Monday, December 20, 2010

No Amygdala, No Fear

An interesting article in the NY Times discusses a woman without an amygdala. The article can be found at:

Essentially,the woman has no fear. So one wonders if a stutterer with a similar condition would only exhibit primary stuttering as discussed in the posts on the "Anxious Mind."

Sunday, December 19, 2010

Antidepressants May Affect Stuttering

Antidepressants such as Prozac, Zoloft, Celexa, and a host of others are known to affect levels of the neurotransmitter serotonin in the brain alleviating depression.. But the question is: How might they affect stuttering?

Antidepressants are selective serotonin reuptake inhibitors (SSRIs), which means that they:

     - reduce reuptake of serotonin into presynaptic neurons
     - increasing serotonin concentrations in the synapses between the pre- and post-
       synaptic neurons
     - encouraging uptake into the post-synaptic neurons.

(see the August 25, 2010 post entitled "Stuttering and Neurons" for a graphical depiction of the workings of neurons)

In this way, SSRIs allow serotonin to perform its task as a chemical messenger enabling neurons to trigger nerve impulses in neighboring neurons, which presumably reduces symptoms of depression.

However, recent research has raised the possibility that SSRIs may have a more complex effect on neurotransmission. Reduction of depression may result also from SSRI's activation of the dopaminergic system in addition to the serotonergic system.

SSRIs prevent reuptake of serotonin by inhibiting the action of serotonin transporters (SERTs). These are molecular cargo carriers that recycle serotonin back neuronal storage sacs called vesicles located on presynaptic neurons.

But in addition to SERTs, there also are dopamine transporters (DATs) that are involved in a similar fashion with dopamine reuptake. Increased DAT activity has been associated with clinical depression since they act to reduce the levels of synaptic dopamine. Normally DATs exhibit a low affinity for serotonin, but higher serotonin levels lead to the uptake of serotonin by DATS. In this way, the DATs are effectively highjacked by higher serotonin concentrations and cannot function as "dopamine absorbers" leading to

       - less reuptake of dopamine by the presynaptic neurons
       - greater concentrations of dopamine in the synapses
       - enhanced dopamine uptake into postsynaptic neurons

This enhancement of the dopaminergic system reduces the symptoms of depression. The relatively inefficient and slow process of the hijacking of DATs by serotonin may explain why it takes weeks before anti-depressive effects are observed during SSRI treatment.

But while enhanced dopaminergic activity may be beneficial for relieving depression, it might not be appropriate for improving fluency if the dopaminergic hypothesis of stuttering is correct. Among stutterers using antidepressants there have been reports of greater disfluency. although, to my knowledge, no large scale studies regarding the effects of antidepressants on fluency have been conducted.

Thursday, December 16, 2010

Can Viruses Cause Stuttering, Part 2?

If the viral hypothesis were correct, then the therapeutic treatment of stuttering would be drastically modified. In particular, anti-infective agents might be administered to tamp down any infection that may arouse an implicated retrovirus or to attack the retrovirus directly. One of the approaches that is being taken for schizophrenia is to indirectly neutralize the HERV-W retrovirus using the drug artemisinin. And in the case of multiple sclerosis, an antibody is being tested that attacks a primary virus protein.

In addition, the identification of prenatal care strategies or postnatal vaccinations could prevent infections that might put individuals on the path to stuttering. Infections in the mother prior to an infant's birth may put the infant into a high risk category. In which case, these infants might be identified and receive an appropriate therapeutic treatment to forestall the onset of stuttering.

I am always amazed at the glacial progress in medicine. Aside from relatively rare serendipitous discoveries that lead to punctuated advances of medical knowledge/treatment, the accretion of understanding of many ailments' causes and their treatment is a tediously slow process. For example, not too long ago, hemochromatosis--too much iron in the blood--killed people. And the remedy, when it was found involved something as simple as draining blood (e.g., by the use of leeches).

And so it is regarding the understanding of the causes and possible treatments of stuttering. Only recently was the dopamine hypothesis of stuttering taken seriously even though it was first put forward in the 1930's.

I suspect that any testing and/or acceptance of a viral hypothesis for stuttering might likewise be a protracted process. But if the current research concerning schizophrenia and multiple sclerosis bears fruit, then there will be impetus for examining other neurologically based ailments such as stuttering.

Granted it is very difficult to identify viruses or viral infections and associate their presences with specific medical problems as the Discovery magazine article attests. Nevertheless, it might be useful to engage in large scale epidemiological studies to identify correlates with stuttering. Epidemiology is the study of patterns of health and illness and associated factors at the population level. It informs evidence-based medicine in order to identify health care risk factors, approaches for preventative medicine, and optimal treatment regimens.

An epidemiological study of stuttering would involve both the collection of medical histories of people with this infliction as well as appropriate blood/bodily fluid/tissue samples. In addition, both functional and structural brain imaging should be conducted for a substantial proportion of subjects.

The idea behind an intensive epidemiological study would be to contribute to a causative theory of stuttering, to identify possible subgroups of stutterers, and to develop therapeutic approaches based on any new knowledge.

Saturday, December 11, 2010

Can Viruses Cause Stuttering, Part 1?

In previous posts, we discussed the dopaminergic hypothesis of stuttering, i.e., that the root cause of stuttering may be excessive dopaminergic activity in the basal ganglia area of the brain. We can now ask what might be the root cause of the abnormal dopaminergic activity. Many think that it may be a genetic cause--through inheritance or through an unlucky throw of the genetic dice, stutterers have a faulty genetic system that expresses itself as excessive dopaminergic activity.

