Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis.

Exposure to psychological trauma (for example, childhood/early life adversity, exposure to violence or assault, combat exposure, accidents or natural disasters) is known to increase one's risk of developing certain chronic medical conditions. Clinical and population studies provide evidence of systemic inflammatory activity in trauma survivors with various psychiatric and nonpsychiatric conditions. This transdiagnostic meta-analysis quantitatively integrates the literature on the relationship of inflammatory biomarkers to trauma exposure and related symptomatology. We conducted random effects meta-analyses relating trauma exposure to log-transformed inflammatory biomarker concentrations, using meta-regression models to test the effects of study quality and psychiatric symptomatology on the inflammatory outcomes. Across k=36 independent samples and n=14,991 participants, trauma exposure was positively associated with C-reactive protein (CRP), interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α (mean rs =0.2455, 0.3067, 0.2890, and 0.2998, respectively). No significant relationships were noted with fibrinogen, IL-2, IL-4, IL-8, or IL-10. In meta-regression models, the presence of psychiatric symptoms was a significant predictor of increased effect sizes for IL-1ß and IL-6 (ß=1.0175 and 0.3568, respectively), whereas study quality assessment scores were associated with increased effect sizes for IL-6 (ß=0.3812). Positive correlations between inflammation and trauma exposure across a range of sample types and diagnoses were found. Although reviewed studies spanned an array of populations, research on any one specific psychiatric diagnosis was generally limited to one or two studies. The results suggest that chronic inflammation likely represents one potential mechanism underlying risk of health problems in trauma survivors.

Cognitive distortions in an acutely traumatized sample: an investigation of predictive power and neural correlates.

BACKGROUND: Current theories of post-traumatic stress disorder (PTSD) place considerable emphasis on the role cognitive distortions such as self-blame, hopelessness or preoccupation with danger play in the etiology and maintenance of the disorder. Previous studies have shown that cognitive distortions in the early aftermath of traumatic events can predict future PTSD severity but, to date, no studies have investigated the neural correlates of this association. METHOD: We conducted a prospective study with 106 acutely traumatized subjects, assessing symptom severity at three time points within the first 3 months post-trauma. A subsample of 20 subjects additionally underwent a functional 4-T magnetic resonance imaging (MRI) scan at 2 to 4 months post-trauma. RESULTS: Cognitive distortions proved to be a significant predictor of concurrent symptom severity in addition to diagnostic status, but did not predict future symptom severity or diagnostic status over and above the initial symptom severity. Cognitive distortions were correlated with blood oxygen level-dependent (BOLD) signal strength in brain regions previously implicated in visual processing, imagery and autobiographic memory recall. Intrusion characteristics accounted for most of these correlations. CONCLUSIONS: This investigation revealed significant predictive value of cognitive distortions concerning concurrent PTSD severity and also established a significant relationship between cognitive distortions and neural activations during trauma recall in an acutely traumatized sample. These data indicate a direct link between the extent of cognitive distortions and the intrusive nature of trauma memories.

Default mode network connectivity as a predictor of post-traumatic stress disorder symptom severity in acutely traumatized subjects.

OBJECTIVE: The goal of this study was to investigate the relationship between default mode network connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in a sample of eleven acutely traumatized subjects. METHOD: Participants underwent a 5.5 min resting functional magnetic resonance imaging scan. Brain areas whose activity positively correlated with that of the posterior cingulate/precuneus (PCC) were assessed. To assess the relationship between severity of PTSD symptoms and PCC connectivity, the contrast image representing areas positively correlated with the PCC was correlated with the subjects' Clinician Administered PTSD Scale scores. RESULTS: Results suggest that resting state connectivity of the PCC with the perigenual anterior cingulate and the right amygdala is associated with current PTSD symptoms and that correlation with the right amygdala predicts future PTSD symptoms. CONCLUSION: These results may contribute to the development of prognostic tools to distinguish between those who will and those who will not develop PTSD.

Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network.

Spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. A "default network" of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulus-independent thought. Negatively correlated with this network are regions activated during attention-demanding tasks. Both these networks involve brain regions and functions that have been linked with schizophrenia in previous research. The present study examined spontaneous slow fluctuations in the BOLD signal at rest, as measured by correlation with low-frequency oscillations in the posterior cingulate, in 17 schizophrenic patients, and 17 comparable healthy volunteers. Healthy volunteers demonstrated correlation between spontaneous low-frequency fluctuations of the BOLD signal in the posterior cingulate and fluctuations in the lateral parietal, medial prefrontal, and cerebellar regions, similar to previous reports. Schizophrenic patients had significantly less correlation between spontaneous slow activity in the posterior cingulate and that in the lateral parietal, medial prefrontal, and cerebellar regions. Connectivity of the posterior cingulate was found to vary with both positive and negative symptoms in schizophrenic patients. Because these data suggest significant abnormalities in resting-state neural networks in schizophrenia, further investigations of spontaneous slow fluctuations of the BOLD signal seem warranted in this population.

The nature of traumatic memories: a 4-T FMRI functional connectivity analysis.

OBJECTIVE: This study used functional connectivity analyses to assess interregional brain activity correlations during the recall of traumatic memories in traumatized subjects with and without posttraumatic stress disorder (PTSD). METHOD: Both 4-T functional magnetic resonance imaging (fMRI) and functional connectivity analyses were used to assess interregional brain activity correlations during script-driven symptom provocation in traumatized subjects with (N=11) and without (N=13) PTSD. Functional connectivity analyses were carried out by using data for brain regions activated in both the PTSD group and the comparison group. The use of functional connectivity analyses in addition to subtraction analyses allowed assessment of specific brain regions involved in the recall of traumatic events and of the neuronal networks underlying the recall of such events. RESULTS: Significant between-group differences in functional connectivity were found. Comparison of connectivity maps at coordinates x=2, y=20, z=36 (right anterior cingulate gyrus) for the two groups showed that the subjects without PTSD had greater correlation than the PTSD subjects in the left superior frontal gyrus (Brodmann's area 9), left anterior cingulate gyrus (Brodmann's area 32), left striatum (caudate), left parietal lobe (Brodmann's areas 40 and 43), and left insula (Brodmann's area 13). In contrast, the PTSD subjects showed greater correlation than the subjects without PTSD in the right posterior cingulate gyrus (Brodmann's area 29), right caudate, right parietal lobe (Brodmann's areas 7 and 40), and right occipital lobe (Brodmann's area 19). CONCLUSIONS: The differences in brain connectivity between PTSD and comparison subjects may account for the nonverbal nature of traumatic memory recall in PTSD subjects, compared to a more verbal pattern of traumatic memory recall in comparison subjects.

The thought disorder questionnaire.

OBJECTIVE: To describe the development of the Thought Disorder Questionnaire (TDQ), including data on reliability and validity, and to explain the questionnaire's feasibility and diagnostic accuracy. METHODS: The TDQ has 6 scales, each with 10 items (on a scale from 0 [for never] to 4 [for always]). The 6 scales measure content of thought, control of thought, orientation, perception, fantasy, and symptoms. RESULTS: The TDQ is a reliable 60-item, self-report questionnaire that measures the quantity and quality of disordered thinking in patients with mental disorders. It has established reliability and validity. CONCLUSION: The TDQ's clinical and research utility remains to be determined.

An evaluation of a stress management program for individuals with schizophrenia.

Vulnerability-stress models suggest that training in specific stress management techniques should yield benefits to those suffering from schizophrenia and related disorders. In this paper, we describe an evaluation of the impact of adding a stress management program to other medical and psychosocial interventions for such patients. Outcomes were compared for 121 patients randomly assigned to receive either a 12-week stress management program with follow-up sessions or participation in a social activities group. The two treatment conditions did not differ in levels of symptoms, perceived stress or life skills immediately after completion of treatment or at 1-year follow-up. Patients who received the stress management program did have fewer hospital admissions in the year following treatment. This effect of stress management was most apparent for those who showed high levels of attendance for treatment sessions. It was concluded that training in stress management may provide patients with skills for coping with acute stressors and reduce the likelihood of subsequent acute exacerbation of symptoms with need for hospitalization.

Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation.

