Regenerative Biology: In-Depth Description

Regenerative Biology is the study of how organisms repair, replace, or restore damaged or missing cells, tissues, organs, and even entire body parts to regain full physiological function. The field focuses on understanding the intrinsic cellular and molecular mechanisms that govern tissue renewal and exploring how these natural abilities—which vary vastly across different species—can be stimulated or harnessed to repair injuries and cure diseases.

Gut Microbiome Influences Hydrogen Supplement for Sleep

Principal coordinate analysis (PCoA) of the gut microbiome before the intervention. Placebo (left) and hydrogen (right) groups, respectively. In the hydrogen group, there is distinct clustering between individuals classified as ‘improved’ or ‘not improved’ based on whether their mean change in sleep-quality VAS (Visual Analog Scale) indicated greater or lesser improvement than the median.
Image Credit: Fumiko Higashikawa, Keishi Kanno. Scientific Reports. July 27, 2026

Scientific Frontline: Extended "At a Glance" Summary: Gut Microbiome and Hydrogen Supplementation on Sleep Quality

The Core Concept: A clinical study investigating how individual variations in gut hydrogen-producing bacteria affect the efficacy of exogenous molecular hydrogen supplementation on improving sleep quality and reducing mental stress.

Key Distinction/Mechanism: While overall results showed no significant difference between the hydrogen supplementation group and the placebo group, subgroup analyses revealed that individuals with a lower baseline abundance of gut hydrogen-producing bacteria experienced greater improvements in sleep quality. The mechanism suggests that exogenous hydrogen provides a more pronounced biological effect in individuals who naturally produce less hydrogen through microbial fermentation, whereas those with high baseline production may not benefit additionally from supplementation.

Origin/History: The study builds on two decades of research establishing the antioxidant, anti-inflammatory, and anti-apoptotic properties of molecular hydrogen, particularly its ability to mitigate oxidative stress linked to sleep disturbances.

Major Frameworks/Components:

• An 8-week, randomized, double-blind, placebo-controlled clinical trial involving 44 healthy participants.
• Supplementation consisted of 0.9 mg per day of hydrogen via jelly packets (or air in placebo).
• Fecal sample analysis for gut microbiome profiling, utilizing principal coordinate analysis (PCoA) and beta-diversity analysis.
• Identification of significant interindividual variation in hydrogen-producing bacterial genera (e.g., Bacteroides), with combined relative abundance ranging from 0.1% to 57.5%.

MS Treatment Rituximab Linked to Bowel Disease Risk

Image Credit: Scientific Frontline / stock image

Scientific Frontline: Extended "At a Glance" Summary: Rituximab and Inflammatory Bowel Disease Risk

The Core Concept: Rituximab, an anti-CD20 therapy frequently used to treat multiple sclerosis, is associated with a significantly increased, though absolutely low, risk of developing inflammatory bowel disease compared to other highly effective multiple sclerosis treatments.

Key Distinction/Mechanism: While highly effective at preventing multiple sclerosis relapses by targeting CD20-positive B cells, rituximab is linked to an approximately tenfold higher relative risk of inflammatory bowel disease, particularly Crohn's disease, when compared to alternative therapies like natalizumab, dimethyl fumarate, and fingolimod.

Major Frameworks/Components:

• The study analyzed data from Swedish registers covering nearly 14,000 treatment episodes in patients with relapsing-remitting multiple sclerosis.
• Researchers compared rituximab against three other therapies: natalizumab, dimethyl fumarate, and fingolimod.
• The absolute risk remains low, with fewer than 2% of patients in any treatment group developing inflammatory bowel disease within 10 years of starting treatment.
• The risk increase translates to roughly one additional case of inflammatory bowel disease for every 131 patients treated with rituximab for five years instead of an alternative treatment.

SARS-CoV-2 Infects Human Neural Stem Cells

Photo shows Ann Song (left), Cori Zuvia (center), and Prue Talbot.
Photo Credit: UCR/Talbot lab

Scientific Frontline: Extended "At a Glance" Summary: Human Neural Stem Cell Susceptibility to SARS-CoV-2

The Core Concept: Human neural stem cells, the foundational cells for the brain and spinal cord, demonstrate a high susceptibility to infection by SARS-CoV-2, including the original viral spike and the Omicron variants (BA.1 and BA.2).

