I found a number of podcasts all available free on ITunes. I gather that most of these can be found also on the web. They include:
Stuttertalk.com by Peter Reties and Eric Jackson (165 episodes)
Stuttering is Cool by Daniele Rossi (114)
Stuttering 101 by the Stuttertalk people (26)
Stuttering Me by Greg@Stuttering.Me (39)
Make Room for the Stuttering by Pamela Mertz (50)
Stuttering John Smith (28)
In addition, you can buy the complete episodes of Porky Pig for about $20 or one episode entitled "The Case of the Stuttering Pig" for about $2.00. But it is questionable as to whether Porky was a stutterer--he may have been a clutterer or maybe even a stutterer/clutterer.
Friday, March 25, 2011
Thursday, March 17, 2011
Is Gene Therapy for Stuttering Near?
A fascinating article appearing in the Wall Street Journal ("Gene Therapy Raises Hopes for Parkinson's Treatment," March 17, p. A5) discusses a phase II trial for a Parkinson's gene therapy treatment. While in many ways, Parkinson's disease is the opposite of stuttering--too little dopamine vs. too much--the specific treatment may be applicable to stuttering.
Patients with Parkinson's also lose GABA. The therapy involves delivering a glutamic acid decarboxylase (GAD) gene to the bilateral subthalamic nuclei (STN) in the brain via an inert virus. The gene is responsible for making the chemical GABA and the therapy is said to improve motor function in Parkinson's victims.
Since some drugs such as benzodiazepines and pagoclone act to enhance the GABAergic system, it appears that the therapy cited above for Parkinson's might function also to increase GABA levels in people who stutter.
The controlled double blind phase II trials have been quite successful and Neurologix, Inc. is working with the USFDA to launch a phase III trial. And gene therapy for stuttering may be closer than you think.
A website providing more info can be found at:
www.fiercebiotech.com/story/neurologixs-gene-therpay-shows-parkinsons-promise/2011-03-17
A news release from Neurologix can be found at:
http://www.fiercebiotech.com/press-releases/neurologix-inc-therapy-lets-parkinson-patients-walk-carry-groceries
Patients with Parkinson's also lose GABA. The therapy involves delivering a glutamic acid decarboxylase (GAD) gene to the bilateral subthalamic nuclei (STN) in the brain via an inert virus. The gene is responsible for making the chemical GABA and the therapy is said to improve motor function in Parkinson's victims.
Since some drugs such as benzodiazepines and pagoclone act to enhance the GABAergic system, it appears that the therapy cited above for Parkinson's might function also to increase GABA levels in people who stutter.
The controlled double blind phase II trials have been quite successful and Neurologix, Inc. is working with the USFDA to launch a phase III trial. And gene therapy for stuttering may be closer than you think.
A website providing more info can be found at:
www.fiercebiotech.com/story/neurologixs-gene-therpay-shows-parkinsons-promise/2011-03-17
A news release from Neurologix can be found at:
http://www.fiercebiotech.com/press-releases/neurologix-inc-therapy-lets-parkinson-patients-walk-carry-groceries
Stuttering and the Medial Premotor System
In previous posts we have discussed the possible role of dopamine imbalances in the basal ganglia as a cause of stuttering. We now elaborate in greater detail as to how these imbalances may lead to disfluency by means of a model for speech production initially proposed by Van Riper and further elaborated by Per Alm.
Figure 1 is a schematic representation of the medial premotor system, the components of which are responsible for the production of speech. The medial premotor cortex (a part of the brain in the cerebral cortex responsible for the planning, selection and execution of actions) sends signals to the basal ganglia. These signals pass via neuronal pathways and are mediated by neurotransmitters.
In turn, the basal ganglia provides signals to the supplementary motor area (SMA). The SMA is an area in the cerebral cortex involved in actions under internal control, like the performance of a sequence of movements from memory. Speaking the syllables making up a word constitutes such a sequence.
In both of these cases, the problem may originate either directly in the basal ganglia or, alternatively, through impaired inputs from the premotor area leading to an out of control basal ganglia with either a too weak signal or one attenuated by too much noise.
The medial premotor system, connecting the cerebral cortex to the basal ganglia, involves the nigrostriatal pathway. This pathway has close associations with the mesolimbic pathway (governing emotions), and because of this association, emotional states engendered by a particular context may influence motor activities such as those involving speech (see the previous "Anxious Brain" posts).
In a subsequent post, we will discuss the role of the lateral premotor system in the production of speech.
