New Unger study suggests biological cause

[Esther12]

Thanks Firestormm

 

[oceanblue]

Thanks for the update, Firestormm. Have to say the p values for differences between patients and controls look a little underwhelming given the propensity of fMRI studies to throw up false positives:

The MRI results showed significantly less activation of the right caudate nucleus (P=0.014) and right globus pallidus (P=0.019) in the patients with CFS versus the control group.

But I'm pleased they used the '94 criteria (Fukuda), and the correlation of reduction of activity with fatigue levels is certainly encouraging:

"The reduction in activity (in the CFS group) correlated with measures of fatigue; the greater the fatigue, the greater the reduction in activation," Unger and colleagues stated in their presentation.

I can't imagine Bill Reeves either leading a study like this or presenting the results in such a fashion.

 

[Little Bluestem]

those with chronic fatigue experienced significantly less change in blood flow to the basal ganglia in response to winning a simple card game meant to stimulate feelings of reward

Maybe those with CFS were just too exhausted and had too much else on their minds to care much about winning a simple card game. It sure wouldnt do anything for me. I would like to see the change in blood flow to the basal ganglia if they were offered the chance to take a nap.

 

[alex3619]

Yeah, what if its just boredom? I too would be totally underwhelmed, even if money were involved.

 

[Firestormm]

I don't actually think it has as much to do with the nature of the exercise as perhaps some are thinking (thinking being an appropriate word perhaps given the nature of the experiment).

I mean these are established tests and I also just wanted to say that this was (or sounds like) a small almost unplanned bit of research - spur of the moment inspiration almost.

I don't recall hearing that funding had been set aside for it specifically is what I mean I guess. However, if it leads to a focus on the basal ganglia (in this instance) or on more funding for research into specific neurology, then I'm all in favour of course.

I read it all as a 'sweetner' something that might inspire others (as well as in this case the CDC) to move in this direction in future studies.

I wouldn't be expecting much more to be gained from reading the full paper to be honest. I think the internet media have made much out of this simply because it points (again for others) but maybe for the first time for the CDC - to specific (if what goes on in the basal ganglia can be called specific) biological involvement.

Had there been funding made available or a plan in place to specifically look at basal ganglian involvement I think we would be witnessing a far more thorough bit of research here. I just don't think in this case (or perhaps in any other) we should consider this piddly bit of research in isolation.

Anyway, that aside - I was quite chuffed to see my condition featured in the Neurology pages and I hope it does stimulate more CDC research in this little understood area because it might account for pretty much all the debilitation I experience and yes that will include - as does all neurology to an extent - behavioural/emotional features.

Where would I be without me old mate Wiki?

The basal ganglia play a central role in a number of neurological conditions, including several movement disorders. The most notable are Parkinson's disease, which involves degeneration of the melanin-pigmented dopamine-producing cells in the substantia nigra pars compacta (SNc), and Huntington's disease, which primarily involves damage to the striatum.[1][5]

Basal ganglia dysfunction is also implicated in some other disorders of behavior control such as the Tourette's syndrome, ballismus (particularly hemibalismus), obsessivecompulsive disorder (OCD), and Wilson's disease (Hepatolenticular degeneration). With the exception of Wilson's disease and hemiballismus, the neuropathological mechanisms underlying diseases of ganglia such as Parkinsons' and Huntington's are not very well understood or are at best still developing theories. http://en.wikipedia.org/wiki/Basal_ganglia

You know after 14 years and at the end of the day I don't give a Macaque-monkey's what is causing/contributing to my condition or what names they apply to it, I just want it isolated and treated effectively

 

[oceanblue]

(The FASEB Journal. 2012;26:1035.20) 2012 FASEB

Decreased basal ganglia activation in Chronic Fatigue Syndrome subjects is associated with increased fatigue
Elizabeth R. Unger1, Andrew H. Miller2, James F. Jones1, Daniel F. Drake2, Hao Tian1 and Giuseppe Pagnoni3

1 Centers for Disease Control and Prevention, Atlanta, GA
2 Emory University School of Medicine, Atlanta, GA
3 University of Modena and Reggio Emilia, Modena, Italy

Objectives: Conduct a functional magnetic resonance (fMRI) study using a monetary win-lose gambling task that strongly activates basal ganglia to test hypothesis of decreased basal ganglia function in chronic fatigue syndrome (CFS).

