Schizophrenia Research Forum - A Catalyst for Creative Thinking

Live Discussion: Synchronized Neural Oscillations in the Pathophysiology of Schizophrenia


Peter Uhlhaas

Kevin Spencer

View article

On 16 December 2008, at 12:00 noon (US Eastern time), Peter Uhlhaas of the Max-Planck Institute for Brain Research, Frankfurt, and Kevin Spencer of Harvard University will lead us in a discussion of the possible role of synchronized, oscillatory activity in the pathophysiology of schizophrenia. Not only will they assess the current evidence, they will take a critical look at the methods and interpretation of data. The online chat will also allow attendees to discuss the possible mechanisms underlying these proposed abnormalities and possible neurodevelopmental antecedents.

Our live discussions always go best when the wheels are "greased" with some preliminary comments, so please read and comment on the backgrounder below and the review article by Uhlhaas and colleagues. (Our special thanks to Schizophrenia Bulletin, the Maryland Psychiatric Research Center, and Oxford Press for allowing us to post this free article!)

Uhlhaas PJ, Haenschel C, Nikolić D, Singer W. The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophr Bull. 2008 Sep;34(5):927-43. Abstract

Watch a two-part explication of the discussion topic: Part 1 by Kevin Spencer and Part 2 by Peter Uhlhaas, and then please read and comment on the backgrounder and the review article by Uhlhaas and colleagues.

View Transcript of Live Discussion — Posted 6 January 2009

View Comments By:
Didier Pinault — Posted 13 December 2008
Georg Winterer — Posted 10 January 2011


Background Text
by Kevin Spencer and Peter Uhlhaas

Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. By now, there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neural responses are associated with synchronized oscillatory activity in the θ-, α-, β-, and γ-band, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to its role during normal brain functioning, neural synchrony may be altered in major neuropsychiatric disorders, such as schizophrenia. Thus, there is good evidence on the alterations in high-frequency oscillations in schizophrenia as well as preliminary evidence for impairments in θ- and α-band activity. Accordingly, altered neural synchrony may represent the functional correlate of dysconnectivity in cortical networks that underlie the characteristic fragmentation of mind and behavior in schizophrenia. Impaired neural synchrony may also be linked directly to altered neurotransmitter systems in schizophrenia as much is already known about the underlying neurotransmitter systems involved in the generation of oscillations. Manipulation of neurotransmitter systems in in-vitro experiments, for example, allows a direct test of the involvement of specific receptors systems in the generation of abnormal rhythmic activity that provide critical tests for pathophysiological mechanisms in schizophrenia.

Although the initial evidence for a role of neural synchrony in the pathophysiology of schizophrenia seems promising, we nonetheless consider a number of issues critical for the progress in this field. Some provisional questions for discussion will be the following:

1. What is the evidence for impaired neural synchrony in schizophrenia? Are specific frequencies affected? Is it a generalized impairment? Is it specific to schizophrenia?

2. Which methods have yielded the best results? Do we need standardization of methods?

3. What are the possible mechanisms underlying impaired neural synchrony in schizophrenia?

4. How can neural synchrony account for the neurodevelopmental profile of schizophrenia?

Background
Singer and colleagues proposed the “temporal correlation hypothesis” (e.g., Singer, 1999), that precise (ms) synchronization of neural firing mediates the “binding” of information coded by separate neurons into coherent representations. This neuronal synchronization could be mediated by oscillatory activity across different frequency bands:

Delta (δ): 1-4 Hz
Theta (θ): 4-8 Hz
Alpha (α): 8-13 Hz
Beta (β): 13-30 Hz
Gamma (γ): 30-100 Hz

(It should be noted that the exact definitions of frequency bands vary among researchers.)

It has been proposed that fast oscillations (β, γ) may synchronize neurons within local circuits, while slower oscillations (δ, θ, α) may coordinate the synchronization of neurons across brain regions, and also gate high-frequency oscillations (e.g., Sirota et al., 2008).

Methods
To analyze oscillatory synchronization, it is necessary to decompose the EEG in the frequency domain. Simple methods are filtering and frequency analysis within a fixed epoch, but these are limited in time and frequency resolution. Better methods perform a joint time/frequency analysis, such as with wavelets or a windowed Fast Fourier Transform (FFT). There are also methods to analyze oscillatory synchrony between brain regions, which typically involve the application of wavelets or windowed FFTs to obtain power or phase coherence between the signals measured at separate sensors. (For review, see Roach and Mathalon, 2008).

Two basic types of oscillations have been defined: 1) evoked oscillations, which are phase-locked to a stimulus (or other reference time point); and 2) induced oscillations, which are not strongly phase-locked to the stimulus, but are jittered in latency across trials. The measures of oscillations that are commonly used complement these definitions: evoked power measures the power of oscillations that are phase-locked to the stimulus, and are computed from the average of single trials (the average ERP). Total power includes both evoked and induced oscillations, and is measured in the average of single-trial power spectra. The phase-locking factor (or value) measures the degree to which an oscillation is phase-locked to a stimulus, and is independent of power.

Oscillation Abnormalities in Schizophrenia
A variety of abnormalities of fast oscillations have been observed in schizophrenia. A partial list includes the following:

NMDA receptor hypofunction.