Key Distinction/Mechanism: The study used modified, non-replicating virus particles (pseudoparticles) to safely observe infection. The research revealed that Omicron pseudoparticles infect neural stem cells primarily through endocytosis (cell engulfment), a pathway that could be blocked by the compound filipin. Furthermore, neural stem cells possess a sparse cell-surface sugar layer (glycocalyx); removing these sugar molecules increased viral entry twofold to fourfold, suggesting the layer normally limits viral access.

Origin/History: The research, led by Professor Prue Talbot at the University of California, Riverside, and published in PLOS One (October 2026), addresses the potential consequences of maternal COVID-19 infection on fetal neurodevelopment, aligning with large health-record studies linking maternal infection to increased risks of neurodevelopmental diagnoses in children by age three.

Major Frameworks/Components:

• Ectodermal Differentiation: Human embryonic stem cells differentiated into neural stem cells.
• Viral Entry Mechanisms: Utilization of spike pseudoparticles to model SARS-CoV-2 cellular invasion via endocytosis.
• Glycocalyx Interference: The role of cell-surface sugar groups in modulating viral access.

Cold Temperatures, BH2, and Longevity: New Anti-Aging Mechanism

Moderate cold increases BH2 levels in the muscle of the nematode C. elegans. The muscle is an important source of BH2 and acts as a metabolic hub.
Image Credit: © David Vilchez / CECAD

Scientific Frontline: Extended "At a Glance" Summary: Cold Temperatures, BH2, and Longevity

The Core Concept: Moderately cold temperatures activate a metabolic pathway involving the metabolite dihydrobiopterin (BH2), which delays aging and protects against age-related neurodegenerative diseases by preserving protein homeostasis.

Key Distinction/Mechanism: Muscle tissue acts as a central hub, synthesizing and releasing BH2, which is transported to other tissues to induce the production of the amino acid tyrosine, strengthening the cellular machinery responsible for maintaining functional proteins.

Major Frameworks/Components:

• Caenorhabditis elegans utilized as the primary in vivo model organism.
• Human cell models of Huntington's disease and amyotrophic lateral sclerosis (ALS) used for validation.
• Proteostasis (protein homeostasis) identified as the primary protective mechanism against protein misfolding.
• Supplementation of BH2 and tyrosine demonstrated protective effects independently of temperature changes.

Biohybrid Sensors: Locusts & Nanomaterials Detect Chemicals

A future hybrid system could deploy these locusts to detect chemical vapors in search-and-rescue operations or war zones, quickly identifying particular chemicals based on neural response signatures in the organism and pinpointing their locations before responders enter the scene. The foam on the antenna and wing can enhance an organism’s innate sensory system, collect samples, and detect trace chemical signatures.
Photo Credit: Raman lab

Scientific Frontline: Extended "At a Glance" Summary: Plasmonic Foam-Enabled Dual-Modal Biohybrid Chemical Sensor

The Core Concept: A hybrid chemical sensing approach that augments the innate olfactory system of locusts with a surface-enhanced Raman scattering (SERS) substrate—specifically, a highly porous collagen foam—applied to their antennae and wings to improve trace chemical detection and sample collection.

Key Distinction/Mechanism: While living insect olfactory systems are extremely sensitive but limited in the breadth of compounds they can identify, and synthetic sensors are highly accurate but lack biological nimbleness, this system merges both. The ultralight nanomaterial coating boosts signals from targeted molecules (including TNT) without impairing the insect's natural sensory or physiological functions, allowing the biological and artificial systems to complement each other.

Major Frameworks/Components:

• SERS (surface-enhanced Raman scattering) substrate techniques for boosting molecular signals on nanostructure metal surfaces.
• Plasmonic nanomaterials utilized as an ultralight collagen foam.
• Integration with biological insect olfactory receptor neurons (specifically in locusts, which possess roughly 50,000 such neurons per antenna).

Machine Learning Detects Radiation via Standard Blood Tests

Hang Chang, a computational staff scientist in the Biosciences Area, examines microscopy images of tissue. Chang developed a machine learning model to identify radiation exposure based on results from a complete blood count (CBC).
Photo Credit: Robinson Kuntz/Berkeley Lab

Scientific Frontline: Extended "At a Glance" Summary: Sparse CBC Biodosimetry Model

The Core Concept: Sparse CBC is an open-source machine learning model designed to detect and quantify a subject's past radiation exposure using data from a standard complete blood count.