Figure 1 is a schematic representation of the medial premotor system, the components of which are responsible for the production of speech. The medial premotor cortex (a part of the brain in the cerebral cortex responsible for the planning, selection and execution of actions) sends signals to the basal ganglia. These signals pass via neuronal pathways and are mediated by neurotransmitters.In turn, the basal ganglia provides signals to the supplementary motor area (SMA). The SMA is an area in the cerebral cortex involved in actions under internal control, like the performance of a sequence of movements from memory. Speaking the syllables making up a word constitutes such a sequence.
The basal ganglia play a role in the initiation and regulation of motor commands. In particular, the basal ganglia system may very well contain the timer that influences the production of speech. Speech is a sequential motor task requiring exact timing and in order to execute each syllable, a "go" signal is required. The signal that is provided by the basal ganglia as a feed into the SMA cues the SMA to release the next segment (i.e., syllable) in the word sequence. Stuttering is viewed as a disruption of this sequencing of the syllables making up a word as a result of disturbed timing. If the signal is weak, then the next segment may not be released resulting in repetitions, haltings, and prolongations of the previous segment.
The neurotransmitter dopamine is the principal mediator of basal ganglia functions such as timing. The timing resulting from "normal" levels of dopamine is shown in Figure 2. A weak timing signal from the basal ganglia can occur in two ways. First, insufficient dopaminergic activity in the basal ganglia may lead to a weak signal feeding into the SMA, as shown in Figure 3.
Secondly, excessive levels of dopamine in the basal ganglia may result in an effectively weakened signal to the SMA due to noise drowning out much of the signal. This situation is shown in Figure 4. The "useful" part of the signal is that portion jutting above the noise and its amplitude is obviously diminished. Medications that reduce the level of dopaminergic activity and reduce the noise would be appropriate for this group of stutterers.
In both of these cases, the problem may originate either directly in the basal ganglia or, alternatively, through impaired inputs from the premotor area leading to an out of control basal ganglia with either a too weak signal or one attenuated by too much noise.
The medial premotor system, connecting the cerebral cortex to the basal ganglia, involves the nigrostriatal pathway. This pathway has close associations with the mesolimbic pathway (governing emotions), and because of this association, emotional states engendered by a particular context may influence motor activities such as those involving speech (see the previous "Anxious Brain" posts).
In a subsequent post, we will discuss the role of the lateral premotor system in the production of speech.
Wednesday, March 9, 2011
Neurofeedback and Stuttering
Functional magnetic resonance imaging (FMRI) has provided insights into the possible neurological sources of stuttering. FMRI measures the change in blood flow as a result of neural activity in the brain and can document the active regions and functional activity of the brain at work in almost real-time. Evidence for the dopamine hypothesis of stuttering was provided by FMRI studies.
But FMRI has more recently been used to help individuals to control their brains through a neurofeedback mechanism. A cover article on "Understanding Pain," appeared in a recent issue of Time magazine (March 7, 2011). Specifically, subjects were given live access to an image of their brains' functional activity and were taught to control pain when a heat probe was applied to their arms. Their brains were essentially retrained to control the activation of neural pathways by targeting specific brain regions and processes.
The success of neurofeedback to control pain raises the question as to whether stutterers can cultivate the ability to control their brain processes so as to achieve greater fluency. Stuttering, being basically a mind/body problem, could possibly be amenable to such an approach. Dopaminergic pathways in both the motor neuron and the mesolimbic (governing emotions) sections of the brain might be controllable through neurofeedback mechanisms.
Anecdotal evidence that some individuals can control their fluencies to some extent has been discussed in a previous post (i.e., "Endogenously Reducing Dopamine"). It is interesting to speculate that these individuals may be engaging in some sort of neurofeedback at a subliminal level. In addition, certain aspects of speech therapy may informally and implicitly use neurofeedback (as well as biofeedback) approaches.
The exact mechanisms by which this fluency control is accomplished have not been identified. For example, whether dopaminergic activity is actually reduced or merely over-ridden is in question. However, with the use of FMRI, this question might be resolved and approaches developed whereby neurofeedback to improve fluency would be made available to a larger audience.
The use of FMRI has limitations with respect to the expense of the FMRI apparatus and the artificiality of the environment (i.e., lying on one's back and surrounded with noisy machinery) in which the subject would be placed.
A different method to study brain function is electroencephalography (EEG). Benefits of EEG compared to FMRI are that hardware costs are substantially lower, the machinery is less bulky and can be deployed in a wider variety of environments, and greater temporal resolution is enabled (on the order of milliseconds rather than seconds). In addition, the EEG is relatively tolerant of subject movement and is silent.
The limitations of EEG are that it has significantly lower spatial resolution and analyses of EEG results use relatively simple paradigms, compared with FMRI studies. Moreover, the EEG is most sensitive to postsynaptic potentials generated by the superficial layers of the cortex, namely the pyramidal neurons of the cortex because they are well-aligned and fire together. Voltage fields fall off with the square of the distance so activity from deep sources is more difficult to detect than currents near the skull. Thus, neuronal activity that emanates from the dorsal and ventral striata and the amygdala, potentially influencing fluency but deep within the brain, contribute far less to the EEG signal.
