This is a quick outline of what we are going to cover today.  We’re going to start out with some background of the illness and then proceed quickly to highlighting the importance of cognition as was pointed out to the recovery process in schizophrenia, and then cover briefly the main domains that are seemingly affected in the illness, and then give you a brief introduction to what oscillations are and how neurons in the brain oscillate together and what kind of function that might serve.  And then go on to explore how some of these same mechanisms are actually disturbed in the illness. And then finally try to bring this all together and talk about how all this knowledge might inform the development of novel therapies for cognitive impairment in the illness.

Okay, so schizophrenia is a severe, chronic disabling mental disorder marked by delusions, hallucinations, disorganization and problems with motivation and expression of emotions. It affects approximately 1% of the population worldwide and it clearly has a very important public health impact as evidenced by 10% of recipients of permanent disability in the U.S. having a diagnosis of schizophrenia.  As well there are estimates of the direct and indirect costs of the illness amounting to approximately $65 billion in the U.S. on an annual basis. That’s actually a somewhat dated number, so it’s probably much more at this point. 

So how has the therapeutic approaches, I think therapeutic approaches evolved over time, so historically somewhat unfortunately the prevailing view has been really influenced by a very prominent psychiatrist, Emil Kraepelin, who was prominent around the 1900 and that kind of period, and his view was that schizophrenia was characterized by really a progressive and inevitable decline.  Another psychiatrist around the same time, Eugene Bleuler had a somewhat different view and a somewhat more optimistic view.  He thought that while there were typically some aspects of the illness that would always stay with patients suffering from the illness, that there was still a lot more potential for recovery and improvement in symptoms than was thought by Emil Kraepelin.  And this more optimistic view has really informed more recent thinking about therapeutic approaches to schizophrenia, which really focus on a more positive outlook and focus on a recovery process. 

So what do I mean by recovery then? Well, traditionally one thinks of sustained symptom improvement, so those typical symptoms like delusions, hallucinations, disorganization can one reduce those symptoms in a sustained way? And that’s been the more traditional view.  More recently there has been much greater focus on functional outcomes, so our individuals with the illness functioning well in the community, do they have good role functioning, good social adjustment? And I think that is typically what’s considered much more important by patients and their families, these are the things that really matter to leading sort of fulfilling and productive lives.

Okay, so with functional outcome being so important, it’s natural to ask then what might be a good predictor of good outcomes?  And as alluded to by both Drs. Chengupon and Frankel, cognition is you know since the ‘90s has been recognized as being very critical to functional outcome. So there was a seminal study by Michael Green in 1996 which is a review of a number of other studies that looked at predictions of functional outcomes, so he reviewed some studies that looked at community functioning, social problem solving and psychosocial skill acquisition, and asked the question you know can cognition predict the outcome and contrast that with the clinical predictors.  And to give you the simple short version of the answer, if we can get to it, so the results basically came out as the cognitive measures and in this instance measures that tap things like attention and memory processes seem to be the best predictors of functional outcomes.  A somewhat surprising and non-intuitive result was the negative findings of psychotic symptoms not significantly associated with any of the outcome measures. So one would think that someone suffering from severe delusions and hallucinations might not do so well long term; and that that is obviously very intuitive and natural assumption, but it turns out when you actually look at the data a better predictor is looking at their cognitive status not their clinical status.

So if we have established that cognition is so important to longer term functional outcomes, a natural next question then is can we do anything to improve it?  So I’ve outlined some basic steps here that would be necessary for that kind of process.  So the first not so simple thing is obviously to identify what those specific cognitive impairments are and what are the underlying associated brain disturbances.  If you get some sort of understanding of that, then that can inform the development of new therapeutic targets and interventions, whether they be cognitive processes that you’ve identified as being impaired, or molecular targets as identified by neurobiological studies. And then once you have some potential interventions one can then test those and measure the therapeutic efficacy with your refined cognitive and neuroimaging measures. 

