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Julian E. Bailes, Marc L. Leavitt, Edward Teeple Jr., Joseph C. Maroon, Shou-Ren Shih, Merlin Marquardt, Amr El Rifai and Leo Manack

✓ The potential for hypothermia to prevent or ameliorate ischemic injury to the central nervous system is well known. To determine if a more prolonged period of metabolic suppression with blood substitution is possible, a method was developed to lower body temperature to near the freezing point. Eight adult mongrel dogs underwent closed-chest extracorporeal circulation with both external and internal body cooling. As they were cooled, progressive hemodilution was employed until complete exsanguination and blood substitution with an aqueous solution was accomplished. Continuous circulation and a core temperature at a mean of 1.7°C were maintained from 2½ to 3 hours. After rewarming to 20°C, the animals were autotransfused and allowed to recover. Of the eight animals, two died due to technical factors related to cardiac defibrillation. Of the six surviving animals, five survived over a long period and one died on the 10th postoperative day with hepatorenal failure resulting from a presumed blood transfusion incompatability reaction. All six showed normal neurological function and kennel behavior, except one dog with mild weakness of a hindlimb. When the dogs were sacrificed 1 to 2 months postoperatively, all organs were histologically normal. Specifically, there was no gross or microscopic evidence of ischemic or hypoxic injury to any central nervous system structures.

This pilot study demonstrates that it is possible to successfully achieve complete exsanguination, blood substitution, and ultraprofound body temperature, while continuous circulation of the blood substitute is maintained. With the capability of controlling and repeatedly performing washout of the extracellular environment and by reaching lower temperatures, it may be possible to attain greater cellular metabolic suppression. This perhaps will extend the allowable times for circulatory arrest procedures. In addition, “bloodless ischemia” may be beneficial in removing both blood substances and formed elements which may mediate organ ischemia. With replacement of blood at warm temperatures, coagulopathy is avoided. This preliminary evidence demonstrates potential in the combination of ultraprofound hypothermia and complete blood component substitution. However, further study is required to confirm the potential of achieving circulatory arrest of longer duration.

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W. Bryan Wilent, Michael Y. Oh, Catherine Buetefisch, Julian E. Bailes, Diane Cantella, Cindy Angle and Donald M. Whiting

Major contributions to the understanding of human brain function have come from detailed clinical reports of responses evoked by electrical stimulation and specific brain regions during neurosurgical procedures in awake humans. In this study, microstimulation evoked responses and extracellular unit recordings were obtained intraoperatively in 3 awake patients undergoing bilateral implantation of deep brain stimulation electrodes in the lateral hypothalamus. The microstimulation evoked responses exhibited a clear anatomical distribution. Anxiety was most reliably evoked by stimulation directed ventromedially within or adjacent to the ventromedial nucleus of the hypothalamus, nausea was most reliably evoked by stimulation directed at the center of the lateral hypothalamus, and paresthesias were most reliably evoked by stimulation at the border of the lateral hypothalamus and basal nuclei. Regarding the unit recordings, the firing rates of individual neurons did not have an anatomical distribution, but a small subpopulation of neurons located at the border of the lateral hypothalamus and basal nuclei exhibited a fast rhythmically bursting behavior with an intraburst frequency of 200–400 Hz and an interburst frequency of 10–20 Hz. Based on animal studies, the lateral hypothalamic area and surrounding hypothalamic nuclei are putatively involved with a variety of physiological, behavioral, and sensory functions. The lateral hypothalamus is situated to play a dynamic and complex role in human behavior and this report further shows that to be true. In addition, this report should serve as a valuable resource for future intracranial work in which accurate targeting within this region is required.

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W. Bryan Wilent, Michael Y. Oh, Cathrin M. Buetefisch, Julian E. Bailes, Diane Cantella, Cindy Angle and Donald M. Whiting

Panic attacks are sudden debilitating attacks of intense distress often accompanied by physical symptoms such as shortness of breath and heart palpitations. Numerous brain regions, hormones, and neurotransmitter systems are putatively involved, but the etiology and neurocircuitry of panic attacks is far from established. One particular brain region of interest is the ventromedial hypothalamus (VMH). In cats and rats, electrical stimulation delivered to the VMH has been shown to evoke an emotional “panic attack–like” escape behavior, and in humans, stimulation targeting nuclei just posterior or anterior to the VMH has reportedly induced panic attacks. The authors report findings obtained in an awake patient undergoing bilateral implantation of deep brain stimulation electrodes into the hypothalamus that strongly implicates the VMH as being critically involved in the genesis of panic attacks. First, as the stimulating electrode progressed deeper into the VMH, the intensity of stimulation required to evoke an attack systematically decreased; second, while stimulation of the VMH in either hemisphere evoked panic, stimulation that appeared to be in the center of the VMH was more potent. Thus, this evidence supports the role of the VMH in the induction of panic attacks purported by animal studies.

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Brandon P. Lucke-Wold, Ryan C. Turner, Aric F. Logsdon, Linda Nguyen, Julian E. Bailes, John M. Lee, Matthew J. Robson, Bennet I. Omalu, Jason D. Huber and Charles L. Rosen

OBJECT

Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration.

METHODS

The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors’ clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler.

RESULTS

The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase–3β. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy.

CONCLUSIONS

Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.

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Donald M. Whiting, Nestor D. Tomycz, Julian Bailes, Lilian de Jonge, Virgile Lecoultre, Bryan Wilent, Dunbar Alcindor, E. Richard Prostko, Boyle C. Cheng, Cynthia Angle, Diane Cantella, Benjamin B. Whiting, J. Scott Mizes, Kirk W. Finnis, Eric Ravussin and Michael Y. Oh

Object

Deep brain stimulation (DBS) of the lateral hypothalamic area (LHA) has been suggested as a potential treatment for intractable obesity. The authors present the 2-year safety results as well as early efficacy and metabolic effects in 3 patients undergoing bilateral LHA DBS in the first study of this approach in humans.

Methods

Three patients meeting strict criteria for intractable obesity, including failed bariatric surgery, underwent bilateral implantation of LHA DBS electrodes as part of an institutional review board– and FDA-approved pilot study. The primary focus of the study was safety; however, the authors also received approval to collect data on early efficacy including weight change and energy metabolism.

Results

No serious adverse effects, including detrimental psychological consequences, were observed with continuous LHA DBS after a mean follow-up of 35 months (range 30–39 months). Three-dimensional nonlinear transformation of postoperative imaging superimposed onto brain atlas anatomy was used to confirm and study DBS contact proximity to the LHA. No significant weight loss trends were seen when DBS was programmed using standard settings derived from movement disorder DBS surgery. However, promising weight loss trends have been observed when monopolar DBS stimulation has been applied via specific contacts found to increase the resting metabolic rate measured in a respiratory chamber.

Conclusions

Deep brain stimulation of the LHA may be applied safely to humans with intractable obesity. Early evidence for some weight loss under metabolically optimized settings provides the first “proof of principle” for this novel antiobesity strategy. A larger follow-up study focused on efficacy along with a more rigorous metabolic analysis is planned to further explore the benefits and therapeutic mechanism behind this investigational therapy.