EEG Artifacts Lab

Follow this link for examples of the glossokinetic, ocular, neck, back, and shoulder tension artifacts in the EEG trace.  http://www.flickr.com/photos/76739807@N03/

Each example comes with a:

• description of the artifact
• its non-cerebral source
• potential problems for analysis that it causes

Be sure to check out both pages of examples!

How do you look at your EEG data? I recommend using this matlab add-in or stand-alone program.
To download the EEG lab  toolkit for Matlab follow this link:

http://sccn.ucsd.edu/eeglab/. 

Follow this link to learn about how to reject epochs with artifacts using EEGlab: http://sccn.ucsd.edu/wiki/Chapter_01:_Rejecting_Artifacts .

Trisomy 21 and early brain development

In paper citation (Haydar and Reeves, 2011).

I am currently working on my third rotation at Boston University studying the effects of down syndrome (DS) on cortical development in mice. As I looked more intently into DS, I learned a lot about the disorder. Here are my notes from a very relevant overview article that my advisor wrote just last year.

Trisomy 21 is a triplication of human chromosome 21 that causes Down Syndrome. Surprisingly, EVERY child with down syndrome develops Alzheimer's disease later in life. DS also increases the risk of childhood leukemia and causes abnormalities in cardiac and gastrointestinal formation.  The average IQ of DS children is around 50. I would like to study why the gene triplication causes intellectual disability.

Mice are not humans, but they do have a mammalian genotype. The homologous region of human chromosome 21 in the mouse is mmu16. I am currently working with a mouse model that has the majority of mmu16 triplicated, Ts65Dn. This mouse model was developed in the early 90's. There are other models, including ones with less of mmu16 triplicated, and one that carries the actual human chromosome 21.

Studying this mouse model is not the same as studying humans with down syndrome, but it does give us a means to examine the development of the brain under similar conditions.

Mouse models of DS have revealed that  less excitatory neurons develop in the forebrain of trisomic mammals, and that these neuron differentiate later in development. They also form less excitatory synapses and have more dendritic spine abnormalities. DS model mice also have more PARV and SOM positive cells from the Medial ganglion eminence. This basically indicates an overproduction of inhibitory neurons in the forebrain. One reason for the overproduction of inhibitory neurons might be that Olig1 and Olig 2 are not specifying MGE precursors into oligodendrocytes, thus leaving them to become inhibitory interneurons.

Myelination tends to occur later in the DS model mice, and the cerebellum of DS model mice is smaller with fewer purkinje neurons and only 2/3 of the normal number of granule cells.

One of the major challenges of studying the development of DS model mice is that triplication of various genes does not just affect the expression of those genes, but that it then affects the expression of euploid genes as well. Thus some phenotypes do not arise the same way in cultured cells.

More details to come on individual genes and transcription factors that may be relevant to the DS phenotype in the DS model mice.

T-maze alternation in the rodent

In paper citation: (Deacon & Rawlins, 2006).

Introduction: T-mazes provide a valid way to study the working memory and hippocampal function of an animal, especially rats.

• Spontaneous alteration: When two trials are given in quick succession, the rat spontaneously chooses the arm not visited before. 
• Rewarded alteration: Reinforcing the rat's spontaneous alteration with a food reward.
• Typical spontaneous alternation rates are around 75%.

Working memory vs. Reference memory:

• A working memory task involves the rat remembering what he has just done (i.e. altering between sides of the T-maze). 
• A reference memory task involves learning a rule that does not change (i.e. run down the white side of the maze) regardless of whether it is left or right.

•  A rat learns reference memories in about 40 trials. 
• Rats naturally alternate, and can be given food rewards for alternation.
• Detects more subtle changes than the Morris Water Maze.

T-maze vs. Y-maze:

• T-maze has discrete trials. Y-maze has continuous trials.
• T-maze has less variance in trial time. Y-maze has more variance in trial time.
• T-maze has more human interference/animal handling. Y-maze has no human interference/animal handling.
• Alternation rates are lower in the Y maze (~65%).
• Rats with hippocampus removed adopt side preferences, and will still score highly in a continuous trials procedure. 

Ambition is a crime.

For those who would argue that the United States public school system provides fair and equal access to education, please think again.

In America, you purchase your education when you purchase your house. If you want your kids to go to better schools, you move out of the city and into a better school district or pay for a private education. In a few cases,  there may be a charter-school or test school option. But otherwise, you are stuck. This system drives healthy families out of cities, and pigeon-holes the children of the poor into poverty.