Okay, so there’s been decades and decades of research in cognition and schizophrenia, and this has culminated more recently in these collaborative efforts that have been supported by the national funding agency, NIH.  The first sort of collaboration was the so-called MATRICS, which stands for Measurement and Treatment Research to Improve Cognition in Schizophrenia.  So this was a collaboration between academia, industry, the FDA and federal funding agencies as a concerted effort to try to identify the key domains of cognitive impairment in the illness, and to think in a sort of sophisticated way about how best to measure impairment in those domains, and then potentially to measure improvements with new therapeutic interventions.  The next stage with CNTRICS, which is a kind of variant on MATRICS, the Cognition Neuroscience Treatment Research to Improve Cognition Schizophrenia really has similar aims, but brought in the tools and insights from cognitive psychology and newer neuroimaging techniques to address those same kind of questions.   

So as you can see here, the kinds of domains that were identified by both those kinds of efforts are very similar, there’s a lot of overlap.  I’m going to highlight the first one in each of these lists, working memory, because that’s what we are going to be focusing on mostly for the rest of the talk today. 

So working memory describes the active maintenance and manipulation of information over a very short period of time, sort of like a mental blackboard. So if you are remembering a phone number while you run to the phone to try to dial it before you forget, you are using your working memory to hold those numbers in mind. If you are doing mental arithmetic, again you are holding numbers in mind and you are manipulating them, you are again using your working memory.  So it’s obviously useful in those kind of more simple tasks, but it can also hold representations of higher order, more abstract information that can help guide goal directed behavior such as problem solving, reasoning and planning.

Okay, just to give you an example about how some of these kinds of processes are tested I’m going to introduce the so-called preparing to overcome prepotency or the POP task, and if you can wake up a little because I’m going to get a little bit of audience participation here in a second.  So this task involves – okay, the presentation of these colored boxes followed by arrow stimuli, which are arrows pointing to the right or to the left of the screen. So these are presented on a computer and subjects are asked to press either a right button or a left button. 

The key here is that for green squares the subject knows to press the button in the same direction of the arrow, if on the other hand there is a red square, you are supposed to press the button in the opposite direction that the arrow is pointing.  Okay?  So here is the audience participation component. Did you all get that?  I’m going to ask you to instead of, obviously you don’t have buttons in front of you but I’m going to ask you to raise your hand, either the right hand or the left hand, okay?  So if you see a green square you are going to see an arrow that follows it and for that condition you are going to raise the hand that goes in the same direction as that arrow that points, and then for the red square it’s going to be the opposite, you are going in the opposite direction, raise your other hand. So for instance for this arrow, you would raise your left hand. Okay, everybody got that?  All right.

And the key is these, these trials typically proceed at a pretty quick rate.  They are not going to give you minutes or hours to cogitate on this, you really have to respond as quickly as possible.  And don’t be afraid of what your neighbors think, I’m the only one looking at your performance right now, okay?  All right, are you ready?  Okay, good.  Little quicker now.  Okay, don’t raise your hand yet, you need to wait for the arrow. Okay, there you go.  Okay, very good.  Okay. I think it’s kind of advancing on its own sometimes. 

So what did you all think of each of those trials?  Did they kind of feel similar or was there something a little different about them?  Who would say the green trial is easier, put up your hand? Who would say the red trial is easier, put up your hand?  Okay, it’s a small minority.  So in most subjects the red trial is indeed more difficult and that’s because the task is exploiting a natural tendency to want to respond in the same direction as the arrow and so in the red trial you are having to actually keep actively in mind this representation to go opposite, because that’s not the natural thing to do. 

And if you look at the performance of most subjects, healthy controls will show this pattern of making more errors in the red condition compared to the green condition, and patients have the same pattern but in a more marked way, so that there is an actual amplified difference for the schizophrenia patients. And that’s possibly due to the well known working memory impairment in the illness, patients seem to have some more difficulty in maintaining this act of task representation so that they respond appropriately to the upcoming arrow.  And one can see that that kind of impairment might then impact your day to day activities, because that’s very important, you have to know the context to be able to respond appropriately to an upcoming  stimulus. 

And if you ask subjects to do a neuroimaging version of this task we see that key brain areas that are known to be important for working memory such as the dorsolateral prefrontal cortex modulate in the expected ways, the red condition has a bigger modulation kind of in preparation for the upcoming arrow stimulus in comparison with the green condition; whereas the schizophrenia patients don’t seem to be able to recruit that kind of same modulation in the same way.

Okay, I mentioned the dorsolateral prefrontal cortex, so this is known to be very critical for a working memory and in schizophrenia patients both in chronic medicated patients as well as first episode medication-naïve patients there have been a number of studies that indicate that there are these dorsolateral prefrontal cortex disturbances that are found, disturbances in association with working memory impairment in the illness. 

