This is called systems identification. An advantage of the systems approach is that formal mathematical approaches exist for evaluating changes in the system itself as in the time-varying transfer function method [ 73 ] , as well as the extension to multiple inputs or multiple outputs of the system.
By considering how the system changes with a disease process or a proposed treatment, quantitative understanding of an intervention becomes possible. The identification of an absorber mechanism specifically at the cardiac frequency indicates an important role for CSF pulsations in preventing strong arterial pulsations from entering the cranium and having potentially damaging effects on the cranial microvasculature. Similar methodology was recently implemented in a canine model of obstructive HC, showing the deterioration of the pulsation absorption mechanism in chronic HC [ 95 ].
These results highlight the importance of complex data analysis techniques with a systems approach in interpreting intracranial pulsatility measurements, and their changes with disease. Systems analysis of the intracranial pulse pressure and the concept of transfer function. Because the intracranial pressure wave is a complex result of both the shape of the incoming arterial pressure wave, as well as the biomechanics of the intracranial compartment, additional analysis is needed to extract information about the biomechanics of the intracranial system independent of pressure waveform morphology.
In systems analysis, the concept of transfer function is used to accomplish this. In these experiments, both arterial and intraparenchymal pressure were measured. The frequency-domain transfer function relates these two waveforms, i. This work showed the existence of a "notch" in the transfer function specifically in the vicinity of the heart rate dip in signal seen in the lower right-hand corner indicating minimal transmission of the fundamental cardiac frequency from the arterial pressure into the parenchymal pressure.
However, under conditions of raised ICP through CSF volume loading, this notch disappears reddish area just above the lower right corner, coincident with the increase in ICP seen in the blue curve because of the increase in the fundamental cardiac frequency component of the intracranial pressure wave figure reproduced with permission, with modifications, from Zou et al [ 73 ]. The earliest investigations into intracranial pulse waves, their origin and their changes with disease, date back to the work of Bering in the 's [ 96 , 97 ] and later to Dunbar in the 's [ 98 ].
Most of this early work was performed in dogs, and led to the conclusion that the intracranial pulse wave is a product of the arterial pulsations entering the cranium, and is only influenced secondarily e. Hamer was one of the first to look at physiological modifications of the pulse pressure wave, also concluding that the arterial pulse wave predominately determines the pulse wave, except under conditions of cardiac insufficiency and increases in central venous pressure, when it can take on more venous character [ 99 ].
Interestingly, this work was one of the first to suggest that alterations in brain tissue compliance could have a deleterious effect on the pulse wave and might affect "vascular damping" of the arterial pulse wave with subsequent transmission of the pulse wave into the cerebral capillary bed.
Portnoy and Chopp continued this work throughout the 's, and were the first to use systems analysis of the ICP wave [ 29 , 30 , 70 ]. While their basic conclusion may have been similar to prior work, i. This observation was thus the first to show that there are frequency-dependent changes in the pulse pressure wave which may have relevance to normal brain function and its change with disease. Furthermore, in contrast to the earlier work, they concluded that the intracranial pulse wave is primarily venous in nature: According to this assumption, the similarity of the venous and intracranial pulse wave would then be due to the transfer of pressure waves from the parenchyma into the veins, rather than vice-versa.
More recent work has further supported the importance of frequency-dependent changes showing that the unique response transfer function at the cardiac frequency is similar to a resonant notch filter, a response which may serve to prevent the primary component of the arterial pulse pressure wave from being transmitted into the intracranial pulse wave under normal conditions [ 73 , 74 ].
The frequency dependence of a difference in gain how the input amplitude is translated to the output amplitude or phase, suggests that the concept of a unique, single-value "compliance" which would relate any shape of input to the output i. Systems analysis using transfer functions, however, allows consideration of a multi-value compliance as a function of input frequency--and the specific behavior of this function near the observed heart rate is of particular interest for probing the ability of the cranium i.
Intracranial pulsatility has also been investigated in animal models attempting to mimic diseases of impaired intracranial compliance, such as intracranial hypertension e. Portnoy and Chopp showed that while conditions of hypercapnia, hypoxia and volume loading all produced increased pressure pulsatility as measured by the arterial-to-CSF transfer function , the latter condition produced less of a change at any given mean ICP [ 29 ]. In addition, these conditions all produced a "rounding" of the pulse wave, similar to that noted by other authors [ 74 , 82 , ] in the frequency domain, this is consistent with increased pulsatility primarily in the fundamental cardiac component.
Using extensive systems analysis of pulsatility of the ICP wave, Piper and colleagues also showed that intracranial and arterial hypertension as well as hypercapnia produce increases in the pulse wave, with most of the change again occurring at the fundamental frequency [ 75 ]. Intracranial compliance was dramatically reduced during intracranial hypertension, but only marginally with hypercapnia. Unique to this study was the added use of phase information; while their finding of a negative phase shift i.
