Peter Bachman

Abnormally high EEG alpha synchrony during working memory maintenance in twins discordant for schizophrenia

BACKGROUND The present analyses aimed to test the prediction that schizophrenia patients and their non-schizophrenic co-twins would display reduced efficiency of the neurocognitive mechanisms subserving active maintenance of spatial information in working memory. METHODS Upper alpha frequency band EEG event-related desynchronization and synchronization (ERD/ERS) were calculated as percent changes in power relative to an inter-trial baseline across 4 memory loads in a spatial delayed-response task. RESULTS During the delay, the diagnostic groups showed equivalent ERD/ERS activity over posterior scalp regions at the lowest memory load; however, as memory load increased, patients, and to an intermediate degree, their non-schizophrenic co-twins (monozygotic and dizygotic pairs collapsed together), showed significantly greater increases in ERD/ERS amplitude as compared with controls. CONCLUSIONS These findings demonstrate abnormally increased ERD/ERS amplitudes with increasing memory load in patients with schizophrenia and their co-twins, consistent with inefficiency of the neurocognitive mechanisms supporting active maintenance of information across a delay.

Genetic influence on the working memory circuitry: behavior, structure, function and extensions to illness.

Working memory is a highly heritable complex cognitive trait that is critical for a number of higher-level functions. However, the neural substrates of this behavioral phenotype are intricate and it is unknown through what precise biological mechanism variation in working memory is transmitted. In this review we explore different functional and structural components of the working memory circuitry, and the degree to which each of them is contributed to by genetic factors. Specifically, we consider dopaminergic function, glutamatergic function, white matter integrity and gray matter structure all of which provide potential mechanisms for the inheritance of working memory deficits. In addition to discussing the overall heritability of these measures we also address specific genes that may play a role. Each of these heritable components has the potential to uniquely contribute to the working memory deficits observed in genetic disorders, including 22q deletion syndrome, fragile X syndrome, phenylketonuria (PKU), and schizophrenia. By observing the individual contributions of disruptions in different components of the working memory circuitry to behavioral performance, we highlight the concept that there may be many routes to a working memory deficit; even though the same cognitive measure may be a valid endophenotype across different disorders, the underlying cause of, and treatment for, the deficit may differ. This has implications for our understanding of the transmission of working memory deficits in both healthy and disordered populations.

Integrity of emotional and motivational states during the prodromal, first-episode, and chronic phases of schizophrenia

Emotional and motivational dysfunction is fundamental to schizophrenia, and yet, the nature and scope of associated deficits are not well understood. This study assessed the integrity of emotional responding from the perspective of its underlying motivational systems during different phases of schizophrenia. Evaluative, somatic, and autonomic responses were measured during viewing of pictures categorized by emotional content, including threat, mutilation, contamination, illness, pollution, mild erotica, families, food, and nature. Participants were 13 patients at ultra high risk or prodromal for psychosis, 40 first-episode schizophrenia patients, 37 chronic schizophrenia patients, and 74 healthy comparison subjects. Irrespective of phase of illness, schizophrenia patients showed a robust and normal pattern of response across multiple systems, with differential engagement of the defensive and appetitive systems as a function of the motivational significance assigned to specific emotional contexts. Although the integrity of core motivational states also appeared to be intact in prodromal patients, a less consistent pattern of response was observed. As continuing efforts are made to identify emotional and motivational abnormalities in schizophrenia, identified deficits will likely be independent of a fundamental dysfunction in basic emotion and motivation response systems and involve integration with higher order processes.

Coping styles of individuals at clinical high risk for developing psychosis.

There is a wealth of evidence suggesting that patients with schizophrenia tend to respond to life stressors using less effective coping skills, which are in turn related to poor outcome. However, the contribution of coping strategies to outcome in youth at clinical high risk (CHR) for developing psychosis has not been investigated.

Verbal recall and recognition in twins discordant for schizophrenia.

The nature, neural underpinnings, and etiology of deficits in verbal declarative memory in patients with schizophrenia remain unclear. To examine the contributions of genes and environment to verbal recall and recognition performance in this disorder, the California Verbal Learning Test was administered to a large population-based Finnish twin sample, which included schizophrenic and schizoaffective patients, their non-ill monozygotic (MZ) and dizygotic (DZ) co-twins, and healthy control twins. Compared with controls, patients and their co-twins showed relatively greater performance deficits on free recall compared with recognition. Intra-pair differences between patients and their non-ill co-twins in hippocampal volume and memory performance were highly positively correlated. These findings are consistent with the view that genetic influences are associated with reduced verbal recall in schizophrenia, but that non-genetic influences further compromise these abnormalities in patients who manifest the full-blown schizophrenia phenotype, with this additional degree of disease-related declarative memory deficit mediated in part by hippocampal pathology.