Okay, and just to summarize then findings in this field, these DLPFC disturbances are present in both chronic and first episode patients. They are, these disturbances are found between psychotic episodes and as mentioned earlier, also in first degree relatives of schizophrenia patients.  This seems – these set of findings really to seem to point to working memory and associated DLPFC disturbances being a really core feature of the illness.  So the question is then how can we understand the underlying mechanisms of those disturbances?  And the kinds of data that I’m going to show you now are from EEG studies which can get at the physiology of the prefrontal cortex in a little bit more of a refined way as compared with standard FMRI techniques. 

So just as a bit of background I’m going to try to go through how do we get from a brain to getting a typical data set that kind of looks like that with an EEG experiment? So just to show you a few quick pictures to walk you through, here is the brain, you could take a cross-section of the brain, for instance at this red line we see this, at the cortex here, that is that sort of thin rim of tissue that’s outside on the outer surface of the brain, bordering this white matter area, if you magnify this cortex you see this very dense array of cells, comprised, the visible ones are mostly excitatory cells, but in there, there is a lot of inhibitory cells too. And as Gordon Frankel outlined, there is both input and output aspects of these neurons. The input goes in here, the message, the signal travels along this cable like structure and then the output is here.  Now if you have an arrangement of these type of neurons with a specific geometry like this, you can actually measure the signal that they are outputting. 

And just to outline the, the basic point of what we are measuring in EEG then you need three kind of requirements for you to be able to detect a signal at the scalp with the EEG recordings.  So the first is that you need lots and lots of neurons to fire.  Each individual neuron sends out a very, very tiny signal, so as a result to be able to measure it at the scalp you need lots and lots of neurons to be doing the same thing. As I mentioned geometry is important, fortunately the main excitatory cells, the paramental cells, many of them are pointing in the same direction and towards the, the cortical surface which we can then, the signals summate and we can access that signal through our EEG recordings.  And then very importantly, especially for the purpose of this talk, is that last requirement, that they fire all at the same time; so if you have lots of neurons firing all pointing the same direction and firing at the same time, then we can detect some of that signal at the cortical surface.

Okay, so here is a top view of a person’s head with the nodes and the electrode array here. This is just to demonstrate that when you measure EEG signals very often we see evidence of rhythmic oscillations, rhythmic activity, and that rhythm can go slow, very fast or at intermediate frequencies. And you can do analyses to break the signal down and discover exactly at what frequency you see that, that signal oscillating at.

Okay, and how do we get a whole bunch of neurons to oscillate like that then?  Well, there is a couple of very basic mechanisms. One is using a pacemaker mechanism that’s very much like in your heart where you have a pacemaker and it basically sets the rhythm for the whole heart; well there are similar types of neurons in our brains that serve such a pacemaker role and can sort of entrain other neurons to, to kind of oscillate or beat at the same frequency.  That pacemaker maybe can be remote or local, but most cognitive and perceptual processes are thought to be observed by oscillations that are due to just local interactions between neurons themselves without some external pacemaker driving the process. 

So if this seems a little bit abstract to you I’m going to try to make it more concrete by the next stage of audience participation. We are going to start off a little easy, we’ll start off with the remote pacemaker scenario, and what I’m basically going to be asking you to do is to be – each of you will be a single neuron and I’m going to be the remote pacemaker.  So you can warm up your arms and shake them out. I’m going to ask you to basically clap to my rhythm. I’m going to clap, just regular clapping and if you could try to copy me as best you can, and so we are all going to clap in the same regular rhythm. Okay, are you ready? 

Okay, very good.  And thank you very much.  So that’s a very simple demonstration of how one can get oscillations, that’s not – that actually does exist in the brain, but that’s perhaps less interesting for the types of cognitive impairments that we’re seeing in schizophrenia.  So the more interesting mechanism is that network mechanism, which is a bit more complicated and I’m going to ask you to do something similar. And frankly I have no idea whether this will work because I  haven’t tried this out before.  But I’m going to ask you to each look at your neighbors and listen and look and try to clap in unison with them.  I think initially we are not going to start off all the same but if this all works out well I’ll be clapping the same rhythm again. And just to sort of set the overall rate I’m going to ask you to clap approximately this quickly again. 

