iiinova — where your digital self keeps evolving

Bratislav Misic @misicbata.bsky.social · 25/09/2026

6️⃣ There are a few other fun things in the supplement, including the mapping of other aquaporins and comparisons with MRI measurements of the glymphatic system (intrathecal CSF tracer gadobutrol).

111

Bratislav Misic @misicbata.bsky.social · 25/09/2026

5️⃣ Finally, we show that peritumoral edema is most frequent in AQP4-enriched regions and is further shaped by regional inflammatory tone.

110

Bratislav Misic @misicbata.bsky.social · 25/09/2026

4️⃣ Incorporating normative PET markers of neuroinflammation typically strengthens the spatial alignment between AQP4 expression and disease atrophy, suggesting that inflammatory tone and glymphatic-related architecture jointly shape vulnerability.

120

Bratislav Misic @misicbata.bsky.social · 25/09/2026

3️⃣ Turning to neurodegeneration, we find that atrophy patterns across multiple neurodegenerative diseases co-localize with AQP4 expression—most strongly for tau and TDP-43 proteinopathies—and high-atrophy regions lie close to AQP4 hotspots.

110

Bratislav Misic @misicbata.bsky.social · 25/09/2026

2️⃣ Linking AQP4 expression to vascular organization, we find that AQP4-enriched regions show lower normative blood perfusion and lower vein density, suggesting that this axis is not simply explained by vascular supply or large-vessel anatomy.

110

Bratislav Misic @misicbata.bsky.social · 25/09/2026

1️⃣ Aquaporin-4 (AQP4) water channels support the glymphatic system, a brain-wide pathway that clears cerebral waste products. Here we use AQP4 gene expression as a molecular anchor to reconstruct a whole-brain glymphatic-related topography.

111

Bratislav Misic @misicbata.bsky.social · 24/09/2026

3️⃣ We showcase three walkthroughs of biologically-relevant questions that can be answered using netneurotools, related to structure-function coupling, multimodal connectivity, dynamics and gradients.

120

Bratislav Misic @misicbata.bsky.social · 24/09/2026

2️⃣ By design, netneurotools is trainee-centric and focuses on accessibility and usability. The functions are grouped into intuitive modules, covering the full lifecycle of a project. Like "desire paths" in urban design — we only pave the routes people are already walking.

130

Bratislav Misic @misicbata.bsky.social · 17/03/2026

8⃣ Finally, we replicate all findings using alternative processing and analytical choices. We also conduct multiple sanity check/domain knowledge experiments, including detailed analysis of peptides related to feeding, sexual dimorphism and vasomodulation.

120

Bratislav Misic @misicbata.bsky.social · 17/03/2026

7⃣ Evolutionary analysis indicates extended positive selection for neuropeptides in early mammals, suggesting that refinement of neuropeptides coincides with the emergence of neocortex and higher cognitive function.

120

Bratislav Misic @misicbata.bsky.social · 17/03/2026

6⃣ To investigate the behavioural consequences of distributed neuropeptide systems, we apply meta-analytic decoding to neuropeptide maps and show a gradient of functions that mirrors neuropeptide expression, from sensory-cognitive to reward and bodily functions.

120

Bratislav Misic @misicbata.bsky.social · 17/03/2026

5️⃣ Looking to related chemical signalling systems, we find that neuropeptides preferentially co-localize with metabotropic neurotransmitters, suggesting a brain-wide correspondence between slow-acting molecular signaling mechanisms.

130

Bratislav Misic @misicbata.bsky.social · 17/03/2026

4️⃣ How does neuropeptide organization align with the anatomy of the hypothalamus, the nexus of neuropeptide communication? Across eight hypothalamic nuclei, we find a tuberal to mammillary gradient (tracking embryogenesis), and a mediolateral gradient (tracking cytoarchitecture).

130

Bratislav Misic @misicbata.bsky.social · 17/03/2026

3⃣ Most neuropeptide receptors are highly expressed either in cortex or subcortex, delineating an anatomical cortical-subcortical gradient. We find lots of 'textbook' hits (e.g. oxytocin in amygdala, leptin in hypothalamus, opioid in accumbens).

