deep brain stimulation


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deep brain stimulation

Postby shilpashah » Sat Mar 28, 2009 8:38 pm

Has anyone heard about deep brain stimulation and PSP.
ss
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Postby Robin » Sat Mar 28, 2009 9:25 pm

shilpashah,

DBS in the area of the brain targeted for PD (which is the STN) is not advisable for PSP. There is a special study going on now in Canada of DBS targeting a different brain area in PSP patients. You can do a search of posts containing the word "DBS" and I'm sure you'll find a post about this study.

Robin
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Postby josephblanc » Sun Mar 29, 2009 8:02 am

There is a June 2008 UK article dealing with the problem I have copied the entire item, but immediately below is the major conclusion.

What does the outcome of this research mean for people with PSP?
The research aim was to assist development of treatments designed to protect, restore or stimulate the PPN and thus hopefully relieve some of the most disabling symptoms of PSP. We have shown that muscarinic receptors are present and hence available, but that as there are differences in cholinergic parameters between PSP and PD the response to deep brain stimulation of the PPN in PSP may differ from PD. It has been suggested that in PSP DBS of the PPN will give greater benefit if combined with DBS of the STN, as in advanced PD (Stefani A et al 2007; Benatru I et al 2008). Our results indicate that cholinergic modulation in the midbrain may show positive effect combined with pro-dopaminergic medication.


***

Cholinergic dysfunction resulting from degeneration of the pedunculopontine tegmental nucleus in PSP: A major determinant of clinical features?

Margaret Piggott - NEW2 - web.jpgLead researchers Dr Margaret Piggott and Professor David Burn
Co-researchers Professor Andrew J Lees, Dr David R Williams, Professor Tamas Revesz, Professor Robert Perry, Professor Philip Winn

Institution Institute for Ageing and Health, Newcastle University

Duration 27 months
Start April 2006 End June 2008

Grant £89,400

Aim of research
• To test the hypothesis that falls, slowness, rigidity, and poor response to levodopa in PSP may be caused by degeneration of the cholinergic projections in the pedunculopontine nucleus (PPN).
• To test the hypothesis that there are differences in acetylcholine neurotransmission between patients with PSP-Parkinson (PSP-P) and the more typical PSP-Richardson's syndrome (PSP-R) and with patients with Parkinson's disease.

About the research
Many PSP patients can be subdivided into two groups, PSP-P which resembles Parkinson's disease in the early stages and PSP-R, which does not (Williams DR et al, 2005). In ‘Richardson's syndrome' falls and eye movement problems are prominent and early features, while in ‘PSP-P' falls and eye movement problems tend to occur later, or not at all. This research is aimed at elucidating the underlying reasons for these differences which may help in the development of an effective treatment for PSP.

The pedunculopontine nucleus (PPN) is a small area in the midbrain (at the upper end of the brainstem) which produces acetylcholine and releases it in the thalamus. It consists of a compact part (PPNc) with a higher density of cholinergic neurons, and a diffuse part (PPNd) which has glutamatergic and other neuron types as well as cholinergic. The PPN has an influence on the movement control circuits in the brain, and is a potential target for deep brain stimulation in Parkinson's disease and PSP.

The midbrain just below the PPN also has the cholinergic laterodorsal tegmental nucleus - of interest in PSP as it is involved in sleep. The substantia nigra lies at the rostral end of the PPN and is a target for PPN neurons. The SN produces dopamine, which is reduced in PSP and PD.

We collected frozen midbrain samples donated to the Queen Square Brain Bank from 9 cases of PSP-P, 10 cases of PSP-R, 10 cases of PD and 10 normal elderly control cases, supplemented with 6 cases of PSP (not clinically classified), 5 PD and 10 controls from the Newcastle Brain Tissue Resource. For further disease comparison we sampled cases of Parkinson's disease dementia and dementia with Lewy bodies, which have some attributes in common with PSP, e.g. poor response to levodopa and a tendency to falls.

