Brain multiphysics最新文献

Scaling in the brain 大脑中的缩放

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-11-02 DOI: 10.1016/j.brain.2024.100102

D. Le Bihan

Proper scaling is an important concept in physics. It allows theoretical frameworks originally developed to address a specific question to be generalized or recycled to solve another problem at a different scale. The rescaling of the theory of heat to link diffusion and Brownian motion is a famous example set out by Einstein. We have recently shown how the special and general relativity theories could be scaled down to the action potential propagation speed in the brain to explain some of its functioning: Functional “distances” between neural nodes (geodesics), depend on both the spatial distances between nodes and the time to propagate between them, through a connectome spacetime with four intricated dimensions. This spacetime may further be curved by neural activity suggesting how conscious activity could act in a similar the gravitational field curved the physical spacetime. Indeed, the apparent gap between the microscopic and macroscopic connectome scales may find an echo in the AdS/CFT correspondence. Applied to the brain connectome, this means that consciousness may appear as the emergence in a 5D spacetime of the neural activity present as its boundaries, the 4D cortical spacetime, as a holographic 5D construction by our inner brain. We explore here how the conflict between ‘consciousness and matter’ could be resolved by considering that the spacetime of our cerebral connectome has five dimensions, the fifth dimension allowing the natural, immaterial emergence of consciousness as a dual form of the 4D spacetime embedded in our material cerebral cortex.

Statement Of Significance

Scaling to the brain the AdS/CFT framework which shows how the General Gravity framework, hence gravitation, naturally (mathematically) emerges from a “flat”, gravitationless Quantum 4D spacetime once a fifth dimension is considered, we conjecture that the conflict between ‘consciousness and matter’ might be ill-posed and could be resolved by considering that the spacetime of our cerebral connectome has five dimensions, the fifth dimension allowing the natural, immaterial (mind, private) emergence of consciousness as a dual form of the 4D spacetime activity embedded in our material (body, public) cerebral cortex.

适当缩放是物理学中的一个重要概念。它允许将原本为解决特定问题而开发的理论框架加以推广或再造，以解决不同尺度上的另一个问题。爱因斯坦提出了一个著名的例子，即重新调整热理论的尺度，将扩散和布朗运动联系起来。最近，我们展示了如何将狭义相对论和广义相对论缩小到大脑中的动作电位传播速度，以解释大脑的某些功能：神经节点之间的功能 "距离"（大地线）取决于节点之间的空间距离和节点之间的传播时间，并通过一个具有四个复杂维度的连接体时空传播。这个时空可能会被神经活动进一步弯曲，这表明有意识的活动是如何以类似于引力场弯曲物理时空的方式发挥作用的。事实上，微观和宏观连接组尺度之间的明显差距可能在 AdS/CFT 对应中找到了呼应。应用于大脑连接组，这意味着意识可能是作为其边界的神经活动在 5D 时空中的出现，即 4D 大脑皮层时空，是我们大脑内部的全息 5D 构建。我们在此探讨如何通过考虑我们大脑连接体的时空有五个维度来解决 "意识与物质 "之间的冲突，第五维度允许意识作为嵌入我们物质大脑皮层的 4D 时空的双重形式自然、非物质地出现。意义声明将 AdS/CFT 框架扩展到大脑，表明一旦考虑到第五维度，广义引力框架（即引力）是如何从 "平坦"、无引力的量子四维时空中自然（数学地）产生的、我们猜想，"意识与物质 "之间的冲突可能是不恰当的，可以通过考虑我们大脑连接体的时空有五个维度来解决，第五维度允许自然、非物质（心灵、私人）的意识出现，作为嵌入我们物质（身体、公共）大脑皮层的四维时空活动的双重形式。

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引用次数: 0

Quantifying CSF Dynamics disruption in idiopathic normal pressure hydrocephalus using phase lag between transmantle pressure and volumetric flow rate 利用跨端面压力和容积流量之间的相位滞后量化特发性正常压力脑积水的脑脊液动力学紊乱情况

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-10-01 DOI: 10.1016/j.brain.2024.100101

