Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome, Finkelmeyer et al, 2018

[Indigophoton]

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200068

 

[Inara]

For those (like me) who don't know what intracranial compliance is:

Intracranial compliance (ICC) represents the change in volume (ΔV) per unit change in pressure (ΔP), and is exactly the inverse of elastance. In other words, ICC determines the ability of the intracranial compartment to accommodate an increase in volume without a large increase in intracranial pressure (ICP).

Compliance= ΔV/ΔP = 1/elastance

In normal conditions (normal intracranial volumes and ICP), there is high intracranial compliance. This explains why, despite having a small increase in intracranial volume (e.g. cerebral haematoma or cerebral oedema), there are minimal changes in ICP values.

The highly compliant nature of the intracranial system can be explained by mechanisms such as:

• CSF displacement through foramen magnum into the paraspinal space
• blood displacement from compressed brain tissue

When these mechanisms are exhausted, further increases in volume are directly reflected as increases in ICP.

https://radiopaedia.org/articles/intracranial-compliance

 

[Jonathan Edwards]

Can anyone understand the physics of this? I cannot see how you measure compliance without a pressure measurement. And the intracranial volume does not change anyway - the cranium is rigid bone and has a fixed volume for all intents and purposes. They seem to be measuring something else but I cannot work out what.

 

[Indigophoton]

According to the paper,

Flow-velocities of the CSF were used to calculate a pressure gradient profile (ΔP(t)/d) as described elsewhere [25].

The reference (abstract below) suggests that there is a method of deducing the intracranial pressure based on using CSF velocity in the Navier-Stokes (fluid flow) equation.

PURPOSE: To develop a noninvasive method for intracranial elastance and intra-cranial pressure (ICP) measurement.

MATERIALS AND METHODS: Intracranial volume and pressure changes were calculated from magnetic resonance (MR) imaging measurements of cerebrospinal fluid (CSF) and blood flow. The volume change was calculated from the net transcranial CSF and blood volumetric flow rates. The change in pressure was derived from the change in the CSF pressure gradient calculated from CSF velocity. An elastance index was derived from the ratio of pressure to volume change. The
reproducibility of the elastance index measurement was established from four to five measurements in five healthy volunteers. The elastance index was measured and compared with invasive ICP measurements in five patients with an intraventricular catheter at MR imaging. False-positive and false-negative rates were established by using 25 measurements in eight healthy volunteers and six in four patients with chronically elevated ICP.

RESULTS: The mean of the fractional SD of the elastance index in humans was 19.6%. The elastance index in the five patients with intraventricular catheters correlated well with the invasively measured ICP (R2 5 0.965; P , .005). MR
imaging–derived ICPs in the eight healthy volunteers were 4.2–12.4 mm Hg, all within normal range. Measurements in three of the four patients with chronically elevated ICP were 20.5–34.0 mm Hg, substantially higher than the normal limit.

CONCLUSION: MR imaging–derived elastance index correlates with ICP over a wide range of ICP values. The sensitivity of the technique allows differentiation between normal and elevated ICP.

 

[Jonathan Edwards]

I suppose I should read through the method papers. But I remain puzzled as to exactly what it is they think they are measuring. I would have thought the elastane of the cranium was largely a matter of how much the medulla and cranial nerves slide in and out of the skull. And I am still unclear what volume changes they are trying to infer pressure changes in response to. Maybe it is the volume change during the cardiac cycle - from arterial systole to diastole. But would this be at all relevant to standing up, when the CSF pressure in the spinal column will change for gravitational reasons etc.

It all sounds very clever but I would like to know how it could explain anything! I am being a bit bear with a sore head here but I am a bit preoccupied with other things this week.

 

[Indigophoton]

I am still unclear what volume changes they are trying to infer pressure changes in response to.

Cerebral blood flow varies with heartbeat. The brain accommodates the blood volume changes by varying the pressure of the cerebrospinal fluid.

They are relying on something called the Monro-Kellie hypothesis, which describes the pressure–volume relationship between intracranial pressure, volume of cerebrospinal fluid (CSF), blood, and brain tissue, and cerebral perfusion pressure:

The Monro–Kellie hypothesis states that the cranial compartment is incompressible and that the volume inside the cranium is fixed. The cranium and its constituents (blood, CSF, and brain tissue) create a state of volume equilibrium, such that any increase in volume of one of the cranial constituents must be compensated by a decrease in volume of another.

The principal buffers for increased volumes include CSF and, to a lesser extent, blood volume. These buffers respond to increases in volume of the remaining intracranial constituents. For example, an increase in lesion volume (e.g., epidural hematoma) will be compensated by the downward displacement of CSF and venous blood.

According to the paper,

For intracranial compliance, a set of three cardiac-gated phase contrast scans were performed to quantify the intracranial volume and pressure change profile across to the cardiac cycle. .... These scans ... were chosen to maximize the sensitivity of the measurements to arterial, venous and cerebrospinal fluid (CSF) flow. Sixty phases of the cardiac cycle were acquired with each scan.

Cerebral perfusion was assessed using flow-sensitive alternating inversion recovery (FAIR) arterial spin labelling (ASL) scans.

