Association of Retinal Nerve Fiber Layer Thickness with Brain Microstructural Changes in Participants with White Matter Hyperintensities.

PURPOSE: White matter hyperintensity (WMH) is suggested to cause stroke and dementia in older adults. Retinal structural thicknesses revealed by optical coherence tomography (OCT) are associated with structural changes in the brain. We aimed to explore the association between the peripapillary retinal nerve fiber layer (RNFL) and cerebral microstructural changes in participants with white matter hyperintensities (WMH). METHODS: Seventy-four participants (37 controls, healthy control (HC), and 37 older adults with WMH) underwent retinal and brain imaging using OCT and magnetic resonance imaging (MRI) respectively. Peripapillary RNFL thickness was assessed by the OCT. Gray matter volume (GMV) was assessed from a T1-weighted MRI. White matter integrity was assessed with diffusion tensor imaging (DTI) while WMH severity was assessed with the Fazekas scale. All participants underwent a neuropsychological examination (Mini-Mental State Examination, MMSE). RESULTS: Older adults with WMH showed thinner peripapillary RNFL (p = 0.004) thickness when compared with the control group after adjusting for age, hypertension and gender. In our older adults with WMH, RNFL thickness correlated with fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF) (Rho = -0.331, p < 0.001). In older adults with WMH, RNFL was significantly associated with MMSE scores (Rho = 0.422, p < 0.001) and Fazekas scores (Rho = -0.381, p = 0.022) respectively. CONCLUSIONS: We suggest neurodegeneration of peripapillary RNFL in older adults with WMH was associated with cerebral microstructural volume, impaired cerebral axonal damage, and cognitive performances. OCT metrics may provide evidence of neurodegeneration that may underpin WMH and cerebral microstructural changes in the brain. CLINICAL TRIAL REGISTRATION: This study was registered online at the China Clinical Trial Registration Center (registration number: ChiCTR-ROC-17011819).

Phlorizin, a novel caloric restriction mimetic, stimulates hypoxia and protects cardiomyocytes through activating autophagy via modulating the Hif-1α/Bnip3 axis in sepsis-induced myocardial dysfunction.

BACKGROUND: Sepsis is a systemic inflammatory syndrome that can lead to multiple organ dysfunction and life-threatening complications. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to be present in half of patients with septic shock, increasing their mortality rate to 70-90%. The pathogenesis of SIMD is complex, and no specific clinical treatment has yet been developed. Caloric restriction mimetics (CRM), compounds that simulate the biochemical and functional properties of CR, can improve cardiovascular injury by activating autophagy. This study investigated the effect of a new type of CRM which can induce hypoxia, the SGLT nonspecific inhibitor phlorizin on SIMD. MATERIALS AND METHODS: In vivo, phlorizin was administered at 1 mg/kg/day intragastrically for 28 days. In vitro, AC16 was treated with 120 µM phlorizin for 48 h. Echocardiography was used to assess cardiac function. Myocardial injury markers were detected in serum and cell supernatant. Western blotting was employed to detect changed proteins associated with apoptosis and autophagy. Immunofluorescence, immunohistochemistry, co-immunoprecipitation, molecular docking, and other methods were also used to illustrate cellular changes. RESULTS: In vivo, phlorizin significantly improved the survival rate and cardiac function after sepsis injury, reduced markers of myocardial injury, inhibited myocardial apoptosis and oxidative stress, and promoted autophagy. In vitro, phlorizin alleviated the apoptosis of AC16, as well as inhibited oxidative stress and apoptotic enzyme activity. Phlorizin acts on autophagy at multiple sites through low energy (activation of AMPK) and hypoxia (release of Beclin-1 by Hif-1α/Bnip3 axis), promoting the formation and degradation of autophagosomes. CONCLUSION: We indicated for the first time that phlorizin could inhibit glucose uptake via GLUT-1 and conforms to the metabolic characteristics of CRM, it can induce the hypoxic transcriptional paradigm. In addition, it inhibits apoptosis and improves SIMD by promoting autophagy generation and unobstructing autophagy flux. Moreover, it affects autophagy by releasing Beclin-1 through the Hif-1α/Bnip3 axis.

