fMRI during affect discrimination in bipolar affective disorder.

OBJECTIVE: It has been hypothesized that disturbances in affect may represent distinct etiologic factors for bipolar affective disorder. The neural mechanisms mediating affective processes and their relationship to brain development and the pathophysiology of bipolar affective disorder remain to be clarified. Recent advances in neuroimaging techniques have made possible the non-invasive examination of specific brain regions during cortical challenge paradigms. This study reports findings based on fMRI data acquired during fearful and happy affect recognition paradigms in patients with bipolar affective disorder and in healthy adult subjects. METHODS: Prior to the scan, subjects were instructed to view the stimuli and to identify the type of facial expression presented. Echo planar scanning was performed on a 1.5 Tesla scanner which had been retrofitted with a whole body echo planar coil, using a head coil. RESULTS: The data indicate that in adult subjects with bipolar affective disorder, there is a reduction in dorsolateral prefrontal cortex activation and an increase in amygdalar activation in response to fearful facial affect. In a healthy comparison group, signal intensity changes were not found in these regions. In addition, although the patients with bipolar affective disorder completed the task demands, they demonstrated an impaired ability to correctly identify fearful facial affect but not the happy facial affect displayed. CONCLUSION: These findings are consistent with the hypothesis that in some patients with bipolar affective disorder, there may be a reduction of frontal cortical function which may be associated with affective as well as attentional processing deficits.

Functional magnetic resonance imaging of facial affect recognition in children and adolescents.

OBJECTIVE: To examine further the role of the amygdala in the recognition of facial expression in adolescents. METHOD: Twelve healthy adolescents were studied using functional magnetic resonance imaging technology during a task of facial affect recognition and a visual control task. RESULTS: All subjects demonstrated a significant increase in signal intensity in the amygdala for the facial expression recognition task. CONCLUSIONS: The data are consistent with previous work in healthy adult subjects implicating the amygdala as essential for the recognition of fearful facial expression.

Obsessive-compulsive disorder among schizophrenic patients: an exploratory study using functional magnetic resonance imaging data.

Despite the growing research on the etiology of obsessive-compulsive disorder (OCD), and schizophrenia, the clinical distinction between the two disorders is not clearly understood. In the present investigation, we sought to better understand the relationship between OCD and psychotic disorders by examining functional magnetic resonance imaging (fMRI) data from a group of schizophrenic patients with varying degrees of OCD symptomatology, based on results of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the National Institute of Mental Health (NIMH) rating scales of OCD. While subjects performed a cognitive challenge paradigm that included a verbal fluency task, activation data from the left dorsolateral prefrontal cortex were collected and analyzed. We hypothesized that the fMRI signal patterns in schizophrenic patients with high levels of OCD symptomatology would differ from that of schizophrenic patients with a low level of OCD. For the group as a whole, no significant relationship was found for scores of either rating scale and fMRI signal change; however, a significant association was found for a subgroup of patients. For these schizophrenics, there was a negative relationship between OCD symptomatology and activation of the left dorsolateral prefrontal cortex. These results support the suggestion of several researchers that a relationship between OCD severity and neurophysiological activity exists in schizophrenia.

Chorionic gonadotrophin and embryo-maternal recognition during the peri-implantation period in primates.

Genes for chorionic gonadotrophin (CG) are transcribed by the 16-cell embryo stage in humans, but there is no clear evidence of CG secretion as a bioactive dimer before attachment and trophoblast outgrowth stages of implantation. The studies summarized question the timing of CG expression and secretion, the possible roles of CG for intraembryonic differentiation and at the implantation site, and the recognition of this primate embryo-derived signal in support of the corpus luteum. The data suggest that the implantation window in primates may be broader than in non-primate species, where a closer synchrony between embryonic, tubal and uterine events appears to be necessary for embryonic survival. Some preliminary data concerning an association between peripheral thrombocytopenia, ovarian inhibin secretion and peri-implantation stages of embryo development indicate that an unknown embryonic signal may be secreted before bioactive CG can be detected.

Membrane hyperpolarization, cyclic nucleotide levels and relaxation in the guinea-pig internal anal sphincter.

