Multimodal Neuroimaging in Schizophrenia: Description and Dissemination.

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).

The neural networks underlying auditory sensory gating.

One of the most consistent electrophysiological deficits reported in the schizophrenia literature is the failure to inhibit, or properly gate, the neuronal response to the second stimulus of an identical pair (i.e., sensory gating). Although animal and invasive human studies have consistently implicated the auditory cortex, prefrontal cortex and hippocampus in mediating the sensory gating response, localized activation in these structures has not always been reported during non-invasive imaging modalities. In the current experiment, event-related FMRI and a variant of the traditional gating paradigm were utilized to examine how the gating network differentially responded to the processing of pairs of identical and non-identical tones. Two single-tone conditions were also presented so that they could be used to estimate the HRF for paired stimuli, reconstructed based on actual hemodynamic responses, to serve as a control non-gating condition. Results supported an emerging theory that the gating response for both paired-tone conditions was primarily mediated by auditory and prefrontal cortex, with potential contributions from the thalamus. Results also indicated that the left auditory cortex may play a preferential role in determining the stimuli that should be inhibited (gated) or receive further processing due to novelty of information. In contrast, there was no evidence of hippocampal involvement, suggesting that future work is needed to determine what role it may play in the gating response.

[Auditory gating deficits in schizophrenia: unimodal or heteromodal dysfunction?]. / Fallos en el filtraje de información auditiva en esquizofrenia: ¿disfunción de cortezas uni o heteromodales?

Failure filtering out redundant auditory information is the most replicated neurophysiological abnormality observed in patients with schizophrenia. However, the brain structures involved in this deficit remains obscure. Two main hypotheses have been proposed to explain this phenomenon. The first maintains that the auditory gating deficit in schizophrenia is related to abnormal function of microcircuits within the hippocampal formation. The second hypothesis proposes that the deficit may be linked to impaired prefrontal cortex function. In both scenarios, auditory gating is conceptualized as a process dependent on the functional indemnity of cortical areas that integrate information from different sensory modalities. When filtering out redundant information, heteromodal cortices (hippocampal formation or prefrontal cortex), ensure that redundant stimuli do not reach higher-order levels of information processing in the brain and do not interfere with working memory performance. Findings from our lab, using magnetoencephalography (MEG), and data from other labs using electroencephalography (EEG), suggest an alternative hypothesis. We hypothesize that auditory gating deficit in schizophrenia is due to the abnormal function of unimodal microcircuits within left auditory cortex, independent from abnormalities in heteromodal cortices. Explaining whether auditory gating deficit in schizophrenia is determined by a primary dysfunction of unimodal or multimodal cortices may help elucidate the mechanisms involved in the sensory information overload and the characteristic cognitive deficits found in this disorder.

Commonalities and differences among vectorized beamformers in electromagnetic source imaging.

A number of beamformers have been introduced to localize neuronal activity using magnetoencephalography (MEG) and electroencephalography (EEG). However, currently available information about the major aspects of existing beamformers is incomplete. In the present study, detailed analyses are performed to study the commonalities and differences among vectorized versions of existing beamformers in both theory and practice. In addition, a novel beamformer based on higher-order covariance analysis is introduced. Theoretical formulas are provided on all major aspects of each beamformer; to examine their performance, computer simulations with different levels of correlation and signal-to-noise ratio are studied. Then, an empirical data set of human MEG median-nerve responses with a large number of neuronal generators is analyzed using the different beamformers. The results show substantial differences among existing MEG/EEG beamformers in their ways of describing the spatial map of neuronal activity. Differences in performance are observed among existing beamformers in terms of their spatial resolution, false-positive background activity, and robustness to highly correlated signals. Superior performance is obtained using our novel beamformer with higher-order covariance analysis in simulated data. Excellent agreement is also found between the results of our beamformer and the known neurophysiology of the median-nerve MEG response.

Auditory sensory gating deficit and cortical thickness in schizophrenia.

