Brainiacs: Natelson and Shungu Take On the CFS Brain

By K. Kimberly McCleary

brain-300x300A recent guest post, “CFS: Is It All in the Brain?”, by Benjamin Natelson, M.D., generated a lot of interest and excitement about his new study, for which funding of $379,000 was recently announced by the National Institutes of Health. This study is a collaborative effort between Dr. Natelson’s group at Beth Israel Medical Center and the MRI Research laboratory of Dikoma Shungu, Ph.D., at Weill Medical College of Cornell University, where Dr. Nora Weiduschat in his group will oversee the study as a Co-Principal Investigator.

I talked with Dr. Natelson (identified as BHN in the Q&A) and Dr. Shungu (DCS) about the study and their work together. Here’s what I (KKM) learned.

KKM: How did this collaboration come about?

BHN: About three years ago, shortly after I moved my clinical practice and research activities to the Beth Israel Medical Center in Manhattan, Dr. Shungu contacted me to seek my collaboration to serve as a clinician with CFS expertise on grant proposals that he was planning to submit to the CFIDS Association and to the NIH to continue his brain imaging studies of interesting chemical changes that they had found in people with CFS. I accepted enthusiastically and we have been active and close collaborators since.

KKM: In your new study, you will set out to test one group of well-characterized CFS subjects for several different findings you and others have reported in earlier studies. First, some basics. How many CFS subjects will you enroll in the study? Will there be a control or comparison group?

BHN: We will study 36 carefully characterized CFS patients. There will also be 18 healthy people enrolled. For our studies, the healthy people will be on no medicines other than birth control pills or those who are on stable thyroid treatment.

KKM: Case definition and various symptom criteria have received intense scrutiny in the studies looking for evidence of XMRV infection in CFS patients. What are the case defining characteristics you’ll assess in subjects for inclusion in the study?


Benjamin H. Natelson, M.D.

BHN: We will continue to use the 1994 CDC case definition, but modified to make the patient pool less varying. To do this, we have inserted a symptom severity criterion that was lacking in the original case definition. Patients will have to report having “substantial” problems with both their fatigue and their CFS-related symptoms in the month prior to intake. And second, they will have to have endorsed brain fog, unrefreshing sleep and increased symptoms with minimal exertion – again as producing at least “substantial” problems – to be included.

KKM: You have stated your belief that CFS is the result of dysfunction in the brain. To test that idea, you will evaluate subjects using three very different techniques to look for brain dysfunction:
(a) objective neuropsychological testing to assess cognitive function;
(b) measuring the biochemical composition of spinal fluid samples; and
(c) measuring regional cerebral blood flow and ventricular lactate by magnetic resonance imaging and spectroscopy.

Most individuals with CFS are eager to participate in research studies, but this seems like a pretty rigorous battery of tests. What can volunteers expect in terms of the amount of time, over what period of days, it will take to complete all the tests?

BHN: Because one of the goals of the study is to look at the relations among these test results, we hope to do all the studies within a short time frame. If a patient is up to it, we could collect all of these data in one study day. The imaging will be done at Cornell and will take about an hour and a half. Getting from Cornell to Beth Israel will take about 20 minutes. Then, the remaining testing will be done at Beth Israel as follows:  the neuropsych testing will take about 30 minutes and the spinal tap another hour. If this is too much for a patient volunteer, we would hope to complete collecting data over two visits within the same week.

KKM: Brain imaging tests can be uncomfortable, due to the closed-in nature of some machine designs, the need to be injected with contrast solution, or the loud noise from magnets. Dr. Shungu, is there anything invasive about the MRS testing that will be done in this study? Has the scan been well-tolerated by the CFS patients you’ve tested in earlier studies?


Tesla 3.0 MRI at Weill Cornell

DCS: The type of brain imaging scans that we do, which are just like standard MRI scans, have been well tolerated by almost all the CFS patients we have enrolled over the past six years. The scans are very safe because they do not use any radioactive material, nor do we require the injection of contrast agents or dyes. I, in fact, have volunteered for similar brain scans, which can last up to one hour, and even with the loud banging noise that the scanner makes, I usually fell asleep within the first five to 10 minutes, as scanner noise becomes quite monotonous. Our experience is that most of the patients also tend to fall asleep during these scans, which we think is another factor for why most have found the studies tolerable. The only aspect of the scans that is difficult to tolerate is claustrophobia, because one has to be enclosed in the long and narrow doughnut-shaped bore of the MRI magnet. For people who are truly claustrophobic, this is simply intolerable. Fortunately, most people are not that claustrophobic, and many of our CFS patients had previously had regular brain MRI scans and knew what to expect.

