Examining the long-term effects of traumatic brain injury on fear extinction in male rats.

There is a strong association between traumatic brain injuries (TBIs) and the development of psychiatric disorders, including post-traumatic stress disorder (PTSD). Exposure-based therapy is a first-line intervention for individuals who suffer from PTSD and other anxiety-related disorders; however, up to 50% of individuals with PTSD do not respond well to this approach. Fear extinction, a core mechanism underlying exposure-based therapy, is a procedure in which a repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus leads to a decrease in fear expression, and is a useful tool to better understand exposure-based therapy. Identifying predictors of extinction would be useful in developing alternative treatments for the non-responders. We recently found that CO2 reactivity predicts extinction phenotypes in rats, likely through the activation of orexin receptors in the lateral hypothalamus. While studies have reported mixed results in extinction of fear after TBI, none have examined the long-term durability of this phenotype in the more chronically injured brain. Here we tested the hypothesis that TBI results in a long-term deficit in fear extinction, and that CO2 reactivity would be predictive of this extinction phenotype. Isoflurane-anesthetized adult male rats received TBI (n = 59) (produced by a controlled cortical impactor) or sham surgery (n = 29). One month post-injury or sham surgery, rats underwent a CO2 or air challenge, followed by fear conditioning, extinction, and fear expression testing. TBI rats exposed to CO2 (TBI-CO2) showed no difference during extinction or fear expression relative to shams exposed to CO2 (sham-CO2). However, TBI-CO2 rats, showed significantly better fear expression than TBI rats exposed to air (TBI-air). In contrast to previous findings, we observed no relationship between CO2 reactivity and post-extinction fear expression in either the sham or TBI rats. However, compared to the previously observed naïve sample, we observed more variability in post-extinction fear expression but a very similar distribution of CO2 reactivity in the current sample. Isoflurane anesthesia may lead to interoceptive threat habituation, possibly via action on orexin receptors in the lateral hypothalamus, and may interact with CO2 exposure, resulting in enhanced extinction. Future work will directly test this possibility.

The superior longitudinal fasciculus and its functional triple-network mechanisms in brooding.

Brooding, which refers to a repetitive focus on one's distress, is associated with functional connectivity within Default-Mode, Salience, and Executive-Control networks (DMN; SN; ECN), comprising the so-called "triple-network" of attention. Individual differences in brain structure that might perseverate dysfunctional connectivity of brain networks associated with brooding are less clear, however. Using diffusion and functional Magnetic Resonance Imaging, we explored multimodal relationships between brooding severity, white-matter microstructure, and resting-state functional connectivity in depressed adults (N = 32-44), and then examined whether findings directly replicated in a demographically-similar, independent sample (N = 36-45). Among the fully-replicated results, three core findings emerged. First, brooding severity is associated with functional integration and segregation of the triple-network, particularly with a Precuneal subnetwork of the DMN. Second, microstructural asymmetry of the Superior Longitudinal Fasciculus (SLF) provides a robust structural connectivity basis for brooding and may account for over 20% of its severity (Discovery: adj. R2 = 0.18; Replication: adj. R2 = 0.22; MSE = 0.06, Predictive R2 = 0.22). Finally, microstructure of the right SLF and auxiliary white-matter is associated with the functional connectivity correlates of brooding, both within and between components of the triple-network (Discovery: adj. R2 = 0.21; Replication: adj. R2 = 0.18; MSE = 0.03, Predictive R2 = 0.21-0.22). By cross-validating multimodal discovery with replication, the present findings help to reproducibly unify disparate perspectives of brooding etiology. Based on that synthesis, our study reformulates brooding as a microstructural-functional connectivity neurophenotype.

Predicting extinction phenotype to optimize fear reduction.