Okay, so stop, stop, stop, okay. That’s the overall rhythm. So I’m just going to ask you now to start on your own when I say go and we’ll see whether we can as a group entrain each other in this sort of group oscillation.  Are you ready?  Okay, go.

Okay, that’s – we are collectively a very good brain apparently. That was pretty quick.  Yeah, so obviously this analogy is very rough, but similar things are happening in the brain where both on the input and output end there is mechanisms for monitoring what the other neurons around you are doing and then you in turn influence other neurons, and then as a network you can try to sustain that kind of synchronous oscillations, i.e. oscillations that are happening at the same time across a whole network.

There’s been a lot of work in trying to understand the mechanisms of synchrony, how that arises, E stands for excitatory, I stands for inhibitory, there’s a lot of different arrangements you can have and a lot of smart theoreticians are trying to figure out the mechanisms about how oscillations might arise in these different situations.  For our purposes it’s just important to note that along with excitatory, inhibitory cells are also very important to this process. 

Okay, so to answer the question what might oscillations actually be good for? Well, this was first kind of couched to the question of the binding problem. This is a question first posed in the visual system where there is lots of different features one can notice about your visual scenery, like color, motion, texture, form, etc; or in this case to make a more concrete example, a picture of for instance of your grandmother.  There’s a lot of different features that you can see in your grandmother for instance, they type of glasses she might wear, the type of hairstyle she might have, the particular wrinkle pattern of her eyebrows and forehead and so forth; but the interesting thing is that there doesn’t seem to be a part in the brain where this all comes together. There is no so-called grandmother cell where all these features might converge and create the image of your grandmother.  So how might that coherent perception actually arrive in the brain?  Well, the thought is that if there’s different brain areas that might encode each of these different features, if they are temporally active at the same time that that’s sufficient for creating these coherent percepts.  So these kind  of oscillations happening at the same time across a network are one way to sort of bind all these different features to, to say that’s my grandmother.

Okay, so the kind of idea as far as typically ways to entrain the appropriate network in the service of cognition or perception really seem to catch fire and spread to other types of cognitive processes and perceptual processes. And in particular, very fast frequency oscillations like those in the gamma band range which describes 30 to 80 hertz, hertz is just how many times you are oscillating per second, so there’s been a lot of studies both in animals and humans and both perception and cognition that outline the utility of these kind of oscillations in serving cognitive perceptual processes.

And this is a map of connections across the brain. There’s obviously lots of them and as I said, there doesn’t seem to be any one place that everything comes together. So this kind of way of entraining different networks all at the same time may be one way to say you know connect this node to this node to this node without actually having them all converge in one place. 

So I talked a little bit about the basic mechanisms of oscillations, what might this actually mean to schizophrenia?  Well, in schizophrenia there are some very well replicated findings of disturbances in the GABA system. GABA is the main inhibitory neurotransmitter in the brain and as I alluded to before, in addition it’s actually critical for making these oscillations work and Gordon Frankel outlined nicely some of the changes, I’m not going into the details here, but suffice it to say these very well replicated findings could very well lead to disturbances in oscillations and the associated cognitive impairment.

So this is just to point out that there is a lot of different studies that measure different aspects of oscillations in the brain, particularly in the gamma range, that’s high frequency oscillations. I’m not going to go into the, the specifics of the different types of oscillations but the – suffice it to say that this seems to be a consensus finding that across the board whether you look at perception or cognition that gamma in association with those processes is disturbed in, in the illness.

I mentioned working memory before, I’m going to now jump into how these oscillations might actually explain some of the working memory disturbances that are observed in the illness.  Okay, so in our first study of gamma disturbances in schizophrenia we asked the question well, if gamma oscillations are indeed so important as a potential mechanism for entraining a network of neurons in the service of cognition in the control group we should see evidence that gamma oscillations increase when we need more working memory resources. And then because of the known neurobiological disturbances in schizophrenia that might lead to problems with sustaining these same kind of oscillations we would hypothesize that we don’t see that same kind of modulation. 

So again, this is that POP test that we’ve all participated in now.  And the basic findings are that indeed with healthy controls that these bright red spots are evidence that you have increases in gamma oscillations in that higher working memory load condition, that red square condition when you compare it to the green square condition. Whereas in chronic medicated schizophrenia patients you don’t see that same type of modulation.

