Tuesday, September 8, 2009

Trauma Alters Brain Function... So What?

According to a new paper in the prestigous journal PNAS, High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China.

The earthquake, you'll remember, happened on 12th May last year in central China. Over 60,000 people died. The authors of this paper took 44 earthquake survivors, and 32 control volunteers who had not experienced the disaster.

The volunteers underwent a "resting state" fMRI scan; survivors were scanned between 13 and 25 days after the earthquake. Resting state fMRI is simply a scan conducted while lying in the scanner, not doing anything in particular. Previous work has shown that fMRI can be used to measure resting state neural activity in the form of low-frequency oscillations.

The authors found differences in the resting state low-frequency activity (ALFF) between the trauma survivors and the controls. In survivors, resting state activity was increased in several areas:
"The whole-brain analysis indicated that, vs. controls, survivors showed significantly increased ALFF in the left prefrontal cortex and the left precentral gyrus, extending medially to the left presupplementary motor area... [and] region of interest (ROI) analyses revealed significantly increased ALFF in bilateral insula and caudate and the left putamen in the survivor group..."
They also reported correlations between resting activity in some of these areas and self-reported anxiety and depression symptoms in the survivors.

Finally, survivors showed reduced functional connectivity between a wide range of areas ("a distributed network that included the bilateral amygdala, hippocampus, caudate, putamen, insula, anterior cingulate cortex, and cerebellum.") Functional connectivity analysis measures the correlation in activity across different areas of the brain - whether the areas tend to activate at the same time or not.

Now - what does all this mean? And does it help us understand the brain?

The fact that there are differences between the two groups is neither informative nor surprising. "Resting state" neural activity presumably reflects whatever is going through a person's mind. Recent earthquake survivors are going to be thinking about rather different things compared to luckier people who didn't experience such trauma. It doesn't take a brain scan to tell you that, but that's all these scans really tell us.

But these weren't just any differences - they were particular differences in particular brain regions. Does that make knowing about them more interesting and useful?

Not as such, because we don't know what they represent, or what causes them. So living through an earthquake gives you "Increased ALFF in the left prefrontal cortex" - but what does that mean? It could mean almost anything. The left prefrontal cortex is a big chunk of the brain, and its functions probably include most complex cognitive processes. Ditto for the other areas mentioned.

The authors link their findings to previous work with frankly vague statements such as "The increased regional activity and reduced functional connectivity in frontolimbic and striatal regions occurred in areas known to be important for emotion processing". But anatomically speaking, most of the brain is either "fronto-limbic" or "striatal", and almost everywhere is involved in "emotion processing" in one way or another.

So I don't think we understand the brain much better for reading this paper. Further work, building on these results, might give insights. We might, say, learn that decreased connectivity between Regions X and Y is because trauma decreases serotonin levels, which prevents signals being communicated between these areas, which is why trauma victims can't use X to deliberately stop recalling traumatic memories, which is what Y does.

I just made that up. But that's a theory which could be tested. Much of today's neuroimaging research doesn't involve testable theories - it is merely the exploratory search for neural differences between two groups. Neuroimaging technology is powerful, and more advanced techniques are always being developed. What with resting state, functional connectivity, pattern-classification analysis, and other fancy methods, the scope for finding differences between groups is enormous and growing. I'm being rather unfair in criticizing this paper; there are hundreds like it. I picked this one because it was published last week in a good journal.

Exploratory work can be useful as a starting point, but at least in my opinion, there is too much of it. If you want to understand the brain, as opposed to simply getting published papers to your name, you need a theory sooner or later. That's what science is about.

ResearchBlogging.orgLui, S., Huang, X., Chen, L., Tang, H., Zhang, T., Li, X., Li, D., Kuang, W., Chan, R., Mechelli, A., Sweeney, J., & Gong, Q. (2009). High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0812751106

Trauma Alters Brain Function... So What?

According to a new paper in the prestigous journal PNAS, High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China.

The earthquake, you'll remember, happened on 12th May last year in central China. Over 60,000 people died. The authors of this paper took 44 earthquake survivors, and 32 control volunteers who had not experienced the disaster.

The volunteers underwent a "resting state" fMRI scan; survivors were scanned between 13 and 25 days after the earthquake. Resting state fMRI is simply a scan conducted while lying in the scanner, not doing anything in particular. Previous work has shown that fMRI can be used to measure resting state neural activity in the form of low-frequency oscillations.