Methods: Participants included 18 CFS subjects (1994 case definition) and 41 non-fatigued controls matched on age, sex and race who were free of psychotropic medications and significant depression (Zung Depression score <60). The general activation pattern for win-lose contrast across all subjects was determined. The resulting statistical parametric brain map thresholded at p<0.05, corrected for multiple comparisons, was intersected with basal ganglia regions of interest (ROIs). For each subject, the average value of win-lose activation contrast in each ROI was extracted.

Results: CFS subjects showed decreased right caudate (p=0.01) and right globus pallidus (p=0.02) activation compared to controls. The decreased globus pallidus activation correlated with increased mental fatigue (r[SUP]2[/SUP]=0.49, p=0.001), general fatigue (r[SUP]2[/SUP]=0.34, p=0.01) and reduced activity (r[SUP]2[/SUP]=0.29, p=0.02) Multidimensional Fatigue Inventory scores of CFS subjects but not controls.

Conclusion: Reduced basal ganglia activation may contribute to symptoms of fatigue in CFS subjects.

The findings in this report are those of the authors and do not necessarily reflect the views of the funding agency (CDC).

1. If those correlations with fatigue really are r[SUP]2,[/SUP] rather than r then they are very impressive: the correlation with mental fatigue of r[SUP]2[/SUP]=0.49 equates to a normal correlation coefficient of R=0.70, which is unusually high (min=0.0. max=1.0).

The resulting statistical parametric brain map thresholded at p<0.05, corrected for multiple comparisons, was intersected with basal ganglia regions of interest (ROIs). For each subject, the average value of win-lose activation contrast in each ROI was extracted.

So it does look like they only looked at changes in basal ganglie, not the whole brain - just as adreno suggested

 

[peggy-sue]

"Anhedonia" is a very major feature of depression - this is completely consistent with there being a lack of response in the "reward systems".

This study worries me - as being support for psychologisers and depression (which is organic) being a "cause".

(and does everybody play cards for money? - I certainly don't, much as though I love playing cards.)

 

[Vitalic]

Sounds like this would be easily accommodated by the biopsychosocial model, I suspect they would say that it is a consequence of deconditioning and avoidance behaviour that over time has diminished the patient's reward/response system which is why they are reluctant to challenge themselves to overcome their aberrant illness beliefs, they no longer view getting better as a reward so have no motivation to challenge the condition.

The problem is that there is no way to falsify such claims, because every CFS patient (by definition in order to be diagnosed) has had the illness for such a period of time that it is impossible to say whether these neurological impairments are causal or something that develops over time during the course of the illness.

If you could select a group of patients who have had CFS for only a few weeks and see if the same abnormalities are present then you could rule out deconditioning, however you can't actually find anyone like that because it takes so long to find out you've even got the illness, I feel like this is what lies at the heart of many of our problems, I can't think of many other conditions that you have to have had for 6 months to even know you've got the condition.

 

[Firestormm]

"Anhedonia" is a very major feature of depression - this is completely consistent with there being a lack of response in the "reward systems".

This study worries me - as being support for psychologisers and depression (which is organic) being a "cause".

(and does everybody play cards for money? - I certainly don't, much as though I love playing cards.)

Morning Peggy-sue,

Like I said (not very well above) if a simple 'card-game' (which wasn't really a card game at all when you consider what they did) could provoke the basal ganglian responses shown in the abstract and commented upon by Blue above - I personally think that a more complex e.g. card-game like SNAP would produce an even greater response/lack of response/stimulant/whatever observable signs. And SNAP is hardly a complex game either - imagine recording a game of chess! Christ my 'basal ganglia' would be all over the shop!

 

[Marco]

I wonder if Gulf War vets would find a game of cards equally unrewarding?


Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum.

Note : The striatum is the largest component of the basal ganglia.

