Asynchrony and the Brain—Gamma Deficits Linked to Poor Cognitive Control
12 December 2006. Some people may have no rhythm, but they do have synchrony, at least at the cellular level. Without it the heart would be a wriggling, useless mass and the capability of cerebral cortex, with millions of neurons firing in sophisticated unison, would be compromised. Though neuronal synchrony is not well understood, there are indications that it is crucial for normal brain function and behavior. In particular, recent evidence suggests that rhythmic disturbance among specific groups of neurons in the cerebral cortex may be associated with symptoms of schizophrenia. That view is supported by a recent study from Cameron Carter of the University of California, Davis, and collaborators at the University of Pittsburgh. The findings, reported in this week’s early online edition of PNAS, suggest that poor synchrony among neurons that generate specific brain oscillations called gamma waves is associated with altered cognitive control in schizophrenia patients.
Impaired cognition is a key aspect of schizophrenia and is thought to be a greater predictor of the inability to function on a daily level than are the more obvious positive symptoms, such as psychosis and delusions. Current antipsychotic drugs are of little help with cognitive problems, and some may even make matters worse. Cognitive deficits have been traced to alterations in the dorsolateral prefrontal cortex (DLPFC). Though the precise physiological impairments that lead to DLPFC problems are unclear, MRI studies have shown less activity in this region of the brain in schizophrenics, an indication that neurons may not be working at maximum capacity. In addition, postmortem analysis of brain tissue has shown that there may be compromised neurotransmission in a specific group of DLPFC inhibitory neurons called chandelier cells (see Lewis et al., 2005), whose sole job is to innervate and modulate pyramidal neurons, the major excitatory neurons of the cortex and the ones that give rise to measurable oscillations in the gamma band range (30-80 Hertz). “What our study does is tie these observations together. It suggests that what is driving the disabling cognitive deficits in schizophrenia is the inability to mount oscillations in the gamma frequencies in the prefrontal cortex, and it connects the behavioral and neuroimaging findings with the result of postmortem studies,” said Carter in an interview with SRF.
A POP Quiz
While other studies have looked at gamma band oscillations in schizophrenia, most of these have focused on evoked oscillations, those driven by a sensory stimulus or a task involving perceiving or tracking a stimulus (see SRF Current Hypothesis by Woo and colleagues). In the current study, first author Raymond Cho of the University of Pittsburgh and colleagues focused on induced gamma rhythms, which are driven not by any externally applied stimulus, but by tasks that call into play executive control processes of cognition. The authors used a cognitive task called the “preparing to overcome prepotency” task, or POP test, to address the question of whether gamma oscillations correlate with cognitive control in schizophrenia. In this test, volunteers were shown a fleeting green or red square followed one second later by an arrow. When the arrow followed the green prompt, the volunteer had to respond by clicking a button with the same hand (right arrow, right hand), but if the arrow followed the red prompt, then the volunteer was required to respond with the opposite hand (right arrow, left hand), a scenario that requires more cognitive control. The researchers specifically chose this task because it is well-known to activate the DLPFC and because that activation correlates well with performance in the task. The researchers found that schizophrenia patients had significantly more errors in the task that required high cognitive control, and that they also took significantly longer to respond in both high- and low-control cases.
To look for difference in gamma band oscillations that might correlate with the poorer performance, Cho and colleagues used a battery of electrodes to take EEG measurements. They found that in normal subjects, two electrodes, one in the right frontal region (electrode 2 or AF8, for those familiar with EEG nomenclature) and one in the left (electrode 21 or FC1), recorded significantly higher gamma band power differences between the high- and low-control tests; this difference was much lower in the schizophrenia patients, suggesting that they had more difficulty in mounting gamma band responses to the stimuli.
To try to understand the significance of these findings, Cho and colleagues correlated the gamma differences at these two electrodes with schizophrenia symptoms. They looked at disorganization—a classic symptom of the disease and which negatively correlates with activation of the DLPFC—and behavioral performance, also compromised in schizophrenia as demonstrated by the higher error rates in the cognitive test. The researchers found a positive correlation between the right frontal electrode measurements and disorganization, while the gamma oscillations detected by the left frontal electrode positively correlated with accuracy in the test.