But there may be an alternative explanation. An intriguing article in Discover magazine raises the possibility of a virus being the root cause of other neurological diseases such as schizophrenia, bipolar disorder, and multiple sclerosis. The website for this article can be found at

Much like stuttering, imbalances of dopaminergic activity have been observed in the brains of individuals suffering from schizophrenia, but this abnormal activity occurs in a different combination of the brain's anatomical regions. And until recently schizophrenia was also thought to result from bad genes.

The Discover magazine article raises the possibility that schizophrenia begins with an infection. Many schizophrenics show chronic inflammation with respect to their infection-fighting white blood cells. Moreover, they often carry antibodies resulting from viral infections but not the viruses themselves, suggesting that they had been exposed to those infectious agents at some earlier point in their lives.

Viruses are not necessarily passed from person to person by bodily fluids or other contact. Rather, some may live permanently in the human body at the very deepest level intermingled with human DNA. Some researchers now believe that retroviruses, which are types of viruses that convert RNA into DNA, could be the culprits explaining a number of neurological ailments.

Viruses like influenza or measles kill cells when they infect them. But when retroviruses infect a cell, they often let the cell live and splice their genes into its DNA. When the cell divides, the resulting pair of cells carry the retrovirus’s genetic code in their DNA into future generations.

Although it is a rare random event, over the last 100 million years various retroviruses have gotten into human genomes by having infecting one of our animal ancestors in the evolutionary chain. About 100,000 retrovirus sequences appear in human DNA, accounting for more than 40 percent of all DNA. These retroviruses are usually tied up in tight stacks of proteins, but once in a while they slip out, switch on, and start manufacturing proteins beginning the process of infection. About 5 percent of the RNA produced in the brain arises from what appears to be “junk” DNA, which also includes endogenous retroviruses. The presence of RNA could mean that viral proteins are being manufactured in the body more frequently than previously thought since RNA is a step in the path to making proteins.

Although the body tries to keep endogenous retroviruses under control, infections can destabilize this balance. Many infections, such as herpes, toxoplasma, cytomegalovirus, and a dozen others may awaken a retrovirus. The retrovirus contains proteins that activate the immune system during these infections and the white blood cells produce inflammatory molecules called cytokines that attract more immune cells generating a cascading effect.

Whether people develop a specific neurological problem may depend on how their immune system responds to a retrovirus. Several studies implicate immune genes called human leukocyte antigens (HLAs) that are instrumental in the body’s ability to detect invading pathogens. The response to an infectious agent may be why one individual develops a specific neurological ailment and another person does not.

As a concrete example, human DNA has been found to have human endogenous retrovirus W (HERV-W) at specific addresses on chromosomes 6 and 7. Several studies have found active elements of HERV-W in the blood or brain fluids of people with schizophrenia (49% of schizophrenics vs. 4% of healthy people). The more of these active elements they had, the more inflammation they exhibited. In schizophrenia inflammation may overstimulate neurons. The neurons, being excited by these inflammatory signals, discharge neurotransmitters, leading to such symptoms of schizophrenia like hallucinations, delusions, paranoia, and hyper-suicidal tendencies. Some initial infection could have set off a lifelong pattern in which later infections reawaken HERV-W, causing more inflammation and eventually symptoms, explaining why schizophrenia waxes and wanes like a chronic infection.

In summary, genes may lead to a specific neurological problem only in conjunction with certain environmental kicks and a genome’s myriad of parasitical retroviruses might provide part of that kick. Retroviruses can be activated by inflammation resulting from infection and possibly even cigarette smoke or drinking water/food pollutants. In addition, we cannot rule out at this point that a stressor activating a retrovirus might be an emotional trauma affecting the immune system rather than some initial physical invasion. Since stuttering has some parallels to schizophrenia in terms of dopaminergic activity imbalances, a viral cause of this ailment should certainly be considered.

Sunday, December 5, 2010

An Anxious Mind Affects Stuttering, Part 3

In this post, we continue to recast earlier posts in terms of the anxious mind perspective of the last two posts. In particular, we revisit the diagram presented in the post entitled "Parkinson's Disease, Dopamine, and Stuttering." This diagram can now be presented from a more (structurally) neurological perspective.

The node previously characterized as "Excessive dopamine activity" is replaced by "Striatum" and the node characterized as "Mind" is replaced by "Amygdala."  Anxiety is regarded as a manifestation of a hyperactive amygdala and, as such, is not regarded from this perspective as a causative factor. The striatum affects fluency by virtue of its excessive dopaminergic activity the source of which is the substantia nigra (not shown in the diagram). Similarly, the amygdala by way of the ventral segmental area (not shown in the diagram) feeds additional dopamine to the striatum further affecting fluency.

Finally, in keeping with the previous post on "Stuttering, Placebos, and Nocebos," the "Context" node is replaced by "Conditioned Stimulus." The idea here is that a previous (otherwise neutral) event/situation becomes associated with (consciously or subconsciously) an episode of disfluency; so essentially that event/situation (e.g., speaking before an audience) is a conditioned stimulus that triggers greater activity (i.e., a conditioned response) in the amygdala.

What has not been taken into account in this diagram is that secondary stuttering is qualitatively different from primary stuttering. An amygdala that becomes excited does not only change the frequency of disfluency but also leads to modifications in the nature of the disfluency (i.e., blocks vs. easy rhythmical repetitions).

From a mechanical point of view, we can understand what is happening: A child experiencing primary stuttering develops awareness of his problem and, attempting to consciously intervene, then develops secondary symptoms like blocking. The motor neuron system simply will not allow him to bypass and override the rhythmical repetitions. But from a neurological perspective, the mechanism of action is, at this point in time, not clear. So we have to limit the applicability of the diagram above to individuals already in the secondary stuttering phase.