Bradykinesia

The most important functional disturbance in patients with PD is a disorder of voluntary movement prominently characterized by slowness. This phenomenon is generally called bradykinesia, although it has at least two components, which can be designated as bradykinesia and akinesia (Berardelli et al., 2001). Bradykinesia refers to slowness of movement that is ongoing. Akinesia refers to failure of willed movement to occur. There are two possible reasons for the absence of expected movement. One is that the movement is so slow (and small) that it cannot be seen. A second is that the time needed to initiate the movement becomes excessively long.

While self-paced movements can give information about bradykinesia, the study of reaction time movements can yield information about both akinesia and bradykinesia. In the reaction time situation, a stimulus is presented to a subject, and the subject must make a movement as rapidly as possible. The time between the stimulus and the start of movement is the reaction time; the time from initiation to completion of movement is the movement time. Using this logic, prolongation of reaction time is akinesia, and prolongation of movement time is bradykinesia. Studies of PD patients confirm that both reaction time and movement time are prolonged. However, the extent of abnormality of one does not necessarily correlate with the extent of abnormality of the other (Evarts et al., 1981). This suggests that they may be impaired by separable physiologic mechanisms. In general, prolongation of movement time (bradykinesia) is better correlated with the clinical impression of slowness than is prolongation of reaction time (akinesia).

Some contributing features of bradykinesia are established. One is that there is a failure to energize muscles up to the level necessary to complete a movement in a standard amount of time. This has been demonstrated clearly with attempted rapid, monophasic movements at a single joint (Hallett and Khoshbin, 1980). In this circumstance, movements of different angular distances are accomplished in approximately the same time by making longer movements faster. The electromyographic (EMG) activity underlying the movement begins with a burst of activity in the agonist muscle of 50–100 ms, followed by a burst of activity in the antagonist muscle of 50–100 ms, followed variably by a third burst of activity in the agonist. This “triphasic” pattern has relatively fixed timing with movements of different distance, correlating with the fact of similar total time for movements of different distance. Different distances are accomplished by altering the magnitude of the EMG within the fixed duration burst. The pattern is correct in patients with PD, but there is insufficient EMG activity in the burst to accomplish the movement. These patients often must go thorough two or more cycles of the triphasic pattern to accomplish the movement. Interestingly, such activity looks virtually identical to the tremor-at-rest seen in these patients. The longer the desired movement, the more likely it is to require additional cycles. These findings were reproduced by Baroni et al. (1984), who also showed that levodopa normalized the pattern and reduced the number of bursts.

Berardelli and colleagues (1986) showed that PD patients could vary the size and duration of the first agonist EMG burst with movement size and added load in the normal way. However, there was a failure to match these parameters appropriately to the size of movement required. This suggests an additional problem in scaling of actual movement to the required movement. A problem in sensory scaling of kinesthesia was demonstrated by Demirci et al. (1997). PD patients used kinesthetic perception to estimate the amplitude of passive angular displacements of the index finger about the metacarpophalangeal joint and to scale them as a percentage of a reference stimulus. The reference stimulus was either a standard kinesthetic stimulus preceding each test stimulus (task K) or a visual representation of the standard kinesthetic stimulus (task V). The PD patients’ underestimation of the amplitudes of finger perturbations was significantly greater in task V than in task K. Thus, when kinesthesia is used to match a visual target, distances are perceived to be shorter by the PD patients. Assuming that visual perception is normal, kinesthesia must be “reduced” in PD patients. This reduced kinesthesia, when combined with the well-known reduced motor output and probably reduced corollary discharges, implies that the sensorimotor apparatus is “set” smaller in PD patients than in normal subjects.

In a slower, multijoint movement task, PD patients show a reduced rate of rise of muscle activity that also implies deficient activation (Godaux et al., 1992). On the other hand, Jordan and colleagues (1992) showed that release of force was just as slowed as increase of force, suggesting that slowness to change and not deficient energization was the main problem. If termination of activity is an active process, then this finding really does not argue against deficient energization.

