Faith M. Hanlon

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. Hippocampus 2001;11:27–42.

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.

M50 sensory gating predicts negative symptoms in schizophrenia.

Impaired auditory sensory gating is considered characteristic of schizophrenia and a marker of the information processing deficit inherent to that disorder. Predominance of negative symptoms also reflects the degree of deficit in schizophrenia and is associated with poorer pre-morbid functioning, lower IQ, and poorer outcomes. However, a consistent relationship between auditory sensory gating and negative symptoms in schizophrenia has yet to be demonstrated. The absence of such a finding is surprising, since both impaired auditory gating and negative symptoms have been linked with impaired fronto-temporal cortical function. The present study measured auditory gating using the P50 event related potential (ERP) in a paired-click paradigm and capitalized on the relative localization advantage of magnetoencephalography (MEG) to assess auditory sensory gating in terms of the event related field (ERF) M50 source dipoles on bilateral superior temporal gyrus (STG). The primary hypothesis was that there would be a positive correlation between lateralized M50 auditory sensory gating measures and negative symptoms in patients with schizophrenia. A standard paired-click paradigm was used during simultaneous EEG and MEG data collection to determine S2/S1 sensory gating ratios in a group of 20 patients for both neuroimaging techniques. Participants were administered the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Consistent with previous reports, there was no relationship between ERP P50 sensory gating and negative symptoms. However, right (not left) hemisphere ERF M50 sensory gating ratio was significantly and positively correlated with negative symptoms. This finding is compatible with information processing theories of negative symptoms and with more recent findings of fronto-temporal abnormality in patients with predominantly negative symptoms.

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.

A parietal-frontal network studied by somatosensory oddball MEG responses, and its cross-modal consistency.

Previous studies using functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs) of the brain have found that a distributed parietal-frontal neuronal network is activated in normals during both auditory and visual oddball tasks. The common cortical regions in this network are inferior parietal lobule (IPL)/supramarginal gyrus (SMG), anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). It is not clear whether the same network is activated by oddball tasks during somatosensory stimulation. The present study addressed this question by testing healthy adults as they performed a novel median-nerve oddball paradigm while undergoing magnetoencephalography (MEG). An automated multiple dipole analysis technique, the Multi-Start Spatio-Temporal (MSST) algorithm, localized multiple neuronal generators, and identified their time-courses. IPL/SMG, ACC, and DLPFC were reliably localized in the MEG median-nerve oddball responses, with IPL/SMG activation significantly preceding ACC and DLPFC activation. Thus, the same parietal-frontal neuronal network that shows activation during auditory and visual oddball tests is activated in a median-nerve oddball paradigm. Regions uniquely related to somatosensory oddball responses (e.g., primary and secondary somatosensory, dorsal premotor, primary motor, and supplementary motor areas) were also localized. Since the parietal-frontal network supports attentional allocation during performance of the task, this study may provide a novel method, as well as normative baseline data, for examining attention-related deficits in the somatosensory system of patients with neurological or psychiatric disorders.

Semantic information alters neural activation during transverse patterning performance.

Memory tasks can be performed using multiple cognitive strategies, which are mediated by different brain systems. The transverse patterning (TP) task is dependent upon the integrity of the hippocampal system, however, we previously demonstrated successful TP following hippocampal damage using meaningful stimuli and relations (Moses, S.N., Ostreicher, M.L., Rosenbaum, R.S., Ryan, J.D., 2008. Successful transverse patterning in amnesia using semantic knowledge. Hippocampus 18, 121-124). Here, we used magnetoencephalgraphy (MEG) to directly observe the neural underpinnings of TP, and the changes that occur as stimuli and relations become more meaningful. In order to optimize our ability to detect signal from deep, non-dominant, brain sources we implemented the event-related synthetic aperture magnetometry minimum-variance beamformer algorithm (ER-SAM; Cheyne, D., Bakhtazad, L., Gaetz, W., 2006. Spatiotemporal mapping of cortical activity accompanying voluntary movements using an event-related beamforming approach. Human Brain Mapping 27, 213-229) coupled with the partial least squares (PLS) multivariate statistical approach (McIntosh, A.R., Bookstein, F.L., Haxby, J.V., Grady, C.L., 1996. Spatial pattern analysis of function brain images using partial least squares. NeuroImage 3, 143-157; McIntosh, A.R., Lobaugh, N.J., 2004. Partial least squares analysis of neuroimaging data: Applications and advances. NeuroImage 23, S250-S263). We found that increased meaningfulness elicited reduced bilateral hippocampal activation, along with increased activation of left prefrontal and temporal cortical structures, including inferior frontal (IFG), as well as anterior temporal and perirhinal cortices. These activation patterns may represent a shift towards reliance upon existing semantic knowledge. This shift likely permits successful TP performance with meaningful stimuli and relations following hippocampal damage.

