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We aim to develop fMRI neurofeedback as a treatment for obsessive compulsive disorder (OCD). In prior work, we found that providing neurofeedback of activity in the anterior prefrontal cortex (aPFC) improved control over contamination anxiety in a subclinical population. Here, we present the results of a randomized, double-blind clinical trial (NCT02206945) testing this intervention in patients with OCD. We recruited patients with primary symptoms in the fear-of-harm/checking or contamination/washing domains. During neurofeedback, they viewed symptom provocative images and attempted to up- and down-regulate the aPFC during different blocks of time. The active group received two sessions of neurofeedback and the control group received yoked sham feedback. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Symptom scale. The secondary outcome was control over aPFC. Thirty-six participants completed feedback training (18 active, 18 control). The active group had a slightly but significantly greater reduction of obsessive-compulsive symptoms after neurofeedback compared to the control group (p<.05) but no significant differences in control over the aPFC. These data demonstrate that neurofeedback targeting the aPFC can reduce symptoms in OCD. Future investigations should seek to optimize the training protocol to yield larger effects and to clarify the mechanism of action., Competing Interests: Declaration of Competing Interest Dr. Michelle Hampson is the editor of fMRI Neurofeedback, Academic Press and Dr. Chris Pittenger is the editor of Obsessive-Compulsive Disorder: Phenomenology, Pathophysiology, and Treatment, Oxford University Press, 2017. Dr. Brian Zaboski and Dr. Chris Pittenger consult for and receive research support from Biohaven Pharmaceuticals and Ceruvia Lifesciences. Dr. Chris Pittenger consults for and receives research support from Transcend Therapeutics and Freedom Biosciences, consults for UCB Biopharma, Nobilis Therapeutics, and F-Prime Capital Partners, and holds equity in Alco Therapeutics. Dr. Mariela Rance, Dr. Zhiying Zhao, Stephen A. Kichuk, Emma Romaker, William N. Koller, Christopher Walsh, Cheyenne Harris-Starling, Suzanne Wasylink, Dr. Thomas Adams Jr., and Dr. Patricia Gruner report no financial interests or potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Deficits in implicit learning, a process by which knowledge is acquired accretively through practice independent of conscious awareness, have been implicated in Obsessive-Compulsive Disorder (OCD). The weather-prediction task (WPT) was used to assess implicit learning in 26 unmedicated patients with OCD and 23 healthy controls. An additional analysis compared these two groups with 25 medicated patients with OCD. In the comparison of unmedicated patients with healthy controls there was a subtle but statistically significant group-by-block interaction. Patients with OCD showed slower improvement in performance during the middle phase of learning. In a three-group comparison, there was no main effect of group; in post-hoc tests, medicated patients with OCD differed from unmedicated patients and were not different from healthy controls. Unmedicated patients with OCD have a subtle deficit in implicit learning in the WPT. This may be mitigated by pharmacotherapy, although prospective studies would be required to confirm this conclusion.

The administration of small dosages of endotoxin to sheep results in cardiopulmonary changes characterized by an elevation in pulmonary lymph flow, vascular resistance, and hemoconcentration, and a reduction in cardiac output. These changes are not as great when the narcotic antagonist, naloxone (2 mg/kg/h for 5 h), is infused prior to and during the endotoxin response. The present study evaluates the ovine response to endotoxin when naloxone is administered 1 h after the endotoxin infusion. Sheep were prepared by implanting cardiopulmonary and lung lymphatic catheters. One week following the last surgical procedure, the sheep, in the awake state, were given 0.75 micrograms/kg of endotoxin and the variables were measured. Three days later, a second dose of endotoxin was administered and variables were again measured. An infusion of naloxone was given with one of the dosages of lipopolysaccharide. Two dosages of the narcotic antagonist were used. One group received 2 mg/kg bolus + 2 mg/kg/h for 5 h; another group was given twice this amount. Both dosages were started 1 h after endotoxin. The response to endotoxin was essentially the same whether or not the sheep were treated with naloxone. If naloxone pretreatment is effective and posttreatment is not, then it is possible that an opiatelike substance might be released by endotoxin which in turn results in the ultimate release of the lesion-producing substance.

