HippocampoCingulotastic Mashup

Hippocampal Neurogenesis v Area 25

OR, Is Hippocampal Neurogenesis Really Responsible for Antidepressant Treatment Response? [Maybe it's just a convenient marker of neural plasticity...]

How do we resolve the differences between rodent studies that implicate the hippocampus and human studies that implicate the midline prefrontal cortex [Brodmann area 25 aka subgenual cingulate aka sad cingulate] [in major depression]? Of course, the discrepancies might be attributed to neuroanatomical differences between rodent and human brains. Rodents have at most a primitive subgenual anterior cingulate cortex, whereas this region in the primate brain shows extensive connections with subcortical and cortical targets. But other fundamental issues should be kept in mind when jumping from studies of rodent behavior to human psychopathology. Human psychiatric disorders are complicated amalgams of affective, cognitive, and behavioral abnormalities. We might model aspects of one of these dimensions, such as helplessness or memory loss, in rodents; but we are then studying an aspect of the disorder, not the disorder itself. [Insel, 2007]

The quote above and the one in the previous post (both by Insel, 2007) were part of a commentary on a new paper in Science (Airan et al., 2007) that did optical imaging of hippocampal slices taken from rats who had been exposed to chronic mild stress (Willner, 2005), an animal model of depression. Here's the abstract of the article by Airan et al. (2007):

The hippocampus, as an integral component of the limbic system, is a focus of depression research, drives other brain regions implicated in depression, and appears to serve as a primary site of action for antidepressants that inhibit pathological hyperactivity. Complicating this picture, however, is evidence suggesting that antidepressants can stimulate hippocampal activity. Antidepressant-induced hippocampal neurogenesis is linked to behavioral responses; moreover, excitatory hippocampal neurons are injured by chronic stress. Animal models have proven useful in identifying molecular and cellular markers relevant to depression but have not identified neurophysiological final common pathways relevant to behavior. Voltage-sensitive dye imaging (VSDI) could allow analysis of disease-related neural activity on millisecond time scales, with micrometer spatial resolution and a scope spanning entire brain networks. We applied VSDI to hippocampal physiology in the chronic mild stress (CMS) model, a well-validated rodent model of core depressive behavioral symptoms.

But back to the commentary. Insel is just so quotable! Here he is on the pitfalls of the new fMRI phrenology:

Major depressive disorder, the result of an unfortunate convergence of genetic and environmental factors, is certainly more than the sum of its observable parts. Identifying brain regions correlated with "the parts" will be an important next step for human imaging studies, but the field will need to avoid high-tech phrenology.

References

Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K (2007). High-Speed Imaging Reveals Neurophysiological Links to Behavior in an Animal Model of Depression. Science 317:819-823.

Insel TR. (2007). Shining a Light on Depression. Science 317:757-758.

Willner P. (2005). Chronic Mild Stress (CMS) Revisited: Consistency and Behavioural-Neurobiological Concordance in the Effects of CMS. Neuropsychobiology 52:90-111.

The Merger of Neurology and Psychiatry

Thomas R. Insel, Shining a Light on Depression.
Science 10 August 2007: Vol. 317. no. 5839, pp. 757 - 758.

Just as research during the Decade of the Brain (1990-2000) forged the bridge between the mind and the brain, research in the current decade is helping us to understand mental illnesses as brain disorders. As a result, the distinction between disorders of neurology (e.g., Parkinson's and Alzheimer's diseases) and disorders of psychiatry (e.g., schizophrenia and depression) may turn out to be increasingly subtle. That is, the former may result from focal lesions in the brain, whereas the latter arise from abnormal activity in specific brain circuits in the absence of a detectable lesion. As we become more adept at detecting lesions that lead to abnormal function, it is even possible that the distinction between neurological and psychiatric disorders will vanish, leading to a combined discipline of clinical neuroscience.

A Difficult Balancing Act

Two recent incidents illustrate the opposing challenges of the current clinical trial and drug approval system. In the first, a 36 year old woman was enrolled as a subject in a Phase I clinical trial of gene therapy for rheumatoid arthritis, with an adeno-associated virus(AAV) as the delivery vector:

In the trial, the AAV vector delivered a transgene encoding the receptor for tumor necrosis factor (TNF)-alpha, a cytokine that causes joint swelling in arthritis patients. The receptor, secreted by the target cells, binds to TNF-alpha, to reduce inflammation and protect the joint.