KKM: Dr. Shungu, will this study look at the same variables (blood flow and lactate) that you’ve investigated in research funded by the CFIDS Association, or do you have the opportunity to explore some new areas of brain function and chemistry?


Dikoma C. Shungu, Ph.

DCS: That is a very timely question! Just last week, we were informed by the editor of the journal NMR in Biomedicine that a paper in which we are reporting, for the very first time, that brain levels of the antioxidant glutathione are decreased in CFS patients compared to healthy controls, has been accepted for publication pending minor revisions. So, yes, in addition to lactate and blood flow, we will be measuring levels of glutathione in all participants in this new study, as another objective marker of brain-based dysfunction in CFS. Your readers should be pleased to know that this new study was almost entirely funded by the CFIDS Association, support for which we are very grateful.

KKM: That’s fantastic news! We are so gratified with the many important insights that you and the other five teams funded in our 2009-2010 grants have made. We look forward to sharing the publication as soon as it’s released!

Another challenging aspect of study design and subject recruitment is controlling for medication use to avoid confounds that can arise from specific treatments and cloud results. Dr. Natelson, you indicated in your description of the new study that patients will have to be off any medications that act on the central nervous system. What are some of the common medications that CFS patients use that they will have to stop taking in order to participate? Canprescription-300x199 you explain why this is important?

BHN: Many medicines that doctors prescribe for CFS cross into the brain. Common examples are anti-depressants, sleep-inducing drugs and pain-reducing drugs. If patients are taking these drugs during our studies, then we are studying the effect of treatment per se rather than studying the critically important CFS-affected brain. All too often, however, these medicines are not of much help in CFS. But because patients are often not sure whether they are helping or not, they continue to take them – even though they may actually not be helping. We would hope to work with patients and their doctors to come off these medicines for a week or a week and a half. After the study is completed, of course, patients can resume taking these medicines.

KKM: At the NIH State of the Knowledge Workshop held this spring, there was general agreement that CFS (as it’s currently defined) represents a pretty broad spectrum of illness. Yet, there are very different ideas about the optimum way to narrow that spectrum to find to better diagnostics and treatments than we have now. Over the years, different subsetting approaches have been used by investigators that reflect their interests, expertise and hypotheses. For instance, studies looking for infectious agents often require subjects to have had an acute, flu-like onset. But different subsetting approaches that vary by study can complicate comparisons between groups, even for the same variable. How does your approach to subsetting on the basis of the absence or presence of co-morbid psychopathology attempt to improve our understanding of the role of these brain-related variables in CFS?

BHN: Despite its logical appeal, only a few groups have used the “splitter’s” or subsetting approach.  In general, most studies have used the approach to take in all CFS patients who meet the broad CDC definition. However, the subject-to-subject variability in disease presentation that enrolling “all comers” produces may be one reason that there is so much difficulty in replicating results across laboratories. The “splitter’s” approach is the path medical history has proven to work. Take heart failure, for example. It has a myriad of causes, all leading to the same clinical syndrome of shortness of breath and swelling in feet and ankles. When a cause is found, then specific treatments can be developed to stop disease progression so that heart failure never even occurs. So, this should be the same with CFS too. If we can split out a group of patients that all have the same objective findings, then those patients no longer have CFS. Their illness will be given another name and that illness will be a discrete target for new therapeutic interventions.

I should hasten to say that this approach runs parallel to our efforts to identify biomarkers in spinal fluid using modern proteomics techniques.  If we are right in believing that patients with no psychiatric diagnosis  (the no-psych group) have a different cause for their CFS from patients with a co-existing psychiatric diagnosis (the psych group), then we should expect to be able to find a different protein signature within the spinal fluids of these two groups. At that point we could use spinal fluid proteome testing as the basis of diagnosis.  But getting to this point is arduous and very expensive. Frankly, I can’t predict just when this answer might come. So until then, I think it makes the most sense to advance with the tools we have at our fingertips. That’s why I am so excited by this new NIH grant.

KKM: Does stratifying patients on the basis of psych/no-psych give “ammunition” to people who think CFS is primarily a psychiatric disorder?

