Administration of selective brain hypothermia using a simple cooling device in neonatal rats.

BACKGROUND: The interruption of oxygen and blood supply to the newborn brain around the time of birth is a risk factor for hypoxic-ischemic encephalopathy and may lead to infant mortality or lifelong neurological impairments. Currently, therapeutic hypothermia, the cooling of the infant's head or entire body, is the only treatment to curb the extent of brain damage. NEW METHOD: In this study, we designed a focal brain cooling device that circulates cooled water at a steady state temperature of 19 ± 1 °C through a coil of tubing fitted onto the neonatal rat's head. We tested its ability to selectively decrease brain temperature and offer neuroprotection in a neonatal rat model of hypoxic-ischemic brain injury. RESULTS: Our method cooled the brain to 30-33 °C in conscious pups, while keeping the core body temperature approximately 3.2 °C warmer. Furthermore, the application of the cooling device to the neonatal rat model demonstrated a reduction in brain volume loss compared to pups maintained at normothermia and achieved a level of brain tissue protection the same as that of whole-body cooling. COMPARISON WITH EXISTING METHODS: Prevailing methods of selective brain hypothermia are designed for adult animal models rather than for immature animals such as the rat as a conventional model of developmental brain pathology. Contrary to existing methods, our method of cooling does not require surgical manipulation or anaesthesia. CONCLUSION: Our simple, economical, and effective method of selective brain cooling is a useful tool for rodent studies in neonatal brain injury and adaptive therapeutic interventions.

A Focal Cooling Method for the Cervical Spinal Cord: A Percutaneous Approach to the Dorsal Neck in Dogs.

For the treatment of acute cervical spinal cord injuries, a local epidural cooling system using a percutaneous technique was proposed. In this animal study, regional low temperature was obtained stably in the cervical epidural space (CED) without decreasing temperatures at the rectum and the thoracic epidural space. Three stainless steel tubes were inserted percutaneously using the lateral approach into 3 serial interspinous spaces of the neck of 12 beagles under radiographic guidance. Two temperature probes were inserted into the CEDs at the level of the middle cooling tube. A third temperature probe was inserted into the epidural space at the Th13 level. A fourth temperature probe was placed in the rectum as a control. Iced water was circulated in the cooling tubes for 60 minutes. Temperatures were monitored every 10 seconds for 90 minutes, with the minimum temperatures during the period being recorded. The mean minimum temperatures recorded in the dorsal CED (min-CED-dorsal), the lateral CED (min-CED-lateral), the Th13 epidural space (min-T13ED), and the rectum (min-rectum), were 16.0 ± 0.6°C, 22.6 ± 1.6°C, 35.4 ± 0.2°C, and 35.5 ± 0.2°C, respectively. There was a statistically significant difference between the mean min-CED-dorsal and min-rectum temperatures (p < 0.0001). The method introduced above was effective in reducing cervical epidural temperature selectively.

Rapid focal cooling attenuates cortical seizures in a primate epilepsy model.

Rapid focal cooling is an attractive nondestructive strategy to control and possibly prevent focal seizures. However, the temperature threshold necessary to abort seizures in primates is still unknown. Here, we explored this issue in a primate epilepsy model and observed the effect of rapid cooling on different electroencephalogram frequency bands, aiming at providing necessary experimental data for future clinical translational studies and exploring the mechanism of focal cooling in terminating seizures. We induced focal neocortical seizures using microinjection of 4-aminopyridine into premotor cortex in five anesthetized cynomolgus monkeys. The rapid focal cooling was implemented by using a thermoelectric (Peltier) device. As a result, the average durations of seizures and interictal intervals before cooling were 94.3±4.0s and 62.3±6.9s, respectively. When the cortex was cooled to 20°C or 18°C, there was no effect on seizure duration (109.4±30.0s, 91.3±19.3s) or interictal duration (99.4±26.8s, 83.2±11.5s, P>0.05). But when the cortex was cooled to 16°C, the seizure duration was reduced to 54.1±4.9s and the interictal duration was extended to 175.0±16.7s (P<0.05). Electroencephalogram spectral analysis showed that the power of delta, alpha, beta, gamma and ripples bands in seizures were significantly reduced at 20°C and 18°C. At 16°C, the power of theta band in seizures was also significantly reduced along with the other bands. Our data reveal that the temperature threshold in rapid focal cooling required to significantly shorten neocortical seizures in nonhuman primates is 16°C, and inhibition of electroencephalogram broadband spectrum power, especially power of theta band, may be the underlying mechanism to control seizures.

Selective Brain Hypothermia Mitigates Brain Damage and Improves Neurological Outcome after Post-Traumatic Decompressive Craniectomy in Mice.

Hypothermia and decompressive craniectomy (DC) have been considered as treatment for traumatic brain injury. The present study investigates whether selective brain hypothermia added to craniectomy could improve neurological outcome after brain trauma. Male CD-1 mice were assigned into the following groups: sham; DC; closed head injury (CHI); CHI followed by craniectomy (CHI+DC); and CHI+DC followed by focal hypothermia (CHI+DC+H). At 24 h post-trauma, animals were subjected to Neurological Severity Score (NSS) test and Beam Balance Score test. At the same time point, magnetic resonance imaging using a 9.4 Tesla scanner and subsequent volumetric evaluation of edema and contusion were performed. Thereafter, the animals were sacrificed and subjected to histopathological analysis. According to NSS, there was a significant impairment among all the groups subjected to trauma. Animals with both trauma and craniectomy performed significantly worse than animals with craniectomy alone. This deleterious effect disappeared when additional hypothermia was applied. BBS was significantly worse in the CHI and CHI+DC groups, but not in the CHI+DC+H group, compared to the sham animals. Edema and contusion volumes were significantly increased in CHI+DC animals, but not in the CHI+DC+H group, compared to the DC group. Histopathological analysis showed that neuronal loss and contusional blossoming could be attenuated by application of selective brain hypothermia. Selective brain cooling applied post-trauma and craniectomy improved neurological function and reduced structural damage and may be therefore an alternative to complication-burdened systemic hypothermia. Clinical studies are recommended in order to explore the potential of this treatment.