1. Changes in membrane potential (measured with an intracellular microelectrode) and in cyclic nucleotide (adenosine 3':5'-cyclic monophosphate, cyclic AMP and guanosine 3':5'-cyclic monophosphate, cyclic GMP) levels (measured by radioimmunoassay) in response to inhibitory non-adrenergic non-cholinergic (NANC) field stimulation and drugs were investigated in the guinea-pig internal and anal sphincter (gpIAS) in the presence of phentolamine and atropine (each 10(-6) M). 2. Inhibitory NANC nerve stimulation (single pulse, 5 pulses at 5, 10 and 20 Hz, 0.5 ms supramaximal voltage) and adenosine triphosphate (ATP, 10(-7)-10(-3) M) inhibited spike discharge, hyperpolarized the membrane and relaxed the sphincter. The effects of inhibitory nerve stimulation were blocked by tetrodotoxin (TTX, 10(-6) M) and, with those of ATP, were blocked by apamin (5 x 10(-6) M). 3. Isoprenaline (10(-9)-10(-4) M), cromakalim (10(-9)-10(-5) M), sodium nitroprusside (NaNP 10(-5) M), M&B 22948 (10(-4) M) and 8-bromocyclic GMP (8-Br-cyclic GMP, 10(-4) M) also inhibited spike discharge, hyperpolarized the membrane and relaxed the sphincter. The effects of isoprenaline were blocked by propranolol (10(-6) M). However, forskolin (10(-9)-10(-7) M), M&B 22948 (10(-9)-10(-5) M) and lower concentrations of NaNP (10(-9)-10(-6) M) relaxed the sphincter without affecting the membrane potential. 4. The characteristics of the membrane potential changes in response to different inhibitory stimuli in the gpIAS differed. Hyperpolarization produced by inhibitory NANC nerve stimulation and ATP were rapid in onset, of brief duration and of comparable amplitude. Isoprenaline and direct electrical stimulation also hyperpolarized the membrane and relaxed the muscle although the extent of the relaxation in these two cases was much less than that with nerve stimulation and ATP. In each case, the membrane potential change preceded relaxation and probably accounted for it. 5. Both inhibitory NANC nerve stimulation (80 pulses 8Hz supramaximal voltage 0.5 ms) and ATP (10-aM) raised levels of cyclic GMP significantly and to a comparable degree and relaxed the sphincter. The effect of nerve stimulation was prevented by TTX (10- 6M) but not by apamin (5 x 10- 6M). Isoprenaline (10-s M), cromakalim (10 5 M) and forskolin (10 5M) were ineffective. 6. Inhibitory NANC nerve stimulation (80 pulses 8Hz 0.5ms supramaximal voltage) and ATP (10-4M) raised levels of cyclic AMP significantly to a comparable degree and relaxed the sphincter. The increase produced by nerve stimulation was abolished by TTX (10-6M) and apamin (5 x 10-6M). Isoprenaline (10-4M), cromakalim (10-5 M) and forskolin (10-5 M) raised levels of this nucleotide significantly.

Embryonic signals during the peri-implantation period in primates.

During the peri-implantation period of pregnancy in primates, chorionic gonadotrophin (CG) is the first clear signal of the embryo's presence and viability. In the marmoset (Callithrix jacchus) implantation begins on Day 11-12 after ovulation and CG is secreted by the embryo from this time. The inner cell mass is necessary for the normal secretion of CG by the trophoblast. Implantation can be disrupted both in vivo and in vitro by antisera to the hCG-beta subunit. The secretion of a platelet activating factor by the preimplantation embryo has yet to be confirmed, as has the physiological function of this and other preimplantation signals. Local sampling by perfusion of the corpus luteum allows a direct measurement of the interactions between luteotrophins and luteolysins, as well as a method of screening potential new agents for regulating the function of the corpus luteum.

Use of a bioassay for embryo-derived platelet-activating factor as a means of assessing quality and pregnancy potential of human embryos.

The production of an embryo-derived platelet-activating factor (PAF) was recently shown to have a correlation with embryo quality and viability. The detection of this factor was used as a means of examining the effect of various aspects of the in vitro fertilization and embryo transfer procedure on human preimplantation embryo quality. Embryos that resulted in pregnancy produced significantly higher levels of embryo-derived PAF in vitro than embryos that failed to result in pregnancy. Of a further 85 embryos, 43% had a level of embryo-derived PAF that fell in the same range as the embryos that resulted in pregnancy. The production of embryo-derived PAF was related to the type of treatment used to induce follicular development (with clomiphene citrate and human menopausal gonadotropin commencing on day 5 giving best results); the size and estradiol production of the follicles producing the embryo; the age of the embryo culture medium; and the morphology and cell number of the embryos.

Effects of growth hormone on pregnancy-associated murine protein-1.

In male mice which normally do not synthesize measurable amounts of the pregnancy-associated murine protein-1 (PAMP-1), synthesis occurred when there was continuous infusion of hGH but not by repeated subcutaneous injections. The decrease in PAMP-1 values after hypophysectomy in female mice was rapidly restored by continuous infusion of hGH, 80 micrograms daily. PAMP-1 has generally been regarded as an 'oestrogen-inducible' protein regulated by the oestrogen/androgen balance. Our results suggest that the apparent effects of sex steroids are mediated via the pituitary and possibly growth hormone secretion.

