focus and context, part IIa: ADHD and rejection

The following post is in part an answer to a question in a randform comment.

ADHD is a socalled disorder. Among its symptoms are a “unusual way” of focusing/concentrating. The symptoms of ADHD are gradually. Thus weak forms of ADHD may not necessarily be seen as disorder, but as a normal condition.

Although the clinical investigations are not yet sufficient there exist strong indications that neurophysiological components play an imminent role in ADHD. And these may also be play a role in understanding rejection.

In particular the concentration level of a certain neurotransmitter called Dopamine seem to be smaller in ADHD patients than in non-ADHD patients, moreover the reuptake of Dopamine seems to be faster in ADHD patients. Since Dopamine steers the neural activity of a lot of neurons (“dopaminergic neurons”), the faster reuptake (and may be also the general lower level) of Dopamine seems to lead to a faster decrease of neural activity/stimulation (see plasticity). Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area (VTA). The production of Dopamine can be influenced by components including genetic disposition and nutrition.

Among others SPECT scans found people with ADHD to have reduced blood circulation (indicating low neural activity), and a significantly higher concentration of dopamine transporters in the striatum. Medications (such as methylphenidate) thus focused on treating ADHD by blocking the dopamine transporter and thus reducing dopamine reuptake in certain areas of the brain, such as those that control and regulate attention. As explained above dopamine is a stimulant, thus methylphenidate increases neural activity.

The level and reuptake of Dopamine seems to be accompagnied by emotional states, such as motivation (ADHD patients can actually “hyperfocus” if motivated), but as it seems also be connected to negative experiences/responses:

In der klinischen Praxis kann in diesem Zusammenhang immer wieder beobachtet werden, dass diese Patienten sich primär an negative und traumatisierende Erlebnisse erinnern. Nur massive Traumata vermögen bei ihnen Spuren im Gedächtnis zu hinterlassen. Fatalerweise sind es dann in erster Linie diese schmerzhaften Erinnerungen, welche das Grundgerüst des Selbstgefühls bilden.

translation (without guarantee of correctness):
In the clinical practice one can repeatedly observe, that patients recall primarily negative and traumatising experiences. Only massive Traumata may leave Traces in their memory. Badly enough these painful memories are then predominantly the memories which form the basic framework which forms self-assurance.

As a result ADHD patients have a tendency to easier develop comorbidities such as anxiety disorder, depression etc.

Emotional memories are partially triggered by activity in the Nucleus accumbens.
Major inputs to the nucleus accumbens include prefrontal association cortices, basolateral amygdala, and dopaminergic neurons which are located in the already above mentioned ventral tegmental area (VTA). Due to its role in the development of positive emotions the Nucleus accumbens is also called the “pleasure or reward center” of the brain.

However research suggests that in addition to its prominent role in appetitive learning, the nucleus accumbens (NAC) may also be involved in fear conditioning.

I couldn’t find a study with regard to this, but it is thus not far fetched to assume that a different activation pattern of the Nucleus accumbens may also be due to a different (way of/rate of) change of the dopamine level (this may also be a feedback mechanism). On a first guess this could imply that the positive activation of the Nucleus accumbens may be less easy for people with e.g. a faster/differently changing Dopamine level (such as ADHD patients), in particular this different dopamine regulation may (again this is guessing) even lead to a rather complete inactivation of the Nucleus accumbens and thus enforce negative emotions, like the above mentioned fear conditioning. Moreover if the Nucleus accumbens is inactivated it could be rather resistent to positive stimulation. As a simple reference: It is generally not easy to cheer someone up who is grumpy.

Concluding -it may be at least for a certain group of people very important to avoid negative experiences. This could explain also why some people may appear to “hyperreact” when e.g. being critized or rejected. And – it may be sensible to focus on investigating the mechanisms of rejection as these may dominate the mechanisms of reward. This may also be useful with regard to understanding Traumata which may be the result of a severe form of rejection such as in betrayal and abuse.

In short -it is important to understand why people feel rejected. In particular the experience of rejection is not only an individual feature, but is certainly influenced by other factors, like general societal (e.g. stress) factors, or like cultural conditions, which include religious constructions, conceptions of honor, but also arrangements on how to “institutionally” avoid that people feel rejected. These arrangements may reach as far as from pink slip parties to hospices.

addition Aug. 11, 2020:
There is a popular science read at the magazine Quanta (“Mitochondria May Hold Keys to Anxiety and Mental Health”) about the role of -in particular- mitochondria in the brain in conjunction with neural dysfunctions:

“mitochondria are often anchored at key positions within neurons, such as near the synapses, apparently to help their function. Mitochondrial effects might also be exerted through the brain’s non-neuronal glial cells, such as the oligodendrocytes that sheath neurons in myelin and the astrocytes that support neurons’ health.”

Amongst others it is hypothesized that a:

“deficit of cellular energy production in critical neural circuits might explain an overall lack of motivation and self-esteem seen in anxiety-prone people.”

So in particular:

When Sandi put rats in competition to establish a social hierarchy, she saw that the animals with less anxiety were more likely to acquire dominant rank. Further study showed that these less anxious animals had greater mitochondrial function in the nucleus accumbens, a part of the brain vital to motivated behavior and the production of effort.