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Transcript

Attendees/Participants

Chris Bowie, Queen's University, Canada
Carlos Cortes, MPRC, University of Maryland
Richard Deth, Northeastern University
Derek Fisher, Carleton University, Ottawa, Canada
Sharon Graw, University of Colorado Denver
John Gruner, JAG/Cephalon, Inc.
Corinna Haenschel, Max-Planck Institute for Brain Research
Harsha Halahalli, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India
Mei-hua Hall
Hakon Heimer, Schizophrenia Research Forum
Patricio O'Donnell, University of Maryland
Didier Pinault, Inserm, University of Strasbourg, France
Patrick Roberts, Oregon Health & Science University
Kevin Spencer, VA Boston and Harvard Medical School
Peter Uhlhaas, Max-Planck Institute for Brain Research
James Waltz, Maryland Psychiatric Research Center

Note: Transcript has been edited for clarity and accuracy.


Hakon Heimer
I would like to introduce and thank our chat leaders, Peter Uhlhaas and Kevin Spencer. I think it's accurate to say that between them, and their colleagues Wolf Singer and Bob McCarley, they have done a substantial portion of the work teasing out the possible links between aberrations in neural synchrony and schizophrenia pathophysiology. I thank them for bringing us this idea and for their work to prepare the discussion. I'll now turn the floor over to, if I'm not mistaken, Peter, who will take lead first.

Peter Uhlhaas
Hello everybody from Frankfurt!

Didier Pinault
It looks to be a big party. Let's go for synchrony.

Kevin Spencer
Perhaps we could ask, does anyone disagree that there is evidence for impaired neural synchrony in schizophrenia?

Peter Uhlhaas
To be more precise: How good/consistent is the data?

Didier Pinault
Maybe start with the definition of different forms of synchrony?

Peter Uhlhaas
You are referring to the difference between task-dependent and resting-state activity?

Didier Pinault
Yes, for instance.

Kevin Spencer
Didier, okay, that's a good idea. In schizophrenia it is not at all uncommon to find abnormalities in some measure X, whatever that is (neural, cognitive, etc.).

Peter Uhlhaas
I would suggest we first talk about task-induced data. We will go then to the second area.

Didier Pinault
Of course, possible links between ongoing and task-related synchronies.

Kevin Spencer
Okay, there is the notion that when there is a stimulus, there is a reorganization of ongoing activity. So to what extent are the abnormalities that we see in schizophrenia reflecting abnormal modifications of ongoing activity?

Derek Fisher
Well, from what I've read, it appears that there is good evidence to support abnormal neural synchrony in schizophrenia (as indexed by gamma oscillations) in response to visual stimuli, but not to auditory stimuli.

Peter Uhlhaas
It seems to be a very general impairment, and there is more evidence emerging that a lot of systems are affected…motor, sensory, executive.

Kevin Spencer
Derek, well, actually there are a number of studies showing deficits in the auditory steady-state response. but one issue is why the early auditory evoked gamma seems to be unaffected (so far, at least).

Derek Fisher
Kevin, true. I was thinking specifically of evoked gamma (in response to a task). I'm curious as to whether different subsets of schizophrenia patients may exhibit different auditory evoked gamma responses. Perhaps when patients are grouped together, there is too much variation to pull out the significant differences.

Peter Uhlhaas
Derek, quite right.

Kevin Spencer
Derek, yes, that is a very good question. We really need to see more studies, with broader range of samples, to try to parse the intersubject variability. I don't know if Mei-hua Hall is still on, but I know she's looking at the early auditory gamma and genetics.

Derek Fisher
Kevin, that would be very interesting to see if specific genetic cohorts exhibit differences. I really enjoyed your paper in Biol Psychiatry (2008) and am hoping to examine what effect the presence/absence of auditory hallucinations would have on auditory evoked gamma.

Kevin Spencer
Derek, you know, I thought I was getting some effects of auditory hallucinations in that data set, but they were not convincing enough (at least to the reviewers).

Derek Fisher
Kevin, how did you group your sample? Did one group have hallucinations and the other did not, or did the hallucinations move along a continuum? The data set I intend to analyze will have two schizophrenia groups: those with modest auditory hallucinations (~3 on the hall item of the PANSS0 and those with no hallucinations whatsoever).

Kevin Spencer
Derek, I looked at both correlations across the range of symptom scores, and between-group differences, doing a median split on the patients.

Derek Fisher
Kevin, what did your potential auditory hallucination effects suggest? Did it lean towards those with AHs showing reduced AGOs?

Kevin Spencer
Derek, yes, I believe so.

Mei-hua Hall
Hi, Kevin. I agree that we need more studies. In my schizophrenia twin sample from IOP, I found that the evoked gamma was impaired in both identical schizophrenia twin members as well as their unaffected co-twins and heritability of evoked gamma is about 65 percent, suggesting that there is a genetic component in gamma band and impairments are due to genes.

Kevin Spencer
Hi Mei-hua! Those results are very interesting. Didier, no, unfortunately, I haven't. All of ours are well medicated and not really hallucinating.

James Waltz
Peter/Kevin, are we approaching an agreed-upon method for normalization? There are 100 ways to do it.

Peter Uhlhaas
Hi Jim. Well, this is problematic. Ideally, one should analyze the data different ways. Some agreement here....