Rounding of the intracranial pulse wave as a result of increased ICP. Elevated ICP leads to decreased intracranial compliance, which investigators have found to result in amplification of the lower harmonic content of the intracranial pulse pressure wave, relative to the higher harmonic component. This behavior appears as a rounding of the pulse wave demonstrated here by CSF volume loading in the dog upper panel: The data also illustrate the timing, or phase, difference between the ABP and ICP waveforms, and the phase change with changes with mean ICP figure reproduced with permission from Wagshul et al [ 74 ].
In work more directly related to disease pathology, Di Rocco and colleagues showed that manipulation of the ventricular pulse pressure wave could lead to ventricular enlargement [ ]. They mechanically enhanced the ventricular pulse wave with an intraventricular balloon in sheep, and showed that the size of the manipulated ventricle increased compared to the contralateral one. This was the first demonstration of the importance of CSF pulsatility with respect to ventricular dilation. Throughout the 's, investigators continued to show the importance of the CSF pulse wave, in particular in animal models of HC, mostly involving kaolin injection into the cisternum magnum [ 16 , 18 , 83 , - ].
Foltz and colleagues demonstrated a marked increase in resting state pulsatility as well as in the pulsatility response to increases in mean pressure [ 16 ]. Again using systems analysis methods, Portnoy and Chopp showed a marked increase in the amplitude of the pulse wave with HC induction, although there was no correlation with ventricle size [ 83 ].
By observing arterial systemic pressure , CSF ventricular and venous sagittal sinus pressure waveforms, they were able to investigate the effect of both arterial and venous pulsatility on the CSF pulse wave. The primary conclusion was that pulse wave changes in HC are very similar to those due to intracranial hypertension and are not unique to HC. More recently, Penn and colleagues used a dog model of HC to show that there is no transmantle gradient i. This result held both during the acute development phase of the disease, with markedly increased mean and pulsatile pressure, and in the chronic phase with normalized mean and pulsatile pressures.
The existence of a transmantle gradient either in mean or pulse pressure has been hypothesized as one possible explanation for ventricular dilation in HC [ , ], although a recent study by Eide and Saehle in NPH patients showed no evidence of pulsatile trans- or intra-mantle pressure gradients [ 2 ]. All of the studies considered above used direct measurements of ICP and the pressure pulse. The advent of transcranial Doppler ultrasound allowed the non-invasive study of intracranial pulsatility in vascular flow.
Before proceeding to review these studies, however, a word of caution is in order, as noted above. TCD studies look at flow in intracranial blood vessels, while invasive pressure measurements typically observe parenchymal or ventricular pressure. While ICP pulsatility and intravascular flow pulsatility are certainly related, they are measures of different aspects of pulsation in the brain and distinct differences can be expected.
The number of studies investigating changes in TCD-based pulsatility in an animal model is quite limited, presumably due to the ease with which TCD can be done clinically and its non-invasive nature. Clinical studies will be reviewed in detail below. Nonetheless, as with pressure monitoring investigations, the few studies that exist generally found an increase in flow pulsatility with intracranial hypertension, again an indication of the reduced intracranial compliance [ - ].
Czosnyka et al used TCD in rabbits to observe changes in PI with intracranial hypertension, and concluded that PI can be a good indicator of cerebrovascular resistance, but only under conditions of intact perfusion pressure [ ]. The relatively new technology of MRI has also only been applied to animal models in a few instances, likely because of the expense of MRI technology and its ready availability in clinical studies.
Wagshul et al found markedly increased aqueductal CSF flow pulsatility in a rat model of HC [ ], a result which has been well documented in communicating HC patients, and Alperin et al have shown elevated CSF flow pulsatility at the CCJ by volume loading [ ] in a baboon model. A unique dog model of Chiari malformation, a condition in which jet-like pulsatile CSF flow occurs at the CCJ, has been used to document pulsatility changes with this condition [ ]. In summary, numerous studies over the last three decades, mostly using invasive pressure monitoring, have led to the general conclusion that pressure pulsatility serves as a sensitive indicator of intracranial compliance, with the increase in pulsatility in HC being an indication of reduced intracranial compliance due to raised ICP and compression from the enlarged ventricles.
Studies have also shown that there are important frequency-dependent factors which affect the way the pulse wave is transmitted into the cranium and how it is changed with disease. However, no study has clearly demonstrated the importance of intracranial pulsatility as a causative factor in the development of the disease process in either HC or TBI. Intracranial pulsatility has been measured clinically for years, ever since the report of Bering in [ 97 ], and until the advent of transcranial Doppler, the only evidence of these pulsations was from invasive pressure monitoring.
Foltz reported that the intracranial pulse pressure was times higher than normal in communicating HC, with "an even more striking pulse pressure increase" in obstructive HC cases [ 16 ].
They also noted that the peak of the pulse wave occurred earlier than normal in these patients; in our view, another indication of the reduced intracranial compliance. Avezzat and colleagues showed a marked increase in pulse pressure in a various etiologies e. However, they also noted a word of caution in using such pulse pressure as a reliable measure of intracranial compliance: There are, however, some studies which contradict these general conclusions of elevated pulse pressure in HC.