A second physiologic mechanism of bradykinesia is that there is difficulty with simultaneous and sequential movements (Benecke et al., 1987). That PD patients have more difficulty with simultaneous movements than with isolated movements was first pointed out by Schwab and colleagues (1954). Quantitative studies show that slowness in accomplishing simultaneous or sequential movements is more than would be predicted from the slowness of each individual movement. With sequential movements, there is another parameter of interest, the time between the two movements designated the inter-onset latency (IOL) by Benecke and colleagues (1987). The IOL is also prolonged in patients with PD. This problem, similar to the problem with simple movements, can also be interpreted as insufficient motor energy.

Akinesia would seem to be multifactorial, and a number of contributing factors are already known. As noted above, one type of akinesia is the limit of bradykinesia from the point of view of energizing muscles. If the muscle is selected but not energized, then there will be no movement. Such phenomena can be recognized on some occasions with EMG studies where EMG activity will be initiated but will be insufficient to move the body part. Another type of akinesia, again as noted above, is prolongation of reaction time; the patient is preparing to move, but the movement has not yet occurred. Considerable attention has been paid to mechanisms of prolongation of reaction time. One factor is easily demonstrable in patients with rest tremor, who appear to have to wait to initiate the movement together with a beat of tremor in the agonist muscle of the willed movement (Hallett et al., 1977; Staude et al., 1995).

Another mechanism of prolongation of reaction time can be seen in those circumstances where eye movement must be coordinated with limb movement (Warabi et al., 1988). In this situation, there is a visual target that moves into the periphery of the visual field. Normally, there is a coordinated movement of eyes and limb, the eyes beginning slightly earlier. In PD, some patients do not begin to move the limb until the eye movement is completed. This might be due to a problem with simultaneous movements, as noted above. Alternatively, it might be that PD patients need to foveate a target before they are able to move to it.

Many studies have evaluated reaction time quantitatively with neuropsychological methods (Hallett, 1990). The goal of these studies is to determine the abnormalities in the motor processes that must occur before a movement can be initiated. In order to understand reaction time studies, it is useful to consider from a theoretical point of view the tasks that the brain must accomplish. The starting point is the “set” for the movement. This includes the environmental conditions, initial positions of body parts, understanding the nature of the experiment and, in particular, some understanding of the expected movement. In some circumstances, the expected movement is described completely, without ambiguity. This is the “simple reaction time” condition. The movement can be fully planned. It then needs to be held in store until the stimulus comes to initiate the execution of the movement. In other circumstances, the set does not include a complete description of the required movement. It is intended that the description be completed at the time of the stimulus that calls for the movement initiation. This is the “choice reaction time” condition. In this circumstance, the programming of the movement occurs between the stimulus and the response. Choice reaction time is always longer than simple reaction, and the time difference is due to this movement programming.

In most studies, simple reaction time is significantly prolonged in patients compared with normal subjects (Hallett, 1990). On the other hand, patients appear to have normal choice reaction times or the increase of choice reaction time over simple reaction time is the same in patients and normal subjects. Many studies in which cognitive activity was required for a decision on the correct motor response have shown that PD patients do not have apparent slowing of thinking, called bradyphrenia. The study of choice reaction times was extended by considering three different choice reaction time tasks that required the same simple movement, but differed in the difficulty of the decision of which movement to make (Brown et al., 1993). Comparing PD patients to normal subjects, the patients had a longer reaction time in all three conditions, but the difference was largest when the task was the easiest and smallest when the task was the most difficult. Thus, the greater the proportion of time there is in the reaction time devoted to motor program selection, the closer to normal are the PD results. Labutta et al. (1994) have shown that PD patients have no difficulty holding a motor program in store. Hence, the difficulty must be in executing the motor program. Execution of the movement, however, lies at the end of choice reaction time, just as it does for simple reaction time. How then can it be abnormal and choice reaction time be normal? The answer may be that in the choice reaction time situation both motor programming and motor execution can proceed in parallel.

