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Showing posts with label fMRI. Show all posts
Showing posts with label fMRI. Show all posts

Thursday, October 22, 2009

Absolutes, Relatives, Brain Imaging & Steroids

The functional brain imaging methods most commonly used in humans today are functional magnetic resonance imaging (fMRI) using blood oxygen-level dependent (BOLD) signals and the subtractive water method with positron emission tomography (PET). Both procedures record changes in local cerebral blood flow from a baseline. Local cerebral blood flow is associated with energy demands of activated nerve cells. The cells consume glucose sugar and oxygen to process information which cannot be stored in the brain and must be supplied on demand with the blood stream. Hence, blood flow increases with increased nerve cell activity. In the simplest conception of both procedures known as block design, measurements acquired over several minutes of mental activation are compared with measurements acquired during equivalent epochs of rest. The statistically significant difference is considered the result of cerebral activation.

In conventional fMRI, blood oxygen-level dependent signals are used to detected changes in blood flow (Ogawa and others, 1993). With the subtractive water method (Fox and others, 1984), water labeled with 15O, a radioactive positron-emitting isotope of oxygen, is used as tracer that freely diffuses into the brain tissue. The local concentration of the tracer is commensurate with local blood flow and can be imaged in a PET scanner. However, calibration for absolute blood flow is wrought with difficulty and has not found wide-spread application. Because the blood flow is not quantified, the differences between the compared mental states remain relative. That is, cerebral activation is usually expressed in percent difference from the state used as reference or in units of statistically significant difference (statistical parametric mapping).

By contrast, the cerebral glucose consumption is more directly related to nerve cell activity than cerebral blood flow. The deoxyglucose method of Sokoloff and others (1977) permits us to measure the local cerebral rate of glucose utilization. Deoxyglucose is an analogue to glucose that accumulates in the brain tissue commensurate with glucose consumption. Tagging deoxyglucose with 18F, a radioactive positron-emitting isotope of fluorine, the tracer's accumulation in the brain can be imaged with PET. The [18F]fluorodeoxyglucose method, therefore, provides a snapshot of the brain's energy consumption (Reivich and others, 1979). Although this snapshot needs 90 minutes to develop because of the tracer kinetics involved, the procedure constitutes an indispensable tool for the detection of long-term, pseudo-stationary changes in absolute cerebral metabolic activity as a consequence of disease or trauma. Below, I discuss one example.

After the collapse of the regime of Nicolae Ceauşescu at the end of 1989, U.S. parents began to adopt children from Romanian orphanages. The children had been kept in circumstances of great depravity, producing profound behavioral problems similar to autism (American RadioWorks report, 2006). Visiting scientists reported behavioral patterns resembling those the eminent American psychologist Harry Harlow had so aptly described in primates raised in isolation and with surrogates.


Although the adoptees were brought to the U.S. at very young age, some developed cognitive and behavioral differences, including impulsive reactions as well as attention and social deficits, in the years after their arrival.

Research at the orphanages provided evidence that the children had persistently augmented levels of cortisol n their blood stream as a result of the severe stress they endured (Carlson and Earls, 1997). Cortisol is a known steroid stress hormone produced in the adrenal glands and can fundamentally affect brain maturation. The hormone suppresses the activity of glia. A type of glia, astrocytes, helps regulate the extracellular glutamate concentration. Glutamate constitutes the most prevalent excitatory neurotransmitter in the brain, playing a major role in the stabilization of connections between nerve cells during brain maturation. Elevated concentrations of extracellular glutamate can trigger pre-programmed cell death known as apoptosis, otherwise occurring only during early stages of brain development. Presumably, the orphans' excessive stress-related exposure to cortisol led to modifications of nerve cell networks, underlying the children's behavioral differences. Imaging the brain's energy consumption provided a method to uncover whether and where nerve cell activity changed in cerebral cortex as a consequence of the children's stay in the orphanages. 

Using the fluorodeoxyglucose method, Chugani and others (2001) could show that the use of glucose was drastically reduced in the cerebral cortex of the orphans enrolled in the study, particularly in temporal and prefrontal cortical areas and in structures of the limbic system, notably the amygdala. The cortical regions are involved in executive functions and short-term memory crucial for social behavior and affect. The amygdala play an important role in fearful reactions. The observed reductions in energy consumption could not have been detected with the standard fMRI or PET procedures discussed above. The fluorodeoxyglucose method, hence, constitutes the procedure of choice when the fundamental metabolic state of the brain is in question.