Cerebral Neural Changes in Venous-Arterial Extracorporeal Membrane Oxygenation Survivors.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is used as temporary cardiorespiratory support in patients with critical ailments, but very little is known about the functional cerebral changes in ECMO survivors. Degree centrality (DC), a graph-based assessment of network organization, was performed to explore the neural connectivity changes in ECMO survivors compared to controls and their correlation with cognitive and neurological measures. METHODS: This exploratory observational study was conducted from August 2020 to May 2022. ECMO survivors and controls underwent functional magnetic resonance imaging (fMRI) of the brain. We performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity with other voxels. DC was measured by the fMRI graph method and comparisons between the two groups were performed. All participants underwent neuropsychological assessment (Montreal Cognitive Assessment, MoCA). Blood serum neuron-specific enolase and the Glasgow Coma Scale (GCS) were assessed in ECMO survivors. RESULTS: DC values in the right insula and right precuneus gyrus were lower in ECMO survivors and higher in the right medial superior frontal gyrus compared to controls (all p < 0.001). Decreased connectivity in the right insular and right precuneus gyrus correlated with total MoCA scores, delayed recollection, and calculation (all p < 0.05). Increased serum NSE levels, GCS score, and GCS-motor response correlated with decreased connectivity in the right insular and right precuneus gyrus and increased connectivity in the right medial superior frontal gyrus (all p < 0.05). CONCLUSIONS: We showed that both functional impairment and adaptation were observed in survivors of ECMO, suggesting that neural connectivity changes may provide insights into the mechanisms that may potentially link ECMO survivors to neurological and cognitive disorders.

Neural Dysconnectivity in the Hippocampus Correlates With White Matter Lesions and Cognitive Measures in Patients With Coronary Artery Disease.

Purpose: Recent neuroimaging reports have shown the microstructural changes in coronary artery disease (CAD) and its correlation with cognitive dysfunction while little is known about the functional characteristics of CAD. We hypothesize that functional characteristics may give clues to underlying pathology in CAD and its link with cognitive dysfunction. Degree centrality (DC), a graph-based assessment of network organization was performed to explore the neural connectivity changes in CAD patients compared with healthy controls and their correlation with cognitive measures. Methods: Thirty CAD patients and 36 healthy controls were included in our study. All participants underwent functional magnetic resonance imaging (fMRI) of the brain. We performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity with other voxels. DC was measured by the fMRI graph method and comparisons between the two groups were done. All participants underwent neuropsychological assessment (Montreal Cognitive Assessment, MoCA and Mini-Mental State Examination, MMSE). Results: Our data analysis included 30 CAD patients (59.90 ± 7.53 years) and 36 HCs (61.61 ± 6.19 years). CAD patients showed a greater prevalence of white matter lesions using the Fazekas score than healthy controls (P < 0.001). Importantly, CAD patients showed significantly lower (P < 0.001) MoCA and MMSE scores compared with healthy controls. CAD patients showed significantly decreased DC value (P < 0.001) in the right hippocampus (hippocampus_R), right lingual gyrus (lingual_R), and significantly increased DC value (P < 0.001) in the left middle frontal gyrus (Frontal_Mid_L) when compared with healthy controls respectively. DC value in the hippocampus_R significantly correlated (P < 0.00) with MMSE and MoCA scores in CAD patients. Fazekas scores in CAD patients showed a significant correlation (P < 0.001) with the DC value in the hippocampus_R. Conclusion: These findings suggest that reduced cerebral neural connectivity in CAD may contribute to their cognitive impairment and white matter microstructural damage.

Irregular Baseline Brain Activity in Coronary Artery Disease Patients with Cognitive Impairment: A Resting-state Functional Magnetic Resonance Imaging Study.