Transcranial magnetic stimulation (TMS) can be used to study the initiation of execution. With low levels of TMS, it is possible to find a level that will not produce any motor evoked potentials (MEPs) at rest, but will produce an MEP when there is voluntary activation. Using such a stimulus in a reaction time situation between the stimulus to move and the response, Starr et al. (1988) showed that stimulation close to movement onset would produce a response even though there was still no voluntary EMG activity. A small response first appeared about 80 ms before EMG onset and grew in magnitude closer to onset. This method divides the reaction time into two periods. In the first period, the motor cortex remains “unexcitable”; in the second, the cortex becomes increasingly “excitable” as it prepares to trigger the movement. Most of the prolongation of the reaction time appeared due to prolongation of the later period of rising excitability (Pascual-Leone et al., 1994a). This result has been confirmed (Chen et al., 2001). The finding of prolonged initiation time in PD patients is supported by studies of motor cortex neuronal activity in reaction time movements in monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Watts and Mandir, 1992). In these investigations, there was a prolonged time between initial activation of motor cortex neurons and movement onset.

Thus, an important component of akinesia is the difficulty in initiating a planned movement. This statement would not be a surprise to PD patients, who often say that they know what they want to do, but they just cannot do it. A major problem in bradykinesia is a deficiency in activation of muscles, whereas the problem in akinesia seems to be a deficiency in activation of motor cortex. The dopaminergic system apparently provides energy to many different motor tasks, and the deficiency of this system in PD leads to both bradykinesia and akinesia.

Another factor that should be kept in mind is that patients appear to have much more difficulty initiating internally triggered movements than externally triggered movements. This is clear clinically in that external cues are often helpful in movement initiation. Examples include improving walking by providing an object to step over or playing march music. This can also be demonstrated in the laboratory with a variety of paradigms (Curra et al., 1997; Majsak et al., 1998).

How does bradykinesia arise from dysfunction of the nigrostriatal pathway? Thinking about the simple basal ganglia diagram, dopamine facilitates the direct pathway and inhibits the indirect pathway. Loss of dopamine will lead to lack of facilitation of movement in both pathways. This could certainly be represented by bradykinesia. This has been referred to as a loss of “motor motivation” (Mazzoni et al., 2007).The origin of rigidity and tremor is less understandable, but also less directly linked to dopamine deficiency clinically (Rodriguez-Oroz et al., 2009).

Rigidity

Tone is defined as the resistance to passive stretch. Rigidity is one form of increased tone that is seen in disorders of the basal ganglia (“extrapyramidal disorders”), and is particularly prominent in PD. Increased tone can result from changes in (1) muscle properties or joint characteristics, (2) amount of background contraction of the muscle, and (3) magnitude of stretch reflexes. There is evidence for all three of these aspects contributing to rigidity. For quantitative purposes, responses can be measured to controlled stretches delivered by devices that contain torque motors. The stretch can be produced by altering the torque of the motor or by altering the position of the shaft of the motor. The perturbation can be a single step or more complex, such as a sinusoid. The mechanical response of the limb can be measured: the positional change if the motor alters force or the force change if the motor alters position. Such mechanical measurements can directly mimic and quantify the clinical impression (Hallett et al., 1994; Hallett, 1999).

Patients with PD do not relax well and often have slight contraction at rest. This is a standard clinical as well as electrophysiologic observation, and it is clear that this mechanism plays a significant part in rigidity.

There are increases in long-latency reflexes in PD patients. Generally, this is neurophysiologically distinct from the increases in the short-latency reflexes seen in spasticity, increase in tone of “pyramidal” type. The short-latency reflex is the monosynaptic reflex. Reflexes occurring at a longer latency than this are designated long latency. When a relaxed muscle is stretched, in general only a short-latency reflex is produced. When a muscle is stretched while it is active, one or more distinct long-latency reflexes are produced following the short-latency reflex and prior to the time needed to produce a voluntary response to the stretch. These reflexes are recognized as separate because of brief time gaps between them, giving rise to the appearance of distinct “humps” on a rectified EMG trace. Each component reflex, either short or long in latency, has about the same duration, approximately 20–40 ms. They appear to be true reflexes in that their appearance and magnitude depend primarily on the amount of background force that the muscle was exerting at the time of the stretch and the mechanical parameters of the stretch; they do not vary much with whatever the subject might want to do after experiencing the muscle stretch. By contrast, the voluntary response that occurs after a reaction time from the stretch stimulus is strongly dependent on the will of the subject.