Addendum
  • Take some time and listen to this show on National Public Radio's This American Life with the title "Unconditional Love". The first half of the show is about an orphaned Romanian boy adopted by an American couple at the age of eight. It demonstrates in great clarity the at times overwhelming difficulties the family faced to remedy important steps of personality development that were missed early in the boy's life. Finally, the challenges were overcome with passion and a professional attitude. It is reassuring to find out that success is possible (10/23/10).

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Sunday, April 19, 2009

Gustav Fechner & Functional Brain Imaging

Today we celebrate the birthday of Gustav Theodor Fechner. He was born in 1801. Anecdotes have it that he was a late-night owl and that, as a young student, he liked to stay in bed daydreaming in the mornings and was notoriously tardy even for ten-o'clock c.t. lectures (Boring EG, 1970). In the German academic system, the suffix c.t. stands for cum tempore and means that the lecture actually begins fifteen minute past the hour.

He must have spent his time with the right thoughts. At the age of 34, he had completed his M.D. and Ph.D. degrees and was tenured as full professor on his way to become one of the first and most eminent experimental psychologists. He believed that the physical world and our perception of it were complementary and set out to find a mathematical relationship between the physical world and its mental image.

While Fechner began to explore methods to quantify mental work, he became aware of Ernst Heinrich Weber's studies. Weber had asked blindfolded participants to compare packages of differing weight placed in each hand. He observed that the smallest weight that could be judged as different changed in fixed proportion with the weight of reference. The heavier the reference weight, the greater the difference in weight had to be to be noticed. The reported change in sensation Δs was a function of the ratio between the difference in weight Δw and the reference weight W multiplied by a factor r:

(1)    f(Δs) = r x  Δw/W

Integrating function (1) and substituting weight for stimulus R results in:

(2)    f(S) = r x ln(R) + Smin

where sensation S is a function of the natural logarithm of stimulus R multiplied by factor r plus a constant Smin which constitutes the smallest noticeable difference in R. Hence, sensation S increases in direct proportion with the logarithm of stimulus R with the slope of factor r. Consequently, stimulus magnitude had to be doubled for the increase to be noticed.

In reverence of Weber's work, Fechner called the direct proportionality between sensation and the logarithm of stimulus strength Weber's law, proposing that the relationship may apply to all senses. Confirming his hypothesis, he could provide evidence that Weber's law adequately described the relationship between perceived luminosity and the brightness of stars. He believed that the law might open ways to indirectly measure mental processes, trailblazing a science of quantifying mental activity. Alas mind work remained inferred from the participants' judgment. In acknowledgment of the pioneering contributions to experimental psychology of both men, the law is known as Weber-Fechner law today.

One hundred-fifty years later, the direct measurement of mental processes remains elusive. However, methods have been found to measure cerebral work. Brain cells utilize glucose and oxygen to process information. Both have to be supplied by blood flow on demand, since they cannot be stored in the brain tissue. Thus, local cerebral blood flow increases with the increase in nerve cell activity.

Since the 1940's, Seymour Kety, Lou Sokoloff, and others were working out methods to measure local cerebral blood flow with radioactive tracers, initially at the University of Pennsylvania and later at the National Institutes of Health (Sokoloff, 2000). Around 1970, Lou Sokoloff and others succeeded in developing a method with which the rates of local cerebral glucose utilization could be determined in animals (Sokoloff and others, 1977).

With the advent of Positron Emission Tomography (PET), both methods became widely used in humans. Since then, numerous studies have demonstrated that brain work and blood flow indeed increase in logarithmic proportion with the magnitude of stimulation. Electrical nerve cell discharges known as spikes encode stimulus magnitude. My colleagues and I observed with micro-electrode recordings from nerve cells in the cerebral cortex that the cells are limited in their ability to increase the spike rate with increasing frequency of stimulation. Instead, they dynamically scale down their responsiveness with increasing frequency, while continuing to respond time-locked to the stimuli (Melzer and others, 2006). This ability, known as gain control, may underlie the logarithmic relationship between sensory stimulus, brain cell response and mental perception.

Combining PET with functional magnetic resonance imaging (fMRI), Dettmers and others (1996) were able to show a tight association between stimulus-related increases in local cerebral blood flow measured with PET and the blood oxygen level-dependent (BOLD) signal measured with fMRI. Hence, modern non-invasive tomographic brain imaging methods support that the law of Weber and Fechner may apply to brain work. This is not exactly the outcome Professor Fechner had in mind, but he would certainly find the findings exciting, were he still alive today.