The neurological effects of organophosphate (OP) pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here, we characterized the effects of the broadly used insecticide chlorpyrifos (CPF) on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry.

Thus, consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration.

http://www.ncbi.nlm.nih.gov/pubmed/21848865


Why the authors (Unger et al) focused solely on the reward aspect when many basal ganglia disorders involve motor/movement deficits and PEM is the cardinal symptom of ME/CFS (although not for Fukuda) is a little bizarre.


In another GWS study the researchers did at least have a rationale for looking at the basal ganglia particularly which had little to do with reward :

Brain Abnormalities in Gulf War Syndrome: Evaluation with 1H MR Spectroscopy

Our rationale for focusing MR spectroscopy on the basal ganglia and brainstem was that the range of symptoms reported by these Gulf War veterans is consistent with the early presenting symptoms of well-understood degenerative diseases of the basal ganglia and brainstem. These include Huntington disease, which initially affects the caudate nucleus; Wilson hepatolenticular degeneration, which initially affects the putamen; and Fahr disease, which initially involves calcification of the globus pallidus (11).

These classic neurodegenerative diseases often begin with personality changes; irritability; cognitive impairments particularly in executive function, memory, concentration, and attention; changes in speech; attacks of vertigo; abnormalities of ocular pursuit and saccadic eye movement; central pain; and mood disorders (11,68).

Since these symptoms often begin before the development of objective neurologic findings, the diagnosis is often delayed until the inevitable appearance of objective signs.

CONCLUSION:

Veterans with different Gulf War syndromes have biochemical evidence of neuronal damage in different distributions in the basal ganglia and brainstem.

http://radiology.rsna.org/content/215/3/807.full

 

[peggy-sue]

Just the *thought* of a game of Bridge gets my basal ganglia all fired up, Firestormm!
Unless, of course, I've got depression at the time.

 

[RustyJ]

Authors of study: Elizabeth R. Unger1, Andrew H. Miller2, James F. Jones1, Daniel F. Drake2, Hao Tian1 and Giuseppe Pagnoni3

Is depression an inflammatory disorder?
Raison CL, Miller AH.
Curr Psychiatry Rep. 2011 Dec;13(6):467-75. Review.
PMID: 21927805 [PubMed - indexed for MEDLINE]

Psychosom Med. 2008 Apr;70(3):298-305. Epub 2008 Mar 31.Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome.

Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, Heim C.

http://www.ncbi.nlm.nih.gov/pubmed/18378875

Reeves and Miller worked on many papers together. Now Klimas is working with Miller.

Miller had done a lot of work on depression in disease. Many diseases have inflammation. Many diseases cause depression. Ergo depression causes inflammation causes disease.

 

[Firestormm]

There was an International Psychiatrists Conference in Brighton last year that had Depression and (if I remember correctly) Inflammation together for a lecture. It's nothing new I don't think. And so what? I really couldn't give a flying monkey as I've said before.

I can't see them determining that some itty-bitty bit of the brain is somehow unique to causing neurological conditions that doesn't also impinge on what are categorised as 'psychiatric'. I mean it's all biological at the end of the day.

It would be interesting to see this Unger study repeated with 'ME', Depression, and Normal patients don't get me wrong. Let's see just to what degree this (and other parts) of the brain are working poorly or in overtime mode. Let's see if there are definite differences. But I bet any differences will not be as significant in all areas as some might like.

Then again I could be wrong. I don't mind either way. Wish they'd just change the spark plugs and get on with it. Might help prevent all the misfiring when it comes to research direction

 

[FancyMyBlood]

Authors of study: Elizabeth R. Unger1, Andrew H. Miller2, James F. Jones1, Daniel F. Drake2, Hao Tian1 and Giuseppe Pagnoni3





Reeves and Miller worked on many papers together. Now Klimas is working with Miller.

Miller had done a lot of work on depression in disease. Many diseases have inflammation. Many diseases cause depression. Ergo depression causes inflammation causes disease.

Actually he believes it's the other way around. Can we please get the conspiracy theories behind us?