The authors found differences in the resting state low-frequency activity (ALFF) between the trauma survivors and the controls. In survivors, resting state activity was increased in several areas:
"The whole-brain analysis indicated that, vs. controls, survivors showed significantly increased ALFF in the left prefrontal cortex and the left precentral gyrus, extending medially to the left presupplementary motor area... [and] region of interest (ROI) analyses revealed significantly increased ALFF in bilateral insula and caudate and the left putamen in the survivor group..."
They also reported correlations between resting activity in some of these areas and self-reported anxiety and depression symptoms in the survivors.

Finally, survivors showed reduced functional connectivity between a wide range of areas ("a distributed network that included the bilateral amygdala, hippocampus, caudate, putamen, insula, anterior cingulate cortex, and cerebellum.") Functional connectivity analysis measures the correlation in activity across different areas of the brain - whether the areas tend to activate at the same time or not.

Now - what does all this mean? And does it help us understand the brain?

The fact that there are differences between the two groups is neither informative nor surprising. "Resting state" neural activity presumably reflects whatever is going through a person's mind. Recent earthquake survivors are going to be thinking about rather different things compared to luckier people who didn't experience such trauma. It doesn't take a brain scan to tell you that, but that's all these scans really tell us.

But these weren't just any differences - they were particular differences in particular brain regions. Does that make knowing about them more interesting and useful?

Not as such, because we don't know what they represent, or what causes them. So living through an earthquake gives you "Increased ALFF in the left prefrontal cortex" - but what does that mean? It could mean almost anything. The left prefrontal cortex is a big chunk of the brain, and its functions probably include most complex cognitive processes. Ditto for the other areas mentioned.

The authors link their findings to previous work with frankly vague statements such as "The increased regional activity and reduced functional connectivity in frontolimbic and striatal regions occurred in areas known to be important for emotion processing". But anatomically speaking, most of the brain is either "fronto-limbic" or "striatal", and almost everywhere is involved in "emotion processing" in one way or another.

So I don't think we understand the brain much better for reading this paper. Further work, building on these results, might give insights. We might, say, learn that decreased connectivity between Regions X and Y is because trauma decreases serotonin levels, which prevents signals being communicated between these areas, which is why trauma victims can't use X to deliberately stop recalling traumatic memories, which is what Y does.

I just made that up. But that's a theory which could be tested. Much of today's neuroimaging research doesn't involve testable theories - it is merely the exploratory search for neural differences between two groups. Neuroimaging technology is powerful, and more advanced techniques are always being developed. What with resting state, functional connectivity, pattern-classification analysis, and other fancy methods, the scope for finding differences between groups is enormous and growing. I'm being rather unfair in criticizing this paper; there are hundreds like it. I picked this one because it was published last week in a good journal.

Exploratory work can be useful as a starting point, but at least in my opinion, there is too much of it. If you want to understand the brain, as opposed to simply getting published papers to your name, you need a theory sooner or later. That's what science is about.

ResearchBlogging.orgLui, S., Huang, X., Chen, L., Tang, H., Zhang, T., Li, X., Li, D., Kuang, W., Chan, R., Mechelli, A., Sweeney, J., & Gong, Q. (2009). High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0812751106

TEMPORAL FORA DE ÉPOCA....

Aqui no Sul, exatamente Jaraguá do Sul, onde moro está chovendo muito.
Ontem a noite deu ventos muitos fortes. Muitas casas foram destelhadas.
Na minha casa, uma janela, pequena que só estava encostada, foi arrancado com a força do vento.
Próximo a minha casa, do outro do lado da rua, um galpão inteiro foi destruido.
Muitas árvores arrancadas. Ficamos sem energia, até as 10h30 da manhã.
Por causa das árvores que caíram na madruga, com os fortes ventos.
Nunca vi uma coisas dessas, assim tão fortes em Jaraguá do Sul.
Na escola que trabalho, as telhas foram todas arrancadas.
Ficou 03 salas, totalmente molhada.
Foi uma loucura o vento da madrugada.
No Oeste de Santa Catarina muitos vendavais aconteceram.
RGS., também sofreu, além do PR.
http://dl5.glitter-graphics.net/pub/701/701385r06wjfj744.gif

Mas sabemos, perfeitamente o que é isso.
É a resposta da Mãe Natureza, sofrendo pelos abusos aos Meio Ambientes.
Tudo vai se transformando e causando seus efeitos.
Como tudo tem causa e efeito, a Mãe Natureza, pede Socorro.