For parents who want better for their children, they can apply to bussing  programs and participate in lotteries for charter schools. But these options are limited. Not every child gets into a better school. When some ambitious parents who wanted better opportunities for their children falsified their address so that their child could attend a better school, they were arrested. When these parents were caught, instead of rewarding their ambition, states arrested them and the school districts pressed charges for "education theft." To make matters worse, some school districts are spending tax dollars to spy on children that they suspect do not live in the district in order to kick them out of their schools.

For the whole story, see the Wall-Street-Journal  Post : http://online.wsj.com/article/SB10001424053111903285704576557610352019804.html?mod=opinion_newsreel .


America is a nation that loves choices, and claims to provide the tools to climb the socioeconomic ladder, but as long as parents need to "buy" their way into better schools, we will never achieve equality.

Effects of REM sleep awakenings and related wakening paradigms on the ultradian sleep cycle and the symptoms in depression

In paper citation (Grozinger, Kogel, & Roschke, 2002).

In 1975, Vogel and colleagues executed a "heroic" experiment whereby severely depressed inpatients were chronically REM-sleep deprived for three weeks. They found that suppressing REM sleep had an antidepressant effect on patients with endogenous depression, namely depression that does not result from a stressful event. They used fifty-two patients, and the patients that responded to the REM deprivation treatment were less likely to require rehospitalization or another form of treatment in the future.

As the literature linking depression and sleep has progressed, many scientists have called for a confirmation of this study. Unfortunately, it takes a lot of time and resources to monitor sleeping patients. To work around this problem, Grozinger and colleagues developed a computer algorithm that wakes a patient up as soon as it detects REM sleep. Unfortunately, this system does not catch the initial moments of REM, and it only reduces REM sleep by about 50%.

Grozinger and colleagues do not replicate Vogel's results. Interestingly though, they show that both REM deprivation and sleep deprivation dramatically decrease a subject's self-reported symptoms of depression (both groups lowered their average score by ~7 points (out of an average of 22) after 11 days of treatment). I think that this is pretty strong evidence for the placebo effect. Every subject who participated in this experiment would have assumed that they were in the "treatment" group getting REM sleep deprivation because both sets of subjects were woken up almost 50 times each night. Thus each subject would want to deliver good news to the experimenter, and would thus focus on the progress that they had made since they started in the experiment. I also believe that the paradigm is so unique that it might "give hope" to a patient who has been treatment resistant.

I do not completely buy the theory that REM suppression is one of the main mechanisms of antidepressant therapy. For cognition, researchers are always trying to increase REM sleep to promote memory consolidation. I still assume that REM sleep deprivation is caused by something deeper that actually mediates the antidepressant effects of most medications/placebos.

'Til next time...

Selective Serotonin Reuptake Inhibitor (SSRI) treatment of early postnatal mice reverses their prenatal stress-induced brain dysfunction

In paper citation: (Ishiwata, Shiga & Okado, 2005).

The last review that I read about SSRIs in development talked about their paradoxical effects, and the long-term damage that they can cause. This paper comes in from a completely different angle and looks at the benefits of SSRIs immediately after birth. I have to say that I am simply fascinated at the extent to which SSRIs seem to affect development.

Important background:

• Serotonin concentration and synaptic density in the hippocampus, as well as spatial learning ability are reduced after prenatal stress (Hayashi, et al., 1998)
• 5HT and noradrenaline (NA) are involved in the regulation of mineralocorticoid (MR) and glucocorticoid (GR) mRNA expression (Seckl & Fink, 1992)
• SSRIs suppress HPA axis activity, decrease CRF mRNA expression and increase neurogenesis in the hippocampus of adult rodents.
• There were five groups in this study:
• Mice from non-stressed mothers, no SSRI treatment (C)
• Mice from non-stressed mothers with SSRI treatment from 1-3 weeks (CS)
• Mice from stressed mothers with no SSRI treatment (S)
• Mice from stressed mothers with SSRI treatment from 1-3 weeks (SS)
• Mice from stressed mothers who received SSRIs at 6-8 weeks of age (L-SS)

The new findings from this paper:

• Corticosterone levels:
• Mice from group S had 21% higher circulating corticosterone after restraint stress at week 3.
• Mice from group SS had corticosterone concentrations similar to controls.
• Monoamine concentrations:
• Mice from group SS and CS had significantly higher levels of serotonin (5-HT) than controls at postnatal week 3 and 6 by about 30% in the control treated mice and 60% in the stressed treated mice. 
• The 5-HT metabolite, 5HIAA was elevated in S mice compared to C mice. 
• Thus the 5-HT turnover rate was markedly elevated (77% greater) compared to controls. 
• Dendritic spine and synapse density:
• At week 3, spine density at the stratum radiatum in the S mice was 21% less than the control mice.
• At week 3, the SS mice had significantly more spines than S mice and resembled the control mice.
• At week 9, the S mice had 19% less spine and synapse density than controls.
• At week 9, the SS mice looked like normal mice.
• The mice with later SSRI treatment increased their spine density by 10%, but this was not significant.
• Spatial learning:
• C, CS, and SS mice all performed equally well at the Morris Water maze, but the S and LSS mice had learning impairments at the second and third exposure to the maze. These two groups also showed impairments at the reversal. 

Further information:

• Neonatal handling also reverses prenatal stress-induced behavioral deficits (Wakshlak & Weinstock, 1990).
• Chronic tianeptine treatment also reverses immobility time in the forced swim task (Morley-Fletcher, et al., 2003) *I'm surprised that this wasn't mentioned in the animal model overview.
• Hippocampal glucocorticoids are reduced in prenatally stressed animals, which is not what you would expect at first for cell death (Szuran, et al., 2000).
• The age of the rat may account for its stress response differences between prenatally stressed rats and controls (McCormick et al., 1995). 
• The first 3 postnatal weeks are very important for the development of the HPA axis. The concentration of GR in the rat hippocampus is low during week 1, then increases to adult values (Olpe & McEwen, 1976; Clayton, et al., 1977). The HPA axis reached adult levels of functionality by postnatal week 3. 

Remaining questions:

What happens to mice from stressed mothers who are raised by surrogates? Is it the mother's glucocorticoid levels that programs these mice or is it the mother's caregiving behaviors?

What happens to female rats who are in the same paradigm?

How did they get monoamine concentrations from both week 3 and week 6? Did they just plow through mice?

If mice postnatal week 0- postnatal week 2 correlate to the third trimester of primate births, could SSRI therapy actually help reverse learning impairments if administered acutely and early?

Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication

In paper citation (Kirsch & Sapirstein, 1998)

This paper specifically looks at the effects of the placebo in placebo-controlled drug studies treating depression. This analysis only includes drug studies before 1995 and therefore misses most of the modern drugs prescribed today. However, Kirsch and Sapirstein's results are really shocking. They find that in drug studies, the placebo group improves in proportion to the effectiveness of the drug. The correlation between the placebo response and the drug response is r=.90, p<.001 and the placebo response is 75% of the drug response. So if the drug response in a sertraline drug trial was 2.0, the placebo response in that trial would be around 1.5. These numbers were slightly higher for active placebos... side effects actually may convince people that they are receiving full treatment, and therefore cause them to expect a better response. This is also interesting in light of the more modern Turner and colleagues meta-analysis, which found that 49% of FDA approved clinical trials show no significant difference between placebo and antidepressant trials. Perhaps both the experimental and control patients are improving in proportion to the expected efficacy of the drug, and so only the most effective drugs will come out ahead of their placebos.

Furthermore, the authors compared the effect of taking a placebo pill to receiving no treatment while on a wait-list for psychotherapy trials. For the people on wait-lists, or receiving no placebo treatment at all, their depression scores worsened overall during the course of the study. This shows that the placebo pill is more effective than no treatment.

My remaining questions actually involve the rating scales of depression. It could be that different research centers treat their patients more holistically, and that is why the scores are so well correlated, but it could also be that people respond to the depression interviews in a rote manner. For example, if I know the symptoms of depression, and I want to be a good research subject, I may describe my pre-treatment symptoms in a way so that the doctor will give me the quick fix and treat me with an antidepressant. Then when the doctor asks me follow ups, I also know what improvement should look like, and I've been looking out for that in my daily life, and so I focus on the improvement for my follow up questionnaire. Whether the drug has actually improved my mood is hard to tell, because I started by looking for symptoms to describe to my doctor, and then I started looking for improvements to tell to my doctor. Thus the placebo effect.

Does anyone else think that is totally plausible? I guess Kirsch & Sapirstein would, but they do not mention it in their discussion. In cases of mild to moderate depression, I would like to see a study that looks at various types of placebos to see what works best. Inert substances should be better for our bodies in the long run, and especially useful for pregnant mothers who desire treatment for mood disorders.