Kevin Spencer
Peter/James, yes, unfortunately there are too many ways to analyze one's data.

Peter Uhlhaas
It's like psychoanalysis.

James Waltz
In your experience, do you find that normalization method affects gamma-band changes?

Kevin Spencer
Regarding analysis methods, I’ll say that my philosophy is to try to stick as closely as possible to the original data without too much standardization or transformation.

Peter Uhlhaas
Some agreement/common procedures would be very useful; otherwise the literature will become quite confusing.

Mei-hua Hall
Peter, also there is different usage of the same terminology which makes the literature confusing and difficult to understand the methodology from one study to another.

Peter Uhlhaas
Yes, Mei-hua.

Kevin Spencer
Peter, yes indeed. I think that one practice that should be avoided is just filtering the EEG/MEG, not doing a time/frequency analysis that shows the evolution across the whole spectrum. No more reporting just 40 Hz!

Peter Uhlhaas
Si, si....

Kevin Spencer
Mei-hua, yes, and "synchrony" is one of the most misused terms.

James Waltz
But gamma-band power in the EEG implies a certain level of synchrony, no? Otherwise it would not show up as power.

Peter Uhlhaas
Jim, this is also true. Ideally, we have a common set of procedures of how we are going about to analyze and report data, but my feeling is that this is too difficult to achieve given the different methods, paradigms, etc. This is not even the case in studies looking at normal populations.

Kevin Spencer
James, that's a good question. The EEG does show a 1/f distribution, so a certain amount of power will be expected at all frequencies.

Mei-hua Hall
Peter/Kevin, is there any way to somehow standardize the methodology or at least unify the terminology in this field?

Kevin Spencer
Mei-hua, that would be nice, but the ERP world still hasn't united between plotting positive down or up! One problem I have is that some studies preselect a frequency band of interest without showing that there are any real oscillatory effects present there.

Mei-hua Hall
Kevin, following your comments, each of these frequency bands is not isolated but interrelated; so far we seem to look into each frequency band as a separate entity.

Kevin Spencer
Mei-hua, yes. The problem is that this area is still so young. We need to look at all the bands both separately and together. Ugh!

James Waltz
But I mean, a change in gamma power in the EEG from time 1 to time 2 implies also a change in local synchrony, in that detectable EEG oscillations depend on a certain amount of synchrony.

Peter Uhlhaas
Of course, Jim. By the way, I find it quite encouraging that basic scientists can talk to EEG-people and find a common language. This is certainly progress.

Hakon Heimer
Kevin, you mentioned very briefly in the introductory text the new paper (Sirota et al., 2008). Perhaps everyone has not seen this. Do you have some preliminary thoughts to share?

Kevin Spencer
Hakon, well, I haven't thoroughly read the paper yet, but the results seem to be a nice addition to the story that there is a hierarchical organization of oscillations in the brain, with low frequencies modulating high frequencies. So for us, it is natural to ask whether this modulation is abnormal in schizophrenia. Could it be that gamma abnormalities are to some extent due to low-frequency impairments?

Peter Uhlhaas
This will be something that we have to look into. This is a necessary part of the picture, which definitely will make the whole story more complex! But the brain is rather complex!

Kevin Spencer
I should mention that John Lisman showed some interesting animal data on delta oscillations at ACNP.

Hakon Heimer
Kevin, were those Lisman data in thalamus?

Kevin Spencer
Hakon, yes, they were; thanks for reminding me. We really need to take into account thalamocortical interactions. I have some preliminary data which suggest abnormal delta modulation of the 40 Hz ASSR in schizophrenia, so that could be a cause. I shouldn't say much until the reviewers have had their say, though. Okay, everyone, we seem to be veering into mechanisms. This is a very exciting area, with lots of interesting convergences between the human and animal model data.

Peter Uhlhaas
Didier, do you actually have an explanation of how mechanistically NMDA-antagonists increase gamma oscillations?

Didier Pinault
Peter, from a mechanistic point of view it is difficult to give a definitive conclusion. The most accepted would be first inhibition in GABAergic cells and subsequent excitation of glutamate neurons. Also see the interesting Roopun review.

Patricio O’Donnell
Peter, regarding NMDA antagonists, I think the basic science data are quite strong in indicating they suppress fast-spiking interneuron activity (thought to be responsible of gamma activity); therefore, they would suppress gamma, not increase it.

Richard Deth
Involvement of different interneuron populations (e.g., parvalbumin in gamma) with different calcium binding proteins, which vary in their calcium binding kinetics, illustrates how different frequency ranges can be modulated to higher participation. Calcium levels limit frequency by their influence on afterhyperpolarization duration. Faster frequency requires faster calcium kinetics. Neurotransmitters like dopamine or glutamate can modulate participation of networks in a given frequency by modulating calcium status.

Peter Uhlhaas
Patricio, a couple of people have found the opposite.

Patricio O’Donnell
I think that Bita Moghaddam's data in awake animals illustrate quite well that pyramidal neurons increase their firing with ketamine, and emerging data from several animal models in which fast-spiking interneurons are affected show failure to obtain activity-induced gamma.

Didier Pinault
Yes, I fully agree with Patricio.