Midbrains were sectioned and at intervals stained and assessed to visualize and map the anatomy and indicate acetylcholinesterase activity. Cholinergic receptors were measured by radioactively labelled drugs which bind to receptors and can be shown up by sensitive film autoradiography. We examined several areas in the midbrain as well as the PPN. Cholinergic muscarinic M1, M2, M4, and M3/M5 receptors were measured, and the relative preservation or degree of atrophy of the midbrain nuclei assessed by acetylcholinesterase staining and cross-sectional area in the autoradiographs. Nicotinic cholinergic receptors were also measured, giving an additional parameter of cholinergic loss.

Findings
Currently, we are analyzing the results and preparing them for publication.

We have confirmed our initial hypothesis, finding reduced acetylcholinesterase staining density in PPNc in both PSP-R and PSP-P compared to controls, while staining density in PD was not significantly reduced compared to controls. PSP-R cases tended to have lower acetylcholinesterase than PSP-P.

The hope of assessing PPN cholinergic neurons by quantifying urotensin receptors, reported to be uniquely expressed in cholinergic neurons in rat PPN, was not fulfilled; urotensin binding in the human PPN proved elusive.

For muscarinic receptors, the midbrain has mostly M2, then M3/M5, at higher density than M1 or M4. There were no significant changes between groups for either M1 or M4 receptors. Preliminary results for the M2 receptors show they were significantly higher (20-30%) in PSP cases compared to either controls or PD in the PPNd, but there was not a difference between PSP-P and PSP-R subgroups. Comparison of M3/M5 binding density is not yet complete.

We will correlate our findings with the results of our completed and published investigations of cholinergic systems, particularly in the thalamus, but also in striatum and cortex of PSP (Warren NM et al 2005; 2007a and b; 2008).

What does the outcome of this research mean for people with PSP?
The research aim was to assist development of treatments designed to protect, restore or stimulate the PPN and thus hopefully relieve some of the most disabling symptoms of PSP. We have shown that muscarinic receptors are present and hence available, but that as there are differences in cholinergic parameters between PSP and PD the response to deep brain stimulation of the PPN in PSP may differ from PD. It has been suggested that in PSP DBS of the PPN will give greater benefit if combined with DBS of the STN, as in advanced PD (Stefani A et al 2007; Benatru I et al 2008). Our results indicate that cholinergic modulation in the midbrain may show positive effect combined with pro-dopaminergic medication.

Publications arising directly from the research
Piggott MA, Wright Muelas M, Burn DJ
British Neuroscience Association Abstracts 2007 Cholinergic neurons in human midbrain labelled with 125I Urotensin II in post-mortem tissue in Progressive Supranuclear Palsy and normal elderly.

Weblinks

Institute for Ageing and Health

Professor David Burn

References

Benatru I, Vaugoyeau M, Azulay JP. Postural disorders in Parkinson's disease. Neurophysiologie Clinique/Clinical Neurophysiology In Press.

Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E, Mazzone P. 2007. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 130(Pt 6):1596-1607.

Warren NM, Piggott MA, Lees AJ, Burn DJ. 2007a. The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases. Journal of Neurology, Neurosurgery, and Psychiatry 78(6):571-575.

Warren NM, Piggott MA, Lees AJ, Burn DJ. 2007b. Muscarinic receptors in the thalamus in progressive supranuclear palsy and other neurodegenerative disorders. J Neuropathology and Experimental Neurology 66(5):399-404.

Warren NM, Piggott MA, Lees AJ, Perry EK, Burn DJ. 2008. Intact coupling of M1 receptors and preserved M2 and M4 receptors in the cortex in progressive supranuclear palsy: Contrast with other dementias. Journal of Chemical Neuroanatomy 35(3):268-274.

Warren NM, Piggott MA, Perry EK, Burn DJ. 2005. Cholinergic systems in progressive supranuclear palsy. Brain 128(Pt 2):239-249.

Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, Holton JL, Revesz T, Lees AJ. 2005. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 128(Pt 6):1247-1258.


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josephblanc
 

Postby eplowman » Sun Mar 29, 2009 2:41 pm

Joe,

Good find. Thanks for posting.