A previsão ainda é de muita chuva.
Nos preocupamos, pois no Ano passado, O Sul passou por fortes tregédias.
E Jaraguá do Sul, não se escapou.

Teve 11 mortes, e muito deslizamento de terras.

Mas, vamos ser Otimista. Tudo vai melhorar e ficar bem...
A chuva também faz parte do ciclo sa Natureza.

FALANDO EM COISA BOA. HOJE É O ÚLTIMO DIA PARA VOCÊ SE INCREVER E PARTICIPAR DA NOSSA BLOGAGEM COLETIVA.

AMANHÃ, POSTAREI A LISTA DOS PARTICIPANTES.

ESPERO POR VOCÊ, MEU QUERIDO AMIGO VIRTUAL.

O BLOG UMA INTERAÇÃO DE AMIGOS ESTÁ COMEMORANDO
10.000MIL VISITAS.
VENHA BUSCAR SEU PRESENTE.
Blog Coletivo-Uma Interação de Amigos

Monday, September 7, 2009

INDEPENDÊNCIA DO BRASIL- 7 DE SETEMBRO.

AINDA TEMOS QUE LUTAR MUITO, PARA SERMOS UM BRASIL,
TOTALMENTE LIVRE.
SOMOS DEPENDENTE DE UMA SOCIEDADE CASTRADORA,
SEM A IGUALDADE SOCIAL.

DE UM PAIS QUE É RICO EM RIQUEZAS NATURAIS, E A FOME MATANDO MUITOS. QUE BRASIL É ESTE??
TODOS OS ANOS, SE COMEMORA ESTA INDEPENDÊNCIA.
MAS, ONDE FICA A LIBERDADE DE EXPRESSÃO,
DA MISÉRIA, DA FOME, DAS INJUSTIÇAS, DAS CORRUPÇÕES,
DAS VIOLÊNCIAS E MALDADES, PRATICADAS PELOS HOMENS.

AINDA ESTAMOS PRESOS, POR ESTA DESIGUALDADE SOCIAL.
POR ISSO TEMOS QUE LEVANTAR ESTA BANDEIRA DA PAZ.
REAJA POVO BRASILEIRO.
EMBORA SOFRIDO, MAS LUTADOR DOS SEUS DIREITOS.
QUE PÁTRIA É ESSA??? O QUE TEMOS PARA COMEMORAR?
QUANDO MUITOS NÃO TEM ONDE DORMIR,

O QUE VESTIR, O QUE COMER?

SÃO DOENTES FÍSICOS, EMOCIONAIS,
E PRINCIPALMENTE DOENTES PELAS INJUSTIÇAS DOS HOMENS.

http://lh3.ggpht.com/_juDnfPWIuVQ/Sp9SOJNLWDI/AAAAAAAAB1Q/V0gkBVYDmg0/7Setembrobrava_thumb%5B9%5D.jpg?imgmax=800
imagem do blog da Andreia

PARTICIPE DA FESTA DA CURIOSA. DEIXE SEU SIM, PARA A BLOGAGEM COLETIVA.
VEJA NA POSTAGEM ABAIXO, COMO VAI FUNCIONAR.

Saturday, September 5, 2009

POR QUE VOCÊ CRIOU O SEU BLOG?

BLOGAGEM COLETIVA DIAS 10 DE SETEMBRO




PARA COMEMORAR ACHEI LEGAL FAZER UMA COLETIVA, JUNTO COM VOCÊS.

POR ISSO NO DIA 10 DE SETEMBRO, DATA DO ANIVERSÁRIO DO BLOG CURIOSA, GOSTARIA DE ENCONTRAR VOCÊ AQUI PARTICIPANDO DA BLOGAGEM COLETIVA.



ESTE É O SELO DA BLOGAGEM -
LEVEM PARA SEU BLOG E DIVULGEM ESTE MOMENTO.




PRIMEIRA Blogagem Coletiva da CURIOSA em comemoração ao 1º ANO DO SEU ANIVERSÁRIO!


Vamos dividir este momento especial.
Gostaria muito de ver você participando!


Escreva POR QUE VOCÊ CRIOU O SEU BLOG? E o que te marcou durante este de blog.
Participe desse momento.