And this is just to demonstrate that because the previous study was in chronic medicated schizophrenia patients, one has to always think about the possible confound of medication effects and of illness chronicity.  So in a cohort of first episode medication-naïve subjects we see that this analysis is slightly differently, but showing basically gamma activity across the scalp over time in the front and back of the head so during that same delay period we see evidence of the expected modulation gamma whereas in the patient group we don’t.  And this is just a comparison between groups.  So this seems to indicate that it’s not simply a medication effect. 

Okay, and this is the results of a study that I did in collaboration with Gordon Frankel, and the same subjects, we had PET scans and the EG data collected using that same task, and this just demonstrates that, and this is just healthy controls, that there is a good correlation between the degree of ability to release GABA and the ability to sustain gamma oscillations.  So the thought that these, these GABA related disturbances in the illness might lead to the observed oscillatory disturbances and cognitive impairments in the illness is well supported by this, that there is indeed a relationship between GABA and gamma.

Okay, so how might we bring this all together and think about how we can develop new treatments for say improving oscillations and therefore the cognitive impairments observed in the illness?  So we have the clinical entity, and talked a little bit about the cognitive and brain disturbances and we can use the tools of cognitive neuroscience like the imaging modalities, EEG, FMRI and so forth.  You can link this to the underlying neurobiological disturbances such as those observed in the GABA system.  And then hopefully be able to come up with novel treatments. And as I mentioned before, if we are able to come up with new targets, new treatment we can then use these same measures to assess how are those, how effective those novel treatments are.

So for the rest of the talk I’m just going to outline one sort of proof of concept study that we’ve done in line with this kind of approach.  So as Gordon Frankel mentioned, we are doing relatively poorly in the field of psychiatry as far as coming up with novel mechanisms for treating schizophrenia.  If you compare depression and schizophrenia to say heart disease, which has had much more success at developing mechanistically new medications, we are doing pretty poorly in our field. Not for lack of trying recently, but as far as actual medications in clinical use we are doing pretty poorly.

So just to give an example of the kind of approach that we might take, we have this potential molecular target that could be related to the oscillatory and working memory disturbances in the illness. We have these GABA disturbances which can be interpreted basically as a lack of adequate GABA neurotransmission.  If we can find a way to augment and amplify that signal perhaps we can remediate the oscillatory disturbances and in turn remediate some of the cognitive impairments. 

So our small proof of concept study involved a, a compound from Merck, MK0777, it’s a medication that acts at the benzodiazepine receptor, so it’s benzodiazepine-like, but because it has specificity to a certain type of receptor it doesn’t cause sedation, sedation is mediated by the other, another subtype.  So for all those – all of you that have had experience with benzodiazepines, you might naturally ask well how could you take a benzo to improve cognition?  Well, that’s the reason why, it has very specific affinity for this receptor subtype that doesn’t mediate sedation.

But the basic function then is that this medication would not directly stimulate the GABA receptor but like benzodiazepines increase the activity across the channel when GABA hits that receptor.  So it’s basically increasing the gain or the sort of potency that GABA may have when it hits the, the receptor. And that’s a critical feature actually because when you are concerned about timing of neuro impulses you want to be able to preserve that timing if that’s important for sub-serving the cognitive processes. If you have something that just sort of nonspecifically stimulates the GABA receptor all the time you are not going to get that timing characteristic preserved.

Okay, so this study involved chronic medicated schizophrenia patients in a double blind placebo control fashion, 9 were on the active drug and 6 on placebo. It was a 4 week trial and the outcome measures were the neuropsychological battery, the RBANS and then cognitive tasks, the POP which I’ve introduced, the N-back which Gordon Frankel introduced and another working memory type task called the AX-CPT.  And then just in the POP task we were able to acquire some EEG data.

Okay, and the basic results, the RBANS I should note really didn’t distinguish well between the active treatment and the placebo group. There was one subscale, I believe it was delayed memory that did show some between group differences in favor of the treatment group, but the summary measure actually didn’t come out significant.  On the other hand, if you look at the specific cognitive tasks, I won’t go through all the details of this table, but basically it’s outlining the results of the AX-CPT task, the N-back and the POP task and comparing the placebo to the active drug group. The numbers here basically show whether you have a significant between group effect, and positive numbers mean that there is a beneficial effect of the medication and negative numbers would mean the opposite effect. And as you can see, most of these measures really indicate a relatively strong effect of the medication in a positive way. There was just one exception down here that was negative, and the magnitude of these numbers are actually pretty surprising, anything close to 1 really means that there is quite a big effect.