OBJECTIVE: Cognitive impairment has been suggested to be associated with coronary artery disease [CAD]; however, the underlying mechanism is not fully understood. Our current study aimed to explore the brain activity in CAD patients compared to healthy controls [HCs]. METHODS: Twenty-two CAD patients and 23 HCs were enrolled in our study. A low-frequency oscillation at the voxel level in all participants based on the amplitude of low-frequency fluctuations [ALFF] was measured using resting-state functional magnetic resonance imaging. All participants underwent neuropsychological examinations [Mini-Mental State Examination, MMSE and Montreal Cognitive Assessment, MoCA] and visual acuity examination. RESULTS: CAD patients showed significantly lower ALFF values [P < 0.05] in the right precuneus gyrus [Precuneus_R], left supramarginal gyrus [Supramarginal_L], left angular gyrus [Angular_L], and left middle cingulum gyrus [Cingulum_Mid_L] than healthy controls. Lower MoCA scores in CAD patients significantly correlated with lower Supramarginal_L [P = 0.001] and Cingulate_ Mid_L [P = 0.004] ALFF values. Reduced visual acuity significantly correlated with lower Precuneus_R [P = 0.019] and Cingulate_Mid_L [P = 0.011] ALFF values in CAD patients. CONCLUSION: These findings may provide further insight into the underlying neuropathophysiology of CAD with cognitive impairment.

Irregular degree centrality in neuromyelitis optica spectrum disorder patients with optic neuritis: A resting-state functional magnetic resonance imaging study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disorder that causes significant changes in brain connectivity and visual impairment. Degree centrality (DC), a graph-based assessment of network organization was performed to explore the connectivity changes in NMOSD patients and their correlation with clinical consequences. METHODS: Twenty-two NMOSD patients and 22 healthy controls (HC) were included. Participants underwent visual acuity examination and resting-state functional magnetic resonance imaging (fMRI) of the brain. We first performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity (FC) with other voxels. DC was calculated by the fMRI graph method and comparison between the two groups was done by two-sample t-test. GraphPad Prism was used to assess the association between DC changes and clinical consequences. RESULTS: Out of the 22 NMOSD patients, 7 (31.82%) had ON once while 15 (68.18%) had ON twice or more. Decreased DC value (P < 0.001) in the left frontal superior orbital gyrus (ORBsup), left angular gyrus (ANG) and right parietal superior gyrus (SPG) was found in NMOSD patients when compared with healthy controls respectively. Reduced visual acuity significantly correlated (R2 = 0.212, P = 0.040) with DC values in SPG while the frequency of ON significantly correlated (R2 = 0.04, P = 0.040) with DC values in the ANG in NMOSD patients. CONCLUSIONS: NMOSD patients experience neural network dysfunction which may be associated with their clinical implications.

The Relationship of the Type of Intracerebral Hemorrhage to Early Disease Evolution and Long-Term Prognosis After r-tPA Thrombolysis.

To investigate the relationship of different subtypes of intracerebral hemorrhage (ICH) to early disease evolution and long-term prognosis in patients with acute cerebral infarction after intravenous recombinant tissue plasminogen activator(r-tPA). Seventy ischemic stroke patients treated with intravenous r-tPA who underwent computed tomography (CT) within 24 hours after thrombolysis were divided into 4 types (hemorrhagic infarction type 1 [HI-1], HI-2, parenchymal hemorrhage type 1 [PH-1], or PH-2 which according to the size of the hematoma and the presence or absence of space-occupying effect). Early evolution of the disease was observed by the change in the National Institutes of Health Stroke Scale (NIHSS) score within 24 hours after thrombolysis. The long-term prognosis was assessed by the modified Rankin Scale (mRS) score at the third month. There were 17 (24.3%) patients with ICH. Compared with patients in the non-ICH group, HI did not affect early neurological function or clinical outcome at the third month. PH-1 did not increase the risk of early neurological deterioration; however, PH-1 has a tendency to increase the risk of death at the third month (50% vs 11.3%, P = 0.090). PH-2 was significantly related to early neurological deterioration (66.7% vs 3.8%, P < 0.001) and mortality at the third month (50.0% vs 11.3%, P = 0.040). Patients with different subtypes of ICH after thrombolysis have different clinical outcomes. PH-2 is significantly associated with early neurological deterioration and increases mortality at the third month.

Clinical activity changes in the neurology department of Wenzhou during the COVID-19 pandemic: an observational analysis.

