Education, tips and tricks to help you conduct better fMRI experiments.
Sure, you can try to fix it during data processing, but you're usually better off fixing the acquisition!

Thursday, June 14, 2018

FMRI data modulators 3: Low frequency oscillations - part II


In the previous post, I laid out four broad categories of low frequency oscillation (LFO) that arise in fMRI data. The first three categories are mentioned quite often in fMRI literature, with aliasing of respiratory and cardiac pulsations being the best known of all “physiological noise” components. In this post, I am going to dig into the fourth category: blood-borne agents. Specifically, I want to review the evidence and investigate the possibility that non-stationary arterial CO₂ might be producing an LFO that is at least as important as aliased mechanical effects. At first blush, this is unsurprising. We all claim to know CO₂ is a potent vasodilator, so we can think of CO₂ in blood as a sort of changing contrast agent that perturbs the arterial diameter – producing changes in cerebral blood volume - whenever the arterial CO₂ concentration departs from steady state.

Why would arterial CO₂ fluctuate? Why isn't it constant? Simply put, we don't breathe perfectly uniformly. If you monitor your own breathing you’ll notice all sorts of pauses and changes of pace. Much of it depends on what you’re doing or thinking about, which of course gets right to the heart of the potential for fluctuations in CO to be a confound for fMRI.

I had hoped to begin this post with a review of CO transport in the blood, and from there to relay what I’ve found on the biochemical mechanism(s) underlying vasodilation caused by CO. But after several weeks of searching and background reading, I still don’t have sufficient understanding of the biochemistry to give you a concise overview. The CO transport mechanisms are quite well understood, it seems. But how a change in one or more components of CO in arterial blood produces changes in the arterial smooth muscle wall, that is a more complicated story. For the purposes of this post, then, we shall have to content ourselves with the idea that CO is, indeed, a potent vasodilator. The detailed biochemistry will have to wait for a later post. For those of you who simply can’t wait, I suggest you read the review articles given in Note 1. They aren’t aimed at an fMRI audience, so unless you are a biochemist or physiologist, you may not get the sort of intuitive understanding that I have been searching for.


First indications that arterial CO might be an important source of LFO in fMRI data

The effects of respiration on BOLD data were recognized in the mid-nineties as an important consideration for fMRI experiments. By the late nineties, several groups began to investigate the effects of intentionally held breaths on BOLD signal dynamics, using as their basis the phenomenon of arterial CO as a vasodilator. Other groups (e.g. Mitra et al., 1997) observed low frequency fluctuations in BOLD data that suggested a vasomotor origin, or found fluctuations in cerebral blood flow (CBF) measured by non-MR means (e.g. Obrig et al., 2000). It wasn’t until 2004, however, that Wise et al. showed definitively how slow variations of arterial CO concentration were related to, and likely driving, low frequency variations in BOLD time series data:
PETCO-related BOLD signal fluctuations showed regional differences across the grey matter, suggesting variability of the responsiveness to carbon dioxide at rest.”
“Significant PETCO-correlated fluctuations in [middle cerebral artery] MCA blood velocity were observed with a lag of 6.3 +/- 1.2 s (mean +/- standard error) with respect to PETCO changes.”

The spatial-temporal dynamics observed by Wise et al. certainly fit a blood-borne agent. That is, we should expect lag variations dependent on the total arterial distance between the heart and the tissue of interest; in their case, the MCA.

Saturday, March 24, 2018

FMRI data modulators 3: Low frequency oscillations - part I


Low frequency oscillations (LFOs) may be one of the the most important sources of signal variance for resting-state fMRI. Consider this quote from a recent paper by Tong & Frederick:
"we found that the effects of pLFOs [physiological LFOs] dominated many prominent ICA components, which suggests that, contrary to the popular belief that aliased cardiac and respiration signals are the main physiological noise source in BOLD fMRI, pLFOs may be the most influential physiological signals. Understanding and measuring these pLFOs are important for denoising and accurately modeling BOLD signals."

