MSc Introduction © Callie Clark, 2008

ABSTRACT

Diseases of the central and peripheral nervous systems affect one in five people in North America. Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease, and occurs in approximately 1% of the general North American population. PD is a progressive movement disorder that is characterized by resting tremor, rigidity, bradykinesia (slowness of movement) or akinesia (absence of spontaneous movement), as well as postural instability. Current treatment of PD is symptom-based, and no pharmacological treatment currently exists to slow the progression of bradykinesia and akinesia. In fact, pharmacological therapies produce motor side effects in advanced stages of the disease. Given the difficulty in initiating and controlling movement as PD advances, and the ineffectiveness of medical therapies after prolonged treatment, physical and music therapies can be used to supplement classical therapies. Listening to, and performing, music affects a number of neural regions, including those that mediate motor behaviour, arousal or activation, and emotion. Despite anatomical connections between the auditory and motor systems at the level of the spinal cord, brain stem, midbrain, and cortex, the neural and behavioural mechanisms for sound-induced activation remains unclear. It is known, however, that PD patients recruit external sensory stimuli to improve movement. The aim of the current research was to create an animal model of sound-induced activation and to test the effect of previous motoric experience on the potency of auditory stimuli. To investigate behavioural activation in the normal and haloperidol-treated rat, two tasks were used: 1) orienting responses were analyzed for movement components in saline and haloperidol treated rats to find out if rats responded in the same to a variety of naturally produced and generated activating sounds, and 2) a grid climbing task allowed for the righting components of naïve and familiar cataleptic rats to be compared. Our findings revealed that familiar auditory cues could release parkinsonian rats from catalepsy. The current research supports the theory that auditory stimulation retains “special access” to motor regions otherwise impaired in PD and likely bypasses basal ganglia circuitry to normalize movement through alternative pathways.


INTRODUCTION

This thesis will present experiments conducted on sound-induced behavioural activation in a rat model of akinesia in Parkinson’s disease (PD). In three sections, this introduction will review the literature on PD, the literature on behavioural activation, and the literature on the use of sensory cueing and music in the treatment of PD symptoms.


Parkinson’s disease
The discovery of Parkinson’s disease as a unique clinical condition and the recognition of nigral dopamine as a central feature of the disease shape our current understanding. British physician James Parkinson first described PD as a distinct disease almost 200 years ago, in 1817 in “An Essay on the Shaking Palsy.” Parkinson published six case studies of men in his community who exhibited a worsening of motor abnormalities in gait and posture over a number of years. In his pivotal essay on paralysis agitans, the shaking palsy, Parkinson was the first to note three cardinal symptoms of the disease (excluding rigidity) and comment on its progressive nature (1817, p.225):

As the disease proceeds towards its last stage, the trunk is almost permanently bowed, the muscular power is more decidedly diminished, and the tremulous agitation becomes violent. The patients walks now with great difficulty, and unable any longer to support himself with his stick, he does not venture on this exercise, unless assisted by an attendant, who walking backwards before him, prevents his falling forwards, by the pressure of his hands against the fore part of his shoulders.

Further, Parkinson hypothesized that the basis of the disease resulted from damage to the medulla, but was unable to test this idea in his lifetime. One decade following the publication of Parkinson’s essay, physician J.-M. Charcot (1877) met with patients who he diagnosed with Parkinson’s disease, and wrote on the unilateral and progressive nature of PD. Although it was noted in the late nineteenth century that melanin-containing cells of the SNc are reduced in PD (Fig 1.1), it was not until 50 years later that researchers were able to connect PD symptoms with the death of these dopamine (DA) neurons in the SNc that provide dopaminergic (DAergic) innervation of the striatum. The following discoveries made this connection possible: 1) Rosegay (1944) published the first clear demonstration of a pathway from the SNc to the striatum; 2) Carlsson (1959) showed that dopamine functions as a neurotransmitter; 3) Hornykiewicz (1963) showed that dopamine concentrations are decreased in the striatum of PD patients, particularly in the side of the brain contralateral to symptom onset.