The study shows that increased demand on cognitive control leads to increased gamma band oscillations in normal and schizophrenia patients, but that in two specific regions of the brain the patient response was poorer than control subjects. That the gamma oscillations in these left and right frontal regions also correlated with disorganization and accuracy, respectively, in the schizophrenia patients suggests that these particular regions of the brain may play distinct roles in the disease. As such, the study suggests several diagnostic, screening, and treatment approaches. “EEG assessment of prefrontal gamma synchrony, then, may provide a useful tool for assessing impairment of prefrontal cortical circuits in tandem with behavioral measures of cognitive control disturbances in schizophrenia,” write the authors.
In addition, because they are a lot easier and less invasive to do than MRI, EEGs could be used in large-scale studies of intermediary or endophenotypes, comparing these with, for example, genetic studies. And last, but not least, because the findings are consistent with predictions that others have made about the role of interneurons in schizophrenia, “some of the molecular targets that have been identified in those brain circuits now become treatment targets,” suggested Carter. These would include subsets of receptors and transporters for GABA, the major neurotransmitter involved in modulating gamma frequency oscillations (see SRF related news story).—Tom Fagan.
Cho RY, Konecky RO, Carter CS. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. PNAS early edition. 11 December 2006. Abstract
Comments on News and Primary Papers
Comment by: Richard Deth
Submitted 14 December 2006
Posted 15 December 2006
Schizophrenia is associated with dopaminergic dysfunction, impaired gamma synchronization and impaired methylation. It is therefore of interest that the D4 dopamine receptor is involved in gamma synchronization (Demiralp et al., 2006) and that the D4 dopamine receptor uniquely carries out methylation of membrane phospholipids (Sharma et al., 1999). A reasonable and unifying hypothesis would be that schizophrenia results from a failure of methylation to adequately support dopamine-stimulated phospholipid methylation, leading to impaired gamma synchronization. Synchronization in response to dopamine can provide a molecular mechanism for attention, as information in participating neural networks is able to bind together to create cognitive experience involving multiple brain regions.
View all comments by Richard DethComment by: Fred Sabb
Submitted 12 January 2007
Posted 12 January 2007
I recommend the Primary Papers
Cho and colleagues find patients with schizophrenia showed a reduction in induced gamma band activity in the dorsolateral prefrontal cortex compared to healthy control subjects during a behavioral task that is known to challenge cognitive control processes. Importantly, the induced gamma band activity was correlated with better performance in healthy subjects, and negatively correlated with higher disorganization symptoms in patients with schizophrenia. These findings help explain previous post-mortem evidence of disruptions in thalamofrontocortical circuits in these patients.
These findings tie together several different previously identified phenotypes into a unifying story. The ability to link phenotypes across translational research domains is paramount to understanding complex neuropsychiatric diseases like schizophrenia. Cho and colleagues provide an excellent example for connecting evidence from symptom rating scales with behavioral, neural systems and neurophysiological data. Although not specifically addressed by the authors, these data may have important implications for understanding the neural basis of thought disorder as well. Hopefully, these findings will provide a frame-work for examining more informed and specific phenotypes relevant to schizophrenia.
View all comments by Fred Sabb
Comments on Related News
Related News: In Sync—Orchestrating Perfect Harmony in Neuronal NetworksComment by: Kevin Spencer
Submitted 9 February 2006
Posted 9 February 2006
I recommend the Primary PapersRelated News: Gamma Band Plays a Sour Note in Entorhinal Cortex of Schizophrenia ModelsComment by: Bita Moghaddam, SRF Advisor
Submitted 3 April 2006
Posted 3 April 2006
Cortical dysfunction in schizophrenia has been attributed to both inhibitory GABA and excitatory glutamate neurotransmission. Abnormalities in cortical GABA neurons have been observed primarily in the subset of GABA interneurons that contain the calcium-binding protein parvalbumin (PV). The glutamatergic dysfunction is suspected primarily because reducing glutamate neurotransmission at the NMDA receptors produces behavioral deficits that resemble symptoms of schizophrenia. These two mechanisms have been generally treated as separate conjectures when conceptualizing theories of schizophrenia. The paper by Cunningham et al. demonstrates that, in fact, disruptions in PV positive cortical GABA neurons and blockade of NMDA receptors produce similar disruptions to the function of cortical networks.