Miller's hypothesis is that something in the immune system causes inflammation, which in turn causes depression and other diseases. Personally, I'm very glad to have him involved in ME/CFS. If you take a look at his earlier research instead of cherry-picking some studies that don't even demonstrate your theory, you'd notice he is one of the 'good guys'.

For example, he recently demonstrated that Depression and fatigue during chronic IFN-? administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.
He also did a clinical trial to see if a monoclonal antibody (infliximab), which is used in auto-immune diseases, helps to treat treatment resistant major depression. That study is completed and the results are promising. This also further supports his hypothesis about immunological abnormalities in MDD.
But the most important thing is that, in this study, he nowhere suggests that depression or psychological factors are responsible for decreased activation of the basal ganglia. In fact, he suggest infection (amongst other things) may be responsible for this.

 

[RustyJ]

Actually he believes it's the other way around. Can we please get the conspiracy theories behind us?

Miller's hypothesis is that something in the immune system causes inflammation, which in turn causes depression and other diseases. Personally, I'm very glad to have him involved in ME/CFS. If you take a look at his earlier research instead of cherry-picking some studies that don't even demonstrate your theory, you'd notice he is one of the 'good guys'.

For example, he recently demonstrated that Depression and fatigue during chronic IFN-? administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.
He also did a clinical trial to see if a monoclonal antibody (infliximab), which is used in auto-immune diseases, helps to treat treatment resistant major depression. That study is completed and the results are promising. This also further supports his hypothesis about immunological abnormalities in MDD.
But the most important thing is that, in this study, he nowhere suggests that depression or psychological factors are responsible for decreased activation of the basal ganglia. In fact, he suggest infection (amongst other things) may be responsible for this.

Bolded section does not negate what I said. Nowhere above does he say inflammation causes depression. He actually says depression causes immunological changes and further on links immunological changes to disease causation.

Even more clearly he states in this interview that depressed patients produce an increased inflammatory response which possibly leads to disease.

Please leave out the inflammatory remarks about me being a conspiracy monger. I have been around long enough to know that most associated with Reeves do not believe me/cfs is biological. Reeves has gone on record to say as much and has thwarted any attempt to further biological research.

Depressed patients experience excessive inflammation during stressful situations

ATLANTA--Individuals with major depression have an exaggerated inflammatory response to psychological stress compared to those who do not suffer from depression, according to a study by researchers at Emory University School of Medicine. Because an overactive inflammatory response may contribute to a number of medical disorders as well as to depression, the findings suggest that increased inflammatory responses to stress in depressed patients may be a link between depression and other diseases, including heart disease, as well as contributing to depression itself.

Results of the study, led by Andrew Miller, MD, and Christine Heim, PhD, of Emory's Department of Psychiatry and Behavioral Sciences, are published in the Sept. 1 issue of the American Journal of Psychiatry.

"Several examples of increased resting inflammation in depressed patients already exist in the literature, but this is the first time anyone has shown evidence to suggest that the inflammatory response to stress may be greater in depressed people," says Dr. Miller.

The study included 28 medically healthy male participants, half of whom were diagnosed with major depression and half of whom were not depressed. The participants were exposed to two moderately stressful situations during a 20-minute time period. Blood was collected every 15 minutes starting immediately before and then up to an hour and a half after the test to check for key indicators of inflammation. The researchers measured levels of a pro-inflammatory cytokine (a regulatory protein secreted by the immune system) called interleukin-6, and the activity of a pro-inflammatory signaling molecule in white blood cells called nuclear factor-kB.

While at rest (before the stress challenge), the depressed patients had increased inflammation relative to the control group. Both the depressed and the healthy groups showed an inflammatory response to the stress challenge, but people who were currently depressed exhibited the greatest increases of interleukin-6 and nuclear factor-kB.

"While inflammation is essential for us to fight bacterial and viral infections, too much inflammation can cause harm," says Dr. Miller. "There's always some collateral damage when the immune system gets fired up, and we now believe that too much inflammation, either at rest or during stress, may predispose people to become depressed or stay depressed." In addition, medical research over the last decade has shown that runaway inflammation may play a role in a number of disorders, including heart disease, cancer, and diabetes, all of which have been associated with depression.