Matsumoto et al , for example, "could not find high pulse pressure of the ICP pulse wave" in their communicating HC patients [ 18 ]. It may be that some of the variability in results is related to the period of time over which ICP and pulse pressure are monitored. Moreover, shunt-responsive NPH patients with so-called "normal" pressure nonetheless have elevated pulse pressure, with amplitudes comparably high to those in stroke patients in the intensive care unit [ ].
These observations may indicate that it is the reduction of intracranial compliance, and not necessarily raised ICP, which causes the elevated pulse pressure amplitudes. To quantify these temporal effects, Eide and colleagues developed a method for analyzing single wave pulsatility in the time domain [ ]. While the pulse pressure measured with this technique is very similar to that used in other studies, the authors used a very different philosophy in analyzing their data.
Long-term monitoring was used, typically hours, and the pulse pressure then categorized based on the percentage of time it remained above a certain critical value. This technique highlights the dynamic nature of the pulse pressure, showing that even under pathological conditions the pulse pressure is not necessary always high. The effect of shunting on mean pulse wave amplitude. Mean amplitude of the pulse pressure wave has been used both as an indication of disease severity and as an indicator of the likelihood of shunt success in hydrocephalus.
In this patient, it can be seen that not only is the mean wave amplitude dramatically reduced following shunting leftmost vs. One major advantage of invasive monitoring as compared to non-invasive techniques is the ability to simultaneously monitor the pulse wave in different intracranial regions, providing the opportunity of comparing pulse pressure in different compartments.
While the mean ICP varies between locations, because of differences in baseline pressure e. A recent study, however, showed that some HC cases are associated with pulse pressure gradients, and these gradients may be related to the disease process [ ]. More studies are needed to confirm this important finding. Because of the obvious significant risk of marked elevation of ICP following TBI, this is another field which has seen increased interest in using pulse pressure waveforms for clinical diagnosis.
While ICP monitoring has been used for decades in this population, it was not until the mid 's that investigators began to utilize the pulse pressure for diagnostic purposes. Czosnyka et al used frequency domain analyses and introduced the concept of AMP or amplitude of the fundamental frequency component, and showed a close correlation with ICP [ 31 ]. Interestingly, they also noted that by using only the fundamental harmonic component of the pulse wave for their calculation of AMP, as opposed to the peak-to-peak amplitude of the waveform, a much better correlation to mean ICP was obtained.
In this work, they also introduced the concept of pulse pressure variability denoted RAP as a measure of compensatory reserve of the craniospinal compliance, and showed that this measure can be used to distinguish patients who will recover from those who will not [ 84 ]. One disadvantage to this approach is the use of lumbar infusion, which the authors argue is necessary in order to manipulate the ICP in a controlled manner, as compared to most other work which relies on observation of the natural course of the intracranial pulse pressure.
Nonetheless, this work has shown important results; more recent studies with these techniques have explored the potential benefits of decompressive craniectomy and its effect on ICP dynamics [ ]. These techniques have also been applied to HC patients, and can be used to distinguish ventricular dilation in HC from brain atrophy, although there is some overlap between these populations [ 88 ]. Correlation between pressure and pulse amplitude RAP. The RAP concept can best be understood through this figure showing the expected pulse amplitude behavior with increasing ICP.
Under normal ICP conditions left , the shallow slope of the pressure-volume curve leads to a weak relationship between pulse amplitude and pressure; RAP is close to zero. As ICP rises middle , and with it the slope of the pressure-volume response, there is a clear positive correlation between pulse amplitude and mean pressure; as pressure rises, so does pulse pressure, resulting in an RAP close to 1.
This relationship indicates a loss of compensatory reserve in the pressure-volume response. Finally, when ICP reaches a critical point right , the slope of the pressure-volume curve decreases sharply resulting in a negative pulse amplitude-pressure relationship; RAP becomes negative. In TBI, negative RAP has been shown to predict patients who are unlikely to recover figure reproduced with permission from Czosnyka and Pickard [ ].
Systems analysis of the pulse pressure waveform has also been used in TBI [ 34 , 35 , 75 , , ]. As compared to other studies, however, this work has focused not on the fundamental cardiac frequency, but on the higher harmonic components. Following up on earlier work with volume loading in dogs [ 72 ], it was shown that there exists a high frequency resonance which is a natural characteristic of the intracranial cavity and highly dependent on intracranial compliance. The systems analysis approach can be a very powerful tool in that different portions of the frequency spectrum may be indicative of various aspects of the pathophysiology.
For example, Piper et al showed that TBI patients could be categorized into four different characteristic frequency-domain patterns, which they associate with changes in cerebrovascular tone low frequency region and intracranial compliance high frequency region [ 35 ]. Lin et al similarly used systems analysis to show the existence of a high frequency component which was only present in TBI patients with good outcome.
This feature disappeared in patients with moderate or poor outcome, which the authors interpret as a pathological increase in cerebrovascular resistance, not as a change in intracranial compliance as is usually assumed [ ]. This work also highlights the advantage of using systems analysis over more straightforward waveform analysis; only the systems analysis approach was able to differentiate patients with good from those with intermediate outcome.