OBJECTIVE: To explore the activity changes in neurology clinical practice that have occurred in tertiary public hospitals during the COVID-19 pandemic. METHODS: Outpatient and inpatient data from the neurology department were extracted from the electronic medical record system of three tertiary Grade A hospitals in Wenzhou. Data were analyzed across 5 months following the beginning of the pandemic (from January 13 to May 17) and compared with the same period in 2019. Data on reperfusion therapy for acute infarction stroke were extracted monthly from January to April. RESULTS: The number of outpatients declined from 102,300 in 2019 to 75,154 in 2020 (26.54%), while the number of inpatients in the three tertiary Grade A hospitals decreased from 4641 to 3437 (25.94%). The latter trend showed a significant drop from the 3rd week to the 7th week. The number of patients in these hospitals decreased significantly, and a significant drop was seen in the neurology department. As usual, stroke was the most common disease observed; however, anxiety/depression and insomnia increased dramatically in the outpatient consultation department. CONCLUSIONS: The results of our study revealed the effects of the COVID-19 pandemic in the clinical practice of neurology in Wenzhou during the outbreak. Understanding the pandemic's trends and impact on neurological patients and health systems will allow for better preparation of neurologists in the future.

Stroke Type, Etiology, Clinical Features and Prognosis of Diabetic Patients in Southern China.

To analyze the type, etiology, clinical features and prognosis of stroke in southern China diabetic patients. From January to August 2019, acute stroke patients were prospectively enrolled in the Wenzhou Stroke Registry within 7 days of admission to the Hospital. The differences between the 2 groups of stroke patients with or without diabetes were in the following aspects: bleeding site of hemorrhagic stroke, different ischemic stroke etiology, Oxfordshire Community Stroke Project (OCSP) classification, death and disability within 3 months. Of the 497 patients enrolled, 104 (20.9%) were diabetic patients. 114(22.9%) patients had hemorrhagic stroke. The incidence of hemorrhagic stroke in the diabetic group was 10.6%, deep hemorrhage stroke account for 90.9%.In patients with ischemic stroke, the proportions of the new Trial of Org 10172 in Acute Stroke Treatment (TOAST) etiological subtype classifications (atherothrombosis (AT), cardioembolism (CE), small artery disease (SAD), stroke of other determined etiology (SOD) and stroke of undetermined etiology (SUD)) in the diabetic (non-diabetic) group was 43% (31%), 7.5% (14.1%), 27.9% (16.9%), 1% (0.3%), and 20.4% (37.6%), respectively; the proportion of The OCSP classifications(total anterior circulation infarcts(TACI), partial anterior circulation infarcts(PACI), lacunar infarcts(LACI) and posterior circulation infarcts(POCI)) in the diabetic (non-diabetic) group was16.1% (22%), 30.1%(37.2%), 42% (31.4%), and 10.8% (9%), respectively. The 3-month poor prognosis of the diabetic and non-diabetic groups was 23.1% and 28.2%. For diabetic patients, the incidence of hemorrhagic stroke is low, deep hemorrhage is common; SAD and LACI are common in the ischemic stroke; There was no significant difference in the 3-month prognosis between the 2 groups.

Predictors of the Prevalence of Dyslipidemia and Influencing Factors for Young Health Examination Cohort: A Cross-Sectional Survey.

Objectives: The objective of this study was to estimate the prevalence of dyslipidemia and associated influencing factors in young adults in the southeastern coastal area of China. Methods: This study adopted a cross-sectional survey and included 7,859 young people who underwent examinations at three hospitals in Wenzhou, Zhejiang Province, China. All subjects completed a questionnaire in the form of face-to-face interviews and underwent anthropometric measurements and biochemical tests. The continuous data are presented as the means ± standard deviations and were compared using Student's t-tests. The categorical variables are presented as proportions. The influencing factors associated with dyslipidemia were evaluated through a multivariate logistic regression. Results: The prevalence of dyslipidemia among young adults aged 18-45 years in the southeastern coast of China was high with 7.1, 15.0, 22.9, and 4.0% for high-total cholesterol (TC), high-triglyceride (TG), low-high-density lipoprotein cholesterol (HDL-C), and high-low-density lipoprotein cholesterol (LDL-C). Among those with dyslipidemia, a statistically significant difference in sex was observed, and all types of dyslipidemia were associated with smoking and alcohol consumption. However, those with high-TG, high-LDL, and low-HDL levels did not significantly differ in education level or occupation. The presence of dyslipidemia was significantly associated with increased age, the male sex (OR: 1.85, 95% CI: 1.39-2.21), smoking (OR: 2.02, 95% CI: 1.98-2.13), alcohol consumption (OR: 1.33, 95% CI: 1.16-1.63), overweight or obesity (OR: 2.01, 95% CI: 1.79-2.41), and intellectual work (OR: 1.36, 95% CI: 1.11-1.72). Conclusion: The prevalence of dyslipidemia among young adults aged 18-45 years in the southeastern coast of China was high. To prevent dyslipidemia at an early age, it is essential to conduct effective intervention programs targeting risk factors and to implement routine screening programs.

