# I love the way you overexcite

## But first… [Yo, a new arch dropped!](https://venturebeat.com/business/liquid-ais-new-star-model-architecture-outshines-transformer-efficiency)

![](https://cdn.hashnode.com/res/hashnode/image/upload/v1733372476440/36af61a9-f777-4bff-9585-ed5e28b56230.png align="center")

Should’ve screenshotted myself, we’re on step 6 now…

🔖 [Paper link](https://arxiv.org/pdf/2411.17800)

* Using **STAR genome** - hierarchical NN architecture encoding
    
* **Evolutionary algorigthm to improve the network architecture** for a particular case
    
* **Cache** ⬇️90% compared to transformers and ⬇️37% compared to hybrid models (e.g. Mamba-based)
    
* **Parameter** [count](https://www.youtube.com/watch?v=6AXPnH0C9UA): ⬇️13% <s>(infer slowly slowly slowly getting faster once I start inferring it’s really hard to stop)</s>
    

Anyway, putting the bets on Liquid AI as both their liquid network and STAR are good (IMO):

![Liquid Neural Networks: A Paradigm Shift in Artificial Intelligence | by  Shinde Vinayak rao patil | Medium](https://miro.medium.com/v2/resize:fit:1400/1*FqpxOqhXHj5Sv5nIbL8inw.png align="left")

## [So the mom and pa were right?](https://www.reddit.com/r/ScientificNutrition/comments/1h6byo5/depressive_symptoms_and_vegetarian_diets_results/)

* **Exclusion of any food group** of \[meat, fish, vegetables\] ➡️ increase of depressive symptoms Odds Ratio, adjusted for age, sex, sociodemographics etc.:
    
    * 🚫 Meat → 1.37 \[1.24–1.52\]
        
    * 🚫 Fish → 1.40 \[1.31–1.50\]
        
    * 🚫 Vegetables → 1.71 \[1.49–1.97\]
        
    * 🍣 Pesco-vegetarian → 1.43 \[1.19–1.72\]
        
    * 🍳 Lacto-ovo-vegetarian → 1.36 \[1.09–1.70\]
        
* Full table:
    
    ![](https://cdn.hashnode.com/res/hashnode/image/upload/v1733373494928/0b571689-1f84-4454-8ec4-f01f184792f7.png align="center")
    
* Don’t deprive yourself of more than 1 product:
    

![](https://cdn.hashnode.com/res/hashnode/image/upload/v1733373556501/09b53e1b-8a65-48f2-bb93-513397e1534d.png align="center")

* A reasonable Reddit comment: **where’s ketogenic** in here?
    

![Ketogenic diet for depression: A potential dietary regimen to maintain  euthymia? - ScienceDirect](https://ars.els-cdn.com/content/image/1-s2.0-S0278584621000166-gr1.jpg align="center")

* That, and **kynurenine effect** (wrote on it [while postCOVID bitchslapped everyone](https://t.me/ohmyboi/758)):
    
    * ⬆️ Kynurenic acid ([⬇️ excitability + neuroprotective + decreased in depression and bipolar + antagonist at NMDA, AMPA, Kainate receptors](https://en.wikipedia.org/wiki/Kynurenic_acid))
        
    * ⬇️ [Kynurenine](https://en.wikipedia.org/wiki/Kynurenine) (decreased in bipolar + increased in depression, schizophrenia and Alzheimer’s + metabolizes into potentially excitotoxic Quinolinic acid)
        

![Changes in tryptophan and kynurenine pathway metabolites in the blood of  children treated with ketogenic diet for refractory epilepsy - Seizure -  European Journal of Epilepsy](https://www.seizure-journal.com/cms/10.1016/j.seizure.2019.05.006/asset/6ed2cd1b-784a-4df4-8f1a-551a59ef7708/main.assets/gr3_lrg.jpg align="left")

And, huh (don’t forget the [6%/year kidney stone risk, and time accordingly](https://t.me/ohmyboi/774))