A number of studies suggest that there are sensorimotor abnormalities, and thus the conception of PD as a strictly motor disorder is incomplete (Abruzzese and Berardelli, 2002; Marsden, 1982; Morris et al., 1994b). Non-motor symptoms that increase with disease severity include depression, cognitive decline, pain, and sleep (Friedman and Friedman, 1993; Koller, 1984; Norman et al., 2002; Quinn and Marsden, 1986). A diagnosis of PD is based on clinical observation of a neurologist and can only be confirmed through post-mortem autopsy. A clinical diagnosis can also be supported by the unilateral appearance of symptoms, a positive response to treatment with levodopa, and the absence of another movement disorder that might lead to signs of PD (Ebadi and Pfeiffer, 2004).

Model of basal ganglia function
The cardinal symptoms of PD have been associated with abnormal intrinsic basal ganglia (BG) activity that leads to decreased activation and control of motor cortex (Ridding, Inzelberg, and Rothwell, 1995; Watts and Mandir, 1992). The BG are subcortical nuclei that provide background tonic activity for motor cortex (Ebadi and Pfeiffer, 2004) and through dopamine-glutamate interactions, increase the signal-to-noise ratio of corticothalamic activity (Horvitz, 2002; Rebec, 2006). The BG consist of three nuclei, including the striatum (composed of the caudate body and putamen) and the globus pallidus and comprise the major nuclei of the extra-pyramidal motor system. The primary input structure to the striatum is the substantia nigra pars compacta (SNc). The output structures of the BG are the internal capsule of the globus pallidus and the substantia nigra pars reticulata (SNr). The current understanding of BG function emphasizes two functional pathways that are known as the “indirect pathway” and the “direct pathway” (Albin, Young, and Penney, 1989; DeLong, 1990). Normally, DA provides a net excitatory input to thalamocortical projections and controls movement force, movement initiation, and planning based on motor set through disinhibition of the thalamus (Fig. 1.2) (Ebadi and Pfeiffer, 2004; Tecuapetla et al., 2007). The direct and indirect pathways for movement allow for permissive and restrictive motor signals, respectively. The direct pathway travels from the caudate-putamen (striatum) to the internal globus pallidus (GPi), and serves to decrease inhibition of the ventrolateral nucleus of the thalamus (VL thalamus). The indirect pathway proceeds from the striatum to the external globus pallidus (GPe), which then excites the GPi via the subthalamic nucleus (STN). In PD, reduced dopaminergic influx to the striatum produces a net increase in inhibition, leading to decreased excitation of motor cortex by the VL thalamus and resultant hypokinesia.

The BG is involved in the production of motor behaviour. Evidence also highlights a role in sensorimotor integration, selection of a single motor program, tonic background activity for ongoing locomotion, control of movement force, inhibition of competing motor programs (Escola et al., 2002). In addition to the direct/indirect BG model of motor dysfunction, PD is related to fronto-striatal executive deficits that typically worsen with disease progression (Owen et al., 1992; Rowe et al., 2008).

A closer look at PD patients within the laboratory and the real world suggest that the motor symptoms of bradykinesia (slowness of movement) and akinesia (absence of spontaneous movement) have a sensory component (Bazyan, Getsova, and Orlova, 2000; McDowell and Harris, 1997; Sacrey, Clark, and Whishaw, unpublished). In PD, external cues can have a disproportionately large effect on movement initiation and execution (Almeida, Wishart, and Lee, 2002; McDowell and Harris, 1997) and internally guided movements become particularly difficult (Jahanshahi et al., 1995). Attention is influenced by the interplay of external stimuli and behavioural arousal, and altered DA transmission is known to produce attention deficits during continuous performance tasks in neuroleptic-treated human subjects and animal subjects (Fowler, 1999). A dose-dependent decrease in responding to incentive stimuli has been documented following treatment with DA antagonists (Beninger, 1982). That is, neuroleptic-induced catalepsy is not simply an inability to move “normally,” but is an active and complex behavioural state (De Ryck, Schallert, and Teitelbaum, 1980). When parkinsonian akinesia is experimentally produced in animals, the subjects become less responsive to sensory stimuli that would normally activate behaviour (Teitelbaum, Schallert, and Whishaw, 1983). Additionally, cells of the SN show increased activity following conditioned and non-conditioned sensory events (Horvitz et al., 1997) and display altered responses to sensory stimuli in animal models of PD (Schneider, 1991), providing a putative mechanism for behaviours left intact in PD. Reduced evoked somatosensory potentials observed in PD and Huntington’s disease are believed to result from deficient sensory integration by the BG and contribute to deficits in postural control and other motor deficits (Boecker et al., 1999; Cham et al., 2007), and complement findings that there is increased activation of lateral sensorimotor areas during movement (Cunnington et al., 1995).