Both an EEG P50 sensory gating deficit and abnormalities of the temporal lobe structure are considered characteristic of schizophrenia. The standard P50 sensory gating measure does not foster differential assessment of left- and right-hemisphere contributions, but its analogous MEG M50 component may be used to measure gating of distinct auditory source dipoles localizing to left- and right-hemisphere primary auditory cortex. The present study sought to determine how sensory gating ratio may relate to cortical thickness at the site of the auditory dipole localization. A standard auditory paired-click paradigm was used during MEG for patients (n=22) and normal controls (n=11). Sensory gating ratios were determined by measuring the strength of the 50 ms response to the second click divided by that of the first click (S2/S1). Cortical thickness was assessed by two reliable raters using 3D sMRI. Results showed that: (1) patients had a P50 and left M50 sensory gating deficit relative to controls; (2) cortex in both hemispheres was thicker in the control group; (3) in schizophrenia, poorer left-hemisphere M50 sensory gating correlated with thinner left-hemisphere auditory cortical thickness; and (4) poorer right-hemisphere M50 auditory sensory gating ratio correlated with thinner right-hemisphere auditory cortical thickness in patients. The MEG-assessed hemisphere-specific auditory sensory gating ratio may be driven by this structural abnormality in auditory cortex.

Interpreting abnormality: an EEG and MEG study of P50 and the auditory paired-stimulus paradigm.

Interpretation of neurophysiological differences between control and patient groups on the basis of scalp-recorded event-related brain potentials (ERPs), although common and promising, is often complicated in the absence of information on the distinct neural generators contributing to the ERP, particularly information regarding individual differences in the generators. For example, while sensory gating differences frequently observed in patients with schizophrenia in the P50 paired-click gating paradigm are typically interpreted as reflecting group differences in generator source strength, differences in the latency and/or orientation of P50 generators may also account for observed group differences. The present study examined how variability in source strength, amplitude, or orientation affects the P50 component of the scalp-recorded ERP. In Experiment 1, simulations examined the effect of changes in source strength, orientation, or latency in superior temporal gyrus (STG) dipoles on P50 recorded at Cz. In Experiment 2, within- and between-subject variability in left and right M50 STG dipole source strength, latency, and orientation was examined in 19 subjects. Given the frequently reported differences in left and right STG anatomy and function, substantial inter-subject and inter-hemispheric variability in these parameters were expected, with important consequences for how P50 at Cz reflects brain activity from relevant generators. In Experiment 1, simulated P50 responses were computed from hypothetical left- and right-hemisphere STG generators, with latency, amplitude, and orientation of the generators varied systematically. In Experiment 2, electroencephalographic (EEG) and magnetoencephalographic (MEG) data were collected from 19 subjects. Generators were modeled from the MEG data to assess and illustrate the generator variability evaluated parametrically in Experiment 1. In Experiment 1, realistic amounts of variability in generator latency, amplitude, and orientation produced ERPs in which P50 scoring was compromised and interpretation complicated. In Experiment 2, significant within and between subject variability was observed in the left and right hemisphere STG M50 sources. Given the variability in M50 source strength, orientation, and amplitude observed here in nonpatient subjects, future studies should examine whether group differences in P50 gating ratios typically observed for patient vs. control groups are specific to a particular hemisphere, as well as whether the group differences are due to differences in dipole source strength, latency, orientation, or a combination of these parameters. Present analyses focused on P50/M50 merely as an example of the broader need to evaluate scalp phenomena in light of underlying generators. The development and widespread use of EEG/MEG source localization methods will greatly enhance the interpretation and value of EEG/MEG data.

Predicting EEG responses using MEG sources in superior temporal gyrus reveals source asynchrony in patients with schizophrenia.