The authors used lysophosphatidic acid 1 receptor (LPA-1)-deficient mice which, they argue, are a relevant model of schizophrenia because these animals display sensorimotor gating deficits, a critical feature of schizophrenia. They demonstrate that, similar to schizophrenia, the number of PV positive GABA neurons is significantly reduced in LPA-1-deficient mice. Furthermore, the γ frequency network oscillation disruptions they observe in these animals are similar to those seen in wild-type mice treated with the NMDA antagonist ketamine. (γ oscillations have been associated with sensory processing and deficits in γ rhythm generation have been reported in patients with schizophrenia during performance of sensory processing tasks.) The disruptive effect of ketamine on γ oscillations was mediated by a decrease in the output of fast-spiking GABA interneurons causing a disinhibition (i.e., increased firing) of glutamate neurons. These findings are significant because they suggest that cortical NMDA hypofunction may cause the reported GABA interneuron deficits in schizophrenia.
View all comments by Bita Moghaddam
Related News: Gamma Band Plays a Sour Note in Entorhinal Cortex of Schizophrenia Models
Comment by: Patricio O'Donnell, SRF Advisor
Submitted 7 April 2006
Posted 7 April 2006
Animal models of schizophrenia and other psychiatric disorders are receiving increasing interest, as they provide useful tools to test possible pathophysiological scenarios. Some models have been tested with a wide array of approaches and many others continue to develop. If one focuses on possible cortical alterations, a critical issue emerging from many different lines of research using several different models is the apparent contradiction between the hypo-NMDA concept and the data suggesting a loss of cortical interneurons. Is there a hypo- or a hyperactive cortex?
This conundrum has been present since earlier days in the postmortem and clinical research literature, but with the advent of more refined animal models, it may be time to provide a possible way in which these discrepant sets of data can be reconciled. Whether this was the authors’ intention or not, the article by Cunningham and colleagues is an excellent step in that direction. This study used mice deficient in lysophosphatidic acid 1 receptor, a manipulation that reduced the GABA and parvalbumin-containing interneuron population by about 40 percent and disrupted γ (rapid) oscillations in the entorhinal cortex. A key element in this study was the finding that a similar alteration in rapid cortical oscillations was observed with the noncompeting NMDA antagonist ketamine. There is a large body of evidence indicating that interneurons (in particular, the fast-spiking type that include parvalbumin-positive neurons) are critical for synchronization of fast cortical oscillatory activity. As fast oscillations can be envisioned as phenomena with deep impact on cognitive functions, these findings may have bearing on possible pathophysiological scenarios underlying cognitive deficits in schizophrenia. This article does provide a strong indication that antagonism of NMDA receptors may selectively target cortical interneurons. This is in agreement with the work of Bita Moghaddam, who has shown that noncompeting NMDA antagonists can indeed increase pyramidal cell firing and glutamate levels in the prefrontal cortex. Thus, it is conceivable that psychotomimetic agents such as PCP or ketamine exert their cognitive effects by impairing interneuronal activity, hampering the fine-tuning of pyramidal cell firing that is expressed as fast cortical oscillations.