Pathways for voluntary movement
There are at least two pathways to motor cortex from basal ganglia for voluntary movement. In healthy subjects, the basal ganglia send excitatory innervation to the SMA via the ventrolateral nucleus of the thalamus. The SMA then sends projections to primary motor cortex via the PMA. An alternative pathway, hypothesized to mediate compensation in PD, extends from the BG to the cerebellum to the PMA, thus bypassing the SMA when external cues are given. Using TMS, Cunnington et al (1995) revealed that patients, in contrast to healthy controls, use SMA only during internally driven movements and during both cued and non-cued conditions during sequential movements. It is evident from the above electrophysiological and behavioural studies that sensory systems are changed in PD patients, thus providing a possible therapeutic avenue.

Neurophysiological changes
In addition to changes in BG and motor cortex, changes in additional brain regions also contribute to PD symptomology. PD is a progressive neurodegenerative disease associated with the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc), the presence of cytoplasmic inclusions known as Lewy bodies, and changes in virtually every neurochemical system of the central nervous system (Bernheimer, Birkmayer, and Hornykiewicz, 1961; Hughes et al., 2001). Because basal ganglia output through GPi and SNr is disrupted, cortical regions responsible for movement, including the SMA and PMA, exhibit a decrease of normal activity and an increase in synchronicity (Ridding, Inzelberg, and Rothwell, 1995). In particular, SMA, a region known to mediate internally generated movement, loses its primary source of excitatory input, whereas the PMA mediates externally driven movements (Cunnington et al., 2001; Taniwaki et al., 2003). Altered motor cortex processing and reduced recruitment of spinal motor units are associated with altered gait and signal detection performance in which PD patients become disproportionately sensitive to external cues to guide their movements as proprioceptive deficits lead to impairment and akinesia (Caviness et al., 2000; Escola et al., 2002; McDowell and Harris, 1997).

Epidemiology and causes
When considering incidence and prevalence rates for PD, it is important to note that epidemiological studies are based on clinical diagnoses and thus can, and do, vary between regions (Ebadi and Pfeiffer, 2004). PD does not have a known cause, but a number of environmental and genetic factors appear to play a role. Thus, the majority of PD cases are referred to as “idiopathic,” or being without a known cause. Age is the strongest predictor of PD and is rarely diagnosed in people under the age of 50 years old. In addition to age, risk factors include living in a rural environment, closed head injury, family history (some cases of early-onset familial PD have been associated with mutation in the Parkin gene), and exposure to industrial chemicals or pesticides (Quinn, Critchley, and Marsden, 1987; Olanow and Tatton, 1999). Exposure to compounds that inhibit DA cells, including MPTP and neuroleptics, produce parkinsonism in patients and animals. Animals showing neuroleptic-induced catalepsy can be reversed by electrical stimulation of sites used therapeutically in human patients (Degos et al., 2005). A loss of 80-90% of the DAergic cells of the SNc (Fig. 1.1) produce signs of parkinsonism, and although the ultimate cause of this cell death is not yet known, PD is linked to dysfunction of mitochondrial complex 1 through exposure to environmental toxins or chemicals (Gu et al., 1998; Schapira, Cooper, Dexter, Clark, Jenner, and Marsden, 2008). A number of hypotheses (e.g., excitotoxicity, rotenone exposure, oxidative stress, exposure to heavy metals) support this essential mechanism in the cellular death observed in PD (Ebadi and Pfeiffer, 2004; Schapira et al., 1990).