OBJECTIVE: An integrated analysis using Electroencephalography (EEG) and magnetoencephalography (MEG) is introduced to study abnormalities in early cortical responses to auditory stimuli in schizophrenia. METHODS: Auditory responses were recorded simultaneously using EEG and MEG from 20 patients with schizophrenia and 19 control subjects. Bilateral superior temporal gyrus (STG) sources and their time courses were obtained using MEG for the 30-100 ms post-stimulus interval. The MEG STG source time courses were used to predict the EEG signal at electrode Cz. RESULTS: In control subjects, the STG sources predicted the EEG Cz recording very well (97% variance explained). In schizophrenia patients, the STG sources accounted for substantially (86%) and significantly (P<0.0002) less variance. After MEG-derived STG activity was removed from the EEG Cz signal, the residual signal was dominated by 40 Hz activity, an indication that the remaining variance in EEG is probably contributed by other brain generators, rather than by random noise. CONCLUSIONS: Integrated MEG and EEG analysis can differentiate patients and controls, and suggests a basis for a well established abnormality in the cortical auditory response in schizophrenia, implicating a disorder of functional connectivity in the relationship between STG sources and other brain generators.

Divalproex in posttraumatic stress disorder: an open-label clinical trial.

Posttraumatic stress disorder (PTSD) is characterized by intrusive, avoidance, and hyperarousal symptoms. This study was conducted to investigate the effectiveness of divalproex in reducing PTSD symptoms, depression, and anxiety in patients with PTSD. Sixteen patients with a DSM-IV diagnosis of PTSD at the Albuquerque VAMC outpatient PTSD treatment program received an open-label trial of divalproex. The patients were evaluated at baseline and at 8 weeks by a trained rater using the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A). Plasma valproate levels were measured at the 8-week post-treatment assessment. Three patients stopped the medications due to side effects. Intrusion and hyperarousal symptoms decreased significantly, while no significant change was seen in avoidance/numbing symptoms. Depressive symptoms, as measured by the HAM-D, unexpectedly decreased at post-treatment assessment. HAM-A scores also decreased significantly. Controlled trials are needed to further study the efficacy of divalproex in the treatment of PTSD.

Bupropion treatment in veterans with posttraumatic stress disorder: an open study.

This study was designed to investigate the efficacy of the antidepressant drug bupropion in the treatment of posttraumatic stress disorder (PTSD). Seventeen male combat veterans with chronic PTSD were treated with bupropion in an open-label fashion for 6 weeks. Patients were evaluated with the Clinical Global Impressions Scale for Improvement (CGI-I) at follow-up and rated blindly at baseline and posttreatment with the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D), and the Hamilton Rating Scale for Anxiety. Three patients discontinued bupropion prematurely because of side effects. Of the remaining 14 patients, 10 were classified as treatment responders by the CGI-I. HAM-D scores decreased significantly from baseline to follow-up. The improvement seen in hyperarousal symptoms was significant but was less significant than the change in depressive symptoms. There was no significant change in Intrusion, Avoidance, or total CAPS scores. It was concluded that bupropion was well tolerated. Patients who had experienced sexual dysfunction with selective serotonin reuptake inhibitors reported no complaints during bupropion treatment. Bupropion decreased depressive symptoms and most patients reported global improvement, although PTSD symptoms remained mostly unchanged. Controlled trials should further clarify the role of bupropion in the treatment of PTSD.

Spontaneous brain magnetic activity in schizophrenia patients treated with aripiprazole.

This magnetoencaphalographic (MEG) study was conducted as part of a multicenter clinical trial to study the efficacy of aripiprazole. Participants included 5 DSM-IV schizophrenia subjects and 10 age-matched normal controls. The schizophrenia subjects underwent a second MEG recording after 8 weeks of open-label treatment with aripiprazole. Overall, control subjects showed no abnormal spontaneous magnetic brain activity. At washout, 3 patients showed increased delta and theta activity along with paraxosymal bitemporal slow waves. In 2 of these patients, the slow waves were generated in the superior temporal plane, as determined by dipole modeling. In the third patient, the slow waves appeared to have been generated at multiple regions throughout the temporal and inferior parietal lobes. As a group, schizophrenia patients, when compared with normal controls, demonstrated significant decreases in alpha peak frequency and power. Following treatment, aripiprazole had a significant normalizing effect on delta and theta activity. Patients on aripiprazole continued to demonstrate significant abnormalities in alpha frequency and power.