The involvement of endorphins in the ovine cardiopulmonary response to endotoxin was evaluated by measuring blood levels of opiate receptor binding substances and administering the opiate receptor blocking agent naloxone prior to and after the administration of lipopolysaccharide. The animals were prepared for chronic study by placement of cardiovascular catheters and cannulation of the lung lymphatic at least 1 wk prior to study. The sheep were given endotoxin (0.75 micrograms/kg) and studied for 6 h. This was accomplished twice in the same animal. Naloxone (2 mg/kg bolus + 2 mg X kg-1 X h-1) was given with one of the two doses of the lipopolysaccharide. The response to endotoxin could be divided into two phases. In phase 1, there was an increase in protein-poor lung lymph and a marked increase in pulmonary artery pressure. In phase 2, the pulmonary lymph flow was elevated but the lymph protein level was higher than in phase 1. The pulmonary artery pressure, however, was near normal. During both phases leukocytes and cardiac output were reduced and the hematocrit was elevated. There was an increase in opiatelike materials in the plasma of these animals, and the response to endotoxin was partially blocked by naloxone. This suggested that endorphin-like materials were involved in the response to endotoxin.

Endotoxin (0.75 micrograms/kg) was administered to unanesthetized sheep with and without premedication with ibuprofen, a cyclooxygenase inhibitor, and diphenhydramine, an antihistamine. The effect of the endotoxin on cardiopulmonary and lung lymph data and their alteration by the drug regimen was assessed. The cardiopulmonary responses to endotoxin can be defined into two phases. In phase I there is an elevation in protein-poor lung lymph flow, in pulmonary artery pressure (PA), and in hematocrit, and a reduction in cardiac index and leukocyte count. Phase II occurs late and shows much the same changes as phase I except that the PA is not as high and the lymph protein is increased. The drug combination (ibuprofen and diphenhydramine) virtually eliminates the phase I response. The phase II changes in lymph flow and protein content are affected by diphenhydramine but not ibuprofen. The cardiovascular changes which occur during this period are not affected by either agent.

We studied the effects of superoxide dismutase (SOD), an enzyme that converts superoxide into peroxide, on the cardiopulmonary response to endotoxin in sheep. Sheep (n = 18) were prepared for chronic measurement of cardiopulmonary variables, including lung lymph flow, by surgically implanting catheters under halothane anesthesia. Nine of the animals were studied before and after the administration of endotoxin (0.75 microgram/kg) with and without SOD. An additional nine animals received SOD without the lipopolysaccharide. Endotoxin produced an increase in lung lymph flow that was initially associated with a marked pulmonary arterial (PA) hypertension and reduced lymph-to-plasma protein ratio (L/P). The lymph flow remained elevated later in the response, but there was only a mild increase in PA pressure, and the L/P was normal. There was also a fall in blood neutrophils and in cardiac index. SOD increased this secondary elevation in lung lymph flow, and the corresponding L/P was greater than the preendotoxin value. The fall in neutrophil count, cardiac output, and the elevation in PA pressure seen with endotoxin were not affected by SOD. When administered in the absence of endotoxin, SOD produced no perceptible change in the cardiopulmonary and lymph values. We conclude that peroxide, hydroxyl ion, and/or other free radicals formed by the action of SOD must be responsible for a portion of the endotoxin response rather than superoxide itself.

Gabexate mesilate (GM), a proteolytic enzyme inhibitor, was given to 31 chronically instrumented sheep either as a pretreatment or treatment to determine its effects on the cardiopulmonary response to endotoxin (ET). Twelve sheep received GM prior to endotoxin (0.75 microgram/kg), 10 after ET and 9 received GM without ET. A typical biphasic response was noted; phase I showed increased lymph flow (QL), reduced lymph to plasma protein ratio (L/P) and increased pulmonary artery pressure (PAP). Phase II occurred two hours after ET; the lymph flow remained elevated and the L/P ratio rose slightly above control. Both phases demonstrated an elevation in total peripheral vascular resistance (TPR) and hematocrit but a reduction in cardiac output (CO). In phase II, QL was reduced 35% with pretreatment; the L/P ratio did not rise as much and the PAP was unchanged. There was also a 35% reduction in lymph flow; no change in the lymph to plasma protein ratio but there was an elevation in pulmonary microvascular pressure. Pretreatment with GM diminished the fall in CO and the rise in TPR seen with endotoxin. The values were unaffected by treatment alone.