Key Distinction/Mechanism: Unlike traditional biodosimetry methods that require time-intensive, specialized laboratory testing to identify physical DNA damage, this approach uses unsupervised sparse representation learning to uncover hidden biomarker signatures within routine clinical blood tests across a wide range of doses and post-exposure timeframes.

Origin/History: Developed by researchers at Lawrence Berkeley National Laboratory and published in Nature's Communications Medicine in 2026, the project was funded by the Intelligence Advanced Research Projects Activity under the Targeted Evaluation of Ionizing Radiation Exposure program.

Major Frameworks/Components:

• Biodosimetry: The measurement of biological changes to confirm and estimate absorbed radiation doses.
• Standard complete blood count: The routine clinical input data used to identify complex, system-wide biomarker signatures.
• Unsupervised sparse representation learning: The specific machine learning algorithm utilized to analyze complex data patterns and extract exposure signals that are not apparent from individual parameters.
• Genetically diverse animal models: The use of curated laboratory mice to simulate human genetic diversity, ensuring the algorithm accounts for variables like age, health status, and genetic background when calculating radiation response.

Gut Microbiome Predicts Mild Cognitive Impairment Decline

Image Credit: Scientific Frontline / AI generated

Scientific Frontline: Extended "At a Glance" Summary: Gut Microbiome and Mild Cognitive Impairment Prediction

The Core Concept: A diagnostic approach utilizing machine learning to analyze the composition of gut bacteria and chemical metabolites in fecal samples to identify individuals with mild cognitive impairment and predict their rate of memory and cognitive decline.

Key Distinction/Mechanism: Rather than relying solely on cognitive testing or brain imaging, this method analyzes the combined profile of both gut bacteria (microbiome) and the chemicals they produce (metabolites) as an early, non-invasive biomarker for neurological changes.

Major Frameworks/Components:

• Diagnostic Markers (Mild Cognitive Impairment): Elevated levels of Izemoplasmatales spp. and the chemical proline; decreased levels of Ruminococcus spp., Lachnospira spp., and fumaric acid.
• Prognostic Markers (Faster Decline): Higher initial levels of Bilophila spp., arginine, aspartic acid, and hypoxanthine; lower levels of Coprococcus spp. strongly linked to faster cognitive decline over a one-year follow-up.
• Analytical Method: Application of machine learning algorithms to distinguish between healthy individuals and those with cognitive impairment with high accuracy.

Enzyme ADK Predicts Leukemia Response to Triciribine

Image Credit: Scientific Frontline / AI generated 

Scientific Frontline: Extended "At a Glance" Summary: Triciribine and Adenosine Kinase in Acute Lymphoblastic Leukemia

The Core Concept: Adenosine kinase (ADK) is an enzyme essential for activating the therapeutic compound triciribine in patients with acute lymphoblastic leukemia (ALL). Recent multi-omics research indicates that higher cellular levels of ADK correlate with a stronger inhibitory response against leukemia cells, presenting a critical biomarker for targeted cancer treatments.

Key Distinction/Mechanism: Unlike many conventional treatments that operate broadly, triciribine must be intracellularly converted into its active form by ADK. Once activated, the compound disrupts the synthesis of essential nucleic acid building blocks (DNA and RNA), thereby halting the growth and division of leukemia cells.

Major Frameworks/Components:

• Target Compound: Triciribine, an antimetabolite drug previously hindered by variable clinical efficacy.
• Enzymatic Catalyst: Adenosine kinase (ADK), the protein responsible for metabolizing triciribine into its active, cancer-inhibiting state.
• Multi-Omics Profiling: The robust analytical approach used to map large networks of cellular proteins, revealing that triciribine disrupts the production of RNA and DNA building blocks in ALL cells.

How Cellular Senescence Rewires the Human Proteome

Proteomics analysis reveals coordinated changes during senescence.
Image Credit: ©: IMB

Scientific Frontline: Extended "At a Glance" Summary: Cellular Senescence and Proteome Rewiring

The Core Concept: Cellular senescence is a biological state in which cells permanently stop dividing but remain metabolically active, undergoing widespread, coordinated changes to thousands of proteins that drive the aging process.