And I mentioned that we were able to gather EEG data in just one of the tasks, the POP task, and this is again comparing the active drug to the placebo group and doing the subtraction. And although the T test, that’s the statistical way of saying whether something had a significant effect or not, none of this actually came out significant but just the overall mean difference between the groups had some indication that maybe the drug was actually doing something beneficial for the gamma oscillations.

Okay, so just to summarize the findings of this study then. So there were impairments in working memory in association with the disturbances in DLPSD function in schizophrenia.  So these may be related to disturbances in gamma oscillations and GABA neurotransmissions, and what the study showed just as a preliminary kind of study was to show that correcting the disturbances in GABA inhibition might actually help to restore gamma oscillations and working memory function. 

This schematic circuit diagram is just to point out that while myself and colleagues are very interested in the GABA system there are clearly many other neurotransmitters such as glutamate and dopamine neurotransmitter systems that would be necessary to be intact to make this whole thing work out. And so there is – there is a lot of work on this just to point out on other neurotransmitter systems, both for improving oscillations but other aspects of neuro network functioning.

Okay, so just some future directions noted here.  I started off this talk talking about long term functional outcome. There is growing evidence that early detection and intervention in the illness can be very beneficial.  Obviously the kind of treatments that we can think of have to be safe and I guess even safer for the earlier and earlier stages of the illness.  So I think the state-of-the-art right now is not so advanced that we can as a rule give the antipsychotics to people that don’t quite express the full expression of the illness but the science is trying to move in that direction, to try to better identify who might actually convert to the full disorder and who might not, so that you can then safely target the people for treatment. 

There is a, as I noted before, a focus on cognitive remediation as a critical component of recovery and this can obviously involve both pharmacologic approaches as I’ve outlined here, but also nonpharmacologic more psychosocially and cognitively oriented cognitive rehabilitation. 

As I pointed out before, novel therapeutics might have a benefit of an improved cost benefit ratio, specifying earlier treatment. As most of you know our current treatments while having great benefit also have a lot of potential sometimes very serious side effects, and that really makes it hard to justify that if you are not quite sure that someone say schizophrenia or some related psychotic disorder that it’s not really justifiable that you start that person on a medication because of the potential risks.  If novel therapeutics on the other hand have potential benefit without the same kinds of risk involved, that may justify moving treatment to earlier in the detection and illness course stage.

One kind of interesting point may be that because of our focus on functional outcome we might be willing actually to accept that if some novel therapeutic intervention is able to bring about substantial improvement in functional outcome that might be accomplished while you don’t get perfection on the clinical symptom side. So I think probably many of you know that there are actually a lot of patients with schizophrenia that are functioning relatively well, have jobs, have good relationships and so forth all the while having some residual set of symptoms, maybe a little bit of paranoia here and there, hearing voices every now and then, and I would argue that that’s really more fulfilling to the patients and families and as a society is sort of tough question may be the more important aspect of our treatment approach.

Okay, so just to conclude then with a general summary then, to highlight the main points, I want to try to point out that cognition is one of the strongest predictors of functional outcome, that working memory is one of the core deficits in the illness, that the disturbances in the ability to – for neurons to coordinate their activity through these kind of oscillations may underlie working memory and other deficits in schizophrenia, and that the recovery oriented treatment I think will include both pharmacologic and nonpharmacologic approaches to cognitive remediation as a way of improving functional outcomes in the long term. Thank you.

We take about 5 minutes of questions before we break for coffee. 

Q:        If neurons and oscillations are misaligned can they be realigned by sensor stimuli outside the brain such as music or movement or other external mental stimulation?

Okay, so I think the question was if the organization of neuronal activity through these oscillations is not working optimally can some sort of external stimulation sort of reorient an activity and improve the oscillations.  As far as I know I don’t know that there have been any systematic studies of things like music or other sorts of more complex stimuli in improving these kind of oscillations.  There, there are some types of task paradigms that use external auditory or visual stimuli that themselves are oscillating at these high frequencies. Those type of studies seem to show that similar to the data that I showed here, healthy controls seem to be able to entrain their neural activity to the frequency of those stimuli, whereas schizophrenia patients have some more difficulty in keeping up that sort of high frequency oscillation that the stimulus is going at.  So I guess rather than being an intervention that might improve oscillations for the illness, we have at least at the very sort of low, low perceptual level a way of measuring whether oscillations are being improved.  You know, so you know I don’t know if that answers your question, but as far as I know there is no actual interventions that can improve oscillations through external stimulus.