Acute burn wound sepsis is a common clinical entity resulting from a showering of the circulation with gram-negative organisms which grow abundantly in the burn. We duplicate this state in our laboratory by creating 40%, third degree burns (anesthetic burns) in chronically instrumented sheep. Three days following the thermal insult, the burn wound is infected by injecting gram-negative organisms (3 X 10(10)) into it. Cardiopulmonary variables and pulmonary lymph flux data are monitored two hours prior to the injection of organisms and for three hours following it. Three different organisms were used in this study; Pseudomonas aeruginosa (N = 12), Escherichia coli (N = 9), and Klebsiella pneumoniae (N = 2). The injection of all three organisms resulted in a similar response; an early marked pulmonary hypertension and a late increase in microvascular permeability. These changes occur concomitantly with an elevation in hematocrit and an early marked fall in neutrophils. The cardiac output gradually falls over the period of observation despite vigorous body shivering associated with a febrile response. The data from the sheep were compared to similarly instrumented animals (N = 12) which were not burned, but received a very small dosage of E coli endotoxin (0.75 micrograms/kg). The cardiopulmonary response was qualitatively identical to that seen with live organisms. However, the quantitative changes in several of the cardiopulmonary variables were much more marked with endotoxin. It is concluded that the cardiopulmonary response noted with burn wound sepsis is produced by endotoxin.

This study compares qualitative and quantitative differences between the cardiopulmonary responses to Salmonella typhimurium and Escherichia coli 055:B5 endotoxins (Difco) in the same sheep model. Lipopolysaccharides, 0.75 micrograms/kg, were infused into chronically instrumented sheep over 30 min. Cardiopulmonary and pulmonary lymph flux data were collected for 2 h prior to and 6 h following this. One week later the sequence was repeated with another endotoxin. The administration of the two endotoxins was varied: some received S. typhimurium first; others received E. coli. A total of 13 animals were studied; 8 had intact pulmonary lymphatic catheters. Following each injection of endotoxin these animals showed a typical response of early high pressure-mediated increase in pulmonary lymph flow and later lymph flow elevation associated with a very mild increase in microvascular pressure and lymph with normal protein levels. These changes were associated with hemoconcentration, lowered arterial oxygen partial pressure, cardiac index, and blood neutrophil count. It is concluded that Difco S. typhimurium and E. coli endotoxins are similar in their mechanism of action and potency and can be studied in the same animal.

The administration of endotoxin produces an early increase in hydrostatic pressure and pulmonary lymph flow, which is associated with elevated levels of thromboxane A2 in the lymph and can be blocked by the cyclooxygenase inhibitor ibuprofen. Two hours after the administration of endotoxin a secondary response is seen. The pulmonary lymph flow is elevated in association with a change in microvascular permeability to protein, this phase of the response can be reduced by the administration of the proteolytic enzyme inhibitor gabexate mesilate. In the present study we administered both compounds to eight sheep prepared for chronic cardiopulmonary and lung lymph studies to reduce both phases with the drug combination. The phase I response was reduced but the changes in lung lymph flow, associated with the phase II response, were unaffected by treatment. It is concluded that the effect of gabexate mesilate on the secondary response to endotoxin must in some way be related to the release of prostanoids.