OBJECTIVE: The neuronal circuitry underlying posttraumatic stress disorder (PTSD) was studied in traumatized subjects with and without PTSD. METHOD: Traumatized subjects with (N=9) and without (N=9) PTSD were studied by using the script-driven symptom provocation paradigm adapted to functional magnetic resonance imaging at a 4-T field strength. RESULTS: PTSD subjects showed significantly less activation of the thalamus, the anterior cingulate gyrus (Brodmann's area 32), and the medial frontal gyrus (Brodmann's area 10/11) than did the comparison subjects. CONCLUSIONS: The findings suggest anterior cingulate, frontal, and thalamic involvement in the neuronal circuitry underlying PTSD.

Declining of memory functions of normal elderly persons.

Two studies examined the declining of memory functions in normal elderly persons using the Yokota memory test (YMT), which includes 15 items concerning verbal and non-verbal memory functions. In the first study, 552 subjects over 40 years of age in five age groups were examined. Factor analysis revealed that YMT consisted of two factors pertaining to short-term/working memory, and two factors pertaining to long-term memory. It is suggested that the former was more affected than the latter, with aging. In the second study, YMT was examined in relation to the revised version of Hasegawa dementia scale (HDS-R), which was the most popular intelligence scale for the elderly in Japan. As a result, memory functions differentially declined with the decreasing score of HDS-R, which suggests that memory functions differentially declined with progressive risk of dementia.

Cognitive processing of multidimensional stimuli in schizophrenia: formal modeling of judgment speed and content.

This article presents a formal, mathematical account of relations between response times on simple cognitive tasks and content of complex judgments involving multiple stimulus dimensions for people with schizophrenia. Changes in multidimensional judgments were viewed as the result of interference from increased stages of encoding with respect to the individual dimensions. Information on dimensional properties encoded earlier in a judgment trial was considered to be more susceptible to loss over the rest of the trial, because of a larger number of encoding stages applied to the remaining dimensional properties. Model predictions were tested with samples of paranoid and nonparanoid schizophrenic participants and controls. Unidimensional encoding speed was assessed by reaction times in an explicit similarity ratings task, and multidimensional judgment content was assessed by the relative importance of different stimulus dimensions to participants' ratings in an implicit similarity ratings task. Results support validity of the model.

A short echo proton magnetic resonance spectroscopy study of the left mesial-temporal lobe in first-onset schizophrenic patients.

BACKGROUND: Past 1H magnetic resonance spectroscopy (MRS) studies of the temporal lobe in schizophrenic patients have shown decreased levels of N-acetylaspartate (NAA) suggesting reduced neuronal density in this region. However, the measured volumes have been large and included contributions from mostly white matter. METHODS: Short echo 1H MRS was used to measure levels of NAA and other metabolites (i.e., glutamate and glutamine) from a 6 cm3 volume in the left mesial-temporal lobe of 11 first-episode schizophrenic patients and 11 healthy control subjects of comparable age, gender, handedness, education, and parental education levels. Spectra were quantified without operator interaction using automated software developed in our laboratory. Metabolite levels were normalized to the internal water concentration of each volume studied. Images were also obtained to determine temporal lobe gray and white matter volumes. RESULTS: No significant differences were found between levels of NAA or other metabolites, or gray and white matter volumes, in first-episode schizophrenic patients and comparison subjects. CONCLUSIONS: Since the volume studied was small compared to previous studies and contained mostly gray matter, this result suggests consequential NAA decreases may be restricted to regions of white matter.

A 1H-decoupled 31P chemical shift imaging study of medicated schizophrenic patients and healthy controls.