![New Study: Serious Mental Illness Improves on Ketogenic Diet | Psychology  Today](https://cdn.psychologytoday.com/sites/default/files/styles/image-article_inline_full_caption/public/field_blog_entry_images/2022-07/keto_diet_for_mental_illness-case_series_abstract.png?itok=sRGL614y align="center")

## So, bipolar…

### [Lithium is modulatory](https://t.me/psy_and_neuro/2999). How exactly?

![](https://psyandneuro.ru/wp-content/uploads/2023/11/Snimok-jekrana-2023-11-28-v-16.14.39.png align="center")

Been [rewriting a lithium overview before](https://posts.teleogenic.com/going-mediterranean), time to add some more insights.

#### Mechanisms of lithium, revisited

* Inhibits **GSK-3b** (influences metabolism and the whole nervous system cell lifecycle) → neuroprotection and normotimic effects. **But you’re not here for that, right?**
    
* ⬆️ **glutamate** reuptake with chronic use
    
* ⬇️ postsynaptic **NMDA** activation ← ⬇️ **phosphorylation** *(papa ATP gives the P to tha cell, and she wan the P so bad ayy)*
    
    ![Phosphorylation Basics](https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/marketing/global/images/technical-documents/articles/protein-biology/protein-labeling-and-modification/phosphorylation-substrate-level-small/phosphorylation-substrate-level-small.png align="center")
    
* ⬇️ excess dopamine signalling in PFC (presumably [akin to what aripiprazole does?](https://www.researchgate.net/figure/Dopamine-system-stabilizer-DSS-activity-of-aripiprazole_fig2_351425776))
    

---

#### Inflammation/autoimmune and mental health

* A recent study had shown **48.1% of bipolar patients** have autoimmune or allergic diseases
    
* Cytokines [influence kynurenine pathway at large](https://www.mdpi.com/1422-0067/22/11/5903) in a complex interplay:
    
    ![Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid  System and the Kynurenine Pathway in Depression](https://pub.mdpi-res.com/ijms/ijms-22-05903/article_deploy/html/images/ijms-22-05903-g001.png?1622552757 align="left")
    
* Cytokines can also influence BBB permeability → antibodies and [molecular mimicry agents](https://www.nature.com/articles/s41467-024-53658-8) going in and out like it’s their home
    
* Different studies incl. Modabbernia et al. (2013) found that bipolar has:
    
    * ⬆️ IL 2,4,6, TNF-α, sIL-6R
        
    * Mania → ⬆️ IL-1 antagonist (IL-1RA), sIL-2R & sTNFR1
        
    * Depression → ⬆️ IL-10 (weird as it’s [immunomodulatory](https://t.me/ohmyboi/808))
        
    * ⬆️ IL-1β & kynurenic acid in spinal fluid
        
    * Post-mortem: ⬆️MyD88, NF-κB → IL-1 pathway activators
        
        ![Frontiers | Cleavage-Mediated Regulation of Myd88 Signaling by  Inflammasome-Activated Caspase-1](https://www.frontiersin.org/files/Articles/790258/fimmu-12-790258-HTML-r1/image_m/fimmu-12-790258-g008.jpg align="left")
        
    * ⬆️ PDE4B → ⬆️ inflammation due to cAMP degradation
        
    * ⬆️ neutrophil/lymphocyte ratio, ⬆️ RBC/lymphocytes during mania
        

---

#### Lithium and immunity (likely downstream effects)

* ⬆️ IGF-1 expression in lithium responders. IGF-1 inhibits apoptosis → ⬆️ cell survival
    
* ⬆️ TNF-α & IL-4 after 8 weeks of lithium
    
* ⬆️ IL-1β and ⬇️ IL-6 after 6 months of lithium
    

#### Conclusion (criminally simplified)

⬆️ Inflammation → ⬆️ Involvement of kynurenine pathway → ⬆️ Quinolinic acid ⬇️ 5-HTP ⬇️ Kynurenine → (chance of) ⬆️ Excitability

### [PVT calcium intake/myto dysfunction and bipolar](https://www.nature.com/articles/d42473-024-00245-6)

1. Tadafumi Kato, a neuroscientist at Juntendo University in Tokyo
    

* “In mice, the neurons in the PVT **branch off into both the amygdala**, influencing negative emotions like fear, and **to the nucleus accumbens**, influencing positive emotions linked to reward,” says Kato.
    