However, she tragically died after receiving her second injection of the AAV, even though she was otherwise healthy:

Robb Mohr sat by his wife's hospital bed two weeks ago, trying to take it all in. His wife, Jolee Mohr, was breathing with the help of a ventilator in a Chicago intensive care unit -- her body bloated from internal bleeding, her liver failing -- and no one could figure out what was wrong with her.

Robb Mohr had his suspicions. Jolee, 36, had been feeling fine just a few weeks earlier, save for occasional stiffness from her arthritis. Her decline had begun the day after her right knee was injected with an experimental drug made of genetically engineered viruses. Doctors at the hospital shared his concern.

Jolee Mohr died from massive bleeding and organ failure July 24, leaving behind a 5-year-old daughter and a host of questions about why she was recruited into a gene therapy experiment whose chief goal was to test the safety of a novel arthritis treatment that had virtually no chance of helping her.

No one knows yet whether the treatment was to blame. ...

And as noted by the blog Health Care Renewal:

The Washington Post reported that a US National Institutes of Health (NIH) panel that reviewed the initial project protocol had some serious doubts.

How serious were these doubts?

Suspended Gene Therapy Test Had Drawn Early Questions

A gene therapy experiment that has triggered a federal investigation after the death of a patient on Tuesday raised a variety of concerns when it was first proposed to federal reviewers in 2003.

Unlike the vast majority of such proposals, all of which aim to treat diseases by giving patients new genes, the plan to inject trillions of genetically engineered viruses into the joints of patients with arthritis was flagged for a special public review by the federal Recombinant DNA Advisory Committee, part of the National Institutes of Health.

At that Sept. 17, 2003, meeting, representatives of the sponsoring company, Targeted Genetics Corp. of Seattle, listened as a panel of experts wondered aloud why such a novel and possibly risky approach was to be offered to patients who were not especially ill, including some who had not even tried standard treatments.

Reviewers questioned the justification for the study, given that animal studies had found only a "limited correlation" between the treatment and any improvements in subjects' condition. And they asked for more assurance that the engineered viruses were not going to spread around the body or cause untoward immune system reactions in patients.

Some also expressed concern that the informed consent document the researchers planned to use to describe the risks and benefits to participating patients was not upfront enough about the fact that the study was unlikely to help them and was designed merely to test the new approach's safety.

The second incident deals with the opposite end of the spectrum. An appeals court ruled that dying patients do not have a constitutional right to receive unapproved drugs that may prolong their lives:

Court Rejects the Right to Use Drugs Being Tested

A federal appeals court ruled yesterday that patients with terminal illnesses do not have a constitutional right to use medicines that have not yet won regulatory approval.

The 8-to-2 decision by the Court of Appeals for the District of Columbia Circuit came in a closely watched and emotional case that pitted desperate patients willing to try unproven, even risky, therapies against those arguing that drugs should be proved safe and effective before they are made available.

The decision preserves the current regulatory system. If it had gone the other way "it would have undermined the entire drug approval process," said William B. Schultz, a former deputy commissioner of the Food and Drug Administration, who wrote an amicus brief arguing against the early access to drugs.

The case was filed against the Food and Drug Administration in 2003 by the Abigail Alliance for Better Access to Developmental Drugs, a group founded by a man whose daughter Abigail died from cancer after a long battle to receive treatment with experimental drugs that were eventually approved.

The group, joined by the Washington Legal Foundation, argued that forcing patients to wait years for a drug to go through the process of clinical trials deprived dying patients of their right to self-defense and violated the Fifth Amendment clause stating that people cannot be deprived of life, liberty or property without due process of law.

It's a difficult task to determine the most ethical stance in each of these instances. Who decides? People's lives hang in the balance.

Crayon Removed From Man's Head

HOMR

... During one experiment [at his job at a medical testing center], the doctors find a crayon lodged in Homer's brain from when he was a child, which has been the cause of his life-long stupidity.

After the crayon is removed, Homer's IQ goes up to 105 points, which allows him to form a bond with Lisa. Homer then writes a report on the nuclear plant's safety, which results in the plant's shutting down, and the laying off of all employees. Homer's friends, initially thrilled to have a smarter Homer around, quickly reject him, and Homer is even burned in effigy at Moe's Tavern. Lisa tries to explain, with the aid of a graph, that as you get smarter, happiness decreases. Homer decides to put a crayon back in his brain, with the aid of Moe—who says he is an unlicensed surgeon. He arrives home his old, dumb, self, which initially disappoints Lisa. However, she finds a letter Homer wrote to her before the surgery, explaining that he now understands what it is like to be smart like her, and how much more he appreciates her because of this. Instead of being upset over her father's decision, the episode ends with Lisa embracing him.

No, wait...

