Is the prefrontal cortex organized by supramodal or modality-specific sensory demands during adolescence?

Attention is inherently biased towards the visual modality during most multisensory scenarios in adults, but the developmental trajectory towards visual dominance has not been fully elucidated. More recent evidence in primates and adult humans suggests a modality-specific stratification of the prefrontal cortex. The current study therefore used functional magnetic resonance imaging (fMRI) to investigate the neuronal correlates of proactive (following cues) and reactive (following probes) cognitive control for simultaneous audio-visual stimulation in 67 healthy adolescents (13-18 years old). Behavioral results were only partially supportive of visual dominance in adolescents, with both reduced response times and accuracy during attend-visual relative to attend-auditory trials. Differential activation of medial and lateral prefrontal cortex for processing incongruent relative to congruent stimuli (reactive control) was also only observed during attend-visual trials. There was no evidence of modality-specific prefrontal cortex stratification during the active processing of multisensory stimuli or during separate functional connectivity analyses. Attention-related modulations were also greater within visual relative to auditory cortex, but were less robust than observed in previous adult studies. Collectively, current results suggest a continued transition towards visual dominance in adolescence, as well as limited modality-specific specialization of prefrontal cortex and attentional modulations of unisensory cortex.

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 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.

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.

Lesion size and amphetamine hyperlocomotion after neonatal ventral hippocampal lesions: more is less.

Neonatal hippocampal lesions in rats produce behavioral and neurochemical abnormalities post-puberty that are used in animal models for developmentally linked pathology in schizophrenia. In one model, adult rats exhibit enhanced sensitivity to the locomotor-activating effects of amphetamine, if they had sustained excitotoxic lesions of the ventral hippocampus on post-natal day 7. The hippocampal elements responsible for these lesion-induced developmental changes have not been fully characterized. The present study assessed the locomotor-activating effects of amphetamine in adult rats that on day 7 had sustained either sham or ibotenic acid lesions of the ventral hippocampus alone ("standard lesions"), or the ventral hippocampus plus surrounding portions of entorhinal cortex and dorsal hippocampus ("large lesions"). "Standard lesions" produced the expected "supersensitive" locomotor response to amphetamine, while "large lesions" did not. No differences between these lesion groups were observed in baseline levels of locomotor activity or habituation. These data suggest that models of enhanced behavioral sensitivity to dopamine agonists after neonatal hippocampal lesions require functionality in the entorhinal cortex and/or dorsal hippocampus. It is possible that the behavioral abnormalities in the "neonatal hippocampal lesion model" reflect, at least in part, aberrant function within spared elements of the hippocampal complex.

Regulation of sensorimotor gating in rats by hippocampal NMDA: anatomical localization.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating that is reduced in humans with certain neuropsychiatric disorders, including schizophrenia, and in rats after manipulations of limbic cortico-striato-pallido-pontine circuitry. We have reported that PPI is reduced after specific manipulations of the hippocampal complex (HPC) in rats, but the mechanisms for these effects remain poorly understood. For example, dopaminergic substrates clearly regulate PPI, but the PPI-disruptive effects of intra-HPC carbachol or NMDA are not reversed by D2 receptor antagonists. This study examined the anatomical specificity within the hippocampal complex of the PPI-disruptive effects of NMDA infusion. Startle magnitude and PPI were assessed after acute bilateral infusion of NMDA (0, 0.4 or 0.8 microg) into the dorsal subiculum (DS), region CA1, the ventral subiculum (VS), the rostral entorhinal cortex (ECr) and the caudal entorhinal cortex (ECc). A dorsal-ventral gradient for NMDA effects was observed, with a dose-dependent disruption of PPI after NMDA infusion into the VS or EC, but not the DS, and with intermediate level effects observed after NMDA infusion into CA1. A second set of studies confirmed that the failure of NMDA effects in the DS did not reflect site-related differences in startle magnitude or baseline levels of PPI. These findings demonstrate the importance of the ventral, but not the dorsal HPC, in the glutamatergic regulation of PPI.

Retrograde amnesia after hippocampal damage: recent vs. remote memories in two tasks.

We review evidence from experiments conducted in our laboratory on retrograde amnesia in rats with damage to the hippocampal formation. In a new experiment reported here, we show that N-methyl-D-aspartate (NMDA)-induced hippocampal damage produced retrograde amnesia for both hidden platform and two-choice visible platform discriminations in the Morris water task. For both problems there was a significant trend for longer training-surgery intervals to be associated with worse retention performance. Little support is offered by our work for the concept that there is a process involving hippocampal-dependent consolidation of memories in extrahippocampal permanent storage sites. Long-term memory consolidation may take place within the hippocampus. The hippocampus may be involved permanently in storage and/or retrieval of a variety of relational and nonrelational memories if it was intact at the time of learning, even involving information which is definitely not affected in anterograde amnesia after hippocampal damage.

Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully assessed drug effects on sensorimotor gating in SD versus W strains, across rat suppliers (H vs BK). Significantly greater SDH than WH apomorphine sensitivity in PPI measures was observed in both adult and 18 d pups, confirming that these strain differences are both robust and innate. These strain differences in apomorphine sensitivity were not found in adult BK rats. Supplier differences in sensitivity (SDH > SDBK) were also evident in the PPI-disruptive effects of D1 but not D2-family agonists; PPI was clearly disrupted by quinpirole in both SDH and SDBK rats. These findings demonstrate robust, innate, neurochemically specific, and apparently heritable phenotypic differences in an animal model of sensorimotor gating deficits in human neuropsychiatric disorders.

Changes in adult brain and behavior caused by neonatal limbic damage: implications for the etiology of schizophrenia.

We tested the hypothesis that limbic damage in early development can cause aberrant maturation of brain structures known to be abnormal in adult schizophrenics: the hippocampus, prefrontal cortex, ventricles, and forebrain dopamine systems. We measured brain morphology, locomotor response to apomorphine, and cognitive processes in adult rats which received electrolytic damage to amygdala or hippocampus 48 h after birth. The behavioral measurements involved tasks which depend upon the integrity of the hippocampus or prefrontal cortex, and a task sensitive to forebrain dopamine system activation. The tasks included place navigation, egocentric spatial ability, and apomorphine-induced locomotion. The rats with lesions showed poor performance on the place navigation and egocentric spatial tasks and more apomorphine-induced locomotion after puberty than the sham lesion group. Regardless of lesion location, the adult rats showed smaller amygdalae and hippocampi, and larger lateral ventricles. Analyzing the lesion and sham rats together, adult amygdala volume was found to be positively correlated with cerebral cortex, prefrontal cortex, and hippocampal volumes and place navigation performance, and was negatively correlated with lateral ventricle volume. This study contributes to our understanding of the pathogenesis of schizophrenia by showing that early damage to limbic structures produced behavioral, morphological, and neuropharmacological abnormalities related to pathology in adult schizophrenics.