Can’t or Won’t? Immunometabolic Constraints on Dopaminergic Drive. Treadway MT et al. Trends Cogn Sci. (2019)

[leokitten]

Interesting review of research on the impact of inflammation on the dopamine system as well as a theoretical model and computational method trying to connect it all.

Could be a hypothesis as to why Abilify and dopaminergic agents have some partial efficacy in ME, even if it is temporary (so only a part of the ME symptom story, not for example what are the cause(s) of the chronic inflammation).


Can’t or Won’t? Immunometabolic Constraints on Dopaminergic Drive
Treadway MT et al. Trends Cogn Sci. (2019)

Inflammatory cytokines have been shown to have a direct effect on mesolimbic dopamine (DA) that is associated with a reduced willingness to expend effort for reward. To date, however, the broader implications of this communication between inflammation and mesolimbic DA have yet to be explored. Here, we suggest that the metabolic demands of chronic low-grade inflammation induce a reduction of striatal DA that in turn leads to a steeper effort-discounting curve because of reduced perceived ability (can’t) versus preference (won’t) for reward. This theoretical framework can inform how the mesolimbic DA system responds to increased immunometabolic demands during chronic inflammation, ultimately contributing to motivational impairments in psychiatric and other medical disorders.

News summary from ScienceDaily:

How chronic inflammation may drive down dopamine and motivation

 

[chrisb]

I don't understand it, but it sounds interesting. I wonder whether they could find anything in the inflammatory model to account for relapse and remission.

 

[Woolie]

This is absolutely fascinating - thanks for posting!

I think this paper is really important for ME, because it provides a framework for understanding how inflammation might lead to the subjective experience of fatigue. It does so with no handwaves about the evolutionary function of "sickness behaviour" and no generalisations about low mood/depression. And it goes further than just the same old crap about "if the fatigue is not peripheral, then it must be central" (as if "central" were somehow an informative thing, and not just the negative of peripheral).

I was diagnosed with ME ("CFS") in 1993, and since have been diagnosed as having a rare autoinflammatory disease. So may be a bit different to many of you here. But when I have a flare, it feels like a concrete slab is pushing down on my diaphragm, neck and head. Everything, even watching TV on my computer, is an effort I can sustain only for short periods. Although I often have raised inflammatory markers like CRP, these don't accurately track the concrete slab feeling, so I'm guessing that its probably the outcome of not one, but a lot of different kinds of inflammatory signalling.

People here often say that the fatigue is not their main limitation, the problem is more managing activity to avoid PEM. But during PEM, many here experience that crushing exhaustion, both mental and physical, in addition to an overall sick feeling.

 

[Woolie]

To explain a bit more, the authors propose that the subjective feeling of fatigue has a specific behaviorual manifestation that's measureable: a change in what they call "effort discounting" (a tendency to choose low effort behaviours that provide low rewards over high effort behaviors, even if they provide higher rewards).

They propose a route whereby current inflammatory markers can feed information in to subcortical structures that decide how to trade-off current effort against potential reward. Specifically, those mechanisms can "turn down" effort in response to high levels of inflammation.

So its about reduced capacity, not reduced interest in the reward. So its "can't" not "won't".

To pick out a bit which I think explains their main point:

Based on the data summarized above regarding the effects of immune signaling on striatal DA and effortful behavior, we suggest a new model where the subjective value for an action is scaled according to estimates of the current immunometabolic state as indexed by markers of inflammation

The article is mainly about how individuals might behave when they have high levels of inflammation, but of course, there is likely to be a subjective experience associated with this "turning down" too - something like what we experience as inflammation-related fatigue.

Everyone here knows that ME fatigue is qualitatively different from fatigue due to normal exertion (or even overexertion), and i think this framework is compatible with that.

 

[Snow Leopard]

I don't buy this model at all. It is the effort that is disproportionately high, not the (motivational) willingness to expend effort that is the problem.

