Elsevier

Experimental Neurology

Volume 220, Issue 2, December 2009, Pages 283-292
Experimental Neurology

What can man do without basal ganglia motor output? The effect of combined unilateral subthalamotomy and pallidotomy in a patient with Parkinson's disease

https://doi.org/10.1016/j.expneurol.2009.08.030Get rights and content

Abstract

We have studied motor performance in a man with Parkinson's disease (PD) in whom thermolytic lesions of the left subthalamic and left globus pallidus nuclei interrupted the basal ganglia (BG)-thalamo-cortical motor circuit in the left hemisphere. This allowed us to study remaining motor capabilities in the absence of aberrant BG activity typical of PD. Movements of the left arm were slow and parkinsonian whereas movement speed and simple reaction times (RT) of the right (operated) arm were within the normal range with no obvious deficits in a range of daily life activities. Two main abnormalities were found with the right hand. (a) Implicit sequence learning in a probabilistic serial reaction time task was absent. (b) In a go/no-go task when the percent of no-go trials increased, the RT superiority with the right hand was lost. These deficits are best explained by a failure of the cortex, deprived of BG input, to facilitate responses in a probabilistic context. Our findings confirm the idea that it is better to stop BG activity than allowing faulty activity to disrupt the motor system but dispute earlier claims that interrupting BG output in PD goes without an apparent deficit. From a practical viewpoint, our observations indicate that the risk of persistent dyskinesias need not be viewed as a contraindication to subthalamotomy in PD patients since they can be eliminated if necessary by a subsequent pallidotomy without producing deficits that impair activities of daily life.

Introduction

Precise understanding of the function of the basal ganglia (BG) in motor control remains elusive. The pathophysiological model developed in the late 1980 divided striato-pallidal projections into the “direct” and “indirect” circuits. The former being implicated in movement facilitation and the latter in movement inhibition. In that model, lack of striatal dopamine input in Parkinson's disease (PD) reduced activity in the direct pathway and increased activity in the indirect pathway leading to increased inhibitory output from the pallidum and reduced thalamic facilitation of motor cortex, which was posited as the basis for bradykinesia (Albin et al., 1989; Crossman, 1987, DeLong, 1990).

The accumulated evidence from contemporary surgery of the BG has highlighted two recognized paradoxes of the original BG model, namely, that pallidotomy eliminates dyskinesias (including levodopa-induced dyskinesias), when the opposite would be expected, and the absence of obvious additional motor deficits following ablative surgery of the BG or thalamus in patients with PD (Marsden and Obeso, 1994, Brown and Eusebio, 2008). In recent years the model has been refined to include the importance of neuronal patterns of discharge within the BG and its degree of synchrony with target structures (Wichmann and DeLong, 1996, Lozano et al., 2000, Obeso et al., 2000, Vitek and Giroux, 2000, Brown and Eusebio, 2008). The underlying implication is that surgery may improve both parkinsonian features and dyskinesias by removing or blocking the abnormal firing patterns that interfere with other components of the motor system (Mink, 1996, Lozano et al., 2000, Vitek and Giroux, 2000, Alonso-Frech et al., 2006). On the other hand, how the BG and thalamus tolerate the effect of lesions is still not well explained. To some extent, the patient described here provides the opportunity to assess the contribution of the BG to motor control. Subthalamotomy is routinely performed in the Centro Internacional de Restauración Neurológica (CIREN, La Habana, Cuba) as a surgical alternative to deep brain stimulation (DBS) (Alvarez et al., 2001, 2005, 2009). Following a thermolytic lesion of the subthalamic nucleus (STN), patients often develop transient hemichorea or hemiballism that in most instances resolves spontaneously within hours or days while motor improvement remains. However, in a minor proportion (around 8%) of patients the hemichorea-ballism may be severe and persistent enough to warrant placing a second lesion in the motor region of the globus pallidum pars interna (GPi), which is well known to eradicate hemichorea-ballism following STN lesions both in monkeys and humans (Carpenter et al., 1950, Suarez et al., 1997, Alvarez et al., 2009). We have studied one of these patients who received sequential STN and GPi lesions in the most affected (parkinsonian) hemisphere. This effectively leads to a functional removal of the cortico-BG-thalamo-cortical motor loop (Fig. 1A), thus allowing us to explore what a person can or cannot do with his limbs when deprived, by and large, of BG output to the motor cortex in one hemisphere.

