This study examines the effects of metformin on brain functions focusing on the variability of the results reported in the literature. While some studies suggest that metformin may have neuroprotective effects in diabetic patients, others report an insignificant impact of metformin on cognitive function, or even a negative effect. We propose that this inconsistency may be due to intrinsic cellular-level variability among individuals, which we term “biovariance”. Biovariance persists even in demographically homogeneous samples due to complex and stochastic biological processes. Additionally, the complex metabolic actions of metformin, including its influence on neuroenergetics and neuronal survival, may produce different effects depending on individual metabolic characteristics.

Hypothalamic hamartomas (HH) are infrequent, non-neoplastic malformations of the hypothalamus with heterogeneous clinical features, with symptoms including gelastic seizures, central precocious puberty, and cognitive or behavioral deficits. This narrative review synthesizes current knowledge regarding the etiology, clinical manifestations, diagnostic advances, and therapeutic approaches for HH. Genetic insights highlight the role of postzygotic mosaicism and dysregulated Sonic Hedgehog signaling in HH development, emphasizing their relevance in potential therapeutic strategies. Diagnostic modalities such as MRI, PET, and SEEG are pivotal in identifying and characterizing HHs, enabling precise treatment planning. Therapeutic interventions span pharmacological, surgical, and neuromodulatory approaches. While surgical approaches, such as transcallosal resection or stereotactic radiosurgery, can offer considerable seizure control, newer modalities, such as laser interstitial laser thermal therapy (LITT) as well as stereotactic radiofrequency thermocoagulation, prioritize minimizing both cognitive and behavioral sequelae. The use of pharmacologic management and neuromodulation provides adjuvant benefits, specifically in drug-resistant epilepsy; despite progress, limitations still remain, including variability of outcomes and not enough long-term studies. This review underscores the need for multidisciplinary care and advanced research to optimize outcomes and improve the quality of life for patients with HH.

Hypothalamic hamartomas (HHs) are rare, non-neoplastic malformations of the hypothalamus with heterogeneous clinical presentations, including gelastic seizure, central precocious puberty, and cognitive or behavioural impairments. This narrative review synthesizes current knowledge regarding the etiology, clinical manifestations, diagnostic advances, and therapeutic approaches for HH. Genetic insights highlight the role of postzygotic mosaicism and dysregulated Sonic Hedgehog signalling in HH development, emphasizing their relevance in potential therapeutic strategies. Diagnostic modalities such as MRI, PET, and SEEG play pivotal roles in identifying and characterizing HHs, enabling precise treatment planning. Therapeutic interventions span pharmacological, surgical, and neuromodulatory approaches. While surgical techniques such as transcallosal resection or stereotactic radiosurgery offer substantial seizure control, newer modalities like laser interstitial thermal therapy (LITT) and stereotactic radiofrequency thermocoagulation prioritize minimizing cognitive and behavioural sequelae. Pharmacological management and neuromodulation offer adjunctive benefits, particularly in drug-resistant epilepsy despite advancements, limitations persist, including outcome variability and insufficient long-term studies. This review underscores the need for multidisciplinary care and advanced research to optimize outcomes and improve the quality of life for patients with HH.

The study examines the effects of metformin on brain functions focusing on the variability of results reported in the literature. While some studies suggest that metformin may have neuroprotective effects in diabetic patients, others report an insignificant impact of metformin on cognitive function, or even a negative effect. We propose that this inconsistency may be due to intrinsic cellular-level variability among individuals, which we term “biovariance”. Biovariance persists even in demographically homogeneous samples due to complex and stochastic biological processes. Additionally, the complex metabolic actions of metformin, including AMPK activation and mTOR inhibition, may produce different effects depending on individual metabolic characteristics.