The authors do not seem to understand what perception of effort actually is and it's relationship with proprioception and motor drive.

 

[Sid]

The authors do not seem to understand what perception of effort actually is

Could you say more about what’s wrong with their understanding of effort? If you feel up to it of course.

 

[Woolie]

I don't buy this model at all. It is the effort that is disproportionately high, not the (motivational) willingness to expend effort that is the problem.

That seemed to me to be exactly what they were saying - but its not my area, so maybe I missed something?

 

[Mithriel]

Despite how long I have been ill, I have a continuing battle to not do too much. On many occasions, I have wanted to do something so badly I have ignored my body and gone ahead. Which is common in ME.

I presume it is because I am working on adrenalin that I usually manage but the damage goes on underneath. The epitome of that was when I thought I was cured for 4 weeks then my legs gave under me and I have never walked more than a few steps since.

If this effect they have found is correct, it is most likely a protective mechanism.

The professional cyclists who died after taking cocaine to have increased their endurance are thought to have died because normal fatigue stops us keeping going when we should stop.

 

[Mij]

Didn't Dr. Paul Cheney have a theory on the heart, and that fatigue could be a protective mechanism against damage or death for pwME?

 

[Snow Leopard]

That seemed to me to be exactly what they were saying - but its not my area, so maybe I missed something?

Um...

They make it quite clear that it is a motivational model. The mesolimbic area is colloquially referred to as the "reward pathway".

Over the past several decades, our understanding of the neurobiological mechanisms that govern exploratory behavior and goal pursuit has expanded exponentially. This work has revealed a central role for mesolimbic signaling of the phylogenetically conserved neurotransmitter dopamine (DA) in shaping willingness to expend energy [2–5] or forage [6–8] and the drive to overcome obstacles [9,10] in pursuit of rewards. To date, however, the majority of studies have focused on the behavioral consequences of mesolimbic DA signaling within the striatal, limbic, and cortical areas that mediate various aspects of normal and abnormal reward-seeking behavior. By contrast, a smaller body of work has focused on inputs to the mesolimbic DAergic system from sources outside the CNS that communicate relevant bodily states to influence the responsivity of DAergic neurons and the calculus of effort based decision-making.

Specifically, we suggest that immune signaling may suppress the DAergic system’s estimate of value, subsequently adapting what is ‘worth the effort’ to the body’s current metabolic capacity

Herein, we propose that inflammatory signaling molecules play a critical role in communicating information relevant to shifts in immunometabolism that impact available energy resources in the body – a prerequisite for the mesolimbic DA system to generate accurate estimates of expected value of reward and guide effort allocation and energy expenditure.

Figure 2 shows hypothetical functions of "subjective value" versus normalised "Effort required", quite clearly showing that their model is about motivation.

Translational Implications
Given the impact of inflammation on fundamental aspects of reward processing, a logical consideration of the findings above is that inflammation may play a role in the core symptoms of psychiatric disorders related to effort expenditure for reward, including anhedonia in depression, anxiety disorders, and post-traumatic stress disorder as well as negative symptoms in schizophrenia. All of these psychiatric conditions have been reliably associated with increased peripheral blood inflammatory markers [53] and in many cases the concentration of inflammatory markers has been directly associated with symptoms of impaired motivation [41,53]. Moreover, alterations in effort expenditure for reward have been demonstrated in patients with depression and schizophrenia [83,84], although to our knowledge no study has linked inflammatory makers to these findings. Based on the work described above, inflammation would be expected to have specific inhibitory effects on effort expenditure for reward as opposed to sensitivity to reward, a hypothesis that warrants further exploration in psychiatric patient populations.

The main problem is that there is a lack of empirical evidence for such a subconscious feedback system that it is involved in determining some sort of body-wide "metabolic capacity". Nor is there a fundamental need for such an alteration of cortical drive through such input when the brain already has a variety of more direct strategies - namely sensation of pain (when there is serious inflammation), and conscious cognitive strategies that calculate these motivational strategies based on prior experiences.