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Tuesday, March 31, 2009

fMRI III: Religiosity & Brain Activation

The first installment of my trilogy on functional magnetic resonance imaging (fMRI) was published on Mar. 23, 2009. In the second installment, I discussed a study with a simple task design that yielded unequivocal results (Harrison and Tong, 2009). The present post contains the concluding essay of this trilogy. The tasks in that study involves abstract ideas, the judgment of which lie very much in the eye of the participant. Animal models that permit us to examine the nerve cell mechanisms underlying the observed cerebral activation are unavailable. Thus, the findings are more open to interpretation.

Dimitrios Kapogiannis and others at the National institute of Neurological Disorders and Stroke examined statistical associations between cerebral activation and religiosity, that is one's personal attitudes toward religious believes. The findings of this study were published online in The Proceedings of the National Academy of Sciences on Mar. 9, 2009, and the principal investigator discussed them with Jon Hamilton in a segment entitled "To The Brain, God Is Just Another Guy" on National Public Radio's All Things Considered the same day.

The study consisted of two parts. For the first part, the researchers recruited 26 people who proclaimed faith in a god to varying degree. The recruits were adults of both sexes with post-secondary school education. The participants were required to answer questions and score their sentiments concerning their (1) relational (2) emotional and (3) doctrinal/experiential appreciation of God. Statistical multi-factorial linear modeling was used to isolate three factors that best differentiated the participants' answers, quantifying their religiosity. The factors were then used to correlate profiles of cerebral activation with the profiles of answers typical for each aspect of religious belief.

For the second part, 40 participants of similar background as recruited for the first part answered the same questions, while their cerebral activation was mapped with fMRI. The factors that were associated strongest with the types of answer in the study's first part were used to determine the tightness of association between the recorded cerebral activation and the participants' religiosity. The researchers found foci of activation in all lobes of cerebral cortex. Local differences in activation were statistically significantly associated with the three types of question, regardless of religiosity. The observed regions are known to be engaged in higher cognitive processes:

  1. Only statements concerned with God's perceived lack of involvement in our lives influenced cerebral activation statistically significantly. Foci of activation were found in the frontal, temporal, occipital and parietal (precuneus) lobe on the right hemisphere as well as the left inferior frontal gyrus.
  2. Statements concerned with emotional affect influenced cerebral activation in the right frontal, (God's love) and the left temporal lobe (God's anger).
  3. Statements concerned with doctrinal religious knowledge influenced cerebral activation in the cingulate gyrus as well as in regions of the temporal and parietal lobes. Statements concerned with experiential religious knowledge affected cerebral activity in the parietal (precuneus), frontal, and occipital lobes, particularly in areas of early processing of visual input, that is primary (V1) and secondary visual (V2) cortex in both hemispheres. Occipital visual areas are activated during visual mental imagery, that is while seeing in front of your mind's eye.
Cerebral activation did not co-vary statistically significantly with religious or non-religious, except in the precuneus of the parietal lobe, the middle occipital gyrus of the occipital lobe and the middle frontal gyrus of the frontal lobe on the left hemisphere. In most people language is processed on the left hemisphere. However, a direct statistical comparison between the  religious and the non-religious did not yield any significant differences in cerebral activation.

The involvement of the precuneus in the processing of religious ideas is of note. This region of the parietal lobe is located on the inner surface of the cortical hemisphere adjacent to the cuneus of the occipital lobe and opposite angular gyrus at the temporoparietal junction on the outer surface of the cortical hemisphere. The cortical areas processing hearing, vision and touch meet at angular gyrus. Recording electrical nerve cell activity in in this part of cortex of monkeys, the eminent Italian neuroscientist Giacomo Rizzolatti and his colleagues found nerve cells that become active when the monkeys see their actions reflected in a mirror. Moreover, they were activated when the monkeys saw someone imitating their behavior. Rizzolatti named these nerve cells mirror neurons. He suggests that they are dedicated to processing shared experience, discussing the implications for the mind in a recent book entitled "Mirrors in the Brain: How Our Minds Share Actions, Emotions, and Experience". 