If true, it's strange that LFOs aren't higher on many lists of problems in fMRI. They seem to be an afterthought, if thought about at all. I suspect that nomenclature may be partly responsible for much of the oversight. A lot of different processes end up in the bucket labeled "LFO." The term is used differently in different contexts, with the context most often defined by the methodology under consideration. Folks using laser Doppler flow cytometry may be referring to something quite different than fMRI folks. Or not. Which rather makes my point. In this post I shall try to sort the contents of the LFO bucket, and in at least one later post, I shall dig more deeply into "systemic LFOs." These are the LFOs having truly physiological origin; where the adjective is used according to its physiological definition:


The description I pulled up from the Google dictionary tells us the essential nature of systemic LFOs: at least some of them are likely to involve the blood gases. And I'll give you a clue to keep you interested. It's the CO component that may end up being most relevant to us.


What exactly do we mean by low frequency oscillations anyway?

"Low frequency" generally refers to fluctuations in fMRI signal that arise, apparently spontaneously, with a frequency of around 0.1 Hz. The precise range of frequencies isn't of critical importance for this post, but it's common to find a bandwidth of 0.05 - 0.15 Hz under discussion in the LFO literature. I'll just say ~ 0.1 Hz and move on. I added "apparently spontaneously" as a caveat because some of mechanisms aren't all that spontaneous, it turns out.

For the purposes of this post we're talking about variations in BOLD signal intensity in a time series with a variation of ~ 0.1 Hz. There may be other brain processes that oscillate at low frequencies, such as electrical activity, but here I am specifically concerned with processes that can leave an imprint on a BOLD-contrasted time series. Thus, neurovascular coupling resulting in LFO is relevant, whereas low frequency brain electrical activity per se is not, because the associated magnetic fields (in the nanotesla range, implied from MEG) are far too small to matter.

Is LFO the lowest modulation of interest? No. There are physiological perturbations that arise at even lower frequencies. These are often termed very low frequency oscillations (VLFOs) because, well, we scientists are an imaginative bunch. These VLFOs generally happen below about 0.05 Hz. The biological processes that fluctuate once or twice a minute may well be related to the LFOs that are the focus here, but I am going to leave them for another day.

Friday, March 2, 2018

Monitoring gradient cable temperature


While the gradient set is water-cooled, the gradient cables and gradient filters still rely upon air cooling in many scanner suites, such as mine. In the case of the gradient filters, the filter box on my Siemens Trio came with an opaque cover, which we replaced with clear plastic to allow easy inspection and temperature monitoring with an infrared (IR) thermometer:

The gradient filter box in the wall behind my Siemens Trio magnet. It's up at ceiling height, in the lowest possible stray magnetic field. The clear plastic cover is custom. The standard box is opaque white.


Siemens now has a smoke detector inside the gradient filter box, after at least one instance of the gradient filters disintegrating with excess heat. Still, a clear inspection panel is a handy thing to have.

The gradient cables between the filter box and the back of the magnet can also decay with use. If this happens, the load experienced by the gradient amplifier changes and this can affect gradient control fidelity. (More on this below.) The cables can be damaged by excess heat, and this damage leads to higher resistance which itself produces more heating. A classic feedback loop!


The Fluke 561 IR thermometer and a K type thermocouple, purchased separately.

Wednesday, December 13, 2017

COBIDAcq?


WARNING: this post contains sarcasm and some swearing.
(But only where absolutely necessary.)


COBIDAcq, pronounced "Koby-dack," is the Committee on Best Practice in Data Acquisition. It is based on the similarly dodgy acronym, COBIDAS: Committee on Best Practice in Data Analysis and Sharing. I suppose COBPIDAAS sounds like a medical procedure and CBPDAS is unpronounceable, so COBIDAS here we are.