View all comments by Patricio O'Donnell
Related News: GABA Receptor Drug for Schizophrenia Is Put Through Its Paces
Comment by: Robert McCarley
Submitted 7 November 2008
Posted 7 November 2008
This paper is further evidence of an important and laudable new trend in schizophrenia psychopharmacology: namely the development and test of compounds on the basis of their relationship to circuit abnormalities, evidence derived from postmortem, genetic, and animal model studies. The authors based their choice of MK-0777 for test in schizophrenia on evidence for decreased cortical GABA neurotransmission onto pyramidal neurons at receptors having the α2 subunit, and other evidence pointing to the GABA-pyramidal neuron interaction as important in cognition and in generation of γ band oscillations. In this add-on, double-blind placebo study, the Ns were underpowered and more subjects need to be studied to be certain about clinical effects. However, one test, the Preparing to Overcome Prepotency Test (POP), had significant improvements in response latency and showed concomitant improvement in increased frontal γ band activity induced during the task, although not meeting the criterion for statistical significance. POP requires subjects either to “go with the flow” (indicated by a green light) and respond in the same direction as an arrow, or when cued by a red light to “go upstream” and point in the opposite direction, a test previously used in the Cho et al. 2006 PNAS paper and found to be accompanied by increased induced γ band oscillations.
γ band activity has justifiably attracted considerable attention, since there is mounting evidence of its relevance to human cognition as well as to basic neuroscience studies of neuronal assembly communication. Its important basis in the GABA cortical neuronal interaction with pyramidal cells makes it especially fascinating in schizophrenia. However, an important caution light was recently flashed by Yuval-Greenberg et al. in an article in Neuron (2008) in which they presented strong evidence that apparent increases or decreases in the “induced γ band oscillations” (those not temporally linked to a response or stimulus) could be the result of the eye muscle activation associated with small saccadic eye movements, “a saccadic spike potential” that could be confused with γ band oscillations. The Yuval-Greenberg article appeared too late for the authors to discuss in the present paper, but its implications for future work using induced γ are important. For studies of induced γ, we all will have to begin using eye movement measures sensitive to mini-saccades. Those of us who measure γ phase-locked to measureable events, such as sensory stimuli or responses, appear to be off the hook since we condition on known events, unlike conditions where induced γ is measured.
Cho RY, Konecky RO, Carter CS. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83. Abstract
Yuval-Greenberg S, Tomer O, Keren AS, Nelken I, Deouell LY. Transient induced gamma-band response in EEG as a manifestation of miniature saccades. Neuron. 2008 May 8;58(3):429-41. Abstract
View all comments by Robert McCarley
Related News: Working Memory Findings Defy What Theories Imply
Comment by: Deanna M. Barch
Submitted 13 July 2010
Posted 13 July 2010
Mechanisms of Capacity Limitations in Working Memory
Gold and colleagues have provided an extremely elegant example of how a precisely controlled behavioral study can be used to directly test implications generated by neurobiological theories of cognitive impairment in schizophrenia. Further, they have provided novel and important data in schizophrenia that should cause us to re-examine theories about the mechanisms underling working memory impairments in this illness.
As noted by Gold, it has been hypothesized that altered GABAergic, glutamatergic, and/or dopaminergic inputs into reverberating and oscillatory networks in prefrontal or parietal cortex among individuals with schizophrenia should render such networks unstable and lead to less precise working memory representations that are particularly prone to decay (Lisman et al., 2008; Durstewitz and Seamans, 2008; Rolls et al., 2008; Lewis et al., 2008). However, Gold and colleagues have shown that working memory representations in schizophrenia (at least of color memory) are neither less precise nor show evidence of exceptionally rapid decay. Instead, individuals with schizophrenia showed clearly reduced working memory capacity.
These data contribute to a systemic body of work generated by Gold and colleagues, who have investigated the many aspects of working memory that could be impaired in schizophrenia. They have also shown that iconic decay is not increased in schizophrenia (Hahn et al., 2010), that feature binding is intact (Gold et al., 2003), and that certain aspects of attentional control over working memory are intact (Gold et al., 2006), though others are impaired (Fuller et al., 2006). However, working memory capacity has consistently been shown to be reduced in schizophrenia across numerous studies (Gold et al., 2006; van Raalten et al., 2008; Silver et al., 2003). If we take these results seriously (and we should), they require us to look closely at the neural mechanisms postulated to modulate capacity limitations in working memory in order to generate clues to the mechanisms that may be leading to reduced working memory capacity in schizophrenia.
