Brain, Vol. 117, No. 4, 877-897, 1994

The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson's disease
C. D. Marsden1,0 and J. A. Obeso2


The basal ganglia play a role in controlling movement. The motor circuits within the striato-pallidal complex are thought to facilitate desired movement and inhibit unwanted movement through their influence via thalamus, mainly on precentral motor cortical regions. Lesions in the motor thalamus, or in the globus pallidus, therefore might be expected to impair voluntary movement.

But stereotaxic lesions in patients with Parkinson's disease directed at the motor thalamus verified at autopsy, and lesions in the globus pallidus, which improve rigidity and tremor, apparently do not worsen parkinsonian hypokinesia and bradykinesia; nor do they regularly cause dyskinesias. Reasons for this discrepancy are reviewed.

It is concluded that the motor circuits of the basal ganglia are part of a distributed motor system which can operate, albeit imperfectly, in the absence of striato-pallido-thalamo-cortical feedback.

There may, however, be subtle defects in motor performance after thalamic and pallidal lesions which have escaped attention. Further consideration leads to two hypotheses concerning normal basal ganglia motor function. First, it seems most likely that it is a pause in firing of medial pallidal and substantia nigra reticulata neurons that, by disinhibition of thalamic targets, permits movements generated by cortical motor areas.
\
An increase in firing of medial pallidal neurons, which so far has been the major focus of attention, may be more concerned with inhibition of unwanted movement. Secondly, we suggest that the basal ganglia play a particular role in motor control. A change in firing of medial pallidal neurons appears to occur too late to initiate a new movement. However, the motor circuit within the striato-pallidal system routinely receives a continuous delayed read-out of cortical motor activity and issues an output directed via thalamus mainly to premotor cortical regions. This may permit the routine automatic execution of sequences of movements generated in cortical motor areas.

There is evidence that other regions of the striatum respond to significant external or internal cues as dictated by their cortical inputs, the significance being determined by memory, novelty, emotional and other contexts. We suggest that such events capture the attention of the non-motor striatum, which then interrupts the routine operation of the motor circuit, perhaps at the level of the medial pallidum and substantia nigra pars reticulata, to permit new cortical motor action.


Received February 15, 1993.

http://brain.oxfordjournals.org/cgi/...ract/117/4/877

Stages in the development of Parkinson’s disease-related pathology

Journal Cell and Tissue Research
Publisher Springer Berlin / Heidelberg
ISSN 0302-766X (Print) 1432-0878 (Online)
Issue Volume 318, Number 1 / October, 2004

Abstract The synucleinopathy, idiopathic Parkinsonrsquos disease, is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins at defined induction sites and advances in a topographically predictable sequence. As the disease progresses, components of the autonomic, limbic, and somatomotor systems become particularly badly damaged.

During presymptomatic stages 1–2, inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus.

In stages 3–4, the substantia nigra and other nuclear grays of the midbrain and forebrain become the focus of initially slight and, then, severe pathological changes.

At this point, most individuals probably cross the threshold to the symptomatic phase of the illness. In the end-stages 5–6, the process enters the mature neocortex, and the disease manifests itself in all of its clinical dimensions.

Distribution and roles of metabotropic glutamate receptors in the basal ganglia motor circuit: implications for treatment of Parkinson's Disease and related disorders

Susan T. Rouse, Michael J. Marino, Stefania R. Bradley, Hazar Awad,

Available online 30 April 2001.

Abstract

The basal ganglia (BG) are a set of interconnected subcortical structures that play a critical role in motor control. The BG are thought to control movements by a delicate balance of transmission through two BG circuits that connect the input and output nuclei: the direct and the indirect pathways. The BG are also involved in a number of movement disorders. Most notably, the primary pathophysiological change that gives rise to the motor symptoms of Parkinson's Disease (PD) is the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) that are involved in modulating function of the striatum and other BG structures.

This ultimately results in an increase in activity of the indirect pathway relative to the direct pathway and the hallmark PD symptoms of rigidity, bradykinesia, and akinesia.

A great deal of effort has been dedicated to finding treatments for this disease. The current pharmacotherapies are aimed at replacing the missing dopamine, while the current surgical treatments are aimed at reducing transmission through the indirect pathway. Dopamine replacement therapy has proven to be helpful, but is associated with severe side effects that limit treatment and a loss of efficacy with progression of the disease. Recently developed surgical therapies have been highly effective, but are highly invasive, expensive, and assessable to a small minority of patients.

For these reasons, new effort has been dedicated to finding pharmacological treatment options that will be effective in reducing transmission through the indirect pathway. Members of the metabotropic glutamate receptor (mGluR) family have emerged as interesting and promising targets for such a treatment.