Long-latency reflexes are best brought out with controlled stretches with a device such as a torque motor. While long-latency reflexes are normally absent at rest, they are prominent in PD patients (Rothwell et al., 1983; Tatton et al., 1984; Hallett et al., 1994; Hallett, 1999). Long-latency reflexes are also enhanced in PD with background contraction. Since some long-latency stretch reflexes appear to be mediated by a loop through the sensory and motor cortices, the enhancement of long-latency reflexes has been generally believed to indicate increased excitability of this central loop.

There is some evidence that at least one component of the increased long-latency stretch reflex in PD is a group II mediated reflex. This suggestion was first made by Berardelli et al. (1983) on the basis of physiologic features, including insensitivity to vibration. It was subsequently supported by the observation that an enhanced late stretch reflex response could not be duplicated with a vibration stimulus (Cody et al., 1986). Some studies show a correlation between clinically measured increased tone and the magnitude of long-latency reflexes (Berardelli et al., 1983), while others do not (Bergui et al., 1992; Meara and Cody, 1993). Long-latency reflexes contribute significantly to rigidity, but are apparently not completely responsible for it.

Tremor-at-rest

The so called “tremor-at-rest” is the classic tremor of PD and other parkinsonian states such as those produced by neuroleptics or other dopamine-blocking agents such as prochlorperazine and metoclopramide (Elble and Koller, 1990; Hallett, 1991, 1999; Elble, 1997). It is present at rest, disappears with action, but may resume with static posture. That the tremor may also be present during postural maintenance is a significant point of confusion in regard to naming this tremor “tremor-at-rest.” It can involve all parts of the body and can be markedly asymmetrical, but it is most typical with a flexion–extension movement at the elbow, pronation and supination of the forearm, and movements of the thumb across the fingers (“pill-rolling”). Its frequency is 3–7 Hz, but is most commonly 4 or 5 Hz; EMG studies show alternating activity in antagonist muscles.

The anatomical basis of the tremor-at-rest may well differ from the classic neuropathology of PD, that of degeneration of the nigrostriatal pathway. For example, 18F-dopa uptake in the caudate and putamen declines with bradykinesia and rigidity, but is unassociated with degree of tremor (Otsuka et al., 1996). Evidence from a PET study suggests that tremor is associated with a serotonergic deficiency (Doder et al., 2003). Another point in favor of this idea is that the tremor may be successfully treated with a stereotactic lesion or deep brain stimulation of the ventral intermediate (VIM) nucleus of the thalamus, a cerebellar relay nucleus (Jankovic et al., 1995; Benabid et al., 1996).

In parkinsonian tremor-at-rest, there may be some mechanical-reflex component and some 8–12 Hz component, but the most significant component comes from a pathologic central oscillator at 3–5 Hz. This tremor component is unaffected by loading. Evidence for the central oscillator includes the facts that the accelerometric record and the EMG are not affected by weighting, and small mechanical perturbations do not affect it. On the other hand, it can be reset by strong peripheral stimuli such as an electrical stimulus that produces a movement of the body part five times more than the amplitude of the tremor itself (Britton et al., 1993a). Where this strong stimulus acts is not clear, but it does not have to be on the peripheral loop. Additionally, the tremor can be reset by TMS (Britton et al., 1993b; Pascual-Leone et al., 1994b), presumably indicating a role of the motor cortex in the central processes that generate the tremor. In the studies of Pascual-Leone et al. (1994b), using a relatively small stimulus, the tremor was reset with TMS, but not with transcranial electrical stimulation. Since TMS affects the intracortical circuitry more, this seems to be further evidence for a role of the motor cortex.