Key Distinction/Mechanism: Unlike general cellular stress responses (such as starvation or oxidative stress), senescence involves a highly specific "fingerprint" of proteomic rewiring, fundamentally altering how cells regulate genes, organize chromatin, and manage protein synthesis and disposal.

Origin/History: Published in Nature Communications in October 2026, this detailed multi-omics research was led by scientists at the Institute of Molecular Biology (IMB) and the University Medical Center in Mainz, Germany.

Major Frameworks/Components:

• Proteomics and Multi-omics: Utilizing mass-spectrometry-based proteomics, researchers quantified nearly 6,000 proteins across successive stages of cell division leading to full senescence.
• Chromatin Reorganization: A significant decline in proteins responsible for gene transcription, RNA processing, and chromosome organization, indicating an ordered restructuring of the nucleus.
• Proteostasis Dysfunction: Reduced activity in the cell's primary protein disposal systems (autophagy and the proteasome), accompanied by over 500 proteins becoming less soluble and prone to disease-causing aggregation.
• Protein Tagging Alterations: Increased activity of specific ubiquitin tags (K11- and K27-linked chains) as senescent cells attempt to manage damaged proteins and reconfigure quality-control systems.

What Is: Aphantasia "No Mind's Eye"

A conceptual visualization contrasts the vivid sensory imagination of a typical mind's eye with the profound visual silence of aphantasia. Despite the complete absence of mental pictures, individuals with this condition often process complex concepts through rich, invisible frameworks of spatial and structural understanding.
Image Credit: Scientific Frontline / AI generated

Scientific Frontline: Extended "At a Glance" Summary: Aphantasia

The Core Concept: Aphantasia is a neurological condition characterized by the complete inability to generate voluntary visual mental imagery, effectively leaving an individual without a functioning "mind's eye."

Key Distinction/Mechanism: Unlike typical cognition that relies on depictive, quasi-pictorial representations in the early visual cortex, individuals with aphantasia route mental processing through abstract, propositional logic and spatial-motor networks, demonstrating a strict neuroanatomical dissociation between visual and spatial imagery.

Origin/History: Long situated at the center of the cognitive science "imagery debate," aphantasia was historically identified through subjective self-reporting instruments, such as the Vividness of Visual Imagery Questionnaire, before modern cognitive neuroscience established objective physiological biomarkers.

Ultra-Processed Foods and Silent Strokes

Photo Credit: Nico Smit

Scientific Frontline: Extended "At a Glance" Summary: Ultra-Processed Foods and Cerebrovascular Damage

The Core Concept: High consumption of ultra-processed foods by healthy middle-aged adults is directly associated with asymptomatic cerebrovascular damage, serving as an early warning sign for clinical stroke and future cognitive decline.

Key Distinction/Mechanism: Unlike acute cardiovascular events, this damage presents as microscopic "silent strokes" detectable only via magnetic resonance imaging (MRI). The neuropathology strongly correlates with increased abdominal adiposity, which initiates systemic inflammation and subsequent cerebral blood vessel degradation.

Major Frameworks/Components:

• Utilization of MRI technology to detect localized, asymptomatic brain lesions in a cohort of nearly 9,000 individuals aged 35 to 69 with no prior history of heart disease.
• Classification of dietary intake based on industrial processing levels, emphasizing diets high in sodium, added sugars, and saturated fats, while lacking essential vitamins and fiber.
• Identification of dietary displacement, demonstrating that high volumes of ultra-processed foods actively crowd out nutrient-dense, minimally processed whole foods rather than simply adding caloric surplus.
• Observation of a pronounced sex-based disparity, where women in the highest consumption quartile exhibited nearly double the risk of brain damage compared to those in the lowest consumption group.

Genetics of Snail Shell Chirality

Photo Credit: Professor Angus Davison

Scientific Frontline: Extended "At a Glance" Summary: Snail Shell Chirality

The Core Concept: The physical coiling direction, or chirality, of a snail shell is determined by natural variations in a gene that produces the protein myosin.

Key Distinction/Mechanism: Small changes in the myosin protein dictate whether cells twist clockwise or counterclockwise during the earliest stages of embryonic development, setting the permanent chiral direction for the adult snail’s shell and internal organs without causing disease or pathology.

Origin/History: Researchers from the University of Nottingham and Tohoku University published these findings in Current Biology in October 2026, based on studies of wild Euhadra snails in a Japanese mountain valley where both left- and right-coiling types successfully interbreed.