Kevin Spencer
Patricio/Didier, I thought the data in the Roopun Schizophrenia Bulletin paper were interesting, showing gamma increases/decreases in different brain regions. These were recorded from kainate-induced states in slices, I believe. Do you have any comments about how that state could differ from in vivo gamma?

Didier Pinault
Kevin, very interesting point. Pretreated rats with MK-801 increase kainate-induced oscillation. I think it was made in HPC slices.

Patricio O’Donnell
Kevin, Miles Whittington's work in general has highlighted that different patterns of oscillation can be obtained in those slice preparations. In fact, when they record in deep cortical layers, they see changes in gamma activity, whereas cholinergic modulation of superficial layers seems to generate high beta oscillations. The point here is that a slice preparation is a very reduced one. That is why I think approaches such as Bita's (in vivo, awake animals) may be more relevant to the "real thing."

Didier Pinault
Yet, the first studies on muscarinic-induced gamma oscillations have demonstrated no involvement of NMDAr in these oscillations.

Kevin Spencer
Didier/Patricio, yes, I recall that the Whittington group looked at NMDA in earlier studies and didn't find any effects.

Didier Pinault
Kevin/Patricio, still from a mechanistic point of view, the mechanisms underlying ketamine-induced gamma hypersynchrony are very complicated. Schizophrenia and cognition impairment are multifunctional and multidimensional disorders, including interaction between several networks and neurotransmission systems (glu, GABA, DA, ACh, etc.).

Patricio O’Donnell
Didier, you are absolutely right. We tend to bias our studies toward the modulator that interests us, but there is a large number of phenomena converging in modulating oscillations. I do think, however, that there is strong evidence indicating fast-spiking interneuron activity (synchronization) implicated in beta2 and gamma oscillations. Now, whether NMDA antagonists act by inhibiting these inhibitory neurons and that the essential mechanism remains to be determined. They do affect NMDA receptors in interneurons, but they are also likely to affect other cell types including pyramidal neurons. Therefore, the picture many of us like (i.e., that NMDA antagonists act by disinhibition) may not be a complete one.

Didier Pinault
Patricio, very interesting.

Kevin Spencer
Didier/Patricio, yes, that is one question I've had about the NMDA modulation studies. How come the presumed effects on interneurons are so much stronger than on pyramidal cells?

Patricio O’Donnell
Kevin, interneurons are much more depolarized than pyramidals; therefore, their NMDA receptors should be beyond the Mg blockade that is observed at negative membrane potentials. Also, some interneurons express NMDA receptors containing the NR2C subunit that makes them more sensitive to non-competing blockade.

Kevin Spencer
Patricio, thanks!

James Waltz
Do you guys think that faulty oscillations can be "fixed,” by a drug such as MK-0777, reported by David Lewis? It seems like timing is easy to screw up, but hard to fix. I think it's worth investigating, of course, but the schizophrenic brain has presumably had faulty timing mechanisms for 15-25 years before it sees drug....

Kevin Spencer
James, that is a great question; we should have thought of it! I predict that in 25 years, nanoprobes will be used to electrically stimulate parts of the brain to control schizophrenia. There, it's off my chest.

Hakon Heimer
Kevin, careful what you say.... Wired magazine will be contacting for a prediction next week.

Kevin Spencer
Hakon, hey, I got into all this because of an article I read in Omni magazine back in high school.

Richard Deth
Autism is another disorder with faulty synchrony, and autistic kids are improved by treatments that improve redox and methylation status. Schizophrenia is associated with low glutathione in the brain and methylation problems.

Didier Pinault
Maybe should we take into consideration the glia, the most important brain elements and known to be involved in oscillations. Are they involved in gamma oscillations?

Patricio O’Donnell
Didier, I think glia may bring a strong modulation into this system, as those cells are critical for modulating the glutamate milieu. We do need to do more to address their role.

Didier Pinault
Patricio, yes, glial cells are strongly involved at least through transporters of gly, glu, and in the regulation of d-serine, etc., all of these with impact on NMDAr.

Richard Deth
Glia are involved in redox because they supply cysteine to neurons to make glutathione.

Peter Uhlhaas
Patricio, perhaps you can share your ideas on how synchrony could be related to the neurodevelopment hypothesis of schizophrenia?

Patricio O’Donnell
Regarding development, one interesting aspect of fast-spiking interneurons is that they mature late, very late. In fact, we have shown that their modulation by dopamine does change during adolescence. Now, we have a recent J. Neurosci paper in which we show that in rats with a neonatal ventral hippocampal lesion, the normal maturation of interneurons in the prefrontal cortex is disrupted.

Peter Uhlhaas
Very good, Patricio....

Derek Fisher
Patricio, do you think your data might point to why schizophrenia tends to develop in late adolescence/early adulthood? Also, were there any gender effects?

Peter Uhlhaas
This would go too far, Derek! But certainly these data possibly show something important. There are also data from the Colorado group that show the MEG-auditory steady-state response in the gamma-range matures relatively late. One could guess that once the system develops its precise timing, a vulnerable brain may not be able to effectively organize its activity according to such a regime.