However, insofar as dopaminergic pathways and feedback loops exist between the deeper regions and the cortex, the measured EEG signals may contain information about the functioning of these deeper regions. An interesting study found at the URL,
www.bmedreport.com/archives/3138
claims to have identified potential EEG markers for stuttering based on comparing the EEGs of 26 children who stuttered with 21 age matched controls. Substantial differences in brain wave patterns exist between the two groups.
In summary, it appears that further explorations of neurofeedback mechanisms to ameliorate disfluency might be warranted, one of the major advantages being the elimination or reduction of the use of drugs.
But FMRI has more recently been used to help individuals to control their brains through a neurofeedback mechanism. A cover article on "Understanding Pain," appeared in a recent issue of Time magazine (March 7, 2011). Specifically, subjects were given live access to an image of their brains' functional activity and were taught to control pain when a heat probe was applied to their arms. Their brains were essentially retrained to control the activation of neural pathways by targeting specific brain regions and processes.
The success of neurofeedback to control pain raises the question as to whether stutterers can cultivate the ability to control their brain processes so as to achieve greater fluency. Stuttering, being basically a mind/body problem, could possibly be amenable to such an approach. Dopaminergic pathways in both the motor neuron and the mesolimbic (governing emotions) sections of the brain might be controllable through neurofeedback mechanisms.
Anecdotal evidence that some individuals can control their fluencies to some extent has been discussed in a previous post (i.e., "Endogenously Reducing Dopamine"). It is interesting to speculate that these individuals may be engaging in some sort of neurofeedback at a subliminal level. In addition, certain aspects of speech therapy may informally and implicitly use neurofeedback (as well as biofeedback) approaches.
The exact mechanisms by which this fluency control is accomplished have not been identified. For example, whether dopaminergic activity is actually reduced or merely over-ridden is in question. However, with the use of FMRI, this question might be resolved and approaches developed whereby neurofeedback to improve fluency would be made available to a larger audience.
The use of FMRI has limitations with respect to the expense of the FMRI apparatus and the artificiality of the environment (i.e., lying on one's back and surrounded with noisy machinery) in which the subject would be placed.
A different method to study brain function is electroencephalography (EEG). Benefits of EEG compared to FMRI are that hardware costs are substantially lower, the machinery is less bulky and can be deployed in a wider variety of environments, and greater temporal resolution is enabled (on the order of milliseconds rather than seconds). In addition, the EEG is relatively tolerant of subject movement and is silent.
The limitations of EEG are that it has significantly lower spatial resolution and analyses of EEG results use relatively simple paradigms, compared with FMRI studies. Moreover, the EEG is most sensitive to postsynaptic potentials generated by the superficial layers of the cortex, namely the pyramidal neurons of the cortex because they are well-aligned and fire together. Voltage fields fall off with the square of the distance so activity from deep sources is more difficult to detect than currents near the skull. Thus, neuronal activity that emanates from the dorsal and ventral striata and the amygdala, potentially influencing fluency but deep within the brain, contribute far less to the EEG signal.
However, insofar as dopaminergic pathways and feedback loops exist between the deeper regions and the cortex, the measured EEG signals may contain information about the functioning of these deeper regions. An interesting study found at the URL,
www.bmedreport.com/archives/3138
claims to have identified potential EEG markers for stuttering based on comparing the EEGs of 26 children who stuttered with 21 age matched controls. Substantial differences in brain wave patterns exist between the two groups.
In summary, it appears that further explorations of neurofeedback mechanisms to ameliorate disfluency might be warranted, one of the major advantages being the elimination or reduction of the use of drugs.
Friday, March 4, 2011
The King's Speech Inspiration
Here is the URL for another New York Times article inspired by "The King's Speech."
http://cityroom.blogs.nytimes.com/2011/03/03/relearning-speech-to-make-it-cushiony-not-jagged/?ref=todayspaper
http://cityroom.blogs.nytimes.com/2011/03/03/relearning-speech-to-make-it-cushiony-not-jagged/?ref=todayspaper
Tuesday, March 1, 2011
Impact of EXPRESS Pagoclone Trial Group Inhomogeneities
In the published results of the EXPRESS (EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study) pagoclone trials*, the pagoclone group and the placebo group were inhomogeneous with respect to at least one characteristic. Specifically, the mean social anxiety of the groups as measured by the Liebowitz Social Anxiety Scale (LSAS) differed--the pagoclone group measured 46, while the placebo group scored 56. So the placebo group tended to have a higher degree of social anxiety.
