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.

  • 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.


  • 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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Wednesday, March 4, 2009

Schrödinger's Cat: Probability, Science & Medicine

Atoms with unstable nuclei decay, emitting ionizing radiation, known as radioactivity. We cannot feel ionizing radiation. Small amounts can be detected with devices such as the fabled Geiger-Müller counter. Radioactive atoms are called radionuclides. Numerous radionuclides have been found. They are listed in the table of nuclides. With most types of radioactive decay, the nucleus transforms into another element with new physical and chemical properties. Since we cannot predict when precisely a radionuclide decays, we are left with probabilistic assessments. According to the law of radioactivity (1), the nuclei decay exponentially. The period of time in which half of the nuclei in a sample decay is constant and characteristic for the radionuclide. This period is known as half-life.

(1) N(texam) = N(t0) x 2-texam,

where N(texam) is the number of radionuclides left at time of examination texam. N(t0) is the number of radionuclides at time t0 when we started our test. τ is the half-life.

After ten half-lives, the chance of finding a nucleus still undecayed has become fleetingly small. Only about one in a thousand nuclei is still left in its original form. We may consider the material decayed. However, when half-lives measure tens of thousands of years and the radiation is detrimental to our health, ten half-lives add up to a serious threat for generations to come. That is why the proponents of nuclear power show intense interest in Yucca Mountain.

Applying the law of radioactivity on just one atomic nucleus, our odds of finding this nucleus decayed after one half-live are 1/2 or 50%. That is, we are equally likely to find the nucleus decayed or in its original form. After seven half-lives, the odds to still detect the original nucleus are less than 1/100. We would call this find a rare event. After ten half-lives the odds diminish to roughly 1/1000. We would find the atom undecayed merely once in a thousand tests and perceive this observation as extremely extraordinary. Try it yourself:

half-lives: odds: 1/

Schrödinger's Thought Experiment
The Austrian physicist and Nobel Prize-laureate Erwin Schrödinger always insisted that his was only a thought experiment. He never contemplated carrying it out in practice. Its design was the following:

Method: A Geiger-Müller counter is set up in front of a radionuclide. The radiation emitted when the radionuclide decays produces a voltage spike in the counter. The spike is used to trigger a hammer installed inside an opaque box, housing a cat. The hammer will smash a vial with poison gas, killing the cat.

Question: Is the cat already dead or still alive once one half-life has passed?

Answer: According to the law of radioactivity discussed above, the chances of finding the cat in either condition are equal. We will only know for sure, when we open the box and look.

Discussion: With this experiment, Schrödinger intended to explain the implications of the wave function, he derived to determine the energetic state of electrons in the shells around the atomic nucleus. In analogy to the solutions for his function, the cat could theoretically exist in both possible states alike. That is, the cat could be dead and alive simultaneously, until checking the box resolves the ambivalence.

Schrödinger's contention, though accurate, is difficult for us to comprehend. We like to live in certainty. Einstein believed that uncertainty was the result of our shortcoming in making the correct predictions. In response to the idea that uncertainty naturally exists, he supposedly exclaimed mildly dismayed: "God does not role dice!"

Our ambivalent feelings toward chance become crystal clear, when we are confronted with a diagnosis of cancer and options for treatment. To the question,"Doc, will I live?" the answer may be, "well, the prognosis in cases like yours is not outright brilliant. But, half of the people in your situation are still alive after two years." Analogous to Schrödinger's thought experiment, this means that in two-years time our odds are 1/2.

With bewilderment, we respond, "but, Doctor, I did not ask how many people on average will still be alive when. I wish to know, whether I shall be alive!" The honest physician will conclude, "I cannot answer this question. But experience tells us that your chances are much improved, if you want to live and remain hopeful."

This uncertain answer fully reveals the dilemma of the medical profession. The physician is asked to divine the faring of a patient based on statistical probabilities derived from groups of patients. As often with cancer, the precise causes of the disease may not be known. Only intensive fundamental research will provide us with a more effective grasp on such complex diseases. Only deepening our knowledge of the molecular signaling mechanisms that trigger tumorous tissue growth will permit us to predict accurately, how the cells will grow and what needs to be particularly done to stop them.

For example, researchers using proteomics may be able to uncover differences in the proteins synthesized in cancerous cells. With this knowledge, physicians may be able to decide which group of patients will benefit the most from a particular type of therapy, and further research will unravel the functions of the proteins.

As to Schrödinger's cat, the experiments at CERN's Hadron supercollider will drastically enhance our understanding of subnuclear particles and their interactions. The findings at CERN may perhaps permit us one day to predict the decay of an unstable nucleus, erasing the uncertainty in Schrödinger's thoughts. The experiments may as well prove this goal elusive or even impossible to attain. In any case, the results of the research at CERN will deeply influence how we reckon with the odds in our lives.

It is regrettable that the U.S. partake only on the sidelines in the pivotal experiments. In the late 1980's, the construction of an even larger collider than Hadron, known as the Superconducting Super Collider, was begun in Texas. After hundreds of millions of dollars spent on digging tunnels, the project was aborted. Another several hundred million dollars were spent to fill in the holes already dug.

  • An example for the use of proteomics to reliably predict therapy outcome in lung cancer is in press here: Stuart Salmon and others (2009) Classification by Mass Spectrometry Can Accurately and Reliably Predict Outcome in Patients with Non-small Cell Lung Cancer Treated With Erlotinib-Containing Regimen. Journal of Thoracic Oncology 4 (6) (04/20/09).
  • Cells of some tumors have been found to contain salient genetic mutations. Notably, deletions at the BRAF gene and substitution at the KRAS gene have been found to promote neoplastic growth. Therapeutics are being developed that may compensate for the defects caused by the mutations, arresting tumor growth. Amy Harmon posted an extensive series of articles for the New York Times on the experimental drug PLX4032 used to stop melanoma in people with BRAF mutations. Her first article in this series with the title "A Roller Coaster Chase for a Cure" appeared Feb. 21, 2010. Today, Ron Winslow reports in his post for The Wall Street Journal with the title "Using Biomarkers to Tailor Cancer Treatment" on the preliminary success of similar strategies in targeting lung cancer. Notably, the drug Nexavar was beneficial to people with KRAS mutations. While the use of these drugs has only succeeded in arresting further tumor growth to date, they hold the promise of profoundly improving the odds (04/18/2010).
  • Siddhartha Mukherjee, a hematologist/oncologist at Columbia University, wrote an informative book entitled "The Emperor of All Maladies: A Biography of Cancer" on recent advances in cancer medicine. The author was awarded a Pulitzer Prize for his exploration earlier this month. Note that he specializes in blood cell cancer and the particular experience influences his assessment of the role of stem cells in tumorigenesis and metastasis. Terry Gross interviewed him Nov. 11, 2010, on National Public Radio's Fresh Air in her show with the title "An Oncologist Writes 'A Biography Of Cancer'" (04/22/11).