In this issue, we are tuning into the electrical symphony of the brain. Using electroencephalography (EEG), researchers can observe the rhythms and patterns of the brain’s activity in real time. These brainwaves are now emerging as powerful biomarkers, tools that could transform how we understand neuropsychiatric disorders and accelerate the search for new treatments.

Science in Sixty Seconds

Making waves with EEG

The brain is a complex organ that control how we think, feel, move, interact with the world and so much more. Each behavior and internal state is encoded by electrical signals. One way to measure these signals is with electroencephalography, or EEG.

EEG measures electrical waveforms generated by cortical pyramidal neurons in the cerebral cortex. During an EEG recording, the subject wears an EEG cap with electrodes positioned over various brain regions. These electrodes detect electrical signals and fluctuations, which are amplified and recorded. Despite considerable variability in EEG measurements—due to environmental signals, movement, or electrical interference—it’s widely used to understand brain activity in normal function, disease states, and in response to therapeutic intervention.

Normal EEG waves, also called rhythms, are categorized based on frequency (measured in hertz, Hz) and are typically classified based on sleep or awake patterns. There are five main types, see figure (made with BioRender; Britton et al., 2016; Nayak & Anilkumar, 2025).

The Alpha Focus. In the drug development space, alpha waves have drawn considerable attention in drug discovery and neuropsychiatric research. Many of these disorders have been associated with anatomical and functional changes, which can be observed through altered alpha synchronization (Ippolito et al., 2022).

For example, patients with Major Depressive Disorder (MDD) show higher alpha-band coherence within the default mode network (DMN; Ho et al., 2024). The DMN includes multiple brain regions, including the medial prefrontal cortex and posterior cingulate cortex, and most active at rest, with activity decreasing during task-dependent attention. In people with MDD, DMN dysregulation may lead to behavioral symptoms like rumination, heightened self-focus, and reduced concentration (Northoff, 2016; Wang et al., 2024).

EEG as a Translational Tool. Researchers and industry scientists have tried to leverage this connection between alpha waves, brain network activity, and neuropsychiatric symptoms to develop new treatments. The scientific evidence is still mixed on whether or not alpha bands represent a true measure of therapeutic efficacy, but it is known that some interventions alter alpha waves in distinct ways.

• Serotonergic psychedelics (such as DMT and psilocybin) significantly reduce alpha bands across DMN-related areas following administration (Gattuso et al., 2022; Godfrey et al., 2025). For example, a study assessing DMT found dysregulation of brain activity, including reductions of alpha power, was associated with increased global functional activity (Timmermann et al., 2023).
• Psychedelic-induced reductions in alpha band power has also been evidenced to be associated with the perceptual changes and subjective experience of psychedelics (Timmermann et al., 2019; Muthukumaraswamy et al., 2013).
• SSRIs like escitalopram also shift alpha activity. One study measured depression symptoms and EEG in MDD patients at two- and eight-weeks post-treatment. Late decreases in alpha power correlated with improved depressive symptoms, while early changes did not (Schwartzmann et al., 2024), suggesting a temporal effect.
• Brain stimulation treatments like electroconvulsive therapy (ECT; Atluri et al., 2018) and transcranial magnetic stimulation (TMS; Zrenner et al., 2019) also show changes in alpha power in relevant brain regions.

Because alpha rhythms track changes in brain network dynamics, they can also serve as a non-invasive translational biomarker. While EEG signatures are not official FDA-approved biomarkers, drug development programs are increasingly utilizing EEG to:

• Confirm target engagement
• Compare compounds to known mechanistic ‘signatures’
• Observe real-time effects in translational models that may predict clinical response

While EEG is emerging as a valuable tool for advancing neurotherapeutics from early research through clinical trials, more work is needed to fully elucidate the relationship between changes in EEG spectra and behavioral states, disease condition, and response to treatment. Xylo Bio is incorporating EEG measures into our own drug development programs to create novel and effective neurotherapeutics.

Xylo Bio Updates

• CSO, Sam Banister spoke on the neuro drug development panel with local and global leaders, like John Donello from Syndeio Biosciences, for Focal Point - a Tenmile sponsored event. See the post here.
• CEO, Josh Ismin participated in the UNSW Pioneering Investor Series – Singapore Edition, where founders and investors came together to discuss APAC innovation.
• We’re excited to welcome two new interns to our Business Development team! Olivia McDonald is an MBA student and participant in the Endless Frontiers Program at NYU and Nick Tsui is an MBA student at UNSW.
• Dr. Eric Nestler, a member of our advisory board, was recently appointed Dean of the Ichan School of Medicine at Mount Sinai. See the post here.

