Incidental Findings from 16,400 Brain MRI Examinations of Research Volunteers.

BACKGROUND AND PURPOSE: Incidental findings are discovered in neuroimaging research, ranging from trivial to life-threatening. We describe the prevalence and characteristics of incidental findings from 16,400 research brain MRIs, comparing spontaneous detection by nonradiology scanning staff versus formal neuroradiologist interpretation. MATERIALS AND METHODS: We prospectively collected 16,400 brain MRIs (7782 males, 8618 females; younger than 1 to 94 years of age; median age, 38 years) under an institutional review board directive intended to identify clinically relevant incidental findings. The study population included 13,150 presumed healthy volunteers and 3250 individuals with known neurologic diagnoses. Scanning staff were asked to flag concerning imaging findings seen during the scan session, and neuroradiologists produced structured reports after reviewing every scan. RESULTS: Neuroradiologists reported 13,593/16,400 (83%) scans as having normal findings, 2193/16,400 (13.3%) with abnormal findings without follow-up recommended, and 614/16,400 (3.7%) with "abnormal findings with follow-up recommended." The most common abnormalities prompting follow-up were vascular (263/614, 43%), neoplastic (130/614, 21%), and congenital (92/614, 15%). Volunteers older than 65 years of age were significantly more likely to have scans with abnormal findings (P < .001); however, among all volunteers with incidental findings, those younger than 65 years of age were more likely to be recommended for follow-up. Nonradiologists flagged <1% of MRIs containing at least 1 abnormality reported by the neuroradiologists to be concerning enough to warrant further evaluation. CONCLUSIONS: Four percent of individuals who undergo research brain MRIs have an incidental, potentially clinically significant finding. Routine neuroradiologist review of all scans yields a much higher rate of significant lesion detection than selective referral from nonradiologists who perform the examinations. Workflow and scan review processes need to be carefully considered when designing research protocols.

Anxiety-related behavioral inhibition in rats: a model to examine mechanisms underlying the risk to develop stress-related psychopathology.

Behavioral inhibition (BI) is an adaptive defensive response to threat; however, children who display extreme BI as a stable trait are at risk for development of anxiety disorders and depression. The present study validates a rodent model of BI based on an ethologically relevant predator exposure paradigm. We show that individual differences in rat BI are stable and trait-like from adolescence into adulthood. Using in situ hybridization to quantify expression of the immediate early genes homer1a and fos as measures of neuronal activation, we show that individual differences in BI are correlated with the activation of various stress-responsive brain regions that include the paraventricular nucleus of the hypothalamus and CA3 region of the hippocampus. Further supporting the concept that threat-induced BI in rodents reflects levels of anxiety, we also show that BI is decreased by administration of the anxiolytic, diazepam. Finally, we developed criteria for identifying extreme BI animals that are stable in their expression of high levels of BI and also show that high BI (HBI) individuals exhibit maladaptive appetitive responses following stress exposure. These findings support the use of predator threat as a stimulus and HBI rats as a model to study mechanisms underlying extreme and stable BI in humans.

Persistent corticotropin-releasing factor(1) receptor desensitization and downregulation in the human neuroblastoma cell line IMR-32.

Brain corticotropin-releasing factor (CRF) systems integrate various responses to stress. Pathological responses to stress may result from errors in CRF receptor regulation in response to changes in synaptic CRF levels. To establish an in vitro model to study brain CRF receptors, we characterized the CRF-induced modulation of CRF(1) receptors in the human neuroblastoma cell line, IMR-32. Treatment with CRF decreased CRF(1) receptor binding and desensitized CRF-induced increases in cAMP. The decrease in binding had an EC(50) of approximately 10 nM, was maximal by 30 min, and was blocked by the CRF receptor antagonist [D-Phe(12), Nle(21,38), C(alpha)-MeLeu(37)]CRF(12-41). The desensitization was homologous as vasoactive intestinal polypeptide-induced increases in cAMP were unchanged, and elevation of cAMP did not alter CRF(1) receptor binding. Treatment with CRF for up to 24 h did not alter CRF(1) receptor mRNA levels, suggesting that a posttranscriptional mechanism maintains the decrease in receptor binding. Interestingly, recovery of CRF receptor binding and CRF-stimulated cAMP production was only partial following exposure to 100 nM CRF. In contrast, receptor binding recovered to control levels following exposure to 10 nM CRF. These data suggest that exposure to high doses of CRF result in permanent changes characterized by only partial recovery. Identifying the mechanisms underlying this partial recovery may provide insights into mechanisms underlying the acute and chronic effects of stress on CRF receptor regulation.

A preliminary description of responses of free-ranging rhesus monkeys to brief capture experiences: behavior, endocrine, immune, and health relationships.

A cohort of free-ranging rhesus monkeys has been followed since birth in 1994 on the island of Cayo Santiago, Puerto Rico. At 3 years of age, subjects were trapped and blood samples were collected after capture and prior to release the following day. Blood samples were processed for natural cytotoxicity toward xenogeneic tumors, phenotyping, and plasma hormones. Intestinal parasites were determined from fresh stool samples collected during trapping. Data were also available from the previous year for antibody titers to latent viruses prevalent in this population. Behavioral traits of each monkey were characterized using a previously developed trait scale for rhesus monkeys. Natural cytotoxicity toward both K562 and Raji targets declined from capture until release the following day. Plasma cortisol rose and plasma prolactin and growth hormone fell during the period of captivity; a rise in insulin was significant. It was expected that individual differences in behavioral traits might predict immune and hormone levels at the time of capture or changes in these parameters during the capture period. Although behavioral adjectives tended to cluster along three orthogonal dimensions (Insecurity, Irritability, and Sociability), they bore no relationship to the physiological parameters collected acutely (in vitro immune and endocrine parameters). The individual difference markers of gender and maternal rank were not related to the magnitude of the observed changes in these in vitro parameters, either. However, an in vivo measure (CMV titer) was related to individual differences in Irritability. It was concluded that the magnitude of the stress associated with capture overwhelmed the individual difference effects.