Major Frameworks/Components:

• Myosin gene variation naturally dictates physical asymmetry.
• Myosin proteins interact with other cellular proteins to construct the cell scaffold and drive cellular movement.
• Embryonic cellular twisting establishes the lifelong anatomical handedness of the organism.
• Natural selection shows evidence of supporting the ancient "lefty" phenotype within this specific snail population.

IRIS AI Model Decodes Cell Signaling & Tissue Development

The developing branching lung in an in vitro culture system
Image Credit: Miram Meziane/Whitehead Institute

Scientific Frontline: Extended "At a Glance" Summary: IRIS Machine Learning Model for Cellular Signaling

The Core Concept: IRIS is a neural network-based machine learning model designed to reconstruct the developmental signaling histories of single cells by analyzing their overall gene activity. It identifies specific chemical communication sequences that guide undifferentiated stem cells to assemble into specialized three-dimensional tissues and organs.

Key Distinction/Mechanism: While researchers previously assumed that the effects of signaling pathways varied too widely across cell types to be mapped universally, this framework demonstrates that each signaling pathway leaves a consistent, unique transcriptional "fingerprint" across diverse cell types. Utilizing transfer learning, IRIS detects these pathway-specific patterns to pinpoint which chemical signals a cell received at different stages of embryonic development, even in previously unencountered cell types or across different species.

Major Frameworks/Components:

• Perturbation Screen Training Atlas: The model was trained on a large experimental dataset measuring how thousands of human embryonic stem cells responded to dozens of combinations of six major signaling pathways across multiple developmental stages.
• Pathway-Specific Transcriptional Fingerprints: Distinctive, conserved patterns of gene expression that reflect the exact multi-step chemical signaling cascades a cell has encountered.
• Cross-Species Transfer Learning: A neural network architecture capable of translating training data from human embryonic stem cells to accurately predict spatiotemporal pathway activations in single cells from mouse embryos during gastrulation—covering heart, gut, muscle, and spinal cord tissue formation.
• Experimental Validation in Lung Morphogenesis: In vivo verification in mouse embryos confirming the model's prediction of specific signaling pathway activations required to drive lung-specific cellular development.

Hypoxia Pill Reverses Parkinson's in Mice

Image Credit: Credit: Susanna Hamilton

Scientific Frontline: Extended "At a Glance" Summary: Hypoxia-in-a-Pill Therapy

The Core Concept: A two-drug combination therapy designed to artificially reduce tissue oxygen levels, mimicking the therapeutic benefits of a low-oxygen environment (hypoxia) without the risks associated with continuously breathing oxygen-depleted air.

Key Distinction/Mechanism: Unlike placing subjects in physically hypoxic environments, which can lead to adverse cardiac side effects, this oral regimen utilizes the small molecule GBT601 to bind to red blood cell hemoglobin to prevent oxygen delivery, while PT2399 inhibits the HIF-2α pathway to block the body's compensatory overproduction of red blood cells.

Origin/History: First established in 2024 as a proof-of-concept by Vamsi Mootha's team at the Broad Institute, the regimen was refined into a highly effective second-generation version and published in the Proceedings of the National Academy of Sciences in October 2026.

Major Frameworks/Components:

• GBT601: A targeted molecule that increases hemoglobin's affinity for oxygen, safely restricting its release into cellular tissues.
• PT2399: An inhibitor drug targeting the HIF-2α pathway, preventing secondary compensatory responses such as the dangerous overproduction of red blood cells.
• Mitochondrial Dysfunction: The underlying cellular pathology targeted by the treatment, where malfunctioning mitochondria fail to consume oxygen properly, resulting in toxic oxygen accumulation and cellular damage.

Cryobiology: In-Depth Description

Cryobiology is the study of the effects of extremely low temperatures on living organisms, biological tissues, and cells. The primary goal of this field is to understand how biological systems adapt to, tolerate, or are damaged by freezing and cold environments, and to apply this knowledge to biological preservation, medical therapies, and agricultural resilience.

Molecular Pharmacology: In-Depth Description

Molecular Pharmacology is the branch of pharmacology concerned with the biochemical and biophysical characteristics of interactions between drug molecules and the cellular targets of a living organism. Its primary goal is to understand the exact mechanisms of drug action at the molecular, cellular, and subcellular levels, uncovering how pharmaceutical agents bind to receptors, influence signaling pathways, and alter cellular function to produce therapeutic or toxic effects.