Foci of activation were found in this region in my own studies, when people with severe visual disabilities read Braille with their finger tips. I have described the findings in my post dated Dec. 9, 2007. Recently, this area has been implicated in out-of-body experiences (Arzy and others, 2006). Sandra Blakeslee reported on this discovery in her article entitled "Out-of-Body Experience? Your Brain Is to Blame" for The New York Times, published online Oct. 6, 2006. Taken together the observations above suggest that the regions in the posterior parietal lobe at the junction with the occipital lobe and the parietal lobe are engaged in the processing of language, thought, and self-consciousness, i.e. functions crucial for a brain-based Theory of Mind.  

The fact that Kapogiannis and others (2009) did not find a difference in brain activation related to religiosity may not be surprising. It is highly questionable whether faith in God has the same meaning to all faithful, even if they claim to believe in a god most fervently. Our concepts of God and the doctrine associated with the belief vary and may remain elusive. The most homogeneous group of religious believers to recruit from may consist of monastic clergy. However, even the most devout may carry a grain of doubt. As we know from her private correspondence with Pope John Paul II, Mother Theresa devoted her life to charitable work in the search of God, only to worry deeply that He might not be there in the end.

Perhaps, it was impossible to compose a sample in which the prevalence of the religious and non-religious is balanced. According to a recent Fox News poll, 92 percent of Americans believe in God, 85 percent in heaven and 82 percent in miracles. Furthermore, according to The Economist, roughly 50 percent of Americans believe that the theory of evolution is false. Under these circumstances, the non-religious may have been underrepresented in the sample, providing too small a contrast to permit the researchers to ascertain differences in cerebral activation between the religious and the non-religious.

The findings of this study could affirm, however, that particular networks of nerve cells distributed across cerebral cortex represent specific types of concepts detached from any one sense, though distinct activation patterns for the faithful remained elusive. The loci of spirituality eluded our grasp once more.

Addenda
  • You may wish to watch Rizzolatti's discovery in a video clip shown on "Charlie Rose Brain Series Episode Four: The Social Brain" originally aired Jan. 19, 2010. The video begins 15:36 minutes into the broadcast. The gushing sound is produced with an audio-monitor that tracks electrical nerve cell activity recorded from thin micro-wire electrodes implanted in the monkey's cerebral cortex. Note that the nerve cell activity increases when the monkey reaches for food as well as when the trainer mimics reaching for food (09/08/10).
  • In his book "Principles of Neurotheology", Andrew Newberg strives to lay out a foundation for neurotheology. Listen to this interview by Neal Conan on National Public Radio's Talk of the Nation with the title "Neurotheology: This Is Your Brain On Religion" broadcast yesterday (12/15/10).

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Friday, March 27, 2009

fMRI II: Memory of Simple Stimuli & Brain Activation

This post constitutes the second installment of my trilogy of essays on recent findings of note with functional magnetic resonance imaging. I introduced this series with my post dated Mar. 23, 2009.

In today's post, I discuss a study published online in the journal Nature (2009) on Feb. 18, 2009. Stepheny Harrison and Frank Tong examined where in visual cerebral cortex information may be retained, permitting us to recall visual cues after they disappeared from view. The selection of suitable participants was straight-forward. Alert college students with passable vision sufficed. No confounds were expected from this sampling bias.

The participants were asked to accomplish a simple and robust delayed orientation discrimination task while their brains scanned. That is, sinusoidal gratings consisting of parallel stripes of dark gray with fading edges were shown at two different orientations on a light gray background for fractions of a second. Then a number was flashed on the screen, instructing the participants whether the first or the second grating was to be remembered. After a pause of 11 seconds, a third grating was shown a few degrees rotated against the preceding ones. The participants were required to decide whether this grating was shifted clockwise or counter-clockwise against the orientation of the one they were previously asked to remember. Functional images were acquired for 32 seconds in total.

With this protocol, the participants were exposed to differing information content at constant stimulus intensity, permitting the researchers to detect memory-related changes in local blood flow. As control, the participants were exposed at random to dissociated letters and gratings. In addition, flickering dots were presented at the center of the screen to map the representation of the visual field in cerebral cortex. Much variability in the detection of the stimulus was not anticipated. Thus, the number of participants could be held small. Only six people were needed in this study to obtain statistically significant results. The concepts used in this study are built on a broad body of knowledge on the precise nature of the cortical processing of visual stimuli obtained from research with non-human primates and other animals. This knowledge permitted the investigators to develop a firm working hypothesis for their study. Conversely, their conclusions can be tested in the animal models that provided the basis for the investigators' hypothesis, permitting us to examine the nerve cell mechanisms underlying their findings. This is the strength of the present study.