    ![Frontiers | The Paraventricular Thalamus as a Critical Node of Motivated  Behavior via the Hypothalamic-Thalamic-Striatal Circuit](https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/706713/fnint-15-706713-HTML/image_m/fnint-15-706713-g001.jpg align="left")
    
* “If so, it would make sense that **overexcitement of the PVT would play a central role in the extreme mood swings** associated with bipolar disorder,” he says.
    

2. Mie Kubota-Sakashita
    

* ⬆️ blood cell calcium in bipolar
    
* 🥴 altered mitochondrial calcium uptake in bipolar
    

#### Conclusion (far-fetched)

Dysfunctional mitochondrial function in PVT (Paraventricular nucleus of the thalamus) → ⬆️ calcium uptake → bipolar

### Limit overexcitability and…?

As I’ve [mentioned before](https://posts.teleogenic.com/neuropharmacology-rants), overexcitability brings a lot to the table - and almost never that’s tasty stuff, mostly nasty.

Things start to look that **overexcitability / inflammation / mitochondrial dysfunction** in separate brain regions (especially PVT given its connectivity) can lead to a lot of trouble: bipolar, schizophrenia, ASD, ADHD etc.

So, I’d say we can expect four drug MoA patterns emerging:

* directly **limiting excitability** or increasing plasticity → acting on ion channels or glutamate/glycine/ampakine/kainate systems, e.g. modulators like rapastinel/[apimostinel](https://en.wikipedia.org/wiki/Apimostinel)/[zelquistinel](https://en.wikipedia.org/wiki/Zelquistinel). Just have a look at, say, list of [investigational antidepressants](https://en.wikipedia.org/wiki/List_of_investigational_antidepressants)
    
* **mitochondrial** enhancers → overmitochondriating the possible deficits
    
* targeted **gene therapy** once potential targets are sifted out
    
* **anti-inflammatory** or **anti-kynurenine**\-pathway-craps treatment
    

### [Memantine and bipolar...](https://pmc.ncbi.nlm.nih.gov/articles/PMC4274590/)

[And again](https://bipolarnews.org/?p=1110), and [again](https://psychopharmacologyinstitute.com/section/memantine-potential-indications-in-children-and-adolescents-2675-5251)

![Use of Memantine in Bipolar Disorder Present evidence and future research  Gustavo Jesus Centro Hospitalar Psiquiátrico de Lisboa April 27th, ppt  download](https://images.slideplayer.com/42/11412663/slides/slide_18.jpg align="left")

* **LAMotrigine + MEMantine → ⬆️ antidepressive effects and faster onset compared to LAM + PLAcebo**
    
* This bad boy [can potentially](https://www.sciencedirect.com/science/article/abs/pii/S0304394008002097) ⬆️ kynurenic acid (the good one) [production](https://www.mdpi.com/2073-4409/13/17/1424)
    

## And ADHD…

### [Disrupted melatonin and ADHD](https://www.reddit.com/r/science/s/GFUZF4mUHf)

![Potential Indications of Melatonin and Secretin in Children and Adolescents  - Psychopharmacology Institute](https://cdn.psychopharmacologyinstitute.com/transcripts/%5B5609%5D%20Potential%20Indications%20of%20Melatonin%20and%20Secretin/image9.jpeg align="center")

* ⬆️ IL-6 in ADHD
    
* Melatonin → ⬇️ IL-6 → any defects in melatonin secretion would lead to an increase in inflammation among other things
    

---

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