Unlike COBIDAS, however, the COBIDAcq doesn't yet exist. Do we need it? The purpose of this post is to wheel out the idea and invite debate on the way we do business.

Saturday, December 9, 2017

FMRI data modulators 2: Blood pressure


If you conduct fMRI experiments then you'll have at least a basic understanding of the cascade of events that we term neurovascular coupling. When the neuronal firing rate increases in a patch of brain tissue, there is a transient, local increase of the cerebral blood flow (CBF). The oxygen utilization remains about the same, however. This produces a mismatch in the rate of oxygen delivered compared to the rate of oxygen consumption. The CBF goes up a lot while the oxygenation usage increases only slightly. Hence, there is a decrease in the concentration of deoxygenated hemoglobin in the veins draining the neural tissue region, in turn reducing the degree of paramagnetism of these veins that yields a signal increase in a T2*-weighted image. The essential point is that it's blood delivery - changes in CBF - that provides the main impetus for BOLD contrast.


How is blood pressure related to CBF?

The average CBF in a normal adult brain is typically maintained at around 50 ml of blood per 100 g of brain tissue per minute (50 ml/100g/min). The average number, while useful, represents considerable spatial and temporal heterogeneity across the brain. The typical CBF in gray matter is approximately double that in white matter, and there is significant variation across each tissue type arising from tight metabolic coupling. (See Note 1.)

At the local level, blood delivery to tissue is controlled by smooth muscles on the walls of arterioles and capillaries. The degree of vessel dilation, relative to that vessel's maximum possible dilation, is called its tone - the vascular tone. There are mechanisms to expand or constrict the smooth muscles, changing the local blood flow in order to maintain the tight local coupling of CBF to metabolic demand while protecting the vasculature and the tissue against damage that might arise with systemic changes in the blood supply from non-neural mechanisms. The totality of these processes is referred to as cerebral autoregulation. More on the non-neural factors later.

This is all very well, but there is something important missing from this picture. We have neglected to consider so far that the force of blood pumped out of the heart creates a pressure gradient across the arteries and the veins, with the tissue providing a resistance in between. It's this pressure gradient that causes the blood to flow. In fact, simple electrical circuits are a convenient model here. For those of you more familiar with electron flow than blood flow, we can think of the CBF as an analog of electrical current, the pressure difference as a voltage and, naturally enough, the tissue's resistance to flow mimics an electrical resistance. Thus we get:

CBF = CPP / CVR

where CPP is the cerebral perfusion pressure, the net pressure gradient - the driving force - that generates perfusion of brain tissue, and CVR is the cerebrovascular resistance. The CVR is the sum total of all mechanisms exerting control over the vascular tone at a particular location. It isn't easily estimated without detailed knowledge of the processes that might be active. The neurovascular coupling pathways contribute to CVR, for example.

Thursday, October 5, 2017

FMRI data modulators 1: Heart rate


It's 2027 and you are preparing to run a new fMRI experiment. Since 2023 you've been working on a custom 7 T scanner that was developed to mitigate several issues which plagued the early decades of fMRI. Long gone are the thermal shim and gradient drifts of yesteryear, courtesy of an intelligent water cooling system that maintains all hardware at near constant temperature even when the scanner is run flat out. Your scanner also has a custom gradient set with active shielding over the subject's chest. It means the rise time of the gradients is limited only by peripheral nerve stimulation in the subject's face and scalp, not by the possibility of causing fibrillation in the heart. You can use a slew rate four times faster than on the scanner you had back in 2017, meaning distortions of your 1 mm cubic voxels, acquired over the entire brain (including cerebellum!) are minuscule. What's more, your images no longer suffer from translations and shearing because of the subject's chest motion. Your scanner tracks the magnetic field across the subject's head and actively compensates for the effects of breathing. When used with the comfortable head restraint system that mates directly to the receiver electronics - which itself monitors changes in coil loading to ensure the 128-channel array coil doesn't impart its own bias field onto your images - you have finally got to the point in your career where you no longer worry about head motion.