This review will explore the most recent advances in the understanding of mGluR localization and function in the BG motor circuit and the implications of those findings for the potential therapeutic role of mGluR-targeted compounds for PD.

FULL ARTICLE:

http://www.sciencedirect.com/science...aa7f454ba3dda8

"The direct and indirect pathways of the BG act as a fine-tuning mechanism in movement control (Alexander et al., 1986). The balance of transmission through the direct and indirect pathways is tightly regulated by a major modulatory projection from dopaminergic neurons in the substantia nigra pars compacta (SNc). This dopamine input to the striatum regulates the direct and indirect pathways differentially, due to the presence of different postsynaptic dopamine receptors on the two populations of medium spiny neurons. D1 receptors are primarily expressed on medium spiny neurons that project directly to SNr, while D2 receptors are primarily expressed on the medium spiny neurons that constitute the indirect pathway (Gerfen et al., 1990). Because of this differential expression, the release of dopamine in the striatum has a net excitatory effect on the direct pathway, and an inhibitory influence on the indirect pathway."

...the primary pathological change giving rise to the motor symptoms of PD is the selective death of dopaminergic neurons in the SNc. The loss of this important modulatory input results in a decrease in activity through the direct pathway and an increase in activity through the indirect pathway (Albin and Wichmann). These changes lead to increased inhibition of thalamocortical neurons, which is believed to underlie the hallmark symptoms of the disease: rigidity, bradykinesia, and akinesia. The right panel of Fig. 1 schematically illustrates the activity changes in BG-thalamocortical circuitry that are thought to occur in PD.....

....there has been a major focus on developing novel treatment strategies that are aimed at acting downstream of the lost dopaminergic neurons to restore balance to the direct and indirect pathways. This effort has led to development of highly effective surgical treatments, such as pallidotomy (Baron and Laitinen) or high-frequency stimulation of the SNT (Limousin et al., 1995), that are aimed at reducing activity through the indirect pathway. .....

Metabotropic glutamate receptors provide novel therapeutic targets for treatment of movement disorders

That part is complicated!

We compensate!

Cortical motor reorganization in akinetic patients with Parkinson's disease
A functional MRI study
U. Sabatini1,5, K. Boulanouar1, N. Fabre1,2, F. Martin1, C. Carel1,2, C. Colonnese5, L. Bozzao5, I. Berry1,3, J. L. Montastruc4, F. Chollet1,2 and O. Rascol1,4


Using functional MRI (fMRI), we have studied the changes induced by the performance of a complex sequential motor task in the cortical areas of six akinetic patients with Parkinson's disease and six normal subjects. Compared with the normal subjects, the patients with Parkinson's disease exhibited a relatively decreased fMRI signal in the rostral part of the supplementary motor area (SMA) and in the right dorsolateral prefrontal cortex, as previously shown in PET studies.

Concomitantly, the same patients exhibited a significant bilateral relative increase in fMRI signal in the primary sensorimotor cortex, lateral premotor cortex, inferior parietal cortex, caudal part of the SMA and anterior cingulate cortex.

These fMRI data confirm that the frontal hypoactivation observed in patients with Parkinson's disease is restricted to the rostral part of the SMA and to the dorsolateral prefrontal cortex.

These results also show that, apart from the lateral premotor and parietal cortices, increased fMRI signals can be found in other cortical motor areas of these patients, including the posterior SMA, the anterior cingulate cortex and the primary sensorimotor cortices, which are then likely to participate in the same putative attempt by the dopamine-denervated brain to recruit parallel motor circuits in order to overcome the functional deficit of the striatocortical motor loops.

Brain, Vol. 123, No. 2, 394-403, February 2000

http://brain.oxfordjournals.org/cgi/...full/123/2/394

TRY THIS!

Motor task
The activation paradigm consisted of a sequential movement performed with the right hand. This sequential task had been chosen among several others, according to preliminary fMRI data from our laboratory, because it induces a clear activation signal in areas known to be involved in both motor programming and motor execution. To perform this task, the subjects had to (i) make finger-to-thumb opposition movements in the specified order of the index, middle, ring and little finger; (ii) open and clench the fist twice; (iii) complete finger-to-thumb oppositions in the opposite order (i.e. little, ring, middle and index finger); (iv) open and clench the fist twice again; and finally (v) repeat the same series of movements during the 30 s of data acquisition. This was intentionally a more complex and cognitively demanding task than generally used in previously published SPECT and PET studies performed in patients with Parkinson's disease.


Conclusions
The present fMRI neuroimaging study shows that the subcortical putaminal dopamine deficit which characterizes Parkinson's disease disorganizes the cortical motor pathways in a complex way.