The researchers still have many theories to check (many references to "may," and phrases like, "it was suggested," etc., point to an unfinished symphony or work in progress), but it's reassuring to know they are still making advances in our understanding of PSP. We'll have a clearer picture in time.

One little niggling thing: I wish they would have elaborated more on the dopamine issue: why it has little or no effect on PSP-R patients, in contrast to many of those with PSP-P. They SEEMED to suggest that ALL patients with PSP have deficits of dopamine --- and, based on what they reported, I'm not so sure that is so. How are dopamine levels measured? It would help to know more of the basic details (without making us go digging in Google for possible answers :) ).

Again, thanks for posting.

ed p.
|My wife of 56 years was Rose b. 1930, dx 1999, symptoms from 1997; d. 06/21/08; PSP autopsy confirmed.
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Postby Robin » Sun Mar 29, 2009 5:23 pm

Ed,
All PSP patients do have deficits in dopamine. It could be that those with RS have greater acetylcholine deficits, which might account for the dementia.
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Postby josephblanc » Mon Mar 30, 2009 1:53 pm

Ed:

Below is the abstract of a 2008 PhD thesis. PhD students often throw in everything that they have learned and done, including the kitchen sink! But that is precisely what you seem want. I am not at all sure that this well help you. We all, at least some of the time, want to know in enormous detail about something [you have the suspicious instinct of a reporter on the beat; I have the optimistic instinct of a scientist who believes what his peers say.] None of us can know everything about everything; we are lucky if there are some of us know “everything” about a few things. For the most part, willy-nilly, we will have to continue to continue to rely on the results of the so-called experts, with the foreknowledge that some of these will turn out to be terribly wrong.

In principle, the work reported here is a nice piece of standard analytic and physical chemistry to find the position and motion of dopamine. I say “in principle” because if it were possible to do it in a laboratory where everything that needed to be controlled was, the results might well be unambiguous. But, that is not the situation here where the experiments are in vivo not in vitro. Indeed, Ms Cropley is careful to note that: “The pitfalls and complexity of radioligand imaging are discussed within the context of [18F]fallypride, [11C]NNC 112 and [18F]FDOPA measurement. Lastly, this thesis demonstrates some promise for using molecular imaging to explore the neurochemical underpinnings of higher cortical function.” The final statement “demonstrates some promise for using molecular imaging to explore the neurochemical underpinnings” is pretty weak, and I’m sure that is the way that it is intended.

Joe Blanc

***

Molecular imaging of striatal and extrastriatal components of the dopamine system : positron emission tomographic studies in healthy subjects and Parkinson Disease

Cropley, Vanessa L.; Swinburne University of Technology
2008; , thesis(phd), thesis
Brain imaging, Dopamine, Dopamine mechanisms, Molecular imaging, Parkinson Disease, Receptors, Positron emission tomography, Radioligland