Gratings can be presented with great temporal accuracy. Nerve cells in the primary visual (V1) area, where visual input feeds into cerebral cortex, respond robustly to this type of stimulus. In addition to V1 cortex, three other  occipital lobe areas (V2-V4) are known to contain nerve cells responding to gratings. Nerve cells in areas V1 and V2 are narrowly tuned to specific angles of orientation, that is they become most active when an edge of a particular orientation passes over the part of the visual field that they are sensitive to. However, the nerve cell response ceases within less than a second. One hypothesis posits that sustained nerve cell activity in subsequent processing areas may help retain information about the vanished stimulus.

In order to test this hypothesis, Harrison and Tong compared blood flow changes in areas V1, V2, V3, and V4. Cerebral blood flow increased in these areas within seconds after the onset of the first grating. Though the magnitude varied locally, the differences were not statistically significant. However, the timing and the duration of the change in blood flow between 6 and 10 seconds after the first grating was presented provided a temporal signature with which Harrison and Tong were able to infer the orientation of the grating to be remembered. They were able to identify such orientation-specific temporal signatures in all four visual areas, providing evidence that the memory of peculiarities of transient visual stimuli can be maintained at early stages of information processing in visual cortex.

The elegant simplicity of the design of this study profoundly facilitated the perspicuity of its findings. Based on their observations, Harrison and Tong suggest that local excitatory and inhibitory nerve cell connections may produce sustained, oscillating nerve cell activity, retaining the memory of the orientation of the gratings. This hypothesis can be tested. Recordings of local electrical nerve cell activity from the scalp (EEG) or associated changes in magnetic field strength (MEG) could provide evidence for such activity.

A role for higher order areas in the parietal and frontal lobes known to be involved in memory yet remains to be established. The authors note that compared with the direct response to the gratings, memory-related activation was substantially diminished. As I pointed out in the initial post of this sequel, these areas may well have been activated even less, hidden from examination under threshold.

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Monday, March 23, 2009

fMRI I: Blood Flow & Mental Processing

Functional magnetic resonance imaging, or fMRI for short, is a non-invasive method with which changes in local cerebral blood flow can be viewed superimposed on anatomical reconstructions of the brain in humans. The spin axes of the nuclei of hydrogen atoms are aligned upright in a strong magnetic field. Short radio pulses deflect the spin axes. Small discrepancies in the time that the nuclei take to newly upright their axes are dependent on the blood oxygenation. fMRI uses blood oxygen level-dependent (BOLD) signals. Brain tissue cannot store the oxygen and sugar brain cells need to function. Therefore, local blood flow increases when nerve cells start processing information and the blood oxygen level rises. Conversely, blood flow diminishes when nerve cell activity is inhibited. With fMRI, scientists exploit the relationship between nerve cell activity and blood flow to reconstruct functional cerebral activation maps. It is important to note that, while nerve cells respond to sensory stimulation within fractions of a second, the blood flow response is slower, taking about two seconds to change. Moreover, more than 10,000 nerve cells must change activity in order to measurably affect blood flow. This is the estimated number of cells (Rakic, 2008) in the smallest volume of cortical tissue in which my colleagues and I could detect a stimulus-related change in BOLD signal at 4.7T (Sachdev and others, 2003). Because the detectable blood flow changes result from the energy requirements of such large populations of nerve cells, we do not know whether the observed changes stem from a high activation of a select subpopulation of particularly responsive nerve cells or from a low activation of a large population of moderately-activated cells. A small number of highly activated nerve cells may introduce a significant partial volume effect into our measurements.

Since Ogawa and others (1993) at Bell Laboratories and Kwong and others (1992) at the National Institutes of Health independently discovered fMRI in the early 1990's, the method has become widely used in the neurosciences. Psychiatrists and psychologists have developed a large body of knowledge on the location of stimulus- and task-related activation in cerebral cortex.

The fMRI signals detected during a scanning session are very dynamic. Signal strength may vary in a wide range. Many repetitions of data collection are needed. As a consequence, brain activation maps obtained with fMRI are rendered from complex statistical analyses and, therefore, are probabilistic. Taking signal strength and variability into consideration, thresholds need to be defined, below which a change in blood flow is no longer considered relevant. Conversely, regions with blood flow above threshold, are often heralded as "lit up". This division in all or nothing imposes limitations on the interpretations of the findings of such studies which I illustrate with an analogy below.