Patricio O’Donnell
Derek, yes indeed!! I think that there may be an early developmental factor (even prenatal) that may affect interneuron function, but as their function (in particular their recruitment by dopamine) does not come online until late adolescence (at least in the prefrontal cortex), that early deficit is not observed in altered behavior, It is only when the periadolescent maturation fails to occur that abnormal oscillations (or lack of the normal evoked ones) may emerge.

Kevin Spencer
Peter, why don't you describe some of your recent data? The stuff you had at SfN?

Peter Uhlhaas
We have these very interesting data that high-frequency oscillations and theta-activity undergo major changes during the transition from normal adolescence to adulthood. The relationship between the late emergence of schizophrenia and brain maturation is an obvious one.

Hakon Heimer
Peter, are there good longitudinal studies of normal development of oscillatory activity?

Peter Uhlhaas
Hakon, none at all!

James Waltz
Peter, what do you do when a brain has had bad timing for 18 years?

Derek Fisher
Peter, I'm curious whether any of these data show gender differences? Or if this has even been looked at?

Peter Uhlhaas
Derek, the sample is not large enough. But we will look at this.

Richard Deth
Dopamine-mediated attention leads to network formation via trophic effects, and subsequently these networks can interact via gamma synchrony in response to dopamine, involving D4 dopamine receptors.

Kevin Spencer
Richard, you have good points about the DA system. These need to be taken into account, too, especially in development.

Richard Deth
Methylation is an important driver of development through epigenetic mechanisms.

Peter Uhlhaas
It should be noted that synchrony is not only related to binding, but is really such a basic mechanism that is relevant for LTP, etc. Accordingly, a system with impaired neural synchrony will be dysfunctional in much more basic ways.

Didier Pinault
Peter, regarding LTP, we have got preliminary data that TC neurotransmission is impaired during ketamine-induced ongoing gamma hyperactivity.

John Gruner
JAG/Cephalon, Inc./CNS Biology. Methodology note: I recently reproduced the results of Didier Pinault in the rat with MK-801 (increased gamma, ~40-100 Hz, 0.3 mpk); did not see an effect of time of day.

Didier Pinault
Well done, John. We have also found that ketamine or MK-801 increases HFO (80-150 Hz, unpublished). Is there any link between gamma (30-80 Hz) and HFO?

John Gruner
Can only record up to about 80 Hz reliably at the moment. I also tried ketamine but did not see an effect (can't find the dose offhand; used IP injection so route may be an issue).

Kevin Spencer
Peter and everyone, one thing that we haven't gotten to is compensation. To what extent are the effects that we see due to compensatory mechanisms?

Peter Uhlhaas
You refer to pathological gamma oscillations? For example, those seen in positive symptoms?

Kevin Spencer
Peter, sure, we can start with gamma. The brain has many homeostatic mechanisms that try to balance excitation and inhibition; for instance. is the acute ketamine model really an adequate model of chronic schizophrenia?

Peter Uhlhaas
Kevin, As regards the ketamine model, I am not sure. Didier, what do you think?

Didier Pinault
Kevin, I don’t think so but, may be a good model for cognitive impairment. The ketamine model is, however, a good tool to understand some aspects/symptoms of schizophrenia.

Kevin Spencer
Didier, you're right, of course; just wanted to say something controversial. ::smoke

Didier Pinault
Kevin, I was also paradoxical! Fortunately, still so many questions and much work to do!

Harsha Halahalli
Peter/Kevin, at what level do you think abnormal synchrony plays a role in pathophysiology of schizophrenia: "lower" sensory/perceptual levels or "higher" executive levels...or possibly both?

Kevin Spencer
Hi Harsha. The evidence seems to be for both, e.g., sensory-evoked oscillations, perception-related activity, working memory, etc.

Peter Uhlhaas
Harsha, I agree.

John Gruner
I have a general question about gamma dysfunction: can increased gamma (MK-801) or decreased (some schizophrenia clinical data) both produce disorganized processing and thus psychotic-like behavior? For example, if everyone in a room is talking or no one can talk, same result: no communication.

Kevin Spencer
John, that is a great question (gamma and symptoms). I think the evidence may lean toward more gamma and disorganization. I'm waiting for the ultimate disorganization/gamma study from Peter. 

Peter Uhlhaas
Kevin, we have this one outlier! :) Problem is that it is difficult to measure really disorganized patients. Kevin, I think your recent data at SfN suggested that it may not always be easy to differentiate between good gamma and bad (pathological), during hallucinations, for example.

Kevin Spencer
Peter, yes, those data suggest that there could be multiple neural abnormalities affecting the same oscillation.

Peter Uhlhaas
Coming back to an earlier point, it seems that we have forgotten that schizophrenia is a very heterogeneous disorder. Therefore we really need perhaps larger samples...look at subtypes.... These should ideally have different oscillatory signatures (in an ideal world).

Kevin Spencer
Peter/Didier, this sounds like the point where we plead for more funding!

Peter Uhlhaas
In addition, we should also consider that alterations in gamma or other frequencies are not specific to schizophrenia.

Kevin Spencer
Peter, yes, it's really important to remember that. As more studies are done, it will be interesting to see what commonalities/differences emerge between schizophrenia and other disorders. For instance, schizophrenia and bipolar show ASSR deficits (possibly with some lateralization differences). And the ASSR is also reduced in autism, I recall.