Family psychoeducational support groups in Spain: parents' distress and burden at none-month follow-up.

Forty-one mothers and twenty-seven fathers agreed to participate in a 6-week, low-cost, multiple-family psychoeducational intervention in Spain. Their knowledge acquisition, subjective distress, annoyance at patient's behavior, perception of social impact of the patient's illness, expectations about patient's recovery, and family burden were measured before and after the intervention and at 9-month follow-up. Ninety-three percent of the fathers and 78% of the mothers attended four or more classes. Although parents acquired a significant amount of knowledge about the illness, no significant score differences were found immediately after the intervention or at follow-up in the other measures. However, significant father-mother differences were revealed. Compared with mothers, fathers were more optimistic throughout the study about the outcome of the illness, became more aware of the social and financial impact of the illness on the family, and reported feeling less annoyed by the patient's behavior at follow-up. The results indicate that low-cost psychoeducational multiple family groups alone do not decrease family distress and burden. These findings also suggest that psychoeducational interventions need to consider differences in gender and family roles and underline the importance of engaging fathers in treatment.

Magnetoencephalographic assessment of spontaneous brain activity in schizophrenia.

Magnetoencephalography (MEG) offers an attractive alternative to electroencephalography (EEG) in the assessment of psychiatric patients. In this study, a whole-head biomagnetometer equipped with 122 super-cooled sensors was used to assess spontaneous neuromagnetic activity in 11 unmedicated schizophrenic patients and 8 schizophrenic patients medicated for more than 8 weeks with novel antipsychotics (5 of whom were initially studied as part of the unmedicated group). Ten normal (nonpsychiatric) controls were also examined. For each subject, 5 minutes of data were collected in an eyes-closed state. Data were visually inspected for gross MEG abnormalities, and average power spectra were calculated for the data at each sensor. No gross abnormalities were identified for control subjects. One unmedicated schizophrenic patient showed epileptiform sharp waves, and 4 showed abnormal slow waves. No gross MEG abnormalities were found for the medicated schizophrenic group (which included 3 patients who had previously shown slow waves in the unmedicated state). Spectral analyses showed that the schizophrenia patients demonstrated lower alpha power and peak frequency than controls. The data are interpreted within the context of previously reported magnetic resonance abnormalities of the thalamus.

Family environment predictors of outcome in schizophrenic patients in Spain: a nine-month follow-up study.

This study investigates the effects of perceived family environment on clinical outcome among patients in Spain who suffer from schizophrenia. Forty-five consecutively admitted DSM-III-R schizophrenic patients were assessed monthly with the Brief Psychiatric Rating Scale during a 9-month period. Patients and parents rated the family environment through the Family Environment Scale (FES). FES factors were considered separately for each family member, since parents' and patient's perceptions of the family environment were weakly correlated. Stepwise multiple regression analysis showed that patients' perceptions of family control and intellectual-cultural orientation predicted rehospitalization. Patients' and mothers' ratings of family control and fathers' scores of conflict and moral religious emphasis predicted psychotic relapse. However, fathers' scores of family cohesion predicted higher negative symptoms. Prior admissions, age of onset and use of depot medication tended to predict outcome in conjunction with the family variables.

The interaction of popular and clinical diagnostic labeling: the case of embrujado.

This paper explores the effect of a popular diagnosis of distress, "bewitchment," on diagnosis, treatment and outcomes of psychiatric illness in a small group of Hispanic patients in New Mexico. Two major approaches to such "culture-bound" illnesses in clinical settings are critiqued and synthesized in suggesting a practical way to understand how both folk and psychiatric explanations can affect experience with, and of psychiatric patients who present with their own culturally patterned diagnoses. Further study suggests that clinically focused ethnography can address the issue of change or persistence in both lay and clinical explanations of illness as they interact in a clinical setting.