Treatment
Although a comprehensive review of medications for PD is beyond the aim of this thesis, a brief review of medical and complementary treatment strategies for PD is relevant. PD treatment is symptomatic and is not able to slow or prevent the progression of the underlying neuropathology (Marsden and Parkes, 1977; Zetusky, Jankovic, and Pirozzolo, 2004). Pharmacological management consists of the administration of levodopa (L-dopa), dopamine agonists, cholinergic blockers, catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO) inhibitors for patients (Ebadi and Pfeiffer, 2004). Early in PD, motor symptoms typically present unilaterally and consist of tremor or rigidity (increased resistance to passive movement) (Zetusky, Jankovic, and Pirozzolo, 2004). Non-motor symptoms can also be present and include olfactory deficits (which are often the first to appear), sleep disturbances, emotional changes, and dementia. PD patients experience balance-related changes in motor control, and report a high incidence of PD-related falls every year (Koller et al., 1989). In advanced PD, akinesia, falls, and postural disturbances affect quality of life and can become resistant to pharmacological intervention (Zetusky, Jankovic, and Pirozzolo, 2004).
Unfortunately, balance deficits are largely unaffected by dopamine agonists and cholinergic blockers (Bloem et al., 2004). Bradykinesia (slowness of movement) is associated with disability as the disease progresses, as postural instability also becomes evident. After patients are treated with L-dopa/carbidopa or dopamine agonists for a number of years, the following complications often occur: 1) wearing off effects; 2) on/off effects; and 3) dyskinesia (Barbeau, 1969; Marsden and Parkes, 1977). Akinesia progresses in the advanced stages of PD, as slowness of movement can advance to absence of movement (Ebadi and Pfeiffer, 2004). Patients with symptoms resistant to pharmacologic treatment may undergo surgical treatment (e.g., subthalamic or pallidal deep brain stimulation), which has been shown to reduce medication requirements (Moro et al., 1999). Complementary therapies can also be used in conjunction with medication (Mak and Hui-Chan, 2004). Non-pharmacological therapies for PD include physical therapy, music therapy, and speech therapy. Thus, treatments that assist patients in adapting to their changing symptoms and medication programs become important for activities of daily living (Ebadi and Pfeiffer, 2005).

Behavioural Activation
Normal locomotion for example consists of numerous motor programs and sensory feedback systems functioning to produce movement. Teitelbaum, Schallert, and Whishaw (1983) review spontaneity in behaviour and the internal and external stimuli that can elicit such behaviour. Distinct neural systems, such as the allied reflexes responsible for postural control (e.g., Sherrington, 1896-1897; Sherrington, 1906), can be independently activated using environmental stimuli (Teitelbaum, Schallert, and Whishaw, 1983). PD, a disorder of movement “organization,” “activation,” or “rhythm” (Sacks, 1973) produces a movement disorder in which the normal pathway for regulating movement timing, force, and initiation is deregulated due to a loss of DAergic innervation. Rats with damage to the hypothalamus and striatum also exhibit a decrease in spontaneous behaviour (Teitelbaum, Schallert, Whishaw, 1983). Acute administration of dopamine antagonists (e.g., haloperidol) in the rat produces a behavioural condition in which sources of activation are ineffective (DeRyck and Teitelbaum, 1983); haloperidol catalepsy is reflected in altered motor cortex activity and spinal motor unit recruitment (Burkhardt et al., 2007). Classically, it is thought that only those reflexes responsible for preserving static stance are left intact. For example, a rat exhibiting haloperidol-induced catalepsy will cling vertically to a grid for an extended duration of time and will only be “released” from catalepsy if presented with a sensory stimulus (e.g., tail pinch or neck bandage; De Ryck, Schallert, and Teitelbaum, 1980; Teitelbaum, Schallert, and Whishaw, 1983; Teitelbaum et al., 1976). Destabilizing the animal can also activate intact postural reflexes (Field, Whishaw, and Pellis, 2000; Teitelbaum, Schallert, and Whishaw, 1983). Thus, catalepsy is a model of PD akinesia in which the environment of a subject can be manipulated to activate isolated postural reflexes (Bazyan et al., 2000; Whishaw, 1989).

Evolutionary Perspectives on Music
Before further discussion of auditory cueing in PD, a discussion of how music is processed in the central nervous system will be useful. Music is a specific environmental stimulus that is virtually ubiquitous in human society and is known to affect a wide range of biological, psychological, and physiological functions of the body (Merker 1999-2000; Povel and Essens, 1985; Thaut et al., 1999). Rhythm is the primary organizing unit of music and emerges as sound elements are grouped together. The profound effect of music on human behaviour has provided a rich source of study for philosophers, musicians, and most recently scientists: “Why do we listen to music?” and “How does it move us?” Currently, there are two theories regarding the emergence of music in human society: 1) the “auditory cheesecake” metaphor in which music has evolved as a byproduct of language, but serves no other psychophysical function beyond pleasure (popularized by Stephen Pinker) or; 2) sexual selection theory in which music and dance (which have been inseparable for most of human history) signal reproductive fitness to potential mates (it is typically the male in a species who performs and the female who elicits the song , a theory originally proposed by Darwin) (Levitin, 2006).