120

Bratislav Misic @misicbata.bsky.social · 17/03/2026

2⃣ Using gene transcription as a proxy, we reconstruct a topographic cortical and subcortical atlas of neuropeptide receptors for 38 neuropeptide receptors, across 14 different neuropeptide families.

120

Bratislav Misic @misicbata.bsky.social · 17/03/2026

1⃣ Neuropeptides are larger amino acid chains that are released from presynaptic axonal terminals into extra-cellular space, thereby acting over a wide range of post-synaptic boutons. They modulate many functions, including sleep, pain, feeding, reward and social cognition.

120

Bratislav Misic @misicbata.bsky.social · 17/03/2026

Organization of neuropeptide systems in the human brain | doi.org/10.1038/s415... Neuropeptides are functionally diverse signaling molecules in the brain and body. @cebric.bsky.social curates an atlas of neuropeptide receptors and relates it to brain function @natneuro.nature.com 🧩 🧠 ⤵️

13919

Bratislav Misic @misicbata.bsky.social · 11/03/2026

8️⃣ Finally we validate synapse density maps in an independent dataset, and confirm our findings are not driven by SNR, in-scanner motion, nor the spatial localization of different cell types.

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

7️⃣ Could short protein lifetime reflect greater synaptic flexibility necessary for more complex processing? We find that short-lifetime PSD95 synapses (but not long-lifetime PSD95 nor SAP102) increase sc-fc coupling _specifically_ in awake (not anaesthetized) mice.

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

5️⃣ Does global network embedding also reflect synaptic architecture? We find that SAP102 synapse density correlates with SC degree while long-lifetime PSD95 synapse density correlates with FC degree. In both cases, longer synapse protein lifetime = stronger relationship.

120

Bratislav Misic @misicbata.bsky.social · 11/03/2026

4️⃣ Long-lifetime PSD5 synapse density is most associated with features of time-invariant stationarity, and SAP102 with features that pick up on the timing and presence of extreme events. (short-lifetime PSD95 synapses are associated with next to nothing)

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

3️⃣ Now for the dynamics: panels a and b show example time-series pulled from regions with variable synapse density (↖️= low density, ↘️= high density). We saw patterns but ran a time-series phenotyping analysis (measuring 6000+ features for each time-series) to confirm.

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

2️⃣ First we map 37 excitatory synapse types based on the synaptic scaffolding protein they express, broadly categorized as long-lifetime PSD95, short-lifetime PSD95, and SAP102 synapses. (“Lifetime” refers to protein turnover rate - it’ll be important)

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

Synaptome architecture shapes regional dynamics in the mouse brain | doi.org/10.1371/jour... How do diverse synapses relate to the spatial patterning of whole-brain dynamics? Justine Hansen explores @plosbiology.org ⤵️

13616

Bratislav Misic @misicbata.bsky.social · 11/03/2026

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

5️⃣ Finally, we show that peritumoral edema is most frequent in AQP4-enriched regions and is further shaped by regional inflammatory tone.

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

100

Bratislav Misic @misicbata.bsky.social · 11/03/2026

110

Bratislav Misic @misicbata.bsky.social · 11/03/2026

120

Bratislav Misic @misicbata.bsky.social · 11/03/2026

Spatial organization of AQP4 channels in the human brain: links with perfusion, edema, and disease vulnerability | doi.org/10.64898/202... Aquaporins are a key component of the brain’s glymphatic system. How are they distributed and how do they relate to healthy brain function and dysfunction? ⤵️

1187

Bratislav Misic @misicbata.bsky.social · 13/02/2026

4️⃣ This suggests that, although population variance is generally greater in subcortex than in cortex, subcortical receptor density is more spatially stable. Indeed, receptors that vary more across brain regions than across individuals also demonstrate greater out-of-sample spatial consistency.

110

Bratislav Misic @misicbata.bsky.social · 13/02/2026

3️⃣ Looking at the distributions more closely, we see greater inter-individual variability in subcortex. How do inter-individual and inter-regional variability compare? Cortex: similar or greater variability across people than regions. Subcortex: less variability across people than regions.

100

Bratislav Misic @misicbata.bsky.social · 13/02/2026

2️⃣ Here they are 😀 Group coefficient of variation maps for 12 receptors and transporters, across >700 individuals. Cortex + subcortex.