Initiation and control of ovulation in the mouse luteal phases. Effects of oestrogen, progesterone and prolactin.

The aim of the present study was to examine the effect of exogenous oestrogen and progesterone on ovulation in early pregnant mice and at the end of pseudopregnancy. The results demonstrate that there are mature follicles during early pregnancy which were induced to ovulate by administration of large doses of oestrogen (greater than or equal to 10 micrograms) on day 4 of pregnancy. Ovulation was also induced by inhibition of progesterone secretion with bromocriptine. If progesterone or prolactin was given in conjunction with bromocriptine, the ovulation effect was abolished. At the end of pseudopregnancy, the spontaneous ovulation was inhibited by injections of progesterone (1.0 mg). Oestrogen given by itself at the end of pseudopregnancy caused the animals to mate earlier than the control animals. This confirms the presence of mature follicles in mice during pregnancy and suggests that the LH peak needed for ovulation can either be provoked by administration of oestrogen or by blocking of progesterone.

Initiation and control of ovulation in the mouse luteal phases. Effects of gonadotropins and gonadotropin releasing hormone.

The aim of the present study was to examine the induction of ovulation during pregnancy, pseudopregnancy, and suckling-delayed pregnancy in mice using exogenous gonadotropins. The present results demonstrate that there are mature follicles in the ovary which can be induced to ovulate with administration of either exogenous human chorionic gonadotropin (hCG) or luteinizing hormone (LH) during pregnancy (Days 1-12) and pseudopregnancy (Days 4-8) in the mouse. hCG was relatively ineffective in initiating ovulation during suckling-delayed pregnancy, and hCG could not induce ovulation on Days 3-6 in any animals, suggesting that follicular growth is not continuous during suckling-delayed pregnancy in the mouse. Ovulation occurred in pregnant and pseudopregnant mice following injection of gonadotropin releasing hormone (GnRH) in a gelatin delay vehicle. Injection of GnRH in saline did not initiate ovulation in pregnant or pseudopregnant mice. A large release of LH was shown to occur following injection of GnRH in gelatin, but no release occurred after the same dose of GnRH in saline. In conclusion, the experiments demonstrate the existence of mature follicles during murine pregnancy and pseudopregnancy, and the lack of inductable follicles during suckling-delayed pregnancy.

Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/estrogen ratios in humans and mice.

Daily blood samples were taken for progesterone (P) and estradiol (E2) measurements from women who showed a platelet response consistent with the presence of viable embryos after in vitro fertilization and embryo transfer procedures. A comparison of steroid levels between those women who became pregnant and those who did not revealed the following: at and after the time of transfer, women who failed to become pregnant had significantly higher E2 levels and a lower ratio of P/E2 than women who became pregnant. The P/E2 ratio was a better predictor of implantation failure than was the absolute level of either hormone. Experiments were done in mice to test the hypothesis that P could protect implantation of the embryo against the inhibitory effects of high E2. In mice, implantation was inhibited by relatively high levels of E2. This effect was overcome by concomitant administration of P. There was a significant dose-response-related interaction of P with the E2.

Maternal blood platelet physiology and luteal-phase endocrinology as a means of monitoring pre- and postimplantation embryo viability following in vitro fertilization.

The discovery that the fertilized mouse ovum triggers an increased demand for platelets and results in thrombocytopenia during the preimplantation phase of pregnancy provides a monitor for embryo survival and viability. This paper reports a study in which the platelet count was significantly reduced throughout the human preimplantation phase of pregnancy and returned to normal following embryo implantation. The human embryo was shown to produce a platelet activating factor in vitro which caused the reduction in platelet count after embryo transfer. This factor in the embryo culture medium could be measured using a bioassay which provided a means of assessing embryo viability prior to transfer. Some women showed no reduction in platelets after transfer. These embryos failed to produce a platelet activating factor in vitro and pregnancy was not established. Other women displayed a reduction in platelets following transfer but failed to become pregnant. All of these women had elevated luteal-phase plasma E2 levels compared to pregnant patients, which may have interfered with the implantation process. Our observations provide a possible rapid and simple means for monitoring the viability of human embryos cultured in vitro and the survival of embryos in utero.

The effect on pregnancy of intrauterine administration of antibodies against two pregnancy-associated murine proteins: murine pregnancy-specific beta 1-glycoprotein and murine pregnancy-associated alpha 2-glycoprotein.

