Characterization of Intracranial Pulsatility in a Rat Model of Communicating Hydrocephalus: An MRI and Two-Photon Microscopy Study
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Introduction Communicating hydrocephalus (CH) is a severe neurodegenerative disorder characterized by an increased volume of cerebrospinal fluid (CSF) within enlarged cerebral ventricles. Previous studies have found that pulsatile CSF flow in the human cerebral aqueduct is elevated in CH, and have suggested that the causes of CH may be related to this increased pulsatility, as opposed to the traditionally accepted view of CSF malabsorption at the arachnoid villi. However, this has yet to be proven. In this dissertation, our goal was to investigate the significance of elevated aqueductal pulsatility in CH. We hypothesized that pulsatile CSF flow is a significant non-invasive marker of clinical outcome in CH. Methods We explored our hypothesis by characterizing the course of CH development in a recently developed rat model of CH, by MRI measurement of the volume of the cerebral ventricles and pulsatile CSF flow in the cerebral aqueduct and studying the relationship between ventricular dilation and aqueductal pulsatility. Aqueductal pulsatility may strongly be influenced by intracranial compliance, which is known to affect intracranial pressure pulsations. To understand how compliance affects aqueductal pulsatility, we studied the changes in aqueductal pulsatility produced by surgical modulation of compliance by shunting and craniectomy. Since increased blood flow pulsatility in the cerebral microvasculature has been suggested as a mechanism of increased CSF pulsatility in CH, we next explored a possible source of elevated aqueductal pulsatility by measuring capillary blood flow pulsatility in the CH rat neocortex with two photon microscopy. Finally, we investigated whether aqueductal pulsatility correlates with severity of CH in our animal model by characterizing behavioral deficits in our CH rats. Results At four weeks following hydrocephalus induction, the volume of the ventricles increased by a factor of 12 on average and aqueductal pulsatile flow of CSF increased by a factor of 101 compared to control rats. Aqueductal pulsatility was correlated to ventricular size, but this relationship varied significantly over the course of CH development, suggesting that both pulsatility and ventricular size may depend on another parameter, such as intracranial compliance. Aqueductal pulsatility had a strong dependence on compliance; increased compliance produced by shunting or craniectomy caused a drop in aqueductal pulsatility. Upon investigation of capillary blood flow pulsatility as a possible source of aqueductal pulsatility, we found that capillary pulsatility in our CH rat model depended on the anesthetic paradigm and was increased by 21% in CH under isoflurane anesthesia, but not under ketamine-xylazine. Finally, aqueductal pulsatility was not correlated to behavioral deficits in motor coordination, even though motor coordination (but not cognitive ability) is impaired in CH rats. Conclusions Our results show that aqueductal pulsatility is elevated in our rat model of CH, and is correlated to ventricular size. However, the relationship varies over time and may be related to changes in intracranial compliance. Decreased aqueductal pulsatility caused by increased compliance support the hypothesis that aqueductal pulsatility is influenced by intracranial compliance. Elevated capillary pulsatility supports the pulsation redistribution theory of hydrocephalus, suggesting that increased microvascular pulsations are an important component of the mechanism of CH. Using our model of communicating hydrocephalus, we have been able to demonstrate that there are clear changes in pulsatile dynamics in the hydrocephalic brain, both macroscopically as measured in the cerebral aqueduct and microscopically within the cerebral microvasculature. While our results have not established a clear link between these marked changes in pulsatility and clinical outcome, our work has laid the groundwork for future studies in experimental hydrocephalus and for future clinical trials looking into alternate mechanisms of communicating hydrocephalus.