A system, apparatus and methods are provided for extra-corporeal blood treatment, and in particular for establishing and maintaining a neck down differential body temperature, while maintaining near normal brain temperatures, to protect the brain from extended or extreme hypothermia or hyperthermia. A blood treatment apparatus and system is provided for differential control of brain temperature and body temperature below the neck. For example, a first bypass circuit with heat exchanger for brain blood circulation maintains a near normal blood temperature, while a second bypass circuit for below the neck blood circulation provides for thermal treatment to induce a temperature differential, e.g. hyperthermia or hypothermia, relative to brain circulation. Such systems and apparatus have application, for example, for diagnostic and therapeutic treatments using hyperthermia, particularly for treatments of extended duration or at elevated temperatures above 42° C., for example, hyperthermia for treatment of cancer, infectious bacterial or viral diseases.