There are also counter examples, namely the "fight or flight" system that increases such motivation, regardless of whether the individual has the "metabolic capacity" to maintain effort for very long.

In the case of motor drive, feedback from muscle afferents directly inhibits motor drive spinally and supraspinally within motor cortex and associated areas of the brain like the supplemental motor area.
Notably, when exercising hard, this reduction in cortical excitability can be offset by increased sympathetic drive.
Importantly, sense of effort is directly proportional to the cortical output. If this sense was arbitrarily modified, it would lead to proprioceptive errors.
Also of note, none of the proposed metabolic markers (leptin/ghrelin/insulin/fatty acid) have much impact on this sense.

This dates back around 150 years to von Helmholz who demonstrated that motor control is feed-forward and the brain essentially has a model of limb function, where an "efferent copy" of the motor drive signal is sent and the resulting proprioceptive afferent inputs is compared to the brain's model (the inputs are primarily type I and II afferents, but can include visual input as well as touch). If the motor force is substantially less than predicted, then this increased uncertainty is sensed as fatigue. It is important to note that this model is slow to adapt and hence does not adapt to rapid increases in peripheral fatigue. I instead suggest that this is the primary purpose of "central fatigue", namely to make motor output more predictable under fatiguing conditions. I will however note that where coordination is poor (doing unfamiliar tasks with non-dominant limbs, for example), the process is more open to afferent feedback to improve the central motor control model.

Understanding the sense of effort during mental tasks is a little trickier, since you can't easily control force output and measure cortical drive, or vice versa.
Hence there is no way of adequately controlling for variations in motivation. Secondly, the reported of sense of effort always has a cognitive overlay that has a variety of biases. Unfortunately, many investigators either are unable to distinguish between these biases and the perception of effort, or are simply choosing to ignore the difference. It is not unreasonable to propose simple models where the sense of effort is relative to fatigue, which is to say the limits are based on how long the cognitive effort can be maintained. (But this is difficult to confirm due to the difficulty in controlling for motivation - task cessation is not the same as fatigue). Hence there are cognitive predictions that are made about the expected mental effort and a specific behaviour/motivational strategy is adopted as a result.

 

[Snow Leopard]

Didn't Dr. Paul Cheney have a theory on the heart, and that fatigue could be a protective mechanism against damage or death for pwME?

There is a protective mechanism against damage or death and it is called pain. Fatigue is not pain.

Notably, central fatigue does not prevent peripheral fatigue, nor damage if the individual continues to push.

 

[Mij]

@Snow Leopard

I'm not referring to fatigue. I am referring to why we get PEM in the first place. The type of 'fatigue' Dr. Cheney is referring to is PEM. It must be sort of protective mechanism, no? I don't have pain so this won't prevent from overdoing.

 

[Snow Leopard]

It must be sort of protective mechanism, no? I don't have pain so this won't prevent from overdoing.

Why does it have to be protective, to prevent from overdoing, rather than simply a sign that something is wrong and performance will suffer as a result?

 

[Mij]

The professional cyclists who died after taking cocaine to have increased their endurance are thought to have died because normal fatigue stops us keeping going when we should stop.

@Snow Leopard

I was responding to what Mithriel wrote. I'm wondering if this is what Dr. Cheney theory was referring to when he used the term "Compensated Idiopathic Cardiomyopathy".

 

[Mij]

"Cheney has long stated he believes the low energy state in CFS may be protective. “This also brings into focus the idea that maybe fatigue isn’t as bad as we think it is. Sometimes fatigue could actually be a protective mechanism against damage from these toxins…..I call this the energy conundrum.

The energy deficit may actually be a defense mechanism as much as a problem in itself, and the real solution to the energy deficit is to get at the deeper problem (Cheney 2001)” This theory is apparently prompted by the negative effects that seemingly innocuous treatments often bring to CFS patients. Some CFS patients seem to be partially frozen into a state of limited energy and efforts to release them from that state must often be done slowly and carefully".