Description
Dopamine plays a pivotal role in the regulation and control of cognition, movement and motivation and is involved in a variety of neurological and psychiatric disorders. Molecular imaging with positron emission tomography (PET) and radiolabeled compounds has enabled the in vivo assessment of the distribution and density of receptors, enzymes and other cellular processes pertaining to the dopamine system in normal and pathological states. Until recently, such measurements have been restricted to the striatum, due to the paucity of appropriate radioligands for measurement of low density targets. With the development of radioligands suitable for extrastriatal measurement, examination of the different components of the dopamine system in not only the striatum, but also extrastriatal regions, is possible, in living human brain. Therefore, the aims of this thesis were to assess, by means of two independent experimental PET studies, the feasibility of imaging pre-, post- and intra-synaptic components of the dopamine system in the striatum, as well as extrastriatal areas. Change in dopamine markers were assessed in human subjects with a compromised dopamine system, altered by pharmacological (Study 1) or pathological (Study 2) means. Specifically, intra-synaptic dopamine transmission (“phasic” and “tonic” dopamine release) was examined with [18F]fallypride (for post-synaptic D2-like receptors) and pharmacological challenges to either increase or decrease dopamine transmission in young healthy subjects (Study 1), whereas pre- and post-synaptic dopamine transmission was assessed with [18F]FDOPA (for pre-synaptic dopamine synthesis) and [11C]NNC 112 (for post-synaptic D1-like receptors) in a patient cohort characterised by chronic dopamine deficiency (Parkinson disease) (Study 2). In each study, associations between these dopamine markers and higher cognitive functions were explored. Findings confirm that [18F]fallypride and [11C]NNC 112 are able to be quantified in striatal and extrastriatal regions. Cortical [18F]FDOPA uptake however, was unable to be quantified. Stimulant-induced dopamine release with d-amphetamine successfully displaced [18F]fallypride binding in striatum and several extrastriatal regions. However, depletion of dopamine with AMPT did not appear to modulate [18F]fallypride in any region (Study 1). Parkinson disease patients did not show alteration of striatal or cortical D1 receptors despite significantly reduced dopamine metabolism in the striatum, which was associated with executive impairment (Study 2). These studies demonstrate the capability of PET, with radioligands targeting presynaptic synthesis and post-synaptic D1 and D2 receptors, to assess different components of the dopamine system in striatum and extrastriatum. The pitfalls and complexity of radioligand imaging are discussed within the context of [18F]fallypride, [11C]NNC 112 and [18F]FDOPA measurement. Lastly, this thesis demonstrates some promise for using molecular imaging to explore the neurochemical underpinnings of higher cortical function.
josephblanc
 

Postby eplowman » Mon Mar 30, 2009 6:34 pm

Joe,

Thanks. Interesting, enlightening stuff (especially after I looked up the meanings of some of the key words in the paper <vbg>). If I understand correctly, the researchers used radioactive substances as markers to trace dopamine's effects, or lack thereon, on metabolism in certain parts of the PD brain. It had no apparent effect on receptors where some impact had been expected. So some of the secrets lie locked deeper in the brain, and researchers are looking forward to technological advances that will allow them to probe the hidden areas.

Is that a fair interpretation of one of the paper's main themes?

ed p.
|My wife of 56 years was Rose b. 1930, dx 1999, symptoms from 1997; d. 06/21/08; PSP autopsy confirmed.
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Postby eplowman » Mon Mar 30, 2009 6:46 pm

Robin,

When you have time: If you come across any authoritative document that states that =all= people with PSP have abnormally low levels of dopamine, can you please post me the URL or other source. I'm having trouble finding one. Many thanks.

ed p.
|My wife of 56 years was Rose b. 1930, dx 1999, symptoms from 1997; d. 06/21/08; PSP autopsy confirmed.
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Postby Robin » Mon Mar 30, 2009 8:00 pm

Ed,

Are you looking for scholarly articles or non-scholarly ones? I'd have to go back to the journal articles I read a few years ago to be sure of the scholarly article references. I can start with the Litvan-authored articles.

If you do a Google search on "PSP dopamine deficiency," nearly all of the first page of results are scholarly articles. In Jonathan Pincus's book on "Behavioral Neurology," he talks about PSP being a dopamine deficiency PLUS other stuff.

For non-scholarly stuff, here's something on the curepsp website:

"The mainstay of drugs for Parkinson's disease are those that enhance, replace or mimic a brain chemical called dopamine. Parkinson's responds better to such drugs than does PSP because in PD, deficiency of dopamine is by far the most important abnormality, while in PSP, deficiencies of several other brain chemicals are at least as severe as the dopamine deficiency, and no good way exists to replace those. Also, in PSP, there is damage to the brain cells that receive the dopamine-encoded messages, while these remain intact in Parkinson's."