People in the study who suffered from depression also had higher rates of early life stressful experiences. "We have found that this kind of personal life history may make people more likely to develop major depression and is actually common in depressed patients," says Dr. Heim.

It was part of a larger project at the Emory Conte Center for the Neuroscience of Mental Disorders led by Charles B. Nemeroff, MD, PhD, Reunette W. Harris Professor and Chair of Emory's Department of Psychiatry and Behavioral Sciences. The Conte Center is dedicated to understanding the contribution of early life abuse and neglect to the neurobiology of adulthood psychiatric disorders. Ongoing studies by Dr. Miller's team of researchers will attempt to determine how early life experiences contribute to excessive inflammatory stress responses.

"According to the Depression and Bipolar Support Alliance, major depression is the leading cause of disability worldwide and costs the U.S. economy $70 billion annually in medical expenditures, lost productivity, and other expenses," says Thaddeus Pace, PhD, lead author on the paper. "This study is leading us toward finding out what actually causes depression and to identifying what aspects of immune system function are abnormal in depressed people. The goal is to find potential targets within the molecular machinery of the immune system so we can better treat major depression and minimize its consequences on health."

###
The study was funded by the National Institute of Mental Health (NIMH) and the National Alliance for Research on Schizophrenia and Depression (NARSAD).

Other contributors to the study include Oyetunde Alagbe, MD, Tanja C. Mletzko, MS, and Dominique Musselman, MD, MS

http://laura-owens.suite101.com/depresssion-anxiety-inflammation-and-disease-a63086

Yes Miller does go on to say the immune response leads to disease, but in our case this is irrelevant.

Since the CDC doesn't think we have a disease, they can say we just have depression with subsequent inflammation/ immune response in some. This is the danger with what they are trying to do.

 

[FancyMyBlood]

Bolded section does not negate what I said. Nowhere above does he say inflammation causes depression. He actually says depression causes immunological changes and further on links immunological changes to disease causation.

He's not saying that depression causes immunological changes. He's merely saying that depressed people have an increased inflammatory response:
''increased inflammatory responses to stress in depressed patients may be a link between depression and other diseases.'' Furthermore he suggests that ''too much inflammation, either at rest or during stress, may predispose people to become depressed or stay depressed.
How you can conclude that he's saying that it's the depression causing inflammation and immunological changes is beyond me.

It's also interesting you referenced one of his studies to support your believe that Miller believes depression causes inflammation. But a look at the full-text reveals a completely different picture:

Two additional lines of evidence lend credence to the
possibility that the increased levels of inflammatory
biomarkers seen in some patients with MDD might
contribute to disease pathophysiology in this depressive
subgroup. First, recent studies have reported that even
mildly elevated levels of CRP and IL-6 independently
predict the subsequent development of depression over a
decade or more, even in individuals with no current or past
history of depression at the time of the immune assay [8,
39]. In contrast, baseline levels of depression did not
predict an increase in inflammatory biomarkers at followup
[39], suggesting that the frequently observed association
between inflammation and depression may be better
explained by a causal arrow running from inflammation to
depression than the reverse.

Please leave out the inflammatory remarks about me being a conspiracy monger. I have been around long enough to know that most associated with Reeves do not believe me/cfs is biological. Reeves has gone on record to say as much and has thwarted any attempt to further biological research.

I mean this in the nicest way possible, but if you twist a scientist's hypothesis just beause he has been associated (in only 3 studies) with Reeves I think it's fair to say that's not an objective argument.

Yes Miller does go on to say the immune response leads to disease, but in our case this is irrelevant.

Have you read Cort's summary of Miller's talk at the Ottawa IACFS conference? I have linked it in one of my above posts and it's very relevant in our case.

Since the CDC doesn't think we have a disease, they can say we just have depression with subsequent inflammation/ immune response in some. This is the danger with what they are trying to do.

There is no evidence they're doing that. Quite the contrary, actually. Unger could easily conclude that as one of her working hypothesis in the FASEB abstract, but instead she concluded it supports a biologic theory of this disease. Miller himself could easily do the same at the IACFS conference, but he actually suggests the results of this study may be caused by infection.