Unfortunately, these techniques have never developed into a viable tool for predicting TBI outcome, possibly due to the technical complexity and the high variability of results with changes in heart rate [ ]. Studies beginning in the late 's began to attempt to utilize invasive pulse pressure monitoring for guiding HC therapy. As with the studies noted above, all showed increased pulse pressure with disease, but there has been much disagreement as to whether or not this increase can be correlated with successful therapy.
In idiopathic NPH patients, Barcena et al showed that the pattern of increased pulse pressure was well correlated with decreased pulse wave latency both an indication of decreased intracranial compliance , and that this pattern was clearly distinct from the pattern seen in healthy subjects as well as in cases of brain atrophy, where increased pulse pressure was correlated with increased latency [ 20 ]. However, within the shunted group, they were unable to differentiate improved and unimproved patients based on either amplitude or latency of the pulse wave; one other study found similar results [ ].
On the other hand, a number of recent studies have shown promise. A very recent study showed excellent separation of responders and non-responders using an intracranial elastance index [ ], derived from the slope of pulse pressure vs. Using a systems analysis approach, Eide et al were able to separate responders from non-responders based on both pulse amplitude and phase information relative timing difference between the ICP and ABP pulse waves, which was smaller in responders [ 78 ].
The importance of intracranial compliance in hydrocephalus management. In this work, intraventricular infusion tests were used to measure the slope of the pressure-volume curve.
From this, the authors derive an intracranial elastance index - not the absolute elastance because they use diastolic pressures rather than mean pressure in the calculations - which is shown here to provide excellent separation between patients who improved white and those who did not improve blue following shunting.
The elastance index used here is proportional to the inverse of intracranial compliance figure reproduced with permission from Anile et al [ ]. In summary, recent advances using quantitative measures extracted from the pulse pressure waveform have shown very promising results and all would appear to support the view that intracranial compliance and its effect on the intracranial pulse amplitude can play a critical role in HC and TBI management. TCD flow velocity measurements follow the same trend as pre-clinical studies discussed above, most indicating an increase in PI with pathology [ - ], and good correlation with clinical condition [ , ].
Others have used more straightforward PI measurement and found good correlation with raised ICP [ , , ]. One study, however, found very weak correlations and concluded that the technique was not adequately sensitive [ ]. With respect to prognosis, PI has been found to fall following various surgical interventions, such as shunting [ , , , , ], CSF drainage [ ] and endoscopic third ventriculostomy [ ] in HC and surgical decompression for TBI [ , ].
However, the same word of caution noted above is needed when considering these studies. While increased PI is often regarded as a measure of reduced intracranial compliance i. In our view, this may explain the wide variability in a recent study of PI following shunting in HC [ ]. Nonetheless, these authors concluded that TCD may be a valuable tool when used in conjunction with other clinical information. Clinical MRI studies of flow pulsatility have mainly focused on measurements in the cerebral aqueduct because of the high flow velocities, although there are a limited number of studies of flow in the prepontine cistern [ 51 ], at the CCJ [ 53 , ], and in the cervical and intracranial vasculature [ 79 , 81 , , - ].
The very early MRI evidence of pulsatile flow in the aqueduct was actually not obtained through quantitative measures, but deduced from a flow artifact leading to decreased CSF signal which is accentuated with increased flow velocities [ - ]. The application of the phase-contrast technique to quantify pulsatile CSF flow was developed in the early 's.
These studies demonstrated the ability to quantify CSF flow through the cerebral aqueduct, in the prepontine cistern and at the craniocervical junction, as well as to identify patterns of brain motion. Based on these studies, it was concluded that pulsatility results in a funnel-like motion of the brain, as if the brain were being pulled in systole by the spinal cord.
This motion was interpreted as due to the venting of the brain and CSF through the tentorial notch and foramen magnum during the systolic arterial expansion [ ]. These landmark studies were followed by measurements of CSF flow in healthy controls, undertaken by numerous groups and focusing mostly on aqueductal flow and demonstrating reliable measurements [ 44 , 45 , 49 , 51 , , ]. Normal flow values i. MRI studies in healthy controls have also documented the normal temporal relationship between arterial or venous pulsatile flow and CSF pulsations. Flow in the cerebral aqueduct from cine phase contrast MRI in a healthy control.
A typical MRI flow study, using the phase contrast technique, consists of the magnitude a, anatomical and phase b, flow image. In this example, cine images were taken as a function of the cardiac cycle by gating the image acquisition to a peripheral pulse signal. The image on the right depicts flow velocities during one phase of the cardiac cycle with caudal CSF flow the bright dot in center of the image shows caudal flow in the aqueduct during this phase of the cycle. By summing over all pixels in the aqueduct, a net flow waveform is obtained c.