Almost. There's no doubt the hardware of the future could be remarkable compared to today's scanners. Our current scanners are clinical products being used for science rather than scientific instruments per se. However, even if we were to supersede BOLD with a non-vascular "neural current" contrast mechanism, the basic physics of MRI suggests that we will have to consider real brain motion in the future, just as we do today. Perhaps we can differentiate this brain motion from the contrast of interest using multiple echoes or some other trick, but I don't envisage being able to ignore the brain's vasculature entirely, whereas I am optimistic that improved scanner engineering might one day ameliorate the mechanical and thermal instabilities. Real brain motion and regional variation in pulsatility are likely to be biological limits that must be accommodated rather than eliminated.


What are the mechanisms of concern?

We can restrain the subject's skull quite well using a bite bar or a printed case. Inside the skull, however, is a gelatinous blob of brain, highly vascularized, under a small positive pressure (the intracranial pressure, ICP). The brain will tend to throb with the heart rate (HR) as blood is pumped into the brain through the arteries. The arterial network is spatially heterogeneous and so we see heterogeneous motion across the brain. The arteries enter at the base of the brain, causing the entire midbrain and brainstem to move relative to the cortex. Locally, tissue close to large vessels can demonstrate greater displacements than tissue just a few millimeters away. These regional perturbations will arise with a range of delays relative to the cardiac output, as the blood pressure wave migrates from the heart. The greater the distance from the heart, the longer the lag. We'll see in a later post how this phenomenon can be used to estimate blood pressure.

There are also cardiac driven pulsations in the cerebrospinal fluid (CSF). These can be visualized as small displacements of tissue adjacent to the ventricular system as well as in sulci of the cortex. Pulsation in CSF and the changing velocity of blood in large vessels also tend to produce image contrast changes. This isn't real brain motion, of course, but it is a consideration if one is attempting to use local signal properties or overall image contrast to ameliorate regional pulsatility. A new paper by Viessmann et al. provides a timely investigation of the issues, concluding that fluctuations in partial volumes of blood and CSF/interstitial fluid give rise to local T2* changes over the cardiac cycle. So the final complexity is again temporal. The cardiac cycle is itself non-stationary, leading to dynamic changes in the locations of blood, CSF and brain tissue.

Tuesday, August 22, 2017

Fluctuations and biases in fMRI data


In my last post I summarized the main routes by which different forms of actual or apparent motion can influence fMRI data. In the next few posts, I want to dig a little deeper into non-neural causes of variation in fMRI data. I am particularly interested in capturing information on the state of the subject at the time of the fMRI experiment. What else can be measured, and why might we consider measuring it? Brains don't float in free space. They have these clever life support systems called bodies. While most neuroimagers reluctantly accept that these body things are useful for providing glucose and oxygen to the brain via the blood, bodies can also produce misleading signatures in fMRI data. My objective in this series of posts is to investigate the main mechanisms giving rise to fluctuations and biases in fMRI data, then consider ways other independent measurements might inform the fMRI results.

Many causes, much complexity

There are three broad categories of fluctuations or biases imprinted in the fMRI data. I've tried to depict them in Figure 1. At top-right, in a cartoon red blood vessel, is the cascade of physiological events leading to BOLD contrast. Next, on the left, there are perturbations arising from the subject's body. Some of these are direct effects, like head motion, and some are propagated via modulation of the same physiological parameters that give rise to BOLD. Breathing is a good example of the latter. A change in breathing depth or frequency can change the arterial concentration of CO2, leading to non-neural BOLD changes. Furthermore, the breathing rate is intricately tied to the heart rate, via the vagus nerve, and so we can also expect altered brain pulsation. In the final category, depicted in my figure as scanner-based mechanisms at the bottom, we have experimental imperfections. In the last group are things that could be reduced or eliminated in principle, such as thermal drift in the gradients, wobbly patient beds, and resonance frequency shifts across the head arising from changing magnetic susceptibility of the chest during breathing. The thin blue lines connecting the different parts of the figure are supposed to show the main influences, with arrowheads to illustrate the directionality.