Pragalv Karki , Stephanie Sincomb , Matthew C. Murphy , Jeffrey L. Gunter , Matthew L. Senjem , Jonathan Graff-Radford , David T. Jones , Hugo Botha , Jeremy K. Cutsforth-Gregory , Benjamin D. Elder , John Huston III , Petrice M. Cogswell

Background and purpose

Idiopathic normal pressure hydrocephalus (iNPH) is a cerebrospinal fluid (CSF) dynamics disorder as evidenced by the delayed ascent of radiotracers over the cerebral convexity on radionuclide cisternography. However, the exact mechanism causing this disruption remains unclear. Elucidating the pathophysiology of iNPH is crucial, as it is a treatable cause of dementia. Improving the diagnosis and treatment prognosis rely on the better understanding of this disease. In this study, we calculated the pulsatile transmantle pressure and investigated the phase lag between this pressure and the volumetric CSF flow rate as a novel biomarker of CSF dynamics disruption in iNPH.

Methods

44 iNPH patients and 44 age- and sex-matched cognitively unimpaired (CU) control participants underwent MRI scans on a 3T Siemens scanner. Pulsatile transmantle pressure was calculated analytically and computationally using volumetric CSF flow rate, cardiac frequency, and aqueduct dimensions as inputs. CSF flow rate through the aqueduct was acquired using phase-contrast MRI. The aqueduct length and radius were measured using 3D T1-weighted anatomical images.

Results

Peak pressure amplitudes and the pressure load (integrated pressure exerted over a cardiac cycle) were similar between the groups, but the non-dimensionalized pressure load (adjusted for anatomical factors) was significantly lower in the iNPH group (p<0.001, Welch's t-test). The phase lag between the pressure and the flow rate, arising due to viscous drag, was significantly higher in the iNPH group (p<0.001).

Conclusion

The increased phase lag is a promising new biomarker for quantifying CSF dynamics dysfunction in iNPH.

Statement of Significance

The exact mechanism causing the disruption of CSF circulation in idiopathic normal pressure hydrocephalus (iNPH) remains unclear. Elucidating the pathophysiology of iNPH is crucial, as it is a treatable cause of dementia. In this study, we provided an analytical and a computational method to calculate the pulsatile transmantle pressure and the phase lag between the pressure and the volumetric CSF flow rate across the cerebral aqueduct. The phase lag was significantly higher in iNPH patients than in controls and may serve as a novel biomarker of CSF dynamics disruption in iNPH.

背景和目的特发性正常压力脑积水（iNPH）是一种脑脊液（CSF）动力学障碍，表现为放射性核素贮水池造影中放射性核素延迟上升至脑凸面。然而，导致这种紊乱的确切机制仍不清楚。阐明 iNPH 的病理生理学至关重要，因为它是一种可治疗的痴呆病因。改善诊断和治疗预后有赖于更好地了解这种疾病。方法44 名 iNPH 患者和 44 名年龄和性别匹配的认知功能未受损（CU）对照组患者在 3T 西门子扫描仪上接受了 MRI 扫描。以 CSF 容积流速、心脏频率和导水管尺寸为输入，通过分析和计算得出搏动性跨阈压力。通过相位对比核磁共振成像获取了通过导水管的 CSF 流速。结果两组之间的峰值压力振幅和压力负荷（一个心动周期内施加的综合压力）相似，但 iNPH 组的无量纲化压力负荷（根据解剖学因素调整）明显较低（p<0.001，韦尔奇 t 检验）。由粘滞阻力引起的压力与流速之间的相位滞后在 iNPH 组明显更高（p<0.001）。阐明 iNPH 的病理生理学至关重要，因为它是一种可治疗的痴呆症病因。在这项研究中，我们提供了一种分析和计算方法来计算搏动性跨幔压力以及压力与跨脑导水管 CSF 容积流速之间的相位滞后。iNPH患者的相位滞后明显高于对照组，可作为iNPH患者CSF动力学紊乱的新型生物标志物。

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引用次数: 0

BMPHI_ Editorial 2024 BMPHI_ 编辑 2

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2023-12-09 DOI: 10.1016/j.brain.2023.100087

