cortical injuries/craniotomies were performed for TBI/sham groups followed by DTI data acquisition on days 1 and 7 post-injury. DTI data were analyzed by using voxelwise analysis and track-based spatial statistics for gray matter and white matter. Further, immunohistochemistry was performed for total-tau and phosphorylated-tau, astrocytes, and microglia. To detect the association of DTI with these pathological markers, a correlation analysis was performed between DTI and histology findings. At day 1 post-TBI, DTI revealed a widespread reduction in fractional anisotropy (FA) and axial diffusivity (AxD) in the TBI group compared to shams. On day 7, further reduction in FA, AxD, and mean diffusivity and increased radial diffusivity were observed. FA was significantly increased in the amygdala and cortex. Correlation results showed that in the ipsilateral hemisphere FA reduction was associated with increased phosphorylated-tau and glial-immunoreactivity, whereas in the contralateral regions, the FA increase was associated with increased immunostaining for astrocytes. This study is the first to exploit DTI to investigate the effect of TBI in tau-transgenic mice. We show that alterations in the DTI signal were associated with glial activity following TBI and would most likely reflect changes that co-occur with/without phosphorylated-tau. In addition, FA may be a promising measure to identify discrete pathological processes such as increased astroglia activation, tau-hyperphosphorylation or both in the brain following TBI.

Are there network differences between the ipsilateral and contralateral hemispheres of pain in patients with migraine?

Background The present study aimed to investigate differences in the structural co-variance network based on structural volume and differences in the functional network based on cerebral blood flow between the ipsilateral and contralateral hemispheres of pain in patients with migraine. Methods We prospectively enrolled 27 patients with migraine without aura, all of whom had unilateral migraine pain that always occurred on the same side. We defined the ipsilateral hemisphere as the side of migraine pain, whereas we defined the contralateral hemisphere as that contralateral to the side of migraine pain. We obtained structural volumes using three-dimensional T1-weighted images and cerebral blood flow measurements using arterial spin labeling MRI. We then analyzed structural co-variance networks based on structural volumes and functional networks based on cerebral blood flow using graph theory. Results There were no significant differences in structural volume or cerebral blood flow between the ipsilateral and contralateral hemispheres. However, there were significant differences in the structural co-variance network and functional network. In the structural co-variance network, the betweenness centrality of the thalamus was lower in the ipsilateral hemisphere than in the contralateral hemisphere. In the functional network, the betweenness centrality of the anterior cingulate and paracingulate gyrus was lower, while that of the opercular part of the inferior frontal gyrus was higher, in the ipsilateral hemisphere than in the contralateral hemisphere. Conclusion The present findings successfully demonstrate that there are significant differences in the structural co-variance network and functional network between the ipsilateral and contralateral hemispheres of pain in patients with migraine. Such findings may be related to the pathogenesis of pain in these patients.