Coming up:

• IEEE Engineering in Medicine and Biology Society (EMBS) Meeting (San Diego, USA, November 11) – Director of Business Development, Samantha Tabone will be attending.
• Reform Conference (Detroit, USA, November 12-14) – Head of Communications, Dr. Alaina Jaster will be attending
• NYU Stern School of Business (New York, USA, Dec. 8-12) —Co-founders Josh Ismin and Dr. Sam Banister will be visiting for partnership program.
• J.P. Morgan Healthcare Conference (San Francisco, USA, January 12-16) — CEO Josh Ismin, Director of Business Development Samantha Tabone, and VP of Research & Development Jack Nguyen will be attending.
• American College of Neuropsychopharmacology Annual Meeting (Paradise Island, Bahamas, January 12-15) — CEO Dr. Sam Banister will be attending.

🤝Join the Team:

We are currently hiring for:

• Chief Medical Officer (flexible)
• Clinical Advisory Board Member – CNS Drug Development

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Research Updates

Preclinical Research

• Understanding the vasoactive effects of serotonin 2A receptor agonism | Many studies use blood-based measures of brain activity, such as fMRI, to understand effects of psychedelics on brain function. Given that serotonin has profound vasoactivity and 5-HT2A receptors are expressed on cells involved in neurovascular coupling, its possible psychedelics may alter vasoactivtiy. The authors found that administration of DOI demonstrated a dissociation between neuronal and hemodynamic signals in measures of functional connectivity, suggesting possible confounds for interpreting fMRI data. Nat Neuro.
• Astrocytes involvement in memory and emotional experience | Memory stabilization is important for cognition and encoding of survival-critical experiences. Astrocytes are found throughout the brain, but their behavioral relevance is underexplored. Using a brain-wide Fos tagging and imaging method, astrocytes were found to respond to fear experiences distinct from neuronal responses. For example, during fear conditioning astrocytes induce rapid calcium release, but undergo slower transcriptional changes that last several days, possibly contributing to stabilization of memories. Nature.
• Structure activity drug design of psychedelic analogues | A large focus of understanding psychedelic effects is in the prefrontal and anterior cingulate cortex (ACC). Only recently have studies have begun to look at areas such as the claustrum, which are abundant with 5-HT2 receptors. Researchers assessed the signaling profile of 5-HT2 expressing neurons in the claustrum projecting to the ACC with and without psychedelics, finding that psychedelic administration produces net changes in synaptic efficacy and long-term potentiation. eNeuro.
• Translational pharmacology characterizes selective GABA-A positive allosteric modulator (PAM) | Benzodiazepines are non-selective GABA-A receptor PAMs. While clinically effective anxiolytic drugs, they have a myriad of side effects related to non-selectivity. Using both mouse models and healthy volunteers, a novel GABA-A receptor PAM selective for specific subunits was evaluated for its efficacy. In rodents, the compound produced anxiolytic like effects without sedation. In healthy human volunteers, the PAM produced central target engagement, minimal effects on alertness and had distinct EEG profiles compared to non-selective PAMs. Cells.
• Nitrous oxide produces signature of analgesic activity and pain affect| Pain is more than just sensory-discrimination, it also involves affective-motivation. Neuronal activity in the anterior cingulate cortex (ACC) has been shown to contribute to the negative affect associated with pain. Using in vivo imaging of calcium dynamics this study reports that the inhaled anaesthetic, nitrous oxide, reduces pain affect but paradoxically increases ACC signaling. This increase in signaling was independent of opioidergic or inhibitory interneurons. PAIN.

Clinical Research

• Genetic variations may contribute to sex differences in major depressive disorder (MDD) | Women tend to experience depression at higher rates than men, with varying symptoms. This genome-wide association meta-analysis discovered potentially higher genetic heritability of MDD in females, which may be driven by a higher number of causal variants. Despite this, male and females were found to have substantial overlap in genetic variants associated with MDD and a novel single-nucleotide polymorphism was identified on the X chromosome, specific to male subjects. Nat Comms.
• Chromatin accessibility altered in specific neurons of MDD patients | Chromatin accessibility plays a large role in gene regulation and expression. Assessing the dorsal lateral prefrontal cortex of patients with MDD compared to neurotypical individuals, results found that almost 80% of differentially accessible regions were less accessible in MDD, specifically related to deep layer excitatory neurons and microglia. These same neurons were also genetically enriched for genetic variants related to transcription factor accessibility and gene expression. Nat Genet.
• Precision medicine to target cognitive biotypes of depression | Depression can be classified into various biotypes, including the cognitive biotype which is characterized by impairments in cognitive control circuitry and behavioral performance. Using a biomarker guided approach, authors linked an α₂ adrenergic receptor agonist to circuit activation in this biotype. In this proof-of-concept study, patients achieved a clinical response after treatment evidenced by depression rating scales and circuit-target engagement. Nat Ment Health.
• Identification of inflammatory biomarkers in depression using brain imaging | Psychiatric disorder phenotypes often include increased levels of stress often with concurrent inflammatory responses. First, an immuno-inflammatory biotype of psychiatric disorders was identified in a cross-sectional sample. In a longitudinal study, the identified markers related to this biotype were confirmed and linked to poorer responses to conventional therapies. Biol. Psychiatry.
• GM-2505 safety profile in healthy volunteers | GM-2505, Gilgamesh’s lead compound, recently went through their first-in-human trials to establish safety, pharmacokinetics and pharmacodynamics. In healthy volunteers that have self-reported prior psychedelic drug experiences, the compound was found to have dose dependent effects on perceptual changes consistent with plasma concentration profiles. Dose dependent effects were also seen in pharmacodynamic endpoints such as EEG. No major adverse events were reported and the most frequently reported was related to sensory processing. J of Psychopharmacol.