The stress hormone cortisol seems to play here an important role:

Specialized receptors carry the cortisol into the nuclei of cells, where it activates about 1,000 genes to help cells prepare for the “fight or flight” response. But the receptors also ferry some of the incoming cortisol into the mitochondria, where it interacts with the mitochondrial DNA and makes energy production more efficient.

Some thoughts on that:
Since we talked about dopamine here it should be mentioned that dopamine is produced in socalled Dopaminergic cell groups. It seems to be currently somewhat well-known that mitochondrial defects are connected with the death of dopaminergic neurons. This connection could thus be a key factor in the question on how mitochondria could be involved in the above described mechanisms of dopamine circulation in the brain and thus in dopamine’s possible role in mental states like anxiety.
The conrete forms of interaction between mitochondria and dopamine seem however not yet so clear. In particular this article from 2008: suggests that “Deleterious effects of dopamine (DA) involving mitochondrial dysfunction have an important role in DA-associated neuronal disorders, including schizophrenia and Parkinson’s disease.”
Here is now a newer study (“PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function “) which highlights the role of PINK1 -a mitochondrial kinase:

We found that in neuronal progenitors, PINK1 regulates mitochondrial morphology, mitochondrial contact to the endoplasmic reticulum (ER) and the phosphorylation of Miro1. A compensatory metabolic shift towards lipid synthesis provides mitochondria with the components needed for membrane renewal and oxidative phosphorylation, maintaining the mitochondrial network once mature.

Cholesterol is increased by loss of PINK1, promoting overall membrane rigidity. This alters the distribution of phosphorylated DAT at synapses and impairs dopamine uptake. PINK1 is required for the phosphorylation of tyrosine hydroxylase at Ser19, dopamine and calcium homeostasis and dopaminergic pacemaking.

We suggest a novel mechanism for PINK1 pathogenicity in Parkinson’s disease in addition to but not exclusive of mitophagy. …

At this place it should be mentioned that next to dopamine there are two more monoamine neurotransmitters one could look at, namely norepinephrine and in particular Serotonin, which is actually more well-known than dopamine to be related to -as Wikipedia says: “modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vasoconstriction.”

9 Responses to “focus and context, part IIa: ADHD and rejection”

  1. Al Aziz Says:

    Thank you for interesting explanation. So you say that high-rank officials who does
    not like to be critized should better take the pills you mentioned, since they probably have this sickness you describe?

    Some say that criminals with hard childhood, who were rejected and sick should be excused. Do you want to say the same? I think murderers shouldn’t be excused.

  2. nad Says:

    @Al Aziz

    Please see this randform post.

    I feel a bit under time prasure thus I’ll answer later to your question:
    Some say that criminals with hard childhood, who were rejected and sick should be excused. Do you want to say the same? I think murderers shouldn’t be excused.

  3. Al Aziz Says:

    why do you not answer my question?
    Do you have anxiety disorder? :)

  4. Chi An Chenk Says:

    Interesting to hear about the PINK1 connection! While it would certainly also be interesting to hear why Mr. Zuckerberg furthers this PINK1 research and while some folks may eventually hear more about your dopamine and depression theories, I think that – given your own last words in the supplement of today that you owe us an explanation about the role of serotonin.

  5. nad Says:

    @Chi An Chenk
    I do not really write blog posts anymore, so in particular I don’t think I will write anything on serotonin in the foreseeable future. I had made the recent addendum in the above post because I had a recent increased interest in biochemical pathways due to some discussions we had here about the medical treatment of someone who might be a so-called covid-19 long-hauler.
    One of the possible long-hauler symptoms is anxiety and thus the dopamine pathways may give some hints. For “our” long-hauler it seemed though that overarching symptoms of anxiety were luckily mostly only prevalent in certain situational environments, so that for that particular patient other problems, like a Tinnitus or a FEV1 distinctively below 50%, were clearly more important. Since the patient’s notional covid-19 symptoms occurred in February (i.e. no testing) and since – as described in the Atlantic article – a many-months-later antibody test was quite typically negative the patients symptoms are basically regarded as non-covid-19 symptoms and are accordingly treated. Our recent discussions thus centered about the question whether a high dose of “shock” or “stress” medication of prednisolone, which is amongst others immunosuppressive could lead to a massive re-onset of covid-19 symptoms due to a hypothesized Sars-2 virus latency.

    My interest in PINK1 and those discussions about mitochondrial involvement was thus amongst others motivated by the fact that Sars-2 seems to heavily interact with the phosphorylization of kinases. The article “The Global Phosphorylation Landscape of SARS-CoV-2 Infection” doesn’t show PINK1 in a list of kinases whose activities are heavily disrupted by Sars-2, but who knows, may be I just need to look more carefully into their database. At this place it should be mentioned that apparently PINK1 is not only in the brain:

    PINK1 is highly expressed in the brain but it is also expressed throughout the rest of the body and has been associated with disease mechanisms in several tissues41, 42 including the progression of some cancers14, 43.