Dynamic neural activity recorded from human amygdala during fear conditioning using magnetoencephalography

Magnetoencephalography (MEG) was used to record the dynamics of amygdala neuronal population activity during fear conditioning in human participants. Activation during conditioning training was compared to habituation and extinction sessions. Conditioned stimuli (CS) were visually presented geometric figures, and unconditioned stimuli (US) were aversive white-noise bursts. The CS+ was paired with the US on 50% of presentations and the CS- was never paired. The precise temporal resolution of MEG allowed us to address the issue of whether the amygdala responds to the onset or offset of the CS+, and/or the expectation of the initiation or offset of the an omitted auditory US. Fear conditioning elicited differential amygdala activation for the unpaired CS+ compared to the CS-, extinction and habituation. This was especially robust in the right hemisphere at CS onset. The strongest peaks of amygdala activity occurred at an average of 270 ms in the right and 306 ms in the left hemisphere following unpaired CS+ onset, and following offset at 21 ms in the left and 161 ms in the right (corresponding to an interval of 108 ms and 248 ms after the anticipated onset of the US, respectively). However, the earliest peaks in this epoch preceded US onset in most subjects. Thus, the activity dynamics suggest that the amygdala both differentially responds to stimuli and anticipates the arrival of stimuli based on prior learning of contingencies. The amygdala also shows stimulus omission-related activation that could potentially provide feedback about experienced stimulus contingencies to modify future responding during learning and extinction.

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.

Hippocampus volume and episodic memory in schizophrenia.

Previous studies of schizophrenia have suggested a linkage between neuropsychological (NP) deficits and hippocampus abnormality. The relationship between hippocampus volume and NP functioning was investigated in 24 patients with chronic schizophrenia and 24 matched healthy controls. Overall intracranial, white and gray matter, and anterior (AH) and posterior (PH) hippocampus volumes were assessed from magnetic resonance images (MRI). NP domains of IQ, attention, and executive function were also evaluated with respect to volumetric measures. It was hypothesized that AH and PH volumes and episodic memory scores would be positively associated in controls and that the schizophrenia group would depart from this normative pattern. NP functioning was impaired overall and AH volume was smaller in the schizophrenia group. In the controls, the hippocampus-memory relationships involved AH and PH, and correlations were significant for verbal memory measures. In the schizophrenia group, positive correlations were constrained to PH. Negative correlations emerged between AH and verbal and visual memory measures. For both groups, cortical volume negatively correlated with age, but a negative correlation between age and hippocampus volume was found only in the schizophrenia group. In this sample of adults with schizophrenia, atypical relationships between regional hippocampus volumes and episodic memory ability were found, as was an atypical negative association between hippocampus volume and age.

Impaired secondary somatosensory gating in patients with schizophrenia

A large and growing literature has demonstrated a deficit in auditory gating in patients with schizophrenia. Although that deficit has been interpreted as a general gating problem, no deficit has been shown in other sensory modalities. Recent research in our laboratory has examined sensory gating effects in the somatosensory system showing no difference in gating of the primary somatosensory response between patients with schizophrenia and control subjects. This is consistent with recent structural studies showing no cortical structural abnormality in primary somatosensory area in schizophrenia. However, a significant decrease in cortical thickness and gray matter volume loss in secondary somatosensory cortex has recently been reported, suggesting this as a focus for impaired somatosensory gating. Thus, the current study was designed (1) to replicate previous work showing a lack of schizophrenia deficit in primary somatosensory cortex (SI) gating, and (2) to investigate a possible deficit in secondary somatosensory cortex (SII) gating. In a paired-pulse paradigm, dipolar sources were assessed in SI and SII contralateral to unilateral median nerve stimulation. Patients demonstrated no impairment in SI gating, but a robust gating deficit in SII, supporting the presence of cross modal gating deficits in schizophrenia.