**6. Effect of anti-Parkinson medication on physiological and biomechanical measures of rigidity**

Rigidity generally responds well to anti-Parkinson medication. Several studies have examined the changes in muscle activation, joint torque resistance and torque-angle slope associated with rigidity reduction as a result of medication therapy (Kirollos et al., 1996; Mera et al., 2009; Powell et al., 2011; Xia & Rymer, 2004; Xia et al., 2006, 2009). Following a standard protocol, patients are tested initially in the Off-medication state, *i.e.*, 12 hours after the last dose of medication when the majority of the beneficial effects of medication therapy are eliminated (Defer et al., 1999). Twelve-hour overnight withdrawal of medication has been broadly used to examine the effect of medication on motor performance and on basal ganglia function (Brown & Marsden, 1999; Corcos et al., 1996; Jahanshahi et al., 2010; Robichaud et al., 2004; Tunik et al., 2004). After the initial tests are completed, patients are retested approximately one hour after taking their regular dose of medication in the Onmedication state. These studies have demonstrated that stretch-reflex and shortening reaction are diminished following the treatment (Powell et al., 2011; Xia & Rymer, 2004). The same effects are observed in the changes associated with torque resistance (Kirollos et al., 1996; Mera et al., 2009; Xia et al., 2006, 2009). Further, torque-angle curves associated with the On-medication test become steeper, manifesting the spring-like feature and the typical length-tension relationship (Gordon et al., 1966; Matthews, 1959; Rack & Westbury, 1969; Xia et al., 2006, see Fig. 2).

Physiological and Biomechanical Analyses of Rigidity in Parkinson's Disease 499

According to the diagnostic criteria, clinical diagnosis is based on two cardinal features of the disease (Fahn & Sulzer, 2004; Lang & Lozano, 1998). Parkinson's disease is a heterogeneous disease both across different patients and during the natural progression of the same patient. The heterogeneity of the disease among different patients is reflected by multiple sub-types of Parkinson's disease, i.e., akinetic-rigid type, tremor-predominant type, and postural instability gait difficulty sub-type (Burn et al., 2006; Hallett, 2003; Jankovic et al., 1990). Bradykinesia is labeled as a negative symptom due to its describing the poverty and slowing of voluntary movement, whereas rigidity and tremor are referred to as positive

Many clinical studies have indicated that the distinctions are significant among the hallmark motor symptoms although they share similarities and common origins (Elias et al., 2008). The distinctive nature has also been revealed by Temperli and coauthors (2003) who studied the reappearance of the clinical signs of Parkinson's disease when subthalamic nucleus deep brain stimulation was switched off in 35 patients treated with implanted deep brain stimulators. Authors reported that a sequential pattern of return of motor signs was observed, with a fast worsening of tremor within 10 to 15 minutes, followed by a smoother, slower worsening of bradykinesia and rigidity over half an hour to an hour, and finally a slow and steady worsening of axial signs over three to four hours. When switching the stimulation "on" again, all motor signs improved with a similar pattern. It was concluded that the four major parkinsonian signs may respond to brain stimulation by different

Our knowledge and understanding of Parkinson's disease have dramatically increased over the past years, consequently shifting the descriptions of this disease. Parkinson's disease, previously considered to be characterized by only motor symptoms (bradykinesia, rigidity, resting tremor and postural instability), is now viewed as a disease affected by both motor symptoms and a range of non-motor symptoms such as depression, disturbed sleeping patterns, fatigue, hallucination, cognitive impairments, changes in ability to taste or smell and a few other domains. Only during the last couple of decades or so, non-motor related symptoms have begun receiving attention in medical and research communities. As a result, a number of clinical rating tools have been developed to target specific or general non-motor

Rigidity is treated as part of parkinsonian motor symptoms. Among the motor symptoms of Parkinson's disease, bradykinesia and rigidity are the signs that are most responsive to medication and surgical treatments. A variety of pharmacological and surgical interventions are available for the management of Parkinson's disease. Levodopa was the first major breakthrough in the treatment of Parkinson's disease, and still remains the "gold standard" in the management of symptoms. Levodopa is converted in the brain into dopamine to replenish the brain's dwindling supply in patients with Parkinson's disease. The introduction of dopamine agonists was a milestone in the treatment of parkinsonian symptoms. In contrast to levodopa, dopamine agonists act directly on dopamine receptors in the brain, and thus can help alleviate the symptoms of Parkinson's disease. Based on preclinical observation, there is an increasingly popular theory known as continuous dopamine agonist stimulation that helps to prevent the occurrence of long-term

motor symptoms.

mechanisms.

complications.