Taxonomy: In-Depth Description

Taxonomy is the scientific discipline concerned with discovering, describing, naming, and classifying biological organisms on the basis of shared characteristics. Its primary goal is to organize the diversity of life into a structured framework that facilitates clear scientific communication and aids in the identification of unknown specimens; contemporary taxonomic frameworks also strive to reflect evolutionary history.

Immune Cell Map Predicts Aging Trajectories

Image Credit: Sara Moser / Washington University School of Medicine in St. Louis

Scientific Frontline: Extended "At a Glance" Summary: Immune Cell Mapping and Aging Trajectories

The Core Concept: Researchers have developed a map of human immune aging that predicts whether an individual is on a healthy or unhealthy aging trajectory based on the ratio of two specific types of white blood cells. This diagnostic approach allows scientists to evaluate biological age and resilience independently of a person's chronological age.

Key Distinction/Mechanism: The system evaluates the balance between effector memory CD8 T cells that produce granzyme B and those that produce granzyme K. While a healthy immune system gradually shifts toward producing more granzyme K cells, an overabundance of granzyme B cells indicates subclinical immune stress, which is strongly associated with the future onset of chronic diseases and an increased risk of mortality.

Origin/History: Published on October 9, 2026, in the journal Immunity, the study was led by researchers at Washington University School of Medicine, Nationwide Children's Hospital, and King's College London, utilizing data from over 12.4 million immune cells and long-term health tracking of 50,000 UK Biobank participants.

Major Frameworks/Components:

• Effector Memory CD8 T Cells: A specific type of white blood cell that utilizes molecular weapons, known as granzymes, to manage immune responses.
• Granzyme B vs. Granzyme K: Granzyme B acts to directly destroy diseased cells, whereas granzyme K is believed to signal and recruit additional immune support.
• Predictive Protein Modeling: Computer models analyzing blood protein tracks were used to determine whether granzyme B or granzyme K cells dominated in a patient's immune system.
• Chronic Disease Correlation: High levels of granzyme B cells in otherwise healthy individuals correlated with higher rates of Type 2 diabetes, hypertension, liver disease, and renal failure up to a decade later.

What Is: Assembloids

Scientific Frontline: Extended "At a Glance" Summary: Assembloids

The Core Concept: Assembloids are modular, three-dimensional microphysiological systems created by physically fusing distinct, region-specific neural organoids to model complex, long-range connectivity within the human central nervous system.

Key Distinction/Mechanism: Unlike traditional, isolated organoids that model single brain regions, assembloids physically connect different regionalized tissues, allowing for the spontaneous extension of axonal tracts, cellular migration across boundaries, and the formation of functional, multi-regional synaptic circuits.

Origin/History: The assembloid methodology was first pioneered in 2017 by researchers at Stanford University to address the functional and developmental plateau of isolated neural organoids.

Major Frameworks/Components:

• Modular Assembly: Utilizes precisely patterned stem cells (e.g., cortical, subpallial, striatal) that are physically approximated—often using 3D-printed microwells—to initiate autonomous fusion over a 72-hour window.
• Cellular Migration: Models the tangential migration of interneurons, capturing distinct modes like "saltatory" movement (medial ganglionic eminence) driven by nucleokinesis and L-type voltage-gated calcium channels, and "chain migration" (caudal ganglionic eminence).
• Electrophysiological Integration: Utilizes high-density multielectrode arrays (HD-MEAs) to capture cellular-resolution readouts, verifying the maturation of fast-spiking parvalbumin-positive interneurons and the emergence of network oscillatory behaviors like gamma rhythms.
• Vascularization and Perfusion: Addresses the diffusion limit of oxygen and necrotic core formation by integrating endothelial cells to form vascular networks, utilizing microfluidic organoid-on-a-chip platforms for active perfusion, or achieving robust vascularization via in vivo transplantation into immunodeficient rodent models.
• Multi-Regional Circuitry: Recreates complex systemic pathways, including cortico-spinal-muscle assembloids (forming neuromuscular junctions), ascending somatosensory pathways, and closed-loop cortico-striatal-thalamic-cortical circuits.