引用次数: 0

Two for tau: Automated model discovery reveals two-stage tau aggregation dynamics in Alzheimer’s disease 两个 tau：自动模型发现揭示了阿尔茨海默病的两阶段 tau 聚集动力学

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-11-12 DOI: 10.1016/j.brain.2024.100103

Charles A. Stockman , Alain Goriely , Ellen Kuhl , Alzheimer’s Disease Neuroimaging Initiative

Alzheimer’s disease is a neurodegenerative disorder characterized by the presence of amyloid-

β

plaques and the accumulation of misfolded tau proteins and neurofibrillary tangles in the brain. A thorough understanding of the local accumulation of tau is critical to develop effective therapeutic strategies. Tau pathology has traditionally been described using reaction–diffusion models, which succeed in capturing the global spread, but fail to accurately describe the local aggregation dynamics. Current mathematical models enforce a single-peak behavior in tau aggregation, which does not align well with clinical observations. Here we identify a more accurate description of tau aggregation that reflects the complex patterns observed in patients. We propose an innovative approach that uses constitutive neural networks to autonomously discover bell-shaped aggregation functions with multiple peaks from clinical positron emission tomography (PET) data of misfolded tau protein. Our method reveals previously overlooked two-stage aggregation dynamics by uncovering a two-term ordinary differential equation that links the local accumulation rate to the tau concentration. When trained on data from amyloid-

β

positive and negative subjects, the neural network clearly distinguishes between both groups and uncovers a more subtle relationship between amyloid-

β

and tau than previously postulated. In line with the amyloid–tau dual pathway hypothesis, our results show that the presence of toxic amyloid-

β

influences the accumulation of tau, particularly in the earlier disease stages. We expect that our approach to autonomously discover the accumulation dynamics of pathological proteins will improve simulations of tau dynamics in Alzheimer’s disease and provide new insights into disease progression.

Significance Statement

In Alzheimer’s disease, understanding the local dynamics of tau protein aggregation is crucial for developing effective treatments. Traditional models for tau protein dynamics use reaction–diffusion models that fail to accurately capture these local patterns. Our study introduces a novel approach that leverages constitutive neural networks to autonomously discover the complex, multi-peak aggregation dynamics from clinical PET data. This method reveals a previously overlooked two-stage tau accumulation process and a nuanced relationship between amyloid-

β

and tau. By distinguishing between amyloid-

β

positive and negative subjects, our model supports the amyloid–tau dual pathway hypothesis and offers novel insights into tau protein aggregation that have the potent to advance our understanding of Alzheimer’s disease progression.

阿尔茨海默氏症是一种神经退行性疾病，其特征是大脑中存在淀粉样β斑块以及折叠错误的 tau 蛋白和神经纤维缠结的积累。透彻了解 tau 蛋白的局部积聚对于制定有效的治疗策略至关重要。传统上，人们使用反应扩散模型来描述 Tau 病理学，这种模型能成功捕捉全球扩散，但却无法准确描述局部聚集动态。目前的数学模型在 Tau 聚集中强制执行单峰行为，这与临床观察结果不符。在此，我们确定了一种更准确的 tau 聚集描述方法，它能反映在患者身上观察到的复杂模式。我们提出了一种创新方法，利用构成神经网络从折叠错误的 tau 蛋白的临床正电子发射断层扫描（PET）数据中自主发现具有多个峰值的钟形聚集函数。我们的方法揭示了以前被忽视的两阶段聚集动力学，发现了一个将局部积累率与 tau 蛋白浓度联系起来的双项常微分方程。在对淀粉样蛋白-β阳性和阴性受试者的数据进行训练时，神经网络能清楚地区分这两个组别，并揭示出淀粉样蛋白-β和tau之间比以前推测的更微妙的关系。与淀粉样蛋白-tau 双通道假说一致，我们的研究结果表明，毒性淀粉样蛋白-β的存在会影响 tau 的积累，尤其是在疾病的早期阶段。我们预计，我们自主发现病理蛋白积累动态的方法将改善对阿尔茨海默氏症中tau动态的模拟，并为疾病进展提供新的见解。传统的 tau 蛋白动态模型使用的是反应扩散模型，无法准确捕捉这些局部模式。我们的研究引入了一种新方法，利用组成神经网络从临床 PET 数据中自主发现复杂的多峰聚集动态。这种方法揭示了以前被忽视的两阶段 tau 积累过程以及淀粉样蛋白-β 和 tau 之间的微妙关系。通过区分淀粉样蛋白-β阳性和阴性受试者，我们的模型支持了淀粉样蛋白-tau双通道假说，并提供了对tau蛋白聚集的新见解，这些见解有望促进我们对阿尔茨海默病进展的理解。