Peter Uhlhaas
Kevin, yes, it is. This is something which really worries me. We need some specificity in the end to discover specific pathways.

Didier Pinault
Peter, can the ketamine model be tested in monkeys?

Peter Uhlhaas
I guess it could...it can even be tested in humans...any volunteers here?

John Gruner
Didier or others, I would like to try ketamine in rat again; 10 mg/kg seems a good dose. Do you know if route is important? Have you tried IP dosing? What is the highest tolerable dose that produces increased gamma?

Didier Pinault
John, have a try with 2.5 and 5 mg/kg, subcutaneous. At 10 mg, you will also record slow waves. Peter, the rodent ketamine model is a transposition of the human ketamine model. But in monkeys you could set up very interesting experimental designs, at least to test the impact of ongoing gamma on task-related gamma?

Kevin Spencer
Didier, you raise an interesting idea. I wonder why no one has tested monkeys with the ketamine model? Perhaps because it's damn hard to test a psychotic monkey?

Peter Uhlhaas
Didier, I guess you could!

Derek Fisher
Kevin, that brings up an interesting question. Do you think a psychotomimetic dose is required to see gamma alterations, or would a subpsychotic dose be all right?

Didier Pinault
Kevin/Peter, testing ketamine in monkeys should be the next experiment to do. Yes, why has this not been tried before?

Peter Uhlhaas
Didier, I am not sure.

Kevin Spencer
Derek, I don't know...interesting question.

Hakon Heimer
Any thoughts on the MAM model? Tony Grace had some data that I don't recall well at SfN looking at PV neurons (with M. Behrens) and I believe, gamma oscillations in the MAM model.

Kevin Spencer
Hakon, yes, I saw the data from the Grace lab at ACNP. Interesting stuff. Nice to see that there is a convergence between that model and the ketamine one. Well, everybody, I think I am going to have to log out. This has been a lot of fun. It would be great to do a synchrony sequel.

Peter Uhlhaas
Kevin, yes, that would be cool. We should do this every week!

Didier Pinault
Thanks a lot to all for these interesting discussions.

Kevin Spencer
Peter, that would be fun!

Didier Pinault
Bye-bye, everyone.

Peter Uhlhaas
Bye, Didier!

Kevin Spencer
Bye, Didier.

John Gruner
Goodbye also and thanks.

Derek Fisher
Thanks, Kevin and Peter (and Hakon for moderating). Very enjoyable! Bye!

Hakon Heimer
Thanks to all who have joined us.

Carlos Cortes
Hasta pronto!!

Peter Uhlhaas
Hakon, thank you also! It was really great!

Kevin Spencer
Thanks to everyone who logged in today, and especially to Hakon, Nico, and the SRF people!

Comments on Online Discussion
Comment by:  Didier Pinault
Submitted 12 December 2008
Posted 13 December 2008

Disruption of the signal-to-noise ratio in schizophrenia?
Brain rhythms are biomarkers of physiological and pathological, resting and active states. Peter Uhlhaas and Kevin Spencer have given extensive evidence relative to schizophrenia. They have further raised an important issue to discuss about the possible role of synchronized oscillations in the pathophysiology of such complex psychiatric disorder. To better understand the diverse alterations in rhythms observed in schizophrenic persons (Whittington, 2008), one strategy would be to apprehend the link between task-related synchronized oscillations and the associated state-related oscillations. The former oscillations are here considered as the signal whereas the latter as contributing to the basal activity or background noise.

From the findings obtained so far, it appears that the relation between gamma frequency (30-80 Hz) oscillations and schizophrenic symptoms is a conflicting field. For instance, increases and decreases in gamma frequency oscillations have been reported in schizophrenic patients and animal models for psychosis (Hermann and Demiralp, 2005). These paradoxical findings likely depend, among other things, on the protocol used, on the cortical region of interest, on the symptoms, and on the brain states.

What do we mean by “synchronized neuronal oscillations in the pathophysiology of schizophrenia”? One may first think about function-related synchrony of fast (gamma, beta) oscillations in many cortical areas. In healthy subjects, synchrony supports the dynamics of thought, cognitive and action processes, whereas it is somehow disrupted in schizophrenic patients (Spencer et al., 2003; Uhlhaas et al., 2006). Others may think about state-dependent synchronies of fast and slower oscillations (changes in basal brain rhythmic activities) (Stephane et al., 2008; Sponheim et al., 2000; Kessler and Kling, 1991). The state and/or the amount of EEG waves may also change with treatments (Hong et al., 2004). So what is the link between function (e.g., cognition)-related and the associated state-related synchronies, especially at fast frequency bands?

This is, I think, an important issue since the state of cortical-related networks in individuals changes from time to time, spatially and temporally, and changes may be different or more dramatic in schizophrenic patients, who suffer from changing psychomotor, affective and emotional disorders, etc. The background slow and fast rhythms should change accordingly in frequency and power (in short, = EEG noise). This could be discussed further in relation to wake and sleep stages and to the administered treatment.

In the following, I am going to talk principally on gamma frequency (30-80 Hz) oscillations, in particular on the spontaneously occurring or baseline gamma noise in rodent.