The patient described here is one of seven patients with PD similarly operated in the CIREN as part of an ongoing subthalamotomy project (Alvarez et al., 2001Alvarez et al., 2005, Alvarez et al., 2009). In all of them the initial subthalamotomy was associated with hemichorea-ballism which required treatment with a pallidotomy within the next few weeks or months. The clinical features and observations regarding movement control of the patient described here are representative of the whole group. He was chosen for this pilot project because of his excellent general health, adequate educational level (school teacher) and a very favorable personal attitude to participate in the study. RP is a 53-year-old right handed man with a 12-year history of PD starting by clumsiness and tremor of the right arm then spreading to the right leg to become generalized after a few years. Initial response to levodopa (600 mg daily) was excellent but after 4 years “wearing off” motor fluctuations and “peak of dose” or “on” dyskinesias in the neck and right extremities developed. These complications became more severe and difficult to manage over the following years despite repeated treatment adjustments. Before surgery (January 2003), UPDRS (Unified Parkinson's Disease Rating Scale) motor (part-III) in the “off” medication (24 h after last dose) state was 46; motor signs were more severe in the right limbs with predominant bradykinesia, tremor and rigidity of the upper limb as well as axial and facial involvement. UPDRS “on” was 11 with a dyskinesias score of 2/4 (CAPIT scale) predominating in neck and right shoulder. In December 2003, a left unilateral subthalamotomy was associated with right hemichorea, beginning immediately after surgery, which reached ballistic magnitude in the right leg over the next 24 h. This did not abate during the next 3 weeks despite withdrawing all anti-parkinsonian medications. Thus, a left pallidotomy targeted to lesion mainly the posterior region of the GPi was performed 23 days after the initial subthalamotomy (Fig. 1B; further information in complementary material). This stopped the hemi-dyskinesias within the operating room without noticeable side-effects. The patient remained very stable and was discharged without complications on treatment with levodopa/benserazide 300 mg/day.

When evaluated in June 2005, UPDRS motor in “off” (16 h without medication) was 21 mainly due to parkinsonian signs in the left side, moderate hypophonia and mild facial hypomimia (see videotape in supplementary material). The only parkinsonian signs in the right limbs consisted of mild bradykinesia with the hand and fingers and cog-wheel rigidity in the upper limbs when moving other body parts (Froment's signs). In the “on” motor state (i.e., 1–2 h after taking 100/25 mg of levodopa/benserazide) UPDRS motor was 9. In the “on” state improvement was bilateral, with both sides showing similar UPDRS motor scores (see video in complementary material). Mild dyskinesias in left shoulder and neck were present. Cognitive evaluation in different cognitive domains (memory, executive function, language and visuospatial function) was typical of PD as evaluated with an extensive neuropsychological battery including, in addition to the global MMSE, the following tests: Stroop, Trail making, Raven's Progressive Matrices, phonemic and semantic verbal fluency, Boston word naming test, copy and retrieval of geometric figures and Buschke selective reminding test. Speech was completely normal. On daily life activities RP performed normally. He could undertake all sorts of tasks without any difficulty and used his right upper limb with extreme efficiency. Automatic movements such as saluting, writing and eating while talking were performed with ease. At the last (March 2008) neurological examination he remained stable (UPDRS motor “on” of 18) but facial and neck dyskinesias had worsened.

MRI of the brain repeated in 2005 showed the STN and pallidal lesions, although reduced in size as expected for the long-term appearance of a thermolytic lesion. An 18-fluorodopa PET (positron emission tomography) revealed a bilateral reduction in the decarboxylation constant (Ki) but more accentuated in the left striatum and particularly in the left posterior putamen (supplementary figure).

Section snippets

Methods

Most studies were performed both “on” and “off” therapy, with the latter defined as a minimum of 24 h without receiving any anti-parkinsonian medication. The study includes a series of motor tests (Table 1) that explore RP's ability to prepare, select and execute movements at single and multiple joints. The excitability of the motor cortex was assessed by transcranial magnetic stimulation (Kujirai et al., 1993, Ridding and Rothwell, 1999) and functional MRI evaluated patterns of

Movement kinematics

The graphs in Fig 2A and B show mean data from a group of age-matched healthy controls and a group of comparable (age, disease severity and duration, treatment, etc.) patients with PD “off” therapy for comparison with the results of patient RP (patients reported in Benecke et al., 1987). In general, patients with PD take longer than normal to flex their elbow through 30° (Fig. 2A) and when they perform the same task at the same time as squeezing a force transducer in their hand (Fig. 2B; “flex

Discussion

The patient described here had evidence of severe striatal dopamine deficiency bilaterally but particularly in the posterolateral region of the left putamen. His initial subthalamotomy led to sustained and disabling dyskinesias of the right arm. However, these were abolished by a subsequent posteroventral pallidotomy on the same side, which abolished the dyskinesias while sustained the clinical benefit to movements on the right side. Thus, the combined lesion of GPi and STN in this patient

Conclusions

Movements of the upper limb are primarily mediated by the cortico-putaminal-pallido-thalamo-cortical motor loop (DeLong et al., 1986). Our results show that derangement of major components of such motor loop probably causing interruption of BG motor output to the thalamo-cortical projection unilaterally does not interfere with routine operations but impairs tasks which require facilitation of appropriate responses in a probabilistic context (SRTT and go/no-go tasks in our study). Accordingly,

Acknowledgments

The collaboration, understanding and help provided by patient RP is greatly appreciated. Authors are particularly thankful to Dr. Julian Alvarez and Dr. Emilio Villa, director and vice-director of CIREN, for their unfailing and decisive support for the subthalamotomy project. This project was funded by the Centro Internacional de Restauración Neurológica (CIREN, La Habana, Cuba), the Medical Research Council (UK), the Fundación Investigación Médica Aplicada (FIMA, University of Navarra,

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