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引用次数: 0

Erratum: Bok's equi-volume principle: Translation, historical context, and a modern perspective 勘误：博克的等体积原则：翻译、历史背景和现代视角

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-08-21 DOI: 10.1016/j.brain.2024.100099

Jack Consolini , Nagehan Demirci , Andrew Fulwider , Jeffrey J. Hutsler , Maria A. Holland

引用次数: 0

Numerical modelling of multiple sclerosis: A tissue-scale model of brain lesions 多发性硬化症的数值建模：脑损伤组织尺度模型

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-08-08 DOI: 10.1016/j.brain.2024.100097

H Hutchison , AC Szekely-Kohn , W Li , DET Shepherd , DM Espino

Multiple Sclerosis (MS) is an autoimmune condition leading to the degeneration of brain tissue, occurring when the immune system attacks the myelin sheath surrounding axons of white brain matter thereby disrupting brain signals. This study aimed to evaluate how MS lesions alter stress distribution through grey and white brain matter with lesions (active, chronic, and inactive). A linear viscoelastic model represents the tissue-scale dynamic deformation and time dependency of brain tissue. A Prony series expansion was used to model viscous effects including stress relaxation. An elastic modulus, within the viscoelastic model, was either reduced by 11 % for active lesions, or increased by 35 % increase for inactive lesions. These material properties were then implemented to model healthy tissue, active, chronically inflamed, and inactive lesions. Finite element analysis enabled stress evaluation in response to a peak cyclic displacement of 0.5 mm (1 % strain) with the healthy model acting as a control model. Chronic lesions had the largest effect on stress induced, in terms of high (171 Pa) and low stress (108 Pa). Inactive lesions induced an increase in stress of 11 Pa with areas of low stress (105 Pa). Active lesions caused the least deviation in peak induced stress (7 Pa). In conclusion, a hierarchy in stress induced across the lesion types has been found, from highest to lowest: chronic, inactive and active, with potential implications for lesion progression. In conclusion, MS lesions within brain tissue should model lesions, avoid assuming homogeneity during degeneration, and should distinguish between active and passive lesions.

多发性硬化症（MS）是一种导致脑组织变性的自身免疫性疾病，当免疫系统攻击白色脑物质轴突周围的髓鞘时，就会破坏脑信号。本研究旨在评估多发性硬化症病变（活动性、慢性和非活动性）如何改变脑灰质和脑白质的应力分布。线性粘弹性模型表示了脑组织的组织尺度动态变形和时间依赖性。普罗尼序列扩展用于模拟粘性效应，包括应力松弛。在粘弹性模型中，活跃病变的弹性模量降低了 11%，不活跃病变的弹性模量增加了 35%。这些材料特性随后被应用于健康组织、活跃病变、慢性炎症病变和非活跃病变的建模。通过有限元分析，可以对 0.5 毫米（1% 应变）的峰值循环位移进行应力评估，健康模型作为对照模型。慢性病变对应力的影响最大，包括高应力（171 帕）和低应力（108 帕）。非活动性病变引起的应力增加了 11 帕，低应力区域为 105 帕。活性病变引起的峰值应力偏差最小（7 Pa）。总之，我们发现不同病变类型引起的应力从高到低：慢性病变、非活动性病变和活动性病变，这对病变的进展具有潜在的影响。总之，脑组织内的多发性硬化病变应建立病变模型，避免假定退化过程中的同质性，并应区分活动性和被动性病变。