Pencil removed from German's head

A woman in Germany who has spent 55 years with part of a pencil inside her head has finally had it removed.

Margret Wegner fell over carrying the pencil when she was four. It punctured her cheek and part of it went into her brain, above the right eye.

The 59-year-old has suffered headaches and nosebleeds for most of her life.

Surgeons in Berlin were able to remove most of the pencil in a two-hour operation, but a 2cm section was so embedded it was impossible to remove.

Professor Hans Behrbohm, a specialist in endoscopic sinus surgery at the Berlin-Weissensee clinic, carried out the operation and said Mrs Wegner was now mobile and not experiencing any pain.

The Luxury Of Neurobranding

Speaking of marketing campaigns, neuromarketing is in the news [or at least, a scientific journal] again, along with other neuro words (more on that later). A recent fMRI study examined branding and the brain by showing participants pictures of logos from "luxury" and "pragmatic" products. The new paper by this research group (Schaefer & Rotte, 2007a) appears to be the third publication (Schaefer & Rotte, 2007b, Schaefer et al., 2006) from the same experiment:

In our previous study we report activation in the prefrontal cortex related to familiar brands (Schaefer et al., 2006). The present study is an extension of this work and uses the same database. [NOTE: they didn't cite their own 2007b paper.]

Well, what did they do and what did they find? Brand logos from 21 car manufacturers (14 familiar, 7 mostly unfamiliar to the German participants) were shown to the subjects while brain scans were taken, and

participants were instructed that they will see logos of car manufacturers and that they should imagine using and driving a product of the brand they see. If they would see a logo of a car manufacturer they did not know they should imagine driving and using a generic car.

The logos were rated on familiarity after the fMRI portion of the experiment. In brief, the medial prefrontal cortex, supposedly associated with self-referential processing,¹ showed a larger response to luxury logos, compared to the unfamiliar logos. In contrast, the economy logos activated brain regions supposedly related to cognitive control.² Why? What kind of cars did the subjects [11 women and 3 men] drive? Did they all drive Ferraris and disdain Citroëns? That information wasn't reported.

Schaefer M, Rotte M. (2007a). Thinking on luxury or pragmatic brand products: Brain responses to different categories of culturally based brands. Brain Res. Jul 5; [Epub ahead of print]

Culturally based brands have a high impact on people's economic actions. Here we aimed to examine whether socioeconomic information conveyed by certain classes of brands (prestigious versus pragmatic classes) differentially evoke brain response. We presented icons of brands while recording subject's brain activity during a functional magnetic resonance imaging (fMRI) session. After the experiment, we asked subjects to assess the brands according to different characteristics. Results revealed an active network of bilateral superior frontal gyri, hippocampus and posterior cingulate related to familiar brands in general. Brands of the category sports and luxury activated regions in medial prefrontal cortex (MPFC) and precuneus. In contrast, brands rated as value products activated the left superior frontal gyrus and anterior cingulate cortex (ACC). The results suggest an active cortical network related to cognitive control for value brands and a network known to be associated with self-relevant processing for prestigious brands. We discuss the results as differential engagement of the prefrontal cortex depending on the attributed characteristic of a brand.

Why is this research important? Commercial Alert has a highly critical take on neuromarketing...

Neuromarketing is a controversial new field of marketing which uses medical technologies such as functional Magnetic Resonance Imaging (fMRI) -- not to heal, but to sell products.

We see three big potential problems with neuromarketing: (1) increased incidence of marketing-related diseases; (2) more effective political propaganda; and, (3) more effective promotion of degraded values.

...whereas the Neuromarketing Blog

is the place to talk about using brain science in Marketing and Sales. We cover both breaking news about relevant brain research as well as “big picture” topics like ethical dilemmas posed by cutting-edge technology.

It's no surprise that the Neurocritic takes the critical view, preferring that expensive research resources be spent on advancing basic and applied knowledge to find cures for diseases (for instance) and not on how the brain responds to luxury and pragmatic products. But automobile manufacturers and soft drink companies aren't about to fund research to help Rwandan refugees with PTSD, now are they?

And what about those neurowords, like neurobranding? You can read a lot more on neurowords at Neurofuture:

OneLook Dictionary Search turns up a long list of neurowords (thanks Shawn!) that do appear in dictionaries online. Others, including neuromarketing, are bound to appear soon. Aspies activists will probably lobby to get "neurotypical" in the Oxford English Dictionary (the ultimate authority on neologism acceptance). Others will appear in time, and in more flexible dictionaries first, as they're noticed.