110

Bratislav Misic @misicbata.bsky.social · 13/02/2026

Inter-individual variability of neurotransmitter receptor and transporter density in the human brain | doi.org/10.1007/s004... How do neuroreceptor distributions vary across people?

13414

Bratislav Misic @misicbata.bsky.social · 18/12/2025

130

Bratislav Misic @misicbata.bsky.social · 18/12/2025

100

Bratislav Misic @misicbata.bsky.social · 18/12/2025

netneurotools: a trainee-oriented approach to network neuroscience | doi.org/10.1101/2025... Our lab’s internal toolkit for accomplishing everyday tasks in brain imaging ⤵️

17535

Bratislav Misic @misicbata.bsky.social · 17/09/2025

6️⃣ So far, we considered considered synthetic graphs, but what about real brains? We implement dMRI brain networks as reservoirs. Again, hierarchical modularity positively contributes to computational performance. Amazingly, reservoir timescales correlate with empirical timescales derived from MEG.

110

Bratislav Misic @misicbata.bsky.social · 17/09/2025

5️⃣ How well do these networks perform multiple tasks simultaneously? We assign memory tasks to half the modules, and non-linear transformation tasks to the other half. Again, we find that higher-order hierarchical modular networks consistently outperform their lower-order counterparts.

110

Bratislav Misic @misicbata.bsky.social · 17/09/2025

4️⃣ To uncover the topological underpinnings of these differences in dynamics, we consider the motif composition of the reservoir. More complex motifs containing at least three edges are all enriched in higher-order hierarchical modular networks, supporting more complex computations.

110

Bratislav Misic @misicbata.bsky.social · 17/09/2025

3️⃣ How does hierarchical modularity shape dynamics to improve memory? We compute timescales from nodal time series at criticality. Higher-order hierarchical modular reservoirs show more variability in timescales, yielding a bigger pool of timescales and richer temporal expansion of input signals.

110

Bratislav Misic @misicbata.bsky.social · 17/09/2025

2️⃣ We start by evaluating the reservoir’s ability to preserve representations of past stimuli with the widely used memory capacity task. Higher-order hierarchical modular networks consistently perform best, particularly at criticality.

110

Bratislav Misic @misicbata.bsky.social · 17/09/2025

1️⃣ We use stochastic block models to generate synthetic multi-level hierarchical modular networks. We then implement them as reservoirs to evaluate their cognitive capacity.

110

Bratislav Misic @misicbata.bsky.social · 17/09/2025

Neuromorphic hierarchical modular reservoirs | doi.org/10.1101/2025... How does hierarchical modularity shape computational function? ⤵️

1229

Bratislav Misic @misicbata.bsky.social · 16/09/2025

8️⃣ Finally, we consider spinal- and bulbar-onset subtypes. Epicenters in spinal-onset are mainly in primary motor cortex and paracentral lobule. In bulbar-onset, epicenters are prominent in lower paracentral gyrus and inferior frontal gyrus, aligning with the clinical presentation of the subtypes.

120

Bratislav Misic @misicbata.bsky.social · 16/09/2025

7️⃣ If cortical epicenters reflect the spatial focus of ALS pathology, do they also correlate with the clinical manifestation? Indeed: epicenter maps are correlated with poor motor function, including abnormal index finger and foot tapping scores, daily physical function, and muscle tone.

110

Bratislav Misic @misicbata.bsky.social · 16/09/2025

6️⃣ We next ask whether the network epicenters of ALS atrophy are enriched for specific biological processes, cellular components, and cell types.

120

Bratislav Misic @misicbata.bsky.social · 16/09/2025

5️⃣ We next investigate whether spreading is more likely between regions that share biological features, including (1) gene expression, (2) neurotransmitter receptors, (3) laminar differentiation, (4) metabolism, and (5) hemodynamics.

120

Bratislav Misic @misicbata.bsky.social · 16/09/2025

4️⃣ We apply two methods to back-reconstruct the spreading trajectory and infer the most likely cortical location of the epicenter: (1) a network-based node ranking method, and (2) a susceptible-infected-removed (SIR) dynamical model. Epicenter rankings are consistent with ALS pathological staging.

110