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引用次数: 0

Diffusive secondary injuries in neuronal networks following a blast impact: A morphological and electrophysiological study using a TBI-on-a-Chip model 爆炸冲击后神经元网络的弥散性继发性损伤：利用创伤性脑损伤芯片模型进行形态学和电生理学研究

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-11-12 DOI: 10.1016/j.brain.2024.100104

Timothy B. Beauclair , Edmond A. Rogers , Jhon Martinez , Shatha J. Mufti , Nikita Krishnan , Riyi Shi

Traumatic brain injury (TBI) is a worldwide health issue. Increasing prevalence of blast-induced TBI (bTBI), a predominantly combat-related injury, is an alarming trend necessitating a better understanding of the associated pathogenesis to develop treatments. Further, most bTBI injuries are mild and undiagnosed, permitting secondary biochemical injuries to propagate beyond possible intervention. Unfortunately, few treatment options are available due to a limited understanding of the underlying mechanisms. Additional investigative tools are urgently needed to elucidate the mechanisms behind immediate and long-term bTBI-induced damage. Therefore, we introduce “bTBI-on-a-Chip,” an in vitro blast injury model, capable of simultaneous morphological, biochemical, and bioelectrical assessments before, during, and after blast injury. We show correlated increases in markers of oxidative stress (acrolein) and inflammation (TNF-α) accompanied by electrophysiological deficits post-blast injury. Additionally, we show that these pathological consequences are mitigated by acrolein scavenging. We also show that injury products released by cultures post-injury diffuse through culture media and instigate biochemical injury in uninjured neuronal networks. Furthermore, we show that acrolein, a diffusive component of post-TBI secondary injury, is sufficient to increase inflammation in uninjured cultures. These findings validate bTBI-on-a-Chip as an appropriate model for recapitulating and investigating blast injury in vitro by showing its capabilities of recreating primary and secondary bTBI, monitoring biochemical and electrophysiological responses to injury, and screening possible pharmacological interventions post-injury. We expect that this model could provide insights into the pathological biochemical mechanisms that will be critical in developing future diagnostic and treatment strategies for bTBI patients.

Statement of Significance

The findings in the current study validate bTBI-on-a-Chip as an appropriate model for recapitulating and investigating blast injury in vitro by demonstrating its capabilities of recreating primary and secondary bTBI, monitoring biochemical and electrophysiological responses to injury, and screening possible pharmacological interventions post-injury. We expect that this model could provide insights into the pathological biochemical mechanisms that will be critical in developing future diagnostic and treatment strategies for bTBI patients.

创伤性脑损伤（TBI）是一个全球性的健康问题。爆炸诱发的创伤性脑损伤（bTBI）是一种主要与战斗有关的损伤，其发病率不断上升的趋势令人担忧，因此有必要更好地了解相关的发病机制，以开发治疗方法。此外，大多数 bTBI 伤情较轻且未被确诊，这使得继发性生化损伤的传播超出了可能的干预范围。遗憾的是，由于对潜在机制的了解有限，可供选择的治疗方法很少。我们迫切需要更多的研究工具来阐明 bTBI 引起的直接和长期损伤背后的机制。因此，我们引入了 "bTBI-on-a-Chip"--一种体外爆炸损伤模型，能够在爆炸损伤前、中、后同时进行形态学、生物化学和生物电评估。我们发现氧化应激标记物（丙烯醛）和炎症标记物（TNF-α）的相关性增加伴随着爆炸损伤后的电生理缺陷。此外，我们还发现清除丙烯醛可减轻这些病理后果。我们还表明，损伤后培养物释放的损伤产物会通过培养基扩散，并引发未损伤神经元网络的生化损伤。此外，我们还发现，创伤后继发性损伤的扩散成分丙烯醛足以增加未损伤培养物中的炎症反应。这些研究结果表明，bTBI-on-a-Chip 能够再现原发性和继发性 bTBI，监测生化和电生理对损伤的反应，并筛选损伤后可能的药物干预措施，从而验证了 bTBI-on-a-Chip 是在体外再现和研究爆炸损伤的合适模型。我们希望该模型能让我们深入了解病理生化机制，这对未来为 bTBI 患者制定诊断和治疗策略至关重要。当前研究的结果验证了 bTBI-on-a-Chip 是在体外重现和研究爆炸损伤的合适模型，证明它具有重现原发性和继发性 bTBI、监测损伤的生化和电生理反应以及筛选损伤后可能的药物干预措施的能力。我们希望该模型能让我们深入了解病理生化机制，这对未来为 bTBI 患者制定诊断和治疗策略至关重要。

