Disrupted GABAergic facilitation of working memory performance in people with schizophrenia.

OBJECTIVES: Gamma-Amiobutyric acid (GABA) is a primary inhibitory neurotransmitter that facilitates neural oscillations that coordinate neural activity between brain networks to facilitate cognition. The present magnetic resonance spectroscopy (MRS) study tests the hypothesis that GABAergic facilitation of working memory is disrupted in people with schizophrenia (PSZ). METHODS: 51 healthy participants and 40 PSZ from the UC Davis Early Psychosis Program performed an item and temporal order working memory (WM) task and underwent resting MRS to measure GABA and glutamate concentrations in dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) regions of interest. MRS was acquired on a 3 Tesla Siemens scanner and GABA and glutamate concentrations were referenced to creatine. Percent correct on the WM task indexed performance and correlation coefficients examined GABAergic or Glutamatergic facilitation of WM, with Fisher's Z transformation testing for group differences. RESULTS: There were no group differences in GABA or glutamate concentrations, but WM correlations were reversed between groups. In patients, higher DLPFC GABA was associated with worse rather than better WM performance. This pattern was not observed for glutamate or in the ACC. Although under-powered, there was no indication of medication effects. CONCLUSIONS AND RELEVANCE: Results cannot be explained by group differences in DLPFC GABA or glutamate concentrations but, instead, indicate that schizophrenia disrupts the GABAergic facilitation of WM seen in healthy individuals. Results appear to parallel post mortem findings in suggesting that schizophrenia alters the distribution of different classes of GABAergic interneurons rather than producing a general deficit across the total population of neurons.

Impact of schizophrenia on anterior and posterior hippocampus during memory for complex scenes.

OBJECTIVES: Hippocampal dysfunction has been proposed as a mechanism for memory deficits in schizophrenia. Available evidence suggests that the anterior and posterior hippocampus could be differentially affected. Accordingly, we used fMRI to test the hypothesis that activity in posterior hippocampus is disproportionately reduced in schizophrenia, particularly during spatial memory retrieval. METHODS: 26 healthy participants and 24 patients with schizophrenia from the UC Davis Early Psychosis Program were studied while fMRI was acquired on a 3 Tesla Siemens scanner. During encoding, participants were oriented to critical items through questions about item features (e.g., "Does the lamp have a square shade?") or spatial location (e.g., "Is the lamp on the table next to the couch?"). At test, participants determined whether scenes were changed or unchanged. fMRI analyses contrasted activation in a priori regions of interest (ROI) in anterior and posterior hippocampus during correct recognition of item changes and spatial changes. RESULTS: As predicted, patients with schizophrenia exhibited reduced activation in the posterior hippocampus during detection of spatial changes but not during detection of item changes. Unexpectedly, patients exhibited increased activation of anterior hippocampus during detection of item changes. Whole brain analyses revealed reduced fronto-parietal and striatal activation in patients for spatial but not for item change trials. CONCLUSIONS: Results suggest a gradient of hippocampal dysfunction in which posterior hippocampus - which is necessary for processing fine-grained spatial relationships - is underactive, and anterior hippocampus - which may process context more globally - is overactive.

The medial temporal lobe and recognition memory.

The ability to recognize a previously experienced stimulus is supported by two processes: recollection of the stimulus in the context of other information associated with the experience, and a sense of familiarity with the features of the stimulus. Although familiarity and recollection are functionally distinct, there is considerable debate about how these kinds of memory are supported by regions in the medial temporal lobes (MTL). Here, we review evidence for the distinction between recollection and familiarity and then consider the evidence regarding the neural mechanisms of these processes. Evidence from neuropsychological, neuroimaging, and neurophysiological studies of humans, monkeys, and rats indicates that different subregions of the MTL make distinct contributions to recollection and familiarity. The data suggest that the hippocampus is critical for recollection but not familiarity. The parahippocampal cortex also contributes to recollection, possibly via the representation and retrieval of contextual (especially spatial) information, whereas perirhinal cortex contributes to and is necessary for familiarity-based recognition. The findings are consistent with an anatomically guided hypothesis about the functional organization of the MTL and suggest mechanisms by which the anatomical components of the MTL interact to support the phenomenology of recollection and familiarity.

Working memory for visual objects: complementary roles of inferior temporal, medial temporal, and prefrontal cortex.

Humans have an extraordinary ability to maintain and manipulate visual image information in the absence of perceptual stimulation. The neural substrates of visual working memory have been extensively researched, but there have been few attempts to integrate these findings into a model of how different cortical areas interact to form and maintain visual memories. In this paper, I review findings from neurophysiological, neuropsychological, and neuroimaging studies of visual working memory in human and nonhuman primates. These data support a model in which visual working memory operations rely on activation of object representations in inferior temporal cortex, via top-down feedback from neocortical areas in the prefrontal and medial temporal cortex, and also from the hippocampus.