Faça um texto e poste em seu blog...
Mas antes confirme sua participação, aqui na CURIOSA.

DIAS PARA INSCRIÇÕES: 05 À 08 de Setembro.

Dia 08 às 20hs as inscrições serão encerradas. E postarei aqui a lista com os participantes da blogagem...

DIA: 09.09.- ATÉ AS 22 hs, SAIRÁ A LISTA DOS PARTICIPANTES.

DATA PARA POSTAGEM: DIA 10.09.09

http://rd.foto.radikal.ru/0707/62/dcaabbc5c5aft.jpghttp://4.bp.blogspot.com/_k00Jmm09EeA/SP0GMv221nI/AAAAAAAAFYQ/ePW_JW6zz8Y/S220/aniv01_002.gif
PARTICIPEM DESTA FESTA!!!

Friday, September 4, 2009

Predicting Antidepressant Response with EEG

One of the limitations of antidepressants is that they don't always work. Worse, they don't work in an unpredictable way. Some people benefit from some drugs, and others don't, but there's no way of knowing in advance what will happen in any particular case - or of telling which pill is right for which person.

As a result, drug treatment for depression generally involves starting with a cheap medication with relatively mild side-effects, and if that fails, moving onto a series of other drugs until one helps. But since it can take several weeks for any new drug to work, this can be a frustrating process for patients and doctors alike.

Some means of predicting the antidepressant response would thus be very useful. Many have been proposed, but none have entered widespread clinical use. Now, a pair of papers(1,2) from UCLA's Andrew Leuchter et al make the case for prediction using quantitative EEG (QEEG).

EEG, electroencephalography, is a crude but effective way of recording electrical activity in the brain via electrodes attached to the head. "Quantitative" EEG just means using EEG to precisely measure the level of certain kinds of activity in the brain.

Leuchter et al's system is straightforward: it uses six electrodes on the front of the head. The patient simply relaxes with their eyes closed for a few minutes while neural activity is recorded.

This procedure is performed twice, once just before antidepressant treatment begins and then again a week later. The claim is that by examining the changes in the EEG signal after one week of drug treatment, the eventual benefit of the drug can be predicted. It's not an implausible idea, and if it did work, it would be rather helpful. But does it?

Leuchter et al say: yes! The first paper reports that in 73 depressed patients who were given the antidepressant escitalopram 10mg/day, QEEG changes after one week predicted clinical improvement six weeks later. Specifically, people who got substantially better at seven weeks had a higher "Antidepressant Treatment Response Index" (ATR) at one week than people who didn't: 59.0 ± 10.2 vs 49.8 ± 7.8, which is highly significant (
p less than 0.001).

In the companion paper, the authors examined patients who started on escitalopram and then either kept taking it or switched to a different antidepressant, bupropion. They found that patients who had a high ATR after a week of escitalopram tended to do well if they stayed on it, while patients who had a low ATR to escitalopram did better when they switched to the other drug.

These are interesting results, and they follow from ten years of previous work (mostly, but not exclusively, from the same group) on the topic. Because the current study didn't include a placebo group, we can't say that the QEEG predicts antidepressant response as such, only that it predicts improvement in depression symptoms. But even this is pretty exciting, if it really works.

In order to verify that it does, other researchers need to replicate this experiment. But they may find this a little difficult. What is the Antidepressant Treatment Response Index use in this study? It's derived from an analysis of the EEG signal, and we're told that you get it from this formula:

Some of the terms here are common parameters that any EEG expert will understand. But "A", "B", and "C" are not. They're constants, which are not given in the paper. They're secret numbers. Without knowing what those numbers are, no-one can calculate the "ATR" even if they have an EEG machine.

Why
keep them secret? Well...
"Financial support of this project was provided by Aspect Medical Systems. Aspect participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript."
Aspect is a large medical electronics company who developed the system used here. Presumably, they want to patent it (or already have). We're told that
"To facilitate independent replication of the work reported here, Aspect intends to make available a limited number of investigational systems for academic researchers. Please contact Scott Greenwald, Ph.D... for further information."
All very nice of them, but if they'd told us the three magic numbers, academics could start trying to independently replicate these results tomorrow. As it is, anyone who wants to do so will have to get Aspect's blessing, which, with the best will in the world, means they will not be entirely "independent".