 

[Woolie]

@Snow Leopard, I agree this statement below can be read to mean they believe "inflammation takes away your interest in doing things". But its fairly clear elsewhere in the article that it is not the instrinsic value of the reward that changes, but the estimation of how much effort would be required to achieve it.

Specifically, we suggest that immune signaling may suppress the DAergic system’s estimate of value, subsequently adapting what is ‘worth the effort’ to the body’s current metabolic capacity

Its a behaviorual neuroscience approach (different from cognitive neuroscience in that it focuses primarily on explaining on behaviour patterns, rather than making inferences about mental processes), and they're interested mainly in the behaviour of not working so hard for a reward when you have inflammation. "Impaired motivation" to them, is a description of this phenomenon.

For me, the crucial thing is that they are not saying that people with inflammation have negative feelings or low mood or have lost their mojo (so don't even want rewards), or their low mood caused the inflammation in the first place, or that they're engaging in "sickness behaviour" to get social rewards/help their community. Or any of the usual BS. They're saying that the inflammation itself directly modulates behaviour - via a signalling path that is preumably there to protect the organism from overexerting when it is mounting an immune response.

That is, they are bothering to consider how inflammation, a set of signals that originate from outside the CNS. may impact on CNS function, which seems to be a real step forward. I have never thought that fatigue in ME (or in what I have) has its origins in the CNS. There is too much evidence that it varies according to bodily states. I have to admit I have little knowledge of behavioural neuroscience, and maybe all this has been done before, but this seemed to me like a huge step forward.

I also don't think the "fight or flight" response is at all incompatible with their view. They are not at all saying that the only thing that influences reward-effort evaluations is inflammation.

It also does not seem incompatible with any of the other mechanisms you mention that operate when normal people feel exhausted (feedback from muscle efferents from continued overexertion).

But when it comes to ME, its seems to me unlikely that the exhaustion is the result of these normal types of signalling. The exhaustion is well out of proportion to the exertion, its effects are hugely variable and it can be extremely delayed. Sometimes there's no clear precipitating exertion at all. So we are searching for an entirely different kind of mechanism in ME (one, I think, is likely to be linked to inflammation).

Importantly, sense of effort is directly proportional to the cortical output. If this sense was arbitrarily modified, it would lead to proprioceptive errors.

But it seems clear to me that our sense of effort can be modified in all kinds of ways in illness - largely by central mechanisms - and although we may experience the occasional odd sensation, like feeling unusually heavy, we do not generally misperceive reality! There are likely to be feedback loops that allow us to take into account our reduced ability to exert effort, which kick in and allow us to experience the change in effort as a change in us, not in the environment.

The main problem is that there is a lack of empirical evidence for such a subconscious feedback system that it is involved in determining some sort of body-wide "metabolic capacity". Nor is there a fundamental need for such an alteration of cortical drive through such input when the brain already has a variety of more direct strategies - namely sensation of pain (when there is serious inflammation), and conscious cognitive strategies that calculate these motivational strategies based on prior experiences.

I'm sceptical about this too. I'm in bed right now. I have no pain, other than a bit of a headache. I'm also not in bed out of a conscious decision to prevent some worse effect later. I'm in bed because I have crushing fatigue, which makes it aversive to do so much as lift my arm. It is entirely this sensation that keeps me in bed. If I didn't have the fatigue, I'd get up. I might decide to take it carefully - because I've been sick for some days - but I'd sit outside in the sun, or go for a drive.

 

[Woolie]

Why does it have to be protective, to prevent from overdoing, rather than simply a sign that something is wrong and performance will suffer as a result?

I agree. It might simply be a signal that energy metabolism is not right. It might have the happy effect of being protective too, but that's not essential to the explanation.