Stroke volume in this instance was MRI studies of flow pulsatility in disease have been primarily in HC, spurred on by the well-known changes in pressure pulsatility demonstrated with invasive monitoring methods discussed above. The primary finding is a marked increase in pulsatile aqueductal flow [ 50 , 52 , 59 , 61 , 62 , 67 , , - ] with pathological values often rising as much as ten times normal. Luetmer et al , for example, used this measure to set a diagnostic criterion for separating idiopathic NPH patients from healthy controls i.
Greitz et al reported a corresponding decrease in pulsatile flow through the CCJ [ 51 ], but these findings were from a limited number of patients, and one later study found no such change in a group of 12 communicating HC patients [ ]. Aside from the amplitude of flow pulsatility, some investigators have also looked at temporal parameters as an indication of pathological dynamics. For example, Baledent et al have shown a shorter systolic flow period compared to healthy controls [ ] and Miyati and coworkers have used systems analysis to show a highly significant correlation between the phase of the aqueductal pulse wave and pressure-volume response [ ] i.
MRI measurement of flow pulsatility at the craniocervical junction has been studied extensively in Chiari malformation. These studies have found increased heterogeneity in the flow pattern, consisting of both local flow jets and bi-direction flow [ - ]. The occurrence of flow jets necessitates the use of peak velocity, rather than net stroke volume, as the best indicator of pathology. Pinna and colleagues [ ] used the temporal information from the flow waveform and found a shorter systolic CSF pulse in the ventral subarachnoid space of Chiari patients without a syrinx compared to those who had developed a syrinx as well as compared to controls.
In light of the discussions throughout the paper of the relationship between CSF pulse wave timing and compliance, these results would appear to indicate the important role of the intraspinal compliance and pulse pressure gradients in Chiari and the formation of spinal syrinxes [ ]. In patients with syringomyelia in the absence of an obvious cause such as Chiari or tumor , Mauer et al used phase contrast MRI to document blockage of CSF flow in the subarachnoid space surrounding the syrinx, finding this technique to be more sensitive compared to myelography [ ].
Following surgical decompression, peak velocities decrease and flow waveforms change from "heterogeneous" to sinusoidal [ 56 , , , ].
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Alperin and colleagues used systems analysis to evaluate changes in intracranial compliance in Chiari, concluding that there was abnormal dynamics of the intracranial volume change over the cardiac cycle, which returned to "more normal-appearing dynamics" following decompression [ ]. In comparison to these studies, which focus almost exclusively on changes in CSF flow pulsatility, Bateman and colleagues have studied changes in vascular flow pulsatility as a measure of flow pathology in HC [ 52 , 68 , 69 , 79 , ], finding a significant decrease in the arterial pulse wave in NPH patients compared to age-matched controls.
The change in arterial pulsatility, coupled with a marked increase in the aqueductal CSF pulse, led to a nearly two-fold decrease in the compliance ratio, a relative measure of intracranial compliance the ratio of aqueduct to arterial pulse wave stroke volume [ 52 ]. They have also shown changes in venous flow pulsation which may be an indication of the importance of venous pathology in HC [ 69 , 79 ]. Most significantly, they found decreased cortical vein flow pulsatility in patients, which reversed and surpassed control values following ventricular shunting.
These studies also showed that vascular flow timing might be used as an indication of intracranial compliance changes in HC, with a marked drop in the arterial-venous delay i. Unfortunately, at the end of the day, a study of shunt responsiveness concluded that none of the measured pulsatile flow parameters could reliably separate shunt surgery responders from non-responders [ ].
With respect to prognostic MRI studies, numerous studies have investigated the association between aqueductal pulsatility and outcome from shunting [ 50 , 54 , 61 , 62 , 67 , , , , , , ]. Other trials, mostly involving NPH patients, however, have not been promising. Using the same measure of stroke volume, but stratifying patients into low, medium and high stroke volume groups, Kahlon et al could find no statistically significant improvement in either cognitive or motor function in any of the pulsatility groups [ ]. In another study using mean aqueductal flow rate, Dixon et al also found no significant association between CSF pulsatility and improvements in gait, cognition or urinary continence [ 62 ].
This same conclusion has been reached in a number of other recent trials [ 67 , , ]. In our view, scrutiny of these studies indicate that highly elevated flow pulsatility is usually a very good predictor of favorable outcome, but patients with normal or mildly elevated pulsatile flow levels will often also improve with shunting, leading to high false negative rates. Of course, some of the variability in results may be related to the temporal variability in pulsatility noted above from pressure monitoring studies [ 22 , 23 , 25 , 77 ], highlighting a distinct disadvantage of the MRI technique; because of the expense, only one point in a dynamically changing pulsatile system is captured.
One unique recent study, in which aqueductal pulsatility was followed over a two year period in patients who refused a shunt, in our view may shed some light on this controversy. Scollato and colleagues showed that pulsatility can change over time with the development and progression of the untreated HC [ ]. Thus, it is also possible that this long-term variability in pulsatility, the source of which is still unknown, is one of the deterrents to accurately predicting shunt outcome using this particular measure.