[BPSDB]


ResearchBlogging.orgLeuchter AF, Cook IA, Gilmer WS, Marangell LB, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, Fava M, Iosifescu D, & Greenwald S (2009). Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder. Psychiatry research PMID: 19709754

Leuchter AF, Cook IA, Marangell LB, Gilmer WS, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, McCracken JT, Fava M, Iosifescu D, & Greenwald S (2009). Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: Results of the BRITE-MD study. Psychiatry research PMID: 19712979

Predicting Antidepressant Response with EEG

One of the limitations of antidepressants is that they don't always work. Worse, they don't work in an unpredictable way. Some people benefit from some drugs, and others don't, but there's no way of knowing in advance what will happen in any particular case - or of telling which pill is right for which person.

As a result, drug treatment for depression generally involves starting with a cheap medication with relatively mild side-effects, and if that fails, moving onto a series of other drugs until one helps. But since it can take several weeks for any new drug to work, this can be a frustrating process for patients and doctors alike.

Some means of predicting the antidepressant response would thus be very useful. Many have been proposed, but none have entered widespread clinical use. Now, a pair of papers(1,2) from UCLA's Andrew Leuchter et al make the case for prediction using quantitative EEG (QEEG).

EEG, electroencephalography, is a crude but effective way of recording electrical activity in the brain via electrodes attached to the head. "Quantitative" EEG just means using EEG to precisely measure the level of certain kinds of activity in the brain.

Leuchter et al's system is straightforward: it uses six electrodes on the front of the head. The patient simply relaxes with their eyes closed for a few minutes while neural activity is recorded.

This procedure is performed twice, once just before antidepressant treatment begins and then again a week later. The claim is that by examining the changes in the EEG signal after one week of drug treatment, the eventual benefit of the drug can be predicted. It's not an implausible idea, and if it did work, it would be rather helpful. But does it?

Leuchter et al say: yes! The first paper reports that in 73 depressed patients who were given the antidepressant escitalopram 10mg/day, QEEG changes after one week predicted clinical improvement six weeks later. Specifically, people who got substantially better at seven weeks had a higher "Antidepressant Treatment Response Index" (ATR) at one week than people who didn't: 59.0 ± 10.2 vs 49.8 ± 7.8, which is highly significant (
p less than 0.001).

In the companion paper, the authors examined patients who started on escitalopram and then either kept taking it or switched to a different antidepressant, bupropion. They found that patients who had a high ATR after a week of escitalopram tended to do well if they stayed on it, while patients who had a low ATR to escitalopram did better when they switched to the other drug.

These are interesting results, and they follow from ten years of previous work (mostly, but not exclusively, from the same group) on the topic. Because the current study didn't include a placebo group, we can't say that the QEEG predicts antidepressant response as such, only that it predicts improvement in depression symptoms. But even this is pretty exciting, if it really works.

In order to verify that it does, other researchers need to replicate this experiment. But they may find this a little difficult. What is the Antidepressant Treatment Response Index use in this study? It's derived from an analysis of the EEG signal, and we're told that you get it from this formula:

Some of the terms here are common parameters that any EEG expert will understand. But "A", "B", and "C" are not. They're constants, which are not given in the paper. They're secret numbers. Without knowing what those numbers are, no-one can calculate the "ATR" even if they have an EEG machine.

Why
keep them secret? Well...
"Financial support of this project was provided by Aspect Medical Systems. Aspect participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript."
Aspect is a large medical electronics company who developed the system used here. Presumably, they want to patent it (or already have). We're told that
"To facilitate independent replication of the work reported here, Aspect intends to make available a limited number of investigational systems for academic researchers. Please contact Scott Greenwald, Ph.D... for further information."
All very nice of them, but if they'd told us the three magic numbers, academics could start trying to independently replicate these results tomorrow. As it is, anyone who wants to do so will have to get Aspect's blessing, which, with the best will in the world, means they will not be entirely "independent".

[BPSDB]


ResearchBlogging.orgLeuchter AF, Cook IA, Gilmer WS, Marangell LB, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, Fava M, Iosifescu D, & Greenwald S (2009). Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder. Psychiatry research PMID: 19709754

Leuchter AF, Cook IA, Marangell LB, Gilmer WS, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, McCracken JT, Fava M, Iosifescu D, & Greenwald S (2009). Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: Results of the BRITE-MD study. Psychiatry research PMID: 19712979