It induces a focal `underactivation' restricted to the rostral SMA and DLPC, possibly responsible for the patients' akinesia. It also induces an abnormal pattern of `overactivation' in most of the other known motor cortical areas, including the caudal SMA, the anterior cingulate cortex, the lateral premotor, the primary sensorimotor and the parietal cortices.

This reorganization, which involves parallel-acting multiple motor areas, can be seen as an attempt at motor recovery.

The general aspect of this reorganization resembles what has been described previously with PET in other motor diseases, such as paresis induced by acute stroke (Chollet et al., 1991Go; Weiller, 1995Go; Chollet and Weiller, 1997). It is also interesting to compare the present results with those reported in patients with cerebellar degeneration (Wessel et al., 1995Go). The pattern of motor activation in this last condition appeared to be the opposite to what we observed in Parkinson's disease: several areas of the lateral motor circuit, including the lateral premotor cortex and the lobus parietalis inferior, were less activated in the cerebellar patients than in the normal controls, probably as a result of defective cerebellar inputs, while, in contrast, other premotor systems, including the SMA, were used more heavily in the cerebellar patients than in the controls. It is thus tempting to speculate that these phenomena illustrate the capacity of the adult human brain for functional plasticity in compensating for one motor circuit deficit by recruiting another parallel one. The exact mechanisms of these phenomena remain to be understood.

ANOTHER ARTICLE:

http://www3.interscience.wiley.com/c...405/HTMLSTARTW

Plasticity of the nigropallidal pathway in Parkinson's disease

From another article:

It is hypothesised that bradykinesia is not simply a compensation for defective preparatory processes, but may reflect a defective internal cue in PD which disrupts and impairs the outflow of motor responses.

http://www.springerlink.com/content/l1wkju7393q363tn/

It seems to me that researchers should consult with knowledgeable patients who can describe how PD really feels, and who can show how their tricks work.

That data is important and is missing from most of the research going on.

When I sit on the train for awhile, when I stand up, it's hard to straighten my legs and takes great effort. Then it's difficult to get my legs moving. It actually feels as if there is some unseen force pulling my legs downward. What IS that?

Then, with great effort my legs move slowly, and I stomp like Frankenstein. I get going with a slow gait, but after a while I can walk faster and my legs don't feel as if they're being pulled downward.

But I must focus on a physical thing on the floor ahead of me. As I approach it, I automatically focus on the next thing on the ground ahead of me. I need to be reaching for something with my feet!

I rely on visual cues. I can't walk in the dark, or with my eyes closed. Well, I can, but it's so slow and tentative it's ridiculous. I can't find one study with PD patients walking with eyes closed. I can't walk backwards, probably because I can't see behind myself!

Hello - you whrithe very good about PD, I will print this , my family needs this explaining, it will make them understand the way I behave.
Let me know if it is o.k.

Annelise

This is a very common practice amongst musicians. It is called mental practicing instead of physical practicing, and it is found to be just important. The performer will go through the movements, and music in their head so that the music is well rehearsed mentally so when they have to play in public, the music is second nature.

Who would've thought about using this for every day living!

In regards to getting the movements going after sitting for awhile, I feel the same thing too. It's as though there is glue or suction cups on my shoes, and I can't get moving, but once I do move I'm okay.

I too wish that the researchers and doctors would consult us more because we really kinow what it's like to live with this. All of the theories in the world don't cover the bases like the real thing.

John

Was the hope of generating data such as this. It is almost insulting that these observations are dismissed as "tricks." It would be different if it was simply our ignorance, but the researchers are the same for much of this.

And, while many of us lack the vocabulary of academia, a good researcher could overcome that with the right questions. Any lurkers out there want to explore this? Not holding my breath, of course.

It is not entirely off the wall to suggest that ldopa's success at the symptomatic level has led to the wrong conclusions. Maybe it is more a matter of data processing of stimuli than we think. There are some interesting similarities between schizophrenia, autism, and PD for example. Sensory overload is a problem in all three as well as stress response.

John, when I played the piano and memorized a piece, I played automatically without thinking at all, as if my hands knew what to do all by themselves, as a result of all the practicing.

Problem was, if I had a glitch and stopped, I had to restart from the beginning!

Maybe if we rehearse enough, some of our movements can become more automatic like they used to be, when our internal cues worked by themselves.

Now we have to develop new loops, that may in time become automatic, if we rehearse long enough.

Rick, a study I read yesterday mentioned the disorders you mentioned, and said that they actually worked in an opposite way than PD. I can't recall the details! I don't have time to find it.

I agree with what you said!

I'm unable (over time limit) to post this is my earlier post, so here it is:

I forgot to say that after I stand up, I rehearse walking in my mind. Thinking of walking side to side helps. I also count, so I have a rhythm...1,2.....1,2.....I still have trouble getting going, but practice and an inner metronome make it easier.