Fear conditioning is widely employed to study dysregulations of the fear system. The repeated presentation of a conditioned stimulus in the absence of a reinforcer leads to a decrease in fear responding-a phenomenon known as extinction. From a translational perspective, identifying whether an individual might respond well to extinction prior to intervention could prove important to treatment outcomes. Here, we test the hypothesis that CO2 reactivity predicts extinction phenotype in rats, and that variability in CO2 reactivity as well as extinction long-term memory (LTM) significantly predicts orexin activity in the lateral hypothalamus (LH). Our results validate a rat model of CO2 reactivity and show that subcomponents of behavioral reactivity following acute CO2 exposure explain a significant portion of the variance in extinction LTM. Furthermore, we show evidence that variability in CO2 reactivity is also significantly predictive of orexin activity in the LH, and that orexin activity, in turn, significantly accounts for LTM variance. Our findings open the possibility that we may be able to use CO2 reactivity as a screening tool to determine if individuals are good candidates for an extinction/exposure-based approach.

Network model of fear extinction and renewal functional pathways.

The objective of this study was to examine the opposite behavior responses of conditioned fear extinction and renewal and how they are represented by network interactions between brain regions. This work is a continuation of a series of brain mapping studies of various inhibitory phenomena, including conditioned inhibition, blocking and extinction. A tone-footshock fear conditioning paradigm in rats was used, followed by extinction and testing in two different contexts. Fluorodeoxyglucose autoradiography was used to compare mean regional brain activity and interregional correlations resulting from the presentation of the extinguished tone in or out of the extinction context. A confirmatory structural equation model, constructed from a neural network proposed to underlie fear extinction, showed a reversal from negative regional interactions during extinction recall to positive interactions during fear renewal. Additionally, the magnitude of direct effects was different between groups, reflecting a change in the strength of the influences conveyed through those pathways. The results suggest that the extinguished tone encountered outside of the extinction context recruits auditory and limbic areas, which in turn influence the interactions of the infralimbic cortex with the amygdala and ventrolateral periaqueductal gray. Interestingly, the results also suggest that two independent pathways influence conditioned freezing: one from the central amygdaloid nucleus and the other from the infralimbic cortex directly to the ventrolateral periaqueductal gray.

Brain differences in newborn rats predisposed to helpless and depressive behavior.

Inborn brain differences in metabolic capacity were mapped in congenitally helpless rats, a genetically selected strain predisposed to show helpless and depressive behavior. There are a number of brain regions showing abnormal metabolism in adult congenitally helpless rats. Some of these alterations may be innate while others may be due to environmental factors, such as maternal care and postnatal stress. To identify which brain structures show innate differences, brains of newborn rats from congenitally helpless and non-helpless strains were compared using cytochrome oxidase histochemistry, an endogenous marker of regional metabolic capacity. A smaller subset of regions affected in adults showed significantly less metabolic activity in the newborn brains, including paraventricular hypothalamus, habenula, hippocampus, subiculum, lateral septal nucleus, anterior cingulate cortex, infralimbic cortex, and medial orbitofrontal cortex. A covariance analysis further revealed a striking reduction of functional connectivity in the congenitally helpless brain, including a complete decoupling of limbic forebrain regions from midbrain/diencephalic regions. This pattern of brain metabolism suggests that helplessness vulnerability is linked to altered functioning of limbic networks that are key to controlling the hypothalamic-pituitary-adrenal axis. This implies that vulnerable animals have innate deficits in brain systems that would normally allow them to cope with stress, predisposing them in this manner to more readily develop helpless and depressive behaviors.

Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior.

Congenitally helpless rats have been selectively bred to display an immediate helpless response to stress in order to model hereditary brain differences that contribute to depression vulnerability. Differences in regional brain metabolism between congenitally helpless and non-helpless rats were investigated using quantitative cytochrome oxidase histochemistry. The results indicated that congenitally helpless rats had 64-71% elevated metabolism in the habenula and a 25% elevation in the related interpeduncular nucleus. In contrast, helpless rats had 28% reduced metabolism in the ventral tegmental area (VTA) and 14-16% reductions in the basal ganglia and basolateral and central amygdala. The opposite metabolic changes in the habenula and ventral tegmental area may be especially important for determining the congenitally helpless rat's global pattern of brain activity, which resembles the metabolic activity pattern produced by dopamine antagonism.

Brain systems underlying susceptibility to helplessness and depression.