Prostaglandins released during inflammatory reactions cause increases in microvascular hydrostatic pressure, a primary cause of edema. Ibuprofen, a nonsteroidal, anti-inflammatory agent that reduces prostaglandin synthesis via inhibition of cyclooxygenase, was used to investigate the possible role of prostaglandins in the cardiopulmonary responses during sepsis. Sheep, surgically prepared for cardiopulmonary studies and collection of lung lymph, were given 0.75 micrograms/kg per 30 min of E. coli endotoxin iv. Ibuprofen (14 mg/kg) was given 15 min before and 1 h 45 min after the administration of endotoxin. We had previously noted a triphasic character to the hypovolemia encountered in endotoxin sepsis. The initial phase occurs during the first hour after endotoxin administration; it is characterized by decreases in PaO2, neutrophil count, and lymph-to-plasma (L/P) protein concentration ratios and by increases in mean arterial pressure, body temperature, hematocrit, lymph flow, and total plasma protein concentration. In the second phase these variables return toward their baseline values. In Phase 3 the same changes are observed an in Phase 1 except for a decrease in total plasma protein concentration and an increase in L/P ratios. Ibuprofen administration results in a statistically significant reduction in magnitude of Phase 1 changes, without notable effect on Phase 2 or Phase 3 values. These observations support the hypothesis that prostaglandins released during inflammatory reactions contribute to the extravascular fluid movement. Ibuprofen appears to lessen the severity of microvascular hydrostatic pressure-induced edema and the hypovolemia that occurs in the early stages of endotoxin.

The involvement of thymocytes in the cardiopulmonary response to endotoxin was studied in chronically instrumented sheep. Four hours after the administration of 0.75 microgram/kg of endotoxin the blood levels of thymocytes were less than 25% of the control value, at a time when there was a marked fall in the cardiac index and a rise in pulmonary lymph flow. In a second series of experiments sheep were depleted of their thymocytes by the administration of antithymocyte serum. When endotoxin was given to these animals the cardiac output did not fall to the same extent, nor did the hematocrit rise as much as it did in the intact animal. It thus appears that the thymocyte may play a contributing role in the cardiopulmonary response to endotoxin.

The mortality rate of inhalation injury was lowered in six chronically instrumented sheep through positive pressure ventilation and positive end-expiratory pressure (PEEP). Six range ewes were prepared for study by implanting catheters to measure lung lymph flow and cardiopulmonary variables. After surgery, these animals were studied in the unanesthetized state and then subjected to an inhalation by insufflating them with smoke from burning cotton. Following the smoking procedure, the animals were studied for 72 hr. All had marked falls in arterial oxygen tension and they developed dyspnea within 24 hr. The inhalation injury produced a marked change in lung lymph flow concomitant with an elevation in the lymph to plasma (L/P) oncotic pressure ratio. This is characteristic of a change in microvascular permeability to protein. A tracheostomy was performed at 72 hr and the animals were connected to positive pressure ventilators with PEEP. All six animals survived. It was concluded that the sheep lung lymph preparation is a very suitable model for the study of inhalation injury and positive pressure ventilation.

Sheep which have been previously prepared for cardiopulmonary studies and collection of lung lymph were given 0.75 micrograms/kg of E coli endotoxin iv. This induced sepsis produced a triphasic response. Phase 1 occurs during the first hour after endotoxin administration and is characterized by a decreased cardiac output, lymph to plasma protein ratio, neutrophil count, and an increased hematocrit, total plasma protein concentration, lymph flow, and pulmonary artery pressure. During phase 2 these variables tend to return toward their baseline values. Phase 3 begins 2.5 hr after the administration of endotoxin and shows many of the same changes that were observed in phase 1. Also during the late phase, the plasma protein concentration and lymphocyte count were reduced and the lymph to plasa protein ratio was increased. It is concluded that (1) An early fall in cardiac output occurs as a consequence of hypovolemia. The decreased volume is the result of fluid movement from the vascular compartment to the interstitial space consequent to a microvascular pressure increase. Since the changes occur coincidentally with a drop in neutrophil count, these cells may bear some causal relationship to the response. (2) The late fall in cardiac output in phase 3, also the result of a diminished vascular volume, occurs secondarily to extravasular fluid movement as a consequence of both an elevated microvascular pressure and an increased permeability to protein. The latter may be causally related to a fall in lymphocytes.