Temporal changes in aqueductal stroke volume in unshunted HC patients. Evidence that CSF flow can change over time with untreated disease may explain the difficulty clinicians have had using this measure for predicting shunt outcome. In this study, nine patients who had refused a shunt were followed over the course of four years the time axis has been normalized for each patient, so that 0 months corresponds to the time of the first reported symptoms. The time at which MRI measurements are taken may play a critical role in their prognostic use for predicting shunt outcome.
Normal stroke volume may only be indicative of poor shunt-responsiveness if taken at later time when stroke volume has decreased, perhaps due to irreversible atrophic changes in the brain which cannot be remedied with shunting. Normal stroke volume during the early development stages of the disease, on the other hand, may simply be an indication that intracranial compliance has not yet changed sufficiently to affect aqueductal flow patterns, and shunting may still prove effective in this patient group figure reproduced with permission from Scollato et al [ ]. An alternative treatment for HC, primarily reserved for obstructive cases, is endoscopic third ventriculostomy ETV.
Cine phase-contrast imaging is an important imaging modality for these cases; pulsatile flow through the stoma is used postoperatively to verify patency [ , ]. A number of publications have surfaced in the last few years, however, suggesting that ETV may also be an appropriate treatment in certain communicating cases.
Greitz recently presented a hydrodynamic theory of communicating HC, arguing that ETV may be an appropriate therapy for restoring pulsatile dynamics without shunting [ ]. Unfortunately, there are only a limited number of case studies which have looked at CSF flow other than for stoma patency before or after ETV. One study, in which most patients had elevated aqueductal stroke volume, showed only a small, non-significant decrease in flow pulsatility after ETV [ ].
A more recent study found no association between ETV success and CSF flow pulsatility in the basal cisterns or at the cervicomedullary junction [ ]. In summary, the MRI techniques developed within the last twenty years have proved invaluable for non-invasive assessment of intracranial pulsatility in HC.
Studies have consistently shown that HC is associated with elevated aqueductal flow pulsatility, as well as with changes in pulsatility in other areas of CSF and vascular flow. However, the strict association between pulsatile aqueductal flow and outcome from shunting remains an open question. A distinct, and we might even say likely, possibility is that flow pulsatility represents only a portion of the pathophysiology of the disease and additional non-invasive measures will need to be combined with flow measurements in order to adequately predict shunt responsiveness.
The pulsating brain: A review of experimental and clinical studies of intracranial pulsatility
With respect to future directions in pulsatility research and its potential clinical use for both diagnosis and prediction of outcome, we would suggest that large-scale clinical trials are needed, with particular attention paid to uniformity in the definition of pulsatility measures to be collected and acquisition methods to be used. Given the success of invasive pulsatility measurements in clinical prognosis [ 77 , , ], studies which can provide a link between changes in pulse pressure and changes in non-invasive TCD- or MRI-based measures of pulsatility will be particularly valuable.
A careful consideration of pulsatile dynamics may make possible a clearer definition of when HC is adequately treated, which will in turn yield new ways to compare the mechanism of action of shunts, endoscopic fenestrations, and other therapeutic options such as pharmacological or genetic interventions, in the future. Consideration of the mechanisms of how pulsations are generated and received by brain and neurovascular tissue may also help us understand and ultimately guide therapy in headache or other mechanisms which resemble those encountered in HC.
Given the importance of intracranial compliance in conditions such as hydrocephalus and traumatic brain injury, which we have shown is central to the existence and changes in brain pulsatility, the ability to directly measure compliance may also play an important role in clinical decision making. Direct measurement of intracranial compliance, however, is technically difficult and usually invasive.
Recently, Alperin et al have devised noninvasive methods for inferring intracranial compliance using MRI, based on the relative distribution of arterial, venous and CSF pulsatility at the craniocervical junction [ , ]. Such techniques may be the answer for a noninvasive method of assessing compliance changes with disease. For example, this technique has recently been used to demonstrate reduced intracranial compliance in NPH [ - ]. The studies we have discussed only imply a passive role for intracranial pulsatility, as an indicator of changes in brain compliance.
More intriguing is the possibility that intracranial pulsations may play an active role in intracranial fluid dynamics, a hypothesis which has been suggested by a number of investigators [ 73 , 74 , 95 , , , ]. By such a hypothesis, changes in the transfer of arterial pulsations into the surrounding subarachnoid spaces e. Indeed, a number of studies have documented decreased capillary density and caliper in experimental HC [ - ], and recent studies have shown that excessive pulsatile stress forces can change endothelial cell homeostasis and thus impair capillary hemodynamics through the potent vasodilator nitric oxide [ , ].
Whether or not such alterations at the microvascular level are a result of, as opposed to a cause of, the HC is still an open question, and is an ongoing investigation in one of our labs MEW, unpublished results. The concept that adequate intracranial management of the pulsatile energy of the arterial input by free movement of CSF has been likened to the need for balance in net production and absorption of the fluid itself, even as far as referring to the need for absorbing pulsations as a "fourth circulation" in the intracranial compartment, in homage to the description of the CSF flow as the "third circulation" [ ].