There has been a relative lack of research into the neurobiological predispositions that confer vulnerability to depression. This article reviews functional brain mappings from a genetic animal model, the congenitally helpless rat, which is predisposed to develop learned helplessness. Neurometabolic findings from this model are integrated with the neuroscientific literature from other animal models of depression as well as depressed humans. Changes in four major brain systems are suggested to underlie susceptibility to helplessness and possibly depression: (a) an unbalanced prefrontal-cingulate cortical system, (b) a dissociated hypothalamic-pituitary-adrenal axis, (c) a dissociated septal-hippocampal system, and (d) a hypoactive brain reward system, as exemplified by a hypermetabolic habenula-interpeduncular nucleus pathway and a hypometabolic ventral tegmental area-striatum pathway. Functional interconnections and causal relationships among these systems are considered and further experiments are suggested, with theoretical attention to how an abnormality in any one system could affect the others.

Dissociation of septo-hippocampal metabolism in the congenitally helpless rat.

Congenitally helpless rats, selectively bred to model features of endogenous depression, appear to have a paraventricular hypothalamic nucleus (PVH) that is markedly hyperactive. This study investigated septal and hippocampal regions purported to regulate the PVH. We found that cytochrome oxidase, an index of oxidative metabolism and neural activity, was significantly elevated in the hippocampus and subiculum of congenitally helpless rats. However, reduced activity was observed in the lateral and medial septal nuclei, the nucleus of the diagonal band, and the bed nucleus of the stria terminalis. This dissociation between hippocampal and septal activity may be a predisposing factor for the development of helpless behavior.

Hypermetabolism of paraventricular hypothalamus in the congenitally helpless rat.

The congenitally helpless rat, selectively bred to model behavioral features of depression, has shown metabolic activity patterns in frontal and cingulate cortex similar to those detected in human imaging studies of depression and sadness. This study extends the same metabolic mapping technique (quantitative cytochrome oxidase histochemistry) to the hypothalamus, where activity levels were assessed in six nuclei: paraventricular nucleus, medial preoptic area, lateral hypothalamic area, supraoptic nucleus, suprachiasmatic nucleus, and ventromedial nucleus. Helpless rats were compared with a strain of non-helpless rats selectively bred for stress resistance. Only the paraventricular nucleus showed a significant group difference, with helpless rats showing elevated metabolism and non-helpless rats showing reduced metabolism relative to normal rats. Thus, paraventricular nucleus activity may be associated with genetic susceptibility to helpless behavior.

Congenital helpless rats as a genetic model for cortex metabolism in depression.

The validity of congenital helplessness as a genetic rat model for human depression was investigated in cortical regions of the rat brain thought to be analogous to those showing abnormalities in human neuroimaging studies. Cortex metabolism was analyzed using quantitative cytochrome oxidase histochemistry. Congenital helpless rats showed changes in frontal and cingulate regions comparable to those that have demonstrated metabolic differences in human depression. Significant metabolic decreases were found in dorsal frontal, medial orbital, and anterior cingulate, whereas a significant increase was found in infraradiata (subgenual) cingulate. The direction of these changes were the same as those seen in human studies. These findings support the validity of congenital helplessness as a model for human depression.

Improving patient care through problem-solving groups.

In a competitive healthcare environment where as much attention must be given to quality of care as to cost containment, hospitals must learn to involve their lowest-paid paraprofessionals in decision making, since often these people have as much or more contact with patients than do physicians and nurses. One effective employee-involvement technique is the problem-solving group (PSG), which works to identify, analyze, choose, and implement solutions to various problems that influence the quality of patient care. A PSG project involving a typical paraprofessional unit was begun in spring 1985 at Emory University Hospital, Atlanta. The project's developmental stages were the following: Gathering data; Identifying problems; Providing feedback; Selecting PSG members; Focusing on problems; Generating solutions; Choosing the best solution; Implementing solutions; Managing successful outcomes. The PSG project was successful in addressing almost all the 15 identified problems in the department. Involving the staff in the PSG project resulted in higher morale, greater satisfaction with management, and a more favorable attitude toward their jobs.