Processing of musical stimuli in the brain
The study of music as a biological function has become a rich field of study in the last decade. The auditory system has evolved to accomplish species- and environment-specific tasks and is comprised of cortical and subcortical nuclei adapted for feature extraction, anticipation, and production of the auditory gestalt (Musacchia et al., 2007; Repp, 2002; Repp, 2003; Repp and Keller, 2004). In fact, frequency resolution tuning curves of primary auditory cortex correspond to their psychophysical equivalent (i.e., biologically meaningful unit of sound) (Ehret and Schreiner, 1997). In musicians and non-musicians alike, engaging in music involves brain areas responsible for audition, language, attention and reward, memory, planning, and anticipation (Blood and Zatorre, 2001; Musaccia et al., 2007). There is a clear lateralization of language and music, with the right hemisphere generally assigned the function of music processing, and the left hemisphere known to play a special role in language perception and production (Sperry, 1961). Recent modern imaging studies highlight the preferential processing of rhythm in the left hemisphere, and prosodic features of speech and music located in the right (Limb et al., 2006). Further, vocal training or extensive experience with playing a musical instrument is known to change the way in which the brain engages in music, such that some functions become left lateralized (Limb, 2006). The considerable overlap between music and language processing across the two hemispheres is also important to note, as well as the components and skills needed for each module (Platel et al., 1997). Case studies and modern brain imaging have provided detailed insight into the neural regions responsible for a number of music-related behaviours. For example, there are multiple reports of aphasia without amusia, highlighting the modularity of the musical and linguistic auditory systems. Within musical stimuli, modern brain imaging has revealed the shared and divergent substrates responsible for processing musical rhythm, syntax, pitch, timbre, and semantics (Limb, 2006). For example, Zatorre (2001) used PET to determine which areas of the brain were most active while subjects listened to a burst of sound or a melody, and revealed that divergent areas are involved in processing different elements of musical pitch. Heschl’s gyrus in primary auditory cortex was activated when listening to a burst of noise, whereas listening to melodies involved frontal cortical areas. Finally, music has a potent effect on arousal and attention correlates during various music tasks. Different patterns of activation for pleasant and unpleasant musical stimuli can be found using functional Magnetic Resonance Imaging (Koelsch et al., 2005).

Auditory-motor connectivity
There is a rich literature highlighting auditory-motor connections throughout the central nervous system (Galazyuk and Volkov, 1994; Paltsev and Elner, 1967; Rossignol and Jones, 1976). Because PD is associated with central processing deficits in timing, therapies that improve the timing of motor acts can be useful for patients (Sacks, 1973). Timing is a distributed function in the brain, and underlying mechanisms can be traced to cortical, midbrain, cerebellar, and spinal networks (Molinari et al., 2003). The role of previous social and motor experience in responding to musical or auditory stimuli is clear, and familiarity with musical pieces and discrete auditory cues can have an effect on non-musical behaviour and physiology (Wöhr, Houx, and Schwarting, 2008). Psychophysical studies suggest subliminal and supraliminal coupling mechanisms underlying motor entrainment and response to auditory stimuli (Thaut, 2005).

Auditory startle versus cued movement
The description of movement following auditory stimuli necessitates a brief discussion of mechanisms responsible for an acoustic startle response to a brief loud sound compared to the pathways involved in a more complex body orienting and righting response following a sound cue. A monosynaptic pathway is known to underlie auditory startle characterized by brief contraction of craniofacial and skeletomotor muscles (Thompson, 2005). Cochlear root neurons project to the ventral pontine reticular formation, which then integrates at a premotor level and sends descending projections to the spinal cord and facial motor nucleus for a brief motor response (Thompson, 2005). Conversely, a righting response that is elicited following key jingle is likely mediated by centers above the level of the reticular formation and is reliant on the integration of visual, somatosensory, proprioceptive, and vestibular inputs. It is known that natural sound stimuli activate neural regions that receive both proprioceptive and auditory afferents at cortical levels (Alexeenko and Verderevskaya, 1976). We hypothesize that sound-induced orienting within an open field, and the inferior colliculus, thalamus, auditory association areas, and parietal areas are involved in the righting movements made during a grid-climbing task.