A single non-anesthetic injection of ketamine, a non-competitive NMDA receptor (NMDAr) antagonist, induces cognitive impairment and psychosis and aggravates schizophrenia symptoms (Adler et al., 1998; Boeijinga et al., 2007); Hetem et al., 2008; Honey et al., 2003; Krystal et al., 1994; Newcomer et al., 1999; Stone et al., 2008). We have demonstrated in the rat that a single injection of ketamine, at a similar dose, induces a brain state characterized by an increase in the power and in the intrinsic frequency of ongoing gamma oscillations . This indicates that the normal, low-amplitude gamma noise (co-existent with other rhythms), which reflects a given state, is abnormally enhanced, that is, metamorphosed into an aberrant, high-amplitude gamma noise, which would reflect a psychotic-like state. Moreover, this aberrant gamma noise is associated with an abnormal and ataxic-like behavior (Pinault, 2008). Such aberrant gamma noise has been recorded in humans during somatic and visual hallucinations (e.g., (Baldeweg et al., 1998; Becker et al., 2008; Spencer et al., 2004).

Therefore, it was important to test whether or not, in our acute rodent ketamine model, non-competitive NMDAr antagonist-induced aberrant cortical gamma oscillations were caused by the brain state that is associated with the psychotic-like behavior (Tolmacheva et al., in preparation). In lightly or deeply anesthetized rats, ketamine dramatically increases the gamma power especially during desynchronized states. Ketamine-induced persistent aberrant gamma oscillations were not dependent on the brain state associated with the abnormal behavior and on conscious/unconscious sensorimotor processing (Tolmacheva et al., in preparation). These findings suggest that, in rodent, NMDAr-related persistent gamma hypersynchrony is an aberrant network noise, the electrophysiological correlate of a psychotic-like brain state. In humans, this aberrant noise would cause cognitive dysfunction, acute psychosis and exacerbate schizophrenia symptoms. The findings we have obtained under anesthesia are somehow in line with clinical data reporting schizophrenic patients displaying psychotic states day and night (Keshavan et al., 1995). It is worth mentioning that previous studies have reported that the power of gamma oscillations recorded under anesthesia is significantly greater than that measured in the awaked basal state (Vanderwolf, 2000).

Therefore, it is tempting to predict that, in schizophrenic patients, such an abnormal enhanced network gamma noise would drown the transient gamma responses, especially the cognition-related coherent gamma synchrony. In other words, such aberrant noise would decrease or annihilate the signal-to-noise of task-related transient gamma synchronies. So if the state-dependent, aberrant gamma noise disrupts synchronized gamma oscillations, which are thought to contribute to higher-order brain operations (Uhlhaas and Singer, 2006), it is tempting to predict that persistent gamma hyperactivity might cause cognitive dysfunction and exacerbate symptoms in schizophrenic patients.

The possible mechanisms underlying NMDAr antagonist-induced gamma hypersynchrony in rodents’ intact circuits are unknown. The current literature suggests that gamma oscillations may be a biomarker of the collective activity of networks of GABAergic interneurons (Bartos et al., 2007); Whittington et al., 1995). A recent comprehensive review discusses the possible mechanisms underlying NMDAr hypofunction ((A HREF="/pap/annotation.asp?powID=118968">Roopun et al., 2008). Although the most likely hypothesis would be a decreased excitation of GABAergic parvalvumin-positive interneurons, duration and frequency of hippocampal gamma oscillations are increased in parvalbumin/NR1 knockout mice (Korotkova et al., FENS meeting 2008).

It is further worth mentioning that corticothalamic systems are composed of neurons with pacemaker properties in the gamma frequency band (Llinas et al., 1991; Nunez et al., 1992; Pinault and Deschênes, 1992; Steriade et al., 1993), which could, in a state-dependent manner, interfere with oscillating cortical networks.



References:
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Baldeweg,T., Spence,S., Hirsch,S.R. and Gruzelier,J., 1998. Gamma-band electroencephalographic oscillations in a patient with somatic hallucinations. Lancet. 352, 620-621. Abstract

Bartos,M., Vida,I. and Jonas,P., 2007. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci. 8, 45-56. Abstract

Becker,C., Gramann,K., Muller,H.J. and Elliott,M.A., 2008. Electrophysiological correlates of flicker-induced color hallucinations. Conscious Cogn. In press. Abstract

Boeijinga,P.H., Soufflet,L., Santoro,F. and Luthringer,R., 2007. Ketamine effects on CNS responses assessed with MEG/EEG in a passive auditory sensory-gating paradigm: an attempt for modelling some symptoms of psychosis in man. J Psychopharmacol. 21, 321-337. Abstract

Herrmann,C.S. and Demiralp,T., 2005. Human EEG gamma oscillations in neuropsychiatric disorders. Clin Neurophysiol. 116, 2719-2733. Abstract

Hetem,L.A., Danion,J.M., Diemunsch,P. and Brandt,C., 2000. Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers. Psychopharmacology (Berl). 152, 283-288. Abstract

Honey,R.A., Turner,D.C., Honey,G.D., Sharar,S.R., Kumaran,D., Pomarol-Clotet,E., McKenna,P., Sahakian,B.J., Robbins,T.W. and Fletcher,P.C., 2003. Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory. Neuropsychopharmacology. 28, 2037-2044. Abstract