In March 2006, Neurofuture held the first-ever neuroword contest, with "neurologism" crowned the winning entry. Turns out the neurologism neologism had been coined in 2004 by Jake Dunagan in Neuro-Futures: The Brain, Politics, and Power (PDF), so a second neuroword contest was held 3 months later. The winning entry this time was

Neurogibberish- Seemingly impressive jargon used by some neuroscientists to hide lack of real findings.

For example,

In our study brands, that were rated as value brands elicited activation of the superior frontal gyrus and ACC. The superior frontal gyrus is thought to contribute to higher cognitive functions. It has been related to working memory (Wager and Smith, 2003), but recently also to cognitions related to moral decisions and judgment (Borg et al., 2006).

[The subjects were making moral judgments of Toyotas?]

More recently, Bohemian Scientist discussed

neo-neuro fields

one of the beauties of neuroscience is its universality: at some level, everything involves the brain. too often, though, people affix "neuro-" to the front of their favorite subject, then claim victory over a paradigm-shifting new discipline. two blogs dealt with this issue recently: neuroaesthetics led to some deep insights, whereas "neuro-leadership" just fell flat. both posts were entertaining and insightful.

Do you have any new neurowords to report?

References

Schaefer M, Rotte M. (2007b). Favorite brands as cultural objects modulate reward circuit. Neuroreport 18:141-5.

Schaefer M, Berens H, Heinze HJ, Rotte M. (2006). Neural correlates of culturally familiar brands of car manufacturers. Neuroimage 31:861-5.

Footnotes
¹ The exact location, however, moves around from study to study.
² However, Table 1 and Fig 4B do not instill great confidence that the anterior cingulate cortex was one of the activated regions.

Tampax Begins New Marketing Campaign

Now here's something unexpected...

Fruit bats discovered to have menstrual cycles

Scientists have discovered that a type of fruit bat menstruate in a similar way to women

They say their findings – published in this month's issue of key journal Biology of Reproduction - could lead to bats being studied by researchers trying to understand human menstrual problems and other reproductive disorders.

. . .

Professor Racey, Regius Professor of Natural History, said: "Although it occurs in primates, menstruation is found in few of the world's 4,000 species of mammals which is why this discovery is so remarkable.

"The finding is significant because it extends our knowledge of the reproductive biology of what is a large group of mammals.

"It also raises the possibility that this type of fruit bat could be studied by those who are trying to increase our understanding of human menstrual dysfunction and other reproductive disorders."

Next up: Sarafem [which is nothing more than fluoxetine, or Prozac] for Premenstrual Dysphoric Disorder.

A Single Gene Controls Emotional Recall!

And the neurotransmitter norepinephrine (NE), which has been in the news lately, plays a key role in the overstated headline of the day:

Emotional recall is in your genes
18:00 29 July 2007
Paul Marks

Image from Fig. 1A of Depue et al. (2007)

Your ability to recall emotional events – such as meeting the love of your life, or the trauma of a painful car crash – is governed by a common variation in a single gene, according to a new study. [NOTE: As if variations in many other genes were tested.]

. . .

Highly emotive incidents trigger the brain to release the hormone and neurotransmitter noradrenaline. This stimulates the amygdala – part of the brain involved with processing emotional reactions – to store memories in the hippocampus and other parts of the brain, says Dominique de Quervain, a neuroscientist at the University of Zurich in Switzerland.

Yet for some reason, recall of emotional events varies a great deal from person to person. So de Quervain wondered if common variations in a gene called ADRA2B, which codes for [one of the subtypes of the alpha-2] noradrenaline receptor, could be responsible. Some 30 per cent of Caucasians and 12 per cent of Africans possess this variant, he says.

So this is the alpha-2 receptor, which responds to clonidine (agonist) and yohimbine (antagonist), rather than the beta-2 receptor, which is antagonized by our old friend, propranolol. According to the NCBI Sequence Viewer v2.0 Summary on ADRA2B adrenergic, alpha-2B-, receptor [Homo sapiens]:

Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. They include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. This gene encodes the alpha2B subtype, which was observed to associate with eIF-2B, a guanine nucleotide exchange protein that functions in regulation of translation. A polymorphic variant of the alpha2B subtype, which lacks 3 glutamic acids from a glutamic acid repeat element, was identified to have decreased G protein-coupled receptor kinase-mediated phosphorylation and desensitization; this polymorphic form is also associated with reduced basal metabolic rate in obese subjects and may therefore contribute to the pathogenesis of obesity. This gene contains no introns in either its coding or untranslated sequences.

Let's return to the New Scientist article.