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引用次数: 0

Exploring tau protein and amyloid-beta propagation: A sensitivity analysis of mathematical models based on biological data 探索 tau 蛋白和淀粉样蛋白-β 的传播：基于生物数据的数学模型敏感性分析

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-08-27 DOI: 10.1016/j.brain.2024.100098

Mattia Corti

Alzheimer’s disease is the most common dementia worldwide. Its pathological development is well known to be connected with the accumulation of two toxic proteins: tau protein and amyloid- $β$ . Mathematical models and numerical simulations can predict the spreading patterns of misfolded proteins in this context. However, the calibration of the model parameters plays a crucial role in the final solution. In this work, we perform a sensitivity analysis of heterodimer and Fisher–Kolmogorov models to evaluate the impact of the equilibrium values of protein concentration on the solution patterns. We adopt advanced numerical methods such as the IMEX-DG method to accurately describe the propagating fronts in the propagation phenomena in a polygonal mesh of sagittal patient-specific brain geometry derived from magnetic resonance images. We calibrate the model parameters using biological measurements in the brain cortex for the tau protein and the amyloid- $β$ in Alzheimer’s patients and controls. Finally, using the sensitivity analysis results, we discuss the applicability of both models in the correct simulation of the spreading of the two proteins.

Statement of significance: Alzheimer’s disease is related to the accumulation of tau protein and amyloid- $β$ . Mathematical models to predict the spreading patterns require accurate parameter calibration. In this work, we perform a sensitivity analysis of heterodimer and Fisher–Kolmogorov models to evaluate the impact of the equilibrium values of protein concentration on the solution patterns obtained with advanced numerical simulations on patient-specific brain geometry derived from magnetic resonance images. By using biological measurements in the brain cortex for the proteins in Alzheimer’s patients and controls, we use sensitivity analysis to discuss the applicability of models in simulating protein spreading.

阿尔茨海默病是全球最常见的痴呆症。众所周知，其病理发展与两种有毒蛋白质的积累有关：tau 蛋白和淀粉样蛋白-β。在这种情况下，数学模型和数值模拟可以预测错误折叠蛋白的扩散模式。然而，模型参数的校准对最终解决方案起着至关重要的作用。在这项工作中，我们对异源二聚体模型和 Fisher-Kolmogorov 模型进行了敏感性分析，以评估蛋白质浓度平衡值对溶液模式的影响。我们采用先进的数值方法（如 IMEX-DG 方法），在根据磁共振图像得出的矢状患者特定脑几何形状的多边形网格中精确描述传播现象中的传播前沿。我们利用对阿尔茨海默氏症患者和对照组大脑皮层中 tau 蛋白和淀粉样蛋白-β 的生物测量结果来校准模型参数。最后，我们利用敏感性分析结果，讨论了两种模型在正确模拟两种蛋白质扩散方面的适用性：阿尔茨海默病与 tau 蛋白和淀粉样蛋白-β 的积累有关。预测扩散模式的数学模型需要精确的参数校准。在这项工作中，我们对异源二聚体模型和费舍尔-科尔莫哥罗夫模型进行了敏感性分析，以评估蛋白质浓度平衡值对根据磁共振图像得出的患者特定大脑几何形状进行高级数值模拟所获得的溶液模式的影响。通过在大脑皮层对阿尔茨海默氏症患者和对照组的蛋白质进行生物测量，我们利用敏感性分析讨论了模型在模拟蛋白质扩散方面的适用性。

