Global Strategies For Assessing Movement Disorders

Although there are many simple tests for motor disorders, devising a strategy for selecting the best tests for specific purposes is more challenging. Many available methods have been demonstrated to provide precise and reliable results for evaluating abnormal motor behavior. Unfortunately, experience with these methods has led to an increasing awareness that they are not adequate for application to most movement disorders. Most methods can detect functional disability, but they generally cannot define the nature of the motor syndrome.

A frequently recommended strategy is to conduct a large battery of motor and non-motor tests to provide a comprehensive assessment of the behavioral phenotype. Unfortunately, the comprehensive battery strategy has limited utility for most movement disorders. As a result, a hypothesis-driven or observation-driven strategy for selecting the most helpful behavioral tests may be more appropriate. The following section describes these three main strategies; sug gested test batteries for specific movement disorders are provided later.

A. Comprehensive Battery Strategy

The comprehensive battery strategy has already been reviewed several times in detail and will be described only briefly here (Crawley 2000; Crawley and Paylor 1997; Rogers et al. 1997; van der Staay and Steckler 2001). The comprehensive evaluation begins with a brief but broad-based observation of simple behaviors. The observations are typically not quantified, although statistical methods can be applied to uncover certain broad patterns of behaviors (Rogers et al. 1999). Instead, the purpose of this initial step is to identify defects that might influence the selection of subsequent tests. For example, simple screens for visual impairment might steer the investigator away from tests that require good eyesight. Several standardized lists of what to look for have been developed. The Irwin and SHIRPA batteries contain hundreds of items, while others have suggested shorter and more focused lists (Crawley 2000). Following the initial observational screen, a battery of secondary tests is applied addressing specific domains (Figure 4). These tests encompass sensory, cognitive, psychological, ingestive, and motor functions. A third round of tests may then proceed, focusing on any abnormalities uncovered in preceding steps.

The obvious advantage of the comprehensive battery strategy is that the assessment is less likely to miss unanticipated abnormalities that might not be detected with a more focused selection of specific tests. An example is provided by the subtle phenotype displayed by mice with targeting disruption of the D5 dopamine receptor (Holmes et al. 2001). This approach also suffers a number of disadvantages. First, it is best suited for large laboratories specializing in behavioral analysis where all the necessary equipment is available for each test in the battery. It is simply not feasible for most laboratories to purchase all of the necessary general activity rotarod performance beam walking skill gait patterns

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FIGURE 4 The comprehensive battery strategy for assessing abnormal motor behavior.

equipment and develop the technical expertise to use it. Second, this strategy may waste valuable resources by directing efforts towards many tests that may not provide informative results and other tests that may be redundant. For example, the value of performing multiple tests for coordinated motor function rather than a single "best" test remains unproven. Third, the comprehensive battery philosophy is at variance with general trends to focus questions on more hypothesis-driven experimentation rather than broad "fishing expeditions" that may yield results of uncertain significance.

The most serious limitation of the comprehensive battery strategy is that it is not adequate for assessing most movement disorders. The batteries provide excellent assessments of cognitive and psychiatric functions, but relatively weak assessments for motor functions. The tests of motor function in these batteries address functional disability, but they do not help determine the nature of the motor disorder. None of the tests in these batteries incorporates methods that allow the investigator to confidently discriminate Parkinsonism, choreoathetosis, dystonia, or cerebellar ataxia. The value of applying multiple sophisticated measures of motor dysfunction is not clear when the nature of the disorder being studied cannot be determined.

B. Hypothesis-Driven Strategy

A hypothesis-driven approach provides an alternative strategy that has proven successful in many recent studies. In this approach, the selection of tests is guided by known or suspected etiologic mechanisms, or by the human condition being modeled (Figure 5).

One example involves the rodent models for Parkin-sonism, which typically focus on identifying abnormalities similar to the human condition or focus on tests thought to be most sensitive for revealing defects associated with its pathogenesis. For example, chronic treatment of rats with rotenone leads to overt motor abnormalities analogous to those of human Parkinsonism, including reduced spontaneous mobility, slowed movements, and flexed postures (Betarbet et al. 2002; Hirsch et al. 2003; Orth and Tabrizi 2003). In this model, observational studies combined with a few tests for gross motor activity and function are adequate. On the other hand, several transgenic and knock-out mouse models focusing on the a-synuclein or parkin genes have resulted in motor phenotypes bearing less obvious resemblances to the human condition (Orth and Tabrizi 2003). In this situation, a hypothesis-driven approach would point to tests more sensitive for subtle motor defects or tests known to be sensitive to dysfunction of basal ganglia dopamine systems.

The advantage of this strategy is that the results obtained have more direct relevance to the human condition being modeled. The obvious disadvantage is that the focused selection of specific tests may result in some important aspect of the behavioral phenotype being overlooked. In addition, the hypothesis-driven approach is obviously not suited for neurotoxicological studies where the outcome is uncertain or transgenic and knock-out mouse models where the functions of the gene product are unknown. In these cases, the comprehensive battery or observation-driven strategies are more appropriate.

C. Observation-Driven Strategy

In some cases, a manipulation provokes an obvious motor phenotype that was not predicted. The manipulation may involve a surgical intervention, drug administration, or gene alteration. In these cases, an observation-driven approach for evaluating the motor syndrome is most appropriate (Figure tremor tremor

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FIGURE 5 Alternative hypothesis-driven or observation-driven strategies for assessing abnormal motor behavior.

5). This approach requires careful observations of the motor syndrome in relation to known motor syndromes of humans, followed by specific tests to confirm or refute similarities.

One example of the observation-driven strategy involves ion channels and dystonia. Administration of an L-type calcium channel activator was shown to provoke a motor syndrome resembling generalized dystonia in mice (Jinnah et al. 2000). Other studies demonstrated that mice carrying mutations in genes encoding P/Q-type calcium channels and related subunits exhibited paroxysmal or generalized dystonia (Campbell and Hess 1999; Fletcher et al. 2001; Khan and Jinnah 2002). These studies have helped point to a link between dystonia and calcium channels that had not been appreciated in prior studies of human dystonia. Further studies have shown that derangements in intracellular calcium handling can also lead to dystonia (Matsumoto et al. 1996; Street et al. 1997). Taken together, these studies establish a strong link between calcium handling and dys-tonia in mice, and similar defects have been uncovered only recently in human dystonia (Giffin et al. 2002; Sethi and Jankovic 2002).

This strategy has the advantage of providing a focused assessment of a motor syndrome that can be directly compared to a human condition. It is also attractive because it can be possible to establish a previously unrecognized link between the manipulation performed and a human motor disorder. The observation-driven strategy shares the same disadvantage as the hypothesis-driven strategy: it is more likely to miss some important aspect of the behavioral phe-notype than the comprehensive approach. It can also be difficult to establish the etiologic relevance of the manipulation to a human condition.

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