I think it’s an interesting idea given that we are beginning of think of novel therapeutics. I think nobody would have thought years ago that therapy would have worked for depression, you know. And so I guess we are just beginning to think outside the box and outside of traditional medicine.

Q:        My question is with cognitive skills in a schizophrenia patient is there any research that, that they can build their skills through I don’t know practice studying or something of that nature?

Can you repeat the question one more time?

Q:        Like the cognitive skills that schizophrenic patients are lacking, is there any research done on ways of building it other than medication?

Right, yeah, so there’s actually been a number of studies that have focused on cognitive and psychosocial rehabilitation, and in fact many of those studies show very, very significant effects of those training programs, often a much bigger effect than some of these kind of drug studies that I’ve been alluding to.  And actually Roy Chengupon mentioned _________, so he really developed something called the Cognitive Enhancement Therapy, which is just such a program. So there were some very impressive both sort of cognitive and neuroimaging results that came out of that. So that was as Roy mentioned, these sort of innovative and new programs that might – you might not think would really significantly affect brain and cognitive functioning but programs like CET show that over the course of a year or two you can actually see very significant improvements in both cognition, psychosocial functioning as well as brain activity.

Q:        Thank you.

Q:        My question has to do with Zyprexa, being a you know benzodiazepine and the pharmacological side of it, why does it work so well but yet have this side effect of weight gain?

Okay, so it certainly is a very effective antipsychotic, unfortunately it has this well known potential side effect of weight gain as well as other metabolic side effects. I think I might actually leave the mechanistic details to Dr. Ohangonguli who will actually be giving a talk later today.  But yes, I guess the short answer might be that it can increase both your appetite as well as affect the metabolism and as we seem to be aware it can cause some very significant weight gain in some patients.  Yes.

I think we can take one last question. Go ahead.

Q:        My question is about Risperdal, is it, do you have to – is it a long time, a certain amount of time that you have to be on it or you know before you get off of it? And what is – will that side effect after you just stop taking it all at once without the doctor’s telling you not to take it? 

Yeah, well, your question is about Risperdal and how to know when you’ve taken it long enough or if you should discontinue if you are experiencing side effects.  I guess what I would say would apply to any antipsychotic, whether that be Risperdal or Ziprasidone or Aripiprazole  or other medications, typically these medications need at least a few weeks if not a couple of months to really see whether they are taking effect. The decision to continue a medication is usually dictated by a number of different factors. One is obviously is it working, is it effectively treating the symptoms?   The other which you alluded to is, is that being done but in the absence or with minimal side effects?  If it’s effective but you are experiencing intolerable side effects, obviously that may be a good reason to consider another therapeutic approach.  I think as a rule whether you are very happy with a medication or whether you are fed up because you are experiences significant side effects I would say any changes in sort of treatment decisions that you could do that in a sort of collaborative way with your treatment team.

Q:        Some psychotic medications I know that you have to like, you can’t be on them a certain amount of time. Like maybe some of them you have to be on them like maybe 2 years, or you know you can’t be on them any longer is, is Risperdal one of those medications?

I wouldn’t say Risperdal or any other medication has that kind of time limit.  The kind of principle that I pointed out would really apply whether you are at the early stage of treatment, you know the first month or two of being on a medication, or whether you’ve been on the same medication for 2 years.  If you’ve been on a medication for 2 years, it’s effective, you are not experiencing significant side effects, I would say that’s probably not a great reason to go off of it.  There are some cases when people just get ill with an illness like schizophrenia or whether I guess more in cases where it’s not so clear whether it’s schizophrenia or some perhaps milder form of psychosis, in those cases sometimes clinicians will consider after resolution of a first episode of psychosis a drug-free trial to see whether then can sustain their overall recovery without medication. But that is usually a, obviously a sort of risky situation where you need sort of very close communication and monitoring with your treatment team.

Q:        Thank you.

Thank you.