While cells in the globus pallidus may have oscillatory activity, they are not as well related to the tremor as the cells in the VIM of the thalamus (Hayase et al., 1998; Hurtado et al., 1999). Lenz and colleagues have studied the physiologic properties of cells in the VIM in relation to tremor production (Zirh et al., 1998). They have tried to see if the pattern of spike activity is consistent with specific hypotheses. They examined whether parkinsonian tremor might be produced by the activity of an intrinsic thalamic pacemaker or by the oscillation of an unstable long loop reflex arc. In one study of 42 cells, they found 11 with a sensory feedback pattern, 1 with a pacemaker pattern, 21 with a completely random pattern, and 9 that did not fit any pattern (Zirh et al., 1998). In another study of thalamic neuron activity, some cells with a pacemaker pattern were seen, but these did not participate in the rhythmic activity correlating with tremor (Magnin et al., 2000). These results confirm those of Lenz et al. suggesting that the thalamic cells are not the pacemaker. Using sophisticated analytical techniques, it can be demonstrated that oscillations both in the VIM and in the STN play an efferent role in tremor generation, but that the tremor itself feeds back to these same structures to influence the oscillation (Tass et al., 2010). This does suggest that in some sense the whole loop is responsible for the tremor. The basal ganglia loop may well trigger the cerebellar loop to produce the tremor (Helmich et al., 2011).

Wherever the pacemaker for the tremor, it is important to note that while the tremor is synchronous within a limb, it is not synchronous between limbs (Hurtado et al., 2000). Hence a single pacemaker does not influence the whole body.

There are other types of tremor in PD including an action tremor looking like essential tremor, but these have not been extensively studied.

Loss of inhibition

A principal finding in focal dystonia is that of loss of inhibition (Hallett, 2004, 2006a, 2006b, 2011). Loss of inhibition is likely responsible for the excessive movement seen in dystonia patients. Excessive movement includes abnormally long bursts of EMG activity, co-contraction of antagonist muscles, and overflow of activity into muscles not intended for the task (Cohen and Hallett, 1988). Loss of inhibition can be demonstrated in spinal and brainstem reflexes. Examples are the loss of reciprocal inhibition in the arm in patients with focal hand dystonia (Nakashima et al., 1989; Panizza et al., 1990) and abnormalities of blink reflex recovery in blepharospasm (Berardelli et al., 1985). Loss of reciprocal inhibition can be partly responsible for the presence of co-contraction of antagonist muscles that characterizes voluntary movement in dystonia.

Loss of inhibition can also be demonstrated for motor cortical function including the transcranial magnetic stimulation techniques of short intracortical inhibition, long intracortical inhibition, and the silent period (Hallett, 2007a, 2011).

Short intracortical inhibition (SICI) is obtained with paired pulse methods and reflects interneuron influences in the cortex (Ziemann et al., 1996). In such studies, an initial conditioning stimulus is given, enough to activate cortical neurons, but small enough that no descending influence on the spinal cord can be detected. A second test stimulus, at suprathreshold level, follows at a short interval. Intracortical influences initiated by the conditioning stimulus modulate the amplitude of the MEP produced by the test stimulus. At short intervals, less than 5 ms, there is inhibition that is likely largely a GABAergic effect, specifically GABA-A (Di Lazzaro et al., 2000). (At intervals between 8 and 30 ms, there is facilitation, called intracortical facilitation, ICF). There is a loss of intracortical inhibition in patients with focal hand dystonia (Ridding et al., 1995). Inhibition was less in both hemispheres of patients with focal hand dystonia, and this indicates that this abnormality is more consistent as a substrate for dystonia.

The silent period (SP) is a pause in ongoing voluntary EMG activity produced by TMS. While the first part of the SP is due in part to spinal cord refractoriness, the latter part is entirely due to cortical inhibition (Fuhr et al., 1991). This type of inhibition is likely mediated by GABA-B receptors (Werhahn et al., 1999). SICI and the SP show different modulation in different circumstances and clearly reflect different aspects of cortical inhibition. The SP is shortened in focal dystonia.

Intracortical inhibition can also be assessed with paired suprathreshold TMS pulses at intervals from 50 to 200 ms (Valls-Solé et al., 1992). This is called long intracortical inhibition, or LICI, to differentiate it from SICI as noted above. LICI and SICI differ as demonstrated by the facts that with increasing test pulse strength, LICI decreases but SICI tends to increase, and that there is no correlation between the degree of SICI and LICI in different individuals (Sanger et al., 2001). The mechanisms of LICI and the SP may be similar in that both seem to depend on GABA-B receptors. Chen et al. (1997) investigated long intracortical inhibition in patients with writer’s cramp and found a deficiency only in the symptomatic hand and only with background contraction. This abnormality is particularly interesting since it is restricted to the symptomatic setting, and therefore might be a correlate of the development of the dystonia.