One group comprised healthy Swiss citizens and the other comprised traumatised survivors of the Rwandan genocide – who were living in a refugee camp in Uganda.

The researchers found that, in both groups, people carrying the ADRA2B gene variant were "substantially more likely" to remember both positive and negative pictures than people with other forms of the gene. Neutral images were recalled to the same degree by people with and without the variant.

However, Rwandans with the variant had far higher recall of negative emotional events than the Europeans who carried it – and this was unrelated to whether or not they suffered from post traumatic stress disorder.

"The genetic variant is related to enhanced emotional memory," concludes de Quervain. "But it also appears to predispose people to stronger traumatic memories when something terrible happens."

Is that the same as saying that a single gene governs your ability to recall emotional events? It certainly appears to influence one's ability to recall emotional events, whether pleasant, unpleasant, or traumatic. That's not to say, however, that other genes do not have any influence over such complicated cognitive and affective processes.

In the paper (de Quervain et al., 2007), a large group of normal Swiss participants (n=435) was shown a series of photographs from the International Affective Picture Set (10 each positive, negative, and neutral in emotional content) and asked to rate them on valence and arousal. Ten minutes later, they were asked to recall the words. Overall, the participants showed an advantage in recalling emotional words relative to neutral words: 57% better for positive and 55% for negative. The breakdown for carriers and noncarriers of the variant are shown in the table below, which illustrates that the carriers showed a significantly greater enhancement in emotional recall.

SWISS
All emotional pictures
carriers (N = 214)	78% +/- 7%
noncarriers (N = 221)	43% +/- 6%
Positive
carriers	77% +/- 8%
noncarriers	43% +/- 7%
Negative
carriers	79% +/- 7%
noncarriers	43% +/- 6%

The second group of participants had survived one of the most horrific events of the 20th century: the 1994 genocide of 1,000,000 human beings in Rwanda over the course of only 100 days (Survivors Fund, SURF). These individuals were in a refugee camp and were recruited to participate not in the trivial picture recall task, but to report their experiences in a clinical setting. At this point, it's best to quote the paper directly:

We hypothesized that deletion carriers would have increased emotional memory for traumatic events reflected in increased re-experiencing symptoms. We tested this hypothesis in 202 refugees who had fled from the Rwandan civil war and were living in the Nakivale refugee camp in Uganda at the time of investigation (100 females, 102 males; median age, 34 years...). All subjects had experienced multiple, highly aversive situations and were examined by trained experts with a structured interview based on the Post-traumatic Diagnostic Scale with the help of trained interviewers chosen from the refugee community. Traumatic events were assessed using a checklist of 31 war- and nonwar-related traumatic-event types (for example, injury by a weapon, rape, accidents). The population consisted of 133 subjects fulfilling the diagnostic criteria of DSM-IV for post-traumatic stress disorder (PTSD) and 69 subjects without PTSD or a history of PTSD. Deletion carriers had a significantly higher score for re-experiencing symptoms per traumatic-event type than did noncarriers (carriers, N=42, 0.47 +/- 0.05; noncarriers, N=160, 0.31 +/- 0.03), whereas the deletion was not significantly associated with hyperarousal or avoidance symptoms. The association of the deletion with increased traumatic memory was independent of the presence of PTSD ... and the genotype was equally distributed across the diagnostic groups. Correcting for gender did not influence the genotype effect on traumatic memory.

Fig. 3 (de Quervain et al., 2007)

The authors' conclusion:

Taken together, we show that a genetically anchored alteration in the noradrenergic system is related to enhanced emotional memory in healthy young Swiss subjects. Furthermore, we found that the same genetic alteration is related to increased traumatic memory in a Sub-Saharan African population of civil war refugees who experienced multiple and highly aversive emotional situations. The present findings suggest that the price for the deletion-related enhancement of emotional memory may be enhanced intrusive and distressing emotional memory for traumatic events.

Reference

de Quervain DJ, Kolassa IT, Ertl V, Onyut PL, Neuner F, Elbert T, Papassotiropoulos A. (2007). A deletion variant of the alpha 2b-adrenoceptor is related to emotional memory in Europeans and Africans. Nature Neurosci. Published online: 29 July 2007.

Emotionally arousing events are recalled better than neutral events. This phenomenon, which helps us to remember important and potentially vital information, depends on the activation of noradrenergic transmission in the brain. Here we show that a deletion variant of ADRA2B, the gene encoding the alpha2b-adrenergic receptor, is related to enhanced emotional memory in healthy Swiss subjects and in survivors of the Rwandan civil war who experienced highly aversive emotional situations.

Symbol Report: ADRA2B