BACKGROUND: Current 31P spectroscopy research in schizophrenia has examined phospholipid metabolism by measuring the sum of phosphomonoesters and the sum of phosphodiester-containing molecules. Proton decoupling was implemented to measure the individual phosphomonoester and phosphodiester components. This is the first study employing this technique to examine schizophrenic patients. METHODS: Multivoxel two-dimensional chemical shift in vivo phosphorous-31 magnetic resonance spectroscopy with proton decoupling was used to examine a 50-cm3 volume in prefrontal, motor, and parieto-occipital regions in the brain. Eleven chronic medicated schizophrenic patients were compared to 11 healthy controls of comparable gender, education, parental education, and handedness. RESULTS: A significant increase in the mobile phospholipid peak area and its full width at half maximum was observed in the medicated schizophrenic patients compared to the healthy controls in the prefrontal region. Inorganic orthophosphate and phosphocholine were lower in the schizophrenic group in the prefrontal region. CONCLUSIONS: The increased sum of phosphodiester [mobile phospholipid + glycerol-3-phosphoethanolamine (GPEth) + glycerol-3-phosphocholine (GPCh)] in schizophrenic patients, measured in earlier studies, arises from the phospholipid peak (MP) and not the more mobile phosphodiesters (GPEth, GPCh) as was originally suspected. A decrease in the phosphocholine component of the phosphomonoesters was also observed in the schizophrenic patients. These findings are consistent with an abnormality in membrane metabolism in the prefrontal region in schizophrenics.

A short echo 1H spectroscopy and volumetric MRI study of the corpus striatum in patients with obsessive-compulsive disorder and comparison subjects.

OBJECTIVE: It is likely that the corpus striatum is involved in obsessive-compulsive disorder (OCD). Prior studies have inconsistently found alterations in caudate volumes in patients with OCD. This study was undertaken in the hope that N-acetylaspartate and volumetric measures together would elucidate the presence and nature of corpus striatum volumetric abnormalities in OCD. METHOD: Thirteen patients meeting the DSM-IV criteria for OCD, who had been medication free for a minimum of 6 weeks, and 13 psychiatrically normal matched comparison subjects participated in the study. Short echo 1H magnetic resonance spectroscopy (1H-MRS) was used to measure levels of N-acetylaspartate and several other cerebral metabolites from a 4.5-cm3 volume in the left corpus striatum of all 26 subjects. Metabolite levels were estimated by fitting the time domain spectroscopy data with a noninteractive computer program. Volumes of the left and right head of the caudate nucleus in each subject were determined by semiautomatic segmentation of the volumetric images. RESULTS: N-Acetylaspartate levels from the left corpus striatum were significantly lower in the patients with OCD than in the comparison subjects. There were no differences in either left or right caudate volume between the two groups. CONCLUSIONS: Despite the lack of differences in caudate volumes between the OCD patients and the comparison subjects, the lower level of N-acetylaspartate in the left corpus striatum of the patients suggests reduced neuronal density in this region. Inconsistent volumetric findings among prior studies may reflect a poorer sensitivity of magnetic resonance imaging morphometry for detecting neuronal loss compared with 1H-MRS measurement of N-acetylaspartate.

Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy.

BACKGROUND: Positron emission tomographic and postmortem studies comparing schizophrenic patients with healthy control subjects have found medial prefrontal cortical and anterior cingulate abnormalities that suggest dysfunction in glutamatergic neurons. The glutamate used for nerve signal transduction is predominantly derived from glutamine. After signal transduction, glutamate released into the synapse is converted to glutamine in glial cells, transported back to the presynaptic neuron, and reconverted to glutamate for reuse. In this study, levels of glutamate and glutamine were examined by means of in vivo proton (1H) magnetic resonance spectroscopy. METHODS: Localized in vivo 1H spectra were acquired from a 4.5-cm3 volume in the left medial prefrontal cortex encompassing portions of Brodmann areas 24, 32, and 9 in 10 never-treated schizophrenic subjects and 10 healthy controls of comparable age, sex, handedness, education, and parental education. From each spectrum, metabolite levels were estimated for glutamate and glutamine, as well as 10 other metabolites and 3 macromolecules, by means of a noninteractive computer program that combined modeled in vitro spectra of every metabolite to reconstruct each in vivo spectrum. RESULTS: A significant increase in glutamine level was found in the medial prefrontal cortex of the schizophrenic patients compared with controls. N-acetylaspartate and other measured metabolites and macromolecules were not significantly changed in schizophrenics. CONCLUSION: Increased glutamine levels in the medial prefrontal region most likely reflect decreased glutamatergic activity in this region in never-treated schizophrenic patients compared with healthy controls.