BHN: I would not understand how this might happen. Patients with chronic disease, be it CFS, heart failure or multiple sclerosis, often suffer from co-existing psychiatric problems such as depression because of the burden of their illness. In fact, rates of psychiatric diagnoses in all of these chronic illnesses are about the same. So simply using the presence or absence of psychiatric diagnosis as a criterion for splitting into groups does not support the belief that CFS is primarily a psychiatric disorder. On the contrary, the fact that some CFS patients have never had a psychiatric diagnosis or problem, the no-psych group we hope to study, totally belies this proposition.

KKM: What are the major differences you see between primary psychiatric disorders and CFS? How do you differentiate between these two populations in the clinic and in your research studies?

BHN: Neither of us is a psychiatrist and so we really cannot answer your first question as to how CFS is different from primary psychiatric disorders. However, as we have shown in our studies, patients with no evidence of any psychiatric problem seem to be the ones who have the worst results on brain-related tests. Probably the best way to get answers to your first question would be to use patients with primary psychiatric disorders as a comparison population to study – the way Dr. Shungu and his colleagues did in their first study. Unfortunately, the funding constraints in our new NIH grant will not allow that for this initial set of studies. We expect that the same group of patients will have reduced  brain blood flow, increased cerebroventricular lactate, poorer scores on neuropsychological testing and more abnormalities in their spinal fluid. With that result, we will request additional funding to allow us to expand our work to include patients with primary psychiatric disorders.

Natelson-study-300x211We do not so much differentiate between primary psychiatric disorders and CFS in our research as much as identify which patients have what. So for our research, we ask our patients to participate in a diagnostic psychiatric interview to determine if they have one of the psychiatric diagnoses that excludes the diagnosis of CFS such as schizophrenia, bipolar disease, or drug/alcohol abuse. If not, the interview allows us to determine if the patient has had or is having psychiatric problems – information which we use for splitting the patients into groups.

I pretty much do the same thing in my clinical practice. I tell patients that depression is my enemy in that it is an “illness multiplier,” making every symptom of every disease worse. When I diagnose depression, I treat it using the best tools possible.  Usually this treatment relieves the depression, but unfortunately, the severe fatigue, achiness, brain fog and other complaints only rarely also disappear. Besides depression, I try to determine if a patient has a problem with anxiety. In addition to asking about symptoms of anxiety, I test the patient’s breathing, looking to see if s/he hyperventilates.  Hyperventilation is often associated with anxiety. I do find that a small number of my patients hyperventilate even though they are totally aware of doing it. I think hyperventilation is a treatable cause of severe fatigue and so would exclude such patients from my research. But I have not found it useful to refer such patients to a psychiatrist. Biofeedback to improve their breathing and reduce hyperventilation seems a better course to take.

KKM: You are among the most highly published researchers on CFS. What changes have you seen over the years, with regard to getting funding for and publishing CFS research? Is it easier or harder? Are colleagues in other fields more or less interested in CFS than in the past?

BHN: Getting federal funding for CFS research remains very very hard. Both Dr. Shungu and I spent several years writing, rewriting and then dealing with rejection prior to getting this grant. So funding has not gotten any easier over the years. And it remains difficult because there is no NIH institute that champions CFS research. And when other scientists hear about how hard it is to get funding, they move to other areas. However, I have a commitment both to the care of CFS patients and certainly to better understanding the causes of CFS. So rejection will not stop my efforts and focus on behalf of CFS.

KKM: How should an individual interested in participating in your study contact your team?

natelson_with_patient_00BHN: We ask interested patients, as well as their healthy friends and relatives, to go to the Pain & Fatigue Study Center website,, to download, complete and then send in the Health Screen Form. That form helps us in the 60-minute medical intake evaluation which is done at no cost to the volunteer. As soon as our office has your form in hand, someone will call you to explain the next step. If you appear to have CFS and are either not taking brain-active drugs or willing to stop taking them for up to a week and a half, we will ask you to sign a document providing your informed consent to participate in research. With your informed consent, we can then move ahead to schedule you for research study.

KKM: Thanks to you both for explaining the study and your thoughts behind it. We look forward to hearing about your progress, the results and the implications for diagnosis and treatment.

Additional Notes:
Dr. Natelson will be speaking at the New Jersey CFS Association’s fall conference, “New Horizons in Public Health, Treatment & Diagnostics in CFS.” The meeting will be held Oct. 16, 2011, in Eatontown, NJ. For more information, please see

Dr. Shungu’s project funded by the CFIDS Association is described in the following materials:
“Brain Power” –
“Study Finds Link Between CFS and High Lactate Leves in the Brain” –
“Expanding Research: Building on Your Investment” (webinar recording) –

K. Kimberly McCleary has served as the Association’s chief staff executive since 1991