The fact that everything within the cranial cavity pulsates with cardiac periodicity has been well established and studied over the last fifty years. While there have been numerous investigations of intracranial pulsatility, focused both on understanding these pulsations as well as on their relationship to neurological disease, these have not yet had a major impact on our approach to clinical diagnosis or treatment. We have shown a clear link between intracranial pulsatility and the compliance of the brain. This link certainly implies an important diagnostic role for intracranial pulsatility in diseases involving dramatic changes in the distribution of the intracranial contents; hence its importance in TBI and HC.
While the search for noninvasive, prognostic tests utilizing pulsatility information is still underway, invasive monitoring of pulsatility is already being used at a number of centers and demonstrating its reliable, prognostic potential. Basic and clinical studies using noninvasive techniques have suggested correlations of pulsatile parameters with outcome, but the critical question is whether management decisions, which could not be made with already available time-independent measures, can be made on the basis of such analysis.
We have gained a tremendous amount of knowledge in the last six decades of research into the origins and significance of intracranial pulsatility in neurological disease. On the other hand, we are still in the early stages of the development of clinically useful techniques based on pulsatility-related measures. The validation of well-accepted modalities for improving patient outcome, using invasive and non-invasive modalities, as well as the formulation and testing of hypotheses regarding the many interesting pathophysiological questions, will depend on future technical advances in how we measure and analyze pulsatility, and our collective investigative imagination in broadening this field of research.
All of the authors contributed to the conception of the review in terms of overall content and focus. MEW contributed the bulk of the drafting of the article, while PKE and JRM contributed with thorough editing of the manuscript, and contributed data used for the figures. All authors have read and approved the final version of the paper. National Center for Biotechnology Information , U. Published online Jan Author information Article notes Copyright and License information Disclaimer.
Received Aug 16; Accepted Jan This article has been cited by other articles in PMC. Abstract The maintenance of adequate blood flow to the brain is critical for normal brain function; cerebral blood flow, its regulation and the effect of alteration in this flow with disease have been studied extensively and are very well understood. Introduction Numerous homeostatic processes in the brain, such as cerebral blood flow and maintenance of interstitial fluid equilibrium, depend critically on the regulation of intracranial pressure ICP and fluid flow.
Pressure and flow "compartments" The contractile variations in cardiac output have two distinct effects on intracranial dynamics, temporal changes in pressure and temporal changes in flow within the brain. Open in a separate window. Pulsatility and compliance It has been recognized for quite some time that pressure and flow pulsatility can change with disease; this has been used as a diagnostic tool in a number of areas. The brain as a pulsatile organ Most clinical applications of pulsatility have been outside of the brain, and the cranium presents a unique challenge for measuring pulsatility as well as a unique biomechanical environment for pulsatility.
How pulsatility is measured and key elements of the pulse wave Before proceeding to discuss the pre-clinical and clinical uses of pulsatility measures, it is important to understand the techniques for measuring pulsatility in the brain. Intracranial pressure Monitoring of ICP waves requires placement of a sensor within the skull either in the brain parenchyma or within a ventricle , or in the spinal compartment. Transcranial Doppler ultrasound TCD is used to non-invasively measure flow in the major arteries entering the brain, most commonly the middle cerebral artery, although other cerebral arteries are accessible [ 37 , 38 ].
Magnetic resonance imaging The technique of phase contrast MRI, in which quantitative velocity information is extracted from the MRI image, led to the non-invasive investigation of flow patterns in the brain [ 42 ]. Other aspects of the pulse wave: Pulse wave shape Intracranial pressure or flow waveforms have a unique morphology, and changes in the morphology have also been used as a clinical marker of disease. The intracranial pulse wave - preclinical studies The earliest investigations into intracranial pulse waves, their origin and their changes with disease, date back to the work of Bering in the 's [ 96 , 97 ] and later to Dunbar in the 's [ 98 ].
The intracranial pulse wave - clinical studies Clinical applications: ICP Intracranial pulsatility has been measured clinically for years, ever since the report of Bering in [ 97 ], and until the advent of transcranial Doppler, the only evidence of these pulsations was from invasive pressure monitoring.
TCD TCD flow velocity measurements follow the same trend as pre-clinical studies discussed above, most indicating an increase in PI with pathology [ - ], and good correlation with clinical condition [ , ]. MRI Clinical MRI studies of flow pulsatility have mainly focused on measurements in the cerebral aqueduct because of the high flow velocities, although there are a limited number of studies of flow in the prepontine cistern [ 51 ], at the CCJ [ 53 , ], and in the cervical and intracranial vasculature [ 79 , 81 , , - ].
Future directions With respect to future directions in pulsatility research and its potential clinical use for both diagnosis and prediction of outcome, we would suggest that large-scale clinical trials are needed, with particular attention paid to uniformity in the definition of pulsatility measures to be collected and acquisition methods to be used. Conclusions The fact that everything within the cranial cavity pulsates with cardiac periodicity has been well established and studied over the last fifty years.