Music therapy
The use of music in therapy has shifted from a strictly socio-emotional application to one of neurological improvement, thus propelling music researchers into the area of neuroscience and movement research. Paltsev and Elner (1967) first showed the sensitivity of the cortical, subcortical, and spinal areas of the motor system to auditory stimuli. There is convergent evidence that regulation of behaviour requires areas beyond classical sensory areas (Radionova and Shmigidina, 1973). There is evidence for immediate synchronization to auditory rhythm during intrinsically rhythmic motor behaviours such as finger tapping and steady state gait in laboratory studies (del Olmo et al., 2006; Thaut et al., 1996). Further, self-paced tapping and sequential movements of the digits involve the premotor cortex, primary motor cortex, supplementary motor area (SMA), and contralateral cerebellum, areas that are changed in PD during movement (Moritz et al., 2000). Neural mechanisms involved in motor entrainment to auditory rhythm in PD could include: 1) reticulospinal pathways to phase-lock motor neurons and increase motor unit excitability prior to movement (Thaut et al., 1999; Rossignol et al., 1976); 2) projections from auditory cortex to basal ganglia which could help compensate for deficient BG activation (Otellin, 1970); 3) activation of premotor area via the cerebellum, bypassing deficient inputs to SMA (Cunnington et al., 2005); 4) activation of the pedunculopontine nucleus and descending motor pathway (Muthusamy et al., 2007; Pahapill and Lozano, 2000); or 5) involvement of the posterior hypothalamus (Jackson et al., 2008). Current theories of music-induced therapeutic benefits for movement disorders emphasize pulse-salient models; intrinsically rhythmic networks synchronize to external felt pulse patterns shaped by anticipation, producing coupled oscillation (Thaut, 2005). That is, variability in movement timing can be improved using external auditory inputs that can be consciously and unconsciously matched (Thaut et al., 1999).

Retrieval of motor programs
Motor behaviour can be entrained or primed immediately to auditory cues through coupled oscillator synchronization or through training effects over time (Ma et al., 2004; Lewis, Byblow, and Walt, 2000; Thaut et al., 1996). These numerous connections between auditory and motor systems allow music to entrain a number of motor behaviours by assisting during learning or the retrieval of learned motor programs. By providing polyphonic and temporal information, music can retrieve motor memories and give sequence to movements (Ma et al., 2003). Sacks (2007) observed that music could be used to prompt recall of learned and well-practiced movements such as walking in patients who were unable to recall how to walk, despite no physical causes. Sacks’ own experience provides a striking example. He had been given a recording of Mendelssohn’s Violin Concerto in E minor, following a climbing accident in which he tore the quadriceps of his left leg. When putting weight on his leg for the first time, he observed that he had seemingly “forgotten” how to walk; the automatic nature of walking had left him. On one occasion, however, he reports that Mendelssohn’s concerto began playing vividly in his mind, and he “suddenly remembered how to walk.” Sacks reports similar cases in patients following hip and bone repair surgeries where the imagining of music has acted as a cue for motor memory and has reinstated walking.