Reviews and Editorials

• Visual Hallucinations in Serotonergic Psychedelics and Lewy Body Diseases | There are some overlapping similarities between hallucinations experienced by those Parkinson’s Disease or dementia with Lewy bodies with effects of psychedelics. Some shared mechanisms may be due to changes in sensory and associative cortical activity and 5-HT2A receptor upregulation. Schizophrenia Bulletin.
• Antidepressants and the endogenous opioid system | The most widely accepted cause of depressive disorder is the imbalance of biogenic amine neurotransmitter, such as serotonin and norepinephrine. Currently used antidepressants like SSRIs and SNRIs target these neurotransmitter systems, but also cause increases in endogenous opioid genes, like proenkephalin. Further, more recent rapid acting antidepressants like ketamine have activity at opioid receptors, suggesting a possible role of this receptor system in depressive disorder. Biochem Pharmacol.
• The allostatic triage model of psychopathology (ATP Model): How reallocation of brain energetic resources under stress elicits psychiatric symptoms | Many neuropsychiatric disorders are comorbid with cardiometabolic and immune disorders. It’s widely known that chronic and traumatic stress dysregulates a variety of physiological processes that in turn can exacerbate psychiatric symptoms. This review proposes a model to explain this bidirectional relationship between stress and psychopathology, with a focus on metabolic energy and its role in allostasis. Neurosci & Biobehav Rev.
• Modeling sex differences of neurological disorders in vitro | Historically, scientific research has focused on males, including in model organisms of preclinical research. Many cite that studying females is more complex, but there is little actual evidence for this, other than expected biological differences across sexes. These differences can include cortical thickness, white matter complexity, transcriptome and signaling, gene expression, male and female sex hormones and synaptic plasticity. The authors suggest embracing the differences across in vitro models and provide a framework for studying sex as a biological variable in these models. Nat Reviews Bioeng.
• A deep learning pipeline for accurate and automated restoration, segmentation, and quantification of dendritic spines | While structural and functional plasticity are of major interest in the field of neuropsychiatry, there are several limitations of current methods—like manual annotation, complex workflows, and lack of standardization. The authors introduce RESPAN — an open-source, fully automated pipeline for reconstructing neuronal morphology and quantifying dendritic spines that integrates deep-learning-based image restoration, segmentation, training, analysis, and validation into a single interface. Cell Reports Methods.

‍New Clinical Trial Registrations

• 25 mg Psilocybin + Trazodone 5 or 30 mg| Treatment Resistant Depression (N=112) | Efficacy of Psilocybin and Trazodone Combination in Treatment-resistant Depression: a Randomized Controlled Proof-of-concept Study (PSILOTRAZ)| Sponsor: Centre Hospitalier St Anne | NCT07210112
• dTMS | Major Depressive Disorder (N=24) | Accelerated Neuromodulation of Anterior Cingulate Cortex for Depression (NACC-D) | Sponsor: Rotman Research Institute at Baycrest | NCT07212465
• rTMS | Postpartum Depression (N=192) |SAINT in Postpartum Depression (PPD) | Sponsor: Magnus Medical | NCT07210255
• Psilocybin | Major Depressive Disorder (N=10) Psilocybin-Assisted Therapy for the Treatment of Major Depressive Disorder in Patients With Non-Small Cell Lung Cancer | Sponsor: Alan Davis | NCT07216404

Jump back to:

• Science in Sixty Seconds – Exploring our adaptable brains
• Xylo Bio Updates – Company news, progress, and highlights.
• Research Updates – Summaries of recent studies shaping the field

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