I used to live in the Lemanic region of Switzerland. The airport to fly in is Cointrin near Geneva. Peering through the window on the approach to Cointrin in November, the observer may conclude more often than not that the Lemanic region consists of an arctic plane stretching from a low mountain range on one side to the high peaks of the Mont Blanc massif on the other. Then, the airplane descends onto the plane, which turns out to consist of thick clouds. Once the layer is penetrated, the observer is surprised to detect a diverse landscape with a large crescent-shaped lake surrounded by ridges of many more mountains. There are cities and towns. There are forests, vineyards, fields and ponds. One glance cannot comprehend the multitude. The observer has to pay attention to one cue at a time.

Analyzing fMRI data consists of a similar experience. Potentially pertinent information remains undiscovered, hidden under the clouds of statistical thresholding. We are pressed to ignore the landscape under the clouds, because of its transience. The profiles change from glance to glance, escaping our scrutiny. We lack the tools of comprehension. Striving for simplicity, we resort to thresholding.

However, the brain areas with the strongest and most statistically significant activation may not be the most instrumental for the mental processes under investigation. In fact, the regions of cerebral cortex that may be involved in making decisions, taking risks, and making plans commonly receive input from multiple senses. The input has been preprocessed in the primary areas, that is the cortical regions first to receive the information from sensory organs. Moreover, the nerve cells in the higher order areas are subject to feedback and re-entrant input, activating the nerve cells with delay. The comparatively small contribution of the stimulus and the delay in nerve cell responses may result in activation too feeble and incoherent for pushing the region above threshold. This complication may pose the greatest impediment in fMRI of higher brain function.

Apart from the statistical variability inherent in the method, the selection of the participants and sample size decisively influence the outcome of a fMRI study. Drugs are commonly tested on more than 1000 patients in phase III clinical trials before the FDA considers approval [Zeke Ashton (2000) The FDA and Clinical Trials: A Short History, THE BODY]. In a widely publicised study (Maggie Fox's and Xavier Briand's post entitled "Brain differences mark those with depression risk" on Reuters, Mar. 23, 2009; Roni Caryn Rabin's post entitled "Study Links Depression to Thinning of Brain’s Cortex" in The New York Times, March 24, 2009), more than 100 participants needed to be recruited to demonstrate a thinning of the cerebral cortex in people predisposed for depression. Social scientists commonly incorporate the responses of 2000 and more participants in their analyses to be able to provide answers of significance. By contrast, fMRI studies on fundamental questions will hardly ever reach the enrollment necessary for assessments on such large-scale because of forbidding cost. Careful consideration is necessary to determine whether a minute difference is located in an area important enough to warrant continued enrollment. In addition, the investigators have to ensure that the participants constitute a representative sample for the question of study, differing only in the feature to be examined. Sampling bias and co-linked differences may introduce systematic errors, leading to observations the underlying mechanisms of which can not be disambiguated.

In the next two essays of this trilogy, I discuss two recent studies illustrating the achievements accomplished with and the limits of fMRI. The underlying neural mechanisms for the findings of the first study could be explored in animal models. By contrast, no animal models are readily available for the findings of the second study. The installments were published Mar. 27 and Mar. 31, 2009.

Addenda

  • Yesterday, National Public Radio's All Things Considered broadcast the third installment of Barbara Bradley Hagerty's journalistic journey into spirituality and the brain entitled "Prayer May Reshape Your Brain...And Your Reality". The description of the scientific methods, on which the findings portrayed in this segment were based, was superficial by any standards. The brain does not light up. The compounds used to image cerebral activation with single photon computed tomography (SPECT) are not dyes. They are radioactively-labeled tracers that accumulate in the brain according to local blood flow. Local blood flow is coupled to energy metabolism. The energy metabolism fluctuates with nerve cell activation. The inaccuracies of explanation in this report degrade the scientific validity of methods carefully developed for the use in diagnostic medicine, discrediting the scientific merit of the studies involved (05/21/09).
  • On Jun. 30, 2009,  Public Broadcasting Service's Nova premiered a show on musicophilia with Oliver Sacks entitled "Musical Minds". I have written about Professor Sacks' work on musicophilia in my post dated Jan. 30, 2008. In the video extra accompanying the show, he is undergoing fMRI while listening to pieces of music composed by Bach and Beethoven. Although Professor Sacks confessed his confusion about the provenance of the pieces, fMRI rendered distinctly more activated brain regions in response to the piece by Bach - his favorite - than to the piece by Beethoven. The lead imaging scientist concluded that "your brain can distinguish them, even when you don't!" Such discrepancies are difficult to reconcile. The part was excluded from the show (07/02/09).
  • Today, Jon Hamilton reported in a segment entitled "False Signals Cause Misleading Brain Scans" broadcast on National Public Radio's All Things Considered on the findings of two recent scientific studies published in the journals Nature Neuroscience (Kriegeskorte and others, 2009) and Perspectives on Psychological Science (Vul and others, 2009). The studies demonstrate that recurrent analyses of the same fMRI data, known as double dipping, can produce statistically significant, false positive brain activation (07/07/09).
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Friday, January 23, 2009