Rise in plasma beta-endorphin, ACTH, and cortisol in cancer patients undergoing whole body hyperthermia.

It has been previously reported that sauna-induced fevers (approximately 39 degrees C) result in rises of beta-endorphins in normal volunteers. This report describes changes in plasma beta-endorphins in cancer patients undergoing whole body hyperthermia (40.5 degrees C to 41.8 degrees C). Results presented show that there is a linear relationship between thermal stress, defined in terms of core temperature and/or duration of hyperthermia, and the quantitative rise in plasma beta-endorphin levels. Data relating to changes in ACTH and cortisol levels are in a single temperature range (41.5 degrees C--41.8 degrees C) are also reported.

Neuroendocrine changes in patients undergoing whole body hyperthermia.

A phase I study of whole body hyperthermia (WBH) (52 treatments/12 patients) utilizing a radiant heat device has been completed. This study incorporated a temperature escalation scheme from 39.5 to 41.8 degrees C for up to 150 min. Pain relief or a sense of well being was observed post-WBH in the first three patients entered in this study. We postulated that WBH might result in increases in the opiate peptide beta-endorphin. Therefore we elected to study prospectively the next six patients entered in this study to test the hypothesis that WBH stimulates the neuroendocrine axis. Results are reported which show thermal-induced increases in plasma levels of beta-endorphin as well as prolactin, ACTH and cortisol.

ACTH in plasma and CSF in the rhesus monkey.

Adrenocorticotrophic hormone (ACTH) and other biosynthetically related peptides are found both in the brain and peripherally, but the function and regulation of these substances differ in the brain and in the periphery. It has been suggested that measurement of peptide hormones in the cerebrospinal fluid (CSF) might provide information relevant to the diagnosis and pathophysiology of neurological and psychiatric illnesses. We report experiments using a rhesus monkey model to evaluate parameters affecting CSF ACTH concentrations. We found that CSF ACTH concentrations follow a diurnal rhythm that is markedly different from that in plasma, concentrations of ACTH in monkey CSF, but not in plasma, increased significantly after 4 days of social separation, and CSF ACTH concentrations did not change after hypophysectomy. These results suggest that CSF ACTH concentrations reflect the activity of brain and not peripheral ACTH systems.

Depression in bulimia at 2- to 5-year followup.

Previous research has indicated a strong association between bulimia and affective disorder at the time of initial clinical assessment. To investigate this relationship from a long-term perspective, 30 normal weight female bulimics were evaluated 2 to 5 years posthospital admission with psychometric measures and clinical interviews. Contrary to previous reports, the depression scores of the bulimics were surprisingly low, even though 26 of the 30 continued to fulfill DSM-III criteria for bulimia. Higher depression scores were associated with more intense bulimic symptomatology and attitudes, and greater psychiatric disturbance at followup. Although these data demonstrate a relationship between bulimic symptomatology and depression at long-term followup, they do not support recent assertions that bulimia is a variant of an underlying affective disorder.

Biological correlates of attachment bond disruption in humans and nonhuman primates.

Separations or disruptions in attachment bonds occur frequently in the social lives of humans and have been linked to the development of psychopathology. Separation of social nonhuman primates has been proposed as a model to study the psychological and biological effects of separation in humans. This paper reviews the biological alterations that occur in nonhuman primates undergoing separation and compares these with changes associated with separation in humans. The data reviewed demonstrate that separation in humans and nonhuman primates can be an event with profound behavioral and physiological sequelae.

Indications and guidelines for plasma tricyclic antidepressant concentration monitoring.

Some tricyclic antidepressants appear to have critical ranges of plasma tricyclic antidepressant concentrations necessary for optimal clinical efficacy. For any given dose of tricyclic medication, there are marked interindividual variations in steady-state tricyclic concentrations. Furthermore, plasma tricyclic concentrations may be influenced by factors such as weight, diet, smoking status, differences in bioequivalence among manufacturers, and the addition or withdrawal of concurrent medications. There has been considerable controversy in the literature about the clinical utility of plasma tricyclic level monitoring. These authors believe that, at present, routine plasma level monitoring probably is not warranted, but that there are a variety of instances where plasma tricyclic concentration determinations may be clinically useful. The authors review methodological issues in plasma tricyclic concentration determinations and suggest guidelines for when such determinations may be clinically appropriate.

Dexamethasone fails to suppress beta-endorphin plasma concentrations in humans and rhesus monkeys.

In humans and rhesus monkeys, dexamethasone decreased concentrations of plasma cortisol but did not alter circulating beta-endorphin immunoreactivity. Contrary to current theory suggesting that pituitary beta-endorphin and adrenocorticotropic hormone are controlled by identical regulatory mechanisms for synthesis and release, our evidence suggests that in higher primates the established glucocorticoid feedback mechanism for the adrenocorticotropic hormone-cortisol system does not regulate beta-endorphin secretion in the same way.

Genital and abdominal self-surgery. A case report.

In two separate procedures, a psychiatric patient first performed a bilateral orchiectomy on himself and then later attempted to denervate his adrenal glands. This case suggests that physicians should be alerted to the possibility of self-surgery occurring in patients who have sought elective surgery and have been rejected.