"Locus of control, sensation seeking, and mathematical models of stress and decisional control: comment on De Brabander and Hellemans".

In a recent study, De Brabander and Hellemans (1996) reported that stress (somatic complaints) was inversely related to scores on personality scales of "thrill-and-adventure sensation seeking" and "internal locus of control." These observations, useful in their own right, are of further value when examined in the light of mathematical models of stress and decisional control. It is suggested that diminished stress associated with higher scores on these scales may result from increased engagement and reduced aversiveness of cognitive demands mediating reduction of threat under conditions of decisional control.

Variability in BPRS definitions of positive and negative symptoms.

Reviewing Brief Psychiatric Rating Scale (BPRS) research indicates that combining items to form larger 'symptom factors' (e.g., depression, psychosis) has become the standard methodology. Unfortunately, a single symptom factor may be defined by different combinations of different BPRS items in different studies. To examine the potential impact of these differences, a number of different BPRS definitions of positive and negative symptoms in schizophrenia were culled from previous research. To compare these definitions, one hundred schizophrenics were interviewed with regard to current and recent symptomatology and rated on the BPRS, the Schedule for the Assessment of Negative Symptoms (SANS), and the Schedule for the Assessment of Positive Symptoms (SAPS). The four BPRS negative symptom definitions all correlated highly with one another and with the SANS. There were no differences in the amount that these different definitions of negative symptoms correlated with the SANS. Also, the nine definitions of positive symptoms all correlated highly with one another and with the SAPS. However, there were significant differences in how they correlated with the SAPS. Because of these differences, possible standard definitions for negative and positive symptoms of schizophrenia are proposed for future use of the BPRS in research.

A formal analysis of stressor and stress-proneness effects on simple information processing.

This study examined visual information processing under a stressor of recurring loud sound among groups divided according to psychometrically identified stress susceptibility. Formal models of task performance were employed to address several issues concerning stress effects on cognitive functioning. Examined were effects on parallel versus serial processing structure, task-wise processing capacity, strategies of allocating processing resources to task components, and curtailment of processing of relevant task elements. Contrary to prediction, stressor presence generated slightly more rather than less evidence of a parallel versus serial processing structure. There was some suggestion of central-task capacity depletion among more susceptible subjects, in line with certain theoretical positions. Evidence of curtailed exhaustive processing of relevant stimulus items was negative. Most notable was the disruption by stress among susceptible subjects of performance-enhancing strategies of deploying processing resources across the different task components (elements of the visual display and within-trial stages of processing). Such effects have received relatively little attention in this research domain; their investigation is shown to be made tractable, however, through the application of selected formal models of information processing.

Classification of the schizophrenias according to symptomatology: a two-factor model.

Various methods of subtyping schizophrenia are briefly reviewed. It is concluded that the paranoid-nonparanoid dichotomy has been the most consistently supported both clinically and in experimental research. In an attempt to deal with its limitations, a tentative reconceptualization is proposed for schizophrenia. This new model is based on two independent factors: severity of disorder and severity of symptom. The present dimensional approach is shown to be consistent with a number of empirical findings regarding differences and associations between paranoid and nonparanoid symptomatology. The relative advantages of dimensional and categorical descriptions, as well as their combination, are presented.

Disruption of saccade production during oculomotor tracking in schizophrenia and the use of its changes across target velocity as a discriminator of the disorder.

A clear measure of eye movement disorder (EMD) that reliably separated schizophrenic individuals from others would both give insight into the brain control of the disorder and provide an aid in diagnosis. In the present study, a detailed analysis was carried out of the interactions between the pursuit and saccadic components of eye movements at different target velocities. The subjects comprised schizophrenic patients, unipolar depressed patients, and normal controls. The speed of the slow pursuit component did not differ among the groups, but schizophrenic subjects made more saccadic movements at low target velocities, though they started further away from the target at high target velocities. On the basis of these differences, a slope was computed of the linear function that related the number of saccadic eye movements to the velocity of a ramp visual target. Slope direction was negative for schizophrenic subjects but positive for unipolar depressive and normal subjects, and the correct classification rate for subjects was 84%.