Combined Treatment With 2-(2-Benzofu-Ranyl)-2-Imidazoline and Recombinant Tissue Plasminogen Activator Protects Blood-Brain Barrier Integrity in a Rat Model of Embolic Middle Cerebral Artery Occlusion.

Recombinant tissue plasminogen activator (rt-PA) is used to treat acute ischemic stroke but is only effective if administered within 4.5 h after stroke onset. Delayed rt-PA treatment causes blood-brain barrier (BBB) disruption and hemorrhagic transformation. The compound 2-(-2-benzofuranyl)-2-imidazoline (2-BFI), a newly discovered antagonist of high-affinity postsynaptic N-methyl-D-aspartate (NMDA) receptors, has been shown to have neuroprotective effects in ischemia. Here, we investigated whether combining 2-BFI and rt-PA can ameliorate BBB disruption and prolong the therapeutic window in a rat model of embolic middle cerebral artery occlusion (eMCAO). Ischemia was induced in male Sprague Dawley rats by eMCAO, after which they were treated with 2-BFI (3 mg/kg) at 0.5 h in combination with rt-PA (10 mg/kg) at 6 or 8 h. Control rats were treated with saline or 2-BFI or rt-PA. Combined therapy with 2-BFI and rt-PA (6 h) reduced the infarct volume, denatured cell index, BBB permeability, and brain edema. This was associated with increased expression of aquaporin 4 (AQP4) and tight junction proteins (occludin and ZO-1) and downregulation of intercellular adhesion molecule 1 (ICAM-1) and matrix metalloproteinases 2 and 9 (MMP2 and MMP9). We conclude that 2-BFI protects the BBB from damage caused by delayed rt-PA treatment in ischemia. 2-BFI may therefore extend the therapeutic window up to 6 h after stroke onset in rats and may be a promising therapeutic strategy for humans. However, mechanisms to explain the effects oberved in the present study are not yet elucidated.

Protective Effects of the Soluble Epoxide Hydrolase Inhibitor 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea in a Rat Model of Permanent Middle Cerebral Artery Occlusion.

Acute ischemic stroke is a serious disease that endangers human health. In our efforts to develop an effective therapy, we previously showed that the potent, highly selective inhibitor of soluble epoxide hydrolase called 1-trifuoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) protects the brain against focal ischemia in rats. Here we explored the mechanism of TPPU action by assessing whether it could preserve blood-brain barrier integrity and reduce apoptosis in the brain during permanent middle cerebral artery occlusion in male Sprague-Dawley rats. TPPU administration at the onset of stroke and once daily thereafter led to smaller infarct volume and brain edema as well as milder neurological deficits. TPPU significantly inhibited the activity of soluble epoxide hydrolase and matrix metalloproteases 2 and 9, reducing 14,15-DHET levels, while increasing expression of tight junction proteins. TPPU decreased numbers of apoptotic cells by down-regulating the pro-apoptotic proteins BAX and Caspase-3, while up-regulating the anti-apoptotic protein BCL-2. Our results suggest that TPPU can protect the blood-brain barrier and reduce the apoptosis of brain tissue caused by ischemia.

Risk Factors for Early Intracerebral Hemorrhage after Intravenous Thrombolysis with Alteplase.