The maths,

The change in volume dV is derived from the momentary differences between volumes of blood and CSF that flows into and out of the intracranial vault during the cardiac cycle, and the dP (pulse pressure) is derived from the CSF pressure gradient (PG) waveform, which, in turn, is obtained using the Navier–Stoke relationship...

The change in the ICV during the cardiac cycle [ICV change (ICVC)] is calculated from the net volumetric flow rates as described in (1) using the constraint defined in (2) for scaling the measured venous outflow to match the total arterial inflow,

∆ICVC(t)=[fA(t) − fV(t) − fCSF(t)]∆t. (1)
Σcardiac cycle ∆ICVC(t) = Σ [fA(t) − fV(t) − fCSF(t)]∆t =0 (2)

where fA, fV, and fCSF are the volumetric arterial inflow, venous outflow, and craniospinal CSF flow, respectively.

But would this be at all relevant to standing up, when the CSF pressure in the spinal column will change for gravitational reasons etc.

They do discuss the relevance of posture in making the measurements, and conclude that it's unclear as to whether it's significant, and that it needs further investigation.

It all sounds very clever but I would like to know how it could explain anything!

I wonder if their focus was not so much looking for insight in this case, but maybe for possible avenues for treatment:

...reduced ICC may constitute a risk factor for experiencing symptoms of orthostatic intolerance as it might reduce an individual’s ability for effective cerebral autoregulation. ... If a link between the severity of orthostatic symptoms and ICC can be replicated, this would suggest that patients who experience severe symptoms of OI should be investigated for low levels of ICC. It could then also be investigated whether treatments that raise ICC have ameliorating effects on orthostatic symptoms.

 

[Jonathan Edwards]

Cerebral blood flow varies with heartbeat. The brain accommodates the blood volume changes by varying the pressure of the cerebrospinal fluid.

Well, not quite...

They are relying on something called the Monro-Kellie hypothesis, which describes the pressure–volume relationship between intracranial pressure, volume of cerebrospinal fluid (CSF), blood, and brain tissue, and cerebral perfusion pressure:

Because of this - which is what I think I said was what I thought - cranial compliance is actually zero in practical terms. So these calculations are not about compliance but about convective flow events. So my worry is whether Finkelmeyer actually understands Monro-Kellie?

I ask these questions because these sorts of basic issues about hydrodynamics were relevant to one of my early research areas - the volume control of joint synovial fluid. The textbooks had all got a false assumption in them. Joint fluid has very odd dynamics such that it comes in to the joint through the same route it goes out. There was an assumption that these routes were separate. Physiologists routinely make simple errors like that. Once I had managed to persuade other pshyiologists that the equations lined up differently we found the system collapsed to a simple elegant answer.

What worries me about bringing in a measure of 'cranial compliance' based on pulse waveform is that I cannot see why it should have anything to do with the much slower changes occurring during standing. I realise that rather than being explanatory it might just be exploratory but I would like t get more of an idea as to why it should be thought to lead anywhere in the longer run.

 

[Indigophoton]

So maybe I've completely missed the point. Given that the cranial volume is fixed, I took ICC to refer to the degree of dynamic adaptation that is possible when the volume of some fluid/associated pressure in the head changes. In essence it seemed to be about a balance between quantities of blood and CSF, taking advantage of the brain being connected to the rest of the body to move in/out fluid as required. I assume 'compliance' in this context really refers to, or derives from, the performance of the brain vasculature. Is that not correct?

Why would the change when going from sitting to standing be slow? According to what I've read, cerebral blood flow fluctuates rapidly in response to fast fluctuations in BP. Sit-to-stand tests have been used to assess cerebral autoregulation, CA, by measuring BP and cerebral blood flow. Why would CBV not be influenced by the consequences of BP changes in those with orthostatic intolerance?

Also, apparently, as you probably already know, the autonomic nervous system is thought to possibly play a role in controlling CA on a beat-to-beat cerebral blood flow basis. I'm not at all familiar with the biology (and too brain fogged to read more) but could this be another potential pathway for autonomic dsyregulation to affect/be related to CA/ICC?

 

[Hoopoe]

This may be entirely off topic, but why do I feel pressure in head and a headache when standing up, while also having that feeling malaise and weakness that comes with low blood pressure?

It is possible to have low and high blood pressure simultaneously?

 

[Jonathan Edwards]

When I said sitting to standing would be slow I was referring to the few seconds it normally takes at minimum for orthostatic intolerance to manifest. The shifts in blood and CSF during the cardiac cycle would occur over about 0.7-1.0 seconds as full cycle and return.

Viscoelastic systems with flow, like brain and its fluids, are likely to show resistances or compliances that are very rate dependent and also very non-linear.

 

[Jonathan Edwards]

So maybe I've completely missed the point.

No, I think maybe the authors may not quite have got hold of what they are telling us about. But these things are complicated. My experience is that the important thing is not to accept any jargon as bona fide but treat it like making tea - down to earth things moving about. Equations are particularly beguiling because they may look very convincing but may have the teapot upside down.

 

[Indigophoton]

Equations are particularly beguiling because they may look very convincing but may have the teapot upside down.

Yes, that's one of the frustrating things about not having the biology/medicine background - I don't have the physical feel for it.