Imaging Discord in the Brain

The advent of functional brain imaging has revolutionized the fashion in which psychologists and psychiatrists look at the brain. The pictures of behavior-related cerebral activation provide unprecedented information leading to new hypotheses about the workings of our mind.

However, it is of utmost importance to keep in mind that non-invasive functional brain imaging methods do not allow us to record nerve cell activity directly. With positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), the most-frequently used procedures detect changes in local cerebral blood flow while the participants are exposed to sensory stimulation or execute tasks. Brain cells need sugar and oxygen to fuel the chemical reactions necessary for information processing. Both resources cannot be stored in the brain and thus have to be delivered on demand. Hence, local blood flow increases when nerve cells are activated, resulting in a tight association between nerve cell activity and blood flow under normal physiological conditions.

The molecular mechanisms that couple blood flow to nerve cells activity are not yet fully understood. Glutamate constitutes the predominant excitatory neurotransmitter in the cerebral cortex. This neurotransmitter, its precursors and metabolites as well as its cellular receptors may play a crucial role in the coupling of the two events. However, molecules unrelated to glutamate may also be important. Nitric oxide (NO) and adenosine are known to influence the blood flow response.

In addition to our lack of knowledge on the coupling between the nervous and the vascular response, blood flow measurements inherently cover a volume of brain tissue and do not permit us to identify precisely which nerve cells drive the observed change in flow.

In this week's issue of the journal Nature, Kerri Smith informs us on new findings relevant to the interpretation of functional brain imaging. Yevgeniy Sirotin and Aniruddha Das demonstrate the consequences of the uncertainties discussed above in a letter to Nature entitled "Anticipatory haemodynamic signals in sensory cortex not predicted by local neuronal activity" (Nature 457:475-479). The authors used optical imaging for the fine-grain mapping of changes in blood flow in exposed primary visual cortex of monkeys. The animals were trained to react to a small visual cue. As anticipated, blood flow increased locally in visual cortex after stimulus onset, and the researchers could record concomitantly increased nerve cell activity with wire electrodes inserted into the brain tissue at this location.

Remarkably, blood flow also increased, when the monkeys expected the visual cue to appear, but it was not presented. The anticipation alone was sufficient to significantly increase the local blood flow. By contrast, Sirotin and Das were not able to detect any increase in nerve cell activity that could be related to the anticipatory increase in blood flow.

The apparently discordant findings may not be entirely surprising. The monkeys were accustomed to treats as reward for their participation. Their readiness for the task may have activated neuromodulatory inputs to visual cortex that remain sub-threshold under ordinary conditions and do not trigger nerve cell activity directly, but facilitate the nerve cell response to the imminent stimulus. How such sub-threshold nerve cell signals may increase local blood flow remains an open question.

The discrepancy between blood flow and nerve cell activity Sirotin and Das observed suggests that blood-flow based brain imaging data must be considered with utter prudence, when complex behaviors are examined that involve the subjects' active participation and anticipation. The findings should caution those who strive to correlate patterns of cerebral blood flow with socio-affective mental disorders and criminality in the hope of developing novel predictors for our actions.

Neurolaw is an attempt to associate patterns of brain activity with criminal behavior. Terry Gross interviewed the eminent American neuroscientist Michael Gazzaniga on this issue on National Public Radio's Fresh Air broadcast July 28, 2008. I once wrote down my thoughts on this idea in secret ink. If you wish to spare a few minutes, click on the video, let the magic unfold and enjoy!






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