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Postby eplowman » Tue Mar 31, 2009 12:13 am

Robin,

Thanks. Also thanks for the post of excerpts from the Pincus book you sent by email. This is what I was looking for. What he says there is what I've understood from other limited reading I've done:

Excerpts from:
Behavioral neurology
Jonathan H. Pincus, Gary J. Tucker
4th edition
2003

This is the money paragraph for my purposes (PSP points bolded):

"Thus, there are four kinds of degenerative conditions that are loosely called 'Parkinson's.' One is pure dopamine deficiency. This is true PD. It is eminently treatable and has the best prognosis. The second is Parkinson's Plus, i.e., mostly dopamine deficiency mixed with symptoms that arise from disease of the nervous system beyond dopamine deficiency. The third (SND, OPCA, PSP, MSA, LBD, MID, etc) looks like PD in the sense that there is bradykinesia and postural instability, but these symptoms are only slightly relieved by dopamine replacement therapy as they mostly derive from lesions outside the dopamine system. [The fourth:] The same untreatable diseases can also cause Parkinson-like motor disability and death without ever causing clinically significant dopamine deficiency, and dopamine replacement therapy is completely ineffective." ...


PSP is included in both the third and fourth conditions. If Pincus were writing today and were informed by the Williams et al work, he probably would classify PSP-P under the third condition, and PSP-RS under the fourth.

In short, dopamine deficiency is a non-issue for the majority of PSP patients (those with classic PSP -- the RS variety). And those with PSP-P may receive slight, temporary relief from dopamine replacement therapy (with levodopa, Sinemet, etc.)

Bottom line: In PSP, most or all symptoms come from damage outside the dopamine system. This fact would seem to have implications for those prescribing levodopa and similar drugs for people with PSP.

ed p.
|My wife of 56 years was Rose b. 1930, dx 1999, symptoms from 1997; d. 06/21/08; PSP autopsy confirmed.
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Postby Robin » Tue Mar 31, 2009 1:07 am

Ed,
Maybe but....all PSP patients do have a dopamine deficiency, and I thought that was the bone of contention.
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Postby josephblanc » Tue Mar 31, 2009 8:02 am

Ed:

You asked: "It had no apparent effect on receptors where some impact had been expected. So some of the secrets lie locked deeper in the brain, and researchers are looking forward to technological advances that will allow them to probe the hidden areas. Is that a fair interpretation of one of the paper's main themes?"

Yes. I think you've got it right.

Joe
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Postby eplowman » Tue Mar 31, 2009 8:08 am

Robin,

How does what you just said correlate with what Pincus said:

PSP "can also cause Parkinson-like motor disability and death without ever causing clinically significant dopamine deficiency, and dopamine replacement therapy is completely ineffective." ...

ed p.
|My wife of 56 years was Rose b. 1930, dx 1999, symptoms from 1997; d. 06/21/08; PSP autopsy confirmed.
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Postby yoshi » Sun Apr 05, 2009 8:54 am

From previous post-
Also, in PSP, there is damage to the brain cells that receive the dopamine-encoded messages, while these remain intact in Parkinson's."

Robin
//////////////////////////////////////////
So my question is -
if the brain cell involved in dopamine is dead or damaged or destroyed,what good is drug like levadopa ,sinemet etc?
If the drug works inititally and fails to work later,is it like charging up a battery which is almost dead,the initial positive result is what is left in the battery,after it has been depleted,the battery is totally dead..
this may be off the topic,but Forbes magazine recently published an article of some cancer patients whose cancer disappeared!
One has liver cancer and was told he has 60 days to live,but one day he suffered from stomach ailment and when that recovered,there was no trace of liver cancer .
ANother case was a woman with breast cancer,she came down with a illness and when she recovered,her cancer is gone.
Last case was an Australian,
.
They think it is the immune system which goes into high gear to fight the illnes and wipe out the cancer cells.
the bidy does fight back and it also can grow new cells.
yoshi
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Postby Robin » Sun Apr 05, 2009 11:38 am

Yoshi,
Even if there's damage to dopamine neurons, some neurons might still be functioning in a minor way. Studies (by Williams, et al) have shown that those with PSP-P can be responsive to levodopa for some time.
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Postby yoshi » Mon Apr 06, 2009 4:55 pm

Me think,stem cell implant in the future may just be the only hope ,esp for an older person!
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