Hong,L.E., Summerfelt,A., McMahon,R., Adami,H., Francis,G., Elliott,A., Buchanan,R.W. and Thaker,G.K., 2004. Evoked gamma band synchronization and the liability for schizophrenia. Schizophr Res. 70, 293-302. Abstract

Keshavan,M.S., Miewald,J., Haas,G., Sweeney,J., Ganguli,R. and Reynolds,C.F., 1995. Slow-wave sleep and symptomatology in schizophrenia and related psychotic disorders. J Psychiatr Res. 29, 303-314. Abstract

Kessler,C. and Kling,A., 1991. EEG power variation in schizophrenic subgroups: effects of emotionally salient stimuli. Biol Psychiatry. 30, 335-348. Abstract

Krystal,J.H., Karper,L.P., Seibyl,J.P., Freeman,G.K., Delaney,R., Bremner,J.D., Heninger,G.R., Bowers,M.B., Jr. and Charney,D.S., 1994. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 51, 199-214. Abstract

Llinas,R.R., Grace,A.A. and Yarom,Y., 1991. In vitro neurons in mammalian cortical layer 4 exhibit intrinsic oscillatory activity in the 10- to 50-Hz frequency range. Proc Natl Acad Sci U S A. 88, 897-901. Abstract

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Pinault,D. and Deschênes,M., 1992. Voltage-dependent 40-Hz oscillations in rat reticular thalamic neurons in vivo. Neuroscience. 51, 245-258. Abstract

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View all comments by Didier PinaultComment by:  Georg Winterer (Disclosure)
Submitted 10 January 2011
Posted 10 January 2011

When my former group and I in Berlin, Germany, started in the middle of the 1990s to look into synchronization in schizophrenia, we explicitly decided not to analyze EEG γ (back then computational resources were still limited and you had to make decisions about what you really wanted to analyze). At that time, the work of Freeman and Malsburg in the 1980s and of Singer in the 1990s on γ oscillations (binding) was well known to us. Even so, we made this decision simply because we felt that this high-frequency component is too prone to (muscle) artifacts. (Anyone who has analyzed several thousands of clinical EEGs of schizophrenia patients knows what I am talking about.) In addition, there were a number of other animal and human studies around that clearly suggested that low-frequency synchrony could also be involved in binding (see Winterer and McCarley, 2011).

Although we were first in demonstrating abnormal low-frequency synchrony (termed signal-to-noise ratio) in schizophrenia (. Winterer et al., 2000; 2004; Winterer and Weinberger, 2004; Winterer et al., 2006a; 2006b; 2006c; Rolls et al., 2008), we did not attract the same attention by the research community as did those papers reporting on γ in schizophrenia. I guess it has something to do with trying to create a wave instead of surfing on a wave. Even so, we did a comparison across different frequency bands (auditory oddball task conditions). In this comparison, γ gave the poorest results. Taking into account the artifact problem, and admittedly neglecting the fact that we did not run analogous comparisons in other task conditions, it seems clear to me that synchronization is disturbed across a broad range of frequencies (more or less depending on task conditions) and that γ is not exceptional in this regard. I am quite certain that the future will prove me right.

References:

Winterer, G., Ziller, M., Dorn, H., Frick, K., Wuebben, Y., Mulert, C., Herrmann, W.M., Coppola, R. (2000) Schizophrenia: Reduced signal-to-noise ratio and impaired phase-locking during information processing Clin. Neurophysiol. 111:837-849. Abstract

Winterer, G., Coppola, R., Goldberg, T.E., Egan, M.F., Jones, D.W., Sanchez, C.E., Weinberger, D.R. (2004) Prefrontal broadband noise, working memory & genetic risk for schizophrenia. Am. J. Psychiatry 161(3):490-500. Abstract

Winterer, G., Weinberger, D.R. (2004) Schizophrenia: Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends in Neurosci. 27:683-690. Abstract

Winterer, G., Musso, F., Beckmann, C., Mattay, V., Egan, M.F., Jones, D.W., Callicott, J.H., Coppola, R., Weinberger, D.R. (2006a) Instability of prefrontal signal processing in schizophrenia – An event-related fMRI study. Am J Psychiatry. 2006 Nov;163(11):1960-8. Abstract

Winterer, G., Egan, M.F., Kolachana, B.S., Goldberg, T.E., Coppola, R., Straub, R., Weinberger, D.R. (2006b) Prefrontal noise and COMT genotype pattern in schizophrenia. Biol. Psychiatry 60:578-84. Abstract

Winterer, G., Musso, F., Vucurevic, G., Gallinat, J., Seker, B., Stoeter, P., Konrad, A., Dahmen, N., Weinberger, D.R. (2006c) COMT-genotype predicts BOLD signal and noise characteristics in prefrontal circuits. NeuroImage 32:1722-32. Abstract

Winterer, G., McCarley, R. (2010) Electrophysiology of Schizophrenia. In: Weinberger, D.R., Harrison, P.J. (Eds.), Schizophrenia. Blackwell Publishing, Oxford (2011).

Rolls, E.T., Loh, M., Deco, G., Winterer, G. (2008) Schizophrenia and computational models of dopamine modulation in the prefrontal cortex. Nature Reviews Neuroscience 9:696-709. Abstract

View all comments by Georg Winterer