Behavioral and neural predictors of upcoming decisions.

Although it is widely known that brain regions such as the prefrontal cortex, the amygdala, and the ventral striatum play large roles in decision making, their precise contributions remain unclear. Here, we used functional magnetic resonance imaging and principles of reinforcement learning theory to investigate the relationship between current reinforcements and future decisions. In the experiment, subjects chose between high-risk (i.e., low probability of a large monetary reward) and low-risk (high probability of a small reward) decisions. For each subject, we estimated value functions that represented the degree to which reinforcements affected the value of decision options on the subsequent trial. Individual differences in value functions predicted not only trial-to-trial behavioral strategies, such as choosing high-risk decisions following high-risk rewards, but also the relationship between activity in prefrontal and subcortical regions during one trial and the decision made in the subsequent trial. These findings provide a novel link between behavior and neural activity by demonstrating that value functions are manifested both in adjustments in behavioral strategies and in the neural activity that accompanies those adjustments.

Functional connectivity with anterior cingulate and orbitofrontal cortices during decision-making.

Recent neuroscience research is beginning to discover the brain regions involved in decision-making under uncertainty, but little is known about whether or how these regions functionally interact with each other. Here, we used event-related functional magnetic resonance imaging to examine both changes in overall activity and changes in functional connectivity during risk-taking. Results showed that choosing high-risk over low-risk decisions was associated with increased activity in both anterior cingulate and orbitofrontal cortices. Connectivity analyses revealed that largely distinct, but somewhat overlapping, cortical and subcortical regions exhibited significant functional connectivity with anterior cingulate and orbitofrontal cortices. Additionally, connectivity with the anterior cingulate in some regions, including the orbitofrontal cortex and nucleus accumbens, was modulated by the decision participants chose. These findings (1) elucidate large networks of brain regions that are functionally connected with both anterior cingulate and orbitofrontal cortices during decision-making and (2) demonstrate that the roles of orbitofrontal and anterior cingulate cortices can be functionally differentiated by examining patterns of connectivity.

Medial temporal lobe activity associated with active maintenance of novel information.

Using event-related functional magnetic resonance imaging, we investigated the role of medial temporal regions during active maintenance of information over short delays or working memory. In experiment 1, we observed sustained bilateral hippocampal activation during maintenance of novel faces across a short delay period but not during face encoding or recognition. In contrast, we observed transient right parahippocampal activation during encoding and recognition but not during maintenance. We replicated these findings in experiment 2 and further determined that anterior hippocampal activation was greater during maintenance of novel than familiar faces. Our results reveal the importance of medial temporal lobe regions for the active maintenance of novel information in the absence of perceptual stimulation.

Left anterior prefrontal activation increases with demands to recall specific perceptual information.

Results from neuroimaging studies have led to competing theories regarding the contributions of prefrontal regions to memory formation and retrieval. To investigate this issue, we used event-related functional magnetic resonance imaging to assess prefrontal activation during encoding and retrieval of pictures of objects. Responses to studied and unstudied objects at retrieval were compared between two tests with differing demands for the specificity of information to be retrieved (source vs old-new recognition). Results showed that bilateral ventral [Brodmann's areas (BA) 44, 45, and 47] and right dorsal (BA 9) prefrontal regions were activated during both encoding and retrieval, but activity in these regions was not reliably modulated by the specificity of information to be retrieved. A region in left anterior prefrontal cortex (BA 10/46) was reliably activated during retrieval trials, and activation in this region increased with demands to retrieve perceptually detailed information about studied objects. Our results show that left anterior prefrontal cortex is engaged during the monitoring and evaluation of specific memory characteristics at retrieval-a process critical for accurate episodic remembering.

Use of the California Verbal Learning Test to detect proactive interference in the traumatically brain injured.

Recent studies using the California Verbal Learning Test (CVLT) to investigate the learning and memory capacities of traumatically-brain injured (TBI) individuals have suggested that this population does not show the expected buildup of proactive interference (PI). The purpose of this study was to investigate whether PI could be detected on the CVLT, in a TBI sample, if PI were calculated using alternative methods. CVLT data from 25 TBI individuals with varying degrees of brain injury and 21 healthy controls were compared. Results from the various analyses suggested that TBI individuals show buildup and release from PI when learning and attempting to recall competing forms of information if appropriate methods of analysis are used. Although the CVLT differs considerably from traditional PI paradigms (e.g., Wickens, 1970), our results suggest it can be used to detect PI in TBI individuals.

Neural correlates of memory retrieval and evaluation.