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引用次数: 0

Increased hindbrain motion in Chiari I malformation patients measured through 3D amplified MRI (3D aMRI) 通过三维放大磁共振成像（3D aMRI）测量 Chiari I 畸形患者后脑运动增加的情况

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-09-28 DOI: 10.1016/j.brain.2024.100100

Javid Abderezaei , Fargol Rezayaraghi , Aymeric Pionteck , Ya-Chen Chuang , Alejandro Carrasquilla , Gizem Bilgili , Tianyi Ren , Tyson Lam , Tse-An Lu , Miriam Scadeng , Patrick Fillingham , Peter Morgenstern , Michael R. Levitt , Richard G. Ellenbogen , Yang Yang , Samantha J. Holdsworth , Raj Shrivastava , Mehmet Kurt

Chiari Malformation type 1 (CM-I) is a neurological disorder characterized by morphological defects including excessive cerebellar tonsillar ectopia and associated manifestations. We used 3D amplified MRI on a cohort of healthy and CM-I subjects to investigate the brain’s intrinsic motion, its association with the morphology and patient’s symptomatology, and surgical outcomes. We observed that the regional brain motion in CM-I was significantly higher than that of the healthy subjects, with anterior-posterior (AP) and superior-inferior (SI) displacements in cerebellar tonsils and medulla having the highest differences between the healthy and CM-I (

\sim

45%–

\sim

73% increased motion in the CM-I group). Interestingly, we found the ratio of neural tissue in the foramen magnum to be directly correlated with the SI tonsillar motion (

r = 0.58

). Tonsillar herniation was directly correlated with the AP motion of the tonsils (

r = 0.61

), and AP and medial-lateral (ML) motions of the medulla (

r = 0.66

, and

r = 0.57

). Subjects with higher tonsillar ML motion prior to surgery showed improved outcome (

p = 0.03

, and

A U C = 0.95

). Although we did not observe a significant correlation between the brains motion and morphometrics on the CM-I symptoms (perhaps due to our small sample size), illustrative cases increase our hope for the development of a future tool based on brain biomechanics.

Chiari 畸形 1 型（CM-I）是一种神经系统疾病，其特征是形态缺陷，包括小脑扁桃体过度异位及相关表现。我们使用三维放大核磁共振成像技术对一组健康和 CM-I 患者进行了研究，以了解大脑的固有运动、其与形态学和患者症状的关联以及手术效果。我们观察到，CM-I 患者的大脑区域运动明显高于健康受试者，其中小脑扁桃体和延髓的前后（AP）和上下（SI）位移在健康和 CM-I 之间的差异最大（CM-I 组的运动增加了 45%～73%）。有趣的是，我们发现枕骨大孔中神经组织的比例与扁桃体SI运动直接相关（r=0.58）。扁桃体疝与扁桃体的 AP 运动（r=0.61）以及髓质的 AP 和内外侧（ML）运动（r=0.66 和 r=0.57）直接相关。手术前扁桃体 ML 运动较高的受试者预后较好（P=0.03，AUC=0.95）。虽然我们没有观察到大脑运动与 CM-I 症状上的形态计量学之间存在明显的相关性（可能是由于我们的样本量较小），但说明性的病例增加了我们对未来开发基于大脑生物力学的工具的希望。

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引用次数: 0

Effect of circadian rhythm modulated blood flow on nanoparticle based targeted drug delivery in virtual in vivo arterial geometries 昼夜节律调节的血流对虚拟体内动脉几何结构中基于纳米颗粒的靶向药物递送的影响