Authors' contributions All of the authors contributed to the conception of the review in terms of overall content and focus. Comparison of simultaneous continuous intracranial pressure ICP signals from ICP sensors placed within the brain parenchyma and the epidural space. Is ventriculomegaly in idiopathic normal pressure hydrocephalus associated with a transmantle gradient in pulsatile intracranial pressure? Acta Neurochir Wien ; 6: Compartmental analysis of compliance and outflow resistance of the cerebrospinal fluid system.
Retinal haemodynamics in patients with age-related macular degeneration. Eye Lond ; Arterial pulse wave velocity, Fourier pulsatility index, and blood lipid profiles. Med Sci Sports Exerc. Some aspects of ultrasound in the diagnosis and assessment of aortoiliac disease.
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Renovascular resistance assessed by color Doppler ultrasonography in patients with chronic liver diseases. Value of Doppler ultrasound parameters of portal vein and hepatic artery in the diagnosis of cirrhosis and portal hypertension. Abnormal renovascular impedance in patients with hepatic cirrhosis: Interaction of cardiovascular disease and neurodegeneration: Transcranial Doppler sonography as a diagnostic tool in vascular dementia.
Velocity profiles in the rat cerebral microvessels measured by optical coherence tomography. A nonlinear analysis of the cerebrospinal fluid system and intracranial pressure dynamics. Diagnosis of hydrocephalus by CSF pulse-wave analysis: Hydrocephalus and CSF pulsatility: Clinical and laboratory studies; pp.
Clinical observations on the relationship between cerebrospinal fluid pulse pressure and intracranial pressure. Acta Neurochir Wien ; Changes in intracranial pressure ICP pulse wave following hydrocephalus. Acta Neurol Scand Suppl. Idiopathic normal pressure hydrocephalus: Assessment of childhood intracranial pressure recordings using a new method of processing intracranial pressure signals. Is intracranial pressure waveform analysis useful in the management of pediatric neurosurgical patients? Intracranial pulse pressure amplitude levels determined during preoperative assessment of subjects with possible idiopathic normal pressure hydrocephalus.
Assessment of idiopathic normal pressure patients in neurological practice: Changes in intracranial pulse pressure amplitudes after shunt implantation and adjustment of shunt valve opening pressure in normal pressure hydrocephalus. Intracranial pressure parameters in idiopathic normal pressure hydrocephalus patients with or without improvement of cognitive function after shunt treatment.
Dement Geriatr Cogn Disord. Association between intracranial, arterial pulse pressure amplitudes and cerebral autoregulation in head injury patients. The CSF pulse wave in hydrocephalus. Cerebrospinal fluid pulse wave form analysis during hypercapnia and hypoxia. Fast Fourier transform of individual cerebrospinal fluid pulse waves.
Analysis of intracranial pressure waveform during infusion test. The frequency domain versus time domain methods for processing of intracranial pressure ICP signals. Clinical experience with a continuous monitor of intracranial compliance. Systems analysis of cerebrovascular pressure transmission: Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. Transcranial measurement of blood velocities in the basal cerebral arteries using pulsed Doppler ultrasound: Assessment of intracranial hemodynamics in carotid artery disease by transcranial Doppler ultrasound.
NMR blood flow imaging using multiecho, phase contrast sequences. Phase contrast cine magnetic resonance imaging. Flow dynamics of cerebrospinal fluid: Normal flow patterns of intracranial and spinal cerebrospinal fluid defined with phase-contrast cine MR imaging. Determination of cerebral blood flow with a phase-contrast cine MR imaging technique: Time-resolved 3D MR velocity mapping at 3T: J Magn Reson Imaging. Cerebrospinal fluid flow measured by phase-contrast cine MR.
Phase contrast cine magnetic resonance imaging: Neurosurg Clin N Am. MR imaging of cerebrospinal fluid dynamics in health and disease. On the vascular pathogenesis of communicating hydrocephalus and benign intracranial hypertension. The pathophysiology of the aqueduct stroke volume in normal pressure hydrocephalus: Amplitude and phase of cerebrospinal fluid pulsations: Cerebrospinal fluid dynamics and relation with blood flow: Value of phase contrast magnetic resonance imaging for investigation of cerebral hydrodynamics. Relationship of cine phase-contrast magnetic resonance imaging with outcome after decompression for Chiari I malformations.
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The book is divided into two parts which differ in target and method of utilization. The first part contains the fundamentals of fluid dynamics that are essential for any student new to the subject. This part of the book is organized in a strictly sequential way, i.
The second part of the book is devoted to selected topics that may be of more specific interest to different students. In particular, some theoretical aspects of incompressible flows are first analysed and classical applications of fluid dynamics such as the aerodynamics of airfoils, wings and bluff bodies are then described. The one-dimensional treatment of compressible flows is finally considered, together with its application to the study of the motion in ducts.
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Review The author has succeeded in organizing a comprehensive and still accessible book that, starting from the definition of the concept of fluid touches all the most relevant concepts of the fluid dynamics up to the aerodynamics of bluff bodies and finite wings. To get the free app, enter mobile phone number.