The neural mechanisms leading to working memory capacity limitations are still very much an open source of debate. However, one influential theory is that the number of “items” that can be maintained in working memory is limited by the number of gamma cycles (30-100 Hz) that can be embedded within a theta cycle (Lisman, 2010). Related to the idea that originally drove the design of the Gold study, Lisman and others have hypothesized that individual items within working memory are represented by oscillating neural populations with spike rates phase-locked in a gamma cycle. The oscillatory activity representing different items must be kept isolated, potentially by keeping gamma activity for different items out of phase with each other. One way to accomplish this would be to couple such gamma cycles into a lower frequency theta oscillation that can help regulate and separate activity associated with different items (as well as maintain information about order). Lisman and others have argued that capacity constraints of approximately four items in working memory (Cowan, 2001) thus reflect the number of gamma cycles that can be embedded in a theta cycle (approximately four) (Lisman, 2010; Wolters and Raffone, 2008).
Gold’s results suggest that it may not be the maintenance of the individual gamma-oscillating neural populations representing individual items that is impaired in schizophrenia. Instead, it may be either the ability to establish such synchronous neural activity associated with a specific item, or the ability to couple a number of different gamma-oscillating sub-networks into a theta cycle. Interestingly, a growing number of studies have shown altered gamma activity during working memory in schizophrenia (Barr et al., 2010; Basar-Eroglu et al., 2007; Light et al., 2006; Kissler et al., 2000), as well as some evidence for altered theta activity (Haenschel et al., 2009). However, additional work is needed to specifically examine gamma-theta coupling in schizophrenia and its role in determining capacity limitations in this disease.
The type of network models of working memory put forth by Wang and colleagues suggest that the dynamics of excitatory and inhibitory inputs drive the number of independent “activity bumps” (i.e., items) that can be maintained in a network (Compte et al., 2000). A related idea about the mechanisms driving capacity limitations and variations in these limits across individuals has been put forth by Klingberg and colleagues, who have argued that the dynamics of such lateral inhibitory mechanisms in parietal cortex limit memory capacity to be between two and seven items (Edin et al., 2009). However, they have also argued that such capacity limits can be overcome, at least temporarily, by excitatory inputs into parietal cortex from prefrontal cortex (Edin et al., 2009). They have suggested that this provides a mechanistic account of top-down control over working memory capacity by prefrontal cortex. As such, given the evidence for at least some types of abnormalities in top-down control of attention in schizophrenia (Fuller et al., 2006; Hahn et al., 2010), and evidence for altered connectivity between prefrontal and parietal regions (Barch and Csernansky, 2007; Karlsgodt et al., 2008), another possible source of reduced capacity in working memory in schizophrenia may be a reduction in prefrontal-mediated excitatory input into parietal networks that maintain items in working memory.
One might argue that the same GABA, glutamate, or dopamine mechanisms thought to impair the maintenance of representations in working memory could also impair the initial establishment of gamma oscillating networks representing items, their coupling to a lower-frequency theta cycle, or even the ability of prefrontal cortex to provide excitatory inputs into neural networks supporting the representation of items in working memory. If so, such models will also need to explain how such impairments could lead to reduced working memory capacity in schizophrenia without a change in precision or decay, a challenge for most current neural network models of working memory. As such, the data provided by Gold and colleagues suggest an exciting new pathway for research on working memory in schizophrenia that may allow us to develop more precise mechanistic hypotheses as to the source of these cognitive impairments and their relationship to pathophysiology of this illness.
Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, Grace AA. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 2008;31(5):234-42. Abstract
Durstewitz D, Seamans JK. The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia. Biol Psychiatry. 2008;64(9):739-49. Abstract
Rolls ET, Loh M, Deco G, Winterer G. Computational models of schizophrenia and dopamine modulation in the prefrontal cortex. Nat Rev Neurosci. 2008;9(9):696-709. Abstract
Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry. 2008;165(12):1585-93. Abstract
Hahn B, Kappenman ES, Robinson BM, Fuller RL, Luck SJ, Gold JM. Iconic Decay in Schizophrenia. Schizophr Bull. 2010. 2010 Jan 6. Abstract
Gold JM, Wilk CM, McMahon RP, Buchanan RW, Luck SJ. Working memory for visual features and conjunctions in schizophrenia. J Abnorm Psychol. 2003;112(1):61-71. Abstract
Fuller RL, Luck SJ, Braun EL, Robinson BM, McMahon RP, Gold JM. Impaired control of visual attention in schizophrenia. J Abnorm Psychol. 2006;115(2):266-75. Abstract
Gold JM, Fuller RL, Robinson BM, McMahon RP, Braun EL, Luck SJ. Intact attentional control of working memory encoding in schizophrenia. J Abnorm Psychol. 2006;115(4):658-73. Abstract
van Raalten TR, Ramsey NF, Jansma JM, Jager G, Kahn RS. Automatization and working memory capacity in schizophrenia. Schizophr Res. 2008;100(1-3):161-71. Abstract
Silver H, Feldman P, Bilker W, Gur RC. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. Am J Psychiatry. 2003;160(10):1809-16. Abstract
Lisman J. Working memory: the importance of theta and gamma oscillations. Curr Biol. 2010;20(11):R490-2. Abstract
Cowan N. The magical number 4 in short-term memory: A reconsideration of mental storage capacity. Behav Brain Sci. 2001;24:87-114. Abstract
Wolters G, Raffone A. Coherence and recurrency: maintenance, control and integration in working memory. Cogn Process. 2008;9(1):1-17. Abstract
Barr MS, Farzan F, Tran LC, Chen R, Fitzgerald PB, Daskalakis ZJ. Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory. Schizophr Res. 2010. Abstract
Basar-Eroglu C, Brand A, Hildebrandt H, Karolina Kedzior K, Mathes B, Schmiedt C. Working memory related gamma oscillations in schizophrenia patients. Int J Psychophysiol. 2007;64(1):39-45. Abstract
Light GA, Hsu JL, Hsieh MH, Meyer-Gomes K, Sprock J, Swerdlow NR, Braff DL. Gamma band oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients. Biol Psychiatry. 2006;60(11):1231-40. Abstract
Kissler J, Muller MM, Fehr T, Rockstroh B, Elbert T. MEG gamma band activity in schizophrenia patients and healthy subjects in a mental arithmetic task and at rest. Clin Neurophysiol. 2000;111(11):2079-87. Abstract
Haenschel C, Bittner RA, Waltz J, Haertling F, Wibral M, Singer W, Linden DE, Rodriguez E. Cortical oscillatory activity is critical for working memory as revealed by deficits in early-onset schizophrenia. J Neurosci. 2009;29(30):9481-9. Abstract
Edin F, Klingberg T, Johansson P, McNab F, Tegner J, Compte A. Mechanism for top-down control of working memory capacity. Proc Natl Acad Sci U S A. 2009;106(16):6802-7. Abstract
Compte A, Brunel N, Goldman-Rakic PS, Wang XJ. Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model. Cereb Cortex. 2000;10(9):910-23. Abstract
Hahn B, Robinson BM, Kaiser ST, Harvey AN, Beck VM, Leonard CJ, Kappenman ES, Luck SJ, Gold JM. Failure of schizophrenia patients to overcome salient distractors during working memory encoding. Biol Psychiatry. 2010 June 4. Abstract
Barch DM, Csernansky JG. Abnormal parietal cortex activation during working memory in schizophrenia: verbal phonological coding disturbances versus domain-general executive dysfunction. Am J Psychiatry. 2007;164(7):1090-8. Abstract
Karlsgodt KH, van Erp TG, Poldrack RA, Bearden CE, Nuechterlein KH, Cannon TD. Diffusion tensor imaging of the superior longitudinal fasciculus and working memory in recent-onset schizophrenia. Biol Psychiatry. 2008;63(5):512-8. Abstract
View all comments by Deanna M. Barch