Sensory cueing in Parkinson’s disease
External sensory mechanisms are used to normalize movement in PD patients (Morris et al., 1994b). As mentioned, humans and nonhuman animals can be activated or aroused using external stimulation or by altering brain regions responsible for the ongoing arousal state of the animal. Martin (1967) and Sacks (1973) first documented the potent organizing and initiating effect that sensory (i.e., auditory and visual) cues can have on movement deficits in parkinsonism. Patients who present with freezing often do so in the presence of distracting visual cues such as doorways or other objects that disrupt optical flow (Almeida, Wishart, and Lee, 2002). Providing a patient with horizontal lines or a laser point on the floor, for example, can release patients from freezing and provide an external template to organize movements to. Auditory cues, such as musical pieces with an embedded rhythmic cue on each heavy beat, can improve spatiotemporal parameters of gait in PD patients and reaching movements in stroke patients (Thaut et al., 1999). Martin (1967) was the first to demonstrate that particular visual cues (such as high contrast lines perpendicular to the patient, with a distance slightly greater than their average stride length (Sidaway, 2006; McIntosh et al., 1997; Thaut et al., 1996) could aid locomotion. Sacks (1972) worked with post-encephalitic patients who were severely cataleptic or “frozen” and discovered that salient musical and visual cues could temporarily release patients from periods of akinesia, particularly those patients who had been musical prior to their disease. Currently, the literature on visual and auditory cueing in PD focuses on speed, stride length, symmetry, velocity, and range of motion during gait (Sidaway et al., 2006; Morris, 1994a). Experience with an auditory cue has been shown to slow an increase in disability in patients when the sound stimulus is used in conjunction with a physical therapy program, as compared to non-cued age- and disease-matched controls (Marchese et al., 2001). Interestingly, Chuma et al (2005) found that PD patients were able to reproduce a repetitive thumb movement after training with an auditory cue, and demonstrated that cued movements in PD may be mediated by cerebellar connections with the premotor cortex, bypassing the SMA (Cunnington et al., 1995). Music therapy has been recognized as a distinct discipline since the 1950’s, and now plays an increasingly central role in the management of symptoms associated with disorders of movement, thought, and development. Music therapy, and specifically neurologic music therapy (NMT), applies music to PD symptoms within the guidance of neuroscience research. To summarize, auditory PD is associated with compensatory changes in responding to environmental stimuli, and music therapy is now an allied health discipline that applies neuroscience research based programs (Ebadi and Pfeiffer, 2004).

Unanswered Questions
The organization of motor behaviour is influenced by the activity of striato-thalamic-cortical loops (Berardelli et al., 2001; Parr-Brownlie and Hyland, 2005). Human patients and animal subjects with parkinsonian movement disorders show reduced movement organization, force, and speed (De Ryck et al., 1980; Miklyaeva, Martens, and Whishaw, 1995). In many animal species, sound stimuli convey environmental and conspecific information, and it is well known that sound has physiologic and arousal effects on behaviour (Sadananda, Wöhr, and Schwarting, 2008). It is likely that sound has access to motor areas that would otherwise be left inaccessible in the parkinsonian brain (Brudzynski and Pniak, 2002). The basis of sound-induced movement can be investigated in the rat, a species extensively used in PD and behavioural activation research.
Despite the rich literature on music and the brain, the underlying mechanism for music-induced movement remains unclear, and an animal model of music-induced benefits in PD has not been developed. Specifically, it is not known if sound induces activation through “classical” auditory-motor connections responsible for defensive or orienting behaviour, or if the effect depends on a neural module dedicated to behavioural activation. The roles of motor experience in the context of sound, features of the auditory stimulus, and training constraints could be elucidated to further improve the benefits of music therapy. Research from our laboratory suggests the importance of tailored music therapy programs based on close observation and individual music preferences.

Animal Model of Sound-induced Activation
As the above research highlights, engaging in music can profoundly influence auditory areas of the brain, motor behaviour, and attention or arousal. Despite the rich literature on music and the brain, the underlying mechanism for music-induced movement remains unclear, and an animal model of music-induced benefits in PD has not been developed. Specifically, it is not known if sound induces activation through “classical” auditory-motor connections responsible for defensive behaviour, or if the effect depends on a neural module dedicated to behavioural activation. The roles of motor experience in the context of sound, features of the auditory stimulus, and training constraints could be elucidated to further improve the benefits of music therapy. Research from our laboratory suggests the importance of tailored music therapy programs based on close observation and individual music preferences.