**8. Clinical interventions of Parkinson's disease** 

symptoms (Brown et al., 2005; Chaudhuri et al., 2007).

Fig. 5. Comparison of torque-angle traces between the Passive (dashed) and Active (solid) conditions recorded in a subject with Parkinson's disease under the Off-Medication condition. Under the Active condition, passive movement of the wrist joint was concurrent with a contra-lateral hand gripping activation at 20% of maximal voluntary contraction. Rigidity score, calculated as the integral of the torque with respect to position for the entire cycle of flexion and extension movements, was enhanced under the Active condition. Upper traces are associated with the passive extension movement and the lower ones with the flexion movement [from Powell et al. (2011) with permission].

Effects of deep brain stimulation of the subthalamic nucleus in conjunction with medication have also been evaluated on the work rigidity and clinical rigidity scores in patients with Parkinson's disease (Shapiro et al., 2007). Subjects' elbow joints were tested under four experimental conditions determined by various combinations of medication (Off vs. On) and deep brain stimulation (Off vs. On) status. Treatment by deep brain stimulation reduced rigidity as indicated by work score and by rigidity score on the Unified Parkinson Disease Rating Scale. The results suggested that the surgical treatment may be more effective in alleviating rigidity in the upper limb of parkinsonian patients than medications administered at pre-surgery dosage level.

#### **7. Interaction of rigidity with other motor symptoms**

Parkinson's disease is characterized by both motor and non-motor related symptoms. Motor symptoms, often referred to as cardinal symptoms, include bradykinesia (slowness and decreased amplitude of movement), muscle rigidity, tremor-at-rest, and postural instability.

Fig. 5. Comparison of torque-angle traces between the Passive (dashed) and Active (solid) conditions recorded in a subject with Parkinson's disease under the Off-Medication condition. Under the Active condition, passive movement of the wrist joint was concurrent with a contra-lateral hand gripping activation at 20% of maximal voluntary contraction. Rigidity score, calculated as the integral of the torque with respect to position for the entire cycle of flexion and extension movements, was enhanced under the Active condition. Upper traces are associated with the passive extension movement and the lower ones with the

Effects of deep brain stimulation of the subthalamic nucleus in conjunction with medication have also been evaluated on the work rigidity and clinical rigidity scores in patients with Parkinson's disease (Shapiro et al., 2007). Subjects' elbow joints were tested under four experimental conditions determined by various combinations of medication (Off vs. On) and deep brain stimulation (Off vs. On) status. Treatment by deep brain stimulation reduced rigidity as indicated by work score and by rigidity score on the Unified Parkinson Disease Rating Scale. The results suggested that the surgical treatment may be more effective in alleviating rigidity in the upper limb of parkinsonian patients than medications

Parkinson's disease is characterized by both motor and non-motor related symptoms. Motor symptoms, often referred to as cardinal symptoms, include bradykinesia (slowness and decreased amplitude of movement), muscle rigidity, tremor-at-rest, and postural instability.

flexion movement [from Powell et al. (2011) with permission].

**7. Interaction of rigidity with other motor symptoms** 

administered at pre-surgery dosage level.

According to the diagnostic criteria, clinical diagnosis is based on two cardinal features of the disease (Fahn & Sulzer, 2004; Lang & Lozano, 1998). Parkinson's disease is a heterogeneous disease both across different patients and during the natural progression of the same patient. The heterogeneity of the disease among different patients is reflected by multiple sub-types of Parkinson's disease, i.e., akinetic-rigid type, tremor-predominant type, and postural instability gait difficulty sub-type (Burn et al., 2006; Hallett, 2003; Jankovic et al., 1990). Bradykinesia is labeled as a negative symptom due to its describing the poverty and slowing of voluntary movement, whereas rigidity and tremor are referred to as positive motor symptoms.

Many clinical studies have indicated that the distinctions are significant among the hallmark motor symptoms although they share similarities and common origins (Elias et al., 2008). The distinctive nature has also been revealed by Temperli and coauthors (2003) who studied the reappearance of the clinical signs of Parkinson's disease when subthalamic nucleus deep brain stimulation was switched off in 35 patients treated with implanted deep brain stimulators. Authors reported that a sequential pattern of return of motor signs was observed, with a fast worsening of tremor within 10 to 15 minutes, followed by a smoother, slower worsening of bradykinesia and rigidity over half an hour to an hour, and finally a slow and steady worsening of axial signs over three to four hours. When switching the stimulation "on" again, all motor signs improved with a similar pattern. It was concluded that the four major parkinsonian signs may respond to brain stimulation by different mechanisms.