There is also neuroimaging evidence consistent with a loss of inhibition. Dopamine D2 receptors are deficient in focal dystonias (Perlmutter et al., 1997). There is weak evidence for reduced GABA concentration both in basal ganglia and motor cortex utilizing magnetic resonance spectroscopy (Levy and Hallett, 2002; Herath et al., 2010).

Loss of cortical inhibition in motor cortex can give rise to dystonic-like movements in primates. Matsumura et al. showed that local application of bicuculline, a GABA antagonist, onto the motor cortex led to disordered movement and changed the movement pattern from reciprocal inhibition of antagonist muscles to co-contraction (Matsumura et al., 1991). In a second study, they showed that bicuculline caused cells to lose their crisp directionality, converted unidirectional cells to bidirectional cells, and increased firing rates of most cells including making silent cells into active ones (Matsumura et al., 1992).

There is a valuable animal model for blepharospasm that supports the idea of a combination of genetics and environment, and, specifically, that the background for the development of dystonia could be a loss of inhibition (Schicatano et al., 1997). In this model, rats were lesioned to cause a depletion of dopamine; this reduces inhibition. Then the orbicularis oculi muscle was weakened. This causes an increase in the blink reflex drive in order to produce an adequate blink. Together, but not separately, these two interventions produced spasms of eyelid closure, similar to blepharospasm. Shortly after the animal model was presented, several patients with blepharospasm after a Bell’s palsy were reported (Chuke et al., 1996; Baker et al., 1997). This could be a human analog of the animal experiments. The idea is that those patients who developed blepharospasm were in some way predisposed. A gold weight implanted into the weak lid of one patient, aiding lid closure, improved the condition, suggesting that when the abnormal increase in reflex drive was removed, the dystonia could be ameliorated (Chuke et al., 1996).

Abnormal plasticity

There is abnormal plasticity of the motor cortex in patients with focal hand dystonia (Quartarone et al., 2006; Weise et al., 2006). This has been demonstrated using the technique of paired associative stimulation (PAS) (Stefan et al., 2000). In PAS, a median nerve shock is paired with a TMS pulse to the sensorimotor cortex timed to be immediately after the arrival of the sensory volley. This intervention increases the amplitude of the MEP produced by TMS to the motor cortex. It has been demonstrated that the process of PAS produces motor learning similar to long-term potentiation (LTP). In patients with dystonia, PAS produces a larger increase in the MEP than that seen in normal subjects. There is also an abnormality in homeostatic plasticity. Homeostatic plasticity is the phenomenon whereby plasticity remains within limits; this can be exceeded in dystonia (Quartarone et al., 2006).

Increased plasticity may arise from decreased inhibition so the inhibitory problem may well be more fundamental. This abnormality may be an important link in demonstrating how environmental influences can trigger dystonia. Abnormal plasticity can arise, at least in part, from abnormal synaptic processes in the basal ganglia (Peterson et al., 2010).

The possibility of increased plasticity in dystonia had been suspected for some time given that repetitive activity over long periods seems to be a trigger for its development. An animal model supported this idea (Byl et al., 1996). Monkeys were trained to hold a vibrating manipulandum for long periods. After some time, they became unable to do so, and this motor control abnormality was interpreted as a possible dystonia. The sensory cortex of these animals was studied, and sensory receptive fields were found to be large. The interpretation of these results was that the synchronous sensory input caused the receptive field enlargement, and that the abnormal sensory function led to abnormal motor function. The results suggested that the same thing might be happening in human focal dystonia: repetitive activity caused sensory receptive field changes and led to the motor disorder.

Abnormal sensory function

Stimulated by the findings of sensory dysfunction in the primate model, investigators began examining sensory function in patients with focal hand dystonia and found it to be abnormal. Although there is no apparent sensory loss on a clinical level, detailed testing of spatial and temporal discrimination revealed subtle impairments (Molloy et al., 2003