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain.

Significance Experience-dependent plasticity is the capacity of the brain to undergo changes following environmental input and use, and is a primary means through which the adult brain enables new behavior. In the current study, we provide evidence that enhancing signaling at the glutamate N-methyl-d-aspartate receptor (NMDAR) can enhance the mechanism underlying many forms of experience-dependent plasticity (i.e., long-term potentiation of synaptic currents) and also enhance experience-dependent learning in healthy adult humans. This suggests exciting possibilities for manipulating plasticity in adults and has implications for treating neurological and neuropsychiatric disorders in which experience-dependent plasticity is impaired. Experience-dependent plasticity is a fundamental property of the brain. It is critical for everyday function, is impaired in a range of neurological and psychiatric disorders, and frequently depends on long-term potentiation (LTP). Preclinical studies suggest that augmenting N-methyl-d-aspartate receptor (NMDAR) signaling may promote experience-dependent plasticity; however, a lack of noninvasive methods has limited our ability to test this idea in humans until recently. We examined the effects of enhancing NMDAR signaling using d-cycloserine (DCS) on a recently developed LTP EEG paradigm that uses high-frequency visual stimulation (HFvS) to induce neural potentiation in visual cortex neurons, as well as on three cognitive tasks: a weather prediction task (WPT), an information integration task (IIT), and a n-back task. The WPT and IIT are learning tasks that require practice with feedback to reach optimal performance. The n-back assesses working memory. Healthy adults were randomized to receive DCS (100 mg; n = 32) or placebo (n = 33); groups were similar in IQ and demographic characteristics. Participants who received DCS showed enhanced potentiation of neural responses following repetitive HFvS, as well as enhanced performance on the WPT and IIT. Groups did not differ on the n-back. Augmenting NMDAR signaling using DCS therefore enhanced activity-dependent plasticity in human adults, as demonstrated by lasting enhancement of neural potentiation following repetitive HFvS and accelerated acquisition of two learning tasks. Results highlight the utility of considering cellular mechanisms underlying distinct cognitive functions when investigating potential cognitive enhancers.

Multisensory Encoding Improves Auditory Recognition

Recent studies have challenged the long-held belief that recognition is unfailingly degraded by contextual differences between study and test items. In these studies, recognition of pictures presented in silence was better when during study or initial exposure the images were accompanied by a semantically congruent sound rather than silence. In the present study, we sought to examine the generalization of this phenomenon to auditory recognition and found a significant improvement in the recognition of auditory items when coupled with a congruent picture. We discuss these findings within the framework of the redintegration hypothesis of memory retrieval as well as Bayesian inference and learning.

Electrophysiological Endophenotypes for Schizophrenia.

AbstractEndophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neurobiological associations. We discuss recent findings regarding the genetic architecture of specific electrophysiological endophenotypes, as well as converging evidence from EEG studies implicating disrupted balance of glutamatergic signaling and GABAergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating data sets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype.

Genetic Architecture of Declarative Memory: Implications for Complex Illnesses

Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene disorders, which provide insight into the molecular mechanisms underlying the genetic basis of human memory function.

Novel concepts mediate word retrieval from human episodic associative memory: evidence from event-related potentials

Effects of conceptual fusion on episodic associative retrieval were examined. Subjects attempted to fuse sequentially displayed (800 ms offset) word pairs; pairs subjects were unable to fuse were instead considered associated by juxtaposition. Next, dense-array event-related potentials (ERPs) were recorded while the pairs were redisplayed, half reversed in order. Subjects pressed a button to indicate whether each pair was presented in the previous order. Behavioral results showed that retrieval of fused pairs was faster and more accurate than for juxtaposed pairs. ERP topography to the first word of fused pairs was different from juxtaposed pairs, indicating that fusion can mediate associative retrieval of constituent items. Estimates of current source density at the cortical surface showed that fusion-mediated retrieval elicited left inferior-prefrontal/anterior-temporal activity not typically observed in episodic memory retrieval studies.