Intrauterine administration of 100 arbitrary units (AU) of purified monospecific rabbit anti murine pregnancy specific beta 1-glycoprotein antibodies resulted in the loss of the fetuses in pregnant mice (14 out of 14). By contrast, a similar treatment with 100 AU of rabbit anti murine pregnancy-associated alpha 2-glycoprotein had an effect similar to saline on the outcome of pregnancy. Intravenous administration of 1000 AU of rabbit anti murine pregnancy specific beta 1-glycoprotein during pregnancy in mice had no effect on the outcome of pregnancy.

The influence of pituitary and gonadal hormones on serum levels of pregnancy-associated murine protein-1.

Hypophysectomy of female mice resulted in the disappearance of pregnancy-associated murine protein-1 (PAMP-1) from the circulation within a week. Maintenance of physiological levels of oestrogen, progesterone, testosterone, LH, FSH or prolactin was not sufficient to maintain a normal PAMP-1 level in the hypophysectomized animals. However, administration of oestrogen in large doses to adult male mice with undectatable levels of circulating PAMP-1 caused PAMP-1 to appear in the blood. Testosterone treatment of females inhibited the PAMP-1 synthesis.

Immunochemical demonstration of a new pregnancy protein in the mare.

An antiserum against the serum of a pregnant mare was absorbed with stallion serum. This antiserum then gave two precipitates in crossed immunoelectrophoresis with serum from pregnant mares as the antigen. The two precipitates exhibited beta-1 and alpha-2 electrophoretic mobility. Identity was demonstrated between the alpha-2 mobile protein and PMSG. The absorbed antiserum inhibited the biological action of the PMSG preparation when tested in mouse ovarian weight assays. The beta-1 mobile protein was not detected in the serum from non-pregnant mares, stallions or geldings and was detected earlier in pregnancy (Day 30) than was PMSG (Day 42).

Ovum factor: a first signal of pregnancy?

Previous studies have shown that, in the mouse, a factor is produced by the fertilized ovum within 24 h of mating. It cooperates with prolactin to stimulate ovarian production of component B or early pregnancy factor (EPF). This paper presents an initial characterization of the substance, termed ovum factor (OF). An indirect assay based on the rosette inhibition test for EPF has shown that OF is first released upon penetration of the ovum by the fertilizing spermatozoon. OF continues to be produced at least until blastulation. Processes which parthenogenetically activate the ovum are also capable of stimulating OF release from unfertilized ova. Gel filtration studies reveal that OF exists in multiple MW forms of approximately 160,000; 2,800; and 1,500. A substance with these characteristics has not been described previously; it may represent the first embryonic signal to the mother.

Endocrine control of implantation and delayed implantation in rats and mice.

Progesterone and oestrogen are required for implantation in the mouse and rat. In both animals prolactin and LH stimulate ovarian progesterone production oestrogen is stimulated by FSH in the mouse but both LH and FSH appear to be required in the rat. There is no evidence that preimplantation embryonic gonadotrophins, if they exist in these species, are involved in the initiation of implantation. The delay of implantation in suckling mice and rats is due to a lack of oestrogenic stimulus. This is caused by an inhibition of FSH release from the pituitary gland. The inhibition of FSH release appears to be caused by lack of a competent hypothalamic releasing factor. High circulating levels of prolactin and/or LH and/or progesterone do not seem to be responsible for the FSH inhibition during suckling-induced delayed implantation. Increased or decreased prolactin release does not affect FSH release during early pregnancy in the mouse.

Effects of adrenalectomy on reproduction in the mouse.

Survival of mice treated with sesame seed oil after adrenalectomy was very low and suggested no beneficial effect, whereas treatment with progesterone improved the chances of survival. Treatment with desoxycorticosterone acetate (DOCA) and methyl prednisolone acetate also increased the number of animals surviving after adrenalectomy. The corticosteroids were significantly more effective in ensuring survival than was progesterone. There was no significant difference in survival between mice receiving a single injection of 1.0 mg DOCA and those being given an injection of 1.0 mg DOCA per day for 3 days after the operation. To ensure minimum interference of exogenous corticosteroid with the experimental investigation, animals routinely received only a single injection of 1.0 mg DOCA after the operation. The chance of survival after adrenalectomy was higher in pregnant than in non-pregnant mice. There was a significant linear increase in survival during the first 5 days of pregnancy. Progesterone and prolactin both appeared to be involved in increasing the chance of survival in adrenalectomized pregnant mice. Adrenalectomy had no effect on the number of mice mating and ovulating. Adrenalectomized mice were apparently having normal cycles and 4 weeks after adrenalectomy they were able to mate and ovulate. Compensatory ovulation was seen in hemi-ovariectomized mice and was not abolished by adrenalectomy. Implantation was also unaffected by the operation.