AIM: Intracerebral hemorrhage (ICH) is one of the most severe complications of thrombolysis. Symptomatic ICHs are associated with adverse outcomes. It has been reported that symptomatic ICHs most commonly occur within the first few hours after the initiation of intravenous thrombolysis. Our aim here was to determine the risk factors for early ICH (within 12 h) after thrombolysis. METHODS: We analyzed patients with acute ischemic stroke who received intravenous alteplase at two hospitals affiliated to Wenzhou Medical University between March 2008 and November 2017. The ICH diagnosis time was defined as the time from the intravenous administration of alteplase to the first detection of hemorrhage on computed tomography. Demographic data, medical history, clinical features, and laboratory examination results were collected. Univariate analysis followed by multivariable logistic regression analysis was performed to determine the predictors of early ICH (within 12 h) after thrombolysis. RESULTS: Among 197 patients, early ICH (within 12 h) after thrombolysis occurred in 13 patients (6.6%). In the univariate analysis, patients with early ICHs were significantly correlated with prior stroke (P=0.04). After adjusting for potential confounders in the multivariate analysis, prior stroke (odds ratio [OR]: 5.752, 95% confidence interval [CI]: 1.487-22.248; P=0.011) and atrial fibrillation (OR: 5.428, 95% CI: 1.427-20.640; P=0.013) were associated with early ICH. CONCLUSIONS: Prior stroke and atrial fibrillation are independent risk factors for early ICHs (within 12 h) after intravenous thrombolysis with alteplase.

Macula Structure and Microvascular Changes in Recent Small Subcortical Infarct Patients.

Purpose: This study aimed to assess the macula structure and capillaries in the macula and optic nerve head in recent small subcortical infarct (RSSI) patients. Methods: This observational cross-sectional study included 40 RSSI patients and 46 healthy controls. Optical coherence tomography angiography was used to image the capillaries in the macula and optic nerve head. An inbuilt algorithm was used to measure the densities in the microvasculature of the macula [superficial retinal capillary plexus (SRCP) and deep retinal capillary plexus (DRCP)] and optic nerve head [radial peripapillary capillary (RPC)] and thickness around the optic nerve head, peripapillary retinal nerve fiber layer (pRNFL). Results: Densities in RPC (P < 0.001), SRCP (P = 0.001), and DRCP (P = 0.003) were reduced in RSSI patients when compared with healthy controls. The pRNFL thickness was thinner (P < 0.001) in RSSI patients than healthy controls. In the RSSI group, the SRCP density significantly correlated with the DRCP density (rho = 0.381, P = 0.042). The pRNFL thickness displayed a significant relationship with the RPC density (rho = 0.482, P = 0.003) in the RSSI group. Conclusions: RSSI patients showed interrupted capillary plexuses leading to its significant impairment and neurodegeneration. Our report provides insight into the macula capillary microcirculation changes in RSSI.

Alterations in the Brain Structure and Functional Connectivity in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder.

PURPOSE: To investigate the mechanisms underlying the gray matter volume (GMV) and functional connectivity (FC) changes in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD) patients. METHODS: This cross-sectional study consisted of 21 patients with aquaporin-4 antibody-positive NMOSD and 22 age- and sex-matched healthy controls. All participants underwent cerebral magnetic resonance imaging and testing each individual's visual acuity was done. RESULTS: Neuromyelitis optica spectrum disorder patients showed significantly reduced GMV in the left calcarine, left thalamus and right lingual gyrus of the NMOSD patients when compared to HC (P < 0.05). NMOSD patients showed significantly decreased FC values (P < 0.05) in both the left and right calcarine, right lingual gyrus and left thalamus, respectively, when compared to HC. We also observed a positive correlation between the FC values of the left thalamus, bilateral calcarine gyrus and the visual acuity, respectively (P < 0.05). Furthermore, a negative association was seen between the duration of the disease, frequency of optic neuritis, and the FC values in the lingual gyrus, bilateral calcarine gyrus, and right lingual gyrus, respectively (P < 0.05). CONCLUSION: Reduced visual acuity and frequency of optic neuritis are associated with alterations in the GMV and FC in NMOSD. Our current study, which provides imaging evidence on the impairment involved in NMOSD, sheds light on pathophysiological responses of optic neuritis attack on the brain especially on the visual network.