Wednesday, April 27, 2011

Stuttering Drug Research and the Social Media

Social networking as a means for conducting drug testing was reported in the April 23, 2011 issue of the Wall Street Journal.

A clinical trial to test a drug for Amyotrophic Lateral Sclerosis (ALS) was conducted using social networking to enroll patients and collect data. The results were published in the online journal, Nature Biotechnology. This study, conducted by PatientsLikeMe, a health data sharing company, is an example of how social networking could play a role in the conduct of clinical trials and may be applicable to clinical trials for drugs affecting fluency.

Social network drug trials are not intended to replace conventional randomized double blind placebo controlled trials. However, such trials have become very time consuming and expensive and new drug testing models may be needed. Social network drug trials may have utility for the testing of off-label usage of various drugs that individuals might try to improve fluency but that may never arouse the (economic) interests of pharmaceutical companies. With the exception of pagoclone, which was never brought to market, the drugs tried for improving fluency (mainly atypical antipsychotics) have been previously used for other purposes.

The ALS study involved an online standardized collection of self-reported study participant data. The participants decided whether or not they would be taking the drug. PatientsLikeMe developed an algorithm to match study participants on the drug with at least one other participant not taking the drug in order to reduce the chance of false conclusions. The participants were able to see real-time data for groups and individuals on the website as the drug trial unfolded.

The social network approach took nine months to design, recruit, and present preliminary results, compared to about a year and a half for conventional trials.

Wednesday, April 20, 2011

Stuttering and the Brain Atlas

A recent article in the Wall Street Journal (Wednesday, April 12, 2011) discussed the development of a comprehensive brain map, funded by Paul Allen, a cofounder of Microsoft. This computerized atlas of the human brain provides an interactive research tool to study the anatomy and the genes that underlie the mind and is freely available at

Specifically, the atlas provides a three dimensional interactive archive mapping overall brain anatomy at a high level of detail, nerve structure, cell features, and a comprehensive readout of gene activity. It may help researchers to understand the underlying brain biochemistry as well as where and how genes are at work in the brain. As such, it may provide clues to the root causes of neurological problems such as stuttering.

In the past, linking symptoms of a disease to the biochemistry of the genes that may be responsible for the disease had been very difficult. But the brain map identifies the location where a gene may be active in the brain, which is at the core for understanding how brain diseases work.

About 1000 anatomical landmarks had been catalogued for two normal adult brains (donated for research), which were then linked to the thousands of genes that act in complex combinations for normal neural development and function.

The researchers expect to add eight more brains to the database by the end of next year. It would be interesting to include brains of individuals suffering from various neurological ailments, including stuttering. Anyone wishing to contribute their brain should contact the Allen Institute for Brain Science in Seattle, Washington

Wednesday, April 6, 2011

Stuttering and the Dual Premotor System

Although we discussed the medial and lateral premotor systems separately, they are part of an integrated motor function system known as the dual premotor system as shown in Figure 1. Loop 1 characterizes the medial premotor system, while loop 2 represents the lateral system.

The planning and initiation stages of speech originate in the cerebral cortex and the signals then pass through the basal ganglia back to the cerebral cortex via the supplementary motor area (SMA; not shown). The thalamus regulates the messaging to the SMA. This is the upstream loop for self-initiated, internally cued speaking situations.

For non-stutterers, the segments of motor activity (i.e., syllables), then pass unimpeded through the SMA and various other premotor areas, eventually reaching the cerebellum, which is a part of the downstream loop. On the other hand, stutterers experience impaired signaling in the area of the brain associated with the basal ganglia/SMA and neuronal signals are impeded from reaching the cerebellum.

Note that the inputs to the cerebellum from various regions of the cerebral cortex are more limited than the cerebral inputs to the basal ganglia as indicated by the smaller box within the larger one that denotes the cerebral cortex. The cerebellum promotes coordination and fine motor control of movement by influencing the output of brain motor systems to the peripheral nervous system (not shown in Fig. 1). To achieve this fine motor control, the cerebellum may be engaged in feedback control, going through several iterations in loop 2, modulated by sensory or other input.

As we indicated in the previous post, for certain activities such as chorus speaking, singing, altered auditory feedback, etc., loop 1 may be preempted, allowing the speaker to utilize only loop 2 which does not have the impairments associated with loop 1. Finally, note that there are limbic inputs (related to emotions) to loop 1, implying that emotional factors may further influence (perhaps negatively) the activity of this loop.

Friday, April 1, 2011

Stuttering and the Lateral Premotor System

Individuals who stutter might be perplexed by their sudden fluency in certain contexts. For example, when speaking in unison as part of a chorus, they tend to be quite fluent. Similarly, fluency is enhanced when singing, speaking to the beat of a metronome, or consciously engaging in rhythmic monotonic speech. And the use of altered audio feedback devices improves fluency, at least temporarily.

Speech that is consciously controlled by role playing, imitating a foreign accent, or reducing the speech rate may also enhance fluency. Some individuals also observe that hyper-preparation for a public speaking engagement results in greater fluency by virtue of allowing for greater attention to the speech process; similarly, repeatedly reading a sentence in a clinical setting has been shown to improve fluency.

What all of these instances of enhanced fluency have in common is that the neural circuitry used in these situations circumvents the upstream medial premotor system (see the post on "Stuttering and the Medial Premotor System") which involves the basal ganglia as a timing mechanism. Instead of the medial premotor system, speech production is initiated further downstream by the lateral premotor system. This system involves only the cerebellum as the timing mechanism and, consequently, the faulty timing signals of the basal ganglia/SMA complex does not come into play.

A diagrammatic representation of the lateral premotor system is shown in Figure 1. Note that neural signals are passed from the lateral premotor cortex to the cerebellum, and from there to the arcuate premotor area (APA) in the cortex instead of the supplementary motor area (SMA) as was the case with the medial premotor system. Presumably, the dopamine receptor imbalance that may be present in the basal ganglia/SMA complex is absent from the neural circuitry of the lateral premotor system.

In the speaking contexts cited above, either the speech process relies on external timing cues or the cerebral cortex is relieved of certain planning and initiation actions. In either case, the circumvention of the neurally dysfunctional medial premotor system is facilitated and, instead, the lateral premotor system, operating in relation to sensory input, is directly activated.

On the other hand, the medial premotor system is brought into play for self-initiated, internally cued speaking situations. These situations reflect thoughts and emotions and involve the execution of automatized sequences of learned movements (i.e., speaking syllables of words) without attention. Consequently, such situations may lead to greater disfluency. Also, since there are limbic system inputs (i.e. the system relating to emotions) to the medial premotor system both at the cortical and basal ganglia levels, emotional responses may have an additional impact on fluency.