Haloperidol-induced catalepsy
To develop a model of sound induced activation, the present study used neuroleptic-induced catalepsy, a well-characterized model of akinetic catalepsy in advanced PD. Haloperidol, a classical antipsychotic medication, is a dopamine antagonist and binds primarily to D2 receptors of the striatum. The antagonistic action of haloperidol decreases excitation of the motor cortex and in high doses acts as a model of the akinesia seen in advanced human PD, a disease state in which patients can require a movement “trigger” or cue to release them from cataleptic akinesia (Berardelli et al., 2001; Ma et al., 2004). Haloperidol-induced catalepsy can differ in presentation and neural basis from other forms of experimental catalepsy including morphine-induced catalepsy (DeRyck and Teitelbaum, 1983; Koffer, Berney, and Hornykiewicz, 1978) but is similar in behaviour and mechanism to the akinesia observed carbachol infusion into the pontine reticular formation (Koffer et al., 1977; DeRyck et al., 1980) and SCH23390 or Sulpiride administration into the globus pallidus (Hauber and Lutz, 1999). In the haloperidol model, rats are acutely or chronically administered haloperidol, a D2 receptor antagonist, and display immobility at higher doses that exhibits a trial-to-trial increase. The haloperidol-treated rat displays a characteristic stance that protects the rat from postural challenges. EMG recordings of haloperidol-treated rats are comparable to those found in human patients, such that muscle responses to passive movement are delayed, exaggerated, and synchronous (Lorenc-Koci et al., 1996; Burkhardt et al., 2007). Rats lose access to voluntary movement and associated subsystems but can exhibit postural responses (termed release from catalepsy in this thesis) mediated by intact movement subsystems. The sound-induced release of catalepsy has not been documented in the literature. Haloperidol-induced catalepsy provides a unique paradigm in which the effect of prior motor training (i.e., moving in response to an activating auditory cue) can then be tested while the animal is in a dopamine-depleted state.

Activating sounds for the rat
The following section will review what is known about specific activating sounds in the rat. Nearly all species of animals, including humans, are activated or aroused by sound stimuli. It appears likely that the nervous system is designed to respond to certain salient sounds with behavioural arousal. Conspecific vocalizations in rats, for example, communicate appetitive or affective states and function to release behavioural sequelae associated with parenting and mating behaviour. Rats vocalize in the sonic and ultrasonic ranges, and produce ultrasonic vocalizations (USVs) that are broadly divided into “22-kHz” (i.e., low frequency) and “55-kHz” (i.e., high frequency) calls that have been related to anxiety- (e.g., isolated rat pup) or fear-related social interactions, and appetitive situations (e.g., in the context of cocaine) or positive social interactions, respectively. Although there appears to be a “best frequency” constraint on some sound-released behaviours, the specific effect of single frequencies on rat orienting and righting remains unknown. There are also reports of naturally produced sound stimuli, such as crumpling tin foil (Whishaw, 1993) and key jingle (Barto, 1957) being applied in spatial memory tasks and audiogenic research, respectively. The sound stimuli used in the studies contained within this thesis employ sounds made from jingling keys, crumpling chip bags (tin foil), single frequencies, and ultrasonic calls made by female rats during sexual encounters with males.

Cephalocaudal recovery of behaviour
The experiments presented in this thesis make use of a movement notation system derived from the Eshkol-Wachman Movement Notation (EWMN) system and a five-point movement score based on cephalocaudal movement of the body during orienting and righting responses. Briefly, EWMN describes the body as a series of limbs, defined as an axis located between two fixed joints, located with horizontal and vertical spheres. This thesis will describe the movement of the body in relation to a body system of reference (SoR) and an external SoR, in relation to the sound source. A number of studies have described the recovery of spontaneous movement following lesions of the lateral hypothalamus, neuroleptic-induced catalepsy, or developmental situations in which infant rats exhibit movement in successive stages (Golani et al., 1981; Teitelbaum et al., 1976)

Theory and Hypotheses

Theory
Music as a familiar auditory stimulus affects a distributed network of auditory and motor areas of the brain, and can be used to help patients overcome slowness of movement.

Hypothesis one
Orienting to behaviourally relevant sounds will be diminished in haloperidol-treated rats when compared to saline-treated rats.

Hypothesis two
Behaviourally relevant sounds will release haloperidol-treated rats from catalepsy.

Hypothesis three
Previous experience with behaviourally relevant sounds will increase potency.

Overview
This thesis will present studies that are qualitative in nature on the movements elicited by behaviourally relevant sounds in the rat. Chapter Two will present an experiment on auditory orienting responses in normal and haloperidol-treated rats to naturally produced (single or multiple key jingle, crinkling chip bag) and generated sound stimuli (frequencies from 500 Hz to 65 kHz and ultrasonic vocalization). Chapter Three will present a series of experiments on a model of sound-induced movement (i.e., release from catalepsy) in a rat model of PD using sound stimuli versus vestibular displacement. Chapter Four will present a set of experiments on release from catalepsy following the presentation of frequencies or rat vocalizations. A general discussion on behavioural activation in PD, as informed by the current experiments, will follow in Chapter Five.