    So concluding: I don’t know but I just found the connection of PINK1 to dopamine regulation (and thus anxiety), it’s tight connection with cortisone production (and thus inflammation reactions), it’s main location around mitochondria and ER and its connection to oxidative phosphorylation (Fatigue) in mitochondria rather appalling. But I am not a doctor and all of this is highly hypothetical – I just try to form some sort of a rough idea of what might be going on with long-haulers.

  6. Besserwisser Says:

    Regardless whether you think that PINK1 plays a role in the Corona disease or not – you should acknowledge that it seems that PINK 1 is anyways controlled by JNK and ERK1/2.

    This is beautifully explained in the article: “Clearance of Damaged Mitochondria Through PINK1 Stabilization by JNK and ERK MAPK Signaling in Chlorpyrifos-Treated Neuroblastoma Cells”:

    The simple interpretation of these results is that JNK and ERK1/2 signaling regulates PINK1/Parkin-dependent mitophagy in the mitochondria of CPF-treated cells. Overall, this study proposes a novel molecular regulatory mechanism of PINK1 stabilization under CPF exposure.

    and to be more precise this was shown by ROS-regulating JNK and ERK1/2:

    We observed that PINK1 stabilization was selectively regulated by ROS-mediated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling activation but not p38 signaling. In the mitochondria of CPF-exposed cells, pretreatment with specific inhibitors of JNK and ERK1/2 significantly decreased PINK1 stabilization and Parkin recruitment and blocked the LC3-II protein level.

    and as far as I can tell neither JNK nor ERK1/2 (also called MAPK3/1) (both are mitogen activated kinase not to confused with MAPs) ) are in the list of proteins that interact with Sars-2

  7. nad Says:

    Besserwisser wrote: seems that PINK 1 is anyways controlled by JNK and ERK1/2.

    Well “controlled” is quite a strong word. The article uses “regulated” and I understand this as -yes- there seems to be a strong kind of influence, but as far as I understood this sentence “pretreatment with specific inhibitors of JNK and ERK1/2 significantly decreased PINK1 stabilization and Parkin recruitment ..” means also that this influence has its limitations.

    But anyways thanks for pointing out those references. It actually helps to give a first direct indication of exactly that what I had suspected, namely that Sars-2 may damage PINKs functioning. That is in the article you referenced, which provides the SARS-CoV-2 protein interaction map” it is written about ORF6:

    “ORF6 of SARS-CoV antagonizes host interferon signalling by perturbing nuclear transport^33, and the NUP98–RAE1 interaction with ORF6 may perform the same function for SARS-CoV-2.”

    reference 33. is:
    Frieman, M. et al. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 81, 9812–9824 (2007).
    I understand this as that in particular the open reading frame Nr. 6 (ORF6) of Sars and Sars-2 are identical or at least so similar that the corresponding proteins function in the same way.
    But if this is so then this apparently means that ORF6 may “induce ER stress and JNK-dependent apoptosis” according to the article: A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis.
    The authors also mention the STAT blocking but furthermore a suggestive effect on JNK activation:

    One of the possible causes of ORF-6 inducing ER stress is that ORF-6 blocks STAT1 translocation to the nucleus and sequesters host nuclear import factor KPNA2 into rough ER/Golgi membrane. …. Also, ER stress can activate JNK through IRE1, TRAF2 and ASK1 pathways. Since both ORF-6 and ORF-7a are ER-localized proteins, we hypothesized that ER stress induced by these two proteins will lead to Caspase-3 and JNK activation.

    So this is still just a hypothesis but I actually think that there may be even more connections. Like it might be that parkin recruitment and thus “ubiquitylation” (and thus mitophagy) of damaged mitochondria is eventually directly impaired by Sars-2. I am not sure if you want to hear more about this very vague hypothesis, finally I am hypothizing about things I barely understand.

    addition made on Oct 10, 2020: The phosphorylation landscape article remarks that MAPK1/3 is probably also affected by Sars-Cov-2:

    Kinases predicted to be downregulated include several cell cycle kinases (CDK1/2/5 and AURKA), cellgrowth-related signaling pathway kinases (PRKACA, AKT1/2,MAPK1/3, and PIM1), and the cytoskeleton regulators (PAK1),among others.

    Figure S2A displays for MAPK1 and MAPK3 a considerably small negative change in “predicted kinase activities across different time points post-infection.” This looks however differently for Figure S3E.

  8. Blasentee Says:

    I had a recent increased interest in biochemical pathways due to some discussions we had here about the medical treatment of someone who might be a so-called covid-19 long-hauler.

    What’s up with that? Is the patient still alive? Did the colesterin help?

  9. Thorsten Trinkvogt Says:

    Regardless whether you think that PINK1 plays a role in the Corona disease or not – you should acknowledge that it seems that PINK 1 is anyways controlled by JNK and ERK1/2.

    Nad – Please keep up your writings and don’t feel irritated by critique!
    All efforts should be welcome in order to fight this Corona crisis!

    Likewise literature should be open – I find it is not so good that Springer requires registration for reading Corona articles (example ). But of course some people need to have an income.

    Did you meanwhile find out whether the ORF6 of Sars-2 and Sars is the same? I think the gene sequences are open source.

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