(Click image to enlarge.)

Figure 1. Major routes of modulation in time series data in an fMRI experiment. The flow chart in the depiction of a blood vessel, in red, is based on a figure from Krainik et al. 2013 and shows the main events leading to BOLD via neurovascular coupling. Main body-based mechanisms originate on the left, and scanner-based experimental imperfections are depicted on the bottom. All mechanisms ultimately feed into the fMRI data, depicted at center. Yellow boxes contain some of the main modulators of mechanisms that can produce either fluctuations or systematic biases in fMRI data.

Abbreviations: ANS - autonomic nervous system, HR - heart rate, CBVa - arterial cerebral blood volume, CBVv - venous cerebral blood volume, CMRO2 - cerebral metabolic rate of oxygen utilization, CBF - cerebral blood flow, OEF - oxygen extraction fraction, deoxyHb - deoxyhemoglobin, AR - autoregulation, pO2 - partial pressure of oxygen (O2 tension), pCO2 - partial pressure of carbon dioxide (CO2 tension).


As if that wasn't already a lot of complexity, I'm afraid there's more. In the yellow boxes of Figure 1 are some of the main modulators of the underlying mechanisms responsible for perturbing fMRI data. These modulators are usually considered to be confounds to the main experimental objective. I posted a list of them a few years ago. Caffeine is probably the best known. It modulates both the arterial cerebral blood volume (CBVa) as well as the heart rate (HR). We already saw that HR and breathing are coupled, so this produces a third possible mechanism for caffeine to affect fMRI data. There's also an obvious missing mechanism: its neural effects. Some direct neural modulators are summarized in Figure 2, placed in their own figure simply to make this a tractable project. I'll be going back to reconsider any direct neural effects at the end of the series, to make sure I've not skipped anything useful, but my main emphasis is the contents of Figure 1.

Figure 2. Potential modulators of neural activity during an fMRI experiment.



Measuring the modulators

There are about a dozen mechanisms leading to fluctuations in fMRI data. Note that some paths depicted in Figure 1 may contain multiple discrete mechanisms. The figure would be far too cluttered if every mechanism was depicted. Take head motion. It could be foam compressing through no fault of the subject, or it could be the subject fidgeting, or apparent head motion arising from the sensitivity of the EPI acquisition to off-resonance effects (for which there are at least two main contributions: thermal drift in the scanner and chest motion in the subject). I tried to estimate how many combinations are represented in Figure 1 but quickly gave up. It's several dozen. I'm not sure that knowing the number helps us. Clearly, it's an omelette.

So, what can we do about it? Well, there are only so many things one can measure before, during or after an MRI scan, so we should probably start there. In the first set of posts in this series I'll look at non-MRI measures that can be performed during fMRI data acquisition, to track moment to moment changes in some of the parameters of Figure 1. These will include:
  • Heart rate
  • Blood pressure
  • Vascular low frequency oscillations in the periphery
  • Respiration rate
  • Expired CO2
  • Electrodermal activity
  • Eye tracking
  • Head motion

Then, in the next set of posts I'll shift to assessing ancillary MRI measurements that can inform an fMRI experiment, such as:
  • Anatomical scans
  • Baseline CBF
  • Blood oxygenation
  • Cerebrovascular reactivity
  • Calibrated fMRI (which is actually a slightly different way of doing the fMRI experiment, but requires some ancillary steps)

Finally, I'll consider informative, non-MRI data you could capture from questionnaires or relatively simple non-invasive testing. With better understanding, I am hoping that more researchers begin to consider physiology as earnestly as they do the domains involving psychology and statistics.