Therapeutic hypothermia via hypothalamic neuromodulation: A new approach for stroke brain protection

Stroke continues to be a leading cause of death and long-term neurological disability globally, with current treatment options limited by narrow time windows and insufficient neuroprotective strategies. Over recent decades, research into effective neuroprotective interventions has advanced significantly, shifting from single-target approaches like excitotoxicity modulation to recognizing the diverse protective potential of therapeutic hypothermia (TH). This review summarizes recent advances in TH research, emphasizing its neuroprotective effects through reducing cerebral metabolism, maintaining blood-brain barrier integrity, and decreasing neuronal death. Traditional surface-cooling TH (TH1.0) has produced disappointing clinical results, mainly because shivering thermogenesis increases cerebral oxygen demand and cardiac stress, negating therapeutic benefits. Additional sedation or neuromuscular blockade is also necessary to enhance patient tolerance. New insights into neural thermoregulatory mechanisms that underlie torpor-like states in homeotherms have led to the development of neuromodulation-based TH (TH2.0). Deep-brain stimulation of hypothalamic thermoregulatory neurons allows for swift, stable hypothermia in mouse models, inducing shivering-free torpor and overcoming the main limitations of TH1.0. Because mice are facultative heterotherms, validation in non-human primates is essential for translation. Nevertheless, TH2.0 stands out as a promising, fast, targeted, and reversible approach to induce TH with significant potential to improve stroke treatment.