Q3 Engineering

Brain multiphysics

Pub Date : 2024-12-01 Epub Date: 2024-12-18 DOI: 10.1016/j.brain.2024.100105

Shoaib A. Goraya , Shengzhe Ding , Mariam K. Arif , Hyunjoon Kong , Arif Masud

Drug delivery using nanocarriers that are tethered with vasculature-targeting epitopes aims to maximize the therapeutic efficacy of the drug while minimizing the drug side effects. Circadian rhythm which is governed by the central nervous system has implications for targeted drug delivery due to sleep-wake cycle changes in blood flow dynamics. This paper presents an advanced fluid dynamics modeling method that is based on viscous incompressible shear-rate fluid (blood) coupled with an advection–diffusion equation to simulate the formation of concentration gradients in the blood stream, and buildup of the concentration of drug-carrying nanoparticles at the targeted site. The method is equipped with an experimentally calibrated nanoparticle-endothelial cell adhesion model that employs Robin boundary conditions to describe nanoparticle retention based on the probability of adhesion, a friction model accounting for surface roughness of endothelial cell layer, and a dispersion model based on Taylor-Aris expression for effective diffusion of nanocarriers in the boundary layer. The computational model is first experimentally validated and then tested on engineered bifurcating arterial systems where impedance boundary conditions are applied at the outflow to account for the downstream resistance at each outlet. It is then applied to a virtual geometric model of an in vivo arterial tree developed via MRI-based image processing techniques. These test cases highlight the potential of the proposed modeling method for investigating drug transport, adhesion, and retention at multiple sites in the virtual in vivo models under circadian rhythm modulated blood flow dynamics.

Statement of significance

This paper presents a novel mathematical method that integrate a nanoparticle-based drug delivery model with shear-rate dependent blood flow model for targeted drug delivery in the in vivo arterial networks. The framework is comprised of a unique combination of mechanics-based dispersion model, an asperity model for endothelium surface roughness, and a stochastic nanoparticle-endothelial cell adhesion model. Simulations of MRI based in vivo carotid artery system showcase the effects of vessel geometry on nanoparticle adhesion and retention at the target site. Vessel geometry and target site location impact nanoparticle adhesion; curved and bifurcating regions favor local accumulation of drug carrying nanoparticles. It is also shown that aligning drug administration with circadian rhythm and sleep cycle can enhance the efficacy of drug delivery processes. These simulations demonstrate the potential of the computational modeling method for exploring circadian rhythm modulated blood flow for targeted drug delivery while reducing the in vivo experimentation.

利用与血管靶向表位相连的纳米载体进行药物递送的目的是最大化药物的治疗效果，同时最小化药物的副作用。由中枢神经系统控制的昼夜节律，由于血流动力学中睡眠-觉醒周期的变化，对靶向药物递送具有影响。本文提出了一种先进的流体动力学建模方法，该方法基于粘性不可压缩剪切速率流体（血液），结合平流扩散方程来模拟血液中浓度梯度的形成以及载药纳米颗粒在靶部位的浓度积累。该方法配备了实验校准的纳米颗粒-内皮细胞粘附模型，该模型采用基于粘附概率的Robin边界条件来描述纳米颗粒的保留，考虑内皮细胞层表面粗糙度的摩擦模型，以及基于Taylor-Aris表达的纳米载体在边界层中有效扩散的分散模型。首先通过实验验证了计算模型，然后在工程分叉动脉系统上进行了测试，其中在出口处应用了阻抗边界条件，以考虑每个出口的下游阻力。然后将其应用于通过基于核磁共振成像的图像处理技术开发的体内动脉树的虚拟几何模型。这些测试案例强调了所提出的建模方法在昼夜节律调节的血流动力学下研究药物在虚拟体内模型中多个位点的运输、粘附和保留的潜力。本文提出了一种新的数学方法，将基于纳米颗粒的药物传递模型与剪切速率依赖的血流模型相结合，用于体内动脉网络中的靶向药物传递。该框架由基于力学的分散模型、内皮细胞表面粗糙度的粗糙度模型和随机纳米颗粒-内皮细胞粘附模型的独特组合组成。基于活体颈动脉系统的MRI模拟显示了血管几何形状对纳米颗粒在靶部位的粘附和保留的影响。血管几何形状和靶位位置影响纳米颗粒粘附；弯曲和分叉的区域有利于携带药物的纳米颗粒的局部积累。研究还表明，将给药与昼夜节律和睡眠周期相结合可以提高给药过程的疗效。这些模拟表明，在减少体内实验的同时，计算建模方法在探索昼夜节律调节的血流以靶向药物递送方面具有潜力。

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