Results from recent neuroimaging studies have led to a controversy as to whether right or left prefrontal regions are relatively more important for episodic retrieval. To address this issue, we recorded event-related brain potentials during two recognition tests with identical stimuli but differing retrieval demands. In both tests, participants viewed a sequence of object drawings, half of which were identical to ones viewed earlier except for a change in size and half of which were new. Instructions were to discriminate between old and new objects (general test) or to additionally decide whether old objects were larger or smaller at study (specific test). Frontal brain potentials that were more positive during the specific than during the general test for both old and new objects were interpreted as neural correlates of the process by which specific attributes of test cues are compared with information retrieved from memory. Another ERP difference between the specific and general tests, which was observed for old objects only, had a left posterior scalp topography and was interpreted to reflect the reactivation of memories for studied objects. Frontal and posterior potentials thus reflected two memory processes important for accurate episodic retrieval. Furthermore, our findings suggest that both left and right prefrontal regions were engaged when demands to retrieve and evaluate perceptual information increased.

Frontal brain activity during episodic and semantic retrieval: insights from event-related potentials.

Previous neuropsychological and neuroimaging results have implicated the prefrontal cortex in memory retrieval, although its precise role is unclear. In the present study, we examined patterns of brain electrical activity during retrieval of episodic and semantic memories. In the episodic retrieval task, participants retrieved autobiographical memories in response to event cues. In the semantic retrieval task, participants generated exemplars in response to category cues. Novel sounds presented intermittently during memory retrieval elicited a series of brain potentials including one identifiable as the P3a potential. Based on prior research linking P3a with novelty detection and with the frontal lobes, we predicted that P3a would be reduced to the extent that novelty detection and memory retrieval interfere with each other. Results during episodic and semantic retrieval tasks were compared to results during a task in which subjects attended to the auditory stimuli. P3a amplitudes were reduced during episodic retrieval, particularly at right lateral frontal scalp locations. A similar but less lateralized pattern of frontal P3a reduction was observed during semantic retrieval. These findings support the notion that the right prefrontal cortex is engaged in the service of memory retrieval, particularly for episodic memories.

Frontal brain potentials during recognition are modulated by requirements to retrieve perceptual detail.

To assess the role of prefrontal cortex in retrieval and address the controversy about whether prefrontal retrieval operations are engaged only following successful retrieval, we recorded event-related brain potentials during two recognition tests with differing demands on retrieval effort. Both tests included object drawings that were (1) identical to those studied, (2) the same but with altered aspect ratios, and (3) previously unseen. Instructions were to respond "old" only if drawings were not modified (specific test) or regardless of modifications (general test). Frontal potentials were enhanced during the specific relative to the general test for all three types of drawings. We conclude that these potentials reflected differential engagement of strategic retrieval, that this function relied on left prefrontal cortex, and that it was not contingent on successful retrieval.

Brain waves following remembered faces index conscious recollection.

At a glance, one can often determine whether a face belongs to a known individual. To investigate brain mechanisms underlying this memory feat, we recorded EEG signals time-locked to face presentations. In the study phase, 40 unknown faces were presented, 20 of which were accompanied by a voice simulating that person speaking. Instructions were to remember the faces with spoken biographical information (R-faces) and to forget the others (F-faces). In the test phase, famous and non-famous faces were presented in a visually degraded manner. Subjects made two-choice fame judgments and priming was observed in the form of faster and more accurate responses for old than for new non-famous faces. Priming did not differ between R-faces and F-faces. In a second experiment, faces were not degraded at test and behavioral responses were made only when faces were presented twice in immediate succession. Brain potentials elicited 300 to 900 ms after stimulus onset from frontal and parieto-occipital scalp regions were larger for R-faces than for F-faces. Recognition tested later was more accurate for R-faces than for F-faces. Because the study-phase manipulation influenced recognition but not priming, we conclude that this procedure succeeded in isolating neural correlates of recollective processing from more automatic uses of face memory as indexed by priming.

Preliminary evidence that daily changes in frontal alpha asymmetry correlate with changes in affect in therapy sessions.

Frontal EEG alpha asymmetry was recorded from five depressed outpatients during early EEG biofeedback sessions. Mood was assessed prior to and after each session, and affect change scores were also derived by subtracting pre-session from post-session scores. Alpha magnitude was obtained via Fast Fourier Transforms. All scores (EEG alpha asymmetry and affect) were converted to deviation scores by subtracting each patient's daily score from that patient's mean across all available sessions for that patient. Pearson correlations were then computed between asymmetry and affect scores using the deviation scores combined over patients. There was little evidence of correlation between day-to-day asymmetry score and any single affect score. Strong correlations were obtained, however, between asymmetry score and affect change score and, in particular, between asymmetry score and change in positive affect.