Theta-Band Responses: The EEG Biomarker to Objectively Identify Patients With Cognitive Impairment in Schizophrenia

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Alto Neuroscience today announced positive results from an independent, prospective replication study evaluating electroencephalography (EEG) biomarkers in individuals with schizophrenia. The study successfully replicated previous findings, demonstrating that event-related theta-band responses, particularly theta-band inter-trial coherence (ITC), robustly differentiate individuals with schizophrenia from individuals without schizophrenia.¹

Key findings demonstrated the strength of theta-band responses as biomarkers for cognitive impairment in schizophrenia, and provide strong validation for the use of this measurement in identifying and evaluating patients. Alto is currently utilizing theta ITC as a key biomarker and primary outcome measure in the phase 2 study of ALTO-101, an investigational novel PDE4 inhibitor for the treatment of cognitive impairment in schizophrenia.²

“This successful replication marks an important and significant step forward for Alto and the field as we aim to bring objectivity and precision to complex conditions like schizophrenia,” said Amit Etkin, MD, PhD, founder and chief executive officer of Alto Neuroscience. “For too long, drug development in this area has been hampered by subjective measures and biological heterogeneity. These data provide further compelling evidence that we have a reliable, noninvasive approach to identify specific patient populations and measure the effects of targeted therapies. Previously in a phase 1 trial, ALTO-101 demonstrated significant effects on theta ITC and cognition after a single dose in healthy subjects. These outcomes taken together enhance our confidence in the relevance of theta ITC as a primary outcome in our ongoing phase 2 trial of ALTO-101, as we work to deliver a much-needed new treatment option for patients.”

In the analysis, investigators evaluated 155 individuals with schizophrenia and 272 healthy controls, and sought to replicate and extend prior findings from a large-scale study. The results showed that EEG measures of theta ITC and event-related spectral perturbation (ERSP) had the largest case-control differences, far exceeding traditional EEG and event-related potential measures in their ability to distinguish patients with schizophrenia from healthy controls. Both theta ITC and ERSP were also significantly correlated with processing speed, which is a key domain of cognitive impairment in schizophrenia.

Other important notable findings include strong differentiation: Theta ITC and ERSP showed the largest differences between patients with schizophrenia and healthy controls (Cohen d = 0.64 and 0.78, respectively; P < 0.001), indicating a very strong separation between the groups.

Theta-based measures also far outperformed more traditional biomarkers, including mismatch negativity (Cohen d = 0.41) and resting-state theta power (Cohen d = 0.40). Unlike theta-based measures, neither traditional EEG measures demonstrated significant associations with processing speed. Theta-band responses also demonstrated consistent correlation with cognition. Both theta ITC and ERSP demonstrated a statistically significant correlation with processing speed (P< 0.05 and P< 0.01, respectively).

“The search for reliable biomarkers in psychiatry has been a long and challenging endeavor. The clear and replicable differentiation between patients with schizophrenia and healthy controls shown by these theta-band responses represents a clear advancement,” said L. Elliot Hong, MD, professor of psychiatry at the University of Texas Health Science Center at Houston. “These findings may provide the field with a validated, scalable biomarker that is likely to enhance the rigor of clinical trials and holds the potential to guide clinical practice and personalize patient care in the future. This is the kind of robust scientific validation needed to move the needle in developing new treatments for severe mental illness.”

Alto intends to release the full details of this analysis via upcoming medical conferences and/or peer-reviewed publications.

References

1. Alto Neuroscience announces robust replication of EEG biomarker to objectively identify patients with cognitive impairment in schizophrenia. News release. September 9, 2025. Accessed September 9, 2025. https://investors.altoneuroscience.com/news/news-details/2025/Alto-Neuroscience-Announces-Robust-Replication-of-EEG-Biomarker-to-Objectively-Identify-Patients-with-Cognitive-Impairment-in-Schizophrenia/default.aspx

2. Kuntz L. Phase 2 study initiated: ALTO-101 for cognitive impairment with schizophrenia. Psychiatric Times. June 20, 2024. https://www.psychiatrictimes.com/view/phase-2-study-initiated-alto-101-for-cognitive-impairment-with-schizophrenia