Given that stuttering is both a function of the brain as well as the mind (anxiety being a mind state), we can attempt on a priori grounds to determine the direction of potential bias of the LSAS inhomogeneity with respect to trial outcomes.
One question that arises concerns a potential relationship between social anxiety and suggestibility. Might individuals with high levels of social anxiety be more suggestible? For example, a high anxiety individual might be more strongly motivated to hope or believe in a placebo's positive outcome if only as a relief from the discomfort of an anxious mind. If this were the case, a placebo might have a stronger effect on the higher anxiety placebo group and the difference of the fluency outcomes between the pagoclone and placebo groups would be narrowed. Thus, the efficacy of pagoclone, as measured by the extent that fluency is improved beyond the placebo response, might be biased downward (i.e., underestimated). In addition, the significance level associated with the outcome might also be reduced.
Even if there were no significant correlation between social anxiety and suggestibility, the placebo group, having the higher average LSAS score, might be more responsive to a placebo. In the several previous posts on "The Anxious Mind Affects Stuttering," we emphasized that stuttering is not only a physiological problem associated with the brain, but also a mind problem. A placebo tends to be particularly efficacious for the mind portion of a mind/body problem such as stuttering. So, if this were the case, we might again expect pagoclone efficacy to be underestimated.
The problem of group inhomogeneities is endemic to ANOVA types of analyses, such as was performed in the pagoclone EXPRESS study. Granted that the group numbers in this study were relatively small, but even for larger trials various inhomogeneities may still be a problem.
A possible resolution to this problem might be the use of regression analysis approaches of the type suggested in two of the recent posts discussing a proposal for the analysis of pagoclone trials. The units of observation become the individuals participating in the trial rather than the groups, and the LSAS can be used as an additional explanatory variable in any of the models suggested in those posts. For example, a logarithmic model might be (ignoring the suggestibility variable):
ln(DFA) = a + b*ln(DFB) +c*T + d*ln(LSAS) + e
where the variables DFA, DFB, and T were defined in the post, "A Proposal for Analyzing Pagoclone Trials." In addition, non-linear effects of the LSAS can be explored by entering quadratic terms as well as cross products of LSAS with the other explanatory variables in the model.
* G. Maguire, et al, Journal of Clinical Psychopharmacology (Feb. 2010), pp. 48-56, Vol. 30, Number 1.
(copyright 2011)
Given that stuttering is both a function of the brain as well as the mind (anxiety being a mind state), we can attempt on a priori grounds to determine the direction of potential bias of the LSAS inhomogeneity with respect to trial outcomes.
One question that arises concerns a potential relationship between social anxiety and suggestibility. Might individuals with high levels of social anxiety be more suggestible? For example, a high anxiety individual might be more strongly motivated to hope or believe in a placebo's positive outcome if only as a relief from the discomfort of an anxious mind. If this were the case, a placebo might have a stronger effect on the higher anxiety placebo group and the difference of the fluency outcomes between the pagoclone and placebo groups would be narrowed. Thus, the efficacy of pagoclone, as measured by the extent that fluency is improved beyond the placebo response, might be biased downward (i.e., underestimated). In addition, the significance level associated with the outcome might also be reduced.
Even if there were no significant correlation between social anxiety and suggestibility, the placebo group, having the higher average LSAS score, might be more responsive to a placebo. In the several previous posts on "The Anxious Mind Affects Stuttering," we emphasized that stuttering is not only a physiological problem associated with the brain, but also a mind problem. A placebo tends to be particularly efficacious for the mind portion of a mind/body problem such as stuttering. So, if this were the case, we might again expect pagoclone efficacy to be underestimated.
The problem of group inhomogeneities is endemic to ANOVA types of analyses, such as was performed in the pagoclone EXPRESS study. Granted that the group numbers in this study were relatively small, but even for larger trials various inhomogeneities may still be a problem.
A possible resolution to this problem might be the use of regression analysis approaches of the type suggested in two of the recent posts discussing a proposal for the analysis of pagoclone trials. The units of observation become the individuals participating in the trial rather than the groups, and the LSAS can be used as an additional explanatory variable in any of the models suggested in those posts. For example, a logarithmic model might be (ignoring the suggestibility variable):
ln(DFA) = a + b*ln(DFB) +c*T + d*ln(LSAS) + e
where the variables DFA, DFB, and T were defined in the post, "A Proposal for Analyzing Pagoclone Trials." In addition, non-linear effects of the LSAS can be explored by entering quadratic terms as well as cross products of LSAS with the other explanatory variables in the model.
* G. Maguire, et al, Journal of Clinical Psychopharmacology (Feb. 2010), pp. 48-56, Vol. 30, Number 1.
(copyright 2011)
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