Optimizing real time fMRI neurofeedback for therapeutic discovery and development.

While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.

What's in a name? Neuroimmunomodulation or psychoneuroimmunology?

Compelling evidence is presented to support the hypothesis that psychological processes affect immune function. Consequently, it is argued that psychological processes should be included in human immunological studies and that neuroimmunomodulation could accurately by called psychoneuroimmunology.

Mind-body research in psychooncology.

The biomedical model of disease, though powerful, does not explain all known facts about cancer. It is argued that a broader theoretical framework which includes psychosocial factors is needed. There is empirical evidence that a hopeless/helpless coping style is associated with unfavorable disease outcome in patients with certain cancers. The converse, namely a link between an active, fighting spirit coping style and favorable disease outcome, is under-researched and less clear-cut. The delineation, measurement and psychophysiology of positive states of mind have been sorely neglected. This is a promising area for future research. Psychobiological mechanisms of possible relevance to cancer are considered in terms of psychoneuroimmunology. Despite formidable theoretical and methodological problems, some progress is being made. Recent evidence indicates that psychotherapeutic intervention can augment natural killer cell activity and lymphokine-activated killer cell activity in patients with malignant melanoma and with locally advanced, nonmetastatic breast cancer respectively. These challenging findings, if confirmed, have major implications for our understanding of mind-body interactions in patients with cancer.

5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.

The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insufficient efficacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be "much improved" by the study physician compared to 22 of the 77 patients (29%) on placebo (p = 0.001). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo (p = 0.0001). Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.

Use of 5-fluorodeoxycytidine and tetrahydrouridine to exploit high levels of deoxycytidylate deaminase in tumors to achieve DNA- and target-directed therapies.

In view of the 20- to 80-fold elevation of deoxycytidine-5'-phosphate (dCMP) deaminase in many human malignant tumors, we have utilized 5-fluorodeoxycytidine ( FdCyd ) coadministered with tetrahydrouridine ( H4Urd ) as a combination of antitumor agents against two murine solid tumors which possess high levels of dCMP deaminase. This approach is based on our past studies in which we demonstrated that FdCyd is an excellent substrate for mammalian 2'-deoxycytidine kinase, and that H4Urd increases the toxicity of FdCyd in the mouse. Cell culture studies utilizing 2'- deoxytetrahydrouridine which inhibits cytidine deaminase and as 2'- deoxytetrahydrouridine -5'-monophosphate inhibits dCMP deaminase, provide indirect evidence for the pathway that we had proposed in the past, 2'- Deoxytetrahydrouridine antagonized the toxicity of FdCyd to a greater extent than did H4Urd and showed marked antagonism in cytidine deaminase-deficient cells. Cell lines lacking both cytidine and 2'-deoxycytidine-5'-monophosphate deaminase were markedly resistant to FdCyd . Thymidine and deoxyuridine antagonized toxicity in a manner consistent with the proposed pathway of anabolism of FdCyd and consistent with its resulting in the inhibition of thymidylate synthetase. We have established the efficacy of FdCyd + H4Urd chemotherapy utilizing adenocarcinoma 755 and Lewis lung carcinoma in C57BL X DBA/2 F1 mice. An example of an optimum schedule versus Lewis lung carcinoma is FdCyd , 10 to 12 mg/kg, plus H4Urd , 25 mg/kg, coadministered simultaneously, once per day on Days 1 to 7 after tumor implantation. Tumor inhibitions on Days 12, 14, and 16 were 95, 90, and 80%, respectively, with 8% maximum weight loss. Comparative studies were undertaken only with Lewis lung carcinoma and it was established that FdCyd + H4Urd surpasses the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine as well as FdCyd when administered without H4Urd . We propose that the administration of FdCyd with H4Urd can result in preferential, tumor-directed conversion of a nontoxic nucleoside analogue to a toxic antimetabolite by an enzyme that is markedly elevated in human tumor tissue. The analogues of deoxycytidine are resistant to catabolism and are anabolized by a different subset of enzymes than are 5-fluorouracil or 5-fluorodeoxyuridine; therefore, it is a novel approach. Not only are there intrinsic selectivity, metabolic stability, and the advantages that accrue from prodrug therapy in this strategy, but in addition, the potential for an exclusively DNA-directed effect exists. This is in contrast to approaches with 5-fluorouracil and 5-fluorodeoxyuridine, in which, in addition to DNA effects, parallel effe

Studies on the site of action of vasopressin in inducing adrenocorticotropin secretion.

Hypophysectomized rats bearing three transplanted pituitaries under the kidney capsule responded to synthetic lysine vasopressin or pitressin with a significant elevation of plasma corticosterone, whereas hypophysectomized rats with no grafts did not. This response was completely abolished by pretreatment of animals with dexamethasone but was unaltered by central hypothalamic destruction. Corticotropin-releasing factor content of the hypothalamic median eminence, hypophyseal stal-, or pars nervosa of the posterior pituitary of intact rats was unchanged 5 or 10 min after ip injection of vasopressin compared to the basal level. We conclude that vasopressin and dexamethasone act directly on the adenohypophysis in vivo to exert their stimulatory or inhibitory effect on ACTH secretion.

Changes in plasma thyroxine, triiodothyronine, and TSH during adaptation to iodine deficiency in the rat.

We have measured plasma thyroxine (T4), triiodothyronine (T3), and TSH with specific radioimmunoassays in rats during adaptation to severe iodine deficiency after they had previously received regimens supplying various quantities of iodine. Rats were maintained on a high-iodine diet (HID) containing 3 mg iodine/kg or a low-iodine diet (LID) containing 30 mug iodine/kg supplemented with 0.1, 0.2, or 0.4 mug iodine/ml of drinking water before swtiching to KID alone. Frequent serial blood samples were obtained up to 3 months, using 6 or more animals for each time interval. In animals originally fed HID, T4 remained at 4-6 mug/100 ml unitl the tenth day of LID, then rapidly decreased to a value of less than 0.4 mug/100 ml at 1 month. TSH was initially 50 muU/ml and increased linearly to 165 muU/ml on day 16. Thence there was a much more rapid rate of rise to 640 muU/ml at 38 days. The rats changed to LID alone after having been fed LID with iodine supplementation underwent similar qualitative hormonal changes. However, the decrease in plasma T4 and the increase in plasma TSH occurred sooner in the rats which had drunk water containing only 0.1 or 0.2 mug iodine/ml than in the previous experiment. Rats which had received 0.4 mug iodine/ml showed a pattern essentially identical to that of the animals which had been fed HID. plasma T3 did not change significantly in any of the experiments, remaining at 60-90 ng/100 ml, although there was a tendency for the values to be somewhat lower after several weeks of LID. There was a highly significant negative correlation of plasma T4 with plasma TSH. There was no significant correlation of plasma T3 with either plasma T4 or plasma TSH. It is concluded that the combined physiologic effect of plasma T4 and T3 concentration is more important in determining TSH secretion through negative feedback effects on the hypothalamus and/or pituitary than is the concentration of plasma T3.